A Tandem Conjugate Addition/Cyclization Protocol for the Asymmetric Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives

Stephen G. Davies; Nadeam Mujtaba; Paul M. Roberts; Andrew D. Smith; James E. Thomson

doi:10.1021/ol9004118

A Tandem Conjugate Addition/Cyclization Protocol for the Asymmetric Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives

Stephen G. Davies, Nadeam Mujtaba, Paul M. Roberts, Andrew D. Smith, James E. Thomson

Research output: Contribution to journal › Article › peer-review

Abstract

Condensation of tert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide initiates a tandem conjugate addition/cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield. Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-alpha-methylbenzyl protecting groups without compromise of the diastereo- or enantiopurity.

Original language	English
Pages (from-to)	1959-1962
Number of pages	4
Journal	Organic Letters
Volume	11
Issue number	9
DOIs	https://doi.org/10.1021/ol9004118
Publication status	Published - 7 May 2009

Keywords

PARALLEL KINETIC RESOLUTION
DIELS-ALDER REACTION
HOMOCHIRAL LITHIUM AMIDES
FORMAL TOTAL-SYNTHESIS
BETA-AMINO ACIDS
CYCLIZATION-ELIMINATION REACTION
MARTINELLIC ACID
TETRAHYDROQUINOLINE DERIVATIVES
FACILE SYNTHESIS
ALPHA,BETA-UNSATURATED ESTERS

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title = "A Tandem Conjugate Addition/Cyclization Protocol for the Asymmetric Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives",

abstract = "Condensation of tert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide initiates a tandem conjugate addition/cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield. Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-alpha-methylbenzyl protecting groups without compromise of the diastereo- or enantiopurity.",

keywords = "PARALLEL KINETIC RESOLUTION, DIELS-ALDER REACTION, HOMOCHIRAL LITHIUM AMIDES, FORMAL TOTAL-SYNTHESIS, BETA-AMINO ACIDS, CYCLIZATION-ELIMINATION REACTION, MARTINELLIC ACID, TETRAHYDROQUINOLINE DERIVATIVES, FACILE SYNTHESIS, ALPHA,BETA-UNSATURATED ESTERS",

author = "Davies, {Stephen G.} and Nadeam Mujtaba and Roberts, {Paul M.} and Smith, {Andrew D.} and Thomson, {James E.}",

year = "2009",

month = may,

day = "7",

doi = "10.1021/ol9004118",

language = "English",

volume = "11",

pages = "1959--1962",

journal = "Organic Letters",

issn = "1523-7060",

publisher = "American Chemical Society (ACS)",

number = "9",

}

TY - JOUR

T1 - A Tandem Conjugate Addition/Cyclization Protocol for the Asymmetric Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives

AU - Davies, Stephen G.

AU - Mujtaba, Nadeam

AU - Roberts, Paul M.

AU - Smith, Andrew D.

AU - Thomson, James E.

PY - 2009/5/7

Y1 - 2009/5/7

N2 - Condensation of tert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide initiates a tandem conjugate addition/cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield. Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-alpha-methylbenzyl protecting groups without compromise of the diastereo- or enantiopurity.

AB - Condensation of tert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide initiates a tandem conjugate addition/cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield. Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-alpha-methylbenzyl protecting groups without compromise of the diastereo- or enantiopurity.

KW - PARALLEL KINETIC RESOLUTION

KW - DIELS-ALDER REACTION

KW - HOMOCHIRAL LITHIUM AMIDES

KW - FORMAL TOTAL-SYNTHESIS

KW - BETA-AMINO ACIDS

KW - CYCLIZATION-ELIMINATION REACTION

KW - MARTINELLIC ACID

KW - TETRAHYDROQUINOLINE DERIVATIVES

KW - FACILE SYNTHESIS

KW - ALPHA,BETA-UNSATURATED ESTERS

U2 - 10.1021/ol9004118

DO - 10.1021/ol9004118

M3 - Article

SN - 1523-7060

VL - 11

SP - 1959

EP - 1962

JO - Organic Letters

JF - Organic Letters

IS - 9

ER -

A Tandem Conjugate Addition/Cyclization Protocol for the Asymmetric Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives

Abstract

Keywords

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