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D. Seebach, T. Vettiger, H.-M. Muller, D. A. Plattner, W. Petter 687

Stereoselective Hydroxyalkylations of (S)-2-Azetidinecarboxylic Acid Dieter Seebach"", Thomas Vettiger')", Hans-Martin Miiller*)", Dietmar A. Plattner", and Walter Petterb

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

Institut fur Kristallographie und Petrographie der Eidgenossischen Technischen Hochschule, ETH-Zentrumb, SonneggstraBe 5, CH-8092 Zurich (Switzerland)

Received March 23, 1990

Key Words: a-Alkylation of amino acids / Self-regeneration of stereogenic centers / Oxazolidinones from amino acids and pivalaldehyde / Azetidine-derived (R,R)-a-amino-P-hydroxy carboxylic acid, X-ray crystal structure of

~~~

The enolate generated from S-phenyl (S)-l-benzyl-2-azetidinecarbothioate is converted into racemic products 2 by treatment with electrophiles. The bicyclic oxazolidinone derivative 12 has been prepared from trimethylsilyl (S)-1-(trimethylsily1)- 2-azetidinecarboxylate (1 1) and pivalaldehyde without racemization. Addition of 12 to aldehydes and hydrolysis gives the products 13a- h. The structure of the adduct 13h from 4-pyridinecarbaldehyde was determined by X-ray crystal structure

analysis, proving that the trigonal centers of the bicyclic enolate and of the aldehyde have combined with relative topicity unlike. Thus, the reaction resembles that of the homologous proline derivative described previously, and the novel products are formally D-allo-threonines with an ethylene bridge between the nitrogen and the adjacent carbon atoms (Scheme 4) and with absolute configuration R,R. The mecha- nism of the C - C bond-forming reaction is discussed.

Introduction - the Problem and the Goal In the course of our work on a-alkylations of amino and

hydroxy acids with self-regeneration of the stereogenic cen- ter3,4), we have also studied cyclic amino acids, see derivatives 1-4 in Scheme 1. Aziridinecarboxylic acid can be alkylated by direct enolization of the l-benzyl phenylthio ester and reactions with electrophiles (products l), with the nitrogen in the three-membered ring acting as a stereogenic center which is configurationally stable under the low-temperature reaction conditions '). Our first attempts with azetidinecarboxylic acid go back to the beginning of our in- vestigations in this area6x7): We have not been able to prepare the acetal 3 (R = H) from the parent amino acid without racemization. Afterwards, we have also prepared the l-benzyl thioester 2 (R = H), to find that enolates can be gen-

Scheme 1. Reagents and intermediates for the preparation of cl-alkylated cyclic amino acids

erated and combined with electrophiles in high yields, but with the formation of racemic products", for instance 2, RE = D (see Experimental). The alkylation of proline with retention*) of configuration proceeds readily7x9) via the bicyclic acetal 4. Since the higher homologous cyclic amino acids are not as readily available for alkylations, we have prepared their a-alkyl derivatives 6 from the imidazolidinone 5 [(R)- or (S)-Boc-BMI]"), an alkyl halide, and a 1,n- dihaloalkane, a method which is also applicable to the synthesis of azetidinecarboxylic acid and proline derivatives").

Scheme 2. (S)-2-Azetidinecarboxylic acid and natural products containing this amino acid moiety

R = (CH&OH (Medimnine) r N--R R = (CH2)2CH(NH2)C02H ")

7 8

/COSPh N RE e C O S P h N RE a: y Ph Ph

1 2 3

4 ' 5 6 (n=O,1,2)

X = NHz, Y = H (Mugineic acid)") X = Y = OH (Ni~tianarnine)'~) po/yoxin A) ''1

R = nucleosidic substituent

Thus, there has remained the task to find a way of al- kylating 2-azetidinecarboxylic acid in the position 2 without racemization. The acid 7 itself"") is commercially available; it is isolated from hydrolysates of natural plant protein materials lZb). Its biosynthesis has been shown to start from methi~nine'~'. and it acts as an "anti-rnetab~lite"'~) of

Liebigs Ann. Chem. 1990, 687 - 695 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1990 0170-2041/90/0707 -0687 $03.50+25/0

688

13

R yield [“/4 ds [“lo]

D. Seebach, T. Vettiger, H.-M. Muller, D. A. Plattner, W. Petter

a b C d e f 9 h

CHs C6H5 4-C6H&& 4-((CH&N)CsH4 3,4,5(CH30)3CsH2 2-pyridyl 3-pyridyl 4-pyridyl 15 39 25 17 28 18 19 21 60 >96 >96 >96 >96 >96 >96 >96

pr~l ine’~) . The azetidinecarboxylic acid moiety may be in- corporated into peptides or be part of interesting natural products (see 8- 10 in Scheme 2)”-”), some of which seem to be involved in iron transport processes of certain plants21). Finally, it is worth mentioning here that N,N-diethyl-1 -hydroxy-2-methyl-3-phenyl-2-azetidinecarboxamide has been oxidized to the corresponding p-lactam**). Syntheses of enantiomerically pure 2-azetidinecarboxylic acid involving a resolution or a series of tiansformations starting from homo- serine have been described 23).

Preparation of the Bicyclic Acetal 12 and Its Use for Hy- droxyalkylations of Azetidinecarboxylic Acid (Products 13)

In view of the interesting properties of 2-azetidinecarboxylic acid, we have searched for a nonracemic enolate which

Scheme 3. Preparation of the nonracemic acetal 12 from (S)-2- azetidinecarboxylic acid (7) and pivalaldehyde

g c ~ ~ ~ i ~ e 3 ‘BUCHO &J3 - ‘SiMe, CHpCI2 ’ Y m 1 1 0°C

TMSOTf 11

solvent temp. time ee /yield rc1 [hl W O I

CH2C12 -78-+20 12 0 178

CH2C12 -20--25 3.5 65 CHzCl2 ‘ -20--25 1 72 CHpC12 4 5 - 4 0 15 59 CHzCl2 4 0 - 4 4 96.5/92

pentane 0 1 32

CH2C12 c -50 - noreaction

Scheme 4. Hydroxyalkylations of the bicyclic acetall2 by aldehydes

LiNR;!

THF 1 2 -

-78’

I

would allow to synthesize novel derivatives of this unusual amino acid.

Since neither direct a~etalization~,~,~) with an aldehyde nor transacetalization”) have been successful with the acid 7, we have chosen the “silyl route”, replacing all protons involved by trimethylsilyl groups (Scheme 3): the amino acid was heated at 110 “C with neat N,N-diethyltrimethylsilylamine (Ruhlmann reagent)25) to give the distillable disilyl derivative 11. No racemization takes place under these conditions, as judged from the recovery of optically pure 7 upon hydrolysis of 11, which can be stored for longer peroids of time at room temperature with the exclusion of moisture.

