Angewandte
Chemie
DOI: 10.1002/anie.201408732
Kinetic Resolution
Tungsten-Catalyzed Regio- and Enantioselective Aminolysis of trans-
2,3-Epoxy Alcohols: An Entry to Virtually Enantiopure Amino
Alcohols**
Chuan Wang and Hisashi Yamamoto*
Abstract: The first catalytic enantioselective aminolysis of
trans-2,3-epoxy alcohols has been accomplished. This stereo-
specific ring-opening process was efficiently promoted by
a tungsten/bis(hydroxamic acid) catalytic system, furnishing
various anti-3-amino-1,2-diols with excellent regiocontrol and
high enantioselectivities (up to 95% ee). Moreover, virtually
enantiopure 3-amino-1,2-diols could be obtained by the
sequential combination of two reactions that both involve the
use of a chiral catalyst.
catalytic regioselective and stereospecific ring opening of 2,3-
epoxy alcohols promoted by achiral tungsten salts.[12] As
a continuation of our research in this field, we herein report
the first enantioselective aminolysis of 2,3-epoxy alcohols
with various amines as the nucleophiles using our tungsten/
bis(hydroxamic acid) (W-BHA) catalytic system. Remark-
ably, this catalyst can promote both the epoxidation and the
ring-opening reaction providing a new access to virtually
enantiopure 3-amino-1,2-diols.
For the optimization of the reaction conditions, we used
aniline (1a) and racemic trans-2,3-epoxycinnamyl alcohol
(2a) as the standard substrates. After careful screening of the
ligands, solvents, and temperature, we succeeded in establish-
ing suitable reaction conditions for the kinetic resolution of
2,3-epoxy alcohols through enantioselective aminolysis
(Scheme 1).[13]
The substrate scope of this reaction was then evaluated
(Table 1). We first varied the structure of the amine:
Diversely substituted anilines (1a–k), heterocyclic amines
S
ubstituted 3-amino-1,2-diols are a characteristic structural
unit present in numerous biologically active compounds, such
as leukotriene antagonists,[1] human carbonic anhydrase
inhibitors,[2] and anti-inflammatory agents.[3] Furthermore,
3-amino-1,2-diols are also important synthetic intermediates
of cardiovascular,[4] antibacterial,[5] and sedative agents,[6]
selective norepinephrine reuptake inhibitors,[7] and drug
candidates for the treatment of conditions that are amelio-
rated by monoamine reuptake.[8] Most of these biologically
important molecules are required to be virtually enantiopure
(> 99.8% ee, < 0.1% of the other enantiomer) for the
pharmaceutical applications. Therefore, it is highly desirable
to develop a direct catalytic approach to prepare enantioen-
riched 3-amino-1,2-diols starting from readily available pre-
cursors. Although the enantioselective ring opening of
epoxides using various nucleophiles, such as azides,[9a,b]
amines,[9c–h] water,[9i–m] alcohols,[9d,h,l,m] phenols,[9h,l-p] thiols,[9q,r]
halides,[9s–v] and carbon nucleophiles,[9w–aa] has been inten-
sively studied over the past decades, and tremendous progress
has been achieved, excellent results are usually obtained with
unfunctionalized terminal or meso epoxides, whereas the
kinetic resolution of 2,3-epoxy alcohols is still elusive.[10,11]
The challenge of this reaction lies not only in facial selectivity,
but also in regiocontrol. Recently, our group reported the first
Scheme 1. Optimized reaction conditions for the asymmetric ring
opening of trans-2,3-epoxycinnamyl alcohol with aniline as the nucleo-
phile.
[*] Dr. C. Wang, Prof. Dr. H. Yamamoto
(1l and 1m), as well as secondary aromatic amines (1n–u)
were reacted with 2a. Generally, all of the reactions
proceeded smoothly at 558C in the presence of the W-BHA
catalytic system (2.5 or 5 mol%), providing the products 3a–
u in 71–95% yield and 84–93% ee. Remarkably, all of the
reactions proceeded with complete regioselectivity in favor of
the formation of the C3 regioisomers. Subsequently, we
studied the substrate scope further by varying the structure of
the 2,3-epoxy alcohols. For substituted trans-3-phenylglycidol,
the reactions provided the products 3v–bb in 78–95% yield,
with complete regioselectivity, and 90–95% ee. Aliphatic
trans-2,3-epoxy alcohols turned out to be less reactive and
thus higher catalyst loadings (10 mol%) and longer reaction
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: yamamoto@uchicago.edu
Prof. Dr. H. Yamamoto
Molecular Catalyst Research Center, Chubu University
1200 Matsumoto, Kasugai, Aichi 487-8501 (Japan)
E-mail: hyamamoto@jsc.chubu.ac.jp
[**] The Japan Science Promotion Foundation (JSP-ACT-C) and the
National Institutes of Health (NIH, 2R01GM068433) are greatly
appreciated for providing financial support. C.W. thanks the
Alexander von Humboldt Foundation for his postdoctoral fellow-
ship.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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