Enantioselective synthesis of tertiary alcohols by the desymmetrizing benzoylation of 2-substituted glycerols

Article abstract of DOI:10.1002/anie.200604977

(Chemical Equation Presented) Complementary catalysts have been found for the enantioselective desymmetrization of 2-substituted glycerols by monobenzoylation with benzoyl chloride and Et₃N to give chiral tertiary alcohols with 80 to 94% ee (se

Full text of DOI:10.1002/anie.200604977

Communications
DOI: 10.1002/anie.200604977
Asymmetric Catalysis
Enantioselective Synthesis of Tertiary Alcohols by the Desymmetrizing
Benzoylation of 2-Substituted Glycerols**
Byunghyuck Jung, Mi Sook Hong, and Sung Ho Kang*
The enantioselective desymmetrization of prochiral com-
pounds has great synthetic potential for the creation of
stereogenic centers. Some desymmetrization methods have
been exploited to form stereogenic quaternary carbon
atoms.[1] Representative examples of methods used for the
construction of all-carbon quaternary stereocenters include
the Pd-catalyzed cyclization of prochiral dienes,[2] the chiral-
amine-promoted intramolecular aldol condensation of trike-
tones,[3] salen–Co-catalyzed intramolecular epoxide open-
ing,[4] the Wittig cyclization of chiral phosphonium salts,[5]
the alkylation of ketones mediated by chiral lithium amides,[6]
protocol turned out to be benzoylation with a combination of
BzCl and Et3N. The dependence of the desymmetrizing
monobenzoylation on the solvent, reaction temperature, and
concentration was examined. It was found that THF was far
superior to other solvents, that lowering the reaction temper-
ature exerted an adverse effect on the reaction, and that the
optimal concentration of 1 was 60 mm. Under the optimum
conditions, the desymmetrizing functionalization of 1 was
effected with high enantioselectivity as well as high chemical
conversion (Table 1, entry 1).
and C H bond insertion of diazoketones.[7] However, quater-
À
Table 1: Desymmetrizing monobenzoylation of 1 with complexes of the
bisoxazolines 2–12 and CuCl2, BzCl, and Et3N.[a]
nary stereocenters bonded to heteroatoms have rarely been
installed by desymmetrization. The following methods have
been implemented for the formation of such stereocenters
through desymmetrization: the Sharpless epoxidation of
dienes,[8] ring-closing metathesis of trienes,[9] the intramolec-
ular nucleophilic cleavage of anhydrides,[10] the Rh-catalyzed
conjugate addition–aldol cyclization of enone diketones,[11]
a
hydroxy-directed Heck cyclization,[12] and an intramolecular
Stetter reaction.[13]. As chiral tertiary alcohols are ubiquitous
in physiologically valuable natural products and pharmaceut-
icals, we have been particularly interested in this functionality.
In this context, we have been engaged in developing an
efficient and versatile asymmetric desymmetrization.[14,15]
Herein we describe the enantioselective desymmetrization
of prochiral 2-substituted glycerols by monobenzoylation to
prepare an array of chiral tertiary alcohols with high
stereoinduction.
After an extensive search for prospective asymmetric
catalysts, the effective desymmetrization boundaries were
investigated by monoprotection of the primary hydroxy
groups of the model substrate 1 (30 mm) in the presence of
the CuCl2 complex of the diethylbisoxazoline 2[16] in THF with
various combinations of protecting reagents and bases.