The silylation 7-11 is strongly accelerated by ammonium sulfate”), but the product obtained is a racemic mixture. Treatment of a solution containing the disilyl compound 11 and pivalaldehyde in dichloromethane with 5 - 10 mol% trimethylsilyl trifluoromethanesulfonate (TMS triflate; Noyori acetalizaton)26-2s) at low temperatures gives rise to the desired acetal 12. The degree of racemization in this step depends crucially upon the reaction time and temperature. The process can be followed by NMR spectroscopy, which reveals that no conversion takes place below - 50°C; on the other hand, partially or totally racemic sam- ples are obtained when the temperature has risen above -40°C or when the reaction mixture is stored too long (see the data in Scheme 3). It is also important to quench the reaction mixture, i.e. hydrolytically destroy the catalyst (with exactly 1 equivalent of H20)28) at low temperature. Under optimum conditions, the bicyclic acetal 12 is isolated (by nonaqueous workup) in over 90% yield and with better than 96% enantiomeric excess (ee). The degree of racemization has been determined by hydrolysis of 12 to the amino acid 7 and measurement of the optical activity: The acetal

A B

R 13

x A’

Liebigs Ann. Chem. 1990, 687 - 695

Stereoselective Hydroxyalkylations of (S)-2-Azetidinecarboxylic Acid 689

12 is extremely sensitive to moisture and rapidly cleaved on contact with air. It can be employed for the subsequent reacton without purification, but we have also succeeded in recrystallizing it from pentane at - 30 “C. The acetalization is totally selective: only one diastereoisomer is detected by 300-MHz ’H-NMR spectroscopy. Measurement of the nu- clear Overhauser effect (NOE) clearly proves the exo position of the tert-butyl group on the bicyclo[3.2.0]heptane skel- eton: irradiation with the frequency of the C(CH3)3 protons increases the intensity of the bridgehead hydrogen 5-H. Thus, we assign the (2R,5S) configuration2’) to compound 12.

We are convinced that other readily racemizing amino acid derivatives can be safely converted as well under the conditions described here for the azetidine 7.

The enolate A of the oxazolidinone 12 was generated by treatment with lithium diisopropylamide (LDA) or - pre- ferably3’) - with lithium 2,2,6,6-tetramethylpiperidide (LTMP) in tetrahydrofuran (THF) at dry-ice temperature. When the orange-yellow solution containing A is quenched with deuterioacetic acid, followed by aqueous workup, 2- deuterio-2-azetidinecarboxylic acid is isolated (50 - 60% deuterium incorporation 31), same sign and degree of specific optical rotation 32) as the starting material employed for the preparation of 12). Of the other electrophiles used with the enolate of 12, only aldehydes give satisfactory yields of product~~’) (Scheme 4). The addition of acetaldehyde to 12 yield- ing 13 a is not diastereoselective, while single amino hydroxy acids 13b-h are formed (detected by ‘H-NMR analysis of crude product mixtures) with aromatic and heteroaromatic aldehydes, albeit in modest yields ranging from 15 to 40%. In no case has a bicyclic primary adduct survived the aqueous workup procedure!

We interpret the low yields and the lack of product formation with other, less reactive electrophiles as a conse- quence of the instability of the enolate A. The strain present in the precursor 12 and in the bicyclic adducts B is evident from their facile cleavage to the free amino acids on contact with water (release of strain in the tetrahedral intermediate; the homologous proline7), and hydroxy proline derivati- v e ~ ~ ~ , ~ ~ ) are significantly more stable and so are the monocyclic analog^^,^^-'*)). Upon enolization (12+A), the strain will yet increase, due to the generation of an additional trigonal center, at the bridgehead position between a four- and a five-membered ring39). We are, in fact, convincedm)

02 01

H3

that the bridgehead carbon of A is strongly pyramidalized as indicated in the formula A’.

In Scheme 4 the configuration of the amino hydroxy acids 13 is drawn as being (R,R) - how do we know? In the next section we describe the X-ray structure of the 4-pyridyl derivative 13h which proves beyond doubt that its configuration is like (1). Since this product is optically active (we are sure that our laevorotatory analytical sample is, indeed, enantiomerically pure), it must display either (R,R) or (S ,S) configuration. In the first case, the aldehyde would have approached the enolate trigonal center from the Re face, i.e. from the exo face of the supposedly non planar bicyclic ~ y s t e m ~ , ~ ~ ) , cis to the tert-butyl group (see B’ and C). In the second case, it would have attacked from the Si face, trans to the tert-butyl group, with inversion of configuration on nitrogen which would have placed the tert-butyl group into an endo position. We favor the first possibility for the following reasons: (i) Protonaton of A also takes place from the Re face as shown above; (ii) the corresponding reaction of the homologous enolate derived from (S)-proline also oc- curs with approach of benzaldehyde from the Re face, as demonstrated by crystal structure analysis of the intact bicyclic adduct 7342). Thus, we assign the (R,R) configuration to the product 13h and, by analogy, to all compounds obtained with aromatic aldehydes. They all have comparable NMR spectra (in D20, in most cases with a drop of CF3C02D): the signal of the carbinol CH proton is a characteristic sin- glet between 6 = 5.2 and 5.6. All compounds 13 are laevorotatory (in H 2 0 or aqueous HCl).

The amino hydroxy carboxylic acids 13b-h could be viewed as arylserines with an ethylene bridge between nitrogen and the adjacent carbon atom, and with D-do-threonine-type config~ration~~) (see Fischer projection in Sche- me 4).

X-ray Crystal Structure of the Hydrate of 13 h Data collection and structural analysis. A crystal structure analysis

of 13h was undertaken in order to determine the (relative) configuration. Crystals were obtained by recrystallization of the crude product from a ca. 1 : l mixture of water and acetone at 4°C (ex- cluison of light). Although the compound crystallized as slightly yellow, very thin plates, it was possible to find a somewhat thicker specimen, which was carefully cut into the appropriate size (0.4 x 0.4 x 0.2 mm) for the measurement and transferred into a 0.5-mm diameter glass capillary tube. Determination of the cell parameters

0 2 01

A H 3 1 g’

Figure 1. Stereo ORTEP45) plot of 13h with thermal ellipsoids corresponding to 50% probability (the crystal water has been omitted)


690 D. Seebach, T. Vettiger, H.-M. Muller, D. A. Plattner, W. Petter

C

C

Figure 2. Stereo view of the molecular packing46) of compound 13h . H 2 0

by least square refinement of 18 reflections (20 I 20 I 26", con- straints CL = y = 90") and collection of the reflection intensities were performed on a SYNTEX P2, single-crystal diffractometer (MoK, radiation, graphite monochromatized): monoclinic, space group P21; a = 6.141(1) A, b = 6.675(2) A, c = 13.194(3) A; p = 96.35(2)"; V = 537.5 A3; Z = 2; D, = 1.398 g cmp3. In the range of 3 5 20 5 60" (20 mode) 1710 unique reflections were collected at room temperature (scaled at 3 periodically measured standard reflections), complete number of reflections measured: 1839, of which 1581 with 18'1 2 24.F) were used for the determination and refinement of the structure. The E-value statistics proved that the space group was acentric. The solution of the structure was carried out with direct methods@); the non-hydrogen-atom positions thus determined were refined, first with isotropic temperature parame-

Table 1. Atomic coordinates and temperature parameters of 13h (standard deviatives in parentheses)

Atom x/a Y /b z /b U

c1 c10 c2 c3 c4 c5 C6 c7 C8 c9 N1 N2 01 02 03 04 H03 H10 H11 H12 H21 H22 H31 H32 H41 H42 H5 H7 H8 H9

.3345 (4)

.0518(4)

.3428 (5)

.1702 (5)

.5295(4)

.2922 (4)

.2516(4)

.4187 (5)

.3812 (5)

.0313 (5)

.1344 (4)

.1914 (4)

.7047 (3)

.4960(3)

.1128 (4)

.1220 (4)

.035(7) -.067 (5) .005 (5) .140 (6) .484 (7) .290 (6) .220 (6) .026(7) .132 (5) .254 (6) .435(4) .545 (5) .493(6)

-.114(6)

-.0216(6) -0844 (7) -. 0279 (7) -. 1930 (7)

-.1336(6) .1801(*) .1499(6) .1839 (7) .1452 (7) .0488(7) -. 1573 (6) .0774 (6)

-.0381(6) -. 3036 (6) .2677 (6) .0335(6) .341(7) .069 (6) -. 100 (5)

-.288 (8) -.060 (5) .082 (7)

-.343 (7) -.166 (7) .047 (7) .078 (7) .269 (4) .247 (5) .182 (7) .010 (6)

.8580(2)

.6419 (2)

.9761(2)

.9644 (2)

.8206 (2) -8044 (2) .6902 (2) -6290 (2) .5259(2) -5384 (2) .8508 (2) -4797 (2) .8338(2) .7843(2) .8464 (2) .2674 (2) .806 (3) -680 (2) .834 (2) -805 (3)

1.013(3) 1.000 (3) .981(3) .993 (3) .322 (3) -254 (3) .817 (2) .657 (2) .480 (3) .503 (3)

.016 (1)

.026 (1)

.032 (1)

.035(2)

.021(1)

.024 (1)

.026 (1)

.026 (1)

.041(2)

.039(1)

.017 (1)

.054 (2)

.0170 (9)

.037 (1)

.043(1)

.045 (1)

.07 (1)

.041(8) -038 (9) .10(2) .046 (9) .05(1) .08(1) .07 (1) .03(1) .08(1) -031 (7) .028 (8) .06(1) .06(1)

ters, then with anisotropic ones. From the differential Fourier syntheses all hydrogen-atom positions were obtained. The anisotropic refinement converged finally (isotropic hydrogen atoms) at R = 0.041 (R, = 0.039, w = l/oz~Fo~ + 0.001 IF,)2, number of variables: 200). The calculations were carried out on a MicroVAX 2.

