Group: Organic
＝＝＝＝＝＝＝＝＝
2－奎宁环酮（2-Quinuclidone）：60多年造就的合成
提要：有关twisted amide 跟通常的amide的不同。介绍背景，合成，稳定性，反应活
性。
注：将就看吧，就是流水帐一点，内容安排不是很和逻辑。犯了贪多的缺点，收罗来了
又觉得去掉可惜，就乱乱的放一起，主要是增加知识背景，没想到要写得可读性强些。
欢迎给点批判性的意见。
第一部分
wikipedia上的有关背景和合成：
Quinuclidone,奎宁环酮，是一类双环有机化合物，分子式： C7H11NO，有两个结构异
构体，2－ 和3－Quinuclidone，结构：
先介绍从Wikipedia有一些基本合成。我就直接copy过来，夹着我加的中文，中英文并
茂。
http://en.wikipedia.org/wiki/Quinuclidone
首先是3-Quinuclidone 的合成
3-Quinuclidone (1-azabicyclo[2.2.2]octan-3-one) is an uneventful molecule
that can be synthesized as the hydrochloric acid salt in a Dieckman
condensation
[ref 1: Organic Syntheses, Coll. Vol. 5, p.989 (1973); Vol. 44, p.86 (1964)]
Organic reduction of this compound gives the compound quinuclidine,
structurally related to DABCO（见下图） which has one additional bridgehead
nitrogen atom.
DABCO (1,4-diazabicyclo[2.2.2]octane):
(
http://en.wikipedia.org/wiki/DABCO)
2-quinuclidone的合成
The other isomer, 2-quinuclidone, appears equally uneventful but in fact it
has defied synthesis until 2006.（ref: 见下面） The reason is that this
molecule is very unstable due to the fact that its amide group has the amine
lone pair and the carbonyl group not properly aligned as may be expected
for an amide as a result of steric strain. This behaviour is predicted by
Bredt's Rule and formal amide group resembles in fact an amine as evidenced
by the ease of salt formation.
The organic synthesis of the tetrafluoroborate salt of 2-quinuclidone is a
six-step affair starting from norcamphor the final step being an azide -
ketone Schmidt reaction (38% yield) :
反应步骤：
Reaction sequence: first step is a Baeyer-Villiger oxidation of norcamphor 1
with Meta-Chloroperoxybenzoic acid to bicyclic lactone 2, followed by
organic reduction with lithium aluminum hydride in diethyl ether to diol 3.
The primary alcohol group is replaced by a tosylate group in 4 with tosyl
chloride and triethylamine and in turn displaced by an azide group in 5 by
action of sodium azide in dimethylformamide. Oxidation of the alcohol to the
ketone 6 takes place with Dess-Martin periodinane in dichloromethane. The
final step to 2-quinuclidonium tetrafluoroborate 8 is a Schmidt reaction
through intermediate 7 with hydrogen tetrafluoroborate in diethyl ether.
参考文献：
ref 2: Synthesis and structural analysis of 2-quinuclidonium
tetrafluoroborate Kousuke Tani and Brian M. Stoltz Nature 441, 731-734 (8
June 2006) | DOI:10.1038/nature04842
3：Blogged on
www.totallysynthetic.com (
http://totallysynthetic.com/blog/?p=120)
4：Bethany Halford Amide With A Twist Chemical and Engineering News June 12,
2006 Volume 84, Number 24 p. (
http://pubs.acs.org/cen/news/84/i24/8424notw4.html)
－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－
第二部分
本篇主题文献来源：“The Twisted Amide 2-Quinuclidone: 60 Years in the Making”
Angewandte Chemie International Edition Volume 45, Issue 43, Pages 7118-7120
http://www3.interscience.wiley.c ... 113384983/HTMLSTART
1、理论上的解释和推测
本文讲到了酰胺键之所以稳定是因为：Amide stability is widely accepted to
arise from the delocalization of pi-electrons over the three constituent
amide atoms (N, C, O). As a result, the four substituents around the amide C
－N bond must all lie in the same plane.
