Copper ion-induced activation and asymmetric benzoylation of 1,2-diols: Kinetic chiral molecular recognition

Article abstract of DOI:10.1021/ja0289402

New catalytic ability of copper(II) ion has been exploited for monobenzoylation of 1,2-diols. The catalyst can be readily modified by ligation to acquire higher stereoselectivity. Highly effective kinetic resolution of dl-1,2-diols was achieved. The enant

Full text of DOI:10.1021/ja0289402

Published on Web 01/31/2003
Copper Ion-Induced Activation and Asymmetric Benzoylation of 1,2-Diols:
Kinetic Chiral Molecular Recognition
Yoshihiro Matsumura,* Toshihide Maki, Sachie Murakami, and Osamu Onomura
Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki UniVersity,
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received October 14, 2002 ; E-mail: matumura@net.nagasaki-u.ac.jp
Scheme 1
Metal ions embedded in enzymes catalyze various biological
transformations as the active centers.1 An activation of water by
metalloenzymes is one of the typical examples. Some metallo-
enzymes lower the pKa value of water by the coordination, making
it possible to generate hydroxide ion from water at neutral pH.2
The model studies using dinuclear complexes have recently been
reported.3 In contrast with the activation of water, however, an
activation of the hydroxyl group of alcohols has not been well
established.4 We have considered that a coordination of 1,2-diol 1
with an appropriate metal ion (Mn+) forms an activated form A of
1, which is transformed with a weak base to the metal alkoxide B
to be trapped acyl halides (R2COX) as electrophiles. Provided that
Scheme 2
Mn+ is regenerated with a formation of an acylated product 2, a
catalytic cycle concerning with Mn+ is completed (Scheme 1).
The results thus far obtained based on this concept were an
organotin-catalyzed monobenzoylation of 1,2-diols with the first
kinetic resolution of terminal 1,2-diols using a chiral organotin
catalyst.5 However, a limitation in a structural modification of
organotin compounds has been a barrier to acquire further stereo-
selectivity for many other diols. We report herein an excellent
catalytic ability of copper(II) ion6 for 1,2-diol activation based on
Table 1. Kinetic Resolution of 1,2-Diolsa
the above-mentioned concept. Since the copper catalysts could be
readily modified by chiral ligands, it allowed us to find out the
most suited one for the reaction from well-established ligands.7 That
is, (S,S)-hydrobenzoin8 ((S,S)-1a) was selectively monobenzoylated
with (R,R)-Ph-BOX-CuCl29 as a catalyst with an s10 value of >645
(Scheme 2).
The observed % ee was the highest level of selectivity10 among
the thus-far reported catalytic kinetic resolution of alcohols.11 The
characteristic1,2-diol-selectivity of the new catalytic system was
confirmed by the kinetic resolution of dl-1a in the presence of 1
equiv of n-BuOH which afforded (S,S)-2a in 49% yield with 98%
ee. This result supports a metal-induced activation concept as shown
in Scheme 1.
Table 1 shows the result of a kinetic resolution of various 1,2-
diols dl-1b-f using 5 mol % of (R,R)-Ph-BOX-CuCl2 with a result
of dl-1a.
The selectivity values for dl-1a-d were extremely high irrespec-
tive of the character of substituents on their phenyl groups (runs
1-4). Aliphatic diols dl-1e-g also showed useful level of
selectively (runs 5-7), although the kinetic resolution of dl-1e-g
was not as efficient as that of hydrobenzoin derivatives dl-1a-d.
Interestingly, the selectivity of kinetic resolution of dl-1a strongly
depended on the bulkiness of acylating reagents. When the reaction
was carried out using acetyl (s ) 1.8), propionyl (s ) 4.9),
isobutyryl (s ) 8.3), and pivaloyl chlorides (s ) 11.8),12 the
observed selectivity in the kinetic resolution (Table 3S, Supporting
Information) was closely correlated with number of methyl group
at the R-position of acetyl moiety.
a The reaction was carried out with complex (0.05 mmol), diol (1 mmol),
diisopropylethylamine (DIPEA, 1 mmol), and benzoyl chloride (0.5 mmol)
in CH2Cl2 at 0 °C. b Isolated yield based on diols. c Determined by chiral
solid-phase HPLC. d Reference 10.
This result suggests that the enantiodiscrimination mainly took
place at the acylation step (2 from B in Scheme 1). In fact, the
benzoylaion of dl-1a in the presence of an excess amount (1.5 equiv)
of (R,R)-Ph-box-CuCl2 gave (S,S)-2a with 98% ee with a recovery
of (R,R)-1a with 96% ee, whereas a similar experiment using acetyl
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10.1021/ja0289402 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Scheme 3
followed by the reaction of the activated chiral reagents with
alcohols. On the contrary, the presented method owns an unique
character to recognize 1,2-diols. Further designing of new catalysts
based on our concept as well as mechanistic studies (Scheme 1S,
Supporting Information) are currently under investigation.
Acknowledgment. Y.M. and T.M. thank the Ministry of
Education, Science, and Culture, Japan (a Grant-in-Aid for Scientific
Research on Priority Areas No. 706), Uehara Memorial Foundation
and a Grant-in-Aid for Encouragement of Young Scientists (A) (No.
14771245) from Japan Society for the Promotion of Science,
respectively, for financial support.
Scheme 4
Supporting Information Available: Typical experimental proce-
dure, analytical data including chiral chromatographic analyses of
monobenzoylated products 2a-g and 5 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
chloride afforded 3a in 20% ee which was comparable with that
observed in the catalytic acetylation. The result suggests that (R,R)-
Ph-box-CuCl2 can coordinate with not only (S,S)-1a but also (R,R)-
1a to form the corresponding intermediates B (Scheme 1). The
observed high enantiodiscrimination in the benzoylation of dl-1a
might be primarily explainable in terms of the severe steric repulsion
between benzoyl chloride and B which might be formed from (R,R)-
1a and (R,R)-Ph-box-CuCl2.
To clarify the other factor responsible for the observed high s in
the benzoylation of dl-1a, we carried out a competition reaction
between (S,S)-1a and ethyleneglycol 3 in the presence of CuCl2
with or without (R,R)-Ph-box. In this reaction, the ratios of
monobenzoylated products (S,S)-2a to 2-benzoyloxyethanol 4 were
36/64 without (R,R)-Ph-box and 71/29 with (R,R)-Ph-box (Scheme
3).13 This fact suggests a presence of attractive interaction between
phenyl rings of (S,S)-2a and of (R,R)-Ph-box, which also partici-
pated to some extent in the benzoylation of dl-1a.
The presented method was then applied to an asymmetric
desymmetrization14 of meso-1a, where monobenzoylated 5 was
obtained in 79% yield with 94% ee (Scheme 4).
In conclusion, we presented a new chemo- and stereoselect-
ive monobenzoylation of 1,2-diols. This is a first example of
copper(II) ion-induced enentioselective activation of 1,2-diols. Since
the stereoselectivity in the reaction might be readily modified upon
ligation, the presented concept may provide an important platform
for chemo- and stereoselective manipulation of 1,2-diols in many
synthetic works.
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This asymmetric benzoylation is completely different in its
mechanism from the hitherto-exploited kinetic resolution and
desymmetrization of alcohols11,14 in which acylation reagents such
as acyl halides or acid anhydrides are activated by chiral catalysts
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