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Endogenous Alkaloids in Man, Part 33 [1]. Dimethyl (2S,4S)- and (2/?,4S)-5,5-Dimethyl-l,3-thiazolidine-2,4-dicarboxylates, Two Diastereomeric Glyoxylate-Derived HeterocyclesG erhard Bringm anna **, Doris Feineis3, Wael Saeba, C hristiana H esselm anna,Eva-M aria Petersb, and Karl Petersba Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg,

Germanyb Max-Planck-Institut für Festkörperforschung, Heisenbergstraße 1, D-70506 Stuttgart,

GermanyReprint requests to Prof. Dr. G. Bringmann.Fax: (49) 931 888 4755. E-mail: bringman@chemie.uni-wuerzburg.deZ. Naturforsch. 55b, 208-212 (2000): received December 13, 1999Crystal Structure, Glyoxylate-Derived 1,3-Thiazolidines

Both title compounds were obtained in stereochemically pure form by refluxing 5,5-di­methyl-1 ,3-thiazolidine-2,4-dicarboxylic acid (3) with methanolic HC1, followed by a separa­tion of the two diastereomers 4a and 4b on silica gel. The X-ray structure analyses of these stereoisomers confirm the relative configuration to be cis for 4a and trans for 4b with respect to the two carboxymethyl substituents at C(2) and C(4). For both molecules, an envelope- type conformation of the thiazolidine ring was found with C (5 ) -S ( l) - C ( 2 ) -N (3 ) being lo­cated in a plane showing a small ring torsion angle of -11 .2 ° and -3 .1 ° for the cis- and the rrafts-epimer, respectively. The fram-configured compound 4b adopts a nearly ideal envelope conformation with C(4) being the flap atom, while the c/s-isomer 4a. apparently because of steric interactions of the C(2) and C(4) substituents, shows a twisted envelope conformation.

Introduction

The intentional induction of thiazolidine form a­tion in m am m alian organism constitutes the key step of our ‘chem ical’ model [2 -5 ] for the trea t­m ent of glyoxylate-derived oxalurias, among them the severe inherited m etabolic disorder hyperoxa­luria [6,7]. This therapeutical concept is based on the adm inistration of the unnatural aminothiol D(-)-penicillamine (1), to prevent the fatal accu­m ulation of the highly reactive and cytotoxic C2- aldehyde glyoxylic acid (2 ), by form ation of the polar 1,3-thiazolidines 3a and 3b. These hetero- cyles were found to be of excellent solubility and good physiological compatibility [3]. From NM R experim ents it is known that the precursors 1 and 2 rapidly condense in aqueous solution to give a diastereom eric m ixture of the thiazolidines 3a and 3b. Their ratio is strongly pH -dependent: In neu t­ral and basic media, the c/s-isomer 3a is distinctly favored, whereas under acidic conditions nearly equal am ounts of the two epimers 3a and 3b are found, with a slight preference of the trans-thiazo\- idine 3b [3], With respect to planned investigations on the spontaneous or enzym e-m ediated form a­

tion of these heterocycles in vivo , the exact knowl­edge of the stereostructures of both of the epimers 3a and 3b was highly desirable. In this paper, we report on the ultim ate stereochem ical attribution of these glyoxylate-derived 1,3-thiazolidines 3a and 3b, as already anticipated for the relative con­figuration by NM R experim ents [3,8], and now fi­nally com pleted for the full absolute stereostruc­tures by synthesis and X-ray structure analysis of their corresponding dim ethyl esters 4a and 4b.

h3c ^ c o 2h

/ \HS NH2

CHOIc o 2h

2

h3cc h 3

c o2r

NHVc o 2r

3a R = H — II

4a R = CH3 ^ j

h3c ^ COgR

/ s \S^NH

c o 2r

3b R = H

4b R = CH3

Fig. 1. Conversion of the highly polar alkaloid-type 1,3- thiazolidines 3a and 3b, resulting from a spontaneous condensation of D(-)-penicillamine (1) with the toxic al­dehyde glyoxylic acid (2), into their corresponding di­methyl esters 4a and 4b. - Reagents and conditions: (a) H.O, pH = 1. r.t., 12 h (> 99% for 3a/b); (b) HC1, MeOH. r.t., 8 h; then AT. 48 h (18% for 4a. 32% for 4b).

