Organocatalytic asymmetric vinylogous α-ketol rearrangement: Enantioselective construction of chiral all-carbon quaternary stereocenters in spirocyclic diketones via semipinacol-type 1,2-carbon migration

Article abstract of DOI:10.1021/ja906291n

(Chemical Equation Presented) The catalytic enantioselective synthesis of all-carbon quaternary stereogenic centers in spirocyclic diketones has been achieved for the first time by an unprecedented asymmetric vinylogous α-ketol rearrangement in which an e

Full text of DOI:10.1021/ja906291n

Published on Web 09/28/2009
Organocatalytic Asymmetric Vinylogous r-Ketol Rearrangement:
Enantioselective Construction of Chiral All-Carbon Quaternary Stereocenters
in Spirocyclic Diketones via Semipinacol-Type 1,2-Carbon Migration
En Zhang, Chun-An Fan, Yong-Qiang Tu,* Fu-Min Zhang, and Yan-Lin Song
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou UniVersity,
Lanzhou 730000, P. R. China
Received July 27, 2009; E-mail: tuyq@lzu.edu.cn
Asymmetric construction of chiral quaternary carbon stereo-
centers is one of the most challenging subjects in modern organic
synthesis,1 and the development of synthetic methodologies in this
area of research has always been in high demand. Over the past
several decades, tremendous efforts have been made in the
asymmetric formation of quaternary carbon centers;2 however,
alternative asymmetric access to chiral all-carbon quaternary centers
through semipinacol-type 1,2-carbon migration.5 Herein, we present
our preliminary results on this topic.
catalytic enantioselective synthesis, especially of stereogenic all-
carbon quaternary centers, still remains a major challenge for
synthetic chemists. In the context of our interest in the stereose-
lective construction of 1,3-diheteroatom units with 2-quaternary
During the initial elaboration of standard conditions, cinchona-based
primary amine 3a was examined as a promising catalyst.8 As indicated
in Table 1, the hydroxy enone 1a as a model substrate was subjected
carbon centers, a series of synthetic protocols based on the
Table 1. Optimization Studies on Asymmetric Rearrangementa
semipinacol rearrangement has been developed in our group to
effectively achieve the quaternary carbon stereocenters.3 However,
the asymmetric versions of our previous protocols using the
semipinacol rearrangement strategy were limited to utilizing kinetic
resolution3b or stoichiometric chiral reagents,3c and the catalytic
enantioselective semipinacol rearrangement still remains elusive.4,5
Encompassing the development of catalytic asymmetric synthesis
of all-carbon quaternary stereogenic centers, we envisioned that
the 1,2-sigmatropic migration in the semipinacol rearrangement
might be extended to vinylogous R-hydroxy ketones, which could
analogously result in an electron-deficient electrophilic center next
to the tertiary hydroxyl moiety (Scheme 1), leading to the generation
Entry
Cat.
Acidb
Solvent
t (h)
Yield (%)c
ee (%)d
1
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
CF3CO2H
o-NBA
o-NBA
D-CSA
L-CSA
PTS
CF3CO2H
AcOH
NBLP
THF
THF
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
18
48
3
59
59
39
5
21
15
6
4
32
75
60
59
62
65
91
55
67
52
55
41
84
34
39
53
31
24
14
38
48
62
43
75
77
2
3
4
5
6
Scheme 1. Semipinacol and Related Rearrangements for the
Synthesis of All-Carbon Quaternary Stereocenters
7
8
9
10
11
NBDP
NBLP
NBLP
e
12
a All reactions were performed with 0.1 mmol of 1a, 0.02 mmol of
catalyst, and 0.04 mmol of acid in 2 mL of solvent at 40 °C. b Abbrevia-
tions: o-NBA, 2-nitrobenzoic acid; CSA, camphor-10-sulfonic acid; NBLP,
N-Boc-L-phenylglycine; NBDP ) N-Boc-D-phenylglycine; PTS ) p-Tolu-
enesulfonic acid. c Isolated yield. d Determined by chiral HPLC. e With ad-
diton of 4 Å molecular sieves.
to the combination of 3a and CF3CO2H in THF at 40 °C, and the
spirocyclic diketone 2a was obtained in good yield but with a low ee
of 34% (entry 1). By variation of the solvents and acids (entries 2-10),
it was found that the combination of N-Boc-L-phenylglycine (NBLP)
as the acid9a and CCl4 as the solvent could increase the reaction
enantioselectivity to 62% ee (entry 9). Gratifyingly, when further
optimizations were conducted with multifunctional cinchona-derived
catalyst 3b9b (entries 11 and 12), the enantiocontrol of this vinylogous
R-ketol rearrangement was ultimately improved to 77% ee in the
presence of 4 Å molecular sieves (entry 12).
of an all-carbon quaternary stereogenic center. In light of the
aforementioned semipinacol-type 1,2-carbon migration and inspired
by the chiral iminium catalysis of enones,6 we recently discovered
the first organocatalytic asymmetric vinylogous R-ketol rearrange-
ment via semipinacol-type 1,2-carbon migration for the construction
