Total Synthesis of Myxovirescins, 1 Strategy and Construction of the “Southeastern” Part [O(1)–C(14)]

D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann, A. Neidlein 70 1

Total Synthesis of Myxovirescins, 1 *[‘I Strategy and Construction of the “Southeastern” Part [0(1) - C(l4)] Dieter Seebach”, Miguel A. Maestrolz1, Michael Sefkow131, Geo Adam141, Samuel Hinterrnannl5l, and Axel Neidleinw

Laboratorium fur Organische Chemie der Eidgenossischen Technischen Hochschule, ETH-Zentrum, Universitatstrasse 16, CH-8092 Zurich (Switzerland)

Received April 18, 1994

Key Words: Myxovirescins I Myxococcus virescens Mx v48 I Suzuki coupling I Macrolides I Lactones I Lactams I 1,3-Dioxolanes I 1,3-Dithianes I Antibiotics

In this and the following two papers the synthesis of myxovirescins Al, A2 and M2, 28-membered macrocyclic lactam-lactones with antibiotic acitivity, is described. A retrosynthetic analysis of the myxovirescin family of ca. 30 target molecules leads to a strategy which could be applied to approximately half of them by slight variations of the building blocks used (Schemes 1-3 and following paper). The southeastern part of the molecule, containing the atoms 0(1)-C(14) of myxovirescins A and M is described in this first paper (Scheme 3). The assembly is achieved by using the following appropri- ately protected units: (S)-2-hydroxy-pentanoic acid, ([ 1,3]dithian-2-ylmethyl)-amine (Scheme 4), the triflate of (S,R)-2,2- dimethyl-5-vinyl-[ 1,3]dioxolan-4-ylmethanol, (E)-3-bromo-2- buten- 1-01, and (E)-2-bromo-2-buten- 1,4-diol (Scheme 5), the starting materials for these being malic acid, aminoacetalde-

hyde, ribose, crotyl alcohol and butyne-l,4-diol. The building blocks are put together by using the following key steps: Kolbe electrolysis, amide formation, lithiodithiane alkylation, and Suzuki coupling (Schemes 6 and 8). The only newly cre- ated chirality center [C(6) of the target molecules] is gene- rated stereoselectively by a Li-selectride reduction/Mitsu- nobu inversion (Table 1, Scheme 7). The termini of the 0(1)-C(14) fragment (2 in Scheme 8) carry a (protected) hydroxy acid and an aldehyde group for the Julia coupling and lactonization, respectively, in the final steps of the synthesis. All intermediates are fully characterized. The X-ray crystal structures of two compounds prepared for incorporation as N(4)-C(ll) and as C(12)-C(14) of the target molecules are also described (Figures 1 and 2).

Introduction

The synthesis of complex structures which need not be natural products will always be the acid test for synthetic methodol~gy[~]. In continuation of our efforts towards ma- crolideL81 and macr~diolide[~l synthesis we have recently turned our attention to the myxovirescins 1[Io]. There are altogether 3 1 representatives of myxovirescins, macrocyclic lactam-lactones of antibiotic activity isolated from Myxo- coccus virescens Mx v48, a member of the Myxococcaceae family belonging to the group of gliding bacteria[”]. Our targets of total synthesis have always been chosen so that they lend themselves to a chiral builiding-block approach[’*]. As can be seen from inspection of the formula in Scheme 1 this is true for the myxovirescin~[‘~].

There are at most two pairs of vicinal stereogenic centers in the myxovirescins l a - l i , the others being separated by at least one nonstereogenic center. The list in Scheme 1 con- tains a selection of 16 of the 31 known myxovirescins. The specific structures of these 16 compounds are such that we believe they could all be synthesized by using the general strategy applied to the actual synthesis of two of them, myxovirescins M2 ( la) and Al (lb). Thus, (i) the building block for introducing the stereogenic center C( 16) is equally readily available with R2 = Me (le, If) and Et (lc, Id, lg - l i ) ; (ii) the carbonyl group at C(20) could undoubtedly be reduced (lg) or removed (lc, ld) from the corresponding intermediate of our synthesis; (iii) the way we form the

C(23)-C(24) bond in l a and l b would allow us to not only have R5 = R6 = H but also R5 = R6 = 0 (If, lh), (iv) the intermediate for attaching the methoxymethyl group to C(12) could also serve for producing the carboxylic acid- containing building block (1 i); (v) finally, the 2,4-dimethyl- glutarate providing C(24) - C(28) is available in both diastereoisomeric forms. All of these statements (i)-(v) will become obvious as the reader progresses through the present papers[’].

Retrosynthetic Analysis of l a and l b

Having had very good s u c ~ e s s [ ~ ~ ~ ] with macrolactoniza- tions using Yamaguchi’s method[14], we decided to use this reaction, occurring with retention of configuration at the hydroxylated carbon, as the final key connecting step A (see Scheme 2).

Since there are several reliable methods of olefination in- volving formation of a trans-disubstituted double bond, we chose the C( 14) - C( 15) bond to be the connecting site B of the strategic fragments in a highly convergent approach. In the formula of Scheme 2, we also indicated the further disconnections within these two fragments, leading to the actually employed building blocks in a retrosynthetic sense.

In the present paper we describe the synthesis of what might be called the “southeastern” fragment [0( 1)-C(l4)], while the “northwestern” fragment and the coupling of the

Liebigs Ann. Chem. 1994,701 -717 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1994 0170-2041/94/0707-0701 $10.00+.25/0

702 D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann, A. Neidlein

Scheme 1. Myxovirescins M2 (la) and Al (Ib), our synthetic targets, and 14 additional members of the myxovirescin family (lc-li) which, in principle, could be synthesized following our synthetic approach

OH

No. R' R2 R3 R4 R5 R6 COnf.atC(25) Myxovirescin

M2 I Me Et 0 H H (S) k CH70Me Et 0 H H (R) Ai

epi-la Me Et 0 H H (R) Mi epi-I b CH20Me Et 0 H H (s) A2 I cand epi-lc CH,OMe Et H H H H (R)and (S) C, andC2 l d a n d eoi-id CH,OMe Et H H H H (R)and F, and F, ~

l eand ebi-lk CHiOMe Me ..O H H (Rjand is) I,'and12'

l g a n d epi-1g Me Et H OHX H H @)and (s) 0, ando:)

li and epi-li CO,H Et 0 H H @)and (S) Ti andT,

I f Me Me 0 0 (R) L

l h CH,OMe Et 0 0 (W S

a) The two myxovirescins 0 are mixtures of epimers at C(20).

Scheme 2. Myxovirescins M2 [la, X = H, (25S)I and A, [lb, X = OMe, (25R)], main disconnections A and B, as well as disconnections (dotted lines) in the two strategic fragments 0(1)-C(14) and C(15)-C(28)

two parts will be the subject of the two accompanying papers"].

In Scheme 3 we picture precursors 3-6 which were actually used for the construction of fragment 2. As we go along the presentation of the synthesis, we will outline the reasons for employing the particular building blocks, and, what is as important, for chosing the specific protecting and activating groups shown.

Of course the choices were dictated not so much by logic['5] as by our experiences, and by the ambition to apply synthetic methodology developed previously in our group.

Scheme 3. Target fragment 2 and disconnections with the corresponding building blocks 3-6. The numbering in 2 follows that in myxovirescin itself (see Schemes 1 and 2). Correct no- menclatural numbering will be used throughout the experimental section. - TBDMS = tBuMe2Si, MOM = CH,OMe, TBDPS = tBuPh,Si, Tf = CF3S02

6a, 6b

Preparation of the Carboxylic Acid 3 and of the Dithiane 4 The hydroxypentanoic acid was obtained by a mixed

Kolbe coupling in a coelectrolysis of the (9-malic acid acetal 7[161 with propionic acid in MeOH/Et3N (Scheme 4) as described previously for other combinations of acids[l71. If the temperature was carefully controlled and kept below 1 5°C during electrolysis, the propyl-dioxolanone 8 was isolated (60%); if, on the other hand, the temperature was allowed to rise to 35-40°C in this procedure, the methyl hydroxypentanoate 9 was obtained (65% yield). As it turned out, the OH-protecting group['*] for this ester had to fulfill the following requirements: (i) survive the conditions of ester hydrolysis, of amide bond formation [C(3)-N(4)], of oxidative (alcohol - aldehyde - acid), reductive (sodium amalgam) and strongly basic/nucleophilic (Li sulfone) conditions, and (ii) be cleavable in the presence of various acetal moieties, i.e. under nonacidic conditions. This situation calls for a silyl protection, so we prepared the acids 3, 12 and 14 and the esters 10, 11 and 13 shown in Scheme 4. It turned out that the TBDMS group was not stable in the free acid 12; on the other hand, the TBDPS group did not survive dissolving metal conditions (for debenzylation or Julia coupling), and finally, the SEM-protected amide 20 could not be alkylated by the triflate 5 - all of which we had to learn the hard way! Eventually, we used TBDPS- protected intermediates in the early stages and TBDMS in the later stages of the assembly leading to the 0(1)-C(14) fragment 2.

The dithiane derivative 4 of aminoacetaldehyde was prepared from the commercially available acetal 15 by meth-

Liebigs Ann. Chem. 1994, 701-717

Total Synthesis of Myxovirescins, 1 703

Scheme 4. Fragments 0(1)-C(3) and N(4)-C(6): starting materials, intermediates and building blocks used for the successful and for the not so successful approaches. - SEM = Me3SiCH2CH20CH2

9 R’=Me,R2=H 10 R’ = Me, R2 = TBDPS

8 R=Et 11 R’ = Me, R2 = TBDMS

13 R’ = Me, R2 = SEM

7 R=CO;?H 3 R’ = H, R2= TBDPS

12 R’ =H, R~=TBDMS

14 R’=H, R‘=SEM

15 R = H 4 R=C02Me 16 R=C02Me 18 R=COptBU 17 R=C02tBu 19 R = H

20 R = COCH(0SEM)Pr (acyl group of 14)

oxycarbonylation (+ 16) and trans-thioacetalization with 1,3-propanedithiol (Scheme 4). Since we have acid labile protecting groups elsewhere in the corresponding later intermediates of the syntheses, the methyl carbamates were used rather than the tert-butyl analogues 17 and 18[191.

Preparation of the Dioxolanyl Methyl Triflate 5 and of the Vinyl Bromides 6a and 6b

The cis-(hydroxymethy1)vinyl-substituted dioxolanone 21 was prepared form D-ribose via the D-ribonolactone[20,21], in a total of six steps according to a procedure published by Jager and Hafeler221 (ca. 65% overall yield of the well reproducible sequence from ribose to the alcohol 21). The OH group in 21 may be protected (+= 22[221) for carrying out reactions at the double bond, or it may be activated to become a leaving group (see the triflate 5 in Scheme 5)[23,241.

The bromides 6a (for myxovirescin M) and 6b (for myxovirescin A) were prepared by more or less extensively modified literature procedures. Thus, 2-buten- 1-01 was bro- minated/dehydrobrominated to yield (E)-3-bromo-Zbuten- 1-0 l [~~] (23) which was protected as the 4-methoxybenzyl (MPM) ether 6a (the simple benzyl ether 24 could eventually not be channelled into the synthesis because we failed to find conditions of debenzylation which were not harmful to the C=C bond or other functionalities present in the corresponding intermediates). The methoxylated analogue 6b was prepared from 2-butyne-1,4-diol. This was report- ed[26a] to react with 48% aqueous HBr to give (E)-2,4-dibromo-2-buten- 1-01, the compound we needed for the preparation of the building block 6b, and we actually used this dibromide for our subsequent synthetic work (see 26 and

Liebigs Ann. Chem. 1994, 701 -717

Scheme 5 . Fragments C(7)-C(ll) and C(12)-C(14) for the synthesis of 2a and 2b; Bn = PhCH2. 22, 24 and the (Z)-vinylic bromide derivatives 25-27 were not employed in the successful synthesis. - MPM = 4-MeO-C6H4CH2

23 R = H 6a R=MPM

Br 24 R=Bn RO HO

OH

25 X=Br, R = H &OR 26 X=Br, R=Me

X 27 X=MPMO,R=Me

28 R’ = R2 = H, X = SnBu, 29 R’ = H, R2 = TBDMS, X= SnBu, 30 R’ = Me, R2 = TBDMS, X = SnBu3 31 R’=Me,R2=H,X=SnBu3 32 R’ = Me, R2= MPM, X = SnBu3 6b R’ = Me, R2 = MPM, X = Br

27)[271 until we were alerted by a paper[26b] describing that treatment of 2-butyne-1,4-diol with neat HBr gives (a- 1,2,4-tribrom0-2-butene. We obtained crystals of 25 (m.p. 39-40°C) which were not perfect but good enough to show by X-ray analysis that this dibromo alcohol has indeed (Z) configuration (Figure l), and that we had worked with the wrong stereoisomers. We therefore switched to the hydro- stannylation product 28 of 2-butyne-1 ,4-diol, which had been proved to have ( E ) silylated (-+ 29)[28b], etherified (+ 30) and desilylated it (+ 31). The MPM-protecting group was attached by treatment of a THF solution containing alcohol 31, DMPU (5%), and NaI first with BuLi and then with MPM chloride (+= 32). Fi- nally, SdBr with elemental bromine gave the desired vinyl bromide 6b (overall 39% based on 2-butyne- 1,Cdiol; Scheme 5).

Figure 1. Crystal structure of 25: For clarity the H atoms were added to the plot. Refinement of the H atoms was not possible, due to the poor quality of the data obtained. Nevertheless, the structure shows clearly that the product of hydrobromination of 2-butyne-1,4-diol is (Z)-2,4-dibromo-but-2-en-l-ol (25) and not, as previously as-

signed[26a], the (E) isomer


Preparation of the 0x0 Amide 2 from the Four Building Blocks 3-6

We first tried to build the chain consisting of C(7)-C(14) by adding a vinylic organometallic derivative prepared from bromide 6a to the aldehyde 34, obtained by hydroboration (+ 33) of the TBDMS-protected vinyl dioxolane 22 and subsequent Swern oxidation. The bromide was first subjected to a Br/Li[29,301 and then to a Li/Ce(III) exchangeL3']; the adduct 35 was deoxygenated according to Barton's pro- c e d ~ r e [ ~ ~ ] to give the desired product 36. The overall yield of this coupling procedure was only 10%. On the other hand, the components vinyl halidekerminal olefin are ready for a Pd-catalyzed coupling (through an organoborane) according to Suzuki's protocol[33]. Thus, addition of 9-BBN to a solution of the alkene 22 in THF, followed by combination with the bromide 24, 3 mol-% PdCl,(dppf), and 3 N aqueous NaOH gave, after oxidative workup, the coupling product 36 of the one-pot reaction in 65% yield (Scheme 6). Although these compounds could not be carried for- ward due to problems arising with the nucleophilic substitution on the dioxolane CH2 the Suzuki coupling became our method of choice for connecting carbons C( 1 I ) and C( 12) of the myxovirescin skeleton.

Thus, the sequence of events was reversed, and the triflate 5 was first used for alkylation of the doubly lithiated di- thianyl carbamate 4 to give the vinyl-substituted amide 37 (up to 72% The dithiane moiety was hydrolyzed (+ 38) and the resulting keto group reduced. To do this correctly was easier said than done: the configuration of the newly formed stereogenic center had to be established be- yond doubt, and the reduction had to be carried out stereoselectively. As it turned out, the best selectivity for the hy- dride transfer from the (Re) face of the carbonyl group in 38 was 3:4! The wrong diastereoisomer, on the other hand, could be obtained with an 8: l preference, see Table 1. Therefore, we transformed, after separation, the undesired stereoisomer into the desired one by a Mitsunobu inversion[36,37] almost without loss of material (see also footnote of Table I).

The configuration of the two epimeric alcohols 39 and 40 was first assigned as described in Scheme 7: ozonolysis gave epimeric sugar derivatives (a D-deoxy-mannose derivative from 39 and an L-deoxy-allose derivative from 40). Careful analysis of the coupling pattern in the 'H-NMR spectra, showing that only one anomerL3*] was present in each case, led to the conclusion that 39 has (S) and 40 (R) configuration at the center bearing the hydroxy group.

In one of our Mitsunobu inversion experiments on a gram scale we noticed that a sample containing the isomer 39 crystallized after chromatography while this substance had been isolated as an oil many times before. The crystals (m.p. 49- SOOC) were perfect for an X-ray structural analysis which established (Figure 2) that our NMR assignment was correct.

With the right compound at hand, we MOM-protected the OH group of 39 and submitted the resulting compound 41 to the Suzuki coupling procedure (see bottom part of Scheme 6). The yields of the products without (42a) and

Scheme 6. Assembly of the fragment N(4)-C(14) from the building blocks 4, 5 and 6. The intermediates actually used in the total synthesis are 40a and 40b, since the C(6)-C(7) parts 33 and 34 could not be coupled with the dithiane moiety. - DMPU = N,"-dimethyl-NJ'-propylideneurea, [ 1,3-di- methyltetrahydro-2(1H)-pyrimidinone], 9-BBN = 9-bora- bicyclo[3.3.l]nonane, dppf = 1,1 '-bis(dipheny1phos- phane)ferrocene

,OTBDMS /OTBDMS

33 R=CH,OH 35 R=Bn, X = O H 34 R=CHO 36 R=Bn. X = H

1) BuLi (2 equiv.)/THF

3) Triflate 5 (1 eauiv) I ' won 37 38 X X = Y = O = Y = S-(CH&S

39 X = O H , Y = H 40 X = H , Y = O H

H Me0,CN 'I

I

1) 9-BBN (2 equiv.)/THF

3) bromide 6a or 6b 4) NaOH aq.

H Me02CN I

41

42a R = MPM. X = H 42b R = MPM, X = OMe

RO

43 R = B n , X = H

Table 1. Reducing reagents tested for the stereoselective conversion of the ketocarbamate 38 to the hydroxycarbamates 39 and 40. - DEAD

= diethyl azodicarboxylate

Reductant

NaBH4 NaBH,

LiBHEt3 Me4NBH(OAc)3 Li-Selectride Li-Selectride LiAIH, L~AIH(O~BU)~ LiAIH(OtBu)3 DlBAH

Zn(BH4)2

Solvent (temp) 39/40 ratio

MeOH (0%) 1 :2 MeOH (-78°C) 1 : 3 Et20 (-90°C) 1 :2

THF (-70°C) 1 : 5 THF (-90°C) 1 : 8 Et20 (-90°C) 1 :2 THF (-90%) 1 :2 EtpO (20°C) 3 : 4 4 THF (-20°C) 1 :2

THF (-90°C) 4 : 6 MeCN/AcOH (0°C) 1 : 2

yield (%)

94 96 87 97

95 95 91 95 96 93

aa

a) Mitsunobu inversion 1) DEAD, PPh,, PhC0,H; 2 ) NaOEt, EtOH of the readily separated (flash chromatography on silica gel; CH,Cld Et,O, 1:1) alcohol 40 gave the desired diastereoisomer 39 in 94% overall yield[37].



Scheme 7. Assignment of configuration at the hydroxylated stereogenic center of 39 and 40 by ozonolysis and NMR spec- troscopic analysis of the resulting aminodeoxy sugar derivatives. Double irradiation experiments allowed us to measure some of the significant coupling constants (established by simulation of the signals with the LAO- COON software, kindly provided by Prof. W. Meyer, Uni- versity of Arkansas). - Relevant coupling constants of the o-deoxy-mannose derivative from 39: J2,3 = 5.8 Hz, J3,4ax = 8.6 Hz, J3,4eq = 6.2 Hz (+ 3-H is axial), J4ax,4eq = -13.9 Hz, J4ax,5 = 9.3 Hz (+ 5-H is axial). - Relevant coupling constants of the L-deoxy-allose derivative from

H is equatorial), J4ax,4eq = - 14.9 Hz, J4ax,5 = 9.4 Hz (+ 5-H is axial)

40: 32.3 = 5.1 Hz, J3,4ax = 3.5 Hz, J3,4eq = 3.5 HZ (+ 3-

H

from 40 39 7s) 40 ‘(FI)

Figure 2. Crystal structure of 39: With the known configuration at C(8) and C(9) to be (S) and (R) , respectively, C(6) has the desired (S) configuration, which confirms the assignment made by NMR methods

(see Scheme 7)

with the methoxy group X (42b) were 85 and 7270, respectively. The product 43 with a simple benzyl protection was prepared likewise (in ca. 75% yield).

Attachment of the missing 2-hydroxypentanoic acid moiety was achieved by alkaline hydrolysis (KOH in MeOH/ H20) of the carbamate group in the intermediates 42 and 43I4Il and subsequent acylation of the resulting free amino group with the TBDPS-protected acid 3 under typical pep- tide coupling conditions (BOP chloride/Hunig’s ba~e) [~~.~Ol , producing the amides 44 and 45 (Schemes 6 and 8).

We now reached the point at which the major southeastern fragment had to be prepared for combination with the northwestern portion with formation of the C(14)-C(15) bond. At any rate, the benzylic ether bond in 44 and 45 had to be cleaved first. We found that hydro- genolysis of this bond in the amide 45 under a variety of

conditions[42] was slower than double bond hydrogenation! Also, attempts made under dissolving metal conditions (Na/EtOH or Na/NH3)[ISl led to cleavage of the TBDPS rather than the benzyl ether group! Therefore, we ex- changed the TBDPS for the TBDMS group and used the MPM-protected intermediates, since the MPM group can be removed oxidatively[Isl. The conversions of the MPM- protected TBDPS derivatives 44a and 44b to the corresponding TBDMS derivatives 46a and 46b were effected under standard conditions in essentially quantitative yield. Subsequent treatment with dichlorodicyanoquinone (DDQ) in wet CH2C12[’sl produced the allylic alcohols 47a and 47b, contaminated by appreciable amounts of the corresponding a$-unsaturated aldehydes 2a and 2b (Scheme 8).

Scheme 8. Assembly of the “southeastern” fragment 0(1)-C(14) of myxovirescins. The switch from TBDPS to TBDMS protection at 0(1) was necessary for a later step in the synthesis (see accompanying papers) and gave better reproducible and higher yields in the amide bond-forming step

R‘

44a R’ = Ph, R‘ = MPM, X = H 44b R‘ = Ph, R‘ = MPM, X = OMe

45 R’ = Ph, R‘ = Bn, X = H

46a R‘ = Me, R‘ = MPM, X = H 46b R‘ = Me, R‘ = MPM, X = OMe 47a R’ = Me, R‘ = X = H 47b R’ = Me, R‘ = H, X = OMe

TBDMSO G o

2a X = H 2b X=OMe

At this stage we were free to decide which way to couple the terminal carbon atom bearing the unprotected func- tional group with the future C( 15) carbon of the target molecule: we could take advantage of the terminal carbon elec- trophilic (cf. aldehyde), nucleophilic (cf. organometallic center) or radical character (cf. McMurry coupling). Con- sidering that we are dealing with an allylic or a,p-unsaturated moiety bearing an additional allylic methoxy group in the case of the intermediates leading to myxovirsecin Al (b series), we thought that it would be wisest to choose a



nucleophilic addition to the aldehydes 2a and 2b. More specifically, we hoped to use the Julia coupling for making the C(14)=C(15) bond, a method which is known to be applicable to the synthesis of dienes and even polyenes, with preferential formation of a trans double Therefore, we took all the product from the DDQ oxidation to the stage of the aldehydes [by separation of the alcohol/aldehyde mixture and pyridinium dichromate (PDC) oxidation of the former]. A total yield of the aldehydes 2a and 2b from the MPM-protected precursors 46a and 46b of 85 and 80%, respectively, was obtained. We were surprised to no- tice that the pure (2) precursor 47b gave aldehyde 2b consisting of a 6: 1 mixture of (z) and (@ isomer; furthermore, 2b isomerized to a 1:3 (a/(@ mixture upon storage as a CDCl3 solution (containing traces of HCl!?) while a solution in C6D6 was stable; we therefore used the aldehyde immediately after flash chromatographic purification for the subsequent Julia coupling step.

The aldehydes 2a and 2b were fully characterized by their IR, 'H-, 13C-NMR and mass spectra and elemental analyses. They are ready and available for coupling with the se- cond strategic fragment (see the following two papers in this series).

We gratefully acknowledge some exploratory studies by Dr. E Sternfeld and the friendly expert advice in the interpretation of cer- tain NMR spectra by Prof. W Meyer (University of Arkansas) during his sabbatical stay at ETH Zurich (1991). We thank E Kiihnle for performing the two X-ray crystal structure analyses, and Dr. Rcithrnun (FMC, USA) for supplying us with chlorosilanes employed in the work described in this series of publications.