0932-0776/2000/0200-0208 $06.00 © 2000 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com D

G. Bringmann et al. ■ Two D iastereom eric G lyoxylate-D erived 1,3-Thiazolidines 209

Results and Discussion

The D(-)-penicillamine-derived 1,3-thiazolidines 3a and 3b were converted into their corresponding dimethyl esters 4a and 4b (see Fig. 1) by a stan­dard reaction procedure in dry m ethanol saturated with HC1 gas. Crystallization of the pure d iastereo­meric heterocycles 4a and 4b from diethyl ether afforded crystals of both of the com pounds, suited for X-ray investigations.

We have previously reported on the crystal structure analysis of 4a [9], which revealed both of the voluminous carboxym ethyl groups to be in the energetically favored pseudo-equatorial o rien ta­tion. As shown in Fig. 2, a renew ed single X-ray diffraction analysis of 4a clearly confirms the rela­tive c/s-array of the substituents at C(2) and C(4), and, in addition to the previous X-ray m easure­ments on 4a [9], now provides an unam biguous attribution of the absolute ^-configuration at both of the two stereogenic centers, C(2) and C(4).

09

Fig. 2. S c h a k a l plot showing the molecular structure of the c/s-thiazolidine 4a with a guide of the atomic num­bering system adopted in the X-ray investigation. Hy­drogen atoms have been omitted for reasons of clarity.

By contrast, the crystal structure of 4b, which is presented in Fig. 3, clearly has one of the carboxy­methyl substituents [viz. the one at C(4)] in an axial position, thus minimizing steric interaction with the bulky C(M e)2-part, so that the carboxy­methyl substitutent at C(4) and one of the two methyl groups of C(5) adopt an tiperip lanar posi­tions. The carboxymethyl group at C(2) occupies an equatorial position as expected from the low steric dem and of the neighboring sulphur and ni­trogen ring atoms. The X-ray structure analysis of 4b fully confirms the relative /ram -configuration of the molecule at C(2) and C(4), with the abso­lute configuration of this d iastereom er being 2RAS.

Cu

Fig. 3. S c h a k a l plot showing the molecular structure of the frarts-thiazolidine 4b with a guide of the atomic num­bering system adopted in the X-ray investigation. Hy­drogen atoms have been omitted for reasons of clarity.

As shown in Fig. 4, the equatorial vs. axial orientation of the C(4) substituents for 4a and 4b as well as the different ring conform ations for the two epimers can nicely be visualized by a match plot of the structures. The heterocyclic ring of the trans-epim er 4b adopts a near-ideal envelope-type conform ation. The C(4) atom is located distinctly out of the best plane, which is form ed by the o ther four thiazolidine ring m em ­bers, C(5), S (l), C(2), and N(3), showing a small torsion angle of -3 .1 °. The strong deviation of C(4) (being the top of the envelope) becomes m anifest from the interplanar angle betw een C (5 ) -S ( l) -C (2 ) -N (3 ) and the plane N (3 )- C (4 )-C (5 ), which is 153.7°. By contrast, the cis- diastereom er 4a adopts a twisted envelope-type conform ation. Again, C(4) is located out of the best plane C (5 ) -S ( l) -C (2 ) -N (3 ) , which is now characterized by a torsion angle of -1 1 .2 ° . The in terplanar angle between the best plane and the plane N (3 )-C (4 )-C (5 ) was found to be 138.5 °. Even m ore significantly, in contrast to 4b, the C(4) atom of 4a is no longer below, but above this N (3 ) -C (2 ) -S ( l) -C (5 ) ‘p lane’ (see Fig. 4). As m entioned above, this array allows the two large substitutents at C(2) and C(4) of 4a to adopt, both of them, pseudo-equatorial positions, thus minimizing the steric interactions betw een these now ideally rem ote groups. By contrast, due to its rra/i5-configuration, no such interaction has to be minimized for 4b, thus allowing the above m entioned axial position of the carboxy-

210 G. Bringmann et al. • Two D iastereom eric G lyoxylate-D erived 1,3-Thiazolidines

methyl group at C(4), and the /ra^s-diaxial array of C(9) and C(12) for this diastereom er.

Table I. Selected bond lengths (A) and angles (°) for 4a and 4b.

