Highly Stereoselective and Efficient Synthesis of Functionalized Cyclohexanes with Multiple Stereocenters

Abstract

Chiral 7‐oxo‐2‐enimides 2, which were readily obtained through a silyloxy‐Cope rearrangement of syn‐aldol products 1, have proved to be versatile substrates for a one‐step, highly efficient and stereoselective synthesis of functionalized cyclohexanes. Organocopper and organoaluminum reagents have been employed as nucleophiles that underwent a conjugate addition to the enimide structure of the Cope products. The enolates formed in situ attacked the aldehyde or iminium ion in an intramolecular aldol or Mannich reaction, respectively, to directly yield cyclohexanols 3 and 4 and cyclohexylamines 5, respectively, in moderate to good yields and with excellent stereocontrol.

Catalytic Asymmetric Reactions for Organic Synthesis: The Combined C−H Activation/Siloxy-Cope Rearrangement

“…The Rh 2 ( R -DOSP) 4 -catalyzed reaction followed by microwave-assisted thermal rearrangement of the intermediate gave the (4 R ,5 R )-aldehyde 34 in 35% yield as a single diastereomer with 76% ee (eq 9). The absolute stereochemistry of the product ([α] 23 D −41.8 ( c 0.44, CHCl 3 )) was confirmed by comparison with the literature compound ([α] 20 D −51.0 ( c 1, CHCl 3 )) 5c. As both enantiomers of the catalyst are available, the combined C−H activation/siloxy-Cope rearrangement can be used to prepare selectively any of the four stereoisomers of the product.…”

“…A convenient approach is to establish a proximal stereogenic center through 1,2-asymmetric induction followed by chirality transfer through a sigmatropic rearrangement. , In this way the highly organized transition state of the pericyclic process ensures that the enantioinduction installed in the initial asymmetric step is maintained. A very attractive example of this strategy is the combination of the chiral auxiliary based asymmetric syn -aldol reaction (between the enolate of the unsaturated ester 1 and the unsaturated aldehyde 2 ) to form the β-siloxyester 3 with the siloxy-Cope rearrangement of 3 to form the silyl enol ether 4 (Scheme ). − In this paper we describe an entirely different strategy for achieving the equivalent of the tandem aldol reaction/siloxy-Cope rearrangement. The key step is a rhodium catalyzed enantioselective C−H activation between vinyldiazoacetate 6 and allyl silyl ether 5 , which leads to the formation of 4 either directly or via the β-siloxyester 3 .…”

“…Even though a mixture of the direct C−H activation product 3 and C−H activation/Cope rearrangement product 4 might be formed, the siloxy-Cope rearrangement of 3 could be used to drive the reaction to the desired product 4 . This catalytic approach obviates the need for a chiral auxiliary, which was used in the conventional tandem aldol reaction/siloxy-Cope rearrangement, − enhancing the practical appeal of the chemistry. Herein we describe the realization of the chemistry and outline the scope and limitations of such an approach.…”

Synthesis of Nitrogen-Functionalized Cyclohexanes Using Chemoselective Conjugate Addition of Phenyllithium to Linear .OMEGA.-Nitro-.ALPHA.,.BETA.,.PSI.,.OMEGA.-Unsaturated Ester and Subsequent Stereoselective Intramolecular Nitro-Michael Cyclization

“…[19][20][21][22][23] Based on these progresses, we designed a synthesis of carbocycles with three contiguous chiral centers by the sequential two reactions of the conjugate addition of a nucleophile to a nitroalkene moiety of a w-nitro-a,b,y,w-unsaturated ester and subsequent intramolecular Michael addition of a nitronate to an enoate moiety. [24][25][26][27] We have been involved in the development of the conjugate addition 28) -based cyclization methodology in these years. [29][30][31][32][33][34][35] Described herein is the full details of a new methodology for the construction of nitrogen-functionalized cyclohexanes with three contiguous chiral centers 1 by the sequential nitroalkene-selective conjugate addition of phenyllithium to a w-nitro-a,b,y,w-unsaturated ester 3 and subsequent stereoselective intramolecular nitro-Michael cyclization of 2 (Chart 1).…”