Syn-l,2-diols

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

Though the syn-l,3-diol relationship is ultimately established in the reductive decyanation vide infra), the alkylation is itself highly selective. Selectivities are typically greater than 100 1 in favor of the axial nitrile. This selectivity can be rationalized by a chair-like intermediate 15 (Scheme 3) for which equatorial alkylation is highly favored on steric grounds. Approach of the electrophile from an axial trajectory leads to a syu-pentane-like interaction. 

The syn-l,3-diol acetonide is ultimately established by reductive decyanation. These reactions proceed with exceptionally high selectivity. The selectivity observed in reductive decyanations could in principle have two origins ... 

Our group has also reported that the alkylation products of 4-cyano-l,3-diox-anes can serve as substrates for radical atom transfer reactions [41]. One such example is shown below (Eq. 17). Slow addition of tributyltin hydride/AIBN to a refluxing solution of cyanohydrin 115 generated the radical nitrile transfer product 116. This method, though somewhat limited in scope, can provide access to syn-l,3-diols which maybe unstable to the vigorous Li/NHg reduction conditions. 

Reductive decyanation. This reaction is a key step in a route to syn-l,3-diol acetonides from P-trimethylsilyloxy aldehydes (1). Reaction of 1 with trimethylsilyl cyanide followed by acetonation gives a 1 1 mixture of a protected cyanohydrin (2). This mixture is converted into a single isomer (3) on alkylation of the anion of the cyanohydrin acetonide. Reductive decyanation with Na-NH3 at -78° produces a syn-diol acetonide (4). The apparent retention of configuration in the reduction results from preferential formation of an intermediate axial anion. 

The enolate, generated by TBAF cleavage of the enoxysilane derived from phenylselanylacetone, was trapped with benzaldehyde [39] (Scheme 33). The antUsyn ratio of diastereoisomers, easily identified by and Se NMR, was dependent on the temperature and the E or Z structure of the substrate. The borane reduction followed by a conventional acetonization led to a protected syn, syn-l,3-diol. 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

In the presence of a fluoride ion source, DMS enolates work as bifunctional silicon reagents to enable the tandem aldol-reduction reaction of aldehydes (Scheme 10.35) [102]. The TBAF-catalyzed reaction of DMS enolates with aldehydes produces syn,syn-l,3-diols with moderate to high diastereoselectivity. 

Aldolization and related reactions. Tartaric acid-derived acyloxyborane complexes are shown to be useful catalysts for asymmetric aldol reactions. (5)-4-Isopropyl-3-tosyl-l,3,2-oxazaborolidin-5-one is an excellent cataly.st, not only for the aldolization " between a silyl enol ether and an aldehyde it also reduces the products to afford syn-l,3-diols. ... 

The condensation with f-buylacetoacetate delivers the starting material for the diastereoselective reduction to the racemic syn-l,3-diol. The reason for using the t-butyl ester is, that this, unlike a methyl or ethyl ester, does not cyclise subsequently to a lactone, which moreover would epimerize readily at the allyl... 

As transition state 371 indicates, the transfer of the boron atom to the carbon chain poses a regioselectivity problem. With tricyclohexane phosphine as the Ni-ligand the 1,5-diol 372 is by far the major reaction product (>20 1) and a number of other phosphine ligands led to the same result with varying chemical yields. When, however, trimethylsilyl-phosphine was chosen as the Ni-ligand, the situation changed completely and the syn-l,3-diol 373 was obtained in a 12 1 ratio. 

Backvall and coworkers also reported a DYKAT of unsymmetrical 1,3-diols with one small and one large group [83]. The method makes use of (0 selective enzymatic acylation of the least sterically hindered alcohol ii) epimerization of a secondary alcohol and in) intramolecular acyl migration in a syn-l,3-diol monoacetate in a one-pot procedure. Shvo s catalyst 1 (4 mol%) was used for the epimerization. CALB was used for the enzymatic resolution along with isopropenyl acetate as the acyl donor. The products were obtained in moderate to high yields (53-73%) and with ee values exceeding 99% in all cases. Also, the diastereomeric ratios for the sy -diacetates were consistently high, typically >90% syn (19). 

Rychnovsky SD, Zeller S, Skalitzky DJ, Griesgraber G. Stereoselective synthesis of syn-l,3-diol acetonides by reductive decyanation of cyanohydrins. J. Org. Chem. 1990 55 5550-5551. 

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