The 1,3 diol unit is an extremely common and recurring structural motif in many polypropionate-and polyacetatederived natural products. Given the current availability of a number of enantio-and stereoselective methods for the construction of -hydroxy carbonyl compounds, it is not surprising that one prominent pathway used for the construction of such arrays utilizes the reduction of -hydroxy ketones. A number of processes have been developed for this purpose, invariably involving hydride reducing agents. For example, Zn(BH 4 ) 2 has been commonly used to access syn 1,3 diols from -hydroxy ketones, presumably via formation of an intermediate zinc chelate, which undergoes reduction from the less sterically encumbered face. 1 DiMare has used a similar chelation strategy with protected -hydroxy ketones in which a discrete Lewis acid complex is first established with TiCl 4 , followed by introduction of a hydride reducing agent such as BH 3 ‚Me 2 S, and Prasad has reported a syn-selective reduction using (EtO) 3 B and NaBH 4 . 2 Similarly, boron aldolates can be induced to undergo chelate formation prior to workup and reduced stereoselectively with LiBH 4 , as shown by Patterson. 3 Anti 1,3 diol units are most commonly accessed via the reduction of -hydroxy ketones with tetramethylammonium triacetoxyborohydride, by a process believed to proceed via an internal delivery of hydride, as described by Evans. 4 Evans has also reported a modification of the Tishchenko reduction in which a complex prepared by SmI 2 reduction of benzaldehyde is used to reduce -hydroxy ketones to an anti monobenzoate derivative, 5 wherein hydride transfer occurs via an intramolecular process in a Meerwein-Ponndorf-Verley sense.Notable by their absence are methods based on sequential one-electron transfer, as opposed to hydride transfer. We became intrigued as to whether the structural features present in such -hydroxy or -alkoxy ketones might have a significant influence on the stereochemical outcome of such a sequence. One can readily imagine that chelated intermediates might be formed in "dissolving metal"-type reductions of such systems, particularly with oxophilic metals. We record herein the results of an investigation using SmI 2 in this role, which has led to the development of a very convenient, high-yielding, and stereoselective process.We began with a simple -hydroxy ketone substrate 1a to survey potential reaction conditions and proton sources. 6 Addition of a THF solution of SmI 2 to a solution of 1a in THF at 0°C, containing 2 equiv of water as the proton source, led to a very fast reaction (complete within 10 min) that afforded a 96% isolated yield of the desired diol product as a 83:17 mixture of anti and syn isomers. 7 No reaction was observed at -78°C or with tert-butyl alcohol as the proton source at 0°C (Table 1). Use of an excess (10 equiv) of water led to a 1:1 mixture of diastereomers, again in good yield.Much better results were obtained using MeOH as the proton source. In this case, the use of 2 equiv of MeOH at 0°C led ...

Studies leading to a total synthesis of Epothilones B and D are described. The overall synthetic plan was based on late stage fragment assembly of two segments representing C 1 -C 9 and C 10 -C 21 of the structure. The C 1 -C 9 fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a β-keto ester dianion. An enantioselective addition of such a stannane equivalent for a β-keto ester dianion was also used to fashion one version of the C 10 -C 21 subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C 10 -C 21 subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI 2 reduction of a β-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.

No abstract

A new reduction procedure for the stereoselective reduction of certain beta-alkoxy ketones is described. The method relies upon electron-transfer reduction using samarium diiodide in THF with MeOH as an additive. Reduction is facile for a number of alkoxy groups that can complex samarium effectively but is not observed with TBS or benzyl protecting groups. Experiments with deuterated methanol show that the stereoselectivity arises from protonation of a samarium carbanion intermediate.

No abstract