SULFUR-DIRECTED REGIOSELECTIVE RADICAL CYCLIZATION LEADING TO BETA-LACTAMS - FORMAL SYNTHESIS OF (+/-)-PS-5 AND (+)-THIENAMYCIN
SULFUR-DIRECTED REGIOSELECTIVE RADICAL CYCLIZATION LEADING TO BETA-LACTAMS - FORMAL SYNTHESIS OF (+/-)-PS-5 AND (+)-THIENAMYCIN
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DOI：
10.1021/jo00110a035
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发表时间：
1995-03-10
影响因子：
3.6
通讯作者：
IKEDA, M
中科院分区：
文献类型：
--
作者：
ISHIBASHI, H;KAMEOKA, C;IKEDA, M
报道了一种由三丁基锡氢化物(Bu(3)SNH)催化N-乙烯基-α-溴代酰胺(S)在N-乙烯基端自由基环化合成β-内酰胺的新方法。N-[2-(Phenylthio)ethenyl]-alpha-bromoacetamide(11)在甲苯沸腾条件下与偶氮二异丁腈反应生成β-内酰胺13，但产率较低(22%)，而N-[2，2-二(苯硫基)乙烯]异构体23以70%的总收率环化得到β-内酰胺25和部分脱硫内酰胺13。23的4-exo环化反应的有效性可以用自由基19b中间体的高稳定性来解释。α-溴丁酰胺24与Bu(3)SNH的类似处理得到了β-内酰胺26，产率为58%，它通过醛31转化为合成(+/-)-PS-5(36)的关键中间体35。然后研究了1，2-不对称诱导自由基环化反应生成β-内酰胺类药物。(2S，3R)-3-acetoxy-2-bromo-N-[2-(phenylthio)ethenyl]butanamide(38)的环化反应没有非对映选择性，得到量大致相等的β-内酰胺40a和40b。而2，2-二(苯硫基)异构体39提供了(3R，4R)-2-氮杂二酮41a和(3S，4S)-异构体41b，比例约为2：1。同样，(2R，3S)-丁酰胺47提供了48a作为主要产物。48a的皂化和49的部分脱硫制得乙醇50，再经Mitsunobu转化得到52。该化合物被转化为合成(+)-硫霉素(58)的关键中间体56。讨论了自由基环化反应生成β-内酰胺类药物的可逆性。
A new method for the synthesis of beta-lactams by tributyltin hydride (Bu(3)SnH)-mediated radical cyclizations of N-ethenyl-alpha-bromo amides bearing sulfur-substituent(s) at the terminus of the N-vinylic bond is described. N-[2-(Phenylthio)ethenyl]-alpha-bromoacetamide (11), upon treatment with Bu(3)SnH in the presence of azobis(isobutyronitrile) (AIBN) in boiling toluene, underwent radical cyclization in a 4-exo-trig manner to give beta-lactam 13, but in low yield (22%), whereas N-[2,2-bis(phenylthio)ethenyl] congener 23 cyclized with a high degree of efficiency to give beta-lactam 25 and a partially desulfurized lactam 13 in 70% combined yield. The effectiveness of the 4-exo cyclization of 23 can be explained in terms of the high stability of the intermediate of radical 19b. Similar treatment of alpha-bromobutanamide 24 with Bu(3)SnH afforded, in 58% yield, beta-lactam 26, which was transformed, via aldehyde 31, into the key intermediate 35 for the synthesis of(+/-)-PS-5 (36). 1,2-Asymmetric induction in radical cyclizations leading to beta-lactams was then examined. Cyclization of (2S,3R)-3-acetoxy-2-bromo-N-[2-(phenylthio)ethenyl]butanamide (38) proceeded with no diastereoselectivity to give beta-lactams 40a and 40b in approximately equal amounts. However, 2,2-bis(phenylthio) congener 39 provided (3R,4R)-2-azetidinone 41a and its (3S,4S)-isomer 41b in a ratio of ca. 2:1. Similarly, (2R,3S)-butanamide 47 afforded 48a as a major product. Saponification of 48a followed by partial desulfurization of 49 gave alcohol 50, which was then subjected to Mitsunobu inversion to afford 52. This compound was converted into the key intermediate 56 for the synthesis of (+)-thienamycin (58). Reversibility of the radical cyclization leading to the beta-lactams is discussed.