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substituents away from the Si-TI bond, which results in an increase of one TI-Si-Si angle to almost 120". Only in bis(hyper- silyl)lead(rl) d o even smaller Si-Pb-Si angles of about 1 15' lead to even greater distortions in the geometry of the ligand."']

E.uperiii ieii tul Procedure 3: A solution oTTIN(SiMe,), [I61 (0438 g, 1.201 ininol) in ii-pentane (1OmL) at -30 C wiii quickl) added dropwise 10 a solution of RhSi(SiMe,), [14c] (0.400 g. 1.201 mmol) i i i toluene (10 mL) and stirred. The solution immediately turned blood red. I n tlie coune of 14 h at -60 C inoat of the RbN(SiMe,)2 precipitated in the form of colorless cr)stitls. After repipettine the solution and removal of the solvcnt under ~iiciiuin at i-oom temperature. the residue was taken up in ii-pentane (10 mL) and lhc solution formed wiis filtered off' froin the insoluble gray solid. After a further 14 h. in ;idditioii t o th;tllium. dark red. square pl;i~elets of 3 precipitatcd. 0.197 g. 0.300 minol. yield 47?4. bascd on the RbSi(SiMe,), used. m. p. 130 C; correct

' H NMR (60 MHz. [DJbenzene. 22 'C. TMS): 6 = 0.46 (br): "C NMK (50.324 MH7. [D,]tolucnc, 27 C, TMS): 6 = 5.Y (d(br), 'J(CTI) =

48.2 Hzl. %i N M R (39.761 MHz. [DJtoluene. 17 C. octamethylcyclotetra- silon.ine (OMCT)) . c i = 2.42 (d(br). 'J(SiTI) = 22.4 Hr. Si,Si: Si ,Sinol obscrved); IR(Nujol. F T . 2 0 - 5 0 0 c n i ~ ' ) . P[cm-'] = 465(~).443(sh),434(vs).3X6(rn).286(~). ?60(u) . 232(sh). 21O(s) , 146(mu. br). XO(m): Raniun (ii-pcntane. FT). ifcm-l] = iXO(\v. bi-) 280(mw'). 144(sh). 133(m). 7X(vs).

Received. October 16, 1Y93 [Z6427IE] German version: Aiigm'. Chriii. 1994. 106. 721

W. Uhl. L. .Vo~ii i - /orsc/i . B 1988. 43. 11 13; W. Uhl, M . Layh. T. Hildenbrand. J Oryoiioi i i r . / U i w i i . 1989. 364. 289; W. Uhl. M . Lnyh. W. Hiller. ihid. 1989. 36X. 139: rcvicu. W. Uhl. Aiigcii.. C/iciii. 1993. 105. 1449: A i i ~ y i w . Cliiwi. / i i / . Ed. Eiiyl 1993. 12. 1386. G. E. Coates and K. Wade cited in Orgimniii~/o//ic C ~ i i p ~ i i i i d ~ Vol. 1 (Eds.: G. E C'oates. R. L. H. Green. K. Wade). 3rd edition. Methuen. London, 1967. p. 372. ii per\onal communication by C. A. Wilkie and J. P. Oliver. according to which the lattei. are supposed to have prepared a thiilliuni(ir) salt of the compo- sition K,TI,Mc,, with a TI TI bond by reduction of trimethylthallium with pota\siuiii i n 1.'-dimethoxyethane. However. to our knowledge this work has iicvcr been published. During the reaction of thallium([) halides with organolithium or -magnesium compounds dispi-oportionation reactions also take place (see for example: H. Gilman. R (;. Jones. J. h i . Cl i~ i i i . Soc. 1946. 68. 517; G . Biihr, P. Burba. M ~ / / i i ~ d ~ t i O y . Chcm. (Hoiihoi- W v l ) 4//i (4. IY52-. Bd. 13;4, 1970, p. 369). However. to date in these cases no thallium(rr) derivatives have been detected: instead the corresponding. apparently thermodynamically favored organothal- Iiiimtiti) compounds are formed For the hypersilyl suhstituent. however. the formation o f a thallium(m) derivatire may well be kinetically hindered because o f ii steric ovci-loading of the thallium atom with these sterically extremely demanding groups. The reaction of bis(hypcrsilyl)lead [15]. also synthesized by us. uitli hqpcrsilql alkali metal derivatives to give tris(hypersi1yl)plumbates MPb[Si(SiMc,),], (M = K. Cs) shows that an arrangement of three hypersilyl gt'oupi [ 5 ] arouiid ;in atom of the size of thallinm is in principle possible. E. A . V. Ebswoi-th. A. G. Lee. G. M. Sheldrick. J. C/iei?i. Sue. A 1969. 1052. We adopt here the nomenclature. proposed by N. Wiberg at the Xth Internatio- nal Symposium on Organosilicon Chemistry in Poznan (Poland) in August 1993. :iccordinp to which for the differentiation of the substituents (Me,C),Si and (Me,Si),Si corresponding compounds should he termed supersilyl and hypci-silyl deriwtives. respectively S. P. Mallela. I . Bernal. R. A. Geanangel. I iwrX. Choii. 1992. 3f. 1626. Crystal data of3: dark red. square platelets. monoclinic, spacc group C2;(c(no. 15). 11 = 28.254(.3). h = 32.935(2), c = 23.346(2) A. /j = 126.048(7) , V =

