G Model
CCLET 5283 No. of Pages 4
Chinese Chemical Letters
Communication
Stereospecific access to bridged [n.2.1] skeletons through
gold-catalyzed tandem reaction of indolyl homopropargyl amides
a,**
b,**
Tong-De Tana, Xin-Qi Zhua, Mei Jiaa, Yongjia Linb, Jun Cheng , Yuanzhi Xia
,
Long-Wu Yea,c,
*
a
iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen 361005, China
b
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
c
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient gold-catalyzed anti-Markovnikov cycloisomerization-initiated tandem reaction of Boc-
protected indole tethered homopropargyl amides has been achieved. This method delivers a wide range
of valuable bridged aza-[n.2.1] skeletons (n = 3–7) at room temperature with high diastereoselectivity
and enantioselectivity by a chirality-transfer strategy. Moreover, the gold-catalyzed tandem reaction of
homopropargyl alcohol is also achieved to produce the bridged oxa-[3.2.1] skeleton.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 3 September 2019
Received in revised form 8 October 2019
Accepted 18 October 2019
Available online xxx
Keywords:
Gold
Heterocycles
Cascade
Homogeneous catalysis
Alkynes
Since the last decade, gold-catalyzed nucleophilic addition
reactions to alkynes have received tremendous interest and been
widely used in the facile synthesis of an incredible variety of
complex molecules, especially the valuable cyclic compounds [1].
Among these, the terminal alkynes can undergo various highly
regioselective transformations catalyzed by gold, thus providing an
efficient way for CꢀꢀC, CꢀꢀH and CꢀꢀX bond formation. However,
Markovnikov regioselectivity is normally observed in this kind of
nucleophilic addition (Scheme 1a), and recent reports involving
the anti-Markovnikov regioselectivity are mostly limited to
reactions driven by aromatization [2a–c] and involving the gold
vinylidene intermediate [2d,e]. Of note, the dominance of the
strategy has been applied to the synthesis of various N-hetero-
cycles from readily available homopropargyl alcohols or amides
[4]. Inspired by these results and our recent study on the copper-
catalyzed tandem reaction of sulfonyl-protected indole tethered
homopropargyl amides [4g], we envisioned that the gold anti-
Markovnikov cycloisomerization might be realized by choosing the
suitable protecting groups (Scheme 1b) [5]. However, it remains a
highly challenging task because of the difficulty in preventing the
competing Markovnikov cyclization [6] and achieving the desired
cascade cyclization [7].
Herein, we disclose a gold-catalyzed anti-Markovnikov cyclo-
isomerization-initiated tandem reaction by employing the Boc-
protected indole tethered homopropargyl amides as substrates
[8,9], enabling facile access to a wide range of valuable bridged aza-
[n.2.1] skeletons (n = 3–7) at room temperature with high
diastereoselectivity and enantioselectivity by a chirality-transfer
strategy.
At the outset, Boc-protected indole tethered chiral homopro-
pargyl amide 1a was chosen as the model substrate (Table 1). To
our delight, typical gold catalysts such as Ph3PAuNTf2 and
IPrAuNTf2 could indeed catalyze the cascade cyclization reaction
to produce the desired aza-[3.2.1] skeleton 2a, albeit along with the
byproduct 2aa, which was formed presumably through a direct
gold-catalyzed Markovnikov cycloisomerization-initiated tandem
reaction (entries 1 and 2; Supporting information for details). We
LUMO coefficient on the internal carbon in the
p-complexes of
terminal alkynes and gold(I) complexes has been computed in
detail, even involving a fully relativistic treatment [3]. Recently,
our group has achieved
a variety of gold-catalyzed anti-
Markovnikov cycloisomerization-initiated cascade cyclizations
by utilizing the steric strain in ring formation [4h], and this
* Corresponding author at: iChEM, State Key Laboratory of Physical Chemistry of
Solid Surfaces and Key Laboratory for Chemical Biology of Fujian Province, College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
** Corresponding authors.
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: T.-D. Tan, et al., Stereospecific access to bridged [n.2.1] skeletons through gold-catalyzed tandem reaction of