Bond lengths o f 4a. Bond lengths o f 4b:

S (l)-C (2 ) 1.866(3) S (l)-C (2) 1.850(2)C(2)-C(6) 1.503(3) C(2)-C(6) 1.513(3)C (2)-N (3) 1.432(4) C(2)-N(3) 1.447(3)N (3)-H (3) 0.924(32) N (3)-H (3) 0.875(27)N (3)-C (4) 1.452(3) N(3)-C (4) 1.456(3)C(4)-C(9) 1.518(4) C(4)-C(9) 1.525(3)C(4)-C(5) 1.570(4) C(4)-C(5) 1.556(3)C(5)-C(12) 1.526(4) C(5)-C(12) 1.522(4)C(5)-C(13) 1.525(3) C(5)-C(13) 1.525(4)C (5)-S (l) 1.833(3) C (5)-S (l) 1.826(2)

Bond angles o f 4a: Bond angles o f 4b:

C (2)-S (l)-C (5) 92.5(1) C (2)-S (l)-C (5) 93.1(1)S(l)-C (5)-C (4) 102.5(1) S(l)-C (5)-C (4) 103.2(1)C(5)-C (4)-C(9) 112.3(2) C (5)-C(4)-C(9) 113.5(2)C (4 )-C (9)-0 (10) 110.4(2) C (4)-C (9)-0 (10) 110.4(2)C (5)-C (4)-N (3) 109.6(2) C(5)-C (4)-N(3) 109.3(1)C (9)-C (4)-N (3) 109.8(2) C(9)-C (4)-N(3) 109.5(2)C (4)-N (3)-C (2) 106.9(2) C(4)-N (3)-C(2) 111.3(2)N (3 )-C (2)-S (l) 108.7(2) N (3)-C (2)-S (l) 108.9(2)N (3)-C (2)-C (6) 112.6(2) N(3)-C (2)-C(6) 110.5(2)C (2 )-C (6 )-0 (6 ) 124.9(3) C (2)-C (6)-0 (6) 124.0(2)C (2 )-C (6 )-0 (7 ) 110.1(2) C (2 )-C (6)-0 (7) 111.7(2)S(l)-C (2)-C (6) 109.5(2) S (l)-C (2)-C (6) 109.3(2)

Summarizing, besides unambiguously confirm ­ing the absolute configuration of 4a and 4b, this com parative X-ray study on the crystal structures of both of these two diastereom eric D(-)-penicil- lam ine-derived heterocycles is most helpful to gain valuable knowledge on their completely dif­

ferent thiazolidine ring conformations. Further investigations now focus on the influence of the relative array of the substituents at C(2) and C(4) to optionally prepare exclusively cis- or frans-configured /V-functionalized derivatives of the thiazolidines 3a and 3b. This work is in pro ­gress.

ExperimentalG eneral

'H and 13C N M R spectra were recorded on a B ruker WM 400 or AC 200 spectrom eter, and are referenced to internal pyridine ( 'H , d 8.73, 7.59, and 7.22 ppm ) or internal chloroform (13C, d77.0 ppm ). M elting points were determ ined on a R eichert-Jung Therm ovar hot-stage apparatus and are uncorrected. Infrared spectra were obtained on a Perkin-E lm er Model 1420 spectrophotom e­ter. Optical ro tations were m easured on a Perkin- Elm er 241 MC polarim eter. For mass spectrom e­try (electron ionization 70 eV), a Varian CH7 in­strum ent was used. E lem ental analyses were per­form ed by the M icroanalysis Laboratory of the Institute of Inorganic Chem istry (University of W ürzburg) on a Carlo E rba E lem ental Analyzer M 1106 apparatus.

Preparation o f the tw o diastereom eric dim ethyl 5,5-dim ethyl-1,3-thiazolidine-2,4-dicarboxylates 4a and 4b

A solution of the 5,5-dim ethyl-l,3-thiazolidine-2.4-dicarboxylic acids 3a and 3b (diastereom eric ratio as determ ined by NM R analysis: 80:20) [3] (756 mg, 3.75 m m ol) in dry m ethanol (150 ml) sat­urated with HC1 gas was stirred at room tem per­ature for 8 h. and then heated at reflux for 48 h. A fter rem oval of the solvent in vacuo , purification and separation of the resulting crude diastereo­meric esters 4a and 4b was perform ed on silica gel (eluent: diethyl ether / petroleum ether, 1:1), affording stereochem ically hom ogeneous m aterial of the ds-isom er 4a (157.5 mg, 0.67 mmol. 18% yield) and the /y<7«s-isom er 4b (278.9 mg,1.20 mmol, 32% yield). Crystallization from di­ethyl e ther / petroleum ether provided crystals of both of the pure diastereom ers 4a and 4b.