Experimental General: All reactions requiring anhydrous conditions were performed in

oven-dried glassware, which was allowed to cool in a dessicator over blue silica gel and phosphorus pentoxide. All reactions were carried out under a positive pressure of argon. All solvents were freshly distilled from the appro- priate drying agent before use. THF and Et20 were distilled from potassium henzophenone ketyl under argon. CH2Clz was distilled from P205 under argon. Pyridine was distilled from KOH and diisopropylamine and triethylamine were distilled twice from CdH, under nitrogen and stored over 4-A molecular sieves. All transfers of solutions and solvents were performed by syringe techniques or via a cannula. The solvents were removed under water- aspirator vacuum in a rotary evaporator. - Melting points were determined in open capillaries in a Buchi 510 apparatus equipped with an Anschutz thermometer set and are uncorrected. - Kugelrohr distillation boiling points (b.p.) refer to the external air-bath temperature. ~ Thin-layer chromatographic (TLC) analyses were performed on silica-gel plates Merck 60 FZ5,,(2 X 5 cm, 0.25 mm thickness), components were visualized by irradiation with UV light and/or by treatment with ammonium molybdate(1V) reagent followed by heating. - Column-chromatographic purifications ("flash chromatography") were performed as described by - Optical rotations [a]:' were measured in solution at 589 nm (Na-D line) with a Perkin-Elmer 241 polarimeter in a 1.00-dm cell at room temp. (ca. 22°C); concentration c (in g / IOO ml) and solvent are given in parenthesis. - 'H-NMR spectra were recorded with a Bruker AMX 500 (500 MHz), a Bruker AMX 400 (400 MHz), a Bruker WM 300 or a Varian XL 300 or a Varian Gemini 300 (300 MHz) and a Varian Gemini 200 (200 MHz). CDCI, was used as solvent and as internal reference (6 = 7.26 ppm) unless stated otherwise. Coupling constants J are given in Hertz (Hz); multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept = septet, oct = octet, m = multiplet. - I3C-NMR spectra were recorded with a Bruker AMX 500 (125 MHz), a Bruker AMX 400 (100 MHz), a Bruker WM 300 or a Varian XL 300 or a Varian Gemini 300 (75 MHz) and a Varian Gemini 200 (50 MHz). CDCI, was used as solvent and as internal reference (6 = 77.7 ppm) unless stated otherwise. Carbon multiplicities were assigned by DEPT techniques. The 'H- and I3C-NMR data were correlated to hydrogen and carbon atoms by HETCOR and COSY techniques. - Mass spectra were

recorded with a Hitachi-Perkin-Elmer RMU-6M or a VG Trihrid apparatus. FAB MS spectra were obtained by using 3-nitrobenzyl alcohol (3-NOBA) as a matrix. - Analytical HPL chromatography (HPLC) was performed with a Kontron equipment using a Knauer LiChrosorb Si 100 (7 pm) column, 250 X 4 mm, and preparative HPLC with a Knauer equipment using a LiChrosorb Si 60 (7 pm) column, 250 X 32 mm. - The infrared spectra were recorded with Perkin-Elmer 983 or Perkin-Elmer FT-IR 1600 spectrometers. Crystalline compounds from KBr disks or chlroform solutions, oily compounds on NaCl plates. - Elemental analyses were performed by Mikrola- boratorium der ETH Zurich.

(2S,SS)-2-tert-Butyl-5-propyl-[1,3]dioxolun-4-one (8): A solution of (8- malic acid acetal 7[161 (4.05 g, 20 mmol) in MeOH (140 ml) was treated with Et3N (2.0 ml, 14.4 mmol) and propionic acid (9.0 ml, 0.12 mol). The resulting solution was electrolyzed with 17000 C (3-cmZ rotating Pt electrode, 950 mA) at 15°C. The methanol was then removed under reduced pressure at 25°C and the residue dissolved in Et2O/CH2CI2 (100 ml). The resulting solution was washed with a satd. NaHCO, solution (2 X 25 ml) and brine (1 X 25 ml), dried (MgSO,) and filtered, and the solvent was evaporated from the filtrate in vacuo. The residue was purified, first by column chromatography (5 X 20 cm, 33% CH2C12/pentane), and then by kugelrohr distillation to afford dioxolanone 8 [2.12 g, 57%, b.p. 58-62"C/23 Torr (kugelrohr)] as a colorless oil. - [a]bT = +10.5 (c = 0.95, CHC1,). - IR (film): 5 = 2980 (s), 2890 (s), 1800 (s, C=O), 1490 (m), 1410 (m), 1370 (m), 1320 (m), 1200 (s), 1130 (m). 1100 (m), 1045 (m), 900 (s) cm-'. - 'H NMR (200 MHz): 6 = 5.1 1 (d, J = 1.2 Hz, 1 H, 2-H), 4.24 (ddd, J = 7.0, 4.3 and 1.2 Hz, 1 H, 5-H), 1.95-1.39 (m. 4H, 1'-H and 2'-H), 0.95 (s, 9H, Me,C), 0.95 (t. J = 7.3 Hz, 3H, 3'-H). - 13C NMR (50 MHz): 6 = 173.9 [s, C(4)], 109.3 [d, C(2)], 75.1 [d, C(S)], 33.7 (s, Me,C), 32.7 [t, C(l')], 23.5 (9. Me$), 18.3 [t. C(2')], 13.7 [q, C(3')]. - MS (70 eV): m/z (%) = 187 (0.2) [(M + I)'], 144 ( I ) , 142 (2), 129 (26) [(M - tBu)+], 101 (78), 85 (13), 73 (62), 70 (38), 57 (loo), 55 (96), 43 (42), 41 (SI), 29 (33). - CIOH1803 (186.3): calcd. C 64.49, H 9.74; found C 64.83, H 9.80.

(2s)-Methyl 2-Hydroxy-pentunoute (9). - Method A: To a solution of dioxolanone 8 (1.0 g, 5.4 mmol) in THF (10 ml) was added concd. HCI solution (5 ml). After stirring for 24 h at room temp., water (15 ml) was introduced into the mixture and the aqueous phase extracted with Et20 (5 X 20 ml). The combined organic phases were washed with 1 N aq. NaOH solution (3 X 20 ml). The aqueous washings were acidified to pH = 1 by using 3 N aq. HCI solution, then re-extracted with EtzO (3 X 15 ml). The combined ethereal extracts were dried (MgSO,), filtered, the solvent was removed in vacuo and the residue recrystallized from Et20/hexane yielding 0.30 g (65%) of (2S)-Z-hydroxy-pentanoic acid as a colorless solid. - M.p. = 57°C m.p. = 57.8-58.5"C). - [a]BT = -3.5 (c = 1.20, EtOH)

[u]B = -3.3 (c = 1.00, H,O)). - An ethereal solution of CHzN2 was added dropwise to a solution of (2S)-2-hydroxypentanoic acid (0.30 g, 2.54 mmol) in EtzO (25 ml) at room temp. until the yellow color of the mixture persisted for a period of 10 min. The Et20 was removed carefully under reduced pressure to give the hydroxy ester 9 (colorless liquid, 0.34 g, quantitative yield).

Method B: A solution of dioxolanone 8 (6.72 g, 36 mmol) in MeOH (36 ml) was treated with a concd. HCI solution (18 ml) at room temp. The reaction mixture was stirred for about 12 h. After completion of the reaction, water was added, and the aqueous phase was extracted with CH2C12 (4 X 25 ml). The combined organic phases were washed with a satd. NaHC03 solution (2 X 15 ml), dried (MgSO,), filtered and the filtrate was concentrated to afford pure hydroxy ester 9 (4.25 g, 90%) as a colorless liquid.

Method C: Dioxolanone 8 (4.05 g, 20 mmol) was dissolved in MeOH (140 ml). After addition of Et3N (2.0 ml, 14.4 mmol) and propionic acid (9.0 ml, 0.12 mol) to the solution, the mixture was electrolyzed starting at 15°C with 17000 C (3-cm2 rotating Pt electrode, 950 mA). The temperature reached 35-40°C during the course of the reaction. The MeOH was then removed in vacuo at 25°C and the residue taken up in Etz0/CHzCl2 (100 ml). The organic solution was washed with a satd. NaHC0, solution (1 X 40 ml) and brine (1 X 40 ml), dried (MgSO,), filtered and the solvent evaporated from the filtrate to give the crude product. Column chromatography and subsequent kugelrohr distillation furnished the pentanoate 9 (2.4 g, 90%). - [u]sT = +10.3 (c = 1.25, CHCI,) [u]BT = +9.84 (c = 1.26, CHCI,, ee: 96%)).

(2S)-Methyl2-[(tert-Butyldiphenylsilyl)oxy]-pentunoute (10): tert-Butyl- diphenylsilyl chloride (3.91 g, 14.2 mmol) was added dropwise to a stirred solution of hydroxy ester 9 (1.25 g, 9.5 mmol) and imidazole (1.94 g, 28.5 mmol) in DMF (15 ml) under argon at room temp. The resulting mixture was stirred for 15 h at room temp., poured into ice/water (50 ml) and the aqueous phase extracted with CH2Clz (4 X 25 ml). The combined organic extracts were dried (MgSO,), filtered and concentrated. The crude product was purified by column chromatography (3 X 40 cm, 12.5% Et,O/pentane) to give the silyl ether 10 [3 .25 g, 93%, Rf (12.5% Et20/pentane) = 0.56,



colorless oil]. - [a]B = -33.9 (c = 5.25, CHCI,). - IR (film): 2 = 3070 (w). 3050 (w), 2960 (s), 2930 (s), 2860 (s), 1760 (s, C=O), 1740 (s, C=O), 1470 (m), 1430 (s), 1200 (m), 1140 (s), 11 15 (s), 820 (m), 740 (m), 700 (s) cm-'. - 'H NMR (400 MHz): 6 = 7.67-7.63 (m, 4H, H,,,), 7.44-7.33 (m, 6H, H,,,), 4.23 (t, J = 5.7 Hz, I H , 2-H), 3.46 (s, 3H, COOMe), 1.76-1.61 (m, 2H, 3-H), 1.48-1.27 (m, 2H, 4-H), 1.09 (s, 9H, Me,C), 0.84 (t, J = 7.4 Hz, 3H, 5-H). - I3C NMR (100 MHz): 6 = 173.7 [s, C(l)], 136.0 (d, Carom), 135.8 (d, Carom), 133.5 (s, Carom), 133.3 (s, Carom), 129.8 (d, Carom), 129.7 (d. Carom), 127.6 (d, Carom), 127.5 (d, Carom), 72.6 [d, C(2)], 51.3 (4. COOMe), 37.3 [t, C(3)], 26.9 (q, Me3C), 19.4 (s, Me3C7, 17.9 [t. C(4)], 13.9 [q. C(5)]. - MS (70 eV): m/: (YO) = 370 (0.01) [M+'], 355 (0.2) [(M - Me)+], 313 (70), 285 (20), 213 (loo), 183 (35), 153 (32), 135 (15), 105 ( I I ) , 57 (8), 41 (7). - C22H,o03Si (370.6): calcd. C 71.31, H 8.16; found C 71.51, H 8.29.

(2S)-2-[(tert-Butyldiphenylsilyl)oxy]-pentanoic Acid (3): The silyl ether 10 (3.25 g, 8.78 mmol) was dissolved in a 1 M ethanolic KOH solution (20 ml), and the resulting solution was stirred for 24 h at room temp. The EtOH was then evaporated under reduced pressure, and the resulting oil was dissolved in water. The aqueous solution was extracted with EtzO (1 X 50 ml), acidified to pH = I by using a 1 M aq. HC1 solution with vigorous stirring, then extracted with CHzCl2 (5 X 20 ml). The combined organic extracts were dried (MgSOd), filtered, and the filtrate was concentrated affording the pure silyloxy acid 3 (2.98 g, 95%) as a colorless solid. For the purpose of obtaining analytical data, a small amount of acid 3 was recrystallized from hexane. - M.p. 95.5-97.O"C (hexane). - [a16 = -15.5 (c = 4.25, CHCI,). - IR (KBr): 0 = 3600-2400 (br., OH), 3070 (w). 3020 (w), 2960 (s), 2930 (s), 2860 (s), 1710 (s, C=O), 1460 (m), 1430 (m), 1230 (m), 1145 (s), 1115 (s), 1090 (m), 890 (m), 820 (m). 795 (s), 710 (s), 685 (m) cm-l. - IH NMR (300 MHz): 6 = 7.69-7.64 (m, 4H, H,,,), 7.47-7.36 (m, 6H, H,,,), 4.30 (t. J = 5.2 Hz, IH, 2-H), 1.77-1.24 (m, 4H, 3-H and 4-H), 1.13 (s, 9H, Me,C), 0.83 (t. J = 7.3 Hz, 3H, 5-H). - I3C NMR (75 MHz): 6 = 177.0 [s, C(l)l. 135.8 (d, Carom), 132.9 (s, Carom), 132.4 (s, Carom), 130.1 (d, C,,,), 127.8 (d, C,,,,), 72.5 [d, C(2)], 36.7 [t, C(3)], 26.9 (q, Me,C), 19.4 (s, Me,C), 17.4 [t, C(4)], 13.8 [q, C(5)l. - MS (70 eV): mlz (%) = 311 (2) [(M -

(4% 139 (85), 135 (53), 121 (23), 105 (37), 77 (58). - CZIHZsO3Si (356.5): calcd. C 70.74, H 7.92; found C 70.79, H 8.14.

(2s) -Methyl 2-/( tert-Butyldimethylsilyl) o.uy]-pentanoate (11): A solution of hydroxy ester 9 (0.99 g, 7.5 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (20 ml) was cooled to 0°C under argon before tert-butyldimethylsilyl chloride (2.25 g, 15.0 mmol) was added in portions. The reaction mixture was stirred for 1 h at 0°C then for about 12 h at room temp. The resulting clear solution was filtered through silica gel (3 X 40 cm) in Et20/pentane ( I :7) to remove the DMF. Purification by column chromatography (3 X 40 cm, 7% Et201pentane) gave the silyl ether 11 [1.28 g, 70%, Rf (7% Et20/ pentane) = 0.361 as a colorless oil. - B.p. 9O0C/O.2 Torr (kugelrohr). - [a]B = -36.5 (c = 4.80, CHCI,). - IR (film): 0 = 2960 (s), 2930 (s), 2860 (s), 1760 (s, C=O), 1740 (s, C=O), 1465 (m), 1255 (s), 1200 (m), 1145 (s), 840 (s), 780 (s) cm-'. - 'H NMR (300 MHz): 6 = 4.20 (dd, J = 6.4 and 5.9 Hz, l H , 2-H), 3.72 (s, 3H, COOMe), 1.72-1.64 (m, 2H, 3-H), 1.49-1.30 (m. 2H, 4-H), 0.92 (t. J = 7.3 Hz, 3H, 5-H), 0.91 (s, 9H, Me$), 0.08 (s, 3H, MeSi), 0.05 (s, 3H, MeSi). - "C NMR (75 MHz): 6 = 174.4 [s, C(l)], 72.1 [d, C(2)], 51.7 (q, COOMe), 37.4 [t, C(3)], 25.7 (9. Me&), 18.5 [t, C(4)], 18.3 (s, Me,C), 13.8 [q, C(S)], -5.0 (q, MeSi), -5.3 (4, MeSi). - MS (70 eV): m/z (YO) = 231 (1.5) [(M - Me)+], 203 ( I ) , 189 (63), [(M - tBu)+], 161

(246.4): calcd. C 58.49, H 10.63; found C 58.38, H 10.68. (2s) -2-[( tert-Butyldimethylsilyl/oxy]-pentanoic Acid (12): The silyl ether

11 (1.21 g, 4.92 mmol) was dissolved in an 1 M ethanolic KOH solution (10 ml) at room temp., and the solution was stirred for 24 h. The EtOH was removed under reduced pressure and the resulting oil dissolved in water. The aqueous solution was extracted with CH2C12 (1 X 50 ml), acidified (to pH = 1) with an I N aq. HCI solution with vigorous stirring, then extracted with CH2C12 (5 X 20 ml). The combined dichloromethane extracts were dried (MgSOJ, filtered, and the filtrate was concentrated affording the protected acid 12 (1.05 g, 92%) as a colorless oil. - = -21.3 (c = 4.50, CHCI,). - IR (film): 2 = 3600-2300 (br., OH), 2960 (s), 2930 (s), 2860 (s), 1725 (s, C=O), 1470 (m), 1260 (s), 1150 (s), 900 (m), 835 (s), 780 (s) cm-I. - 'H NMR (300 MHz): 6 = 4.28 (dd, J = 6.0 and 5.0 Hz, I H , 2-H), 1.85-1.66 (m, 2H, 3-H), 1.55-1.32 (m, 2H, 4-H), 0.93 (t, J = 7.2 Hz, 3H, 5-H), 0.93 (s, 9H, Me3C), 0.12 (s, 6H, Me2%). - ''C NMR (75 MHz): 6 = 176.3 [s, C(l)], 72.0 [d, C(2)], 36.9 [t, C(3)], 25.6 (9. Me3C), 18.1 (s, Me3C), 17.8 [t. C(4)], 13.8 [q, C(5)], -5.0 (q, MeSi), -5.2 (q, MeSi). - MS (70 eV): mlz (YO) = 233 (2) [(M + I)+], 217 (2) [(M - Me)+], 187 (16), 175 (84), [(M - tBu),], 147 (36), 105 (31), 75 (100). - CllHZ4O3Si (232.4): calcd. C 56.85, H 10.41; found C 56.90, H 10.25.

(ZS)-Methyl 2-[2-(Trimethylsilyl)etho.uymethyloxy]-pentanoate (13): A solution of hydroxy ester 9 (0.50 g, 3.8 mmol) and diisopropylethylamine (0.58 g, 0.77 ml, 4.5 mmol) in CH2Cl2 (10 ml) was cooled to 0°C under

CO,H)+], 299 (77) [(M - tBu)+], 271 (34), 239 (7), 221 (1 I), 199 (IOO), 181

(23), 131 (7), 115 (5), 101 (8), 89 (loo), 73 (M), 59 (35). - C12H2603Si

argon, and a solution of [2-(chloromethoxy)ethyl]trimethylsilane (SEM-C1) (0.76 g, 0.80 ml, 4.5 mmol) in CHZCI2 (2 ml) was added dropwise. The reaction mixture was warmed to room temp. and stirred for 12 h, then poured into a satd. NH4CI solution (25 ml). The mixture was extracted with Et20 (2 X 30 ml), the combined organic layers were washed with water (1 X 10 ml) and brine (1 X 10 ml), dried (MgS04), filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (1.5 X 10 cm, 2% Et,O/pentane) gave the protected hydroxy acid 13 (0.74 g, 73%) as a colorless oil. - [a]Br = -50.3 (c = 1.03, EtOH). - 1R (CC14): 2 = 2900 (s), 1740 (s, C=O), 1460 (s), 1370 (s), 1290 (m), 1220 (s), 1060 (s), 900 (m), 690 (m) cm-'. - 'H NMR (200 MHz): 6 = 4.70 (s, 2H, OCH,O), 4.10 (t, J = 7.0 Hz, 1 H, 2-H), 3.70 (s, 3H, MeOOC), 3.60 (t, J = 8.5 Hz, 2H, OCHzCH2TMS), 1.72-1.34 (m. 4H, 3-H and 4-H), 0.92-0.81 (m, 5H, 5-H and OCHzCHzTMS), 0.20 (s, 9H, Me,Si). - "C

(t, OCH2CH2TMS), 51.3 (q, MeOOC), 34.4 [t, C(3)], 17.9 [t. C(4)], 17.4 (t. OCH2CH2TMS), 13.0 [q, C(5)], -2.1 (q, Me,Si). - MS (70 eV): mlz (%) = 189 (9) [(M - Me3Si)+], 145 (15), 117 (S), 103 (S), 89 (32), 73 (IOO), 59 (15), 45 (19). - ClZHZ6o4Si (262.4): calcd. C 54.92, H 9.99; found C 54.64, H 10.18.

(2S)-2-[2- (Trimethylsilyl)ethoxymethyloxy]-pentanoic Acid (14): The protected hydroxy acid 13 (0.34 g, 1.40 mmol) was dissolved in MeOH/HzO (2:1, 10 ml), the solution cooled to OT, and then LiOH (0.16 g, 3.9 mmol) was added. The reaction mixture was stirred for 12 h at room temp., poured into brine (25 ml) and then extracted with Et20 (3 X 10 ml). The combined organic layers were dried (MgS04), filtered, and the filtrate was concentrated under reduced pressure, affording the protected acid 14 (0.31 g, 90%) as a colorless oil. - [a]B = -65.1 (c = 1.10, EtOH). - IR (CCI4): 2 = 3620 (w). 3460 (br. OH), 2950 (s), 1730 (s, C=O), 1420 (s), 1250 (s), 1050 (s), 920 (m), 850 (m) cm-I. - 'H NMR (200 MHz): 6 = 4.72 (s, 2H, OCHzO), 4.15 (t, J = 7.0 Hz, IH, 2-H), 3.65 (dd, 2H, OCH2CH2TMS), 1.81-1.42 (m, 4H, 3-H and 4-H), 0.95-0.85 (m, 5H, 5-H and OCH2CH2TMS), 0.20 (s, 9H, Me3Si). - I3C NMR (50 MHz): 6 = 178.0 [s, C(l)], 94.1 (t. OCHzO), 74.9

OCH2CH2TMS), 13.1 [q, C(5)], -2.1 (9. Me,Si). - MS (70 eV): rnlz (YO) = 249 (10) [(M + I)+], 219 (2), 175 (S), 146 (14), 145 (13), 105 (3), 103 (8), 75 (38), 73 (IOO), 55 (9), 45 (10). - CllH2404Si (248.4): calcd. C 53.19, H 9.74; found C 53.44, H 10.02.

Methyl N-(2.2-Diethoxyethyl)-carbamate (16): To a solution of the commercially available aminoacetaldehyde diethyl acetal (15) (13.3 g, 0.10 mol) in CHzC12 (200 ml) was added under argon triethylamine (16.0 ml, 0.22 mol). The solution was cooled to O"C, and methyl chloroformate (9.2 ml, 0.12 mol) was added dropwise. The reaction mixture was warmed to room temp. and stirred for 15 h, then poured into water (250 ml) and extracted with CHZCl2 (3 X 50 ml). The combined organic phases were washed with a satd. CuSO, solution (2 X 25 ml), water (1 X 50 ml) and brine (1 X 50 ml), dried (MgS04), filtered, and the solvent was evaporated under reduced pressure. Distillation of the residue under reduced pressure afforded the carbamate 16 (16.4 g, 86%) as a colorless oil. - B.p. 123-125°C112 Torr. - IR (film): D = 3330 (br., NH), 2970 (s), 2930 (m), 2890 (m), 1725 (s, C=O), 1530 (s), 1375 (m), 1260 (s), 1130 (s), 1060 (s), 1010 (m) cm-I. - 'H NMR (300 MHz): 6 = 4.93 (br. s, 1 H, NH), 4.49 (t. J = 5.4 Hz, 1 H, 2-H), 3.71 (dq, J = 9.4 and 7.0 Hz, 2H, OCHzMe), 3.68 (s, 3H, MeOCONH), 3.54 (dq, J = 9.4 and 7.0 Hz, 2H, OCH,Me), 3.30 (br. t, J = 5.7 Hz, 2H, I-H), 1.22 (t, J = 7.0 Hz, 6H, OCH2Me). - I3C NMR (75 MHz): 6 = 159.8 (s, OCONH), 101.1 [d, C(2)], 62.9 (t. OCHzMe), 52.9 (4, MeOCONH), 43.5 [t. C(l)], 15.3 (9. OCH2Me). - MS (70 eV): mlz ("YO) = 160 (1.2) [(M - OMe)+], 146 (29), 114 (lo), 103 (IOO), 88 (25), 75 (54), 47 (76), 29 (38). - CEH17N04 (191.2): calcd. C 50.25, H 8.96, N 7.32; found C 49.89, H 8.88, N 7.21.

tert-Bufyl N-(2,2-Diethoxyethyl)carbamate (17): To an ice-cold solution of aminoacetaldehyde diethyl acetal(l5) (4.21 g, 31.7 mmol) and triethylamine (5.1 g, 7.0 ml, 50 mmol) in CH2C12 (50 ml) was added BoczO (10.0 g, 45.8 mmol). The reaction mixture was stirred at 0°C for 30 min and at room temp. for 2 h. The solvent was removed under reduced pressure, and Et20 (100 ml) was added to the residue. The organic phase was washed with a 1 M aq. HCI solution (1 X 20 ml), a satd. NaHC0, solution (1 X 20 ml) and brine (1 X 20 ml). The ethereal phase was dried (Na2S04), filtered and the solvent evaporated in vacuo affording crude 17 (8.6 g, quantitative) as a yellowish liquid, which was used without further purification.

Methyl N-([l,3]Dithian-2-ylmethyl)-carbamate (4): A solution of the carbamate 16 (4.78 g, 25 mmol) and propane-1,3-dithiol (2.4 ml, 24 mmol) in CHZCIz (100 ml) at O°C under argon was treated dropwise with diethyl ether - boron trifluoride (6.3 ml, 50 mmol). The reaction mixture was warmed to room temp. and stirred until no starting material was detectable by TLC analysis, then poured into a 2 N aq. KOH solution (150 ml), and the layers were separated. The organic phase was washed with brine (1 X 100 ml), dried (MgS04), filtered and the solvent evaporated under reduced pressure to give the dithiane 4 (4.86 g, 97%) as a white, light powder. - M.p. 79-80°C

NMR (50 MHz): 6 = 173.2 [s, C(l)], 93.9 (t, OCHZO), 74.8 [d, C(2)], 65.2

[d, C(2)], 65.6 (t, OCHzCHzTMS), 34.2 [t, C(3)], 17.9 [t, C(4)], 17.4 (t,



(Et,O). - IR (KBr): 2 = 3350 (s, NH), 2930 (w). 2890 (w), 1700 (s, C=O), 1535 (s), 1435 (s), 1265 (m), 1150 (m), 1075 (m), 1010 (m), 635 (s) cm-'. - 'H NMR (300 MHz): 6 = 5.10 (br. s, 1 H, NH), 4.04 (br. t, J = 6.9 Hz, 1 H, 2-H), 3.69 (s, 3H, MeOCONH), 3.58 (br. t, J = 6.5 Hz, 2H, 1'-H), 2.91 [ddd, J = 14.2, 7.0 and 3.1 Hz, 2H, 4-H,, and 6-H,,], 2.77 [ddd, J = 14.2, 9.4 and 2.9 Hz, 2H, 4-H,, and 6,,-H], 2.09 [dtt, J = 14.1, 7.0 and 2.9 Hz, 1 H, 5-H,,], 1.94 [dtt, J = 14.1, 9.5 and 3.1 Hz, 1 H, 5-H,,]. - I3C NMR (75 MHz): 6 = 156.9(s, OCONH), 52.3 (q, MeOCONH),45.5 [d, C(2)], 44.4 [t, C(l')], 28.1 [t, C(4) and C(6)], 25.6 [t, C(5)l. - MS (70 eV): mlz ("h) =

calcd. C 40.55, H 6.32, N 6.76; found C 40.62, H 6.34, N 6.81. 207 (1.8) [M"], 132 (20), 119 (IOO), 59 (12), 45 (13). - C7H13N02S2 (207.3):

tert-Bufyl N-([1,3]Dithian-2-ylmethyl)-carbamate (18): A solution of the crude carbamate 17 (8.6 g, S33 mmol) and propane-1,3-dithiol (3.79 g, 3.5 ml, 35 mmol) in CH2C12 (100 ml) was cooled to 0°C and treated with diethyl ether-boron trifluoride (4.9 g, 4.3 ml, 35 mmol) under argon. The reaction mixture was stirred for 12 h at room temp., then poured into a 2 N aq. KOH solution (100 ml), and the organic layer was washed with brine (1 X 100 ml), dried (MgSOJ, filtered and the filtrate concentrated to give crude dithiane 18 [8.2 g, 98%, R, (25% Et20/pentane) = 0.221 as a white powder. For the purpose of obtaining analytical data a small amount of the dithiane was purified first by column chromatography (33-50% Et20/pentane, gradient elution) then by recrystallization from hexane. - M.p. 75.6-76.0"C (hexane). - IR (KBr): 2 = 3340 (s, NH), 2980 (m), 2925 (m), 1690 (s, C=O), 1535 (s), 1440 (m), 1365 (m), 1275 (s), 1250 (m). 1170 (s), 1145 (s), 1050 (w), 1000 (m), 670 (m) cm-'. - 'H NMR (300 MHz): 6 = 4.99 (br. s, 1 H, NH),

J = 14.3, 7.1 and 3.1 Hz, 2H, 4-H and 6-H), 2.76 (ddd, J = 14.3, 9.4 and 3.0 Hz, 2H, 4-H and 6-H), 2.06 (dtt, J = 13.9, 7.1 and 3.0 Hz, IH, 5-H), 1.91 (dtt, J = 13.9, 9.4 and 3.1 Hz, I H , 5-H), 1.45 (s, 9H, Me,C). - 13C NMR (75 MHz): 6 = 155.7 (s,OCONH), 79.7 (s, Me3C),45.6 [d,C(2)],44.0 [t. CH2-C(2)], 28.4 (9. Me,C), 28.1 [t. C(4) and C(6)], 25.7 [t, C(5)]. - MS (70 eV): m/z (YO) = 249 (6) [M+'], 193 (31) [(M - C4H8)+], 192 (12) [(M -

CloH19N02S2 (249.4): calcd. C 48.16, H 7.68, N 5.62; found C 48.63, H 7.48, N 5.65.

