Penicillamine: An extractable chiral auxiliary providing excellent stereocontrol

Tetrahedron Asymmetry

Volumn 7, Issue 2, 1996, Pages 427-434

  Richter, Lutz S ^a,b   Gadek, Thomas R ^a  

^a GENENTECH INC   (United States)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

PENICILLAMINE DERIVATIVE;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE; PRIORITY JOURNAL; REACTION ANALYSIS;

EID: 0030041330     PISSN: 09574166     EISSN: None     Source Type: Journal    
DOI: 10.1016/0957-4166(96)00025-0     Document Type: Article

References (20)

1. a) Schöllkopf, U., Tetrahedron 1983, 39, 2085;
2. b) Schöllkopf, U., Pure & Appl. Chem. 1983, 55, 1799;
3. c) Schöllkopf, U., Topics Curr. Chem. 1983, 109, 65.
4. Williams, R.M., Synthesis of Optically Active Amino Acids, Pergamon Press, Oxford, 1989, p. 1-33.
5. Schöllkopf, U.; Groth, U.; Deng, C., Angew. Chem. Int. Ed. Engl. 1981, 20, 798.
6. After hydrolysis of the bislactim ether template, esters of the chiral auxiliary and the target amino acid are obtained. The separation of these compounds by distillation or chromatography is difficult if their boiling points and polarities are similar.
7. The aspect of low stereoselectivity can be overcome by use of tert.-leucine instead of valine (see Schöllkopf, U.; Neubauer, H.J., Synthesis 1982, 861).
8. 4 in 4% aqueous ammonium hydroxide.
9. When the sulfhydryl group is derivatized with a benzyl-type protecting group like 4-methoxybenzyl (see ref. 9), the TFA-salt of penicillamine esters can be extracted into dichloromethane. This allows for facile separation from the TFA-salts of hydrophilic and moderately lipophilic amino acid esters.
10. The free sulfhydryl group is easily be regenerated as described for the synthesis of 6 or by other standard deprotection methods (e.g., Gordon, E.M., Godfrey, N.G., Delaney, N.G., Asaad, M.M., Von Langen, D., Cushman, W. J. Med. Chem. 1988, 31, 2199).
11. Richter, L.S.; Marsters, J.C.; Gadek, T.R., Tetrahedron Lett. 1994, 35, 1631.
12. Triethyloxonium tetrafluoroborate is soluble in dichloromethane and was chosen for convenience. As shown earlier (see Groth, U., Schmeck, C.; Schöllkopf, U., Liebigs Ann. Chem. 1993, 321), the alkyl side chain at the imino ether functionality has very little or no effect on asymmetric induction.
13. Richter, L.S.; Gadek, T.R., unpublished results.
14. This example was chosen because it represents, as compared to other results reported in ref. 3, one of the least successful cases both in terms of stereoselectivity and ease of separation of the target compound from the chiral auxiliary.
15. Under the described conditions, we could not detect any evidence (TLC, NMR) for elimination of 4-methoxybenzyl mercaptide or metallation in the side-chain. After alkylation and workup, the only detectable products were the target compound 9 and the chiral auxiliary 10.
16. 2H-5H transannular coupling constant which is typical for 2,5-trans-substituted dihydropyrazines (see ref. 10 and V. Maywald, dissertation, University of Göttingen 1987).
17. Beulshausen, T.; Groth, U.; Schöllkopf, U., Liebigs Ann. Chem. 1991, 1207.
18. Dale, J.A.; Mosher, H.S., J. Am. Chem. Soc. 1973, 95, 512.
19. Shortly after completion of these studies, S-trityl-penicillamine became commercially available from Bachem Bioscience, Inc. The bulky trityl group should prevent S-alkylation by triethyloxonium tetrafluoroborate and may allow for simultaneous hydrolysis / S-deprotection using appropriate scavengers; see Pearson, D.A.; Blanchette, M.; Baker, M.L.; Guindon, C.A., Tetrahedron Lett. 1989, 30, 2739.
20. Fuji, N.; Otaka, A.; Ikemura, O.; Akaji, K.; Funakoshi, S.; Hayashi, Y.; Kuroda, Y.; Yajima, H., J. Chem. Soc. Chem. Soc. 1987, 274.