Vitamin D synthons

The stereospecific synthesis of an A ring synthon of la-hydroxy vitamin D has been carried out. The ( )-allcene is cyclized to give the (E -c.xo-diene 155, and the (Z)-allcene affords the (Z)-e,xo-diene 156 stereospecifically[125,126]. These results can be understood by the cis addition and syn elimination mechanism. 

An asymmetric synthesis of a vitamin D ring a synthon employed this intramolecular cyclopropanation reaction (eq 23). ... 

Synthesis of a new C/D synthon of vitamin D from hydrodeoxycholic acid was performed by employing the type 11 reaction (Scheme 18). 

Parallel to this, new enzymatic techniques (especially in organic solvents) applied to preparation of several synthon precursors of vitamin D analogs have been developed. Here we summarize some of the major synthetic routes utilized in recent years, in which an enzymatic process was developed to synthesize the hormone la,25-dihydroxyvitamin D3 and its analogs. There are four main methods, three of which center on the preparation of A-ring synthons (A, B, and C) and one on CD-ring synthons (D). 

In method C, dienynes 193 are semihydrogenated to a previtamin structure that undergoes rearrangement to the corresponding vitamin D analog. The chemical synthesis developed in the Okamura laboratory for 194 (X = Y = H), starting with (5)-cavone, is probably the most efficient approach in this area [45], but the regioselective enzymatic acylations [46] and alkoxycarbonylations [47] of the four stereoisomers of 194 open the doors to a new family of synthon precursors to feed this route. 

This first chemoenzymatic synthesis [48] is not included m Fig. 1 but can be considered as a preparation of A-ring synthons in general in the steroid field, and particularly in area of vitamin D (Scheme 9). The stereo control of the quaternary chiral carbon center is one of the important subjects in asymmetrical synthesis. This issue prompted research on the use of chiral monoester 197, which can be obtained in multihundred gram scale by the pig liver esterase (PLE)-mediated hydrolysis of the corresponding symmetrical diester 196 [49]. Thus, an efficient methodology was developed for the preparation of chiral cyclohexene derivatives from cw-diester 196, using PLE in a biphasic system using phosphate buffer and acetone, to afford the chiral half-ester 197. Scheme 9 shows the efficient... 

In the catalyzed inverse electron demand Diels-Alder reaction of dienophile 1 with diene 2, a d.r. of 98 2 is observed. The adduct 3 is converted into the key synthon of la,25-dihydroxy-vitamin D382. 

Isopropylidene-D-erythrose has been obtained from 0-arabinose by a route which does not involve the intermediacy of the lactone.All of these processes suffer from either relatively low overall yields or the requirement of a large number of individual stages. The procedure described here, which is based on a similar oxidative degradation of L-ascorbic acid (vitamin C) to L-threonic acid, is undoubtedly the most expeditious route to the acetonide of Q-erythronolactone available. In addition, the starting material, erythorbic acid, is an inexpensive and readily available substance, commonly used as a food preservative. It is pertinent to note that recently L-ascorbic acid has itself found synthetic utility as a precursor to (R)-glycerol acetonide, an Important C3 chiral synthon, ... 

The synthesis of enynes is of interest in the chemistry of certain natural products. Terminal enynes occur in several natural products such as histrionicotoxin and laurencin, and the internal enyne unit is found along with polyacetylenes and allenes in natural products from Compositae and Umbelliferae. Both internal Z-and. E-enynes are also useful as precursors to stereochemically define d dienes on their partial reduction. A group from Phillips-Duphar has described an efficient synthesis of the functionalized enyne (95), which serves as the C5 synthon for the convergent synthesis of vitamin A. The l,3-dichloro-2-ether (94) is dechlorinated, substituted, and isomerized in one step on reaction with two molar equivalents of sodium acetylide in liquid ammonia, giving (95) with an E Z ratio... 

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