([1.3]Dithian-2-ylmethyl)-amine (19): One drop of trifluoroacetic acid was added to a solution of the carbamate 18 (1.0 g, 4.0 mmol) in MeOH (15 ml). The solution was heated under reflux for 30 min and then the solvent removed in vacuo. Distillation of the residue afforded the dithiane 19 (0.54 g, 90%) as a colorless oil, which turned brown on standing at room temp. - B.p. 9O"ClO.l Torr (kugelrohr). - IR (CHCI,): 2 = 3640 (s, NH), 3590 (br,, NH), 3000 (s), 2880 (m), 1460 (m), 1410 (s), 1200 (s), 1040 (m), 910 (m), 860 (m), 830 (m), 700 (s), 650 (s) cm-'. - 'H NMR (200 MHz): 6 = 3.85 (t, J = 6.3 Hz, 1 H, 2'-H), 2.97 (d, J = 6.3 Hz, 2H, I-H), 2.92-2.61 (m, 4H, 4'-H and 6'-H), 2.10-1.71 [m, 2H, 5'-HI, 1.32 [br. s, 2H, NH2]. - "C NMR (50 MHz): 6 = 49.6 [t. C(l)]. 45.8 [d, C(2')], 28.0 [t, C(4') and C(6')], 25.4 [t, C(5')l. - MS (70 eV): m/: (%) = 149 (8) [M+'], 131 (56), 121 (lo), 120 (12), 119 (loo), 85 (12), 81 (13), 75 (13), 73 (13), 71 (13), 69 (30), 57 (23), 43 (35), 30 (73), 28 (76), 18 (46). - C5HIINS2 (149.3): calcd. C 40.23, H 7.43, N 9.38; found C 40.31, H 7.37, N 9.09.

(ZS)-2-[2-(Trimethylsilyl)ethoxymethoxy]-pentanoic Acid ([1',3']-Di- thiun-2'-ylmethyl)-aide (20): To a solution of the acid 14 (0.23 g, 0.93 mmol) in CHCl, (5 ml) was added Et3N (130 pl, 95 mg, 0.95 mmol), dissolved in CHCI, (2 ml). The solution was cooled to -15"C, then chloro- formic acid ethyl ester (90 pl, 101 mg, 0.94 mmol) was introduced and the resulting mixture stirred for 20 min at - 15°C. Then a solution of amine 19 (140 mg, 0.94 mmol) in CHCI, (1 ml) was added and the reaction mixture allowed to warm to room temp. over a period of 2 h. The solution was diluted with CHC1, (10 ml) and the organic phase washed with a 1 N aq. HCI solution (1 X 5 ml), brine (1 X 5 ml), a 0.5 N KHCO, solution (1 X 5 ml) and brine (1 X 5 ml), the combined aqueous washings were re-extracted with CH,C12 (2 X 10 ml). The combined organic phases were dried (MgS04), filtered, and the filtrate was concentrated. Purification of the residue by column chromatography (1 X 15 cm, 33-50% Et20/pentane, gradient elution) afforded the amide 20 (0.28 g, 79%) as colorless crystals. - M.p. 68°C. - [a]B = -71.3 (c = 1.05, EtOH). - IR (CCh): 2 = 3410 (m, NH), 2950 (s), 2890 (s), 1680 (s, C=O), 1510 (s), 1460 (w), 1420 (m), 1240 (s), 1190 (m), 1120 (m), 1100 (s), 1030 (s), 900 (s), 860 (s), 840 (s) cm-'. - 'H NMR (200 MHz): 6 = 6.91 (br. s, 1 H, NH), 4.76-4.68 (m, 2H, OCH20), 4.14-4.01 (m, 2H, 2-H and 2'-H), 3.80-3.55 (m, 4H, CH2N and TMSCH,CH20), 2.98-2.86 (m, 2H, 4'-H and 6'-H), 2.82-2.68 (m, 2H, 4'-H and 6'-H), 2.17-1.81 (m, 2H, 5'-H), 1.80-1.68 (m. 2H, 3-H), 1.50-1.31 (m, 2H, 4- H), 0.97-0.83 (m, 5H, 5-H and TMSCH2CH20), 0.02 (s, 9H, Me,Si). -

4.02 (t, J = 6.8 Hz, 1 H, 2-H), 3.53 [t, J = 6.5 Hz, 2H, CH2-C(2)], 2.92 (ddd,

tBu)+], 176 (7), 175 (7), 149 (1.7), 132 (24), 119 (IOO), 57 (16). -

I3C NMR (50 MHz): 6 = 172.7 [s, C(l)], 93.9 (t, OCH,O), 76.9 [d, C(2)], 65.6 (t, TMSCH,CH,O), 44.6 [d, C(2')], 41.6 (t, CHzN), 34.4 [t. C(3)], 27.6 [t. C(4') and C(6')], 25.1 [t. C(5')], 17.6 [t, C(4)], 17.5 (t, TMSCH2CH20), 13.3 [q, C(5)], -2.0 (4, Me3Si). - MS (70 eV): m/z ("A) = 380 (2) [(M + I)+], 352 (l.8), 322 (6), 306 (6), 278 (3), 262 (4), 260 (3), 248 (23), 174 (8),

148 (7), 145 (8), 133 (27), 132 (40), 119 (27), 103 (9), 101 (lo), 73 (100). - CI6H,,NO3S2Si (379.7): calcd. C 50.62, H 8.76, N 3.69, S 16.89; found C 50.47, H 8.65, N 3.63, S 16.85.

(4S,5R)-Trifluoromethanesuljonic Acid 2,2-Dimethyl-5-vinyl-[1,3]dioxo- Ian-4-ylmethyl Ester (5): Pyridine (3.3 ml, 40 mmol) was added dropwise to a stirred solution of the alcohol 21[221 (2.05 g, 13.0 mmol) in CH2C12 (60 ml) under argon at room temp. After 5 min the solution was cooled to -3O"C, and trifluoromethanesulfonic anhydride (4.4 ml, 26 mmol) was introduced dropwise. The resulting suspension was stirred at -30°C for 60 min, then at -40°C for a further 2 h and subsequent poured into CH2C12 (100 ml). The organic phase was washed with a 0.5 N aq. HCI solution (1 X 40 ml), water (1 X 30 ml) and a satd. NaHCO, solution (1 X 40 ml), then dried (MgS04). Filtration, removal of the solvent in vacuo and drying of the residue at -2O"C/O.I Torr gave the crude sulfonate 5 (3.63 g, 96%) as a yellowish oil, the purity of which was analyzed by TLC [R, (20Y0 EtOAdhexane) = 0.521. The product was used for the next step without further purification due to its instability.

(El -1 - (3'-Bromo-but-2'-enyloxymethyl) -4-methoxy-benzene (6a): Solid NaH (1.00 g, 23 mmol, 55% suspension in oil) was added in small portions to an ice-cold solution of allylic alcohol 23[251 (3.02 g, 20 mmol) in THF (42 ml) under argon. After H2 evolution had ceased, tetrabutylammonium iodide (90 mg) and p-methoxybenzyl bromide (3.38 ml, 25 mmol) were introduced. The reaction mixture was stirred 18 h at room temp. then cautiously poured into icelwater (200 ml). The aqueous phase was separated and extracted with CH2C12 (3 X 50 ml). The combined organic extracts were washed with brine (1 X 25 ml), dried (MgS04) and concentrated. After column chromatography (5 X 20 cm, CH2C12) of the residue purep-methoxybenzyl ether 6a [2.82 g, 52%, Rf (CH2C12) = 0.541 was obtained as a slightly yellow oil. - IR (film): 2 = 3030 (w), 2930 (m), 2850 (m), 1615 (s), 1515 (s), 1465 (m), 1250 (s), 1170 (m), 1120 (s), 1085 (s), 1035 (s), 820 (s) cm-'. - IH NMR (300 MHz): 6 = 7.25 and 6.88 (AA'XX' system, J = 8.8 Hz, 4H, Harem), 6.07 (tq, J = 7.1 and 1.3 Hz, 1 H, 2'-H), 4.43 (s, 2H, Hbenzyhc), 3.94 (dd, J = 7.1 and 0.7 Hz, 2H, 1'-H), 3.80 (s, 3H, MeOPh), 2.25 (td, J = 1.3 and 0.7 Hz, 3H, 4'-H). - 13C NMR (75 MHz): 6 = 159.4 (s, C,,,), 130.0 (s, C,,,), 129.4 (d, C,,,), 128.8 [d, C(2')], 124.4 [s, C(3')], 113.9 (d, C,,,,), 71.8 (t, Cbenzyhc). 66.0 [t, C(l')]. 55.3 (q, MeOPh), 23.8 [q. C(l')]. - MS (70 eV): m/z ("A) = 272 (3) [M+' ("Br)], 270 (3) [M+' (79Br)], 191 (13) [(M - Br)+], 164 (2), 162 (2), 149 (2), 136 (40), 121 (IOO), 109 (7). - CI2Hl5O2Br (271.2): calcd. C 53.16, H 5.58; found C 53.27, H 5.60.

(E)-(3'-Bromo-but-2'-enyloxymethyl)-benzene (24): To a solution of allylic alcohol 23"" (0.53 g, 3.5 mmol) in THF (6 ml) was added at 0°C under argon NaH (0.18 g, 4.0 mmol, 55% suspension in oil) in small portions. After the H2 evolution was completed, tetrabutylammonium iodide (13 mg) and benzyl bromide (0.43 ml, 3.6 mmol) were added. The solution was stirred for 12 h at room temp., then cooled to 0°C before cautious addition of water (50 ml). The aqueous phase was extracted with EtzO (4 X 25 ml). The combined organic extracts were washed with brine (1 X 25 ml), dried (MgS04), filtered and the solvents evaporated. Purification of the residue by repeated column chromatography (first 20% Et,O/pentane, then CH2C12) furnished the benzyl ether 24 [0.65 g, 770/0, Rr (CH2CI2) = 0.801 as a slightly yellow oil. - IR (film): 2 = 3090 (w). 3065 (w), 3030 (m), 2925 (m), 2860 (m), 1650 (m, C=C), 1455 (m), 1360 (m), 1120 (s), 1095 (s), 1055 (s), 1030 (m). 735 (s), 695 (s) cm-I. - IH NMR (300 MHz): 6 = 7.38-7.27 (m, 5H, H,,,), 6.09 (tq, J = 7.1 and 1.3 Hz, 1 H, 2'-H), 4.50 (s, 2H, H,,,,,,,), 3.97 (d, J = 7.1 Hz, 2H, 1'-H), 2.25 (d, J = 1.3 Hz, 3H, 4'-H). - I3C NMR (75 MHz): 6 = 137.7 (s, C,,,,), 131.8 [d, C(2')], 128.4 (d, C,,,), 127.8 (d, Carom), 124.6 [s, C(3')1, 72.1 (t, Cbenzyilc), 66.3 [t. C(l')l, 23.8 [q, C(4')I. - MS: mlz (%) = 242 (0.1) [M+' ("Br)], 240 (0.1) [M+' (79Br)], 161 (9) [(M - Br)+], 151 (I), 149 (l), 135 (2), 133 (2), 107 (9), 105 (4), 91 (100). - CIIHI30Br (241.1): calcd. C 54.80, h 5.43; found C 54.77, H 5.41.

(Z)-2,4-Dibromo-but-2-en-1-ol(25): Butyne-1,4-diol (4.5 g, 54 mmol) was dissolved in 48% aq. HBr solution (30 ml) at room temp. and the mixture stirred for 68 h at 35"C, during which time it turned black. The reaction mixture was poured into Et20 (100 ml) and idwater (50 ml). A black precipitate was formed. The aqueous solution was re-extracted with Et20 (3 X 70 ml). The combined organic phases were dried (MgS04), filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography (5 X 15 cm, 25% Et20/pentane) yielded the alcohol 25 [4.7 g, 39%, Rf (250/0 Et20/pentane) = 0.391 as a colorless liquid, which crystallized on standing. Recrystallization of a sample of 25 from hexane gave long needles which were used for X-ray analysis. - M.p. 39.2-40.0°C (hexane). - 'H NMR (200 MHz): 6 = 6.35 (tt, J = 7.9 and 1.4 Hz, 1 H, 3-H), 4.29 (br. d, J = 6.7 Hz, 2H, I-H), 4.07 (d, J = 8.0 Hz, 2H, 4-H), 2.62 (t, J = 6.7 Hz, 1 H, OH). - I3C NMR (50 MHz): 6 = 131.4 [s, C(2)], 124.5 [d, C(3)], 67.4 [t. C(l)]. 28.5 [t, C(4)].

X-ray Analysis of 25rs'l: A colorless cube-like crystal of 25 having the approximate dimensions of 0.5 X 0.5 X 0.5 nun was mounted on an Enraf



Nonius CAD 4 four-circle-automated diffractometer with graphite-mono- chromated Mo-K, radiation. Crystal data: C4H6Br20, FW = 229.90, mono- clinic, space group P21,aa = 8.803(3), b = 4.447(3), c = 16.879(13) A, =

90.64(4)", V = 660.8(7) A3, Z = 2, D, = 2.250 g/cm' and p(Mo-K,) = 12.155 mm-I. - The data were collected by using the w scan technique to a maximum 2 0 value of 50". A total of 1178 independent reflections was collected. The data were corrected for Lorentz and polarization effects. - The structure was solved by the Peterson method. The resulting E map revealed the positions of all non-H atoms. The refinement of atomic parameters was carried out by a full-matrix least-squares refinement. Because of the poor data quality, the location and refinement of the H atoms were not possible. The final refinement was based on 862 observed reflections with F > 4.00o(F) and 126 variable parameters and converged R, = 0.1102, WR, = 0.1363. The maximum and minimum peaks on the final difference Fourier map corresponded to 3.91 and -3.08 e/A3, respectively. - All calculations were performed by using the SHELXTL-PLUS and SHEL-XL-92 crystal structure refinement p r 0 g r a m [ ~ ~ , ~ ~ 1 .

(Z)-2,4-Dibromo-I-methoxy-but-2-ene (26): To a suspension of the alcohol 25 (3.0 g, 13 mmol) and K2CO3 (17.9 g, 0.13 mol) in CH2CI2 (70 ml) at room temp. was added in portions trimethyloxonium tetrafluoroborate (5.8 g, 39 mmol). After stirring for 24 h two more equivalents of (MeO):BFT (3.85 g, 26 mmol) were added, and the resulting mixture was stirred for a further 68 h. The precipitated potassium carbonate was filtered off and the clear CH2CI2 solution poured into a satd. NaHCO, solution (100 ml). The aqueous phase was extracted with CH2C12 (3 X 50 ml), the combined organic phases were washed with brine (1 X 50 ml), dried (MgS04), filtered, the filtrate was concentrated and the residue purified by column chromatography (3 X 35 cm, 20% Et20/pentane) to afford the methyl ether 26 [2.8 g, 88%, Rf (25% Et20/pentane) = 0.581 as a yellowish oil, which was further purified by kugelrohr distillation. - B.p. (kugelrohr): 70-80°C, 0.03 Torr. - nD = 1.5353. - IR (film): 5 = 3040 (w), 2985 (m), 2935 (s), 2890 (m), 2825 (s), 1650 (m, C=C), 1450 (m), 1435 (m), 1380 (m), 1360 (m), 1310 (w), 1270 (m), 1205 (s), 1120 (s), 1055 (m). 960 (w), 920 (m), 845 (m), 690 (m), 680 (m) cm-I. - 'H NMR (400 MHz): 6 = 6.34 (tt, J = 7.9 and 1.3 Hz, 1 H, 3-H), 4.12 (dt, J = 1.3 and 0.7 Hz, 2H, I-H), 4.10 (dt, J = 7.9 and 0.7 Hz, 2H, 4-H), 3.38 [s, 3H, MeO-C(1)]. - I3C NMR (50 MHz): 6 = 129.1 [s, C(2)], 126.4 [d, C(3)], 76.9 [t, C(l), 58.4 [q, MeO-C(l)], 28.9 [t. C(4)]. - MS (70 eV): m/z (%) = 246 (0.9) [M+' (2 X 81Br)], 244 (1.9) [M+' (81Br, 79Br)], 242 (0.9) [M+' (2 X 79Br)], 215 (0.2) [(246M - OMe)+], 213 (0.4) [(244M - OMe)+], 211 (0.2) [242M - OMe)+], 165 (67) [(M - HBr)+], 163 (71) [(M - HBr)+], 133 (6) [(M - HBr - OMe)+], 131 (4) [(M - HBr - OMe)+], 121 (4), 119 (S), 84 (100) [(M - 2 X HBr)+], 69 (27), 53 (19), 45 (14), 39 (17). - C5H8Br20 (243.9): calcd. C 24.62, H 3.31; found C 24.42, H 3.29.

(Z)-I- (3'-Bromo-4'-methoxy-but-2'-enyloxymethyl) -4-methoxy-benzene (27): Sodium iodide (2.00 g, 13.3 mmol), p-methoxybenzyl alcohol (1.52 g, 11.0 mmol) and DMPU (8 ml) were dissolved in THF (40 ml) at room temp. under argon. The clear solution was cooled to -2O"C, and BuLi (18 ml, 12 mmol, 1.5 M in hexane) was introduced via a syringe. The mixture was stirred for 30 min, then a solution of bromide 26 (2.43 g, 9.95 mmol) in THF (10 ml), was added. After a few minutes, a white precipitate had formed. The reaction mixture was stirred at -20°C for 72 h, diluted with Et20 (50 ml), and the reaction was quenched with water (50 ml). The aqueous layer was extracted with Et20 (5 X 25 ml), the combined organic phases were dried (MgS04), filtered, and the filtrate was concentrated under reduced pressure. Column chromatographic purification (5 X 15 cm, 33-66% Et20/pentane) of the residue gave the vinyl bromide 27 [1.53 g, 51%, Rf(25% Et20/pentane) = 0.291 as a colorless liquid, containing ca. 6% of the corresponding alkyne. - IR (film): 2 = 2995 (w), 2935 (m), 2835 (m), 1665 (w, C=C), 1610 (m), 1585 (w). 1515 (s), 1465 (m), 1455 (m), 1360 (m), 1300 (m), 1250 (s), 1175 (m), 1105 (s), 1035 (s), 960 (w). 915 (w), 820 (s), 760 (w). 690 (w) cm-'. - 'H NMR (400 MHz): 6 = 7.28 and 6.89 (AA'XX' system, J = 8.7 Hz, 4H,

(dt, J = 5.6 and 1.2 Hz, 2H, 4'-H), 4.08 (9, J = 1.2 Hz, 2H, 1'-H), 3.80 (s, 3H, MeOPh), 3.35 [s, 3H, MeO-C(1')]. - I3C NMR (100 MHz): 6 = 159.3 (s, Carom), 129.9 (s, Carom), 129.5 (d, Carom), 128.7 [d, C(3'11, 124.6 1% C(2')1, 113.8 (d, carom), 77.0 [t, c(I')], 72.3 (t. Cbennyiic), 68.9 [t, c(4')], 57.9 [q. MeO-C(l')]. 55.3 (4. MeOPh). - MS (70 eV): m/z ("h) = 302 (3) [M+' (8'Br)], 300 (3) [M" (79Br)], 271 (1.1) [(302M - OMe)+], 269 (1.1) [(300M - OMe)+], 241 (0.7), 239 (0.7), 220 (0.3) [(M - HBr)'], 189 (50), 136 (21), 121 (loo), 109 (8), 84 (6), 77 (9), 45 (11). - CI3Hl7BrO3 (301.2): calcd. C 51.84, H 5.69; found C 51.72, H 5.60.

( E ) -4-[ (tert-Butyldimethylsilyl) oxy]-l-methoxy-2-tributylstannanyl-but-2- ene (30): To a solution of alcohol 29[28b] (1.48 g, 3.00 mmol) in THF (10 ml) at -78°C was added under argon BuLi (2.0 ml, 3.0 mmol, 1.5 M in hexane). The pale yellow solution was stirred for 30 min at -78OC and Me1 (1.42 g, 0.62 ml, 10 mmol) was introduced. The reaction mixture was allowed to warm to room temp. for about 12 h whereupon water (20 ml) and Et20 (30

H,,,), 6.25 (tt, J = 5.6 and 1.2 HZ, 1 H, 3'-H), 4.46 (S, 2H, Hbenzylic), 4.20

ml) were added. The aqueous layer was extracted with Et20 (3 X 20 ml). The combined organic phases were dried (MgS04), filtered and the solvents evaporated in vacuo. The residue was purified by column chromatography (3 X 20 cm, 5% Et20/pentane) yielding the methyl ether 30 [1.45 g, 95%, Rf (5% Et20/pentane) = 0.551 as a colorless liquid. - IR (film): 0 = 2955 (s), 2925 (s), 2855 (s), 2815 (m), 1615 (m, C=C), 1465 (m), 1360 (m), 1255 (m), 1195 (m), 1095 (s), 1005 (w), 835 (m), 775 (m), 670 (m) cm-'. - 'H NMR (400 MHz): 6 = 5.67 (tt, J = 5.3 and 2.3 Hz, JH.Sn = 69.2 Hz, IH, 3-H), 4.21 (dt, J = 5.4 and 1.1 Hz, JH.Sn = 11.0 Hz, 2H, 4-H), 4.05 (td, J = 2.2 and 1.1 Hz, JH-s" = 35.8 Hz, 2H, I-H), 3.30[s, 3H, MeO-C(l)], 1.58-1.38

(m, 6H, 3 X CHZbutyl), 0.91 (s, 9H, Me3C), 0.89 (t, J = 7.3 Hz, 9H, 3 X Mebut,& 0.07 (s, 6H, Me2Si). - "C NMR (100 MHz): 6 = 144.9 [s, C(2)], 138.8 [d, C(3)], 73.7 [t, C(4)], 61.1 [t, C(l)], 58.0 [q, MeO-C(l)], 29.2 (t,

(m, 6H, 3 X CH2butyl), 1.31 (sext, J = 7.2 HZ, 6H, 3 X CH2butyl), 0.96-0.79

CH2butyl), 27.4 (L CH2butyl). 26.0 (4, Me3c), 18.4 (S, Me3C), 13.8 (q, Meb,,,l), 10.1 (t. CH2bUt,l), -5.1 (q, Me2Si). - MS (70 ev): m/z ("h) = 505 (0.1) [M+'], 449 (18), 417 (S), 365 (12), 291 (S), 265 (IOO), 235 (9), 195 (S), 179 (19), 151 ( I I ) , 121 (5). - C23H5002SiSn (505.4): calcd. C 54.66, H 9.97; found C 54.95, H 9.73.

(E)-4-Methoxy-3-tributylstannanyl-but-2-en-l-ol(31): A solution of the silyl ether 30 (7.80 g, 15.5 mmol) in THF (100 ml) was treated with Bu4NF 3 H 2 0 (5.0 g, 16 mmol) at room temp. The pale yellow solution was stirred for 1 h and the solvent removed under reduced pressure. The residue was purified by column chromatography (5 X 20 cm, 25-100% Et,O/pentane, gradient elution) affording the alcohol 31 [5.9 g, 97%, Rf (25"" Et20/pentane) = 0.241 as a colorless oil. - IR (film): 2 = 3330 (br., OH), 2955 (s), 2930 (s), 2870 (s), 2855 (s), 2815 (m), 1615 (w, C=C), 1465 (m), 1420 (w), 1375 (m), 1195 (m), 1120 (s), 1040 (s), 1000 (m), 970 (m), 875 (m), 690 (m), 675 (m) cm-'. - 'H NMR (400 MHz): d = 5.78 (tt, J = 5.9 and 2.2 Hz, JH-S,, = 74.8 Hz, 1 H, 2-H), 4.17 (br. t, J = 5.8 Hz, 2H, I-H), 4.09 (dt, J = 2.2 and 0.9 Hz, J H . ~ " = 35.4 Hz, 2H, 4-H), 3.32 [s, 3H, MeO-C(4)], 1.93 (br. t, IH, OH), 1.58-1.38 (m. 6H, 3 x CH2butyl), 1.31 (sext, J = 7.3 Hz, 6H, 3 X CH~butyl), 0.97-0.80 (m, 6H, 3 X CHZbutyl), 0.89 (t, J = 7.3 Hz, 9H, 3 X Meb,tyl). - 13C NMR (100 MHz): 6 = 147.2 [s, C(3)], 138.0 [d, c(2)], 73.6 [t, c(l)], 60.1 [t, c(4)], 58.1 [q. hfeo-c(4)], 29.1 (t, CH2buty1). 27.4 (t, CH2butyl), 13.7 (4. Meb,,,l), 10.1 (t, CH2butyl). - MS (70 ev): m/z (%) = 391 (0.5) [M+'], 359 (0.5), 335 (84), 303 (IOO), 273 (56), 265 (41), 235 (13), 179 (45), 151 (40), 121 (19). - C17H3602Sn (391.2): calcd. C 52.20, H 9.28; found C 52.15, H 9.13.