Discussion of the structure. To our knowledge46), this is the first X-ray structure analysis of a 2-azetidinecarboxylic

Table 2. Bond lengths (in Angstrom) of 13h (standard deviations in parentheses)

c 1 -c2 1.553(4) c 1 -c5 1.529(4) c io -c6 1.389(4j C2 - C3 1.525(5) C4-01 1.246(4) C5 - C6 1.513(4) C6-C7 1.393(3) C8 - N2 1.3344)

C1 -C4 1.538(4) C1 -N1 1.522(3) CIO-c9 i.378(4)

1.5 1 O(4) C4 - 0 2 1.240(4) '25-03 1.413(3) C7-C8 1.379(4) C9-N2 1.331(4)

C3-N1

Table 3. Bond angles (in degree) of 13h (standard deviations in parentheses)

C1 -C2-C3 88.5(2) C1 -C4-01 113.4(3) Cl-C4-02 117.8(2) CI-C5-C6 110.1(2) C1 -C5-03 106.4(2) C1 -N1 -C3 90.2(2) C2-C1 -C4 111.6(2) C2-C1 -C5 118.2(2) C2-C1 -N1 89.1(2) C2-C3-N1 90.5(2) C4-C1 -C5 112.2(2) C4-C1-N1 110.q2) C5-Cl -N1 113.6(2) C6-C5 - 0 3 113.3(2) 0 1 -C4-02 128.7(3)

Table 4. Torsion angles (in degree) of 13h

C4-C1 -C2-C3 N1 -C1 -C2-C3 c2-c1 - c4 -02 c5 -c1 -c4-02 N1 -Cl-C4-02 C2-CI-C5-03 C4-CI-C5-03 Nl-Cl-C5-03 C4-C1 -N1 -C3 Cl-C2-C3-N1 CI-C5-C6-C10 0 3 -C5 -C6-C10

-101.4 C5-Cl-C2-C3 9.8 C2-C1 -C4-01

102.4 C5-Cl-C4-01 - 122.3 N1 -C1 -C4-01

5.2 C2-Cl-C5-C6 -47.1 C4-C1 -C5-C6 - 179.2 Nl-Cl-C5-C6

55.2 C2-Cl-Nl-C3 102.7 CS-Cl -Nl -C3 - 9.9 C2-C3-Nl-C1 78.8 C1 -C5 -C6-C7

-40.3 0 3 -C5 -C6- C7

126.3

59.1 -76.1

- 173.3 - 170.3

57.6 - 68.0 -9.9

- 130.5 10.1

- 99.9 141.0

Liebigs Ann. Chem. 1990,687-695

Stereoselective Hydroxyalkylations of (S)-2-Azetidinecarboxylic Acid 69 1

acid, which is C-substituted in position 2. For an ORTEP stereo plot of the molecule see Figure 1, for a PLUTO plot of the molecular packing see Figure 2; atomic coordinates and temperature parameters are provided in Table 1, bond lengths, selected bond and torsion angles in Tables 2-4. A comparison of this structure with that of the parent compound 7, the structure analysis of which was carried out by Bermann et al.47), shows only few significant differences. No C-C bond length in the saturated part of the molecule is out of the range of 1.53 A. The main differences as compared to 7 are the elongation of the C1 -N1 bond from 1.507(3) to 1.522(3) 8, and the decrease of the angle C2-C1 -N1 from 90.5(2)' to 89.1(2)". The azetidine ring of 13h deviates slightly more from a planar conformation (puckering angle in 13h: 14.1 ", in 7: 12.5').

More interesting is the position of the crystal water. As evident from Figure 2, there are four different types of hydrogen bonds in this structure. The first one, connecting the molecules in the direction of the x axis, is located between an oxygen of the carboxylate (01) and a hydrogen of the ammonium (Nl) with a length of 1.89 A. The others involve the water molecules. The hydrogen of the hydroxy group points to the water oxygen (1.82 A). One of the water hy- drogens is directed towards the pyridinium nitrogen (N2) with a distance of 2.08 A, the other is bound to the 0 2 of the carboxylate (1.85 A). Furthermore, the second hydrogen on N1 also points towards the water oxygen, but the distance of 2.14 A is out of the range of a normal hydrogen bond.

We thank B. Kloetzer for carrying out some experiments. This work was supported by the Schweizerischer Nationalfonds zur For- derung der wissenschaflichen Forschung (Gesuch Nr. 20-25276.88) and by the SANDOZ AG (Basel). The BASF AG (D-6700 Ludwigs- hafen) supplied pivalaldehyde and the DEGUSSA AG (D-6450 Hanau-Wolfgang) (S)-2-azetidinecarboxylic acid.

