A versatile chiral building block 1 containing a bicyclo[3.2.1]octane framework has been prepared by employing either chemical or enzymatic resolution method. Thus, racemic alcohol (±)-11 used for chemical resolution and racemic acetate (±)-12 used for enzymatic resolution were first prepared from norbornadiene 5 via racemic enone (±)-1. On the asymmetric hydrogen transfer reaction using a chiral diamine-Ru^<II> complex (Ru^<II>-(IS,2S)-TsDPEN), (±)-11 furnished optically enriched (+)-1 (73%ee) and enantiopure alcohol (-)-11, while (±)-12 furnished enantiopure alcohol (+)-11 and enantiopure acetate (-)-12 under hydrolysis conditions in a buffer solution in the presence of Lipase PS. Enantiopure chiral building block 1 could be obtained in both enantiomeric forms from the resolution products thus obtained by employing conventional procedure. Owing to its biased framework, 1 exhibits inherent convex-face selectivity to give rise to a variety of aldol products 2 containing either a cyclohexanone moiety or cyclopentanone moiety by diastereoselective modification of its enone functionality and the secondary oxygen functionality. The aldols 2 carrying a cyclohexanone afford 3,4-substituted cyclohexanones, while the aldols 2 carrying a cyclopentanone afford 2,3-disubstituted cyclopentanones 4 by retro-aldol reaction. On the basis of the inherent stereochemical nature of the chiral building block 1 and the retro-aldol reactivity, diastereocontrolled synthesis of some natural products, 1α,25-dihydroxyvitarnin D3 calcitriol, an antitumor sesquiterpene (+)-vernolepin, a potential indole alkaloid intermediate yohimbone 39, an antibiotic diterpene (+)-ferruginol, and an analgesic alkaloid (-)-morphine, has been investigated. (1) Synthesis of calcitriol-Although the intended convergent synthesis of calcitriol using both enantiomers of the chiral building block 1 has not been accomplished yet, the construction CD-ring moiety 13 starting from (-)-1 has been completed and very close intermediate 20 of the A-ring moiety starting from (+)-1 has been attained. (2) Synthesis of vernolepin-A close intermediate 33 constituting a formal synthesis of (+)-vernolepin has been attained starting from (-)-1 by employing an acid-catalyzed retro-aldol reaction as the key step. (3) Synthesis of yohimbone-Yohimbone 39 has been accomplished in efficient manner involving one-step conversion of 36 into 38 through an acid-catalyzed tandem retro-aldol and intramolecular Pictet-Spengler reaction. (4) Synthesis of ferruginol-A novel and efficient route to (+)-ferruginol has been established using (+)-1 as starting material by discovering a novel tandem acid-catalyzed retro-aldol and oxonium ion-mediated hydrophenanthrene formation reaction. (5) Synthesis of morphine-Based on the tandem rertro-aldol and oxonium ion-mediated hydrophenanthren formation reaction discovered as the key step, a novel and efficient route to (-)-morphine has been developed starting from (-)-1.