D im ethyl (25',45')-5,5-dimethyl-l,3-thiazolidine-2.4-dicarboxylate (4a): m.p. 114°C (hydrochloride salt); 66 °C (free base). [a]o = + 60.1 (c = 0.66 in CHC13) (hydrochloride salt); [a]o = + 4.3 (c = 1.2 in CHCI3) (free base). IR (KBr. cm -1): v 2950. 2920 (w. CFL), 1790 (s. C = 0 ). 1302 (m. C-O), 1202 (m). ‘H NM R (C5D 5N. 400 MHz): d 1.09 (s. 3H.

Fig. 4. Joint plot of the structures of 4a (light grey) and 4b (dark grey) in the crystal, matched with respect to C (2 )-S ( l) -C (5 ) . Hydrogen atoms have been omitted for reasons of clarity.

G. Bringmann et al. ■ Two D iastereom eric G lyoxylate-D erived 1,3-Thiazolidines 211

5-C H 3); 1.39 (s, 3H, 5-CH3); 3.42 (s, 3H, C O O C H 3); 3.45 (s, 3H, C O O C H ,); 3.71 (s, 1H, 4- H); 5.12 (s, 1H, 2-H). 13C NM R (CDC13, 50 MHz): (3 26.93 (q, C H , at C-5); 27.79 (q, C H , at C-5); 52.71, 53.86 (2q, C O O C H 3); 58.65 (s, C-5); 62.35 (d, C-4); 74.90 (d, C-2); 169.17, 171.99 (2s, C O O C H 3). EI-MS (m /z) (rel. int.) [ion assign­ment] 233 (1.2) [M]+-, 218 (0.3) [M+ - C H 3], 174 (100) [M+ - C O O C H ,], 159 (6) [M+ - C6H 9N 0 4], 114 (56) [C6H 10O 2], 100 (28), 36 (14) [HCl]. C9H 15N 0 4S H C 1 (269.7): Calcd C 40.07, H 5.60, N 5.19. Found C 40.25, H 5.86, N 5.21%.

D im ethyl (2/?,4S)-5,5-dimethyl-l,3-thiazolidine-2,4-dicarboxylate (4b): m.p. 97 °C (free base).[a]o = + 149 (c = 1.00 in CHC13) (free base). IR (KBr, c m '1): v 3300 (s, N H), 2920 (s, C H 3), 1710 (s, C = 0 ), 1290 (s, C-N), 1210, 1200, 1180, 1160 (s). ‘H NM R (C ,D 5N, 400 MHz): d 1.35 (s, 3H, 5- C H 3); 1.48 (s, 3H, 5-CH ,); 3.34 (s, 3H, C O O C H 3); 3.44 (s, 3H, C O O C H 3); 4.26 (s, 1H, 4-H); 5.41 (s, 1H, 2-H). 13C NM R (CDCI3, 50 M Hz): ö 27.36 (q, C H 3 at C-5); 28.79 (q, C H 3 at C-5); 52.65, 52.92 (2q, C O O C H ,); 62.40 (s, C-5); 63.82 (d, C-4); 73.84 (d, C-2); 170.04, 172.27 (2s, C O O C H 3);. EI-M S (m / z) (rel. int.) [ion assignment] 233 (1.9) [M]+-, 218 (0.7) [M+ - C H 3], 174 (100) [M+ - C O O C H ,], 114 (48) [C6H 10O 2], 100 (19). C9H lsN 0 4S (233.3): Calcd C 46.34, H 6.48, N 6.60%. Found C 46.49, H 6.55, N 6.68%.

Single-crystal X -ray diffraction analyses o f 4a and 4b

All m easurem ents of diffraction intensities were perform ed on a Siemens PA diffractom eter using graphite-rnonochrom ated Mo-/Ca radiation (A = 0.71073 A ) in w-scan m ode in the range of 1.75 0< 6 < 27.5 0 [10]. The structures were solved by direct phase determ ination and refined by full-ma- trix anisotropic least-squares with the aid of the program SH ELX TL-PLU S [11]. All non-hy- drogen atoms were refined anisotropically. The position of the hydrogen atom H (3) was estab­lished by difference synthesis and refined. All o ther hydrogen positions were calculated and re­fined using a riding m odel with a com m on isot­ropic therm al param eter of 0.08 A 2. Software used to prepare m aterial for publication: SC H A K A L 88 [12].