6HYX S(14) A'. 2 = 4. h i = 4.97 mm-'. pcd,cd =1.347 gem-? Four-circle dif- lrxlometcr P2, (Syntexl, Wyckofi scm, 7 - = - 100 C: 7078 independent re- Ilections. (Mo,,, 20,,,.,, = 5 5 ): absorption correction with $ sciin (platelets correction; glancing angle 4 ; min.:max. transmission: 0.27:0.78). 328 para- meter\. X X restraints. The structure was solved by direct methods (SHELXTL Plus) and refined with full-matrix least-squares based on F: values (SHELXL 93). TI. Si. and C atoms were refined anisotropically, hydrogen atoms isotropi- cally 'it idealized positions. A tris(trimethylsilyl)silyl group yhows a static posi- tion disordcr; the occupation factor of the preferred orientation was determi- ned l o 0 X37(4). R1 [I.;, > 4rr(F,,)] = 0.041. wR2 [F,' > - 3rr(E2)] = 0.105. GOF = 1 16. Further details of the crystal structure investigation may bc oh- tained from the Fachinformationszentrum Karlsruhe, D-76344 Eggenstein- Leopoldshafen ( F R G ) oii quoting the depository number CSD-578x1. the name, of the authors. and the journal citation. X. He. R. A Bartlett. M. M. Olmstedd. K . Ruhlandt-Sengc. B. E. Sturgeon. P. P. Pouer. Aiigew U i e i i i . 1993, 105. 761 ; A n g i w . Chmi. Inr. Ed Eii*s/. 1993. 32, 717, R . Ll. Schluter. A. H. Couley, D. A. At-ood. R. A. Jones. M. R. Bond. C J . ('arrano. J Am. Chmi. So(.. 1993, 115, 2070.

[9] a) G. Treboux, J.-C. Bai-thelat. J. A m C/iiwi. Soc. 1993. f I 5 . 4870. h) P Schwerdtfeger. Iiiorg. Chmi. 1991, 30, 1660: c) C . Janiak, K. Hoifmann in C'nknri ivtirione//r W d i w/wirkuii,qm i i i r k r C/iimi;i, i i i i , / d / i . w / i i ~ r E/iwiiw/i~ (Ed. : B Ki-ebs). VCH, Weinheim. 1992. p. 45; d ) K. W. K1inkh;in~iner. P. Pyykkli: unpublishcd results. Recently Trcboux and Barthelat did cnlculations on the same system employing different pseudo potenti;tls and ha\I\ \ets. hut tlie optimized TI-TI bond length (277.6 pin) seems to be too short [Y:t]

[lo] The TI-TI (293.5) and TI-Si (370 pm) bond lengths dctcrmined for the Fame crystal by a n additional measurement at + 22 C' are alightly lunger than those determined a t - 100 ('. otherwisc no significant changes i i i the nioleculiir structure itre observed.