Experimental General: THF was distilled under Ar over K, prior to use and

transferred with a syringe. Flasks, stirring bars, and hypodermic needles used for the generation and reactions of organolithium reagents were dried for ca. 12 h at 120°C, and allowed to cool in a desiccator over bluegel. The side arm of the reaction flask was stoppered with a septum cap, and the flasks were connected to an Ar line by three-way taps. A positive pressure of Ar was established by following the operation "flask evacuation/Ar introduction" sev- eral times. - Thin-layer chromatography (TLC): Precoated silica gel 60 FZs4 plates (Merck). Reaction components were visualized under UV (254 nm) illumination. - Column chromtography: Flash (FC), performed on silica gel 60 (230-400 mesh, 0.04-0.063 mm; Fluka) with a pressure of 0.2 bar. - Melting points: Open glass capillaries, Biichi 51 0 apparatus, with a 50"-scaled Anschiitz ther- mometer. - [N]D: Measured at ambient temperature with a Perkin- Elmer 241 polarimeter. - IR spectra: Measured as films or KBr discs with a Perkin-Elmer 283 instrument. The values of the ab- sorption bands are expressed in wave numbers (0) [cm-'1. - NMR spectra: 'H-NMR spectra were measured with a Varian EM-390 (90 MHz) or a Bruker WM-300 (300 MHz) spectrometer. I3C-NMR spectra were measured with a Bruker XL-300 instrument at 75 MHz. Chemical shifts (6) are reported in ppm downfield to TMS (6 = 0), and coupling constants, J , are given in Hz. Unless otherwise

stated, CDCI3 was employed as solvent. D 2 0 with a few drops of [D,]trifluoroacetic acid was the solvent of choice for amino acids, and chemical shift values are reported relative to DSS [3-(trimethylsilyl)propanesulfonic acid, sodium salt, hydrate] as internal standard. - MS: Hitachi-Perkin-Elmer RMU-6M spectrometer, fragment ions indicated in m/z units with relative intensities (%) in parentheses. General Procedures

General Procedure 1: In a dried two-neck flask with a pressure filter funnel on one neck, which was fitted with another two-neck flask, 10 ml(38.6 mmol) of 11 and 5 ml(45 mmol) of pivalaldehyde (distilled over CaO) were dissolved under Ar in 20 ml of dry CH2C12. After dropwise addition of 4 ml of 1 M trimethylsilyl trifluoromethanesulfonate (TMSOTf) in CH2ClZ at - 5 0 T , the solution was stirred for 4 h at -40 to -45°C (acetonitrile, cooled with liquid N2). The catalyst was hydrolyzed at room temp. by the addition of 4 ml of ether, saturated with water. The mixture was warmed to 0°C in about 10 min. The solvent was removed in vacuo at this temp. The oily mass was taken up in 20 ml of dry pentane and filtered. After evaporation of the solvent in vacuo at about O"C, 5.89 g (34.9 mmol, 90%) of product was obtained as fine needles with m.p. 41 -43°C (sealed tube).

General Procedure 2: The freshly prepared bicyclus 12 (1 mmol) was dissolved under Ar in 0.5 ml of THF, cooled to -78"C, de- protonated with 1.1 equiv. of lithium 2,2,6,6-tetramethylpiperidide (LiTMP) of lithium diisopropylamide (LDA) [preparated by treatment of 2,2,6,6-tetramethylpiperidine or diisopropylamine with nBuLi (ca. 1.5 M in hexane)] in 2 ml of THF. After 15 - 30 min the aldehyde was added to the slightly orange solution. The reaction was stopped by the addition of 1.5 ml of 1 M HOAc in ether and 0.5 ml of water. The cooling bath was removed and the reaction mixture was stirred for 1 h.

General Procedure 3: The amino acid was filtered, and washed thoroughly with ether and water.

General Procedure 4: The layers were separated, the aqueous layer was acidified to pH zz 6 and then purified on an ion exchange resin (Dowex 50-WX8). After recrystallization from water/acetone, the amino acids were obtained as thin, white or slightly yellow dates. r--- - - -

Methyl (S)-2-Azetidinecarboxylate Hydrochlorode: At room temp. 10.0 g (98 mmol) (S)-2-azetidinecarboxylic acid (7) was suspended in 70 ml of dry methanol, cooled to 0°C and treated with drowise addition of 30 ml (237 mmol) of chlorotrimethylsilane. Af- ter 4 h the clear solution was concentrated in vacuo. The thick oil was dried under high vacuum. A white hygroscopic solid (15.5 g) was obtained which was pure enough to be used without further purification. A sample was recrystallized from ether/CHzC12; [N]D = -86.8 (c = 0.5, H20). - TR (KBr): B = 3000 br. s, 1750 s, 1580 m, 1448 m, 1415 s, 1320 m, 1290 s, 1275 s, 1230 s, 1200 s, 1035 s, 910 s. - 'H NMR (90 MHz, CDC13): 6 = 2.6-3.0 (m, 2H, 3-H), 3.9 (s, 3H, OCH3), 4.0-4.3 (m, 2H, 4-H), 5.2 (t, 1 H, 2-H), 9.5 (br. s, IH, NH), 10.2 (br. s, IH, NH). - MS: m/z (YO) = 115 (8)

Methyl (S)-l-Benzyl-2-azetidinecarboxylate: To a suspension of 33.1 g (234 mmol) of K2C03 in 10 ml of CHzClz was added 15.0 g (95 mmol) of methyl (S)-2-azetidinecarboxylate hydrochloride. After dropwise addition of 13.3 ml (111 mmol) of benzyl bromide at ca. 5"C, the reaction mixture was stirred at room temp. far ca. 22 h. The suspension was filtered and the solvent of the filtrate was evaporated at room temp. in vacuo. The crude product was purified by FC [hexane/ether (1 :I)] to give 11.2 g (52.4 mmol, 55%) of methyl

[M' - HCI], 56 (loo), 55 (lo), 38 (7), 36 (21), 28 (46).

Liebigs Ann. Chem. 1990, 687-695

692 D. Seebach, T. Vettiger, H.-M. Miiller, D. A. Plattner, W. Petter

(S)-l-benzyl-2-azetidinecarboxylate; Rf = 0.24 [hexane/ether (1 : l)], [alD = -115 (c = 1.3, CH2C12). - IR (film): 0 = 3020-2780 w, 1730 s, 1200 m. - 'H NMR (300 MHz, CDC13): 6 = 2.17-2.26 (m, IH, 3-H), 2.31-2.44 (m, IH, 3-H), 2.91-2.99 (m, 1H, 4-H), 3.30-3.35 (m. IH, 4-H), 3.63 (s, 3H, OCH3), 3.54-3.83 (m, 2H), 7.3 (s, 5H, aromatic H).

S-Phenyl (S)-i-Benzyl-2-azetidinecarbothioate (2, R = H): To a solution of 5.0 ml (42 mmol) of triethylaluminum in 40 ml of CH2C12 at 0°C was added dropwise 4.4 ml(43 mmol) of thiophenol. After stirring for 15 min, the cooling bath was removed, a solution of 5.0 g (24 mmol) methyl (S)-l-benzyl-2-azetidinecarboxylate in 10 ml of CHzClz was added, and the solution was stirred for 2 h. After the addition of 40 ml of ether, the mixture was cooled to -15"C, carefully quenched with 3 ml of 3% HCI (at which time evolution of gas was observed) and the insoluble material was filtered off. The organic layer was washed with 290 ml of 5% NaOH solution, 20 ml satd. NH4C1 solution, 20 ml of H 2 0 and 20 ml of satd. NaCl solution, dried with MgS04, and the solvent was evaporated in vacuo at room temp. The white solid was recrystallized from ether/pentane to yield 5.87 g (20.7 mmol, 859'0) of 2 as white solid with m.p. 67.9-68.0"C, [a]D = - 170.8 (c = 1.3, CH2CIz). - IR (KBr): P = 3080 w, 3020 w, 2960 m, 2860 m, 2800 m, 1690 s, 1490m, 1475 m, 1450m, 1440, 1330 s, 1130m, 1040m, 750 s. - 'H NMR (300 MHz, CDC13): 6 = 2.28-2.44 (m, 2H, 3-H), 2.98-3.07 (m, IH, 4-H), 3.37-3.42 (m, IH, 4-H), 3.53, 4.00 (AB, J = 13, CH,Ph), 3.94-3.96 (d, ZH, 2-H), 7.25-7.43 (m, 10H, aromatic H). - I3C NMR (25 MHz, CDC13): 6 = 23.2 (t), 50.7 (t), 61.8(t), 70.6(d), 127.28, 127.51,127.87, 128.35,128.59,128.97, 130.02, 134.56, 137.16, 190.4 (s). - MS (FAB): m/z (YO) = 284 (50) [M' + 11.