( E ) -I-Methoxy-4-(4'-methoxy-3'-tributylstannanyl-but-2'-enyloxymethyl)- benzene (32): Sodium iodide (5.0 g, 33 mmol), DMPU (5 ml) and the alcohol 31 (9.5 g, 24 mmol) were dissolved in THF (100 ml) at room temp. under argon. The solution was cooled to -75°C and the alcohol deprotonated with BuLi (17 ml, 25 mmol, 1.48 M in hexane). The alcoholate was stirred for 30 min at -75"C, and p-methoxybenzyl chloride (4.6 g, 4.0 ml, 29 mmol) was added. The reaction mixture was allowed to warm to room temp. in a period of about 12 h and stirred for 30 h. The yellow solution was diluted with Et2O (100 ml) and the reaction quenched with water (100 ml). The aqueous layer was extracted with Et20 (4 X 50 ml), the combined organic layers were dried (MgSOd), filtered, and the filtrate was concentrated in vacuo. Column chromatography of the residue (5 X 18 cm, 4-10% Et20/pentane, gradient elution) gave the MPM ether 32 [8.5 g, 69%, Rr (10% Et,O/pentane) = 0.661 as a pale yellow oil. - IR (film): 5 = 3070 (w), 2955 (s), 2925 (s), 2850 (s), 1615 (m), 1585 (w), 1515 (s), 1465 (m), 1360 (m), 1250 (s), 1095 (s), 1040 (m), 820 (m), 690 (m), 670 (m) cm-I. - 'H NMR (500 MHz): 6 = 7.27 and 6.88 (AA'XX' system, J = 8.8 Hz, 4H, H,,,), 5.74 (tt, J = 5.7 and 2.2 Hz, JH.s" = 68.2 Hz, 1 H, 3'-H), 4.44 (s, 2H, Hbenzyhc), 4.04 (dt, J = 2.2 and 1.0 Hz, JH-s" = 35.4 Hz, 2H, 1'-H), 4.02 (dt, J = 5.7 and 1.0 Hz, 2H, 4'-H), 3.80 (s, 3H, MeOPh), 3.29 [s, 3H, MeO-C(I')], 1.57-1.40 (m, 6H, 3 X CH2bUtyJ, 1.31 (sext, J = 7.3 Hz, 6H, 3 X CHZbutyl), 0.95-0.81 (m, 6H, 3 X CH2butyJr 0.89 (t, J = 7.3 Hz, 9H, 3 X Mebuty1). - 13C NMR (125 MHz): 6 = 159.3 (s, C,,,), 148.5 [s, C(2')], 135.1 [d, C(3')], 130.4 (s, C,,,), 129.5 ( 4 Carom), 113.8 ( 4 Carom), 73.8 [L C(4')L 71.8 (4 Cbenzyhc), 66.9 [t, C(l')], 58.0 [q, Meo-c(1')], 55.3 (q, MeOPh), 29.2 (t. CH2butyl), 27.4 (t, CHZ butyl), 13.8 (q, Mebutyi), 10.2 (t, CH2butyl). - MS (70 ev): m/z ("/o) = 455 (5), 303 (8), 273 (0.Q 247 (1.3), 235 (l.O), 217 (0.8), 179 (4), 151 (3), 135 (1.2), 121 (100). - C2,HUO$n (511.3): calcd. C 58.72, H 8.67; found C 59.05, H 8.31.

(E)-I-(3'-Bromo-4'-methoxy-but-2'-enyloxymethyl) -4-methoxy-benzene (6b): To a cold (- 10°C) solution of the vinylstannane 32 (3.12 g, 6.10 mmol) in cc4 (90 ml) was added dropwise bromine (1.00 g, 0.32 ml, 6.2 mmol). The brown solution was stirred for 30 min at - lOT, the solvent evaporated and the residue purified by repeated column chromatography [2 X (4 X 12 cm, 33% Et20/pentane)] affording the vinyl bromide 6b [1.62 g, 88%, Rr (66% Et20/pentane) = 0.631 as a colorless oil. - IR (film): 5 = 3035 (w), 2995 (s), 2935 (s), 2835 (s), 1645 (w, C=C), 1615 (s), 1585 (w). 1515 (s), 1465 (m), 1360 (m), 1300 (m), 1250 (s), 1175 (m), 1100 (s), 1035 (s), 960 (w). 820 (s) cm-I. - lH NMR (400 MHz): 6 = 7.25 and 6.88 (AA'XX' system, J = 8.6 Hz, 4H, Ha,,), 6.33 (t, J = 6.9 Hz, 1 H, 3'-H), 4.44 (s, 2H, Hknryllc),


710 D. Seebach, M. A. Maestro, M. Seflcow, G. Adam, S. Hintermann, A. Neidlein

4.14 (s, 2H, l'-H), 4.04 (d, J = 6.9 Hz, 2H, 4'-H), 3.80 (s, 3H, MeOPh), 3.32 [s, 3H, MeO-C(l')]. - 13C NMR (100 MHz): 6 = 159.4 (s, C,,,), 133.3 [d, C(3')], 129.7 (s, C,,,), 129.5 (d, C,,,), 125.0 [s, C(2')], 113.9 (d, Carom), 72.1 (t, Cbenzyd, 72.0 [t, C(4'11, 65.8 [t, C(l')l, 57.7 [q, MeO-C(l')], 55.3 (q, MeOPh). - MS (70 eV): mlz (%) = 302 (0.6) [M+' (*IBr)], 300 (0.6) [M+' (79Br)], 271 (0.4), 269 (0.4), 241 (0.3), 239 (0.3), 189 (15), 164 (2), 162 (2), 137 (85), 121 (loo), 109 (8), 84 (S), 78 (8), 77 (9). - CI3Hl7BrO3 (301.1): calcd. C 51.84, H 5.46; found C 52.13, H 5.46.

(4'R,S'S) -2- {5'-[ ( tert-Butyldimethylsilyl) oxy]methyl-2'.2'-dimethyl- [1',3']dio.\-olan-4'-ylJ-ethanol (33): A solution of the alkene 22rz21 (1.19 g, 4.38 mmol) in THF (35 ml) was stirred under argon at 0°C and treated dropwise with borane-dimethyl sulfide complex (0.29 ml, 2.9 mmol). The resulting solution was stirred for 30 min at OT, warmed to room temp., stirred for a further 140 min, re-cooled to O"C, and then water (1.75 ml) was added. The resulting mixture was warmed to room temp., then water (1.8 ml), a 3 M aq. NaOH solution (19 ml) and a 30% aq. H202 solution (20 ml) were added. The reaction mixture was stirred for 20 h subsequently poured into water (50 ml) and extracted with Et20 (3 X 25 ml). The combined organic phases were washed with water (2 X 25 ml), dried (MgSO,), filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography (2 X I5 cm, 40-50% EtzO/hexane, gradient elution) afforded the alcohol 33 (0.56 g, 52%) as a colorless oil. - [a]BT = + 14.9 (c = 1.33, CHCl,). - IR (CHCI,): C = 3450 (br., OH), 2930 (s), 2860 (s), 1470 (m), 1370 (s), 1250 (m), 1220 (s), 1085 (s), 835 (s), 775 (s) cm-'. - 'H NMR (300 MHz): 6 = 4.35 (dt, J = 7.8 and 5.7 Hz, 1 H, 4'-H), 4.15 ( d d d , J = 8.3,5.7and4.7Hz, lH,5'-H),3.90-3.72(m,2H, l-H),3.68[dd, J = 10.3and8.3Hz,lH,CH2-C(5')],3.60[dd,J= 10.3and4.7Hz, l H , CHz-C(5')], 2.58 (d, J = 6.0 Hz, l H , OH), 1.93-1.86 (m, 2H, 2-H), 1.42 [d, J = 0.5 Hz, 3H, Me-C(2')], 1.35 [d, J = 0.5 Hz, 3H, Me-C(2')], 0.89 (s, 9H, Me,C), 0.08 (s, 6H, Me2Si). - I3C NMR (50 MHz): 6 = 108 [s, C(2')], 78.0 [d, C(5')l. 72.3 [d, C(4')], 66.1 [t, C(l)], 62.1 [t, CHz-C(5')], 34.3 [t, C(2)], 26.4 [q. Me-C(2')], 25.6 (9, Me3C), 25.0 [q, Me-C(2')], 18 (s, Me,C), -5.8 (q, Me#). - MS (70 eV): mlz (YO) = 289 (1.4) [(M - I)+], 275 (11) [(M - Me)+], 233 (5) ([M - tBu)'], 215 (12), 175 (41), 157 (50), 145 (69), 131 (18), 115 ( I I ) , 105 (23), 83 (52), 75 (IOO), 59 (53). - C14H3004Si (290.5): calcd. C 57.89, H 10.41; found C 57.36, H 10.73.

(4'RS'S)- {5'-[ (tert-Butyldimethylsi[yljoxy]methyl-2',2'-dimethyl-[1'.3']- dioxolan-4'-ylJ-acetaldehyde (34): DMSO (147 pl, 2.07 mmol) was added dropwise to a stirred solution of oxalyl chloride (90 pl, 1.03 mmol) in CH2CI2 (9 ml) at -60°C under argon. After 5 min, a solution of the alcohol 33 (0.20 g, 0.69 mmol) in CH2C12 (5 ml) was added and the mixture allowed to warm up to -40°C over a period of 30 min. Et3N (0.64 ml, 4.69 mmol) was added and the reaction mixture allowed to warm up further over a period of 50 min. After a further 40 min at room temp., water was added (15 ml) and the mixture was extracted with CHzC12 (2 X 15 ml). The combined organic phases were washed with brine (2 X 10 ml), dried (MgS04), filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography (1.5 X 10 cm, 20% Et201hexane) afforded the aldehyde 34 (0.17 g, 85%) as a colorless oil. - [a]gT = +15.7 (c = 1.15, CHCl,). - IR (CHCI,): C = 2930 (s), 2860 (s), 1730 (s, C=O), 1220 (m), 1095 (m), 840 (s), 780 (s) cm-I. - 'H NMR (300 MHz): 6 = 9.79 (t, J = 1.5 Hz, 1 H, I-H), 4.71 (dt, J = 7.8 and 5.9 Hz, 1 H, 4'-H), 4.17 (dt, J = 7.6 and 5.5 Hz, 1 H, 5'-H), 3.63 [dd, J = 10.6 and 5.5 Hz, 1 H, CHz-C(5')], 3.59 [dd, J = 10.6 and 7.7 Hz, 1 H, CH,-C(S')], 2.87 (ddd, J = 17.1, 5.9 and 1.4 Hz, 1 H, 2-H), 2.75 (ddd, J = 17.1, 7.9 and 1.8, l H , 2-H), 1.41 [s, 3H, Me-C(2')], 1.36 [s, 3H, Me-C(2')], 0.88 (s, 9H, Me3C), 0.06 (s, 6H, Mez.%). - I3C NMR (50 MHz): 6 = 199.8 [d, C(l)]. 108.0 [s, C(2')], 77.4 [d, C(5')], 71.6 [d, C(4')], 61.2 [t. CH,-C(S')], 43.4 [t, C(2)], 27.6 [q, Me-C(2')], 25.6 (9. Me3C), 25.1 [q, Me-C(2')], 17.9 (s, Me3C), -5.7 (9, MeSi), -5.8 (4, MeSi). - MS (70 eV): mlz ("h) = 289 (4) [(M + I)'], 273 (1) [(M - Me)+], 247 (4), 229 (3), 213 (5), 189 (14), 173 (76), 155 (21), 143 (39), 129 (62), 117 (18), 101 (31), 89 (25), 75 (loo), 73 (55), 59 (40). - CI4HZ8O4Si (288.5): calcd. C 58.29, H 9.78; found C 58.60, H 10.05.

(2R,3E,4'R,SS) -5-Benzyloxy-I- {S -[ (tert-butyldimethylsilyl)oxy]methyl- 2',2'-dimethyl-[l'.3']dioxolan-4'-yl)-3-methyl-pent-3-en-2-01 and (2S,3E, 4'R,S'S)-5-Benzyloxy-l- {5'-[ (tert-butyldimethylsilyl)oxy]methyl-2'.2'-dimethyl-[I '.3']dioxolan-4'-yl)-3-methyl-pent-3-en-2-01(3S): A stirred solution of the vinyl bromide 24 (0.192 g, 0.90 mmol) in THF (4 ml) was cooled to - 100°C under argon and treated dropwise with a solution of BuLi in hexane (1.6 M, 1.18 ml, 1.89 mmol). The resulting solution was warmed up to -78°C for 30 min. CeCI, . 7 HZO (0.372 g, 1 mmol) was placed in a 50-ml round- bottom flask and dried by means of a kugelrohr (140"C, 0.1 Torr, 2 h). After cooling to room temp., the white powder (anhydrous CeC1,) was suspended in THF (5 ml) under argon and the suspension stirred at room temp. for 2 h before it was re-cooled to -78°C. The vinyllithium derivative solution was transferred into the suspension via a Teflon cannula, and the resulting bright yellow solution was stirred at this temperature for 30 min. A solution of the aldehyde 34 (0.137 g, 0.7 mmol) in THF (2 ml) was slowly added and the

reaction mixture stirred at -78°C for 2 h. Then a satd. NH4C1 solution (25 ml) was added, the reaction mixture warmed up to room temp. and extracted with EtzO (3 X 15 ml). The combined organic phases were washed with water (1 X 25 ml) and brine (1 X 10 ml), dried (MgSO,), filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography (1 X 10 cm, Et20/pentane) gave a diastereoisomeric mixture of the alcohols 35 (0.316 g, 60%). - [a]ST = +7.2 (c = 1.20, CC14). - IR (CC14): C = 3400 (s, OH), 2900 (s), 2845 (m). 1700 (s), 1450 (m), 1380 (s), 1250 (s), 1210 (m), 1150 (w), 1090 (s), 830 (s) cm-I. - IH NMR (200 MHz), major diastereoisomer: 6 = 7.36-7.24 (m, 5H, Harem), 5.72 (m, l H , 4-H), 4.51 (s, 2H, H&,,liJ, 4.50-4.05 (m, 5H, OH, 5-H, 5'-H and 4'-H), 3.70-3.60 [m, 3H, 2-H and CH2-C(S')], 1.95-1.80 (m, 2H, 1-H), 1.63 [s, 3H, Me-C(3)], 1.35 [s, 6H, Me2-C(2')], 0.88 (s, 9H, Me3C), 0.2 (s, 6H, Me2Si); minor diastereoisomer: 6 = 5.72-5.60 (m, l H , 2-H), 4.50 (s, 2H, Hbenzylic). 1.64 [s, 3H, Me-C(3)], 1.43 [s, 3H, Me-C(2')], 1.40 [s, 3H, Me- C(2')], 0.89 (s, 9H, Me3C), 0.7 (s, 6H, MezSi). - I3C NMR (50 MHz): 6 = 128.1, 127.3, 122.0, 121.2, 108.1, 107.3, 77.2, 76.7, 75.8, 74.7, 73.6, 71.7, 71.6, 65.9, 67.4, 61.2, 61.2, 61.1, 33.9, 33.3, 27.7, 27.5, 25.4, 25.3, 25.0, 17.6, 12.3, 11.9, -6.0, -6.1. - MS (70 eV): mlz ("YO) = 449 (0.3) [(M - H)'], 435 (1.7) [(M - Me)+], 375 (lo), 357 (3), 287 (4), 267 (7), 227 (16), 197 (4), 181 (5), 145 (lo), 143 (7), 129 (lo), 117 (Il), 107 (8), 105 (9), 91 (IOO), 75 (31), 73 (25), 55 (11). - C25H4z05Si (450.7): calcd. C 66.63, H 9.39; found C 66.54, H 9.29.

(3'E,4R,5S) -4- (5'-Benzyloxy-3'-methyl-pent-3'-enyl) -5-[ (tert-butyldimethylsilyl)oxy]methyl-2.2-dimethyl-[1,3]dioxolane (36): 9-BBN (0.5 12 g, 4.2 mmol) was added to a stirred solution of the alkene 22["1 (1.088 g, 4.0 mmol) in THF (20 ml) at 0°C under argon. After 30 min the solution was warmed up to room temp. and stirred for 5 h. Then THF (20 ml), PdCl,(dppf) (88 mg, 0.12 mmol), a 3 M aq. NaOH solution (4 ml) and the bromoalkene 24 (1.06 g, 4.4 mmol) were added. The reaction mixture was heated at 75°C for 12 h, then diluted with benzene (20 ml), and an 30% aq. H202 solution (2 ml) was added dropwise. The reaction mixture was stirred for 1 h, then washed with brine (2 X 30 ml), dried (MgS04), filtered and the filtrate concentrated under reduced pressure. The residue was purfied by column chromatography (2% EtOAclhexane) to give the coupled alkene 36 [1.055 g, 60%, Rf (30% EtOAclhexane) = 0.631 as a colorless oil. - [a]BT =

+5.4 (C = 0.84, CHC13). - IR (CCI,): 0 = 3060 (w), 3035 (w), 3000 (w), 2950 (s), 2925 (s), 2900 (s), 2820 (m), 1460 (m), 1370 (m), 1240 (s), 1210 (m), 1080 (s), 930 (w), 830 (s) cm-I. - IH NMR (400 MHz): 6 = 7.36-7.25 (m, 5H, H,,,), 5.44 (tq, J = 6.7 and 1.2 Hz, l H , 4'-H), 4.50 (s, 2H, Hbenzylic), 4.12 (ddd, J = 9.5, 5.8 and 4.1 Hz, l H , 4-H), 4.07 (ddd, J = 7.3, 6.7 and 5.8 Hz, l H , 5-H), 4.03 (d, J = 6.7 Hz, 2H, 5'-H), 3.67 [dd, J = 10.3 and 7.3, I H , CH2-C(5)], 3.61 [dd, J = 10.3 and 4.9, l H , CH2-C(5)], 2.27 (ddd, J = 14.1, 10.3 and 5.3 Hz, l H , 2'-H), 2.09 (ddd, J = 14.1, 10.2 and 6.1 Hz, 1H,2'-H), 1.76(dddd,J= 13.6, 10.3,6.1 and4.1 Hz, I H , 1'-H), 1.67(dddd, J = 13.6, 10.2, 9.5 and 5.3 Hz, l H , 1'-H), 1.66 [s, 3H, Me-C(3')], 1.41 [s, 3H, Me-C(2)], 1.33 [3H, s, Me-C(2)], 0.88 (s, 9H, Me3C), 0.06(s, 3H, MeSi), 0.06 (s, 3H, MeSi). - I3C NMR (100 MHz): 6 = 139.9 (s, C,,,), 138.6 [s, C(3')1, 128.3 (d, C a r d , 127.8 (d, C,,,), 127.5 (d, C,,,), 121.0 [d, C(2')1,

62.0 [t, CHz-C(5)], 36.3 [t, C(2')], 28.3 [q, Me-C(2)], 27.3 [t, C(l')], 25.9 (q, Me3C), 25.6 [q, Me-C(2)], 18.2 (s, Me3C), 16.6 [q. Me-C(3')], -5.3 (9. MeSi), -5.4 (q, MeSi). - MS (70 eV): rnlz (%) = 434 (3) [M+'], 419 (3) [(M - Me)'], 259 (2), 227 (4), 211 (27), 201 (16), 143 (39), 129 (16), 119 (23), 117 (38), 105 (32), 91 (IOO), 81 (30), 75 (52), 73 (55), 59 (25). - C25&204Si (434.7): calcd. C 69.08, H 9.74; found C 69.33, H 10.07.

(4"S,YR) -Methyl N-[2- (2",2"-Dimethyl-Y-vinyl-[l",3"]dioxolan-4"-ylmethyl)-[1,3]dithian-2-ylmethyl]-carbamate (31). - By Means of HMPA: To a stirred and cooled (-40°C) solution of dithiane 4 (9.08 g, 43.8 mmol) in THF (100 ml) was added dropwise under argon BuLi (59.8 ml, 89.8 mmol, 1.5 M in hexane). The resulting solution was stirred for 2 h, the temperature being maintained between -40 and -20°C. The solution was then cooled to -78°C. After dropwise addition of HMPA (freshly distilled from Na under reduced pressure, 15.8 ml, 90 mmol), the resulting bright yellow solution was stirred at -78OC for 1.5 h, then carefully transferred via a cannula to a solution of the triflate S (6.35 g, 21.9 mmol) in THF (100 ml) at -78°C. The reaction mixture was stirred for 5 h while warming to -2O"C, then for 14 h at -20°C and subsequently for a further 4 h at -15°C. The brown reaction mixture was poured into icelwater (400 ml) and the aqueous phase extracted with EtOAc (7 X 50 ml). The combined organic layers were dried (MgSO,), filtered and the solvents evaporated in vacuo. The crude product was purified by column chromatography (5 X 20 cm, 15% EtOAclhexane) giving the coupled dithiane 37 [4.2 g, 55%, Rf (40% EtOAcmexane) = 0.501 as a yellow oil.

By Means of DMPU; To a stirred and cooled (-40°C) solution of dithiane 4 (5.59 g, 27.0 mmol) in THF (150 ml) was added dropwise under argon BuLi (37 ml, 57 mmol, 1.55 M in hexane). The resulting solution was stirred for 2 h, the temperature being maintained between -40 and -20°C. The solution was then cooled to -78OC. After dropwise addition of DMPU

107.7 [S, c(2)], 77.9 [d, c(5)], 77.2 [d, C(4)], 72.0 (t, Cbenqlic), 66.5 [t, c(5')],


Total Synthesis of Myxovirescins, 1 71 1

(freshly distilled from Na, 12 ml, 92 mmol), the resulting solution was stirred at -78°C for 1 h, then carefully transferred via a cannula to a solution of the crude triflate 5 (3.63 g. 12.5 mmol) in THF (80 ml) at -72°C. The reaction mixture was stirred for 4 h while warming to -2O”C, for 13 h at -20°C and then for a further 4 h at -15°C. The reaction mixture was poured into icelwater (200 ml) and the aqueous phase extracted with Et20 (5 x 50 ml). The combined organic layers were dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by column chromatography (5 X 15 cm, 15% EtOAclhexane) giving the coupled dithiane 37 (3.16 g, 72%). - [a]B = -71 (c = 1.18, CHCI,). - IR (film): 5 = 3440 (m, NH), 3375 (br., NH), 3075 (w), 2985 (s), 2935 (s), 1725 (s, C=O), 1515 (s), 1425 (m), 1370 (m), 1225 (s), 1045 (s) cm-’. - ‘H NMR (400 MHz): 6 = 5.75 [ddd, J = 17.1, 10.2 and 7.6 Hz, l H , 2”‘-H (01, 5.71 (br. s, l H , NH), 5.30 [ddd, J = 17.1, 1.5 and 1.0 Hz, l H , 2”’-H (91, 5.26 (ddd, J = 10.2, 1.5 and 0.8 Hz, l H , I”’-H), 4.56-4.49 (m, 2H, 4 - H and 5”-H), 3.93 (dd, J = 14.5 and 7.9 Hz, I H , 1-H), 3.68 (s, 3H, MeOCONH), 3.61 (dd, J = 14.5 and 5.5 Hz, l H , 1-H), 3.24 [ddd, J = 14.5, 12.1 and 2.6 Hz, 1 H, 4-H,, or 6-H,,], 3.09 [ddd, J = 14.5, 11.9 and 2.6 Hz, 1 H, 6-H,, or 4- H,], 2.64 [ddd, J = 14.5, 7.4 and 3.1 Hz, 1 H, 4-H,, or 6-H,,], 2.63 [ddd, J = 14.5,7.4and3.1Hz,1H,6-He,or4-H,,],2.12[dtt,J= 13.9,7.4and 2.6 Hz, 1 H, 5-H,,], 1.95 [d, J = 15.3 Hz, 1 H, 1’-H), 1.85 [dtt, J = 13.9, 12.0 and3.1Hz,1H,5-Ha,],1.81 ( d d , J = 15.3and9.2Hz, lH, l ’ -H), 1.52[s, 3H, Me-C(2”’)], 1.38 [s, 3H, Me-C(2”’)l. - I3C NMR (100 MHz): 6 = 157.3 (s, OCONH), 134.0 [d, C(l”‘)], 119.2 [t. C82)], 108.8 [s, C(2”)], 80.3 [d, C(S”)], 72.7 [d, C(4”)], 52.2 (q, MeOCONH), 52.1 [s, C(2)], 45.2 [t, C(l)], 40.3 [t, C(l‘)], 28.0 [q. Me-C(2)], 26.7 [t, C(4) or C(6)], 26.0 [t. C(6) or C(4)], 25.5 [q. Me-C(2”’)], 25.2 [t, C(5)]. - MS (70 eV): mlz (YO) = 347 (1.6) [M+’], 332 (15) [(M - Me)+], 259 (42), 145 (9), 132 (25), 128 (29), 127 (85), 98 (46), 88 (22), 69 (86), 59 (100). - CI5HZ5NO4S2 (347.5): calcd. C 51.85, H 7.25, N 4.03; found C 51.85, H 7.28, N 4.10.