[ I l l J. Emsley. Tlw E/miwt.s. 2nd edition. Clnrendon. Oxford. 1991. p. 2. [12] In the last few years similar short TI TI distances (400 pm 2 </(TI TI) 2

316 pm) have been determined in several TI(1) compound\. uhich h a w led to an intensive. partly controversial discussion on the bonding in w c h syiteins [<J]

[13] R. Droiiskowski. A. Siinon. Aiigeu.. Chl'?il. 1989. 101. 775; Aii:.cii.. C h i i 1111

[14] a) Ci. Becker. H. M. Hnrtmann, A. Munch. H. Riffel. %. Ai ior . ,~ . AUg. C/icvi?. 1985. 530. 29: b)A. Heine. R. Herbst-Iriner. 0. M. Sheldrick. D. Stalke. I t io rg Cliiwii 1993. 32. 26Y4: c ) K. W. Klinkhminier. W Schwitrz. Z. A t i o i p Al lp . Climii. 1993. 619, 1777.

G I . Ell,./. 1989, 28. 75x.

[I51 K . W. Klinkhaminer. W. Schwarz. unpublishcd results. [I61 K. W. Klinkhaminer. S. Henkel. J. Or,qiiiioiiii'/. C/ieiii , submitted.

Asymmetric Synthesis of Highly Substituted Pyrrolidines by 1,3-DipoIar Cycloadditions of Azomethine Ylides with N-Acryloylproline Benzyl Ester** Herbert Waldmann,* Edwin Bliiser, Martin Jansen, a n d Hans-Peter Letschert Dedicated to Professor Janos RLtej' on the occusioii of his 60th birthday

1,3-Dipolar cycloadditions are among the most efficient meth- ods of organic synthesis. For example, the reaction of azomethine ylides with alkenes makes possible the simultaneous construction of up to four stereocenters and thus provides a direct and efficient entry to highly substituted pyrrolidines."] These heterocycles oc- cur as structural elements in several biologically significant alka- loids''] and are also ofconsiderable interest in the field of medic- inal chemistry, for example as highly effective glycosidase in- hibitorsrZ1 and as antagonists of excitatory amino acids.['! Cy- cloadditions of azomethine ylides are thus increasingly impor- tant as key steps in the synthesis of complex natural products and pharmaceutical^.[^] Thus, the development of efficient chiral aux- iliaries. with which the stereochemical path of these reactions can be controlled, has recently been intensively investigated. Despite these efforts, the results obtained have been mixed.['! We have now found that highly stereoselective 1,3-dipolar cy- cloadditions of azomethine ylides can be successfully carried out with proline benzyl ester as chirdl auxiliary.['!

Schiffs bases 1 of amino acid esters can be prepared simply by condensation of the appropriate aldehyde and an amino acid ester in dichloromethane in the presence of MgSO, as water absorbent.[" These imines are then converted by deprotonation

[*] Prof. Dr. H. Waldmann. DiplLChem. E Bliiser lnstitut fur Organiache Chemie der Universitit Richard-Willst~ttcr-Allee 2, D-761% Karlsruhe ( F R G ) Telefax. Int code +(721)608-4825 Prof. Dr M Janscn. DiplLChein. H. Letschert Iiiatitut fur Anorganische Chcmie der Universitit Bonn (FRG)

[**I This work was funded by the Deutsche Forschungsgemeinschaft and by the Fonds der Chemischen Industrie. Wc thank Degussa AG for the donation of chemicals.

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with triethylamine or 1 .8-diazabicyclo[5.4.O]undec-7-ene (DBU) to the azomethine ylides, which give metalated 1,3-dipoles of fixed configuration in the presence of anhydrous LiBr (Scheme

1

H ii 4 5

Scheme 1. Asymmetric 1.3-dipolar cqcloadditiona between ,~-acryloyl-(S)-prollne benLyl estei- and metalatcd ammethine ylides. Bzl = benzyl.

The complexes 2 react with N-acryloyl-(S)-proline benzyl ester 3 in THF to give the pyrrolidines 4 and 5 in satisfactory yields and very high stereoselectivity even at temperatures between - 78 "C to - 40 "C (Table 1 ) , In each case only four of the eight possible diastereoisomers could be detected; one stereoisomer of each was always formed in large excess. When lithium diiso- propylamide was used as base and for the formation of the metal complex,[91 or when acetonitrile was used as solvent, mixtures of products were formed in which the stereoselectivity was lower.