CI7Hl7NOS (283.4) Calcd. C 72.05 H 6.05 N 4.94 S 11.31 Found C 72.00 H 6.21 N 4.92 S 11.76

S-Phenyl (RS)-i-Benzy1-[2-*H]-2-azetidinecarbothioa~e (2, R = D): At - 100'C 0.5 g (1.8 mmol) of 2 (R = H) in 4 ml of THF was added to 2 equiv. of LDA [generated by treatment of diisopropylamine with nBuLi (1.6 M in hexane) at -78"Cl in 5 ml of THF, after 20 min another equiv. of nBuLi (1.6 M in hexane) was added and the mixture was stirred for 5 min. The reaction was stopped by dropwise addition of 3.5 equiv. of CHiCOOD in 0.5 ml of CD,OD. The mixture was diluted with 30 ml of ether, warmed up to room temp. and washed with 25 ml of 5% NaOH solution, satd. NH4CI solution, H 2 0 and satd. NaCl solution. The organic layer was dried with MgS04 and the solvent evaporated in vacuo at room temp. to give 465 mg (1.63 mmol, 91%) of a white solid; D-incorporation: go%, [N]D = 0.00 (c = 1.3, CH2C12). - 'H NMR (300 MHz, CDCl3): 6 = 2.28-2.44 (m, 2H, 3-H), 2.98-3.07 (m, 1H,4-H), 3.37-3.42(m, IH, 4-H), 3.53,4.00(AB,J = 13,CH2Ph), 3.94-3.96 [d, 1 H (9%), 2-H], 7.25-7.43 (m, ZOH, aromatic H). - MS (FAB): m/z (%) = 285 (56) [M+ + I].

Trimethylsilyl ( S ) - l - ( Trirnethylsilyl)-2-azetidinecarboxylate (11): In a dry round-bottomed flask, fitted with a distillation apparatus, 3.03 g (30 mmol) of (S)-2-azetidinecarboxylic acid (7) was suspended with 13 ml (7.0 mmol) of N,N-Diethyltrimethylsilylamine (DEATMS) and intensively stirred. The oil bath was heated to 110-120°C. The formed diethylamine (b.p. 56-57°C) was con- densed and collected. After ca. 6 h the reaction was considered to he campkte (no more condensation of diethylamine). The mixture was cooled to room temp. and distilled at ca. 0.05 Torr. The fraction which was collected at 40-48"C/0.05 Torr gave 6.75 g (27.5 mmol, 92%) of 11 as clear liquid. (The optical purity was measured by

(C = 1.4, H2O) {Cf. 7 [a]D = -124 (C = 1.5, HzO); 7 ' H2O: [a]D = -108 (c = 3.2, H~O)}~*), e = 0.95 g/moI (room temp.),

[D6]benzene): 6 = -0.10 (s, 9H), 0.17 (s, 9H), 2.12-2.70 (m, 2H, 3-H), 3.42 (t, 2H, 4-H), 4.11 (t, 1 H, 2-H). - 13C NMR (25 MHz, [D6]benzene): 6 = -2.25 (q), 0.44 (q), 24.39 (t), 44.67 (t), 60.15 (d), 175.17 (s).

[ a ] ~ = -96.2 (C = 1.7, THF). - 'H NMR (300 MHz,

CI0H2,NO2Si2 (245.5) Calcd. C 48.93 H 9.44 N 5.70 Found C 49.04 H 9.37 N 5.70

(2R,5S)-2-tert-Butyl-3-oxa-i-azabicy~lo[3.2.0]heptan-4-one (12): This was prepared according to Genera/ Procedure 1 . (The optical purity was measured by hydrolysis of 12 with water to the starting amino acid 7.) The product was dried over P205 under high vacuum for 3 d, [U]o = -118.7 (C = 0.85, H2O) {cf. 7: [a]D = -124 (C =

(300 MHz, [D,]benzene): 6 = 0.75 (s, 9H), 1.8-1.9 ( lH, 6-H), 2.0-2.15 (m, l H , 6-H), 2.8-3.0 (m, l H , 7-H), 3.5-3.65 (dd, J = 2.8 and J = 8.7,l H, 5-H), 4.05 (s, 1 H, 2-H). - 13C NMR (25 MHz, [D6]benzene): 6 = 24.06 (q), 36.72 (s), 54.65 (t), 62.34 (d), 108.39 (d), 177.04 (s).

1.5, HzO); 7 ' H2O: [a]D = -108 (C = 3.2, H20)}48). - 'H NMR

(Sj-i-(Benzyloxycarbonyl)-(2-ZH/-2-azetidine~arboxylic Acid: At -78°C 0.38 g (2.2 mmol) of 12 (67% ee) in 10 ml THF was added to 3.1 ml 1 M LDA [generated by treatment of diisopropylamine with nBuLi (1.6 M in hexane) at -78°C in THF]. After 30 min another equiv. of nBuLi (1.6 M in hexane) was added, and the mixture was stirred for an additional 10 min. The reaction was stopped by dropwise addition of 1 ml of CH,COOD in 0.5 ml of CD30D. After the addition of 6 ml of 2 N HCI, the cooling bath was removed and the mixture was stirred for 1 h. The brown emulsion was diluted with ether and extracted with 2 x 25 ml of water. After evaporation of most of the water in vacuo, the amino acid solution was purified by ion-exchange chromatography (Dowex 50-WX8) to give 210 mg (80%) of crude 7 (. H20). The amino acid was dissolved in 3 ml of 2 N NaOH, treated with 0.4 ml of benzyloxycarbonyl chloride at 0°C for 1 h and at room temp. for 0.5 h. The solution was diluted with 20 ml of water, washed with 2 x 20 ml of ethyl acetate, acidified with 2 N HCI to pH = I and further extracted with 2 x 20 ml of ethyl acetate. After washing of the organic layer with brine and drying in vacuo, 341 mg (64%) of a light brown oil was obtained; D-incorporation: 57% ('H NMR 90 MHz), 58% (MS); [a]D = -89 (c = 0.9, CH2CIz), 64% ee. - 'H NMR (90 MHz, CDCI,): 6 = 2.2-2.8 (m, 2H, 3-H), 3.85-4.15 (m, 2H, 4-H), 5.6-4.85 [m, IH, (43%), 2-H], 5.1 (s, CH2-Ph), 7.3 (s, 5H, aromatic H).

(R)-2-[(R)-f-Hydroxyethyl]-2-azetidinecarboxylic Acid (13a): According to General Procedure f 19.8 mmol of 12 was prepared, according to General Procedure 2 treated with 1.1 ml(20 mmol) of acetaldehyde and worked up according to General Procedure 4 to give 495 mg (3.03 mmol, 15%) of 13a in the diastereomeric ratio of 3: 2 (after ion-exchange chromatography). After a single recrys- tallizaton from water/acetone, 242 mg of the pure main diastereo- mer was obtained; m.p. 188-189°C (evolution of gas), dec. >16O"C, = -94.5 (c = 1.0, H20). - IR (KBr): P = 3400 s, 3100 s, 3000-2500 s, 1650 s, 1630 s, 1570 s, 1400 s. - 'H NMR

(m, IH, 3-H), 2.72-2.82 (m, IH, 3-H), 3.78-3.94 (m, 2H, 4-H), 4.21 (q, 1 H, CH3CH). - 13C NMR (25 MHz, DzO): 6 = 16 (q), 27 (q), 42 (t), 68 (d), 77 (s), 175 (s). - M S m/z (%) = 146 (1) [M+ + I], 130 (4), 101 (52), 100 (46), 82 (29), 54 (88), 45 (20), 28 (100).