of chiral all-carbon quaternary stereocenters in spirocyclic dike-
tones,7 which are versatile building blocks in the synthesis of natural
products and pharmaceutical molecules (eq 1). To our knowledge,
there is no precedent for the catalytic enantioselective vinylogous
R-ketol rearrangement, and the current protocol provides an
With the optimal conditions established above, the scope and
generality of this reaction were then investigated with various cyclic
hydroxy enones (1b-k) bearing a substituted cyclobutanol motif.
From Table 2, it can be seen that all-carbon quaternary stereogenic
9
14626 J. AM. CHEM. SOC. 2009, 131, 14626–14627
10.1021/ja906291n CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Vinylogous R-Ketol Rearrangement
Catalyzed by the 3b/NBLP Catalyst Systema
ingly, highly enantioselective rearrangement reactions were carried
out with 91-97% ee and 80-87% yield (entries 8 and 11-13),
and good diastereoselectivities (8:1 to 26:1 dr) in the products were
also demonstrated. Notably, control experiments with decreased
catalyst loading (1j) and enlarged reaction scale (cis/trans-1h)10a
indicated little influence on the stereoselectivity and yields, but some
effect on the reactivity was found in the former case. To further
clarify the influence of the diastereomeric ratio of the reactants on
the reaction diastereo- and enantioselectivity, cis-1h (entry 9) and
trans-1h (entry 10) were independently subjected to the current
standard conditions. Interestingly, improved and decreased stereo-
selectivity, respectively, for the major isomer product were
observed. This fact clearly demonstrates that the cis isomer is the
matched substrate for the diastereo- and enantioselectivity of this
asymmetric vinylogous R-ketol rearrangement under the current
organocatalysis, while the trans isomer is the unmatched one. It
should be noted that the absolute configuration of the product 2k
was unambiguously assigned by X-ray crystallography.10b
In conclusion, an unprecedented organocatalytic enantioselective
vinylogous R-ketol rearrangement reaction via a semipinacol-type
1,2-carbon migration was discovered for the first time, and chiral
all-carbon quaternary stereocenters in spirocyclic diketones were
constructed with good to excellent enantiocontrol. Our current
methodology for the asymmetric synthesis of quaternary stereogenic
centers constitutes an alternative strategy to classical semipinacol
rearrangement. Further studies of the detailed mechanism and
synthetic applications are under investigation.
Acknowledgment. We gratefully acknowledge financial support
from the NSFC (20621091, 20672048, and 20732002) and the
Chang Jiang Scholars Program.
Supporting Information Available: Experimental details, com-
pound characterization, and X-ray crystallographic data (CIF) for 1j
and 2k. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
a For experimental details, see the Supporting Information. b For entries
11-13, the major cis isomer is described. c For entries 8-13, the absolute
configuration of major diastereoisomer is given. d Isolated yield.
e Determined by chiral HPLC. f The yield in parentheses was based on the
recovered starting material. g The dr value in parentheses was determined
by chiral HPLC. h The dr value in parentheses was determined by 1H NMR.
i The ee value of the major isomer. j 57% ee for the minor isomer. k 41%
ee for the minor isomer. l 77% ee for the minor isomer.
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semipinacol-type 1,2-carbon migration in the enantioselective
vinylogous R-ketol rearrangement, and a wide range of spirocyclic
1,4-diketones 2b-k were obtained with good to excellent enanti-
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yield). Compared with the model substrate 1a (entry 1), hydroxy
enones disubstituted at the C3 position of the cyclobutanol moiety
(1b-d, entries 2-4) underwent the molecular rearrangement with
increased asymmetric induction. When substrates disubstituted at
the R′ and ꢀ′ positions of the cyclohexenone moiety (1e and 1f,
respectively, entries 5 and 6) were used, slightly decreased
enantiocontrol was observed, and R′-substitution caused a dramatic
decrease in the reactivity of this rearrangement reaction (entry 5).
One substrate with a cycloheptenone motif instead of the cyclo-
hexenone unit (1g, entry 7) was also explored and certainly showed
good ee and yield. In addition, some C3-monosubstituted examples
(1h-k, entries 8 and 11-13), in which cis-1,1,3-trisubstituted
cyclobutanes were the major or predominant components of the
starting material, were examined in this catalytic system. Interest-
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