1,4-Addition, Luche reduction

The Luche reduction is an excellent method for the 1,2-reduction of a,p-unsaturated ketones. In addition, ketones are reduced selectively in the presence of aldehydes. 

During the course of developing a synthetic method for the central eight-membered ring of Taxol, the preparation of alcohol 5 was required.7 Thus, the Luche reduction of ketone 4 proceeded smoothly to give 5 with undefined stereochemistry. This reaction best demonstrates the enhanced regioselectivity obtained in the Luche process. In addition to... 

The stereoselectivity seen in the reduction of the seven-membered ketone above has proved to be general. This particular result, rationalized by the propensity for pseudoaxial hydride addition under Luche conditions, proved useful in the convergent total synthesis of Gymnocin-A, a polycyclic ether toxin isolated from the red tide dinoflagellate—Karenia mikimotoi.u The Luche reduction was used for the production of allylic alcohol 9 from ketone 8 in 84% yield. Luche conditions were similarly applied to the synthesis of the related polycyclic ether toxin gambierol.12... 

In addition, the trisaccharides 91 and 92 can be further converted into eight members of the cleistetroside family of natural products (Scheme 1.16 and Scheme 1.17). This divergent route began with the selective Pd-catalyzed glycosylation of the free C-3 alcohol in 91 and 92 and a subsequent Luche reduction to afford tetrasaccharides 93 and 94 (Scheme 1.15). 

This route began with formation of the aryl Grignard reagent firom 18 followed by addition of 3-ethoxy-cyclopent-2-enone 41) to form enone 4 in over 80% yield.( 2) A Luche reduction (77) formed allylic alcohol 10, which was subjected to Mitsunobu conditions with N,0-... 

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

Bu.AlH, Zn(BH4)2, (/-PrO)2TiBH4 9-BBN, and CeCl3-NaBH4 (Luche reagent) favor 1,2-additions. The latter reagent is especially suited for selective reductions of a,P-unsaturated aldehydes and ketones to the corresponding ally lie alcohols. 

J.-L. Luche, L. Rodn guez-Hahn, and P. Crabbe, J.C.S. Chem. Comm., 1978,601. The paper refers to carvone (18) reduction but the formulae depicted correspond to carvotanacetone and carvo-tanacetol. For additional complex metal hydride reduction data, see Vol. 1, p. 39, ref. 155. 

A key step in the preparation of a new gibberellin, GA99, involved the reduction under Luche conditions of a Au -2-one derivative to furnish the critical 2p-stereochemistry.17 While the 2-oxo group in 12 was resistant to reduction, presumably due to in situ ketol formation, the methoxymethyl ester derivative was reduced satisfactorily to the desired 2p-epimer 13 using the combination of CeCU and NaBtU. This combination efficiently and selectively delivered the hydride to the more hindered a-face of the A-ring. This example further demonstrates the propensity for hydride delivery via axial addition under Luche conditions. 

Sol 9. (c) Sodium borohydride in the presence of CeCls selectively reduces a,P-unsaturated carbonyl compounds into allylic alcohols. It is called Luche s reduction. The selective 1,2-addition is facilitated by the strongly oxophilic Ce " " ion, which coordinates with the carbonyl oxygen. The allylic alcohol I then undergoes mercury catalyzed fran -etherification to give allyl vinyl ether (Claisen substrate), which readily undergoes [3,3] shift on heating to give II. 

Trost coined the term chemoselective to describe the process where one of two similar functional groups is made to react, while the other is not affected or affected to a lesser extent [1]. This discrimination usually results from nuanced changes to a reagent s behavior, e.g., by addition of a salt. A typical example is the modification of sodium borohydride reduction by addition of cerium chloride in the Luche process, whereby the double bond of an ot-enone is not saturated during the reaction [85]. Similarly, a new approach to chemoselective reaction of n-pentenyl donors was soon to emerge. 

Petrier and Luche have reported preliminary results from a study of the reductive properties of an aqueous Zn—NiCl2 (9 1) system [235]. Selective reduction of a,p-unsaturated carbonyl compounds was reported to occur in water/ethanol mixtures. Ultrasound increases the rate of the reaction, but its role is not simply that of an initiator as chemical activation of the zinc, using copper iodide or ammonium chloride, fails to effect reduction of the substrate. In addition, the authors stress that reaction does not occur in the absence of water. Reduction occurs preferentially at the double bond of the enone and is virtually complete before reduction of the carbonyl group begins. This degree of selectivity is not observed in the case of a,p-unsaturated aldehydes. 

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