(I’S,S’Rj-Methyl N-[3-(2’.2’-Dimethyl-5’-vinyl-[1’,3‘]dioxolan-l’-yl)-2- 0x0-propyll-curbamate (38): A solution of the dithiane 37 (0.44 g, 1.27 mmol) in acetonitrile (25 ml) was added rapidly to a stirred solution of AgNO, (0.97 g, 5.70 mmol) and NCS (0.68 g, 5.07 mmol) in a mixture of acetonitrilelwater (4: 1, 70 ml). The resulting white suspension was stirred for 3 min, timing from the addition of the first drop of the dithiane solution, then the reaction was quenched by addition of brine (50 ml). The mixture was filtered through a pad of Celite and the solids were washed with brine (3 X 25 ml) and with EtOAc (4 X 25 ml). The organic filtrate was washed with an 10% aq. Na2S03 solution (1 X 100 ml), satd. NaHCO, solution (1 x 50 ml), water ( 1 X 50 ml) and brine (1 X 50 ml), dried (Na2S04), filtered and the filtrate concentrated under reduced pressure. Purification of the residue by column chromatography (3 X 15 cm, 25% EtOAclhexane) furnished the ketone 38 [0.30 g, 93%, Rf (60% EtOAclhexane) = 0.531 as a colorless oil. - [a]BT = -41.5 (c = 1.20, CHC1,). - IR (film): 0 = 3350 (br.), 3080 (w), 2985 (s), 2935 (s), 1715 (s, C=O), 1525 (s), 1380 (m), 1370 (m), 1250 (s), 1215 (m), 1045 (s) cm-’. - ‘H NMR (400 MHz): 6 = 5.72 [ddd, J = 17.2, 10.4 and 6.9 Hz, IH, 2”-H (E)], 5.40 (br. s, l H , NH), 5.34 [ddd, J = 17.2, 1.5 and 1.0 Hz, IH, 2”-H (31, 5.26 [ddd, J = 10.4, 1.5 and 0.7 Hz, l H , 1”- HI, 4.67-4.61 (m, 2H, 4’-H and 5‘-H), 4.09 (br. d, J = 4.8 Hz, 2H, 1-H), 3.69 (s, 3H, MeOCONH), 2.70 (dd, J = 16.1 and 7.4 Hz, IH, 3-H), 2.49 (dd, J = 16.1 and 5.1 Hz, 1 H, 3-H), 1.49 [s, 3H, Me-C(2‘)], 1.36 [s, 3H, Me- C(2’)]. - NMR (100 MHz): 6 = 203.3 [s, C(2)], 156.7 (s, OCONH), 133.3 [d, C(l’’)], 118.9 [t, C(2”)], 108.7 [s, C(2’)], 78.7 [d, C(S’)], 73.9 [d, C(4’)], 52.4 (4, MeOCONH), 51.4 [t, C(l)], 41.7 [t, C(3)], 28.0 [q, Me-C(2’)], 25.3 [q, Me-C(2‘)]. - MS (70 ev): rnlz (%) = 257 (0.3) [M+’], 242 (9) [(M - Me)+], 200 (6), 199 (6), 182 (55), 169 (23), 150 (IS), 127 (29), 111 (55),

(257.3): calcd. C 56.02, H 7.44, N 5.44; found C 55.96, H 7.52, N 5.29.

(2S,4‘S,SrRJ-Methyl N-[3-(2~,2’-Dimethyl-5~-vinyl-[1.3]dioxolan-4-y1)-2- hydroxy-propyll-carbamate (39) and (2R,4’S, 5’ R j -Methyl N-13- (2 ‘,2‘-Dime- thyl-5’-vinyl-[1,3]dioxolan-4-yl)-2-hydroxy-propyl]-carbamafe (40): A solution of ketone 38 (1.93 g, 7.51 mmol) in Et20 (30 ml) was treated in portions at room temp. with Li[Al(OtBu),]H (2.54 g, 10 mmol). The resulting suspension was stirred for 1 h at room temp. then, after addition of H 2 0 (1 ml) and a 10% aq. KOH solution (1 ml), for 0.5 h at room temp. The mixture was dried (MgS04), filtered and the solvent evaporated in vacuo. The diaste- reoisomers were separated by column chromatography (5 X 30 cm, 50% Et20/CH2C12) to afford alcohol 39 [0.79 g, 41%, Rf (50% Et201CH2C12) = 0.241, alcohol 40 [1.03 g, 53%, Rf (50% Et20/CH2C12) = 0.321 and a mixture of these products (0.03 g, 1.5%) as colorless oils. Alcohol 39 crystallized slowly on standing at -20°C.

Compound 39: M.p. 49.5-50.0°C. - [a]gT = -12.9 (c = 1.30, CHC1,). - IR (film): 0 = 3350 (br., NH, OH), 3080 (w), 2985 (s), 2935 (s), 1705 (s, C=O), 1540 (s), 1380 (m), 1370 (m), 1255 (s), 1215 (s), 1045 (m), 930 (m), 875 (m), 780 (m) cm-I. - ‘H NMR (400 MHz): 6 = 5.78 [ddd, J = 17.2, 10.3 and 7.4 Hz, 1 H, 2”-H (E)], 5.32 [ddd, J = 17.2, 1.5 and 1.2 Hz, 1 H, 2”- H(Z)],5.25(ddd,J= 10.3,1.5and1.0Hz,1H,l”-H),5.18(br,s,1H,NH),

107 (55), 98 (66), 88 (66), 83 (57), 69 (loo), 69 (89), 56 (67). - Cl~H19N05

4.57 (dd, J = 7.4 and 6.5 Hz, l H , 5’-H), 4.42 (ddd, J = 10.2, 6.5 and 3.0 Hz, 1 H, 4’-H), 3.93 (dddd, J = 9.8, 5.5, 3.9 and 3.2 Hz, 1 H, 2-H), 3.68 (s, 3H, MeOCONH), 3.40 (ddd, J = 14.2, 6.5 and 3.2 Hz, 1 H, I-H), 3.13 (ddd, J = 14.2, 7.3 and 5.5 Hz, l H , 1-H), 2.95 (br. s, l H , OH), 1.60 (ddd, J = 14.2, 10.2 and 3.9 Hz, l H , 3-H), 1.51 (ddd, J = 14.2, 9.8 and 3.0 Hz, IH, 3-H), 1.49 [s, 3H, Me-C(2‘)], 1.37 [s, 3H, Me-C(2’)]. - I3C NMR (100 MHz): 6 = 157.9 (s, OCONH), 134.0 [d, C(l”)], 118.5 [t, C(2”)], 108.5 [s, C(2‘)], 79.6 [d, C(S’)], 74.7 [d, C(4’)], 69.0 [d, C(2)], 52.3 (9. MeOCONH), 47.2 [t, C(l)], 35.0 [t, C(3)], 28.1 [q, Me-C(2‘)], 25.6 [q. Me-C(2‘)]. - MS (70 eV): rnlz (YO) = 260 (0.4) [(M + l)+], 244 (43) [(M - Me)+], 212 (14), 202 (15), 184 (31), 171 (18), 152 (9), 127 (7), 113 (70), 98 (IOO), 88 (53), 83 (46), 69 (72), 59 (71). - C12H21N05 (259.3): calcd. C 55.58, H 8.16, N 5.40; found C 55.83. H 8.40. N 5.37. Compound 40: [a]BT = -26.3 (c = 1.90, CHCI,). - IR (film): 0 = 3350 (br., NH, OH), 3080 (w), 2985 (s), 2935 (s), 1710 (s, C=O), 1535 (s), 1380 (m), 1370 (m), 1255 (s), 1215 (s), 1045 (m), 930 (m), 875 (m), 780 (m) cm-’. - ‘H NMR (400 MHz): 6 = 5.77 [ddd, J = 17.2, 10.3 and 7.5 Hz, 1 H, 2”-H (E)], 5.34 [ddd, J = 17.2, 1.4 and 0.9 Hz, 1 H, 2”-H (91, 5.27 (ddd, J = 10.3, 1.4 and 1.1 Hz, l H , 1”-H), 5.17 (br. s, 1 H, NH), 4.57 (dd, J = 7.4 and 6.4 Hz, 1 H, 5’-H), 4.38 (ddd, J = 10.2, 6.4 and 3.3 Hz, 1 H, 4’-H), 3.94 (m, 1 H, 2-H), 3.67 (s, 3H, MeOCONH), 3.45 (br. s, IH, OH), 3.35 (ddd, J = 13.7, 6.5 and 3.8 Hz, IH, 1-H), 3.14 (ddd, J = 13.7, 6.9 and 5.6 Hz, IH, I-H), 1.59 (ddd, J = 14.3, 10.2 and 9.0 Hz, 1 H, 3-H), 1.52 (ddd, J = 14.3, 3.3 and 2.9 Hz, l H , 3-H), 1.52 [s, 3H, Me-C(2’)], 1.38 [s, 3H, Me-C(2’)]. - I3C NMR (100 MHz): 6 = 157.5 (s, OCONH), 133.6 [d, C(l”)], 119.0 [t, C(2”)], 109.0 [s, C(2’)], 79.7 [d, C(5’)], 77.7 [d. C(4’)], 70.4 [d, C(2)], 52.2 (q, Me- OCONH), 46.7 [t. C(l)], 34.6 [t, C(3)], 28.0 [q, Me-C(2’)], [q, Me-C(2’)]. - MS (70 eV): rnlz (%) = 260 (1.7) [(M + 1)+], 244 (39) [(M - Me)+], 212 (6). 202 (34), 184 (49, 171 (34), 152 (16), 144 (9), 127 (13), 113 (62), 109 (43), 98 (65), 88 (54), 69 (loo), 59 (93), 55 (73). - C12HZ1N05 (259.3): calcd. C 55.58, H 8.16, N 5.40; found C 55.64, H 8.35, N 5.33.

Configuration Assignment of the Compound 39: A solution of the alcohol 39 (0.075 g, 0.29 mmol) in dry methanol (20 ml) was placed in a dry ozoniza- tion vessel (three-necked round-bottom flask) provided with a magnetic stirring bar. The solution was cooled to -78°C while purging with nitrogen. The nitrogen flow was replaced by a slow stream of ozone until the solution turned grey-blue (ca. 30 min). The ozone stream was replaced by nitrogen until no ozone remained in solution (KI test, ca. 1 h). Me,S (0.7 ml) was added dropwise, and the resulting solution was allowed to reach room temp. (TLC analysis of the reaction showed only one spot). Evaporation of the solvent gave a colorless residue that was purified (column chromatography, 1.5 X 10 cm, 40Y0 EtOAchexane) afforded the o-deoxy-mannose derivative from 39 (0.057 g, 75%, Scheme 7). - ‘H NMR (300 MHz): 6 = 5.39 (br. s, 1 H, I-H), 5.35 (br. s, 1 H, NH), 4.40 (m, 1 H, 3-H), 4.40 (d overlapped with a m, J = 4.7 Hz, 2H, 2-H and 5-H), 3.68 (3H, s, MeOOCNH), 3.40 (m, 1 H, 6-H), 3.20 (m, 1 H, 6-H), 1.90 [m, 1 H, 4-H (eq)], 1.60 [m, 1 H, 4-H (ax)], 1.50 (s, 3H, Me), 1.34 (s, 3H, Me). The signals were assigned by using a COSY experiment. No significant data were obtained with NOE difference spectroscopy; double irradiation experiments [over 3-H, 4-H (eq) and 4-H (ax) signals] in combination with spectral simulation, using the LAOCOON software allowed the determination of the more interesting coupling constants (values in Hz): J2 ,3 = 5.8 Hz, J3,4ax = 8.6 Hz, J,,,, = 6.2 Hz (-. 3-H is axial); J4ax,4eq = -13.9 Hz, J4ax,5 = 9.3 Hz (+ 5-H is axial). Thus, 39 has (S) stereochemistry at the hydroxylated carbon (see Scheme 7).

Configurational Assignment of the Compound 40: A solution of the alcohol 40 (0.13 g, 0.5 mmol) in dry methanol (25 ml) was subjected to the same ozonolysis procedure [-78°C; ozone until the solution turned grey-blue (ca. 1 h); nitrogen stream; Me2S (1 ml); stirring until room temp. was reached] as 39. Evaporation of the solvent gave a colorless residue that was purified (column chromatography, 1.5 X 10 cm, 40% EtOAclhexane) to afford the L- deoxy-allose derivative from 40 (0.125 g, 95%). - ’H NMR (300 MHz): 6 = 5.36 (br. s, 1 H, NH), 4.84 (br. s, 1 H, 1-H), 4.45 (m, 1 H, 3-H), 3.87 (m. 2H, 2-H and 5-H), 3.67 (s, 3H, MeOOCNH), 3.40 (m, l H , 6-H), 3.20 (m, l H , 6-H), 1.98 [m, l H , 4-H (eq)], 1.88 [m. l H , 4-H (ax)], 1.49 (s, 3H, Me), 1.36 (s, 3H, Me). The signals were assigned by using a COSY experiment. No significant data was obtained with NOE difference spectroscopy; double irradiation experiments (over 3-H and 2-Hl5-H signals) in Combination with simulation of the spectra, using the LAOCOON software, allowed the determination of the more interesting coupling constants (values in Hz): J2,, = 5.1 Hz, J3,4ax = 3.5 Hz, J3,&, = 3.5 Hz (4 3-H is equatorial); J4ax,4eq = -14.9 Hz, J4ax,5 = 9.4 Hz (+ 5-H is axial); hence 40 has (R) stereochemistry at the hydroxylated carbon (see Scheme 7).

Mifsunobu Inversion: The alcohol 40 (1.02 g, 3.94 mmol) and triphenyl- phosphane (3.33 g, 12.74 mmol) were dissolved in THF (50 ml) at room temp. The solution obtained was cooled to O”C, then a solution of benzoic acid (2.44 g, 20 mmol) in benzene (50 ml) was added dropwise, followed 5 min later by diethyl azodicarboxylate (2.16 ml, 14.0 mmol). The reaction mixture was stirred at 0°C for 1 h and at room temp. for about 12 h. The



solvents were evaporated, and the residue was purified by column chromatography (3 X 20 cm, 20% EtOAcIhexane) affording the benzoate of alcohol 39 [Rr (20% EtOAdhexane) = 0.281. An ice-cold solution of this benzoate in EtOH (50 ml) was treated with NaOEt (0.68 g, 10 mmol). The resulting pale yellow solution was stirred for 1.5 h at O T until the starting material had been consumed (followed by TLC analysis), then the reaction was quenched with water (50 ml) and the mixture diluted with Et20 (100 ml). The aqueous layer was saturated with NaCl and extracted with Et20 (5 X 30 ml). The combined extracts were dried (MgS04), filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (3 X 20 cm, 10% MeOH/EtzO) yielded alcohol 39 (0.96 g, 94% over two steps) as colorless oil.

X-ray Analysis of 39r511: A colorless prism-like crystal of 39 having the approximate dimensions of 0.3 X 0.4 X 0.6 mm was mounted on an Enraf Nonius CAD 4 four-circle-automated diffractometer with graphite-mono- chromated Mo-K, radiation. Crystal data: CI2HZINOS, FW = 259.30, mo- noclinic, space group P2a, a = 9.798(7), b = 8.998(6), c = 16.225(12) A, p = 102.45(5)", V = 1397(2) A3, Z = 4, D, = 1.233 gkm3 and F(Mo-K,) = 0.095 mm-'. - The data were collected by using the 61 scan technique to a maximum 2 0 value of 49.9". A total of 2631 independent reflections was collected. The data were corrected for Lorentz and polarization effects. - The structure was solved by direct methods. The resulting E map revealed the positions of all non-H atoms. All H atom positions were calculated after anisotropic refinement of the non-H atoms. The refinement of atomic parameters was carried out by a full-matrix least-squares refinement, using anisotropic temperature factors for all non-H atoms and isotropic ones for H atoms. The final refinement was based on 2303 observed reflections with F > 4.00a(F) and 324 variable parameters and converged R, = 0.0472, wR2 = 0.1218. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.276 and -0.203 e/A3, respectively. - All calculations were performed by using the SHELXL-92 crystal structure refinement pro-

(2S, 4'S.S R) - Metlid N-[3- (2 ',2'-Dimethyl-5'-vinyl-[l',3']dioxolan-4'-ylj- 2-metlio.~.~met/io~~~-prop.~l]-carbumute (41): A stirred solution of the alcohol 39 (2.59 g, 10.0 mmol) in CH2C12 (80 ml) was treated at room temp. with EtiPrzN (13.8 ml, 10.5 g, 81 mmol), followed by a catalytic amount of DMAP The mixture was cooled to 0°C and, after stirring for 5 min, methoxymethyl chloride (MOMCI, 3.0 ml, 3.2 g, 40 mmol) was added dropwise. The resulting solution was stirred at 0°C for 2 h and at room temp. for 14 h, then the progress of the reaction was examined by TLC analysis. Due to incomplete conversion of the alcohol 39, additional EtiPr2N (5 ml) and MOMCI ( I ml) were introduced, and the resulting solution was stirred for 72 h. The reaction mixture was poured into CH,C12 (100 ml), washed with a 0.5 N aq. HCI solution (1 X 30 ml) and brine (1 X 40 ml). The aqueous layers were re-extracted with CHZCIz (1 X 30 ml) and the combined organic phases dried (MgSO,), filtered, and the solvent was removed in vacuo. Purifi- cation of the residue by column chromatography (4 X 20 cm, 20% EtzO/ CH2CIZ) afforded the protected olefin 41 [2.83 g, 93%, Rf (20% Et20/ CHZCI,) = 0.391 as a pale yellow oil. - [a16 = +5.9 (c = 1.20, CHCI,). - IR (film): 5 = 3355 (s, NH), 3080 (w), 2985 (s), 2935 (s), 1725 (s, C=O), 1530 (s), 1455 (m), 1380 (s), 1370 (s), 1255 (s), 1220 (s), 1155 (s), 1105 (s), 1040 (s), 925 (m), 875 (m), 780 (m) cm-I. - IH NMR (400 MHz): 6 = 5.77 [ddd, J = 17.2, 10.3 and 7.5 Hz, l H , 2"-H (E)]. 5.39 (br. s, l H , NH), 5.31 [ d d d , J = 17.2,1.6and1.2Hz,lH,2"-H(Z)],5.24(ddd,J= 10.3,1.6and 0.8Hz, lH,I"-H),4.70(s,2H,OCHz0),4.53(dd,J=7.0and6.8Hz,1H, 5'-H), 4.30 (ddd, J = 9.1, 6.2 and 4.3 Hz, l H , 4'-H), 3.80 (m. l H , 2-H), 3.66 (s, 3H, MeOCONH), 3.45 (ddd, J = 13.9, 6.4 and 3.7 Hz, 1 H, 1-H), 3.40 (s, 3H, MeOCH,O), 3.15 (ddd, J = 13.9, 6.0 and 5.5 Hz, l H , 1-H), 1.61-1.50 (m, 2H, 3-H), 1.47 [s, 3H, Me-C(2')], 1.36 [s, 3H, Me-C(2')]. - "C NMR (100 MHz): 6 = 157.2 (s, OCONH), 134.2 [d, C(l")], 118.4 [t, C(2")], 108.4 [s, C(2')], 96.9 (t, OCHZO), 79.5 [d, C(S')], 75.9 [d, C(2)], 74.4 [d, C(4')], 55.7 (4, McOCH~O), 52.1 (4, MeOCONH), 45.3 [t, C(l)], 34.3 [t. C(3)], 28.2 [q, Me-C(2')], 25.6 [q, Me-C(2')]. - MS (70 eV): mlz C/O) = 304 (0.4) [(M + I)+], 288 (9) [(M - Me)+], 272 (2), 256 (69), 214 (33), 196 (lo), 184 (36), 166 (16), 157 (24), 133 (25), 125 (23), 113 (34), 98 (82), 95 (51), 88

N 4.62; found C 54.96, H 8.09, N 4.93.

(2S,4'S,5'R,3"E)-Methyl N-(3-{2',2'-dimethyl-5'-[5"-(4-metho.uy-benz- ~~lo.~~~)-3"-methyl-pent-3"-enyl]-[l',3']diosolan-4'-yl)-2-methosymethosy- propJd)-cnrbamnte (42a): A solution of the alkene 41 (0.54 g, 1.78 mmol) in THF (20 ml) was added dropwise to a cold (OT), stirred solution of 9-BBN (7.5 ml, 3.74 mmol, 0.5 M in THF) under argon. After 2 h, the reaction mixture was brought to room temp. and stirred for 8 h. Subsequent addition of PdCIz(dppf) (39 mg, 0.053 mmol), the vinylic bromide 6a (0.63 g, 3.32 mmol), THF (20 ml) and a 3 N aq. NaOH solution (2.4 ml) and heating at 80°C for 14 h under argon was followed by dilution with benzene (30 ml). The resulting solution was treated dropwise with a 30% aq. H202 solution (2.5 ml), stirred for 30 min, then washed with brine (2 X 25 ml). The com-

(77). 69 (39). 59 (36), 45 (100). - C14H25N06 (304.0): calcd. C 55.43, H 8.31,

bined aqueous washings were re-extracted with EtOAc (5 X 10 ml). The combined organic extracts were dried (Na2S04), filtered, and the filtrate was concentrated under reduced pressure. Column chromatography of the crude product (2 X 20 cm, 25% EtOAclhexane) yielded the coupled alkene 42a [0.75 g, 85%, Rf (50% EtOAchxane) = 0.381 as a colorless oil. - [a]B = +6.0 (c = 1.55, CHC13). - IR (film): 5 = 3350 (br., NH), 3075 (w), 2985 (s), 2935 (s), 2850 (s), 1730 (s, C=O), 1615 (m), 1515 (s), 1455 (m), 1380 (m), 1370 (m), 1250 (s), 1155 (m), I105 (s), 1060 (s), 1035 (s), 820 (m) cm-I. - 'H NMR (400 MHz): 6 = 7.25 and 6.86 (AA'XX' system, J = 8.7 Hz, 4H, H,,,), 5.40 (td, J = 6.7 and 1.2 Hz, IH, 4"-H), 5.39 (br. s, 1 H, NH), 4.69 (s, 2H, OCH20), 4.43 (s, 2H, Hbenzyhc), 4.19 (td, J = 6.7 and 5.8 Hz, IH, 4'-H), 4.03 (ddd, J = 9.7, 5.6 and4.1 Hz, l H , 5'-H), 3.99 (d, J = 6.7 Hz, 2H, 5"-H), 3.81 (m, IH, 2-H), 3.79 (s, 3H, MeOPh), 3.65 (s, 3H, Me- OCONH), 3.45 (ddd, J = 13.9, 6.4 and 3.7 Hz, 1 H, 1-H), 3.39 (s, 3H, Me- OCH20), 3.16 (ddd, J = 13.9, 6.2 and 5.2 Hz, l H , 1-H), 2.23 (ddd, J = 14.1, 10.4and5.0Hz,lH,2"-H),2.02(ddd,J= 14.1, 10.4and5.9Hz, l H , 2"-H), 1.64 [s, 3H, Me-C(3")], 1.63-1.43 (m, 4H, 3-H and I"-H), 1.40 [s, 3H, Me-C(2')], 1.31 [s, 3H, Me-C(2')]. - I3C NMR (100 MHz): 6 = 159.2 (s, C,,,), 157.2 (s, OCONH), 139.5 [s, C(3")], 130.6 (s, C,,,), 129.4 (d, Car,,), 121.3 [d, C(4")], 113.8 (d, C,,,), 107.7 [s, C(2')], 97.0 (t, OCH,O), 77.4 [d, C(5')], 76.0 [d, C(2)], 74.1 [d, C(4')], 71.8 (t, Cbenzyllc), 66.3 [t, C(5")], 55.7 (q, MeOCH2O), 55.3 (q, MeOPh), 52.1 (9, MeOCONH), 45.5 [t, C(l)], 35.9 [t, C(2")], 33.6 [t. C(3)], 28.6 [q. Me-C(2')], 28.1 [t, C(l"))], 26.0 [q, Me- C(2')], 16.6 [q, Me-C(3")]. - MS (70 eV): m/r (%) = 495 (0.1) [M+'], 480 (0.2) [(M - Me)+], 464 (0.1), 448 (0.2), 420 (0.2), 418 (0.2), 406 (0.2), 360 (4), 327 (3), 269 (2), 238 (2), 200 (2), 181 (9, 169 (4), 144 (4), 134 (12), 121 (IOO), 88 ( l l ) , 45 (15). - C26H41N08 (495.6): calcd. C 63.01, H 8.34, N 2.83; found C 63.23, H 8.56, N 2.55.