Higher stereoselectivity was observed with the protecting-
reagent/base couples BzCl/Et3N (84% ee), BzCl/iPr2NEt
(78% ee), BzCl/iPr2NH (72% ee), BzCl/tBuOK (54% ee),
and TESCl/Et3N (53% ee; TES = triethylsilyl) at room tem-
perature than with other combinations. The most adaptable
Entry
Bisoxazoline
Yield [%] (s.m. [%])[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7
8
9
10
11
12
10
10
94 (2)
95 (2)
80 (10)
53 (40)
88 (7)
60 (28)
97
89 (5)
97
97
90 (R)
86 (R)
76 (S)
14 (S)
86 (R)
58 (R)
90 (R)
88 (R)
91 (R)
91 (S)
18 (S)
87 (R)
92 (R)
10
11
12[d]
13[d,e]
26 (65)
78 (15)
97
[a] [1]=60 mm. [b] The values in parentheses refer to the recovery of
starting material (s.m.). [c] The configuration of the major enantiomer is
given in parentheses. [d] Catalyst 10–CuCl2: 5 mol%. [e] Et3N, and the
mixture of 1 and BzCl were added simultaneously, dropwise. Bn=benzyl,
Bz=benzoyl.
[*] B. Jung, M. S. Hong, Prof. Dr. S. H. Kang
Center for Molecular Design and Synthesis
Department of Chemistry, School of Molecular Science (BK21)
KAIST, Daejeon 305-701 (Korea)
Fax: (+82)42-869-2810
Next, structurally diverse bisoxazolines were surveyed as
chiral ligands in the desymmetrization of 1. Some instructive
results are presented in Table 1. In the case of 4-alkyl-
substituted bisoxazolines,[17] the stereoselectivity increased
E-mail: shkang@kaist.ac.kr
[**] This research was supported by the CMDS.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 2: Desymmetrizing monobenzoylation of 14–23 with the bisoxa-
zoline–copper complex 10–CuCl2, BzCl, and Et3N.[a,b]
when methyl were replaced with ethyl substituents, and
decreased steeply as the substituents became bulkier (Table 1,
entries 1–4). The 4-(hydroxyalkyl)-substituted bisoxazo-
lines[18] also seem to dictate the stereoselectivity by a steric
rather than an electronic effect (Table 1, entries 5 and 6). We
believe that the substituent in the 4-position must have an
appropriate size for the catalyst and the substrate to be able to
coordinate tightly and must subsequently impose enough
steric congestion to promote a high level of stereoinduction.
Most of the 4-aryl- and 4-benzyl-substituted bisoxazolines
tested[17c,19] showed excellent enantioselectivity to give the
products with 88–91% ee (Table 1, entries 7–10). Only the use
of the indane-fused bisoxazoline 12[20] led to much lower
reactivity and stereoselectivity, presumably as a result of the
less flexible fused structure, which may impede effective
complexation between the catalyst and the substrate and/or
the acylating reagent (Table 1, entry 11). No better results
were obtained with bisoxazolines bridged by oxalate, tartrate,
phthalate, dibenzofurandicarboxylate, or pyridinedicarboxyl-
ate moieties. The dibenzylbisoxazoline 10 was chosen as the
best chiral ligand on the basis of desymmetrization efficiency
and accessibility (Table 1, entry 9). As it is synthetically
worthwhile to modulate the loading amount of the catalyst,
various quantities were tried. When the catalyst loading was
reduced from 10 to 5 mol%, not only the stereoselectivity but
also the chemical conversion decreased (Table 1, entry 12).
Fortunately, this problem could be surmounted by adding
Et3N, and the mixture of the substrate 1 and BzCl simulta-
neously, dropwise over several minutes (Table 1, entry 13).
Further amelioration of the desymmetrizing enantiodifferen-
tiation was attempted by testing the efficiency of the catalyst
with several different counter anions. However, the chloride
anion proved to be the most effective.
