Bronsted acid catalyzed enantioselective semipinacol rearrangement for the synthesis of chiral spiroethers

Article abstract of DOI:10.1002/anie.200904565

A new twist: The catalytic asymmetric semipinacol rearrangement reaction of 2oxo allylic alcohols 1 in the presence of a catalytic amount of chiral phosphoric acid (R)-2a or its silver salt (R)-2b affords enantiomerically pure spiroethers 3.

Full text of DOI:10.1002/anie.200904565

Communications
DOI: 10.1002/anie.200904565
Asymmetric Catalysis
Brønsted Acid Catalyzed Enantioselective Semipinacol
Rearrangement for the Synthesis of Chiral Spiroethers**
Qing-Wei Zhang, Chun-An Fan, Hai-Jun Zhang, Yong-Qiang Tu,* Yu-Ming Zhao, Peiming Gu,
and Zhi-Min Chen
Spiroethers, which feature two fused rings joined by a single
chiral oxo quaternary carbon center, are a versatile structural
motif found in a variety of biologically significant natural
products and pharmaceuticals.[1] The effective synthesis of
spiroethers,[2] and particularly asymmetric syntheses are of
great importance in modern synthetic chemistry. To date,
Scheme 1. Semipinacol rearrangement in the construction of quater-
however, only a few reports of their chiral synthesis have been
described in the literature, wherein their asymmetric con-
struction was achieved mainly through use of chiral resolution
procedures[3] or chiral substrates.[4] Therefore, the catalytic
enantioselective synthesis of such spiroethers is particularly
appealing.[5] Among the reported syntheses of spiroethers,
one potential pathway involves the semipinacol rearrange-
ment reaction, which is one of the most fundamental carbon–
carbon bond formation reactions.[6] In connection with our
interest in the construction of quaternary carbon stereocen-
ters, we have developed a series of synthetic methodologies
that employ the semipinacol rearrangement of allylic alcohols
(Scheme 1).[7] However, the catalytic asymmetric semipinacol
rearrangement reaction for the construction of chiral oxo
quaternary stereogenic centers in spiroethers remains chal-
lenging and elusive.[5,8,9]
nary carbon stereocenters. Phth=phthalimido.
sioned that the synthesis of chiral spiroether motif 3 might be
achievable by exploring a chiral phosphoric acid catalyzed
semipinacol rearrangement of 2-oxo allylic alcohols
1
(Scheme 2). We postulated that the asymmetric 1,2-migration
of the carbon atom might be initiated, in the presence of
hydrogen bonding, by acidic proton transfer to the enol ether
moiety in A before proceeding enantioselectively via chiral
ion pair transition state B.[13] Herein, we report our prelimi-
nary results for this chiral phosphoric acid catalyzed semi-
pinacol rearrangement reaction.
The initial evaluation of the reaction conditions was
performed using 1a and 10 mol% (R)-2b at room temper-
ature. Among the solvents examined (Table 1, entries 1–7),
nonpolar CCl4 showed the most promising enantioselectiv-
During the past few years, chiral
Brønsted acids have emerged as versatile
enantioselective catalysts,[10] and their use
in a variety of enantioselective procedures
has been widely reported. One such class
of chiral Brønsted acid catalysts, BINOL-
derived phosphoric acids,[11] are promising
catalysts for the asymmetric activation of
Scheme 2. Design of the catalytic enantioselective semipinacol rearrangement reaction in the
synthesis of spiroethers with oxo quaternary carbon centers.
imines or iminium ions,[12] for which the
hydrogen bonding interaction is one of the
crucial factors in controlling enantioselectivity. Inspired by
the successful employment of such chiral BINOL-derived
phosphoric acid catalysts, and following our long-standing
interest in semipinacol rearrangement reactions, we envi-
ities in the control reaction (Table 1, entries 6 and 7).
