Progress in the Development of Methods for Asymmetric Organic Synthesis

Abstract

Methods for the enanticselecuve synthesis of chiral cyclohexane derivatives from aromatic carboxylic acids are presented. Birch reduction-alkylation of chiral benzamides of type 1 occur with high diastereoselectivities to give 1,4-cyclohexadiene derivatives with quaternary centers located at C(6). Early applications of this chemistry provided target structures with a quaternary center derived from C( I) of the starting benzoic acid derivative. Herein are described 1) the development of a more versatile Birch reduction-alkylation, 2) a practical "asymmetric linkage" between aromatic carboxylic acids and chiral acyclic structures, and 3) asymmetric syntheses of unnatural alkaloids; applications to opiate receptor pharmacology. INTRODUC'TlONWehavebeen involved with the development of enanuosetectivc methods for lhe synthesis of chiral cyclohexane derivatives from aromatic carboxylic acids? The inexpensive amino acid L-proline and the product of reduction with LiAll-4, Lsprclinol, serve as chiral auxiliaries to provide good to outstanding stereocontrol. As indicated in Scheme I, a wide range of substitucnts R on the benzoic acid nucleus is tolerated; subsutuents X at C(2) may take the form of alkyl, aryl, alkoxy and ttirnethylsily]. Although 2-dialky-Iamino substituents arc problematic in the chemistry shown in Scheme I, anthranilic adds may be successfully utilized by modiflcauon of the methodology (see Scheme V). Scheme IBirch reduction of the aryl nucleus provides a chiral amide enolate; enolate alkylations occur with high diastcreoselecuvitics to give 1,4-cycJohexadiene derivatives with quaternary centers located at C(6). This process in-volves l,4-chirality transfer from a stereogenic center associated with the chiral auxiliary to an Sp2 center located in the substrate. Jt is believed that enolate alkylations occur by the SN2 mechanism. Product yields are excellent even for sterically demanding alkylation reagents because the enolate center is Ilanked by three Sp2 hybridized carbon atoms (sec enolate 2). In rare cases where electron-transfer appears to be operating, intense colorations are observed and the enolate is converted to the starting bonzamide rather than the alkylated 1,4-cyclohexadiene.Hydrolysis of the enol ether (X =OMe) provides 2,2disubstituted cyclohex-S-cn-l-onca for a variety of synthetic applications.' It also is possible to generate 2,4-cyctonexadien-Lones, which have found utility in Diels-Alder' and 1,3-dipolar 4 cycloadditions.Chiral 2-substituted cyclchex-z-en-j-ones are available by Birch reduction followed by enol ether hydrolysis and double bond migration. Diastereoselective conjugate additions (1,5~hirality transfer) with organometallic reagents,' enol trimethylsHyl ethers" (the Mukaiyama-Michael addition) and allyl silanes" (the Sakurai reaction) provide tertiary stercocenters at CO) of the cyclohexanone ring; additional manipulations give access to trans-2,3disubstituted cyclohexanoncs with high enamiomcric purity.The chiral 2-substituted cyclohcx-2-en-l-one also can be prepared fro...

Photochemical and Acid-Catalyzed Rearrangements of 4-Carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one

“…Birch reduction of methyl 2-(trimethylsilyl)benzoate with lithium in NH 3 −THF in the presence of 1 equiv of tert -butyl alcohol at −78 °C, followed by addition of piperylene to consume excess metal and alkylation with methyl iodide gave diene 6 in 89% yield. The outstanding directive effects of trialkylsilyl substituents together with the potential for absolute stereocontrol by way of the asymmetric analogue of the conversion 5 → 6 suggest that this variant of the Birch reduction−alkylation will find important synthetic application. Allylic oxidation of 6 with t -BuOOH and pyridinium dichromate (catalytic) provided 1 in 86% yield (∼60% overall from benzaldehyde).…”

Preparation and Photochemical Rearrangements of 2-Phenyl-2,5-cyclohexadien-1-ones. An Efficient Route to Highly Substituted Phenols

“…Synthetic applications of the asymmetric Birch reductive alkylation of chiral nonracemic benzoic acid derivatives have been reviewed recently . Although several examples of Birch reduction of biaryl compounds had been described previously, the first report of Birch reductive alkylation of biphenyl carboxylic acid derivatives appeared in 1988 .…”

Organic Synthesis Methodology. Preparation and Diastereoselective Birch Reduction−Alkylation of 3-Substituted 2-Methyl-2,3-dihydroisoindol-1-ones

“…The Birch reduction−alkylation of substituted benzamides derived from l -prolinol has provided a wide range of enantiomerically pure cyclohexane derivatives for utilization in organic synthesis . Asymmetric total syntheses of (−)-longifolene and (+)-apovinamine are two decent examples of the applications by this methodology …”