Imines of aliphatic and aromatic amino esters can be used as precursors to the 1 ._?-dipoles (Table 1 ) . In each case the desired cycloadduct is formed with almost complete Priduirxo selectivity

(regularly >99:1). Only in the case of 4f is the exo adduct detected. In the case of the asymmetric cycloadditions of proline benzyl ester 3. the prefered m d o isomers 4 are formed with excellent diastereomeric excesses. The stereoselectivity of the reaction increases 8s the steric demands of the amino acid side chains of the 1.3-dipole increase (Table 1 ) . Thus 4a and 4b, which are derived from the benzaldimines of glycine and alanine methyl esters. are formed with diastereomeric ratios of 93:7 and 91 :9 respectively. (Table 1 , Nos. 1 and 2). On the other hand, the Schiffs bases obtained from the methyl esters of valine, isoleucine. and phenylglycine deliver products with isomeric ratios of > 95: 5 to > 99: Z (Nos. 3 -- 7). In the cases of pyrrolidines 4c, 4d. and 4e. the corresponding cnclo isomer 5 was completely undetectable. The ratios of stereoisomers were determined by high perfor- mance liquid chromatography (HPLC) of the crude reaction mixtures. The major isomers could be easily separated by simple flash chromatography as colorless solids. Their absolute config- urations were unambiguously assigned by crystal structure anal- ysis of the pyrrolidine 4e.lio1

The removal of the chiral auxiliary from the cycloaddition products was carried out in high yield simply by acid hydrolysis of the proline amide bond with the concomitant hydrolysis of the ester group of the pyrrolidine. This approach is exemplified by compound 4e in Scheme 2. The liberated proline can easily be recovered, for example. by chromatography.

HCI H-Pro-OH

+ HOOC,

\y -i , , 'COOH

6

[ a ] ~ * ~ = +32 4 ( C = 1, CHaOH)

4e

Scheme 2 Removal of the chiral auxiliary from the cycloadduct5.

Enantiomerically pure pyrrolidine-2,4-dicarboxylic acids such as 6 are of interest not only its precursors in the field of alkaloid

but also in their own right as potential pharma- ceuticals, since they act as antagonists of the excitatory glutamic acid and can be used in the study of the glutamic acid receptor.[31

In order to explain the almost total endo/e.uo selectivity and the very high face selectivity attained through the 1,3-dipolar cyclo- addition of the a.B-unsaturated proline benzyl ester amide 3 with the metalated azomethine ylides 2, we assume that the reaction proceeds preferentially via the highly ordered endo

Table 1 Rezults of' the 1.3-dinol:ir cvcloaddiriona betivecn ammethine ylides (2) and M-acryloyl-(S)-proline benzyl ester (3) yielding the pyrrolidines 4 and 5.

4:s Pn<l<llo.c T(1- No. Cmpd. R ' R' 7' Reaction [.IF M.p. Yield [hl [%I [a] ratio [ CI time [h] ( 1 , = 2. CH,CIJ [ C]

1 4 a H Ph - 7 8 - 2 5 72 -99.3 87 43 >99:1 93:?

7 >99:1 2 4b CH 3

Ph -40 - 25 72 -251.0 01 48 >99. I 91:9 4 c iPs [c] Ph -40 - 25 72 -128.0 95 30 >99: I

4 4 d rBu [c] Ph - 40 72 - 153.5 110 30 >99 1 >99:1

6 4f Ph 4-NO,Ph - 40 48 -77.5 I60 60 93:? 97 .3 S 4e Pi1 Ph -7X-25 48 - 74.8 115 67 >99:1 299.1

Ph 4-MeOPh - 40 4X -79.8 53 65 >99:1 95.5 7 4 g

[a] The yields ai-e based on pui-e di;irtereoisomer 4 after chromatographic purification. All pyrrolidines 4 were identified from 400 MHI NMR spectra (CDCI,). and ;ill gave the correct elemental anal)ses. [b] Determined from the crude reaction inixtuse hy HPLC. [c] DBU %as used as base

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transition states A and B (Fig. 1). In both these transition states the lithium cation is coordinated to the azomethine ylide and to the dipolarophile, in such a way that a compact and efficient ordering of the reaction partners results. If the dipole had an exo

