Cyclobutanone mimics of penicillins: Effects of substitution on conformation and hemiketal stability
Cyclobutanone mimics of penicillins: Effects of substitution on conformation and hemiketal stability
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DOI：
10.1021/jo801274m
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发表时间：
2008-09-19
影响因子：
3.6
通讯作者：
Dmitrienko, Gary I.
中科院分区：
文献类型：
--
作者：
Johnson, Jarrod W.;Evanoff, Darryl P.;Dmitrienko, Gary I.
青霉素的碳环类似物发生水合物和半缩酮形成的趋势是它们作为β-内酰胺酶抑制剂的能力的核心。通过两个互补的非对映选择性取代反应，与硫酰氯进行了高度立体选择性的氯化反应，合成了具有C3烷氧基功能的2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates。我们发现，具有3个β取代基的碳环类似物在溶液、固相和气相中倾向于内包络构象，而具有3个α取代基的碳环类似物采用外包络构象。X-射线晶体结构和从头计算的证据表明，反常效应有助于四氢噻吩环的大的构象择优，有利于C3取代基轴向取向。此外，由C3取代基的立体化学决定的自行车的包络构象对环丁酮在甲醇-d(4)中形成半缩酮的能力有很大的影响。
The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as beta-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3 beta substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3 alpha substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d(4).