(300 MHz, D20): 6 = 1.11 (d, J = 3.3, 3H, CH,CH), 2.46-2.56

- . hydrolysis with water to the starting amino acid 7.) The product was dried over P205 under high vacuum for 3 d, [a]D = -123.9

C6HIIN03 . HzO (163.2) Calcd. C 44.16 H 8.03 N 8.58 Found C 43.89 H 8.32 N 8.47



(R)-2-[ (R)-a-HydroxybenzyE]-2-azetidinecarboxylic Acid (13 b): Acording to General Procedure 1 15.4 mmol of 12 was prepared, according to General Procedure 2 treated with 2 ml (20 mmol) of benzaldehyde and worked up according to General Procedure 3 to give 800 mg (3.9 mmol, 39%) of 13b m.p. 210°C (evolution of gas), [WID = -10.5 (c = 1.34, 2 N HCI). - IR (KBr): 5 = 3420 w,

(OCH3), 74.98 (C-I), 78.53 (CHOH), 106.9, 136.1 1, 140.06, 155.67, 173.99 (COOH). - M S mjz (%) = 235 (24) [M+ - 2 OCH3], 220 (9), 196 (57), 182 (loo), 125 (12), 110 (lo), 60 (17), 44 (58), 28 (49), 18 (44).

CI4Hl8NO6 . H 2 0 (314.30) Calcd. C 53.32 H 6.71 N 4.44 Found C 53.17 H 6.64 N 4.38

3060 br. s, 1640 s, 1550 s, 1390 s, 1340 s, 1090 m, 1060 m, 710 s. - ‘H NMR (300 MHz, D 2 0 + CF3C02D): 6 = 2.74-2.84 (m, 1 H, 3-H), 3.20-3.30(m, IH,3-H),4.05-4.14(m,2H,4-H), 5.29(s, I H , CHPh), 7.48 (s, 5H, Aryl-H); 13C NMR (75 MHz, D20): 6 = 25.04 t, 40.97 t, 71.56 d, 74.67 s, 125.72 d, 128.24 d, 128.69 d, 135.56 s, 169.97 s; M S m/z (YO) = 207 (1) [M+, 189 (0.7) [M+ - 181, 118 (34), 107 (24), 106 (12), 101 (IOO), 91 (16), 79 (43), 77 (65), 55 (38), 51 (24), 30 (38), 28 (20).

CllH13N03 (207.23) Calcd. C 63.76 H 6.32 N 6.76 Found C 64.04 H 6.14 N 6.79

(R) -2-/ ( R ) - (4-Biphenylyl) hydroxymethyl/-2-azetidinecarboxylic Acid (13c): According to General Procedure 1 19.8 mmol of 12 was prepared, according to General Procedure 2 treated with 2 ml (20 mmol) of 4-phenylbenzaldehyde and worked up according to General Procedure 3. The crude product was taken up in 10 ml of 2 N HC1 and filtered off. The filtrate was neutralized with ca. 1 N NH3 solution. The amino acid was collected by filtration to give 1.42 g (5.02 mmol, 25%) 13c; m.p. 194-195°C (evolution of gas), [a]D = -22 (c = 0 4 2 N HCl). - IR (KBr): P = 3420 w, 3080 br., s, 1640 s, 1630s, 1550 s, 1490m, 1390 s, 1340 s, 1090 m. - ‘H NMR (300 MHz, D 2 0 + CF3C02D): 6 = 2.73 -2.83 (m, 1 H, 3-H),3.18-3.29(m,1H,3-H),4.06-4.13(m,2H,4-H),5.32(s,1H, CHOH), 7.39-7.70 (s, 9H, aromatic H). - MS: m/z (YO) = 265

(22), 56 (46), 51 (14), 42 (12), 32 (20), 28 (100). (0.1) [M’ - 181, 180 (30), 166 (13), 154 (16), 151 (42), 101 (50), 76

Cl7HI7NO3 . H 2 0 (301.33) Calcd. C 72.07 H 6.05 N 4.94 Found C 71.35 H 5.80 N 4.90

(R) -2-[ ( S ) - H y d r o x y (2-pyridyl) methyl]-2-azetidinecarboxylic Acid (130: According to General Procedure 1 19.8 mmol 12 was prepared, according to General Procedure 2 treated with 1.8 ml (20 rnmol) 2-pyridinecarbaldehyde and worked up according to General Procedure 4 to give 603 mg (2.67 mmol, 18%) of 13f; m.p. 210- 21 1 “C (evolution of gas), [a10 -40.4 (c = 0.25, 2 K HCI). - IR (KBr): P = 3420 w, 3100 br., s, 1630 s, 1600 m, 1580 s, 1390 s, 1330 s, 1080 m. - ‘H NMR (200 MHz, D 2 0 + CF3C02D): 6 = 2.4-2.6 (m, lH), 2.9-3.1 (m, IH), 3.8-4.05 (m, 2H), 5.63 (s, 1 H), 7.8-8.8 (m, 4H). - 13C NMR (50 MHz, D 2 0 + CF3C02D): 6 = 28.57, 43.45, 72.68, 76.48, 127.93, 129.61, 144.29, 149.33, 154.12, 174.11. - MS: m/z (Yo) = 163 (0.5), 145 (2), 118 (4), 109 (l l) , 98 (3), 83 (7), 58 (18), 42 (loo), 32 (18), 28 (71), 15 (15).

C10H12N203 . H 2 0 (226.2)

( R ) -2-[ ( R ) -Hydroxy(3-pyridyl)methyl]-2-azetidinecarboxylic Acid (13g): Acording to General Procedure 1 14.8 mmol of 12 was prepared, according to General Procedure 2 treated with 1.8 ml(20 mmol) of 3-pyridinecarbaldehyde and worked up according to Gen- eral Procedure 4 to give 629 mg (2.80 mmol, 190/,) 13g; m.p. 204-205 “C (evolution of gas), [ale = -6.7 (c = 0.8, H20). - IR (KBr): 0 = 3420 w, 3200 br., s, 1640 s, 1630 s, 1580 s, 1550 s, 1490 m, 1390 s, 1320 s, 1080 m, 720 s. - ‘H NMR (200 MHz, D20): 6 = 2.48-2.64 (m, IH), 2.85-3.05 (m, IH), 3.86-3.95 (m, 2H),5.42(s,1H),7.9-8.0(m,1H),8.45-8.8(m,3H). - ‘,CNMR

142.25, 144.06,147.72, 173.33. - MS: m/z (YO) = 149 (O.?), 137 (0.8),

Calcd. C 53.09 H 6.24 N 12.38 Found C 52.83 H 6.23 N 12.38

(50 MHz, D20): 6 = 28.25, 43.68, 72.00, 76.91, 129.92, 140.64,

(R)-2-~(R)-/4-(Dimethylamino)phlnyl]hydroxymethyl)-2-azetidinecarboxylic Acid (13d): According to General Procedure 1 19 mmol of 12 was prepared, according to General Procedure 2 treated

123 (0.5), 109 (0.5), 95 (0.6), 81 (4), 69 (4), 28 (100). c ~ ~ H , ~ N ~ ~ ~ . ~~0 (226.2) Calcd. c 53.09 H 6.24 N 12.38

Found C 52.95 H 6.13 N 12.36 with 3.0 g (20.1 mmol) of 4-(dirnethy1amino)benzaldehyde (Ehrlich reagent) and worked up according to General Procedure 3 to give 820 mg (3.3 mmol, 17%) of 13d; m.p. 210°C (evolution of gas), [ale = -98.3 (c = 0.6, H20). - IR (KBr): P = 3400 w, 3120 br., s, 1630 s, 1620 s, 1530 s, 1490 m, 1380 s, 1070 m. - ‘H NMR (300 MHz, D20 + CF3CO2D): 6 = 2.67-2.76 (m, 1 H), 3.09-3.19 (m, IH), 3.28 (s, 6H, NCH3), 3.98 -4.05 (m, 2H), 5.32 (s, 1 H), 7.62 (s, 4H). - I3C NMR (75 MHz, D20 + CF3C02D): 6 = 29.62,

173.96. - MS: m/z (%) = 206 (13), 188 (18), 161 (21), 148 (IOO), 134 (54), 120 (17), 118 (17), 105 (17), 91 (15), 77 (26), 73 (II), 69 (17), 60 (15), 56 (28), 51 (17).