Surprisingly, the Lewis basic solvent 1,2-dimethoxyethane
(DME) inhibited this rearrangement reaction completely
(Table 1, entry 5). Importantly, it was found that by varying
the chiral phosphoric acid catalyst (2a and 2c–2e, Table 1,
entries 8–11), the substituents on the 3,3’-positions of the
chiral phosphoric acid (R)-2 played a key role for the
enantioselectivity of this reaction, with the bulky di-(2,4,6-
triisopropylphenyl)-substituted phosphoric acid (R)-2e
affording both a high enantioselectivity (94% ee) and
excellent yield (96%); (Table 1, entry 11). Moreover, the in
situ generation of phosphoric acid (R)-2e was also inves-
tigated by employing the corresponding silver phosphate (R)-
2 f (Table 1, entry 12).[14] The desired spiroether 3a was
obtained with excellent enantiocontrol (98% ee) and high
yield (90%). This procedure, which involves silver–proton
exchange between alcohol 1a and silver phosphate (R)-2 f
[*] Q.-W. Zhang, Prof. Dr. C.-A. Fan, H.-J. Zhang, Prof. Dr. Y.-Q. Tu,
Y.-M. Zhao, Dr. P. Gu, Z.-M. Chen
Department of Chemistry
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
Fax: (+86)931-8912582
E-mail: tuyq@lzu.edu.cn
[**] This work was supported by the NSFC (Nos. 20621091, 20672048,
and 20732002) and the “111” program of MOE. We also thank Prof.
Henri B. Kagan (Universitꢀ de Paris-Sud (XI), France) for helpful
discussion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904565.
8572
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Chemie
Table 1: Optimization of the reaction conditions.[a]
Table 2: Asymmetric semipinacol rearrangement.[a]
Entry
Substrate
2
Product
Yield [%][b]
ee [%][c,d]
1
2
1a
1a
2e
2 f
3a
3a
96
90
94
98
Entry
2
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
2b
2b
2b
2b
2b
2b
2b
2a
2c
2d
2e
2 f
CH2Cl2
n-Hexane
PhH
CH3CN
DME[f]
CCl4
CCl4
CCl4
CCl4
CCl4
94
92
95
80
–
95
96
95
94
90
96
90
16
42
36
ꢀ4
–
52
52
32
48
46
94
98
3
4
5
6
R=Me
R=Et
1b
1c
1d
1e
2 f
2 f
2 f
2 f
3b
3c
3d
3e
81
94
98
91
87 [e]
83 [e]
85 [e]
74
7[d]
8[d,e]
9[d]
10[d]
11[d]
12[d]
7
1 f
2e
3 f
89
95
CCl4
CCl4
[a] 2a: R=H, X=H; 2b: R=Ph, X=H; 2c: R=2-naphthyl, X=H;
2d:R=9-anthryl, X=H; 2e: R=2,4,6-(iPr)3C6H2, X=H; 2 f: R=2,4,6-
(iPr)3C6H2, X=Ag. Conditions: Catalyst 2 (0.01 mmol) and solvent
(0.5 mL) were added to a Schlenk flask. The mixture was stirred for
8
1g
1h
1i
2e
2 f
2 f
3g
3h
3i
91
51
85
77
9
89 [f]
90 [f]
10 min at room temperature, and then
a solution of substrate
(0.1 mmol) in solvent (0.5 mL) was added. The reaction mixture was
stirred for 2 h unless otherwise indicated. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis. [d] 5 ꢁ molecular sieves
(100 mg) were added. [e] Reaction proceeded for 24 h. [f] 1,2-Dimethoxy-
ethane.
10
[a] For experimental details, see the Supporting Information. [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis. [d] The
absolute configuration of 3h (Table 2, entry 9) is assigned as “S” by a
comparison of its optical rotation with the literature value, and
accordingly the absolute stereochemistry of entries 1–8 and 10 was
provisionally established as indicated. [e] The reaction was conducted in
CCl4 (0.4 mL). [f] The reaction proceeded at 08C.
provides relatively mild, less acidic conditions, thus effectively
realizing this semipinacol rearrangement reaction in the
presence of 5 ꢀ molecular sieves.[15] The absence of 5 ꢀ
molecular sieves (apart from Table 1, entries 6 and 7) usually
resulted in the observation of varied, irreproducible ee values
(Table 1, entries 8–12) suggesting that the addition of 5 ꢀ
molecular sieves is necessary for the reproducibility of
reaction enantioselectivity in these cases. Therefore, the
optimal conditions for the asymmetric semipinacol rearrange-
ment reaction were found to be the use of (R)-2e as the
catalyst or the less acidic (R)-2 f as precatalyst.