Entry
R (Substrate/Product)
Yield [%] (s.m. [%])[c]
ee [%][d,e,f]
1
2
3
4
5
(CH2)2Ph (1/13)
Me (14/24)
(CH2)2Me (15/25)
CHMe2 (16/26)
(CH2)2CHMe2 (17/27)
97
96
97
94
92 (R)
94 (R)
92
80 (R)
91
98
=
6
7
8
9
10
11
CH2CH CH2 (18/28)
98
97
67 (30)
68 (27)
94
92 (R)
27 (R)
30 (R)
67 (R)
89
=
CH CH2 (19/29)
Ph (20/30)
CH2Ph (21/31)
CH2OTBDPS (22/32)
(CH2)2OTBDPS (23/33)
94
91 (R)
[a] Et3N and the mixture of substrate and BzCl were added simulta-
neously, dropwise. [b] [Substrate]=60 mm. [c] The values in parentheses
refer to the recovery of starting material. [d] The configuration of the
major enantiomer is given in parentheses. [e] The ee value was
determined by HPLC analysis with a DAICEL AD-H column. [f] For the
determination of absolute configuration, see the Supporting Informa-
tion. TBDPS=tert-butyldiphenylsilyl.
The glycerols 14–23 with a variety of substituents in the 2-
position were desymmetrized by the established procedure as
outlined in Table 2. The asymmetric monobenzoylation
proceeded very efficiently with most alkyl substituents.
However, the enantioselectivity was a little lower with the
bulky isopropyl group (Table 2, entry 4), and both the
stereoinduction and the chemical conversion diminished
appreciably with the benzyl substituent (Table 2, entry 9).
The least satisfying results were obtained with the vinyl and
phenyl triols 19 and 20 (Table 2, entries 7 and 8), the
asymmetric monobenzoylation of which could not be
improved by increasing the quantity of the catalyst.
To overcome the structural limitations of the substrates,
another series of catalysts was prepared in situ from CuCl2
and chiral ligands: the oxazoline amides 34–36, the oxazoline
diphenylphosphane 37, the iminoalcohols 38 and 39, and the
iminooxazolines 40 and 41 (Scheme 1). The desymmetrizing
monobenzoylation of 1 was assayed under similar conditions
to those used for entry 9 of Table 1, but with 10 mol% of the
generated catalysts. Although most catalysts gave products
with less than 10% ee, when the complex 41–CuCl2 was used
with substrate 1, compound 13 was formed with a promising
53% ee (Table 3, entry 1). When the catalyst loading was
tripled from 10 to 30 mol%, the enantioselectivity increased
to 90% ee (Table 3, entry 2). These results led us to attempt
the desymmetrization of 16 and 19–22 under the optimized
Scheme 1. Chiral ligands for desymmetrizing benzoylation.
Table 3: Desymmetrizing benzoylation of 1, 16, and 19–22 with the
complex of ligand 41 and CuCl2, BzCl, and Et3N.[a]
Entry
Substrate
Product
Yield [%] (s.m. [%])[b]
ee [%][c]
1[d]
2
3
4
5
1
1
13
13
26
29
30
31
32
74 (22)
91 (6)
85 (10)
94
94
91 (7)
90 (5)
53 (R)
90 (R)
83 (R)
81 (R)
80 (R)
86 (R)
93
16
19
20
21
22
6
7
[a] [Substrate]=60 mm. [b] The values in parentheses refer to the
recovery of starting material. [c] The configuration of the major
enantiomer is given in parentheses. [d] Quantity of 41–CuCl2: 10 mol%.
benzoylation conditions with the new catalyst complex 41–
CuCl2. The enantioselectivities were enhanced by a few
percent for the alkyl triols 16 and 22 (Table 3, entries 3 and 7),
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Communications
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In conclusion, we have developed a highly enantioselec-
tive monobenzoylation of prochiral 2-substituted 1,2,3-pro-
panetriols to provide access to a variety of chiral tertiary
alcohols with up to 94% ee. The desymmetrizing functional-
ization was elaborated by using two complementary asym-
metric catalysts, the dibenzylbisoxazoline–copper complex
10–CuCl2 and the iminooxazoline 41–CuCl2. The former is
compatible with 2-alkyl-substituted substrates, and the latter
is very effective for substrates with vinyl, phenyl, and benzyl
substituents in the 2-position.
Received: December 8, 2006
Revised: January 19, 2007
Published online: March 2, 2007
Keywords: asymmetric catalysis · benzoylation ·
.
desymmetrization · enantioselectivity · tertiary alcohols
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