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

Abstract

The conjugate addition reaction of a carbonucleophile to a nitroalkene 1) has been proven to be one of the powerful methodologies for a carbon-carbon bond formation. [2][3][4][5][6][7][8][9][10][11][12][13][14] An organolithium reagent rapidly undergoes the Michael addition to a nitroalkene with reasonably high stereoselectivity 15,16) and were incorporated in the total syntheses of biologically active compounds as the critical step 17,18) As well the nitro-Michael reaction has been attracted much attentions due to its relevance in the strategy of synthetic chemistry. [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).Nitroalkene-Selective Conjugate Addition of Phenyllithium The key to our approach sits on the possible chemoselectivity in the conjugate addition of a carbonucleophile to a nitroalkene moiety in the presence of another Michael acceptor, an enoate in the same molecule 3. We found the chemoselectivity was available from a model reaction. The reaction of one equiv of phenyllithium with a mixture of an equal amount of trans-b-nitrostyrene (4) and tertbutyl trans-3-phenylpropenoate (5) in an each 0.05 M THF solution at Ϫ78°C for 15 min afforded a nitroalkene-selective conjugate addition product, 2-nitro-1,1-diphenylethane (6) in 88% isolated yield, and 95% of 5 was recovered unchanged (Chart 2). This reaction clearly demonstrated that the reactivity of a nitroalkene is superior to an enoate, and a nitroalkene-selective reaction is possible with an organolithium reagent.Nitroalkene-Selective Conjugate Addition of Phenyllithium to w w-Nitro-a a,b b,y y,w w-Unsaturated Ester A wnitro-a,b,y,w-unsaturated ester 3 was prepared via four steps from 7 in 65% overall yield by the modified procedure developed by Denmark 36) (Chart 3). The Wittig reaction of 7 gave an alcohol 8, which was then oxidized by the Pfitzner-Moffat method to give a trans-aldehyde 9 after chromatographical separation of Z-isomer. The nitro-aldol reaction of 9 with nitromethane was catalyzed by triethylamine giving 10 and was followed by dehydration with trifluoroacetic anhydride and triethylamine to afford 3 in 65% overall yield from 7.The reaction of 3 with phenyllithium in a 0.05 M THF solution at Ϫ78°C for 15 min gave a nitroalkene-...

Stereocontrolled Access to Enantiopure 7-Substituted cis- and trans-Octahydroindoles

“…The same stereochemical pattern resulted from the chemoselective reduction of 2a – e with Et 3 SiH (or Ph 3 SiH)/ TiCl 4 (see C in Scheme ), affording cis -octahydro­indolones 8a – e and, after Na/liq. NH 3 -promoted debenzylation, 9a – e (Scheme ).…”