Crystal data fo r 4a (free base): The crystal cho­sen for X-ray investigations was a colorless lath with the approxim ate dimensions 0.20 x 0.50 x2.20 mm. C9H 15N 0 4S (233.29 g m ol-1) crystallizes in the monoclinic system, space group P 2 X. with a = 9.781 (2), b = 6.623 (2), c = 10.062 (2) A, ß =

115.14 (2) °, V = 590.1 (2) A 3, Z = 2, n(Mo-Ka) = 0.27 m m '1, and D calcd = 1.313 g c m '3. U nit cell param eters were determ ined by least-squares re­finem ent using 67 centered reflections within17.1 0 < 0 < 30.1 °. A total of 2881 reflections were collected to 20max = 55 0 (h : 0 —» 12, k : - 8 —»•8, / : -1 3 —* 11) of which 2722 were unique. In refinem ents, weights were used according to the scheme w = l/[cr2( /r02) + (0.0933/>)2 + 0.05P], w here P = (F02 + 2Fc2)/3. The refinem ent con­verged to the final agreem ent factors R = 0.047, and R w = 0.049, for 143 param eters and 2658 ob­served reflections with F > 3a(F): data-to-param e- ter ratio being 18.99. The electron density of the largest difference peak was found to be 0.47 e A -3, while that of the largest difference hole was 0.62 e A '3. To establish the absolute configuration [13], 1180 Friedel pairs were employed. The corre­sponding Rogers param eter was found to be 1.3(2).

C rystal data fo r 4b (free base): The crystal cho­sen for X-ray investigations was a colorless prism with the approxim ate dimensions 0.55 x 0.65 x 0.30 mm. C9H 15N 0 4S (233.29 g m ol“1) crystallizes in the monoclinic system, space group P2^ with a = 8.334 (1), b = 7.187 (1), c = 9.891 (1) Ä, ß = 100.61 (1) °, V = 583.0 (1) A 3, Z = 2, f i ( M o - K u) = 0.27 m m -1, and D caicd = 1.329 g c m '3. U nit cell param eters were determ ined by least-squares re­finem ent using 61 centered reflections within14.7 °< 6 < 35.0 °. A total of 4105 reflections were collected to 20max = 55 0 (h : -1 0 —» 1, k : - 9 —►9, / : -1 2 —»• 12) of which 2655 were unique. In refinem ents, weights were used according to the scheme w = l/[a 2(F02) + (0.0888/3)2 + 0.05/*], where P = (FQ2 + 2FC2)I3. The refinem ent con­verged to the final agreem ent factors R = 0.053, and R w = 0.047, for 143 param eters and 2597 observed reflections with F > 3o(F ); data-to- param eter ratio being 18.55. The electron density of the largest difference peak was found to be 0.88 e A “3, while that of the largest difference hole was 0.91 e A -3. To establish the absolute configuration[13], 1221 Friedel pairs were employed. The corre­sponding Rogers param eter was found to be 0.9(2).

Selected bond lengths and angles for 4a and 4b are listed in Table I according to the atom labels of the Figs. 2 and 3. A tom ic param eters and further crystallographic data have been deposited with the Cam bridge Crystallographic D ata C entre, 12 U nion Road, Cam bridge CB2, 1EZ, UK [fax: (+Int.) 44-1223 336 033; e-mail: deposit@ccdc.co- m.ac.uk]. A com plete listing of the atom ic coordi­nates can be obtained free of charge, on request,

212 G. Bringm ann et al. ■ Two D iastereom eric G lyoxylate-D erived 1 ,3 -Thiazolidines

on quoting the depository num ber CCDC-136140 (for 4a) or CCDC-136139 (for 4b).

A cknow ledgm ents

This work was funded by the Fonds der C hem ­ischen Industrie (financial support and a graduate

research fellowship to C. H.). O ne of us (W. S.) thanks the A rab Student A id International for fi­nancial support. Furtherm ore, we are indebted to D ipl.-Chem. M. M ünchbach and D ipl.-Chem. J. K raus for skillful technical help.

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