Ketones, reaction with zinc borohydride

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

The synthesis of Cbz-protected D-valine methyl ester (296) (Scheme 40) begins with addition of an organometallic reagent to the ester function of 282. The resulting phosphonate 290 undergoes a Wittig reaction with isobutyraldehyde to afford 291. Chelation-controlled reduction of the ketone with zinc borohydride furnishes the a /-alcohol 292 (98% de). A [3,3] rearrangement of trifluoroacetimidate 293 produces allylic amine 294. Elaboration of the olefin to an ester furnishes the D-valine derivative 296 with 85% ee [101]. 

Thioketones (6) are slowly oxidised in air to the corresponding ketones, and they are reduced by the majority of common reducing agents to the thiols (29). Sodium borohydride often gives the optimum yield of the thiol. On the other hand, reduction with zinc-hydrochloric acid affords the hydrocarbon (30) the latter reaction is analogous to the Clemmensen reduction of ketones (Scheme 17). 

A modestly enantioselective pyrrole carbinol formation has been investigated <05SL2420>. Treatment of lithium pyrrolate with a ketoaldehyde in the presence of a chiral ligand preferentially led to the formation of pyrrole carbinol 49 (50% ee). A hydroxy-directed reduction of the ketone in the side chain by the addition of zinc borohydride provided 50 (88% de). Pyrrole carbinols serve as convenient precursors to aldehydes. A subsequent deprotective Horner-Wadsworth-Emmons reaction involving 50 and phosphonate ester 51 gave unsaturated ester 52. 

The synthesis of 3-benzoyl-A-homo-3-aza-5) -androstan-16-one (37), an analogue of the alkaloid samanine (36) from Salamandra maculosa, has been reported. Sodium borohydride reduction of the known compound (38) followed by tosylation alTorded the tosylate (39) the nitrile group was reduced by diborane and cyclized by benzoic anhydride-pyridine to the derivative (40a) similar cyclization with acetic anhydride-pyridine yielded the related acetamide (40b). This cyclization requires one equivalent of anhydride and the uncyclized amide is not an intermediate in the reaction. Jones oxidation of (40a) was followed by conversion into a benzylidene ketone derivative (41) with benzaldehyde-KOH in methanol. Reduction of (41) with sodium borohydride and acetylation furnished (42). Treatment of compound (42) with ozone followed by mild zinc reduction produced an acetoxy-ketone, which was further reduced by Zn-HBr-CH2Cl2 to the ketone (37). 

Diselenanes (27) are available through the reactions of 1,3-propanediselenols with aldehydes and ketones in the presence of a Lewis acid such as zinc(II) chloride (Equation (3)) <85T4793, 93TL8517>. The diselenols are normally synthesized from the corresponding diselenocyanates by reduction with, for example, sodium borohydride, or with sodium in liquid ammonia <71BSB639>. 

---