(2$4'S,5'R,YZ)-Methyl N-(3-(2',2'-Dimethyl-5'-[5"-(4-methosy-benz- y l o s y ) -3"-methoxymethyl-pent-3"-enyl]-[l',3']diosolan-l'-yl) -2-methosymethoxy-propylj-earhamate (42b): To an ice-cold, stirred solution of the alkene 41 (1.40 g, 4.62 mmol) in THF (50 ml) was added rapidly under argon 9-BBN (19.4 ml, 9.7 mmol, 0.5 M in THF). After 2 h, the reaction mixture was brought to room temp. and stirred for a further 6 h before the addition of PdCl,(dppf) (0.10 g, 0.14 mmol), the vinylic bromide 6b (2.07 g, 6.87 mmol), THF ( S O ml) and a 3 N aq. NaOH solution (6.2 ml). The mixture was heated between 80°C and 90°C for 15 h, then cooled to room temp., whereupon benzene (80 ml) and a 30% aq. H2O2 solution (7.7 ml) were introduced. The heterogeneous reaction mixture was stirred for 40 min, then poured into brine (100 ml) and the aqueous solution extracted with Et20 (4 X 40 ml). The combined organic solutions were dried (MgS04), filtered and the solvents removed under reduced pressure. Purification of the crude product by column chromatography (4 X 20 cm, Et.0) afforded the coupled alkene 42b [1.75 g, 72%, Rf (Et20) = 0.411 as a pale yellow oil. - [a]ET = +8.0 (c = 2.00, CHC13). - IR (film): 0 = 3345 (m, NH), 2985 (s), 2935 (s), 1730 (s, C=O), 1615 (m), 1585 (w). 1515 (s), 1465 (m), 1455 (m), 1380 (m). 1370 (m), 1300 (w), 1250 (s), 1225 (m), 1170 (m), 1155 (m), 1100 (s), 1035 (s), 915 (m), 820 (m), 780 (w) crn-'. - 'H NMR (500 MHz): 6 = 7.26 and 6.88 (AA'XX' system, J = 8.7 Hz, 4H, H,,,), 5.61 (t, J = 6.7 Hz, 1 H, 4'- H), 5.40 (br. t, l H , NH), 4.70 (s, 2H, OCH20), 4.44 (s, 2H, Hbenzyhc), 4.20 (dt, J = 7.5 and 5.8 Hz, l H , 4'-H), 4.06 (d, J = 6.7 Hz, 2H, 5"-H), 4.06 (ddd, J = 9.6, 5.8 and 3.9 Hz, 1 H, 5'-H), 3.91 [s, 2H, CH2-C(3")], 3.82 (m, 1 H, 2-H), 3.80 (s, 3H, MeOPh), 3.66 (br. s, 3H, MeOCONH), 3.46 (ddd, J = 13.9, 5.9 and 4.0 Hz, IH, 1-H), 3.40 (s, 3H, MeOCH20), 3.26 [s, 3H, MeOCH2-C(3")]. 3.16 (ddd, J = 13.9, 6.3 and 5.1 Hz, l H , I-H), 2.33 (ddd, J = 14.0, 10.8and5.1Hz, IH,2"-H),2,12(ddd,J= 14.0, 10.6and5.8Hz, lH,2"-H), l .62(dddd,J= 13.5,10.6,9.7and5.1Hz,lH,l"-H),1.58-1.56 (m. 2H, 3-H), 1.53 (dddd, J = 13.5, 10.8, 5.8 and 4.0 Hz, l H , 1"-H), 1.41 [s, 3H, Me-C(2')], 1.31 [s, 3H, Me-C(2')]. - "C NMR (125 MHz): 6 = 159.2 (C,,,), 157.2 (s, OCONH), 139.7 [s, C(3")], 130.4 (s, C,,,), 129.4 (d, Carom), 125.7 [d, C(4")], 113.8 (d, Carom), 107.7 [S, C(2')], 97.0 (t, OCHZO), 77.4 [d, C(5')], 76.0 [d, C(2)], 74.1 [d, C(4')], 72.0 (t. Cbemyllc), 69.9 [t. C H 2 -

C(3")], 65.6 [t. C(5")], 58.0 [q, MeOCH2-C(3")], 55.7 (4, MeOCHzO), 55.3 (q, MeOPh), 52.1 (q, MeOCONH), 45.5 [t, C(l)], 33.5 [t, C(3)], 31.6 [t. C(2")], 28.6 [q, Me-C(2')], 28.3 [t, C(l")], 26.0 [q, Me-C(2')]. - MS (70 eV): m/z (%) = 510 (0.04) [(M - Me)+], 478 (O, l ) , 404 (O,l), 390 (0.2), 357 ( O S ) , 325 (l.l), 299 (0.7), 267 (0.6), 254 (0.5), 237 ( 0 . Q 220 (0.7), 205 (1.3), 198 (0.9), 179 (0.9), 161 (0.Q 152 (0.9), 151 (0.9), 144 (1.6), 137 (5) , 121 (loo), 88 (4), 45 (28). - Cz7H43N09 (525.6): calcd. C 61.70, H 8.25, N 2.66; found C 61.79, H 7.98, N 2.40.

(2S4'$5' R,3"Ej -Methyl N- (3- {5'-[5"- (Benzyloxy) -3"-methyl-pent-Y-enyl]- 2',2'-dimethyl-[I ',3']diosolan-4'-y1~-2-methosymethoxy-propyl)-curbamute (43): A solution of the alkene 41 (0.36 g, 1.19 mmol) in THF (5 ml) was introduced dropwise under argon to an ice-cold, stirred solution of 9-BBN (5.0 ml, 2.5 mmol, 0.5 M in THF). After 2 h, the reaction mixture was brought to room temp. and stirred for a further 8 h before the addition of PdC12(dppf) (26 mg, 0.036 mmol), the vinylic bromide 24 (0.38 g, 1.57 mmol), THF (15 ml) and a 3 N aq. NaOH solution (1.6 ml). The mixture was heated at 8OoC for 14 h, then diluted with benzene (20 ml) and treated



dropwise with a 30% aq. Hz02 solution (2.5 ml). After stirring for 30 min, the mixture was poured into brine (50 ml) and the aqueous phase extracted with EtOAc (5 X 10 ml). The combined organic extracts were dried (Na2S04), filtered, and the solvent was removed in vacuo. Column chromatography (2 X 15 cm, 25% EtOAdhexane) of the residue afforded the coupled alkene 43 [0.45 g, 80%, Rf (50% EtOAdhexane) = 0.541 as a yellowish oil. - [a]B = +7.3 (c = 2.18, CHCI,). - IR (film): 2 = 3345 (br., NH), 3065 (w), 3030 (w), 2985 (s), 2935 (s), 2860 (s), 1730 (s, C=O), 1530 (m), 1370 (m). 1245 (s), 1220 (s), 1155 (m), 1100 (s), 1030 (s), 740 (m), 700 (m) cm-I. - ‘H NMR (400 MHz): 6 = 7.35-7.28 (m, 5H, H,,,), 5.41 (td, J = 6.7 and 1.2 Hz, 1 H, 4”-H), 5.39 (br. s, 1 H, NH), 4.70 (s, 2 H, OCH20), 4.50 ($ 2H, Hbenzylic), 4.20 (td, J = 6.6 and 5.9 Hz, 1 H, 4’-H), 4.04 (ddd, J = 9.8, 5.6 and 4.2 Hz, I H , 5’-H), 4.03 (d, J = 6.7 Hz, 2H, 5”-H), 3.82 (dtd, J = 8.4, 5.4 and 3.5 Hz, 1 H, 2-H), 3.66 (s, 3H, MeOCONH), 3.46 (ddd, J = 13.9, 6.4 and 3.5 Hz, I H , I-H), 3.40 (s, 3H, MeOCH20), 3.17 (ddd, J = 13.9, 6.2 and 5.3 Hz, 1 H, I-H), 2.24 (ddd, J = 14.1, 10.7 and 4.9 Hz, 1 H, 2”-H), 2.04 (ddd, J = 14.1, 10.2 and 6.0 Hz, IH, 2”-H), 1.66 [s, 3H, Me- C(3“‘)], 1.64-1.44 (m, 4H, 3-H and I”-H), 1.41 [s, 3H, Me-C(2’)], 1.32 [s, 3H, Me-C(2‘)1. - I3C NMR (100 MHz): 6 = 157.2 (s, OCONH), 139.7 (s,

[d,C(2‘)], 74.1 [d,C(4’)], j2.2 (t, Cbenzylic), 66.6 [t. C(5”)], 55.7 (q, Me0CH20), 52.1 (9. MeOCONH), 45.5 [t, C(l)], 35.9 [t, C(2”)], 33.6 [t, C(3)], 28.6 [q, Me-C(2‘)], 28.1 [t. C(l”)], 26.0 [q, Me,-C(2’)], 16.6 [q, Me-C(3”)]. - MS (70 eV): mlz (YO) = 465 (5) [M”], 450 (3) [(M - Me)’], 433 ( I I ) , 418 (3), 403 (S), 342 (24), 298 (13), 284 (40), 268 (23), 254 (19), 236 (37), 227 (56), 186 (61), 126 (46), 114 (59), 107 (52), 91 (IOO), 88 (64), 81 (65), 45 (65). - C25H39N07 (465.6): calcd. C 64.49, H 8.44, N 3.01; found C 64.16, H 8.53, N 3.52.

(2S,ZrS,4“$.YR,YE) -2-[ ( tert- Butyldiphenylsilyl) oxyl-pentanoic Acid (3‘- {T,Y-Dimethyl-S-[-Is”’- (4-methoxy-benzyloxy) -3-methyl-pent-3’”-enylj[l“,3”]- dioxolan-4”-yl)-2’-methoxymethoxy-propyl)-amide (44a): Solid KOH (0.49 g, 8.8 mmol) was added to a solution of the carbamate 42a (0.87 g, 1.76 mmol) in MeOH/water (2:1, 15 ml). The resulting solution was heated at 100°C for 24 h. TLC analysis showed the presence of residual carbamate 42a, so additional KOH (0.22 g, 4 mmol) was introduced and the solution heated for a further 24 h. This procedure (KOH and reflux for 24 h) was performed a third time, after which the carbamate 42a had been totally consumed. The solvents were partially evaporated, the resulting mixture was poured into brine (50 ml) and the aqueous phase extracted with CH2C12 (5 X 20 ml). The combined organic phases were dried (Na2S04), filtered, and the filtrate was concentrated in vacuo to afford the derivative of 42a, the crude amine[48] [0.77 g, 99%, Rf (50% EtOAclhexane) < 0.051 as a yellowish oil. The product was sufficiently pure (>95%, IH NMR analysis) to be used directly for the amide bond formation. Addition of EtiPr2N (0.47 ml, 2.75 mmol), then his(2-oxo-3-oxazolidinyl)- phosphinic acid chloride (BOP chloride, 0.50 g, 1.97 mmol) to a cold (OT), stirred solution of the acid 3 (0.67 g, 1.88 mmol) in CH2CI2 (10 ml) under argon produced a white suspension, which was stirred for a further 5 min at 0°C and subsequently for 1.5 h at room temp. The resulting solution was cooled to -18”C, then a solution of the obtained crude amine (0.77 g, 1.76 mmol) and EtiPr2N (0.22 ml, 1.30 mmol) in CHzC12 (10 ml) was added dropwise. The reaction mixture was stirred at - 18°C for 1 h, warmed slowly to room temp. (for about 5 h), then stirred for 12 h at room temp. The reaction mixture was then washed with a 5% aq. citric acid solution (3 X 20 ml), a satd. NaHCO, solution (1 X 25 ml) and brine (1 X 25 ml), dried (Na2S0,), filtered, and the solvents were evaporated in vacuo. Column chromatography (2 X 20 cm, 20% EtOAdhexane) of the residue gave the amide 44a [1.06 g, 78%, Rc (50% EtOAc/hexane) = 0.631 as a colorless oil. - [a]BT = -18.8 (c = 1.90, CHCI,). - IR (film): 2 = 3430 (m, NH), 3060 (w). 3045 (w), 2955 (s), 2930 (s), 2860 (s), 1680 (s, C=O), 1615 (m), 1515 (s), 1445 (m), 1380 (m), 1370 (m), 1250 (s), 1110 (s), 1035 (s), 820 (m), 700 (s) cm-’. - IH NMR (400 MHz): 6 = 7.67 and 7.61 (A parts of AA‘XX’ system, J = 6.6 Hz, 4H, H,,,), 7.48-7.35 (m, 6H, Harem), 7.27 and 6.88 (AA’XX‘ system, J = 8.7 Hz, 4H, H,,,,), 7.26 (br. t, J = 5.9 Hz, 1 H, NH), 5.42 (br.

8.6 Hz, IH, OCH20), 4.44 (s, 2H, Hbenzylic), 4.31 (dd, J = 4.6 and 4.0 Hz, 1 H, 2-H), 4.24 (ddd, J = 8.5, 6.0 and 4.0 Hz, 1 H, 4”-H), 4.03 (ddd, J = 9.5, 5.6 and 4.0 Hz, 1 H, 5”-H), 4.00 (d, J = 6.7 Hz, 2H, 5”’-H), 3.89 (dddd, J =

9.0, 5.0, 4.0 and 3.5 Hz, IH, 2’-H), 3.81 (s, 3H, MeOPh), 3.65 (ddd, J = 14.0, 6.0 and 4.0 Hz, IH, 1’-H), 3.40 (s, 3H, MeOCH20), 3.26 (ddd, J = 14.0,5.8and5.0Hz, lH, l ‘ -H),2,24(ddd,J= 14.1,10.5and4.8Hz,1H, 2’”-H),2,04(ddd,J= 14.1, 10.2and6.0Hz, lH,2”’-H), 1.72-1.53(m,4H, 3-H, 3’-H and I”’-H), 1.63 [s, 3H, Me-C(3”’)], 1.47-1.36 (m, 3H, 3-H, 4-H and 1“’-H), 1.43 [s, 3H, Me-C(2”)], 1.34 [s, 3H, Me-C(2”)], 1.21 (m, IH, 4- H), 1.13 (s, 9H, Me3C), 0.75 (t, J = 7.1 Hz, 3H, I-H). - I3C NMR (100 MHz): 6 = 173.4 [s, C(l)]. 159.2 (s, C,,,), 139.5 [s, C(3”’)], 135.7 (d, C,,,), 135.6 (d, Carom), 133.1 (s, Carom), 132.7 (s, Carom), 130.7 ($ Carom), 130.1 (d, Carom), 130.0 (d, Carom), 129.4 (d, C,,,), 127.9 (d, Carom), 127.8 (d, Carom),

t,J=6.6H~,lH,4”’-H),4.74(d,J=8.6H~,lH,OCH20),4.72(d,J=

121.4 [d, C(4)], 113.8 (d, C,,,), 107.7 [s, C(2”)], 96.7 (t, OCHzO), 77.4 [d, C(S’)], 75.0 [d, C(2’)], 74.3 [d, C(2)], 74.1 [d, C(4”)], 71.8 (t. Cbenzylic), 66.3 [t, C(S”)], 55.7 (4. MeOCH20), 55.3 (q, MeOPh), 42.9 [t. C(l’)], 36.8 [t, C(3)], 36.0 [t, C(2”‘)], 33.6 [t. C(3‘)], 28.7 [q, Me-C(2”)], 28.2 [t. C(l”’)], 27.1 (q, Me$), 26.0 [q, Me-C(2”)], 19.3 (s, Me3C), 16.8 [t. C(4)], 16.6 [q, Me- C(3)], 13.9 [q, C(5)]. - MS (70 eV): mlz (%) = 760 ( I ) [(M - Me)+], 718 (11) [(M - tBu)+], 639 (3), 580 (2), 561 (9), 460 (3), 356 (3), 338 (3), 318 (3), 311 (4), 298 (4), 278 (3), 239 (3), 199 (20), 183 (S), 135 (21), 121 (100). - C45H65N08Si (776.1): calcd. C 69.64, H 8.44, N 1.80; found C 69.92, H 8.18, N 1.94.

(2S2’S,4“S,YR,32)-2-[ (tert-Butyldiphenylsi[yl)oxy]-pentanoic Acid (3’- {~,2”-DimethyI-5”-[5’”- (4-methoxy-benzyloxy)-3”’-methoxymethyl-pent- 3 ”’ - enyl]-[l”,3”]dioxolan-4“-yl~-Z’-methoxymethoxy-propyl) -amide (44b): To the carbamate 42b (1.72 g, 3.27 mmol) was added a solution of KOH (1.5 g, 27 mmol) in MeOH/water (2:1, 45 ml). The solution was heated under reflux for 72 h. Every 20 h, KOH (0.5 g) was added to complete the hydrolysis of the carbamate. After all carbamate 42b had been consumed, the solvents were partially evaporated. The resulting mixture was poured into brine (70 ml) and the aqueous phase extracted with Et20 (5 X 50 ml). The combined organic extracts were dried (MgSO,), filtered, and the filtrate was concentrated yielding the crude amino of 42b [1.47 g, 96%, Rf (MeOH) = 0.421 as a yellowish oil, which was used for the amide bond formation without further purification.

Addition of EtiPr2N (1.1 ml, 6.4 mmol), then bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (BOP chloride, 1.07 g, 4.06 mmol) to a cold (OT), stirred solution of the acid 3 (1.45 g, 4.07 mmol) in CH2Clz (20 ml) under argon produced a white suspension, which was stirred for a further 5 min at O°C and for 1.5 h at room temp. The resulting solution was cooled to -2O”C, then a solution of the obtained crude amine (1.47 g, 3.15 mmol) and EtiPrzN (0.45 ml, 2.60 mmol) in CH2Clz (20 ml) was added dropwise. The reaction mixture was stirred at -20°C for 1 h, warmed slowly to room temp. (for about 5 h), then stirred for 12 h. The solvent was evaporated and the the residue purified by column chromatography (4 X 20 cm, Et20, then MeOH) yielding the amide 44b [1.81 g, 71%, Rr (Et20) = 0.631 as a colorless oil. - [a]BT = -16.5 (c = 2.85, CHCI,). - IR (film): 2 = 3430 (w, NH), 3070 (w), 3040 (w), 2955 (s), 2935 (s), 2890 (s), 2860 (s), 1680 (s, C=O), 1615 (m), 1585 (w). 1515 (s), 1465 (m), 1430 (m), 1380 (m), 1370 (m), 1300 (w), 1250 (s), 1220 (m), 1170 (m), 1150 (m), 1105 (s), 1035 (s), 920 (w), 820 (m), 740 (m), 705 (s) cm-’. - ‘H NMR (500 MHz): 6 = 7.65 and 7.60 (A parts of AA‘XX’ system, J = 6.7 Hz, 4H, H,,,,), 7.46-7.34 (m, 6H, H,,,), 7.26 and 6.87 (AA’XX‘ system, J = 8.7 Hz, 4H, H,,,), 7.26 (m, l H , NH), 5.60

6.7 Hz, 1 H, OCH20), 4.43 (s, 2H, Hbenzylic), 4.30 (dd, J = 5.0 and 3.9 Hz, IH, 2-H), 4.22 (dt, J = 8.1, and 5.5 Hz, I H , 4”-H), 4.05 (d, J = 6.6 Hz, 2H, 5“‘-H), 4.03 (ddd, J = 9.6, 5.7 and 3.8 Hz, IH, 4”-H), 3.88 [s, 2H, CH2-C(3”’)], 3.87 (m, IH, 2’-H), 3.79 (s, 3H, MeOPh), 3.64 (ddd, J = 14.0, 6.2 and 4.1 Hz, IH, l’-H), 3.39 (s, 3H, MeOCH,O), 3.24 [s, 3H, MeOCHz- C(3”’)], 3.22 (dt, J = 14.0 and 5.3 Hz, 1 H, 1‘-H), 2.33 (ddd, J = 14.2, 10.6 and 4.9 Hz, 1 H, 2”’-H), 2.12 (ddd, J = 14.2, 10.3 and 5.9 Hz, 1 H, 2”’-H), 1 .67(dddd,J= 13.6,11.1,6.7and3.9Hz,1H,3-H),1.58(dddd,J= 13.5, 10.3,9.6and4.9Hz, IH, I”‘-H), 1.58-1.55(m,2H,3’-H), 1 .46(dddd,J= 13.5, 10.5, 5.9 and 3.8 Hz, IH, I”’-H), 1.44-1.31 (m, 2H, 4-H), 1.42 [s, 3H, Me-C(2”)], 1.32 [s, 3H, Me-C(2”)], 1.18 (dddd, J = 13.6, 10.5, 6.9 and 5.0 Hz, I H , 3-H), 1.11 (s, 9H, Me&), 0.74 (t, J = 7.6 Hz, 3H, 5-H). - I3C NMR (125 MHz): 6 = 173.3 [s, C(l)], 159.2 (s, C,,,,), 139.7 [s, C(3)], 135.7

130.1 (d, C,,,), 130.1 (d, C,,,), 129.4 (d, C,,,), 127.9 (d, C,,,), 127.8 (d, C,,,), 125.7 [d, C(4)], 113.8 (d, C,,,), 107.7 [s, C(2”)], 96.7 (t.

(t, J = 6.6 Hz, IH, 4”‘-H), 4.72 (d, J = 6.7 Hz, I H , OCHZO), 4.70 (d, J =

(d, Carom), 135.7 (d, Carom), 133.1 (s, Carom), 132.6 ( ~ 3 Carom), 130.4 (s, Carom),

OCHzO), 77.4 [d, C(Y)], 75.1 [d, C(2’)], 74.3 [d, C(2)], 74.1 [d, C(4”)], 71.9 (t. Cbenzylic), 69.8 [t, m & ( y ) ] , 65.6 [t, C(5’’’)], 57.9 [q, MeOCH2-C(3“‘)], 55.7 (q, MeOCHlO), 55.3 (9, MeOPh), 43.0 [t, C(l‘)], 36.8 [t. C(3)], 33.5 [t. C(3‘)], 31.6 [t, C(2“‘)], 28.6 [q, Me-C(2”)], 28.3 [t, C(l”’)], 27.0 (9, Me,C), 26.0 [q, Me-C(2”)], 19.3 (s, Me,C), 16.8 [t. C(4)], 13.9 [q, C(5)]. - FAB MS (3- NOBA): m/z (“10) = 1612 (0.3) [M;], 806 (5) [(M + I)+], 748 (7) [(M - tBu)+], 728 (6), 638 (3), 610 (2), 532 (3), 518 (1.8), 500 (4), 470 (3), 408 (1.4), 340 (1.8), 318 (3), 311 (4), 298 (2), 239 (7), 199 (25), 197 (25), 183 (lo), 135 (50), 121 (100). - C46H67N09Si (806.1): calcd. C 68.54, H 8.38, N 1.74; found C 68.29, H 8.52, N 1.72.

(2S.2’ S,4”SStR.3”’E) -2-[ (tert- Butyldiphenylsilyl) oxy]-pentanoic Acid (3’- [Y- (5”-Benzyloxy-Y-methyl-pent-3”’-enyl) -2”,2”-dimethyl-[l”,3”]dioxolan- 4“-yl]-2‘-methoxymethoxy-propyl]-amide (45): Solid KOH (0.24 g, 4.3 mmol) was added to a solution of the carbamate 43 (0.40 g, 0.86 mmol) in MeOH/ water (2:1, 15 ml). The resulting solution was heated at 100°C for 18 h. TLC analysis showed the presence of residual carbamate 43, so additional KOH (0.22 g, 4 mmol) was introduced and the solution heated for a further 34 h, whereupon all the carbamate 43 had reacted. The solvents were partially evaporated, the resulting mixture was poured into brine (20 ml) and the


714 D. Seebach, M. A . Maestro, M . Sefkow, G. Adam, S. Hintermann, A. Neidlein

aqueous phase extracted with CH2C12 (5 X 10 ml). The combined organic phases were dried (Na2S04), filtered, and the CHzClz was removed under reduced pressure to afford the derivative of 43, the crude amine[Sol [0.34 g, 97% Rf (50% EtOAclhexane) < 0.051 as a yellowish oil. The product was sufficiently pure (>950/0, 'H-NMR analysis) to be used directly for the amide bond formation.

Addition of EtiPrzN (0.22 ml, 1.27 mmol), then bis(2-0~0-3-oxazolidinyl)- phosphinic acid chloride (BOP chloride, 0.23 g, 0.89 mmol) to a cold (OT), stirred solution of the acid 3 (0.32 g, 0.89 mmol) in CH2Clz (7 ml) under argon produced a white suspension, which was stirred for a further 5 min at 0°C and for I .5 h at room temp. The resulting solution was cooled to - 18"C, then a solution of the obtained crude amine (0.33 g, 0.81 mmol) and EtiPrzN (0.10 ml, 0.61 mmol) in CH2Cl2 (7 ml) were added dropwise. The reaction mixture was stirred at -18°C for 1 h, warmed slowly to room temp. (for about 5 h), then stirred for 12 h. It was subsequently washed with a 5% aq. citric acid solution (3 X 10 ml), a satd. NaHCO, solution (1 X 20 ml) and brine ( I X 20 ml), dried (Na2S0,), filtered, and the solvents were evaporated in vacuo. Column chromatography (2 X 20 cm, 25% EtOAclhexane) of the residue gave the amide 45 [0.485 g, 76"/0, Rr (50% EtOAclhexane) = 0.671 as a colorless oil. - [a]B = -20.2 (c = 1.30, CHCI,). - IR (film): 2 = 3435 (m), 3070 (w). 3030 (w), 2960 (s), 2935 (s), 2865 (s), 1675 (s, C=O), 1515 (s), 1425 (m), 1370 (m), 1215 (m), 1105 (s), 1035 (s), 820 (m), 740 (m), 700 (s) cm-I. - 'H NMR (400 MHz): S = 7.67 and 7.62 (A parts of AA'XX' system, J = 6.6 Hz, 4H, H,,,), 7.48-7.27 (m, 11 H, H,,,), 7.26 (br. s, 1 H, NH), 5.44 (td, J = 6.7 and 1.2 Hz, IH, 4"'-H), 4.75 (d, J = 9.6 Hz, I H ,

J = 5 . 0 a n d 3 . 8 H z , 1 H , 2 - H ) , 4 . 2 5 ( d d d , J = 8 . 0 , 5 . 6 a n d 4 . 4 H z , 1 H , 4 - H), 4.04 (ddd, J = 9.7, 5.6 and 3.9 Hz, 1 H, Y-H), 4.04 (d, J = 6.8 Hz, 2H, 5"'-H), 3.90 (dq, J = 8.3 and 4.5 Hz, 1 H, 2'-H), 3.66 (ddd, J = 14.0, 6.1 and 4.0 Hz, IH, l'-H), 3.41 (s, 3H, MeOCH20), 3.28 (dt, J = 14.0 and 5.3 Hz, 1 H, l'-H), 2.26 (ddd, J = 14.0, 10.4 and 4.9 Hz, 1 H, Y-H), 2.05 (ddd, J = 14.0, 10.0 and 6.0 Hz, IH, 2-H) , 1.73-1.53 (m, 4H, 3-H, 3'-H and I"'-H), 1.64 [s, 3H, Me-C(3"')], 1.49-1.35 (m, 3H, 3-H, 4-H and 1"'-H), 1.44 [s, 3H, Me-C(2")], 1.35 [s, 3H, Me-C(2")], 1.23 (m, 1 H, 4-H), 1.14 (s, 9H, Me3C),

139.6 (s, C,,,,), 138.6 [s, C(3"')], 135.8 (d, C,,,), 135.7 (d, C,,,), 133.1 (s,

127.9 (d, C,,,,,), 127.8 (d, C,,,), 127.5 (d, C,,,), 121.4 [d, C(4"')], 107.4 [s,

[d, C(4")], 72.1 (t, Cbcnzylic), 66.6 [t, C(5)], 55.7 (q, MeOCHzO), 42.9 [t, C(l')], 36.8 [t, C(3)], 36.0 [t, C(2)], 33.6 [t. C(3')], 28.7 [q. Me-C(2")], 28.2 [t, C(I"')], 27.1 (q, Me&), 26.0 [q, Me-C(2")], 19.3 (s, Me3C), 16.8 [t. C(4)], 16.6 [q, Me-C(3)], 14.0 [q, C(5)]. - MS (70 eV): m/z (%) = 730 (1) [(M - Me)+], 688 (36) [(M - tBu)'], 656 (8), 598 (6), 576 (8), 522 (S), 490 (8), 460 (12), 356 (8), 338 (lo), 311 (12), 298 (14), 281 (8), 255 (8), 239 (8), 213 (8), 199 (66), 183 (20), 139 (20), 135 (62), 105 (18), 91 (IOO), 77 (26), 55 (20), 45 (36). - CWH6,NO7Si (746.1): calcd. C 70.84, H 8.51, N 1.88; found C 70.59, H 8.74, N 1.73.

