Conjugate reduction 420 Subject

Reduction of a conjugated enone to a saturated ketone requires the addition of two electrons and two protons. As in the case of the Birch reduction of aromatic compounds, the exact order of these additions has been the subject of study and speculation. Barton proposed that two electrons add initially giving a dicarbanion of the structure (49) which then is protonated rapidly at the / -position by ammonia, forming the enolate salt (50) of the saturated ketone. Stork later suggested that the radical-anion (51), a one electron... 

Corey and Chaykovsky had discovered that dimethyl sulfoxide is converted to methyl-sulfinyl carbanion upon treatment with sodium hydride114 and that this conjugate base of DMSO reacts with various electrophiles115. This finding has opened up various reactions with a-sulfmyl carbanions derived from sulfoxides, since the sulfinyl function can be removed either by thermolysis or by subjecting the compound to reductive desulfurization. Thus a-sulfmyl carbanions have become versatile synthetically useful reagents. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

That molecule is then subjected to the standard carbonyl reduction, Birch reaction, oxidation, ethynylation and, finally, hydrolysis sequence (see 50 to 53). Hydrolysis of the enol ether under more strenuous conditions than was employed with 53 gives the conjugated ketone 65. The carbonyl group is then reduced to afford the corresponding 3p-alcohol (66). Exhaustive acetylation affords the potent oral progestin methynodiol diacetate (67). 

In contrast to the conjugated system, the reactivity of hexahydro-isoxazolo[2,3-tf] pyridines has been the subject of considerably more attention, which can most certainly be attributed to its greater synthetic potential, as demonstrated by the synthesis of many complex natural products. However, most of the reactions reported since 1996 have been known for many years and the last decade was in fact characterized by their use in syntheses or optimization. After a brief survey of the thermal reactions, procedures involving the reductive cleavage of the N-O bond will be detailed. 

Coumarin (7.88) is a well-known 6-lactone (six-membered ring) of natural origin found in various preparations such as some tobaccos, alcoholic beverages, and cosmetics. Besides reactions of oxidation, reduction, and conjugation, coumarin is also subject to lactone hydration in vivo and in the presence of microsomes [170-174], The resulting metabolites include ortho-coumaric acid (7.89) formed directly from coumarin, 3-(2-hydroxyphenyl)-propionic acid (7.91) formed following reduction of coumarin to dihydrocou-... 

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