44.37, 49.27 (NCH,), 74.50, 78.23, 123.79, 131.58, 142.06, 145.39,

CI3Hl8N2O3 (250.30) Calcd. C 62.38 H 7.25 N 11.19 Found C 62.06 H 7.38 N 11.10

(R) -2-1 ( R ) - Hydroxy (3,4,5-trimethoxyphenylj methyl]-2-azetidinecarboxylic Acid (13e): According to General Procedure I 16.8 mmol 12 was prepared, according to General Procedure 2 treated with 4.0 g (21.7 mmol) of 3,4,5-trimethoxybenzaldehyde and worked up according to General Procedure 3 to give 1.46 g (4.65 mmol, 28%) 13e; m.p. 174-176”C, [alD = -67.5”C (c = 2.65, 2~ HCI). - IR (KBr): 0 = 3420 br., s, 3080 br., m, 1630 s, 1590 s, 1520 m, 1450 s, 1430 s, 1390 m, 1120 m. - ‘H NMR (300 MHz, D20 + CF3C02D): 6 = 2.67-2.76 (m, IH), 3.11-3.21 (m, lH), 3.78 (s, 3H, OCH3), 3.86 (s, 6H, OCH3), 3.87-4.05 (m, 2H), 5.18 (s, IH, CHOH), 6.77 (s, 2H). - I3C NMR (75 MHz, D 2 0 + CF3C02D): 6 = 28.67 (C-3), 44.39 (C-4), 59.16 (OCH3), 63.87

( R ) -2-[ ( R ) -Hydroxy(4-pyridyl)methyl]-2-azetidinecarboxylic Acid (13h): According to General Procedure f 19.8 mmol of 12 was prepared, according to General Procedure 2 treated with 1.8 ml(20 mmol) of 4-pyridinecarbaldehyde and worked up according to Gen- eral Procedure 4 to give 980 mg (4.24 mmol, 21%) of 13h; m.p. 205°C (evolution of gas), [a],, = -104 (c = 1.20, H20). - I R (KBr): 0 = 3420 w, 3100 br. s, 1630 s, 1605 s, 1550 s, 1420 s, 1380 s. - ‘H NMR (300 MHz, D20): 6 = 2.52-2.61 (m, IH), 3.04-3.14(m, IH),3.84-3.99(m,2H),5.15(~, lH),7.96(AA’BB’,

124.60, 150.16, 151.56, 175.28. - MS: m/z (YO) = 209 (3) [M+ + 11, 208 (23), 147 (27), 118 (14), 109 (loo), 101 (12), 93 (16), 80 (17), 78 (12), 56 (15), 54 (21), 28 (62).

CI0Hl2N203 . H 2 0 (226.2)

4H). - 13C NMR (75 MHz, D2O): 6 = 28.77, 43.53, 73.85, 78.70,

Calcd. C 53.09 H 6.24 N 12.38 Found C 52.93 H 6.38 N 12.44

’) Part of the Ph. D. Thesis of Th. V., No. 9100, ETH Zurich 1990. 2, Part of the Master’s Thesis work of H.-M. M., ETH Zurich 1988.

Review article: D. Seebach, R. Naef, G. Calderari, Tetrahedron 40 (1984) 1313 [Tetrahedron Symposia-in-Print Number 15 “Synthesis of Chiral Non-Racemic Compounds” (A. I. Meyers, Guest Ed.)].

4, Review: D. Seebach. R. Imwinkelried. T. Weber. Mod. Svnth. Methods 4 (1986) 125.

’) D. Seebach, R. Haner, Chem. Lett. 1987,49; R. Haner, B. Olano, D. Seebach, Helv. Chim. Acta 70 (1987), 1676; R Haner, Ph. D. Thesis, No. 8265, ETH Zurich 1987.


694 D. Seebach, T. Vettiger, H.-M. Muller, D. A. Plattner, W. Petter

30) The use of lithium tetramethyl piperidide (LTMP) did not im- prove the yields of the reactions with aldehydes, but led to a more readily purified crude-product mixture. The in situ generation of LDA and benzaldehyde from the adduct (diisopropyl- amino -phenyllithium methoxide) of these two species34J did not give better yields of 13b.

31) The deuterium incorporation is not necessarily a measure of the degree of enolate formation: D. Seebach, J. D. Dunitz, T. Laube, Helv. Chim. Acta 68 (1985) 1373.

32) Deuteration with retention*) of proline and other amino acids does not drastically change the optical a ~ t i v i t y ~ , ~ , “ ~ .

33) T. Weber, D. Seebach, Helv. Chim. Acta 68 (1985) 155. 34) Cf. also the corresponding 3-oxa-7-thia-l-azabicyclo[3.3.0]-

octan-4-ones from cysteine: D. Seebach, T. Weber, Tetrahedron Lett. 24 (1983) 3315; D. Seebach, T. Weber, Helv. Chim. Acta 67 (1984) 1650.

D. Seebach, R. Naef, Helv. Chim. Acta 64 (1981) 2704; R. Naef, Ph. D. Thesis, No. 7442, ETH Zurich 1983.

’I D. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc. 105 (1983) 5390; cf. also the analogous reaction with hy- droxyproline [T. Weber, D. Seebach, Helv. Chim. Acta 68 (1985) 1441 and a cysteine derivative (see below, ref.”)).

*) C. E. Wintner, J. Chem. Educ. 60 (1983) 550. 9, Proline alkylations for the modifications of peptides: S. Thais-

rivongs, J. Med. Chem. 30 (1987) 536; R. M. Williams, T. Glinka, E. Kwast, J . Am. Chem. Soc. 110 (1988) 5927.

’‘I R. Fitzi, D. Seebach, Angew. Chem. 98 (1986) 363, Erratum: ibid, 98(1986) 842 Angew. Chem. Znt. Ed. Engl. 25 (1986) 345, Erratum: ibid, 25 (1986) 766; R. Fitzi, D. Seebach, Tetrahedron 44 (1988) 5277 [Tetrahedron Symposia-in-Print Number 33 “a-Amino Acid Synthesis”].

‘I’ D. Seebach, E. Dziadulewicz, L. Behrendt, S. Cantoreggi, R. Fitzi, Liebigs Ann. Chem. 1989, 1215.

I2J I2a) First isolated by L. Fowden [L. Fowden, Nature 176 (1955) 347; L. Fowden, Biochemistry 64 (1956) 3231 and A. Virtanen [A. Virtanen, Nature 176 (1955) 9841, - 1%’ From the protein hydrolysates the amino acid 7 is isolated with the proline fraction. This fraction contains ca, 5% 7 in the of an amino acid mixture from plants. 7 is also found in hydrolysates from animal skins, hooves, horns, and feathers, but in much smaller amount (lop5 to lo-‘ parts of the proline fraction). It is believed to be a true component of the proteins employed in the hydrolysis, and not an artefact of the acid treatment and isolation procedure (private communication by D ~ . G. K~~~~ and K. D ~ ~ ~ ~ , Degussa AG, D-6450 Hanau).

