Hydroxymethylene derivatives reduction

A 1,2-carbonyl transposition sequence based on the Woodward dithioacetalisa-tion reaction was used to relocate a carbonyl group in 95.1 [Scheme 2.95] to the adjacent position in 95 6.190 A total of 6 steps were required in which the key step was the dithioacetalisation of the a-hydroxymethylene derivative 95 2. After reduction of the carbonyl group, the dithiane was hydrolysed to the a-acetoxy ketone whence dissolving metal reduction removed the acetate function. 

The second synthesis of septicine used as starting material ethyl homovera-trate, which was formylated to the a-hydroxymethylene derivative (24). Controlled reduction of (24) with sodium borohydride gave mainly the desired )5-hydroxyester, which was converted into the chloride and condensed with ethyl 2-pyrrolidinyl acetate to yield the diester (25). Dieckmann cyclisation of... 

Since the jS-ketoaldhydes that result from acidification exist with the formyl group extensively enolized, the compounds are often referred to as hydroxymethylene derivatives. The formation of the product is governed by thermodynamic control therefore, the dominant product expected from unsymmetrical ketones can be predicted on the basis of considerations of relative stability. Once formed, hydroxymethylene compounds have several synthetic uses. A hydroxymethylene group can be converted to methyl via reaction with a mercaptan followed by reduction. ... 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

Reactions of Enols and Enolate Anions.—Several methods are described for transposition of an oxo-function to the adjacent site. They involve formation of a suitable a-substituted derivative (hydroxymethylene ° or benzylidene ) and subsequent steps which transform the substituent into an isolated oxo-group. Condensations leading to both the 2-hydroxymethylene- and the 2-arylidene-3-oxo-steroids are described for 3-ketones of the 5jS-series, and also of the 5j8,9j5,10a-( retro ) series.Condensations of aromatic aldehydes at C-2 in the 5 -series are unusually slow enolisation towards C-4 is preferred, but steric compression between C-4 and C-6 in 5/3-compounds severely hinders the condensation reaction at C-4, allowing reaction at C-2 via the 2-enol. Reduction of a 21-hydroxymethylene-pregnan-20-one (337) with sodium borohydride afforded the homopregnanediol (338), although reduction of enolised P-dicarbonyl compounds frequently proceeds via elimination to give enones, and thence allylic alcohols. 

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