Asymmetric synthesis of two new conformationally constrained lysine derivatives

Robert A. Stalker, Tamara E. Munsch, Jacquelyn D. Tran, Xiaoping Nie, Ralf Warmuth, Christer B. Aakeröy

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The asymmetric synthesis of the conformationally constrained L- and D-lysine derivatives methyl (1S,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7, 8-octahydroanthracene-1-carboxylate (4) and methyl (1R,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7, 8-octahydroanthracene-1-carboxylate (5), respectively are described. Application of the Bucherer hydantoin synthesis to the carbonyl group of 2′,3′,4′,5′,6′,7′-hexahydrospiro[1, 3-ethylenedithiole-2,1′-anthracen]-8′-one (18), which was prepared from 1,8-dichloroanthraquinone (14) in nine steps and the deprotection of the masked second ketone of 18 yields rac-21. The latter is the precursor for a novel asymmetric reductive amination protocol using (R)-phenylglycinol as a chiral amino auxiliary and NaBH(OAc)3 as a reducing agent. Using this procedure, the asymmetric reductive amination of α-tetralone derivatives and indanone proceeds with >95% de. Lower diastereomeric excesses are observed for benzosuberone (16.7% de) and acetophenone (27.3% de). rac-21 gave (1′S,8′S,1(R)-25a (38% yield) and (1′R,8′S,1(R)-25b (44.5% yield) with greater than 52 and 78% de, respectively. Cleavage of the amino auxiliary of (1′S,8′S,1(R)-25a and of (1′R,8′S,1(R)-25b with lead(IV) tetraacetate and hydrolysis of the hydantoin ring yields the unprotected analogs of 4 and 5. The latter are transformed into the selectively protected target molecules 4 and 5 through standard protection procedures. The overall yield of the 17- and 18-step synthesis starting from 13 was 0.3% yield for each constrained lysine derivative.

Original languageEnglish (US)
Pages (from-to)4837-4849
Number of pages13
JournalTetrahedron
Volume58
Issue number24
DOIs
StatePublished - Jun 10 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Asymmetric reductive amination
  • Constrained amino acid
  • Lysine

Fingerprint

Dive into the research topics of 'Asymmetric synthesis of two new conformationally constrained lysine derivatives'. Together they form a unique fingerprint.

Cite this