Stereoselective total synthesis of topographically constrained designer amino acids: 2′, 6′-dimethyl-β-methyltyrosines

doi:10.1016/0040-4020(94)00996-8

Tetrahedron

Volume 51, Issue 4, 23 January 1995, Pages 1033-1054

https://doi.org/10.1016/0040-4020(94)00996-8 Get rights and content

Abstract

The constrained aromatic α-amino acid 2′, 6′-dimethyl-β-methyl tyrosine (Figure 1) was designed to provide specific local constraints to peptides or peptide mimetics. We report here methods for the total asymmetric synthesis of all four stereoisomers. The precursors used were α,β-unsaturated acid derivatives, (2E) 3-(4′)-methoxy-2′,6′-dimethyl-2-propenoic acid (5) and crotonyl chloride (6). In order to introduce chirality at both the α- and the β-positions of the amino acids, optically pure 4-phenyl-2-oxazolidinones (Xc) were coupled to 5 and 6. The key steps for the synthesis were: (1) a Michael type addition using either methylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex or 4-methoxy-2,6-dimethylphenylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex as nucleophiles; (2) an asymmetric bromination of the α-position of the N-acyloxazolidinones using di(n-butyl)boron triflate/DIEA/NBS as reagents at low temperature. In both cases, the stereoselectivies and yields were excellent; (3) amination was achieved in nearly quantative yield by treating the bromides with azide exchange resin via an S_N2 mechanism. (Electrophilic azidation using 2,4,6-triisopropylsulfonyl azide also was achieved). The excellent stereoselectivity (80–98% ee/de) and overall yield (30–60%) made these optically pure amino acids available in amounts practical for peptide synthesis and further conformational and structure-activity relationship studies of various peptide analogues.

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References (41)

V.J. Hruby
Life Sciences
(1982)
D.F. Veber et al.
Trends Neurosci.
(1985)
E.J. Milner-White
Trends Pharm. Sci.
(1989)
D. Jiao et al.
Tetrahedron
(1993)
R. Dharanipragada et al.
Tetrahedron Lett.
(1989)
E. Nicolas et al.
Tetrahedron Lett.
(1989)
R. Dharanipragada et al.
Tetrahedron
(1992)
L.W. Boteju et al.
Tetrahedron Lett.
(1992)
L.W. Boteju et al.
Tetrahedron
(1994)
Y. Ito et al.
Tetrahedron
(1991)

P. Magnus et al.

Tetrahedron Lett.

(1992)

K.E. Kövér et al.

J. Magn. Reson.

(1992)

D.A. Evans et al.

Tetrahedron Lett.

(1985)

H. Kessler

Angew. Chem. Int. Ed. Engl.

(1982)

H.I. Mosberg et al.

W. Kazmierski et al.

J. Med. Chem.

(1988)

V.J. Hruby et al.

J. Med. Chem.

(1991)

V.J. Hruby et al.

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Stereoselective total synthesis of topographically constrained designer amino acids: 2′, 6′-dimethyl-β-methyltyrosines

Abstract

Life Sciences

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Trends Pharm. Sci.

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Tetrahedron Lett.

Tetrahedron Lett.

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J. Magn. Reson.

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J. Med. Chem.