OCHZO), 4.73 (d, J = 9.6 Hz, 1 H, OCHzO), 4.52 (s, 2H, Hbenrylic), 4.34 (dd,

0.76 (t, J = 7.2 Hz, 3H, 5-H). - I3C NMR (100 MHz): 6 = 173.4 [s, C(l)],

Car,,), 132.7 (s, Car,,), 130.1 ( 4 Carom), 130.0 (d, Carom), 128.4 (d, Car,,),

C(2")], 96.7 (t, OCHZO), 77.4 [d, C(5")], 75.0 [d, C(2')], 74.3 [d, C(2)], 74.1

(2S,2'S, 4"s. S"R,3"'E) -2-[(rert-Butyldimethylsilyl) oxy J-pentanoic Acid (3'- {T,Y'- Dimethyl-5"-[5"'- (4-methoxy-benzyloxy) -3"'-methyl-pent-Y-enyl]-[1'',3''J-

dioxolan-4"-yl/-2'-niet/ioxymethoxy-propyl)-amide (46a): A solution of silyl ether 4a (0.81 g, 1.04 mmol) in THF (15 ml) was treated with Bu4NF . 3 H 2 0 (0.99 g, 3.13 mmol) at room temp. under argon. The reaction mixture was stirred for 3 h and the solvent evaporated. EtOAc (50 ml) was added to the residue, the solution washed with a 5% aq. HCI solution (1 X 10 ml) and brine (1 X 10 ml), dried (Na2S04), filtered and the solvent removed in vacuo. Column chromatography of the residue (2 X 10 cm, 50% EtOAc/ hexane) gave the corresponding alcohol (0.55 g, 98%) as a colorless oil.

To a solution of this alcohol (0.55 g, 1.02 mmol) and imidazole (0.31 g, 4.51 mmol), in DMF (15 ml) was added tert-butyldimethylsilyl chloride (0.34 g, 2.25 mmol) at room temp. under argon. After stirring for 12 h, the mixture was poured into icelwater (10 ml), the aqueous phase extracted with CH2C12 (5 X 5 ml), the combined organic extracts were dried (Na2SO4), filtered, and the filtrate was concentrated. Column chromatographic purification of the crude product (2 X 15 cm, 15-20% EtOAclhexane) furnished the pure silyle- ther 46a [0.63 g, 95%, Rf (50% EtOAchxane) = 0.571 as a colorless oil. - [a]ET = -22.3 (c = 3.70, CHCI,). - IR (film): 2 = 3430 (m. NH), 2960 (s), 2930 (s), 2860 (s), 1680 (s, C=O), 1615 (m). 1515 (s), 1465 (m), 1380 (m), 1370 (m), 1250 (s), 1220 (m), 1075 (s), 1035 (s), 840 (s), 780 (m) cm-I. - 'H NMR (400 MHz): S = 7.27 and 6.87 (AA'XX' system, J = 8.7 Hz, 4H, H,,,,), 7.05 (br. t, J = 5.8 Hz, 1 H, NH), 5.41 (td, J = 6.7 and 1.2 Hz, 1 H,

and 5.7 Hz, 1 H, 4"-H), 4.17 (dd, J = 5.6 and 4.5 Hz, 1 H, 2-H), 4.03 (ddd, J = 9.7, 5.7 and 3.9 Hz, IH, 5"-H), 3.99 (d, J = 6.7 Hz, 2H, 5"'-H), 3.86 (dddd, J = 6.7, 5.8, 5.1 and 4.3 Hz, 1 H, 2'-H), 3.80 (s, 3H, MeOPh), 3.59 (ddd, J = 14.0, 5.9 and 4.3 Hz, I H , 1'-H), 3.39 (s, 3H, MeOCHzO), 3.30 ( d d d , J = 14.0,5.8and5.1 Hz, I H , l ' -H),2,23(ddd,J= 14.0, 10.3and5.4 Hz, I H , 2 - H ) , 2 , 0 3 ( d d d , J = 14.0, 10.1 and6.0Hz, IH,Y-H) , 1.79-1.52

4 - H ) , 4.70 (s, 2H, OCH,O), 4.43 (s, 2H, Hbenqlic), 4.22 (ddd, J = 7.3, 6.1

(m, 5H, 3-H, 3'-H and I"'-H), 1.64 [d, J = 0.5 Hz, 3H, Me-C(3'")], 1.50-1.28 (m, 3H, 4-H and I"'-H), 1.41 [s, 3H, Me-C(2'7], 1.32 [s, 3H, Me- C(2")], 0.92 (s, 9H, Me$), 0.90 [t, J = 7.4 Hz, 3H, 5-HI, 0.09 (s, 3H, MeSi), 0.07 (s, 3H, MeSi). - I3C NMR (100 MHz): 6 = 173.9 [s, C(l)], 159.2 (s, C,,,), 139.5 [s, C(3"')], 130.6 (s, C,,,), 129.4 (d, C,,,), 121.4 [d, C(4"')], 133.8 (d, Carom), 107.7 [s, C(2")], 96.7 (t, OCHlO), 77.4 [d, C(5")], 74.9 [d, C(2')], 74.1 [d, C(4)], 73.6 [d, C(2)], 71.8 (t. Cben,&, 66.3 [t. C(5"')], 55.7 (q, MeOCH20), 55.3 (q, MeOPh), 42.8 [t. C(l')], 37.6 [t, C(3)], 36.0 [t. C(2)], 33.5 [t, C(3')], 28.6 [q. Me-C(2")], 28.1 [t. C(l"')], 26.0 [q. Me-C(2")], 25.7 (q, Me3C), 18.0 (s, Me,C), 17.5 [t, C(4)], 16.6 [q. Me-C(3"')], 14.1 [q, C(5)], -4.8 (9. MeSi), -5.1 (4, MeSi). - MS (70 eV): mlz (%) = 636 (0.3) [(M - Me)+], 594 (2) [(M - tBu)'], 515 (2), 368 (19, 326 (I), 300 (I), 272 (I) , 232 (4), 216 (2), 214 (3), 187 (20), 136 (6), 121 (IOO), 73 (39, 45 (38). - C35H61NOsSi (652.0): calcd. C 64.48, H 9.43, N 2.15; found C 64.50, H 9.36, N 1.87.

(2$2'S,4"S,5"R,3"'Z)-2-[ (tert-Butyldimethylsilyl)oxy]-pentanoic Acid (3'- (2",2"-Dimethyl-5"-[5"'- (4-methoxy-benzyloxy) -3"-methoxymethyl-pent-3"- enyl]-[l".3"]dioxolan-4"-yl}-2'-methoxymethoxy-propyl)-amide (46b): To a solution of silyl ether 44b (1.80 g, 2.24 mmol) in THF (65 ml) was added B y N F . 3 H 2 0 (0.9 g, 2.8 mmol) at room temp. The reaction mixture was stirred for 1 h, whereupon Et20 (50 ml) and water (50 ml) were added. The aqueous layer was extracted with Et20 (4 X 25 ml), the combined organic extracts were dried (MgSO,), filtered and the solvents evaporated. The crude alcohol, which contained further tert-butyldiphenylsilanol, was used directly for the silylation step.

To a solution of the alcohol (S1.26 g, 2.23 mmol) and imidazole (2.0 g, 29 mmol) in DMF (40 ml) was added tert-butyldimethylsilyl chloride (2.0 g, 13 mmol) at 0°C. After stirring for 1 h at 0°C and for 15 h at room temp., the solvent was removed in vacuo. Purification by column chromatography of the crude product (5 X 20 cm, EtzO) gave the pure silyl ether 46b [1.40 g, 92%, Rr (Et20) = 0.641 as a colourless oil. - [a]ET = -18.9 (c = 3.47, CHC1,). - IR (film): 2 = 3430 (m, NH), 2955 (s), 2930 (s), 2860 (s), 1680 (s, C=O), 1615 (m), 1585 (w). 1515 (s), 1465 (m), 1380 (m), 1370 (m), 1300 (w), 1250 (s), 1220 (m), 1170 (m). 1155 (m). 1105 (s), 1040 (s), 900 (m), 840 (s), 780 (s) cm-I. - 'H NMR (500 MHz): 6 = 7.26 and 6.87 (AA'XX' system, J = 8.7 Hz, 4H, H,,,), 7.05 (br. t, J = 5.9 Hz, 1 H, NH), 5.60 (t,

Hz, 1 H, OCHzO), 4.33 (s, 2H, Hbenryllc), 4.22 (dt, J = 7.6 and 5.7 Hz, 1 H, 4-H), 4.16 (dd, J = 5.7 and 4.5 Hz, 1 H, 2-H), 4.05 (d, J = 6.7 Hz, 2H, 5"'- H), 4.04 (ddd, J = 9.7, 5.7 and 3.9 Hz, 1 H, 5"-H), 3.90 [s, 2H, CH2-C(3"')], 3.85 (m, IH, 2'-H), 3.80 (s, 3H, MeOPh), 3.59 (ddd, J = 14.0, 6.1 and 4.1 Hz, 1 H, 1'-H), 3.39 (s, 3H, MeOCH20), 3.28 (dt, J = 14.0 and 5.5 Hz, IH, 1'-H), 3.26 [q, 3H, MeOCH2-C(3)], 2.34 (ddd, J = 14.3, 10.6 and 4.9 Hz, 1 H, 2-H), 2.12 (ddd, J = 14.3, 10.2 and 5.8 Hz, 1 H, 2-H) , 1.74 (ddt, J = 13.8, 10.9 and 5.5 Hz, 1 H, 2-H), 1.64 (dddd, J = 13.8, 10.8, 5.5 and 4.5 Hz, IH, 2-H), 1.58-1.55 (m, 2H, 3'-H), 1.57 (dddd, 13.5, 10.2, 9.7 and 5.0 Hz, IH, I"'-H), lSO(dddd,J= 13.5, 10.5,5.8and3.9Hz, lH,I"'-H), 1.45-1.27 (m, 2H, 4-H), 1.41 [s, 3H, Me-C(2")], 1.31 [s, 3H, Me-C(2")], 0.92 (s, 9H, Me&), 0.90 ( t , J = 7.4 Hz, 3H, 5-H), 0.09 (s, 3H, MeSi), 0.07 (s, 3H, MeSi). - "C NMR (125 MHz): 6 = 173.9 [s, C(l)], 159.2 (s, C,,,), 139.7 [s, C(3"')], 130.4 (s, C,,,), 129.4 (d, C,,,), 125.7 [d, C(4"')], 113.8 (d, C,,,), 107.7 [s, C(2")], 96.7 (t, OCHZO), 77.4 [d, C(5")], 75.0 [d, C(2')], 74.1 [d, c(4")], 73.6 [d, c(2)], 71.9 (t, Cbenzyllc), 69.9 [t. m,-C(3"')], 65.6 [t. c(5"')],

J = ~ . ~ H z , I H , ~ " ' - H ) , ~ . ~ I ( ~ , J = ~ . ~ H z , IH,OCH20) ,4 .70(d ,J=6 .9

58.0 [q, MeOCHz-C(3"')], 55.7 (9. MeOCH20), 55.3 (4, MeOPh), 42.9 [t, C(l')], 37.6 [t, C(3)], 33.5 [t,C(3')], 31.6 [t. C(2"')], 28.6 [q, Me-C(2")], 28.3 [t. C(l"')], 26.0 [q, Me-C(2")], 25.7 (q, Me,C), 18.0 (s, Me,C), 17.6 [t, C(4)], 14.1 [q. C(5)], -4.9 (q, MeSi), -5.1 (9. MeSi). - FAB MS (3-NOBA): mlz ("A) = 1363 (0.2) [MZ], 682 (5) [(M + I)+], 666 (1.7), 650 (0.4), 624 (4) [(M - tBu)'], 592 (1.3), 560 (0.9), 545 (0.9), 530 (l.O), 486 (3), 472 (1.3), 454 (3), 424 (1.9), 410 (l.l), 398 (I.I), 392 (1.2), 187 (25), 121 (IOO), 73 (59). - C36H63N09Si (682.0): calcd. C 63.40, H 9.31, N 2.05; found C 63.66, H 9.07, N 2.17.

(2S,2'$4"$5"R,YE) -2-[( tert-Butyldimethylsilyl) oxyj-pentanoic Acid {3'- [2",2"- Dimethyl-5"- (5'"-hydroxy-Y-methyl-pent-Y-enyl) -[ 1",3"]dioxolan-4"- yl]-2'-methoxymethoxy-propyl}-amide (47a): DDQ (0.020 g, 0.87 mmol) was added at room temp. under argon to a solution of the amide 46a (0.45 g, 0.69 mmol) in a mixture of CHzClz (13 ml) and water (0.6 ml). The solution was stirred for 9 min before an additional 18 mg of DDQ was added. This procedure (stirring for 9 min, 18 mg DDQ) was repeated twice more. After the addition of last portion of DDQ, the mixture, which had turned from a dark green solution to a light brown suspension during the reaction, was stirred for 18 min, then the reaction was quenched with a satd. NaHCO, solution (5 ml). Water was added to the obtained mixture until two clear phases had formed, and the aqueous layer was extracted with CHzClz (5 X 10 ml). The combined organic extracts were dried (MgS04), filtered, and the solvent was evaporated in vacuo. Column chromatography (3 X 18 cm, 33-66% EtOAc/hexane, gradient elution) of the crude product gave the aldehyde Za [0.080 g, 22%, Rf (33% EtOAdhexane) = 0.171 and the alcohol 47a



[0.265 g, 72%, Rf (33% EtOAclhexane) = 0.101 as colorless oils. - [a]B = -28.3 (c = 2.10, CHCI,). - IR (film): 2 = 3430 (br., NH, OH), 2955 (s), 2930 (s), 2860 (s), 1670 (s, C=O), 1525 (s), 1465 (m), 1380 (m), 1250 (s), 1220 (s), 1155 (m), 1135 (m), 1100 (s), 1035 (s), 840 (m), 780 (m) cm-I. - ‘H NMR (400 MHz): 6 = 7.06 (br. t, J = 5.9 Hz, 1 H, NH), 5.43 (tdd, J = 6.8,2.5and1.2Hz, 1H,4-H),4.71(s,2H,0CH20),4.22(td,J=6.6and 5.9 Hz, 1 H, 5”-H), 4.17 (dd, J = 5.6 and 4.5 Hz, 1 H, 2-H), 4.15 (d, J = 6.7 Hz, 2H, 4“‘-H), 4.03 (ddd, J = 9.6, 5.7 and 4.0 Hz, 1 H, 5”-H), 3.87 (m, IH, 2’-H), 3.58 (ddd, J = 13.9, 6.0 and 4.2 Hz, IH, 1’-H), 3.40 (s, 3H, MeOCH2O), 3.32 (ddd, J = 13.9, 6.1 and 4.9 Hz, 1 H, 1’-H), 2.22 (ddd, J = 14.0, 10.2 and 5.2 Hz, 1 H, Y-H), 2.02 (ddd, J = 14.0, 9.9 and 6.1 Hz, 1 H, 2”’-H), 1.79-1.55 (m, 6H, 3-H, 3’-H, 1”’-H and OH), 1.68 [s, 3H, Me-C(3”’)], 1.51-1.27 (m, 3H, 4-H and I”’-H), 1.42 [s, 3H, Me-C(2”)], 1.32 [s, 3H, Me-C(2’’)], 0.93 (s, 9H, Me&), 0.91 (t, J = 7.3 Hz, 3H, 5-H), 0.10 (s, 3H, MeSi), 0.08 (s, 3H, MeSi). - I3C NMR (100 MHz): 6 = 174.0 [s, C(l)], 138.8 [a C(3”’)], 124.0 [d, C(4)], 107.7 [s, C(2”)], 96.7 (t, OCH20), 77.4 [d, C(S’)], 74.8 [d, C(2’)], 74.1 [d, C(4”)], 73.6 [d, C(2)], 59.3 [t, C(Y)], 55.7 (q, MeOCH20), 42.8 [t, C(l’)], 37.6 [t. C(3)], 35.9 [t, C(2)], 33.5 [t. C(3‘)], 28.6 [q, Me-C(2”)], 28.1 [t, C(l”’)], 26.0 [q, Me-C(2”)], 25.8 (q, Me$), 18.0 (s, Me,C), 17.5 [t, C(4)], 16.3 [q, Me-C(3“‘)], 14.1 [q. C(5)], -4.8 (q, MeSi), -5.1 (4. MeSi). - MS (70 eV): mlz (%) = 531 (0.5) [M+’], 516 (4) [(M - Me)+], 498 (I) , 474 (5 ) , 456 (lo), 424 (3), 398 (20), 366 (24), 354 (12), 336 (22), 232 (26), 187 (loo), 174 (12), 157 (lo), 147 (20), 131 (13), 115 (16), 81 (19), 75 (39), 73 (90), 59 (24), 45 (78). - Cz7Hs3NO7Si (531.8): calcd. C 60.98, H 10.05, N 2.63; found C 61.20, H 9.65, N 2.82.

(2S,2’S,4”~5”R,3”Z)-2-[(tert-Butyldimethylsilyl/oxy]-pentunoic Acid {3’- [2“,2”-Dimethyl-5”-(5”-hydroxy-3”-methoxymethyl-pent-3”-enyl) -[ 1“,3“]dioxolun-4”-yl]-Z‘-methosymethoxy-propyl}-amide (47b): DDQ (0.59 g, 2.60 mmol) was added at room temp. to a solution of the amide 46b (1.19 g, 1.74 mmol) in a mixture of CH2Clz (50 ml) and water (2 ml). The solution was stirred for 9 min before an additional 50 mg of DDQ was added. This procedure (stirring for 9 min, 50 mg DDQ) was repeated four times. After the addition of the last portion of DDQ, the mixture, which had turned from a dark green solution to a light brown suspension during the reaction, was stirred for 15 min, then the reaction was quenched with a satd. NaHC0, solution (30 ml). Water was added until two clear phases had formed, and the aqueous layer was extracted with CHzClz ( 5 X 20 ml). The combined organic extracts were dried (MgSO,), filtered, and the solvent was evaporated in vacuo. Column chromatography (4 X 15 cm, first Et20, then 10% MeOH/EtzO) of the crude product gave the aldehyde 2b [0.35 g, 36%, Rf (Et,O) = 0.541 and the alcohol 47b [0.60 g, 61%, Rf (Et,O) = 0.311 as colorless oils. - [a16 = -23.4 (c = 3.33, CHCI,). - IR (film): 2 = 3600-3200 (br., OH), 3430 (m, NH), 2955 (s), 2935 (s), 2890 (s), 2860 (s), 2820 (m), 1675 (s, C=O), 1525 (s), 1465 (m), 1380 (m), 1370 (m), 1250 (s), 1220 (m), 1150 (m), 1100 (s), 1035 (s), 895 (w), 840 (m), 780 (m) cm-I. - ‘H NMR (500 MHz): 6 = 7.06 (br. t, J = 5.9 Hz, 1 H, NH), 5.68 (t. J = 6.9 Hz, 1 H, 5“‘-H), 4.71 (s, 2H, OCH20), 4.22 (dt, J = 7.6 and 5.8 Hz, 1 H, 4-H), 4.16 (d, J = 7.0 Hz, 2H, 5”’-H), 4.16 (dd, J = 5.5 and 4.3 Hz, I H , 2-H), 4.05 (ddd, J = 9.7, 5.7 and 3.9 Hz, 1 H, Y-H), 3.94 [s, 2H, CH2-C(3”’)], 3.86 (m, 1 H, 2’-H), 3.58 (ddd, J = 14.0, 6.0 and 4.1 Hz, 1 H, 1’-H), 3.40 (s, 3H, MeOCHZO), 3.32 [s, 3 H, MeOCH2-C(3”’)], 3.30 (dt, J = 14.0 and 5.3 Hz, 1 H, I‘-H), 2.32 (ddd, J = 14.3, 10.4 and 4.9 Hz, 1 H, 2”’-H), 2.17 (br. s, 1 H, O H ) , 2 . l l ( d d d , J = 14.3,10.1and6.1Hz,1H,2”’-H),1.74(ddt,J= 13.8, 10.9 and 5.5 Hz, 1 H, 3-H), 1.65 (dddd, J = 13.8, 10.9, 5.5 and 4.3 Hz, 1 H, 2-H), 1.58 (dddd, J = 13.6, 10.4, 9.7 and 4.9 Hz, 1 H, 1”’-H), 1.58-1.55 (m, 2H,3’-H),1.49(dddd,J= 13.6,10.1,6.1and3.9Hz,1H,I”’-H),1.44-1.27 (m, 2H, 4-H), 1.42 [s, 3H, Me-C(2”)], 1.32 [s, 3H, Me-C(2”)], 0.93 (s, 9H, Me3C),0.91 ( t , J = 7.4Hz, 3H, 5-H),0.10(s, 3H, MeSi),O.O8(s,3H,MeSi). - I3C NMR (100 MHz): 6 = 174.0 [s, C(l)], 139.3 [s, C(3“‘)], 128.5 [d, C(4”’)], 107.7 [s, C(2”)], 96.7 (t, OCH,O), 77.4 [d, C(5”)], 74.9 [d, C(2‘)], 74.0 [d, C(4“)], 73.5 [d. C(2)], 70.4 [t, CHz-C(3”’)], 58.6 [t, C(5”’)l. 58.2 [q, Me- OCH2-C(3”’)], 55.7 (4. MeOCH20), 42.8 [t, C(l’)], 37.5 [t. C(3)], 33.5 [t, C(3’)], 32.2 [t. C(2”’)], 28.6 [q. Me-C(2“)], 28.4 [t, C(l’)], 26.0 [q, Me-C(2”)], 25.7 (q, Me$), 18.0 (s, Me3C), 17.5 [t. C(4)], 14.1 [q, C(5)], -4.8 (q, MeSi), -5.1 (9. MeSi). - MS (70 eV): mlz (%) = 560 (0.3) [(M - I)’], 546 (2) [(M - Me)+], 544 (1.0) [(M - OH)’], 528 (0.Q 502 (4), 486 (9, 472 (5), 456 (4), 428 ( I I ) , 414 (6), 396 (15), 384 (6), 366 ( I I ) , 352 (6), 334 (9, 289 (3), 272 (4), 232 (24), 216 (8), 214 (9), 187 (IOO), 174 (16), 157 (13), 147 (22), 131 (19), 115 (19), 75 (38), 73 (83), 45 (50). - C2sH,sNOsSi (561.8): calcd. C 59.86, H 9.87, N 2.49; found C 60.35, H 9.67, N 2.47.

(ZS,2’S,4“$5”R,YE) -2-[ (tert-Butyldimethylsilyl) oxyl-pentanoic Acid {3’- [T3 2”-Dimethyl-5”- (3”’-methyl-5”’-oxo-pent-3”-enyl) -[1”,3”]dioxolan-4”-ylj-2’- methoxymethoxy-propyl}-amide (Za): To a cooled (-20°C) solution of the alcohol 47a (0.17 g, 0.32 mmol) in DMF (3 ml) was added dropwise under argon a solution of PDC (0.16 g, 0.42 mmol) in DMF (1 ml). The cooling bath was then removed and the reaction mixture stirred for 4 h at room temp., whereupon additional PDC (0.015 g) was added and the solution stirred for 1 h. The dark brown solution was then poured into water (25 ml) and the aqueous layer extracted with CH2CIp (5 X 5 ml). The combined

organic phases were dried (MgSO,), filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (2 X 10 cm, 25% EtOAchexane) furnished our target molecule, the aldehyde 2a (0.16 g, 94%) as a colorless oil. - [a ]B = -24.5 (c = 3.18, CHCI,). - IR (film): 5 = 3430 (br., NH), 2960 (s), 2935 (s), 2860 (m), 1680 (s, C=O), 1520 (m), 1465 (m), 1380 (m), 1370 (m), 1250 (m), 1220 (m), 1155 (m), 1110 (s), 1070 (s), 1035 (s), 900 (m), 840 (s), 780 (s) cm-’. - ‘H NMR (400 MHz): 6 = 10.00 (d, J = 8.0 Hz, 1 H, 5”’-H), 7.05 (br. t, J = 5.9 Hz, IH, NH), 5.89 (dq, J = 7.9 and 1.2 Hz, IH, 4 - H ) , 4.72 (d, J = 9.1 Hz, 1 H, OCHZO), 4.70 (d, J = 9.1 Hz, 1 H, OCHzO), 4.25 (dt, J = 7.2 and 6.0 Hz, lH,5”-H),4.17(dd,J=5.6and4.5Hz,lH,2-H),4.03(ddd,J= 10.2, 5.8 and 3.4 Hz, 1 H, 4-H), 3.87 (m, 1 H, 2’-H), 3.58 (ddd, J = 14.0, 5.9 and 4.2 Hz, IH, 1’-H), 3.40 (s, 3H, MeOCH20), 3.33 (ddd, J = 14.0, 6.2 and 4.8 Hz, IH, l‘-H), 2.45 (ddd, J = 14.8, 10.2 and 4.8 Hz, I H , 2”‘-H), 2.24 (ddd, J = 14.8, 10.0 and 5.5 Hz, IH, 2”’-H), 2.18 [d, J = 1.3 Hz, 3H, Me- C(3”’)], 1.79-1.48 (m. 6H, 3-H, 3’-H and I”‘-H), 1.45-1.26 (m, 2H, 4-H), 1.41 [s, 3H, Me-C(2”)], 1.32 [s, 3H, Me-C(2”)], 0.93 (s, 9H, Me$), 0.91 (t. J = 7.3 Hz, 3H, 5-H), 0.10 (s, 3H, MeSi), 0.08 (s, 3H, MeSi). - I3C NMR (100 MHz): S = 191.0 [d, C(5”’)], 174.0 [s, C(l)], 163.0 [s, C(3”’)], 127.4 [d, C(4)], 107.9 [s, C(2”’)], 96.6 (t, OCHzO), 76.9 [d, C(4”)], 74.8 [d, C(2’)], 74.0 [d, C(4”)], 73.5 [d, C(2)], 55.7 (q, MeOCH,O), 42.7 [t. C(l‘)], 37.6 [t, C(3)], 37.1 [t, C(2”‘)], 33.4 [t, C(3‘)], 28.6 [q, Me-C(2”)], 27.8 [t, C(l”’)], 25.9 [q, Me- C(2”)], 25.8 (9, Me,C), 18.0 (s, Me3C), 17.7 [q, Me-C(3”’)], 17.5 [t, C(4)], 14.1 [q. C(5)], -4.8 (q, MeSi), -5.1 (4. MeSi). - MS (70 eV): mlz (%) = 529 (0.1) [M+’], 514 (6) [(M - Me)+], 498 (0.6), 472 (60), 440 (lo), 414 (3), 382 (6), 352 (4), 232 (19), 214 (8), 187 (70), 174 (8), 157 (9), 131 (9), 115 (13), 75 (34), 73 (85), 59 (24), 45 (100). - C27H51N07Si (529.8): calcd. C 61.21, H 9.70, N 2.64 found C 61.58, H 9.40, N 2.68.