A B Fig. 1. Posible ti-ansition states consistent with the stereoselection found in the 1.3-dipolar cycloadditions between N-acryloyl-(S)-proline benzyl ester and metalat- ed azomerhine ylides.

orientation. such double coordination would not be possible. To allow the lithium cation to coordinate through the amide and ester carbonyl groups of the dipolarophile, the acrylamide must assume the proposed cis-anti conformation.[61 In the corre- sponding cis-syn configuration the dipoles of the carbonyl groups would. for electrostatic reasons, lie in an antiparallel, and therefore more favorable, conformation. However, this ef- fect is overridden by the additional coordination of the lithium cation by the ester group. Of the two endo transition states, A is the energetically more favorable, because in B the group R' of the dipole lies close to the COOBzl group of the proline benzyl ester, while in A only an interaction with the sterically unde- manding 1-hydrogen of the proline has to be considered.

Received. October 21. 1993 [Z6437IE] German version: Angew. Chcm. 1994. 106. 717

Review article: W. J. Lown in 1 ,S-Dipo/ur Cj~c l ( iur / r l i~ ion Cheinbtr j , VbI. 1. (Ed.: A. Padwa). Wiley. New Yorh. 1984. See also detailed references in [%I.

G. W Fleet. fbp. ,M1d. Cheni. 1988. 65, 149; h) R. T. Schwarz. R. Dateina. Trmd\ Biodiaiii. Sci. 1984, 32. For more recent work see: V. Wehner. V JBgcr. i l i l f c r i . C h 1 7 1 1 . 1990. 102. 1180: A n p i r Clim?. i n / . Ed. EnxI. 1990. 29. 116Y, and references therein. See. for example. R. J. Bridges, F. E. Lovering. J. M. Humphrey. M. S. Stanley, T. N Blahely, M. F Cristofaro, A. R. Chamherlin, Biorp. Mrd. Chivn. Let/ . 1993, 3. 1 1 5. and references therein. See. lor example. a) G. A. Kraus, J. A. Nagy. Gtruhcdron 1985,41, 3537; b) P. DeShong. D. A. Kell, 7??.rruliedriin L e / / . 1986, 27. 3979: c) C.-L. Wan&. W. C. RipLa. P. N. Confalone, ihirl 1984, 25, 4613; d) P. N. Confalone. R. A. Earl. ihid 1986. 27. '695: e) P. Garner. W. B. Ho. H. Shin. J. Am. Chem. .'or.. 1992. 114. 1767. and references therein; f) S. Takano. K Samizu, K . Ogasawara. Choir L ~ f t . 1990. 1231). Chil-al auxiliaries in 1.3-dipoles: P. Deprez, J. Royer. H.-P. Husson, 7Pfruhc- h n i A . \ w i i i c ~ r r r 1991. 2, 1189; A. S. Anslow. L. M Harwood. H. Philips. D. Watkin. L. F. Wong. ihid. 1991,2. 1343; R. M. Williams. W. Zhai. D. J. Aldous. S. C. Aldous. J. Org. Cheni. 1992.57.6527. Chiral auxiliaries in dipolarophiles: P. Garner. U: B. Ho. ihid. 1990, 55. 3973: S. Kanemasa. T. Hayashi. J. Tanaka, H . Yxnainoto. T. Sakurai. ibid. 1991. 56. 4473; D A. Ban. M. J. Dorrity. R. Grigg. J F Malone. V. Sridharan. ihid. 1991, 32, 5417: A. H . Fray, A. I . Meyers. hid 1992. 33. 3575 Use of proline benzyl ester as chiral auxiliary in carbo-Diels-Alder reactions: H. Wiildinann. J. Oig. Clieni. 1988, 53, 6133: L . i h g . c Aim. Chcn?. 1990. 671 ; in 1.3-dipolar cycloadditions of nitrile oxides: H. Waldmdnn, ibirl. 1990. 1013: in radical additions to carbonyl groups: H. Waldmann. Synlcrr 1990,627; Liehiq Aiiii C./iw??. 1991. 13 17 Reviews of the use of amino esters as chiral auxiliaries: H. Waldmann. M. Braun, Guz:. Chiin. Itul. 1991. 121. 277; H. Waldmann, Koiitokrr 1993 ( I ) , 58; h i d 1993 (2). 34. a ) H . lahashi. H. Omatsu. Chwn. Phurni. Bull. 1978, 26. 466: b) G. Grundhe. W. Kecsc. M. Rippler, S~i i /heos 1987. 13, 11 15. K . .Ainornrahsii. D Barr. G . Donegan. R. Grigg. P. Ratananuhul. V. Srid- hai-an. G/ruhivlroti 1989. 45, 4649. and references therein. D. A . Barr. R Grigg. H. Q. Nimal Gunaratne, J. Kemp. P. McMeehin. V. Sridhai-an. -le/ruhcilroi? 1988. 44. 557 and references therein.

