Tetrahedron Letters
Synthesis of chiral
c-sultams through intramolecular reductive
amination with sulfonylcarbamate as N-source
Bo Song a,b, Yue Ji a, Shu-Bo Hu a, Chang-Bin Yu a, Yong-Gui Zhou a,
⇑
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
b University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and enantioselective palladium-catalyzed intramolecular asymmetric reductive amination
Received 19 January 2017
Revised 28 February 2017
Accepted 3 March 2017
Available online 6 March 2017
with sulfonylcarbamates as N-sources was reported, providing a facile and general access to the chiral
c
-sultam derivatives with up to 97% of enantioselectivity. This tandem process avoids additional depro-
tection manipulation and arduous isolation of the N-sulfonyl-imine intermediates.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Reductive amination
Sulfonylcarbamate
Chiral c-sultams
Asymmetric reductive amination (ARA) represents one of the
most practical methods to enantioenriched amines.1 Over the past
decades, significant advances have been made in development of
highly effective catalyst systems.1 Generally, electron-rich amines
including ammonia, simple alkyl- and arylamine sources are pre-
dominant as N-nucleophiles,2 and examples involving carba-
mates,3 hydrazides4 and Ellman’s sulfinamides5 as less electron-
rich N-nucleophiles have also been reported. In sharp contrast, sul-
fonamides have been rarely used as N-nucleophiles in ARA. Several
factors have impeded the development of efficient ARA with sul-
fonamides as the N-nucleophiles. (a) The intrinsically low nucle-
ophilicity leads to the sluggish formation of N-sulfonylimine
intermediates. (b) Strong Brønsted acids are required to accelerate
the formation of N-sulfonylimines, and molecular sieves may also
be needed to remove the equivalent water byproduct to promote
the equilibrium for reaction of the carbonyls with sulfonamides
toward the formation of unfavorable N-sulfonylimines.6 (c) The
side reaction of ketone direct reduction poses an issue of chemos-
electivity.7 (d) High levels of chemo- and stereocontrol are not
easily fulfilled because most asymmetric hydrogenation systems
are not compatible to moisture and strong acidic conditions.8
In order to overcome these problems and in continuation of our
efforts in exploring catalytic asymmetric synthesis of chiral sul-
tams,6,9 we have successfully developed a palladium-catalyzed
intramolecular reductive amination of ketones with N-tert-butyl
protected sulfonamides as N-nucleophiles in the presence of
Brønsted acid, providing a wide range of chiral -, d-, and -sultams
c
e
(Scheme 1).10 The tolerable palladium catalysis system to water
and Brønsted acid laid the foundation of success for the tandem
sequence of deprotection and subsequent intramolecular asym-
metric reductive amination. The addition of Brønsted acid lead to
easy removal of the protective group (t-Bu) and formation of sul-
fonylimine or enamine intermediates, the palladium catalyst facil-
itated high levels of chemo- and stereoselective control.
Considering the simplicity of synthesis of tert-butyl keto sulfonyl-
carbamates from simple starting marterials.6,9d and ready removal
of Boc protective group by Brønsted acid,11 we wondered the fea-
sibility that the combination of palladium catalysis and Brønsted
acid could promote the intramolecular asymmetric reductive ami-
nation of tert-butyl keto sulfonylcarbamates. Herein, we report the
palladium-catalyzed intramolecular asymmetric reductive amina-
tion using sulfonylcarbamates as N-sources, providing a concise
and efficient access to the chiral c-sultam derivatives (Scheme 1).
To evaluate the proposed transformation, tert-butyl 3-oxo-3-
phenylpropylsulfonylcarbamate (1a), which could be conveniently
synthesized from tert-butyl (methylsulfonyl) carbamate according
to literature procedures,6,9d was selected as the model substrate to
assay reaction conditions. Pd(OCOCF3)2/(S,S)-f-Binaphane complex
was used as hydrogenation catalyst to begin the investigation. Con-
sidering that stoichiometric amount of Brønsted acid, which was
compatible with palladium catalysis system, was required to
remove Boc protecting group in prior, we first examined the effect
of Brønsted acids on reactivity and enantioselectivity. It was found
⇑
Corresponding author.
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.