(2 S, 2 ’ S, 4”s. 5”R,3”Z) -2-[ ( tert- Butyldimethylsilyl) oxy]-pentanoic Acid {3’- [2”,Z”-Dimethyl-5”- (3”’-methoxymethyM“-oxo-pent-3”-enyl)-[l~~,~]dioxolun- 4“-yl]-Z’-methosymethosy-propyl}-amide (2b): To an ice-cold solution of the alcohol 47b (0.60 g, 1.07 mmol) in DMF (10 ml) was added PDC (0.70 g, 1.86 mmol). The cooling bath was removed after 1 h and the reaction mixture stirred for 4 h at room temp. The dark brown solution was then poured into water (25 ml) and the aqueous layer extracted with EtzO (5 X 20 ml). The combined organic extracts were dried (MgSO,), filtered, and the filtrate was concentrated in vacuo. Purification by column chromatography (3 X 20 cm, Et20) furnished our target molecule, the aldehyde 2b (0.51 g, 85%) as a colorless oil, which was shown to be a 5.1 (a/(@ mixture by IH-NMR analysis and isomerize easily on standing in CDC13 to a 1 :2 (Z)l(E) mixture. - [a]BT = -22.7 (c = 1.32, CHCI,). - IR (film): 2 = 3430 (m, NH), 2955 (s), 2935 (s), 2885 (s), 2860 (s), 1680 (s, C=O), 1520 (s), 1465 (m), 1380 (m), 1370 (m), 1255 (m), 1220 (m), 1155 (m), 1115 (s), 1035 (s), 920 (w), 900 (m), 840 (s), 780 (s) cm-’. - ‘H NMR (500 MHz): 6 = 10.09 (d, J = 7.5 Hz, IH,S”’-H),7.05(br. t , J = 6.2Hz, I H , N H ) , 5 . 9 6 ( d t , J = 7.5and I . lHz ,

OCH,O), 4.37 [s, 2H, CHp-C(3”’)], 4.25 (dt, J = 7.5 and 5.8 Hz, 1 H, Y-H), 4 .17(dd ,J= 5.8and4.4Hz, IH,2-H),4,03(ddd,J= 10.3,5.8and3.4Hz, 1 H, 5’-H), 3.85 (m. 1 H, 2‘-H), 3.58 (ddd, J = 13.9, 5.9 and 4.2 Hz, 1 H, 1’- H), 3.40 (s, 3H, MeOCH20), 3.38 [s, 3H, MeOCH2-C(3“‘)], 3.31 (ddd, J = 13.9,6.2and4.9Hz, lH, I1-H),2.52(ddd,J= 14.2,10.4and4.9Hz, lH, 2 - H ) , 2.31 (ddd, J = 14.2, 10.0 and 6.2 Hz, l H , 2“‘-H), 1.74 (ddt, J = 13.7, 10.9 and 5.5 Hz, IH, 3-H), 1.68-1.60 (m, 2H, 3-H and I”’-H), 1.58-1.56 (m, 2H, 3‘-H), 1.54 (m, IH, I“‘-H), 1.46-1.27 (m, 2H, 4-H), 1.42 [s, 3H, Me-C(2”)], 1.32 [s, 3H, Me-C(2”)], 0.93 (s, 9H, Me,C), 0.90 (t, J = 7.4 Hz, 3H, 5-H), 0.10 (s, 3H, MeSi), 0.07 (s, 3H, MeSi). - 13C NMR (100 MHz): 6 = 190.3 [d, C(S)], 174.0 [s, C(l)], 161.0 [s, C(3”’)], 128.8 [d, C(4)], 108.0

73.5 [d, C(2)], 70.6 [t, CH2C(3“’)], 58.7 [q. MeCHz-C(3“‘)], 55.7 (9, MeOCH20), 42.7 [t. C(l’)], 37.5 [t, C(3)], 33.4 [t, C(3‘)], 32.3 [t, C(2’”)], 28.5 [q. Me-C(2”)], 28.2 [t, C(l”’)], 25.9 [q. Me-C(2”)], 25.7 (9, Me$), 18.0 (s, Me3C), 17.5 [t. C(4)], 14.1 [q. C(S)], -4.8 (9, MeSi), -5.1 (q, MeSi). - MS (70 eV): mlz (“h) = 558 (2) [(M - I)+], 544 (1.7) [(M - Me)+], 516 (16), 502 (12) [(M - tBu)+], 500 (14), 486 (7), 468 (S), 458 (4), 426 (4), 412 (4), 396 (3), 384 (3), 304 (5) , 289 (3), 272 (4), 232 (22), 216 (7), 214 (9), 187 (IOO), 174 (17), 157 (15), 147 (17), 131 (17), 115 (20), 75 (46), 73 (82), 45 (68). - C2sHS3NO8Si (559.8): calcd. C 60.07, H 9.54, N 2.50; found C 60.14, H 9.38, N 2.54.

IH, 4”’-H), 4.71 (d, J = 6.7 Hz, l H , OCHpO), 4.69 (d, J = 6.7 Hz, IH,

[s, C(2“‘)], 96.6 (t, OCHZO), 76.9 [d, C(S’)], 74.9 [d, C(2’)], 74.0 [d, C(4”)],

* This series of papers is dedicated to Prof. E. .I Corey (Harvard University) on the occasion of his 65th birthday. This is part 1 of a series of three papers describing the synthesis of myxovirescins Al and M2. For part 2 and 3, see the accompanying papers.

L2] Postdoctoral fellow at ETH Zurich (1990- 1991), with a stipend from the Ministerio de Educacion y Ciencias (Spain). Present address: Departamento de Quimica Fundamental e Industrial,


716 D. Seebach, M. A. Maestro, M. Seflcow, G. Adam, S. Hintermann, A. Neidlein

Facultade de Ciencias, Universidade da Corufia, E-15071 A Co- rufia (Spain).

131 Part of the dissertation (No. 10745) of M. S., ETH Zurich (1994). M. S. was recipient of a Kekule-Stipendium des Fond des Verbandes der Chemischen Industrie (Germany),

L41 Part of the dissertation (No. 8867) of G. A., ETH Zurich (1989). G. A. was recipent of a VCI-Stipendium des Verbandes der Chemischen Industrie (Germany), 1986- 1988.

151 Part of the Diplomarbeit of S. H., ETH Zurich (1992). L6] Part of the dissertation (No. 9477) of A. N., ETH Zurich

(1991). A. N. was recipient of a VCI-Stipendium des Verbandes der Chemischen Industrie (Germany), 1988- 1990.

r71 D. Seebach, Angew. Chem. Int. Ed. Engl. 1990,29, 1320-1367; Angew Chem. 1990, 102, 1363-1409. D. Seebach, G. Adam, R. Zibuck, W. Simon, M. Rouilly, W. L. Meyer, J. F. Hinton, T. A. Privett, G. E. Templeton, D. K. Heiny, U. Gisi, H. Binder, Liebigs Ann. Chem. 1989,

r91 Pyrenophorin, Vermiculin, Grahamimycin, Colletodiol, Con- globatin and Elaiophyliden; see the table in Scheme 1 in - [ya] D. Seebach, H.-F. Chow, R. F. W. Jackson, M. A. Sutter, S. Thaisrivongs, J. Zimmermann, Liebigs Ann. Chem. 1986, 1281-1308. - [9b1 C. Schregenberger, D. Seebach, Liebigs Ann. Ciiem. 1986, 2081 -2103. - LSc] P. Schnurrenberger, E. Hunger- buhler, D. Seebach, Liebigs Ann. Chem. 1987, 733-144.

[ lo ] Preliminary communication of the total synthesis of Myxovires- cin M7: D. Seebach, M. A. Maestro, M. Sefkow, A. Neidlein, F. Sternfeld, G. Adam, T. Sommerfeld, Helv. Chim. Acta 1991,

[ I 1 ] W. Trowitzsch-Kienast, K. Schober, V. Wray, K. Gerth, H. Rei- chenbach, G. Hofle, Liebigs Ann. Chem. 1989, 345-355.

[’‘I Many years ago we have proposed the term “chiral pool synthesis” for this approach (D. Seebach, H.-0. Kalinowski, Nachr. Chem. Techn. Lab. 1976,24, 415-418). Under the influence of Prof. V. Prelog who pointed out that pools are not normally chiral, we, but not others, have subsequently abandoned this term from our language and use “pool of chiral building blocks” instead.

[I3] To the best of our knowledge there is only one ublished total synthesis of a Myxovirescin besides our Myxovirescin B: D. R. Williams, J. M. McGill, J Org. Chem. 1990, 55, 3457 - 3459 (preliminary communication).

[I4] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. SOC. Jpn. 1979,52, 1989-1993.

[I5 ] E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1989.

[I6] D. Seebach, R. Naef, G. Calderari, Tetrahedron 1984, 40,

[I7] D. Seebach, P. Renaud, Helv. Chim. Acta 1985,68,2342-2349. [I8] T. W. Grecne, P. G. M. Wuts, Protective Groups in Organic Syn-

thesis, 2nd ed., John Wiley & Sons, New York, 1991. [I9] As with the 2-(hydroxymethyl)-l,3-dithiane (H. Paulsen, K. Ro-

den, V. Sinnwell, P. Luger, Liebigs Ann. Chem. 1981, 2009-2027) we hoped to be able to doubly lithiate 19 for cre- ating the C(6)-C(7) bond of the target molecules. Unfortuna- tely, the corresponding experiments failed. Also, the amide 20 (from 14 and 19) could be doubly lithiated but again failed to be alkylated with formation of this C(6)-C(7) bond. For review articles on the use of 1,3-dithianes in synthesis see: B.-T. Gro- bel, D. Seebach, Synthesis 1977, 357-402, P. C. Bulman Page, M. B. van Niel, J. C. Prodger, Tetrahedron 1989,45,7643-7677. For a previous preparation of 19 see: H. Hamberger, P. Stutz, G. Schulz, Tetrahedron Lett. 1977, 3623- 3624.

[lo] For a list of references about the use of D-ribonolactone as a chiral building block see: Aldrichim. Acta 1989,22,49 and references cited therein. We thank Prof. S. Hanessian (University of Montreal) for providing us with an excellent procedure for the conversion of D- ribose to D-ribonolactone (>go% yield). V. Jager, B. Hafele, Synthesis 1987, 801 -806.

[131 Replacement of OH by Br and I are also possible but the resulting alkylating agents could not be successfully employed in the dithiane coupling step. Furthermore, we knew from our previous work with tartaric acid-derived alkylating agents that their reactions are very sluggish[9c].

[l4] Attempts to develop a simple route from tartaric acid to compounds of type 5, 21 and 22 have, so far, been futile in spite of hard efforts. For an approach to a non-racemic meso-tartaric

1990-1992.

1233 - 1240.

74, 21 12-2118.

1313-1324.

acid derivative, see: H. J. Bestmann, U. C. Philipp, Angew. Chem. Int. Ed. Engl. 1991, 30, 86-87; Angew. Chem. 1991, 103, 78-79.

[251 E. J. Corey, M. G. Bock, A. P. Kozikowski, A. V. Rama Rao, D. Floyd, B. Lipshutz, Tetrahedron Lett. 1978, 1051- 1054.

[26] [26a] A. W. Johnson, J Chem. SOC. 1946, 68, 1014-1017; F! F. Schuda, M. R. Heimann, .I Org. Chem. 1982, 42, 2484-2487. - [26b] H. Bader, H. Hopf, K. Sieper, Chem. Ber. 1989, 122, 383-384.

[271 The etherification was performed either with Meerwein’s salt ( M e 3 0 + B F ~ ) or with MeI/NaH; the latter reagent producing a mixture of the dibromide 26 and the bromo-iodo compound 26, X = I instead of Br (by nucleophilic replacement of Br- by the in situ formed I-). In fact, the most efficient method for changing from 26 to 27 is in situ replacement of Br by I and replacement of I by 4-MeOPhCH20 (addition of 26 to a mixture prepared from NaI, 4-MeOPhCH20H, BuLi in THF/ DMPU at -20°C). The substitution is tricky because of compe- tin HBr elimination.

55, 1857-1867; H. Miyake, K. Yamamura, Chem. Lett. 1989, 981 -984. - LZxb] Silyl-protected derivatives of 28 (for example 29) have been described and characterized previously: A. G. M. Barrett, T. E. Barta, J. A. Flygare, J Org. Chem. 1989, 54, 4246-4249. - [28c] For the Sn/Br retentive displacement see: S.-M. L. Chen, R. E. Schaub, C. V. Grudzinskas, J Org. Chem. 1978, 43, 3450-3454 and references cited therein.

[291 H. Neumann, D. Seebach, Tetrahedron Lett. 1976, 17, 4839-4842; H. Neumann, D. Seebach, Chem. Ber. 1978, 111,

L3O] W. F. Bailey, E. R. Punzalan, J Org. Chem. 1990, 55,

L3l1 T. Imamoto, Pure Appl. Chem. 1990, 62, 747-752. [321 D. H. R. Barton. J. Cs. Jaszberenvi. Tetrahedron Lett. 1989.

[28a Q H. X. Zhang, F. Guibe, G. Balavoine, J Org. Chem. 1990,

2785-28 12.

5404- 5406.

, , 30, 2619-2622.

[331 N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, A. Suzuki. J Am. Chem. SOC. 1989, 111, 314-321.

[34] The best yield with which we were able to couple 36 (OH instead of OTBDMS) via the triflate (OTf instead of OTBDMS in 36) with a lithium dithiane was ca. 10%.

[351 The triflate 5 was prepared immediately before use (P. J. Stang, M. Hanack, L. R. Subramanian, Synthesis 1982, 85-126) and characterized by NMR spectroscopy. The alkylation of 4 by 5 was more successful in the presence of DMPU than of HMPA (72% vs. 550/0). Normally, replacement of the mutagenic HMPA by DMPU[35a1 gives somewhat lower ields A similar observa- tion has been made by other authors[Ysb]. [35a1 T. Mukhopad- hyay, D. Seebach, Helv. Chim. Acta 1982, 65, 385-391. - [35b1 H. Kotsuki, I. Kadota, M. Ochi, Tetrahedron Lett. 1990, 31,

[361 0. Mitsunobu, Synthesis 1981, 1-28. [371 The hydrolysis of the primarily formed benzoate was delicate:

to avoid cyclization to an oxazolidinone, the reaction time had to be kept as short as possible under the conditions specified.

[381 We assume that it was the a anomer. [391 Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (BOP chlo-

ride): J. Cabre, A. L. Palomo, Synthesis 1984, 413-417. L4”1 S. Hunig, M. Kiessel, Chem. Ber. 1958, 91, 380-392. c4I1 The carbamate cleavage requires several days of heating under

reflux in MeOH/H20/KOH. [421 The conditions applied were also as follows: H2, 5% Pd/C; H2,

10% PdlC; HZ, 5% PtlC; 1,4-cyclohexadiene 5% Pd/C (hydrogen transfer); homogeneous catalysts.

[431 M. Julia, Pure Appl. Chem. 1985, 57, 763-768; M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 4833 -4836. W. C. Still, M. Kahn, A. Mitra, J Org. Chem. 1978, 43, 2923-2925.

[451 M.-J. Kim, G. M. Whitesides, J Am. Chem. SOC. 1988, 110, 2959-2964.

[461 D. Bur, M. A. Luyten, H. Wynn, L. R. Provencher, J. B. Jones, M. Gold, J. D. Friesen, A. R. Clarke, J. J. Holbrook, Can. J Chem. 1989, 67, 1065-1070.

[471 H. C. Brown, G. G. Pai, J Org Chem. 1985, 50, 1384-1394. [481 The amine derived from 42a is (2S,4’S,5’R,3”E)-3- (2’,2’-Di-

methyl-5’-[5”- (4-methoxy-benzyloxy) -3”-methyl-pent-Y-enyl]- [ 1 ‘,3‘]dioxolan-4’-yl}-2-methoxymethoxy-propylamine. For the purpose of collecting analytical data, a small amount of the crude product was purified by column chromatography [66?4 EtOAcl MeOH, Rf (66% EtOAc/MeOH) = 0.361. - [a]BT = f4.1 (c = 3.30,

4609-461 2.



CHCI,). ~ IR (film): 0 = 3385 (br., NH2), 2975 (s), 2930 (s), 2850 (s), 1610 (m), 1510 (s), 1450 (m), 1380 (m), 1370 (m), 1245 (s), 1035 (s), 820 (m) cm-’. - ‘H NMR (400 MHz): 6 = 7.27 and 6.88 (AA’XX’ system, J = 8.8 Hz, 4H, H,,,), 5.41 (td, J = 6.7 and 1.3 Hz, IH, 4’-H), 4.72 (s, 2H, OCHzO), 4.43 (s, 2H, Hbnzylic), 4.22 (ddd, J = 8.2, 5.7 and 5.3 Hz, 1 H, 4‘-H), 4.04 (ddd, J = 9.6, 5.7 and 4.0 Hz, 1 H, 5’-H), 3.99 (d, J = 6.6 Hz, 2H, Y-H), 3.80 (s, 3H, MeOPh), 3.76 (m. 1 H, 2-H), 3.41 (s, 3H, MeOCHZO), 2.94 (dd, J = 13.5 and 3.9 Hz, 1 H, I-H), 2.75 (dd, J = 13.5 and 5.7 Hz, IH, I-H), 2.25 (ddd, J = 14.1, 11.0 and 5.2 Hz, I H , 2”-H), 2.17 (br. s, 2H, NH2). 2.04 (ddd, J = 14.1, 10.4 and 5.9 Hz, I H , 2”-H), 1.67-1.48 (m, 4H, 3-H and 1”-H), 1.65 [s, 3H, Me-C(3”)], 1.42 [s, 3H, Me-C(2’)], 1.32 [s, 3H, Me-C(2‘)]. - I3C NMR (100 MHz): 6 = 159.2 (s, C,,,), 139.6 [s, C(3”)], 130.6 (s, C,,,), 129.4 (d, C,,,),

[d, C(5’) and C(2)], 74.3 [d, C(4’)], 71.8 (t, Cbenzylic), 66.3 [t. C(S’)], 55.7 (q, MeOCH20), 55.3 (4. MeOPh), 46.2 [t, C(l)], 35.9 [t, C(2”)], 33.2 [t, C(3)], 28.6 [q, Me-C(2’)], 28.2 [t, C(l”)], 26.0 [q. Me-C(2’)], 16.7 [q. Me- C(3”)I. - MS (70 eV): m/z (%) = 438 (1.4) [(M + I)+], 422 (3) [(M ~

Me)’], 406 (0.6), 316 (0.7), 301 (9), 284 (l.O), 258 (IS), 242 (l.O), 226

C24H39N06 (437.6): calcd. C 65.88, H 8.98, N 3.20; found C 65.42, H 8.96, N 3.18.

[491 The amine derived from 42b is (2S,4‘S,5‘R,YZ)-3-(2’,2’-Di- methyl-5’-[5”- (4”‘-methoxy-benzyloxy) -3”-methoxymethyl-pent- 3”-enyl]-[l’,3’]dioxolan-4’-yl)-2-methoxymethoxy-propylamine. ‘H NMR (300 MHz): 6 = 7.27 and 6.88 (AA‘XX‘ system, J = 8.7 Hz, 4H, H,,,), 5.62 (t, J = 6.6 Hz, 1 H, 4”-H), 4.73 (s, 2H, OCH20), 4.44 (s, 2H, Hbenzylic), 4.23 (ddd, J = 7.9, 5.7 and 5.4 Hz, 1 H, 4’-H), 4.06 (ddd, J = 9.6, 5.7 and 3.9 Hz, IH, 5’-H), 4.06 (d, J = 6.6 H, 2H, 5“- H), 3.91 [s, 2H, CH,-C(3”)], 3.80 (s, 3H, MeOPh), 3.73 (m, 1 H, 2-H), 3.41 (s, 3H, MeOCH,O), 3.26 [s, 3H, MeOCHz-C(3“)], 2.90 (dd, J = 13.5 and 4.0 Hz, 1 H, I-H), 2.73 (dd, J = 13.6 and 5.3 Hz, 1 H, I-H), 2.35 (ddd, J = 14.2, 10.5 and 5.2 Hz, I H , 2”-H), 2.13 (ddd, J = 14.2, 10.4 and 6.2 Hz, l H , 2”-H), 1.69-1.49 (m, 2H, I”-H), 1.63-1.57 (m, 2H, 3-H), 1.45 (br. s, 2H, NHJ, 1.42 [s, 3H, Me-C(2”)], 1.33 [s, 3H,

121.2 [d, C(4”)], 113.8 (d, Car,.,,), 107.6 [s, C(2’)], 96.8 (t, OCHZO), 77.5

(1.2), 213 (1.8), 196 (0.9), 174 (8), 167 (2), 138 (4), 137 (4), 121 (100). -

Me-C(2’)]. - 13C NMR (75 MHz): 6 = 159.2 (s, C,,,), 139.7 [s, C(3”)], 130.3 (s, C,,,), 129.4 (d, C,,,), 125.6 [d, C(4”)], 113.8 (d, C,,,,), 107.6 [s, C(2’)], 96.7 (t, OCHZO), 77.8 [d, C(2)], 77.5 [d, C(5’)], 74.4 [d, C(4’)], 71.9 (t, Cbenzylic), 69.9 [t, mz-c(3”)], 65.6 [t, c(5”)], 57.9 [q, MeOCH2- C(3”)], 55.6 (q, MeOCH20), 55.2 (9. MeOPh), 46.4 [t. C(l)], 33.0 [t. C(3)], 31.6 [t. C(2”)], 28.6 [q. Me-C(2’)], 28.3 [t, C(l”)], 26.0 [q, Me- C(2’)I. The amine derived from 43 is (2S4’S5’R,3“E)-3-[5’-(5“-Ben- zyloxy-3”-methyl-pent-Y-enyl) -2’,2’-dimethyl-[l’,3’]dioxolan-4’- yl]-2-methoxymethoxy-propylamine. ‘H NMR (200 MHz): 6 = 7.36-7.28 (m. 5H, H,,,,), 5.42 (td, J = 6.7 and 1.2 Hz, 1 H, 4‘-H), 4.72 (s, 2H, OCHzO), 4.50 (s, 2H, Hbenrylic), 4.23 (ddd, J = 8.5, 5.5 and 5.0 Hz, 1 H, 4’-H), 4.04 (m, 1 H, 5’-H), 4.02 (d, J = 6.6 Hz, 2H, 5”-H), 3.73 (m. 1 H, 2-H), 3.40 (s, 3H, s, MeOCHzO), 2.89 (dd, J = 13.5 and 4.1 Hz, 1 H, I-H), 2.72 (dd, J = 13.5 and 5.3 Hz, 1 H, I-H), 2.26 (ddd, J = 14.1, 10.4 and 5.4 Hz, 1 H, 2”-H), 2.03 (ddd, J = 14.1, 10.0 and 6.2 Hz, 1 H, 2”-H), 1.65 [s, 3H, Me-C(3”)], 1.72-1.47 (m, 4H, 3-H and 1”-H), 1.41 [s, 3H, Me-C(2‘)], 1.36 (br. s, 2H, NHz), 1.32 [s, 3H, Me-C(2’)]. - I3C NMR (50 MHz): 6 = 139.9 [s, C(3”)], 138.3 (s, C,,,), 128.4 (d, C,,,), 127.9 (d, C,,,), 127.7 (d, C,,,,), 121.1 [d, C(4”)], 107.7 [s, C(2’)], 96.8 (t. OCH,O), 78.1 [d, C(5‘)], 77.8 [d, C(2)], 74.2 [d, c(4’)], 71.9 (t. Cbenrylic), 66.4 [t, c(5”)], 55.4 (q, MeOCH20), 46.2 [t, C(l)], 35.6 [t. C(2”)], 32.8 [t. C(l”)], 28.3 [q, Me-C(2’)], 27.9 [t, C(l”)], 25.7 [q, Me-C(2‘)], 16.4 [q, Me-C(3”)].

I5l] Further details of the crystal structure investigations are available on request from the Fachinformationszentrum Karlsruhe, Gesellschaft fur wissenschaftlich-technische Information mbH, D-76344 Eggenstein-Leopoldshafen, on quoting the depository number CSD-58310, the names of the authors and the journal citation.

~~1 G. M. Sheldrick, SHELXTL-PLUS 88 Structure Determination Software Programs, Nicolet Instruments Corp., Madison, WI, 1989.

[531 SHELXL-92 (betdgamma release), G. M. Sheldrick, Current Contents (Physical Chemical and Earth Sciences), 1989, 29, 14.

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