An ascending synthesis of adrenalcorticosteroids. The total synthesis of (+)-adrenosterone
An ascending synthesis of adrenalcorticosteroids. The total synthesis of (+)-adrenosterone
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DOI：
10.1021/ja9602509
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发表时间：
1996-05-15
影响因子：
15
通讯作者：
Shea, KJ
中科院分区：
文献类型：
--
作者：
Dzierba, CD;Zandi, KS;Shea, KJ
药学上有用的类固醇可以通过全合成或通过容易获得的天然类固醇的修饰来获得。1全合成路线允许对映体选择2以及获得可能不容易通过降解或官能团转化获得的衍生物。我们报告了甾体骨架的对映体特异性合成的一般策略。该方法通过（+）-肾上腺甾酮（一种肾上腺皮质类固醇）的合成来证明。[3]从逆合成的角度来看，利用Diels-Alder结构将C环附加到A，B片段（AB f ABC f ABCD）的上行策略代表了这类重要天然产物的特别有效的方法。该挑战需要在C环形成步骤中控制区域、立体和π面选择性。通常，形成天然产物的要求抵消了环加成反应的固有偏差。尽管早期的努力，这一战略尚未被利用在肾上腺皮质激素的合成。4利用2型分子内结构控制Diels-Alder反应的立体选择性的最新进展为这些问题提供了可能的解决方案。5合成（+）-肾上腺甾酮的策略概述于方案1中。合成中的关键步骤利用二烯和亲二烯体在2型分子内Diels-Alder（T2 IMDA）反应中暂时结合以形成类固醇的C环。5环加成的目的是在BCD环连接处建立四个立构中心（C8、C9、C13和C14）。此外，该策略具有利用C19甲基在新中心建立正确的绝对构型的潜力。为了避免R，R，-三取代的亲二烯体的低反应性，通过甲氧羰基基团延伸缀合（3，方案1）。尽管这种策略在环加成步骤的化学选择性（将二烯加成到R，-V，γ，δ-双键上）中引入了模糊性，但我们依赖于
Pharmaceutically useful steroids may be obtained by total synthesis or by modification of readily available natural steroids. 1 The total synthesis route allows for enantiomer selection2 as well as access to derivatives that may not be readily available by degradation or functional group conversions. We report a general strategy for the enantiospecific synthesis of the steroid skeleton. The approach is demonstrated by the synthesis of (+)-adrenosterone, an adrenalcorticosteroid. 3 From a retrosynthetic perspective, an ascending strategy that appends the C-ring to an A, B fragment (AB f ABC f ABCD) utilizing a Diels-Alder construction represents a particularly efficient approach to this important class of natural products. The challenge entails control of regio-, stereo-, and π-facial selectivity in the C-ring-forming step. Often, the requirements for formation of the natural product countermand the intrinsic bias of the cycloaddition reaction. Despite earlier efforts, this strategy has not as yet been exploited in adrenalcorticoid synthesis. 4 Recent developments in controlling the stereoselectivity of the Diels-Alder reaction utilizing type 2 intramolecularity offered possible solutions to these problems. 5 The strategy for the synthesis of (+)-adrenosterone is outlined in Scheme 1. A key step in the synthesis utilizes a temporarily union of diene and dienophile in a type 2 intramolecular Diels-Alder (T2IMDA) reaction to form the C-ring of the steroid. 5 The cycloaddition was designed to establish the four stereocenters in the BCD ring junctures (C8, C9, C13, and C14). In addition, the strategy has the potential for exploiting the C19 methyl group to establish the correct absolute configuration at the new centers.Dienophile 3 installs the C18 methyl and the D-ring carbons. To circumvent the low reactivity of the R, R,-trisubstituted dienophile, conjugation was extended through the carbomethoxy group (3, Scheme 1). Although this ploy introduced ambiguity in the chemoselectivity of the cycloaddition step (addition of the diene to the R,-Vs γ, δ-double bond), we relied upon the