Indian Journal of Chemistry Vol. 45B, December 2006, pp. 2736-2744 An enantiospecific strategy to all four diastereomers of A-ring enyne synthon of 1α,25-dihydroxyvitamin D 3 A Srikrishna*, Santosh J Gharpure & P Praveen Kumar Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India E-mail: ask@orgchem.iisc.ernet.in Received 26 June 2006; accepted 22August 2006 Enantiospecific syntheses of derivatives all the four diastereomers of A-ring enyne synthon of 1α,25-dihydroxyvitamin D 3 (5-ethynyl-4-methylcyclohex-4-en-1,3-diol) have been described starting from the abundantly available monoterpene (R)-carvone, exploiting the isopropenyl group of carvone as an equivalent of an hydroxy group. A combination of Criegee rearrangement and Mitsunobu reactions has been strategically employed. Keywords: Vitamin D 3 , calcitriol, Criegee rearrangement, A-ring enyne synthon, carvone IPC Code: Int Cl. 8 C07C Like a chameleon, vitamin D has changed its colours many times over the past 70 years. To the nutritionist who discovered and named it, vitamin D appeared as an essential nutritional factor carrying out some fundamental role in bone. Biochemists showed it to be a sterol derived from 7-dehydrocholesterol 1 in the skin and therefore not a vitamin. To the physiologists working with the molecule in the early seventies, vitamin D revealed itself as a prohormone giving rise to an active principle 1α,25-dihydroxyvitamin D 3 2, and as such playing a major role in calcium homeostasis. The elegant work of Haussler and Pike has showed that 1α,25-dihydroxyvitamin D 3 2 to possess a specific nuclear receptor in target cells and thus to be a true steroid hormone. Through all of these different visions stretching over 80 years of research, the function of vitamin D has not deviated from that of a 'calcemic factor' responsible for maintaining a healthy skeleton. Its actions at the intestine to stimulate calcium and inorganic phosphate absorption, and at the bone, in juxtaposition with parathyroid hormone to stimulate bone resorption, are well established. Most recently vitamin D, through its active form 1α,25-dihydroxyvitamin D 3 2, may have exhibited its latest 'colour' as a potent differentiating agent involved in the recruitment and maturation of bone marrow derived cells into osteoclasts. In recent years, research activity in the synthesis of vitamin D 3 3 and its analogues has grown exponentially owing to the discovery that 1α,25-dihydroxyvitamin D 3 (calcitriol) 2, the hormonally active metabolite of vitamin D 3 and its analogues have much broader spectrum of activity than originally thought, in addition to the classical role of regulating calcium and phosphorous metabolism. Significant numbers of vitamin D analogues are being used as drugs and several of the analogues are at various stages of clinical trials, as drugs, for the treatment of various human disorders ranging from osteoporosis, psoriasis, leukemia, Alzheimer's disease, AIDS and various cancers. Owing to these biological activities, the synthetic activity in the research of vitamin D 3 and its analogues continues to flourish and several research groups have developed synthesis of vitamin D 3 and its analogues 1 . The synthetic approaches to vitamin D 3 3 and its analogues can be broadly classified into two types, viz. (i) Semisynthesis: The classical approach is patterned after the biosynthetic route leading to vitamin D 3 3 and also offer the industrial synthesis of the latter; and (ii) Convergent synthesis: An attractive synthetic approach, originally developed by Lythgoe 2 , is based on the coupling of an appropriate CD-ring fragment with a suitable A-ring fragment. In his pioneering work on vitamin D 3 synthesis, Lythgoe developed three A-ring synthons viz. the phosphine oxide 4, the cyclohexenaldehyde 5 and the enyne 6. Subsequently, many research groups have reported synthesis of A-ring synthons of vitamin D 3 analogues employing a variety of novel and innovative strategies 1 .