[lo] Crystal data: C,,H,,N205. orthorhomblc crystala. space group P?,lf)z (no. 11). with u = 8.473(5), h =17.736(3). c = 8.927(2) A. Z = 2. /I =

95.32(1). 2807 reflections were measured (quadropole diffractometer Enraf Nonius (No. CAD4. Mo,, radiation. graphite monochroimtor). of which 2717 were independent with I > 2u(Z). The Structure determination was car- ried out with direct methods (SHELX-76 and SHELXL-Y3), R = 0.0547. R, = 0.0838. it' = 1 .'02 F ) + 0.0001 F 2 . All C, N. and 0 atoms were anIsotrop- ically refined. The hydrogen atoms are found in the calculated sites with the appropriate isotropic temperature factors for CH. CH,. CH, . and phenyl H . Further details of the crystal structure investigation may be obtained from the Fachinformationszentrum Karlsruhe. D-76344 Eggenstein-Leopoldshafeil (FRG) on quoting the depository number CSD-58112 and the journal citation.

Vanadium(I1)- and Niobium(Ir1)-Induced, Diastereoselective Pinacol Coupling of Peptide Aldehydes to C,-Symmetrical HIV-Protease Inhibitors" * Bernhard Kammermeier,* Gerhard Beck. Detlev Jacobi. and Heiner Jendralla*

In 1993 fifteen European and American pharmaceutical com- panies decided to collaborate on medicinal At DS control.[" Pos- sible synthetic approaches to finding a method for chemothera- peutic intervention in the complex reproduction cycle of the Human Immunodeficiency Virus (HIV) are both diverse and be- set with problems. They range from blocking of the viral gpl20 surface structure to the inhibition of the virus-specific enzyme reverse transcriptase (RT) or to inhibition of the HIV protease. an aspartyl protease whose structure was elucidated in 1989. and which is essential for the maturation of infectious virus partic- les.['] In particular, inhibition of the C,-symmetrical HIV prote- ase by compounds with structures of type 1 (see Scheme has crystallized as a promising therapeutic target. This is primarily for two reasons. First, proteases of the host organism are unable to carry out the proteolytic tasks of an inhibited HIV protease, and second, the aspartyl protease class, which al- so includes renin and pepsin, for example, IS

a class of mechanisti- cally well-characterized proteolytic enzymes.

C,-symmetrical in- hibitors were first syn- thesized and their bio- logical activity studied by Kempf and Erick- son et al. in 1990.[41 A crucial problem in the synthesis of these aminodiols is stereose- lective access to the most effective diastereo- mer type l . I 5 I Because of the molecular sym- metry of the com-

2a, R = C'br 2 b , R = Boc 2 C, K = DSNP

2 d DSNP-OH

Scheme 1. HIV protease inhibitora I and "half' precursor moleculez 2. Cbr: benzyl- oxycarbonyl. Boc: /cr/-but).loxycarbonyl.

[*I Dr. B. Kammermeier. Priv.-Doz. Dr. H. Jendralba. Dr. G. Beck Pharma-Forschung, Hoechst AG Postfach 800320. D-65926 Frankfurt am Main ( F R G ) Telefax: Int. code + (69)331369 Dr. D. Jacobi Landes-Entwichlungs-Gesellschaft, D-70182 Stuttgart ( F R G )

. Inycri . C'heiii. f i i r . Ed. Dig/. 1994. 33, No. 6 (- VCH Vrrlupsyesellschaf/ mbH, 0-69451 Weinhebn, 19Y4 0570-0X~3~Y4/0606-06h' j S 10.00 + .?S,'lI 685