A new powerful strategy for the organocatalytic asymmetric construction of a quaternary carbon stereogenic center

Article abstract of DOI:10.1021/ol100350w

(Figure Presented) A new method for chiral diamine-catalyzed Robinson-type annulation was developed to construct cyclohexenone derivatives bearing a quaternary carbon stereogenic center at the 4-position in high enantiomeric excess. This method was successfully applied to the short synthesis of (+)-sporochnol A.

Full text of DOI:10.1021/ol100350w

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1616-1619
A New Powerful Strategy for the
Organocatalytic Asymmetric
Construction of a Quaternary Carbon
Stereogenic Center
Yogo Inokoishi, Niiha Sasakura, Keiji Nakano, Yoshiyasu Ichikawa, and
Hiyoshizo Kotsuki*
Laboratory of Natural Product Chemistry, Faculty of Science, Kochi UniVersity,
Akebono-cho, Kochi 780-8520, Japan
kotsuki@kochi-u.ac.jp
Received February 10, 2010
ABSTRACT
A new method for chiral diamine-catalyzed Robinson-type annulation was developed to construct cyclohexenone derivatives bearing a quaternary
carbon stereogenic center at the 4-position in high enantiomeric excess. This method was successfully applied to the short synthesis of
(+)-sporochnol A.
The catalytic asymmetric synthesis of quaternary carbon
stereogenic centers, particularly all-carbon substituted centers,
represents a significant synthetic challenge in modern organic
chemistry.1 A number of methods have been reported, which
can be categorized into five major classes: enolate alkylation,
Michael addition, cycloaddition reaction, sigmatropic rear-
rangement, and C-H insertion.2 Organocatalytic asymmetric
versions of these reactions have recently attracted consider-
able attention because of their environmentally friendly
characteristics.3 In our ongoing research, we anticipated that
an organocatalytic Robinson-type annulation could provide
an elegant approach to satisfy the desired stereochemical
requirement, since this method can be frequently used to
obtain complex cyclohexenone derivatives including poly-
cyclic terpenes, steroids, and other natural products.4 How-
ever, except for the examples using a Hajos-Parrish-Eder-
Sauer-Wiechert reaction,5 there has been very limited
success with a practical and straightforward approach to
construct a quaternary carbon stereogenic center at the
4-position on a nonfused cyclohexenone framework with
high enantiomeric excess.6
In 1969, Yamada and Otani reported an asymmetric
synthesis of 4,4-disubstituted cyclohexenone derivatives via
a stepwise strategy in which L-proline enamines were used
as nucleophiles.7 However, our preliminary studies revealed
(4) Review: Varner, M. A.; Grossman, R. B. Tetrahedron 1999, 55,
13867.
(5) Christen, D. P. In Name Reactions for Homologations; Li, J. J., Ed.;
Wiley-VCH: Weinheim, 2009; Part 2, pp 554-582.
(1) Quaternary Stereocenters: Challenge and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
(2) For recent reviews, see: (a) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969.
(6) For related works, see: (a) Carlone, A.; Marigo, M.; North, C.; Landa,
A.; Jørgensen, K. A. Chem. Commun. 2006, 4928. (b) Zhou, J.; Wakchaure,
V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47, 7656. (c) Akiyama,
T.; Katoh, T.; Mori, K. Angew. Chem., Int. Ed. 2009, 48, 4226. (d) Mori,
K.; Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew.
Chem., Int. Ed. 2009, 48, 9652. (e) Li, P.; Yamamoto, H. Chem. Commun.
2009, 5412.
(3) Review : Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(7) Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 10, 4237.
10.1021/ol100350w  2010 American Chemical Society
Published on Web 03/11/2010

