PROTON-TRANSFER STEPS IN STEGLICH ESTERIFICATION - A VERY PRACTICAL NEW METHOD FOR MACROLACTONIZATION
PROTON-TRANSFER STEPS IN STEGLICH ESTERIFICATION - A VERY PRACTICAL NEW METHOD FOR MACROLACTONIZATION
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DOI：
10.1021/jo00213a044
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发表时间：
1985-01-01
影响因子：
3.6
通讯作者：
KECK, GE
中科院分区：
文献类型：
--
作者：
BODEN, EP;KECK, GE
从相应的羟基酸制备大环内酯的合成方法的发展，可能比最近几年的任何其他单一发展都更显著地影响了天然产物全合成领域。本领域的实践者现在可以攻击复杂的大环内酯类抗生素，因为知道有各种方法可用于形成大环，作为合成的倒数第二步，例如Corey，1 Mukaiyama，2 Masamune，3和MIT-Sunobu4的方法，从而将他们的创造性努力集中在与这些材料相关的立体化学挑战上。事实上，将目前“非循环立体化学控制”方法学的爆炸性发展追溯到可靠的大内酯化程序的可获得性，可能并不夸大大内酯化方法学的影响。尽管在这一领域取得了令人印象深刻的进展，但仍然存在一些问题，我们对大环双内酯醇缩二醇5的研究鼓励我们不仅仔细研究这一领域的现有文献，而且考虑“理想的”内酯内酯过程的特点。例如，原位生成活性酯比形成离散的中间体更可取，然后再经过大内酯条件。6此外，羧基功能的激活应以这样的方式完成，即如果中间体被不定水分降解，则允许活性酯的再生。最后，由于这些反应通常是在相当小的规模内进行的，试剂应该可以过量使用，而不会使传统的(例如，TLC)色谱监测或产物分离复杂化。考虑到这些和其他标准，我们研究了Steglich8酯化，这是一种非常成功的双分子酯化方法，即使与叔醇也是如此，作为一种大内酯化方法。在这方面，应该明确指出，从所使用的试剂中得到的唯一在色谱上可移动的(在普通溶剂系统中)组分是二环己基碳二亚胺(DCC)，它可以在分离之前转化为尿素，而尿素通常很容易通过传统的沉淀和层析技术去除。
The development of synthetic methodology for the preparation of large ring lactones from the corresponding-hydroxy acids has, perhaps more than any other single development of recent years, dramatically impacted the field of natural products total synthesis. Practitioners of this art may now attack complex macrolide antibiotics secure in the knowledge that a variety of methods such as those due to Corey, 1 Mukaiyama, 2 Masamune, 3 and Mit-sunobu4 are available for formation of the large ring as the penultimate step in the synthesis and thus focus their creative efforts on the stereochemical challenges associated with such materials. In fact, it is probably not overstating the impact of macrolactonization methodology to trace the current explosion of methodology for “acyclic stereochem-ical control” to the availability of reliable macro-lactonization procedures. Despite the impressive advances in this area, some problems still remain, and our investigations on the macrocyclic bis-lactone colletodiol5 have encouraged us not only toclosely examine the available literature in this area but also to consider the characteristics of an “idealized” lactonization procedure. For example, in situ generation of an active ester is preferable to the formationof a discrete intermediate which is then subjected to macrolactonization conditions. 6 Moreover, activation of the carboxyl function should be accomplished in such a way as to allow for the regeneration of the active ester if the intermediate is de-stroyed by adventitious moisture. Finally, since these reactions are generally performed on rather small scale, reagents should be usable in excess without complicating conventional (eg, TLC) chromatographic monitoring or product isolation. 7Consideration of these andother criteria has led us to examine Steglich8 esterification, a very successful method for bimolecular esterification even with tertiary alcohols, as a method for macrolactonization. In this context it should be explicitly noted that the only chromatograph-ically mobile (in common solvent systems) component derived from the reagents employed is dicyclohexylcarbodiimide (DCC), which can be converted, prior to isolation, to a urea which is generally easily removed by conventional techniques involving precipitation and chromatography.