Further exploration of this novel chiral Brønsted acid
catalyzed asymmetric rearrangement was conducted using a
series of 2-oxo allylic alcohols 1b–i with dihydropyranyl and
dihydrofuranyl moieties (Table 2). For comparison with 1a
(Table 2, entry 1), several substituted dihydropyranyl units
were used (1b–g; Table 2, entries 3–8). Those bearing geminal
dimethyl substitutents at the C4 or C6 position on the
dihydropyranyl ring (Table 2, entries 3–6 and 8) showed some
retardation of enantiocontrol (77–87% ee). For 1b–e
(Table 2, entries 3–6), use of catalyst (R)-2e instead of the
less acidic (R)-2 f as precatalyst was also effective in this
reaction, and comparable enantioselectivities could be
obtained. For 1 f and 1g (Table 2, entries 7 and 8), however,
the more acidic (R)-2e was the only compatible catalyst. If
silver phosphate (R)-2 f was used as precatalyst in the reaction
of 1 f and 1g, the desired rearrangement proceeded very
slowly, and did not go to completion, even after 8 days. We
also examined two substrates with dihydrofuranyl moieties
(1h and 1i; Table 2, entries 9 and 10), which are highly acid–
sensitive.[3a] Good enantioselectivities (about 90% ee) were
achieved at 08C with the less acidic (R)-2 f catalyst, whilst
only about 50% ee could be obtained for the reaction of 1h
using the phosphoric acid catalyst (R)-2e. It should be noted
that the low yield in the reaction of 1h (51%; Table 2, entry 9)
was due to the volatility of the product 3h and its undesired
dimerization.[3a] In order to investigate the enantioselectivity
of this reaction, the absolute configuration of 3h is further
unambiguously assigned as “S” by the comparison of its
optical rotation with the literature data.[3a]
In summary, we have discovered a novel chiral phosphoric
acid, which can also be generated in situ by a silver–proton
exchange process. This acid catalyzed an asymmetric ring
expansion-type semipinacol rearrangement reaction that
affords synthetically relevant chiral spiroethers in up to
98% ee and good to high yields under mild conditions. This
catalytic asymmetric method provides an efficient route to
enantiomerically pure spiroethers containing one chiral oxo
quaternary carbon stereogenic center and one carbonyl keto
group for further synthetic elaboration. The present method
demonstrates the feasibility of the enantioselective 1,2-carbon
migration via an oxocarbonium ion under the catalysis with a
chiral Brønsted acid. Further research on the substrate scope
and the enantioselective mechanism is currently underway.
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Communications
Am. Chem. Soc. 2009, 131, 9178. For the asymmetric a-ketol
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Experimental Section
Typical procedure for the enantioselective semipinacol rearrange-
ment of 1a: 5 ꢀ molecule sieves (100 mg), catalyst (R)-2e or (R)-2 f
(0.01 mmol) and CCl4 (0.5 mL) were added to a Schlenk flask. The
mixture was stirred for 10 min at room temperature, and then a
solution of substrate (0.1 mmol) in CCl4 (0.5 mL) was added. The
reaction was monitored by TLC until the substrate disappeared
completely. The reaction mixture was directly subjected to column
chromatography on silica gel and eluted with pentane/Et2O (10:1!
5:1) to afford 3a as colorless oil (14.7 mg, 96% yield). (Note:
reactions using silver phosphate (R)-2 f as the catalyst were carried
out in the dark.) For further details of the synthesis and character-
ization, see Supporting Information.
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Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31; d) M. Terada,
Chem. Commun. 2008, 4097.
Received: August 16, 2009
Published online: October 8, 2009
Keywords: asymmetric catalysis · Brønsted acids ·
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8574
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Angew. Chem. Int. Ed. 2009, 48, 8572 –8574