Table 1. Catalytic Asymmetric Robinson Annulation: Optimization Studya
entry
cat. (mol %)
acid (mol %)
time (days)
yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
L-Lys (10)
L-Orn (10)
L-Arg (10)
1a (10)
1a (10)
1a (10)
1b (10)
1c (10)
1c (10)
1c (30)
1c (30)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1d (30)
1
6
7
2
2
2
2
8
3
0.38
0.33
3
2
7
3
3
48 (S)
25 (S)
45 (S)
47 (R)
53 (R)
47 (R)
55 (S)
51 (S)
54 (S)
50 (S)
45 (S)
60 (S)
38 (S)
53 (S)
46 (S)
43 (S)
40 (S)
49 (R)
55
31
60
52
52
50
50
41
74
67
82
68
63
61
68
65
21
87
1e (5)
1g (5)
(()-1e (5)
(()-1e (5)
1e (10)
1e (15)
1e (30)
1f (10)
(()-1e (10)
phthalic acid (10)
1g (10)
L-tartaric acid (10)
D-tartaric acid (10)
1f (30)
3
0.33
a Conditions: 2a (1 mmol), MVK (1.5 mmol) in i-PrOH (1.0 mL) in the presence of catalyst and acid. b Determined by chiral HPLC analysis using a
Chiralpak AD.
that the direct treatment of 2-phenylpropionaldehyde (2a)
a significant improvement in enantioselectivity (entries
9-11), and with an increase in catalyst loading (30 mol
%) the reaction went to completion within 8 h to give the
cyclohexenone (S)-3 in 45% yield with 82% ee (entry
11).12,13 The lower efficiency for (R,R)-1c/(S,S)-1f and (R,R)-
1c/racemic-1e highlights the importance of the compatibility
of chirality between the amine and acid catalysts (entries 12
and 13). Similar phenomena were observed for the use of L-
or D-tartaric acid as an acid additive (entries 16 and 17).
The superiority of (R,R)-1e as a cocatalyst in this catalyst
system is clear based on the results shown in entries 8 and
14-17. As expected, the combination of (S,S)-1d and (S,S)-
with methyl vinyl ketone (MVK) in the presence of a
catalytic amount of L-proline (30 mol %) was unsuccessful.
Furthermore, the use of diphenylprolinol methyl ether as a
chiral catalyst under Gellman’s conditions8 was also unsat-
isfactory (7 days, 20% yield, 20% ee).9 These results clearly
suggest that it is inherently difficult to form a sterically
congested enamine species from 2a and secondary amines.
To overcome this difficulty, we sought to devise a new
methodology based on chiral primary amine catalysis10 that
might address the steric-constraint problems.
We report here an efficient method for the construction
of cyclohexenone derivatives bearing a quaternary carbon
stereogenic center at the 4-position based on a novel chiral
diamine-catalyzed Robinson-type annulation.
First, we screened various combinations of chiral
primary amines and carboxylic acids to transform 2-phe-
nylpropionaldehyde (2a) to the desired cyclohexenone 3
by exposure to MVK (Table 1).9 In all cases, the use of
naturally occurring basic amino acids or commercially
available primary amines like 1a and 1b (Figure 1) was
less efficient (entries 1-7). To our delight, the combined
use of (1R,2R)-1,2-cyclohexanediamine (1c) with (1R,2R)-
1,2-cyclohexanedicarboxylic acid (1e) in i-PrOH11led to
Figure 1
present study.
. Organocatalysts and acid additives examined in the
(8) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253.
(9) For a comprehensive compilation of the catalyst-screening results,
see the Supporting Information.
Org. Lett., Vol. 12, No. 7, 2010
1617