于是提出了这样一个问题：
But how important really is delocalization in governing the properties of
amides?
One way to find out is to make amides in which the nitrogen lone pair is
not—and indeed cannot be—delocalized. If an amide is built in which
structural constraints do not allow coplanarity, then delocalization would
be
diminished or impossible. Chemical intuition suggests that such “twisted
amides” will be less stable and will show increased electrophilicity,
closer to that of esters or ketones.
（评论：最后一句话非常中肯，酰胺之所以稳定是因为氮上孤对电子的离域形成部分C
＝N部分双键，而对于“twisted amide”氮上的孤对电子不再离域导致C＝O亲电性增强
，接近于酯和酮。这点跟我们平时学有机的时候认识一样，只是甚少会想到这个例外情
况。）
作为“twisted amides”模型,2-Quinuclidone是最简单，理论上确实最优美的结构。
而这么简单的结构一直不为人所及。自从1938年Lukes提出,经过了60多年，直到2006由
Caltech 的 Stoltz才合成了2-Quinuclidone.HBF4 salt.
2-Quinuclidone is perhaps the simplest and indeed most beautiful of these
theoretically twisted amides—“theoretical” because, incredibly, the
simple 2-quinuclidone structure remained unknown, thwarting every attempt at
synthesis, until early in 2006.
这篇Angrew Chem文章介绍了"twisted amides"的不稳定导致合成上的困难。举了一个
二战时候盘尼西林的生产，而当时penicillin结构仍然未知。Woodward认为penicillin
含有beta-lactam，后来证实了他的推测。在Woodward眼中，penicillind的降解和水解
跟分子中存在“twisted amide”完全符合。
structures of penicillins
2、合成的发展
首次合成penicillin V ：
Synthetic success followed with the first total synthesis of penicillin V by
Sheehan and Henery-Logan at MIT in 1957.
Sheehan and Henery-Logan引入了用DCC（Diyclohexylcarbodiimide）参与的关环反应
，这个方法被用来合成了许多别twisted amides。
但这个合成方法对于合成2-Quinuclidone却遭到了失败。
Stoltz成功合成采取的策略是避开含水的条件和分离出质子化的盐，2-quinuclidonium
tetrafluoroborate。化学界经过60多年的努力终于合成出了2-quinuclidone。
Tani and Stoltz decided to evade its apparent high susceptibility to
hydrolysis by avoiding aqueous conditions and isolating the protonated salt,
2-quinuclidonium tetrafluoroborate. The approach paid off, and the
synthesis of 2-quinuclidone was finally achieved after more than sixty years
of interest.
3、twisted amides化学性质：
twisted amides 在酸性和碱性条件下比平面的amide水解都来得快。
twisted amide可以进行Wittig olefination 和ketal formation of the carbonyl
group。也可以在N上进行甲基化。这些反应对于酰胺类来说，很明显比较特殊。
2-quinuclidonium tetrafluoroborate在D2O立即水解，在亲核溶剂（DMSO, pyridine,
and methanol ）迅速分解，但可以在CH3CN和Et2O里面稳定操作。Attempts to free-
base 1.HBF4 to generate 2-quinuclidone itself were unsuccessful and
generally resulted in the formation of polymeric material.
4、结束语
该文献最后一句：传统上，天然产物的合成被认为是合成最高成就，但也许化学家凭空
想象的非天然产物更具挑战，确实如此。
Natural products have traditionally been seen as the pinnacle of synthetic
achievement, but maybe it is in the form of unnatural products—indeed,
products only of chemists imaginations—that greater challenges lie.
这句话把搞天然产物合成给说得脸面尽失啊。
5、注：
转载请加链接：
http://mitbbs.com/pc/pccon.php?id=155&nid=8246
- 