Conjugate addition asymmetric synthesis

Peltier HM, Ellman JA. A-sulfinyl metalloenamines conjugate additions asymmetric synthesis of piperidines. 7. Org. Chem. 2005 70(18) 7342-7345. 

Davies, S.G., Sanganee, H.J., and Szolessanyi, P. (1999) The SuperQuaf (R)-4-phenyl-5,5-dimethyl oxazohdin-2-one as an effective chiral auxiliary for conjugate additions asymmetric synthesis of (-)-aplysilamide B. Tetrahedron, 55, 3337-3354. 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

The asymmetric synthesis of / -branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to optically active Arabinose-derived c -unsaturated A-acyloxazolidinones (Scheme 47). Efficient stereocontrol was achieved using different optically active bicyclic oxazolidinones, yielding (.R)- or ( -configured / -branched carboxylic acid derivatives.136a... 

Copper has long played a dominant role in stoichiometric organometallic reactions in synthesis. Organocuprate mediated conjugate addition reactions are a cornerstone of carbon-carbon bond-forming reactions. Its preeminence has not been overlooked in the search for asymmetric versions of the reaction (134-136). However, the requirement for stoichiometric amounts of the metal has dampened efforts to introduce chirality into this process. 

Conjugate addition. In general, the use of chiral auxiliaries able to promote chirality transfer with a predictable stereochemistry on newly generated stereocenters is recognized as indispensable in asymmetric synthesis.79... 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series Vol. 9, Pergamon Press, Oxford, 1992 B. E. Rossiter and N. M. Swingle, Chem. Rev., 92, 111 (1992) J. Leonard, E. Dtez-Barra and S. Merino, Ear. J. Org. Chem., 2051 (1998) M. P. Sibi and S. Manyem, Tetrahedron, 56, 8033 (2000) N. Krause and A. Hoffmann-Roder, Synthesis, 171 (2001) K. Tomioka and Y. Nagaoka, in Comprehensive Asymmetric Catalysis (Eds. E. N. Jacobsen, A. Pfaltz and H. Yamamoto), Vol. Ill, Chap. 31.1, Springer, Berlin, 1999 K. Tomioka, in Modem Carbonyl Chemistry (Ed. J. Otera), Chap. 12, Wiley-VCH, Weinheim, 2000. 

Alkenylcatecholborane 11 is a good reagent for the conjugate addition and is easily obtained by the hydroboration of an alkyne with catecholborane. One-pot asymmetric synthesis of the conjugate addition product, /9-alkenyl ketone, is possible starting from an alkyne and catecholborane without isolation of the alkenylcatecholborane [12]. 

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