1f produced cyclohexenone (R)-3 with a completely opposite
configuration (49% yield, 87% ee) (entry 18).14
Table 2. Catalytic Asymmetric Robinson Annulation:Generalitya
With the optimal conditions in hand, we then examined a
variety of R-aryl-substituted propionaldehydes to establish
the general utility of this asymmetric transformation (Table
2). All reactions were performed in i-PrOH at 0 °C in the
presence of 30 mol % of the respective diamine (S,S)-1d
and dicarboxylic acid (S,S)-1f.
Various aldehydes reacted smoothly with MVK or ethyl
vinyl ketone (EVK) in moderate yields (up to 65%) and with
high enantioselectivity (up to 97%) (entries 1-12).13,15,16
A probable mechanism that may account for the observed
absolute configuration of product (R)-3 and this highly
effective catalytic asymmetric process is outlined in Scheme
1. Thus, condensation of bifunctional catalyst 1d with both
2a and MVK in the presence of cocatalyst 1f proceeds
through the formation of an enamine-iminium double-
activation intermediate A, which then causes an intramo-
lecular Michael addition to afford the cyclic enamine-iminium
ion intermediate B. This intermediate collapses spontaneously
via hydrolysis to give the keto-aldehyde precursor C17 and
(10) For reviews, see: (a) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem.
2008, 285, 1. (b) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. (c) Xu,
L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. For recent selected
examples, see: (d) Luo, S.; Qiao, Y.; Zhang, L.; Li, J.; Li, X.; Cheng, J.-P.
J. Org. Chem. 2009, 74, 9521, and references cited therein. (e) Jiang, X.;
Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2009, 11, 153. (f) Li, P.;
Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Org. Lett.
2009, 11, 753. (g) Zhang, X.; Liu, S.; Li, X.; Yan, M.; Chan, A. S. C.
Chem. Commun. 2009, 833. (h) Li, J.; Luo, S.; Cheng, J.-P. J. Org. Chem.
2009, 74, 1747. (i) Kano, T.; Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka,
K. Chem. Commun. 2009, 1956. (j) Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu,
F.-C.; Ma, X.; Jia, Y.-N. J. Org. Chem. 2009, 74, 2541. (k) Wu, F.-C.; Da,
C.-S.; Du, Z.-X.; Guo, Q.-P.; Li, W.-P.; Yi, L.; Jia, Y.-N.; Ma, X. J. Org.
Chem. 2009, 74, 4812. (l) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett. 2009,
11, 2249. (m) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue,
F.; Duan, W.; Wang, W. Org. Lett. 2009, 11, 2864. (n) Rasappan, R.; Reiser,
O. Eur. J. Org. Chem. 2009, 1305. (o) Ma, X.; Da, C.-S.; Yi, L.; Jia, Y.-
N.; Guo, Q.-P.; Che, L.-P.; Wu, F.-C.; Wang, J.-R.; Li, W.-P. Tetrahedron:
Asymmetry 2009, 20, 1419. (p) Dong, L.; Lu, R.; Du, Q.; Zhang, J.; Liu,
S.; Xuan, Y.; Yan, M. Tetrahedron 2009, 65, 4142. (q) Gu, Q.; Guo, X.-
T.; Wu, X.-Y. Tetrahedron 2009, 65, 5265. (r) Luo, G.; Zhang, S.; Duan,
W.; Wang, W. Synthesis 2009, 1564. (s) Liu, J.; Yang, Z.; Liu, X.; Wang,
Z.; Liu, Y.; Bai, S.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009, 7, 4120.
(t) Li, J.; Li, X.; Zhou, P.; Zhang, L.; Luo, S.; Cheng, J.-P. Eur. J. Org.
Chem. 2009, 4486. (u) He, T.; Qian, J.-Y.; Song, H.-L.; Wu, X.,-Y. Synlett
2009, 3195. (v) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti,
A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.sEur. J.
2009, 15, 7846. (w) Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti,
A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196. (x)
Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7892. (y) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang,
F.-M.; Song, Y. L. J. Am. Chem. Soc. 2009, 131, 14626.
a Conditions: aldehyde 2 (1 mmol), MVK or EVK (1.5 mmol) in i-PrOH
(1 mL) at 0 °C in the presence of 30 mol % of catalyst 1d and 30 mol %
of acid 1f. b Isolated yield. c Determined by chiral HPLC analysis using a
Chiralpak AD. d Determined by chiral HPLC analysis using a Chiralpak
AS-H. e Determined by chiral HPLC analysis using a Chiralpak AD-H.
(11) Other solvents found to be less efficient for the present purpose:
MeOH (32 h at 0 °C, 42%, 88% ee), MeCN (42 h at 0 °C, 50%, 61% ee),
DMSO (15 h at rt, 35%, 82% ee).
(12) In contrast, the use of (1R,2R)-1,2-diphenylethylenediamine with
rac-1e caused no asymmetric induction (Supporting Information).
(13) Due to the instability of the starting aldehyde 2 under the conditions,
unidentified complex byproducts were formed.
the catalyst/cocatalyst system composed of 1d and 1f, which
leads back to the catalytic cycle. In this sequence, the vicinal
trans-diamine arrangement in catalyst 1d is essential not only
to activate both the Michael donor and acceptor components
but also to bring them together in close proximity to achieve
carbon-carbon bond formation with the observed enantio-
control.18
(14) The absolute stereochemical sequence in these asymmetric trans-
formations was determined by comparison of the optical rotation data with
those reported in the literature: Meyers, A. I.; Lefker, B. A.; Wanner, K.
Th.; Aitken, R. A. J. Org. Chem. 1986, 51, 1936.
(15) The absolute configurations of unknown products were surmised
by analogy.
(16) Unfortunately, similar reactions using R-alkyl-substituted analogues
as donor molecules were disappointingly very slow, suggesting the
importance of enough acidity for an active R-hydrogen atom.
(17) Although we did not examine this point in detail, it was possible
to isolate the intermediary Michael adduct from the reaction mixture; see
the Supporting Information. See also ref 10g.
To demonstrate the synthetic value of this organocatalytic
asymmetric process, (+)-sporochnol A (15), a chemical fish
(18) Although we did not try, it might be possible to recover the catalyst/
cocatalyst system from the reaction mixture by column purification.
1618
Org. Lett., Vol. 12, No. 7, 2010

