Diastereoselective reactions, a,P-amides

The formation of five-membered tetrahydrothiophene rings using nonsymme-trical reaction partners usually occurs with high regioselectively. In most cases, a stereospecific reaction was observed (9,27,94). Recently, a diastereoselective cycloaddition of the parent species la to various chiral a,p-unsaturated amides was also reported (32,95). 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

This process was also extended to the formation of /3-hydroxylactams from a ,/3-unsaturated amides with tethered keto-amides 249 (Scheme 111) (179-181). Various substrates underwent cyclizations resulting in the corresponding /3-hydroxylactams 250 with high diastereoselectivities (>95 5) and moderate yields (52-70%). The reaction was tolerant of a wide range of ketones including alkyl, aromatic, and heteroaromatic ketones. Substituents on the /3-position of a,p-unsaturated amides were not well tolerated. Acryloyl amides were found to be the best substrates for this type of cyclization. In addition, crotonoyl amide also underwent cyclization, but conversions and reaction rates were diminished. A... 

In a complementary study, the use of Ai-benzyl-2(/ )-methoxy-(-F)-10-bornylamide as chiral lithium amide in the addition to a,p-unsaturated esters, followed by an aldol reaction with aromatic and aliphatic aldehydes, gave products similar to 62 with diastereoselectivities up to 78% [66]. 

Diastereoselectivity in the subsequent cyclization reaction originates from the Lewis acid that catalyzes the reaction. If a chelating Lewis acid such as titanium tetrachloride is used, only the cis-isomer 184 was obtained. If the reaction was catalyzed by boron trifluoroetherate, a 5 1 ratio in favor of the trans-isomer 185 was observed. The cis-isomer stems from the proposed transition state 183, which forces the evolving tertiary alcohol on the same side of the ring as the ester or amide functionahty. The relative stereochemistry of the cis-product was determined by transforming the cyclization product into a P-lactone [61]. 

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