13’ E. Leete, J. Am. Chem. Soc. 86 (1964) 3162. 14) L. Fowden, Adu. Enzymol. 29 (1967) 89; A. Baich, F. 1, Smith,

Experientia 24 (1968) 1107; M. J. Schlesinger in The Enzymes (P.

35) D. Seebach, A. Fadel, Helv. Chim. Acta 68 (1985) 1243. 36) D. Seebach, St. G. Muller, U. Gysel, J. Zimmermann, H e h . Chim.

37’ D.Blaser, unpublished results, ETH Zurich, 1988/89. 3*’ S. Karady, J. S. Amato, L. M. Weinstock, Tetrahedron Lett. 25

(1984) 4337; A. Fadel, J. Salaun, Tetrahedron Lett. 28 (1987) 2243; K. Nebel, M. Mutter, Tetrahedron 44 (1988) 4793; E. Altmann, K.-H. Altmann, M. Mutter, AWew. Chem. 100 (1988) 855; A V e w . Chew. znt. Ed. Engl. 27 (1988) 858.

3yJ Bicyclo[3.l.0]hex-l-ene with a double bond at the bridgehead between a three- and a five-membered ring contains an extremely reactive double bond, and may be called an anti-Bredt molecule: G. Kobrich, Angew. Chem. 85 (1973) 494; Angew. Chem. Int. Ed. Engl. 12 (2973) 464. Compare also: R. M. Williams, B. H. Lee, M. M. Miller, 0. p. Anderson, J. Am. Chem. Soc. 111 (1989)

Acta 71 (1988) 1303.

D. Boyer, Ed,), ~01 . 1, p, 241, Academic Press, New York 1970. 15) 2-Azetidinecarboxylic acid has teratogenic activity: p, Lallier,

16’ H. M. Berman, E. L. McGandy, J. w. Burgner, R. L. VanEtten,

40’ We have just found (by X-ray crystal structure analysis) that the corresponding carbon atoms Of TBDMS silYl enol ethers from the monocyclic 1-methoxycarbonyl- and 1-benzoyl-2-tert-butyl- 3,5-dimethyl-5-imidazolidinone are pyramidalized (D = 0.072

Ziirich, 1990. - D, seebach, Th. ~ ~ ~ t ~ k ~ , B, ~ l ~ ~ t ~ ~ ~ , D. A, Plattner, w, Petter, J. Am. Chem. Sot., in print,

411 The nitrogens corresponding to ~ ( 1 ) o f A in the imidazo1idinone silyl enol ethers, mentioned in the revious footnote4’), are pyramidalized (D = 0.426 and 0.433 1) to such an extent that they may be assigned full sp3 hybridization. Compare also the N,N- dimethylpropionamide lithium (Z)-enolate (D = 0.394 and 8-(dimethylamino)-8-heptafulvenOlate (D = 0.365 A) [W. Bauer, Th. Laube, D. Seebach, Chem. Ber. 118 (1985) 7641.

42) Compare the formulae i and ii, and the PLUTO plot iii of the structure from the “proline paper”7) with R and C in the present paper.

Exp. Cell RKS. 40 (1965) 630.

J. Am. Chem. SOC. 91 (1969) 6177; R. Bani, A. s. Verdini, c. M. Deber, E. R. Blout, Biopolymers 17 (1978) 2385; J. S. Davies, W. A. Thomas, J. Chem. SoC., Perkin Trans. 2,1978,1157; R. Bony, A. S. Verdini, J . Chem. SOC. Perkin Trans. 1, 1974, 2137.

17) Review on the occurrence of nonproteinogenic amino acids: H. Musso, I. Wagner, Angew. Chem. 95 (1983), 827; Angew. C h m . Znt. Ed. Engl. 22 (1983) 816.

I*) S. Fushiya, T. Tamura, T. Tashiro, S. Nozeo, Heterocycles 22 (1984) 1039.

j9’ G. Anderegg, H. Ripperger, J. Urg. Chem. 54 (1989) 647; s. Fu- shiya, S. Nakatsuyma, Y. Sato, S. Nozoe, Heterocycles 15 (1981) 819; Y. Hamada, T. Shioiri, J. Urg. Chem. 51 (1986) 5489.

20) K. Isono, K. Asahi, S. Suzuki, J. Am. Chem. Soc. 91 (1969) 435. 2‘) K. Schreiber, Pure Appl. Chem. 58 (1986) 745. 22) M. L. M. Pennings, D. N. Reinhoudt, Tetrahedron Lett. 23 (1982)

1003. 23J Synthesis starting from 2-bromo- or 2-chloro-4-aminobutanoic

acid: L. Fowden, Biochem. J . 64 (1956) 323. - Synthesis starting from y-butyrolactone including resolution: R. M. Rodebough, N. H. Cromwell, J. Heterocycl. Chem. 6 (1969) 435; R. M. Ro- debough, N. H. Cromwell, J. Heterocycl. Chem. 6 (1969) 993. - Synthesis starting from (S)-N-tosyl-homoserinolactone: M. Mi- yoshi, H. Sugano, T. Fujii, T. Ishibara, N. Yoenda, Chem. Lett. 1973, 5.

24) Pivalaldehyde dimethyl acetal and 7 do not react when treated with catalytic amounts of an acid or Lewis acid2). No test has been carried out with the transition-metal catalysts for extremely mild acetalizations: J. Ott, G. M. Ramos Tombo, B. Schmid, L. M. Venanzi, G. Wang, T. R. Ward, Tetrahedron Lett. 30 (1989)

25J J. Hills, V. Hagen, H. Ludwig, K. Ruhlmann, Chem. Ber. 99

26J E. Noyori, S. Murata, M. Suzuki, Tetrahedron 37 (1981) 3899. 27) A. Eschenmoser, Chem. Soc. Rev. 5 (1976) 377. 2*) This method has been uniquely successful for us in other cases

as well: D. Seebach, R. Imwinkelried, G. Stucky, Helv. Chim. Acta 70 (1987) 448. - Other catalysts were also tested but did not show any advantage over TMSOTf. Among these catalysts employed was trityl chloride/SnC12 (T. Mukaiyama, S. Kobay- ashi, Chem. Lett. 1981, 491).

2yJ The somewhat more stable acetal from (S/-proline and pivalaldehyde has the same configuration7’.

and 0.111 A, respectively): Th, Maetzke, Ph, D, n e s i s , ETH

I ii

6151. 03

(1966) 776.

... I l l



43) The enantiomers of 13 with L-allo-threonine configuration would be available from (R)-azetidinecarboxylic acid 23).

44) G. M. Sheldrick, SHELX76, SHELX86. Program for Crystal Structure Determination. University Chemical Laboratory, Lens- field Road, Cambridge CB2 IEW, England, 1986; SHELXTL PLUS, Release 3.4, Nicolet Instruments Corp., USA (1988).

45) C. K. Johnson, ORTEP-111; Report ORNL-5138, Oak Ridge National Laboratory, Tennessee, USA 1976.

46) The Cambridge Crystallographic Database; Cambridge Crys- tallograph Data Centre, University Chemical Laboratory, Lens- field Road, Cambridge CB2 lEW, England.

47) H. M. Berman, E. L. McGandy, J. W. Burgner 11, R. L. VanEtten, J. Am. Chem. Soc. 91 (1969) 6177.

48) J. P. Greenstein, M. Winitz, Chemistry of the Amino Acids, p. 2544, J. Wiley, New York 1961.

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