Scheme 1. Proposed Catalytic Cycle of Asymmetric Robinson
Scheme 2. Total Synthesis of (+)-Sporochnol A (15)a
Annulation
In conclusion, we have developed an unprecedented
organocatalytic asymmetric synthesis of cyclohexenone
derivatives with a quaternary carbon stereogenic center at
the 4-position with complete control via chiral diamine/
dicarboxylic acid-catalyzed Robinson-type annulation. In
addition, this new methodology was successfully applied to
the short synthesis of (+)-sporochnol A. This method should
be of great value in terms of simplicity, ready availability
of the respective catalysts, and utility in natural product
synthesis. Further studies to extend the scope of this method
are now in progress.
deterrent isolated from the Caribbean marine alga Sporochnus
bolleanus, was targeted (Scheme 2).19 The reaction of 2-(4-
methoxyphenyl)propionaldehyde with MVK under the stan-
dardized conditions using catalyst 1c and acid 1e gave
cyclohexenone (S)-7 (62%, 91% ee). Conjugate addition of
the silyl zincate, developed by Oestreich,20 followed by
Hudrlik’s silicon-directed fragmentation (m-CPBA oxidation;
BF3·OEt2-mediated ꢀ-elimination)21 and subsequent esteri-
fication gave methyl ester 18 (41% total yield), which can
be converted into (+)-sporochnol A (15) as described in the
literature.22
Acknowledgment. This work was supported in part by a
Special Research Grant for Green Science from Kochi
University.
(19) (a) Mart´ın, R.; Buchwald, S. L. Org. Lett. 2008, 10, 4561, and
references cited therein. (b) Yamamoto, D.; Kawano, K.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Heterocycles 2009, 77, 249.
(20) (a) Oestreich, M.; Weiner, B. Synlett 2004, 2139. (b) Auer, G.;
Weiner, B.; Oestreich, M. Synthesis 2006, 2113.
Supporting Information Available: Experimental details
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) (a) Hudrlik, P. F.; Hudrlik, A. M.; Nagendrappa, G.; Yimenu, T.;
Zellers, E. T.; Chin, E. J. Am. Chem. Soc. 1980, 102, 6894. (b) Hudrlik,
P. F.; Hudrlik, A. M.; Yimenu, T.; Waugh, M. A.; Nagendrappa, G.
Tetrahedron 1988, 44, 3791.
(22) Fadel, A.; Vandromme, L. Tetrahedron: Asymmetry 1999, 10, 1153.
OL100350W
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