The Triol Route

It was not readily apparent that the assignment of keto enal 73-a was incorrect until we pursued the subsequent formal [3 + 3] cycloaddition of the alleged 73-a. with pyrone 12. The reactions of keto enal 73-a with 

It is reasonable to propose that a retro-aldol aldot sequence had occurred during the attempted preparation of 73-a at the stage of 

On the other hand, the desired pentacyclc 75 was calculated [AM1-SpartanTW] to be mure stable than 74 by -1.0 kcal mol 1, but attempts using KiCOj/MeOH or DBU to equilibrate 74 to 75 via another retro-aldol-aldo sequence failed 

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Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

To avoid this unexpected ntro-aldol-aldol predicament, the desired pentacyclc 75 was prepared via yet another route. As shown in Scheme 17, the triol 71 was oxidixed using I.cy s TPAP oxidation without protecting... 

The disilyl derivative of all-cix-1,2-epoxycyclopentane-3,5-diol 5 7 was treated with diethyloctynylalane to afford after cleavage of the silylether function the triol 58. This triol was convered via the acetonide to the benzyl ether 59. Hydrolysis with aqueous trifluoroacetic acid yielded the diol benzylether 60 which could be prepared by an alternative route as well. This route proceeds via the monotrityl epoxide 61 and benzylation to the trityl benzylether 62 and then reaction with diethyl octynyl alane to the diolbenzylether 60 and the isomeric 1,3-diol. 

Rubrosterone (424) has also been synthesized by an analogous route (Scheme 30). The 6-keto-diol (420) was converted into the triol (421). This, in turn, was transformed into the enol acetate (422), as indicated in Scheme 29. Reaction... 

Another class of metabolites of testosterone are the 19-carbon triols with hydroxyl groups at positions 3, 16 and 17. Androstane-3a,16a,17/8-triol (LXV) and etiocholane-3a,16a,17/3-triol (LXVII) have been isolated from human urine and on the basis of chemical similarity are believed to be metabolites of testosterone. The configuration of the two hydroxyl groups in ring D is identical with that of estriol, a recognized metabolite of the female sex hormone. All of these are in a quantitative sense minor metabolites, a fact which suggests the production of these substances is not part of the principal route of transformation. 

Mulzer et al. 553) synthesized (-)-nephromopsinic acid by the addition of a chiral allylic bromide to tetradecanal (see Scheme 36). The same group 628, 666) also described total syntheses of (-)- and (+)-roccellaric acid and (-)-dihydroprotolichesterinic acid and secured the relative configuration of (+)-roccellaric acid by an X-ray analysis. One route started from (2S,3E)-l,2-isopropylidene-5-0-benzyl-3-pentene-1,2,5-triol (42) (see Scheme 37). The second route included the ozonisation of methyl-(2RS,3R,4E)-3-benzyloxy-5-hydroxy-oxolan-3-one and subsequent condensation with tridecyltriphenylphosponium bromide (see Scheme 38). Finally they synthesized (-t-)-roccellaric acid and (-l-)-dihydroprotolichesterinic acid from D-glucose as the chiral pool (552) (see Scheme 39). 

A sligth modification of this synthetic methodology allowed the development of a novel route to 4-amino-5-(hydroxymethyl)cyclopentane-l,2,3-triols, some of them display significant glycosidase inhibition properties. In addition, a similar approach starting from L-idose allowed the first polyhydroxylated dspentacine to be prepared.78... 

To avoid the C4a-C5 epoxide issue, a new route to the keto enal "73-a" was pursued [Scheme 15]. Triol 71 could be attained via LAH reduction of epoxy diol 49, and acylation of 71 would lead to the acetate 72 whose stereochemistry was assigned by X-ray analysis. The subsequent TPAP oxidation of 72 followed by deacylation and PCC oxidation led to the keto-enal "73-a" in 73% overall yield. 

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