Synthesis of all-carbon, quaternary center-containing cyclohexenones through an organocatalyzed, multicomponent coupling

Article abstract of DOI:10.1021/ol1011955

Organocatalyzed multicomponent coupling using a new ester-containing, proline aryl sulfonamide has been developed for accessing densely functionalized cyclohexenones, each containing a quaternary center in high enantio- and diastereoselectivity. In contrast to most enamine/iminium-catalyzed reactions, the use of molecular sieves was critical to optimum enantioselectivity.

Full text of DOI:10.1021/ol1011955

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3108-3111
Synthesis of All-Carbon, Quaternary
Center-Containing Cyclohexenones
through an Organocatalyzed,
Multicomponent Coupling
Hua Yang and Rich G. Carter*
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331
rich.carter@oregonstate.edu
Received May 24, 2010
ABSTRACT
Organocatalyzed multicomponent coupling using a new ester-containing, proline aryl sulfonamide has been developed for accessing densely
functionalized cyclohexenones, each containing a quaternary center in high enantio- and diastereoselectivity. In contrast to most enamine/
iminium-catalyzed reactions, the use of molecular sieves was critical to optimum enantioselectivity.
In the history of enantioselective organic synthesis, the
Hajos-Parrish-Eder-Sauer-Wiechert reaction1 represents
one of the first (and still most powerful) transformations
developed for accessing stereogenic (all-carbon) quaternary
centers2 (Scheme 1, eq 1). The widespread presence of this
functionality in natural products has made their construction
a central focus of organic chemistry.3 The Hajos-Parrish
reaction generally necessitates that the quaternary center be
first established on an achiral substrate.4 The prochiral
position is then rendered enantiomerically enriched through
an intramolecular aldol desymmetrization event, normally
catalyzed by the amino acid proline. Recent examples from
several laboratories have utilized the Michael addition itself
as the enantiodetermining step via transition-metal,5 Brønsted
acid,6 and phase-transfer catalysis.7 The vast majority of these
cases have employed two resonance electron-withdrawing
groups on the nucleophilic component, with carbon-based
electron-withdrawing groups normally limited to ketones,
esters, and nitriles.
In contrast, attempts to exploit aldehyde moieties within
the nucleophilic component (e.g., 5) of a Hajos-Parrish-
type reaction have met with only limited success to date
(Scheme 1, eq 2), despite the fact that racemic methods have
(1) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496–497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615–1621. (c) Hajos, Z. G.; Parrish, D. R. Organic Syntheses; Wiley:
New York, 1990; Collect. Vol. VII, pp 363-368. (d) Hoang, L.; Bahmanyar,
S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17. (e) Cheong,
P. H.-Y.; Houk, K. N. Synthesis 2005, 1533–1537.
(5) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187–2210.
(6) Akiyama, T.; Katoh, T.; Mori, K. Angew. Chem., Int. Ed. 2009, 48,
4226–4228.
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2007, 5969–5994. (b) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105–10146.
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Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796–3798. (b) He, R.; Ding,
C.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 4559–4561. (c) Wu, F.;
Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947–950. (d)
Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007,
129, 768–769. (e) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org. Lett. 2008,
10, 2437–2440.
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J.; Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992,
3, 459–505. (c) Przezdziecka, A.; Stepaneko, W.; Wicha, J. Tetrahedron:
Asymmetry 1999, 10, 1589–1598. (d) Bui, T.; Barbas, C. F., III. Tetrahedron
Lett. 2000, 42, 4887–4890.
10.1021/ol1011955  2010 American Chemical Society
Published on Web 06/08/2010

of R,R-disubstituted aldehydes to cyclohexenone; however,
the products from these reactions are inherently incapable
of undergoing elimination. Acyclic enone substrates bring
the added challenge of controlling rotational freedom around
the σ bond connecting the alkene and ketone moieties.15 This
rotational freedom is not a stereochemical issue with un-
substituted acyclic enones such as methyl vinyl ketone. If a
one-step method could be developed to provide useful levels
of enantio- and diastereoselectivity on acyclic, ꢀ-substituted
enones (e.g., Scheme 1, eq 3), the annulation product 12
might prove to be a powerful synthetic building block as
illustrated by its presence in natural products such as viridin
(13)16 and hinokione (14)17 as well as manipulation of the
benzene ring to provide access to other natural product
scaffolds such as dysidolide (15).18
Scheme 1. Enantioselective Robinson Annulations
One option to facilitate catalyst turnover would be the
addition of an achiral additive, which might also help to
augment the nucleophilicity of the aldehyde component 9.
Recently, our laboratory demonstrated that benzylamine is
effective in this role through presumably the transient
formation of enamine 10 and its subsequent reaction with
cyclohexenone to make bicyclo[2.2.2]octanone scaffolds.14b
Herein, we disclose the synthesis of enantioenriched enones
12 containing two contiguous stereogenic centers including
an all-carbon-quaternary carbon through an organocatalyzed,
multicomponent coupling.
Our exploration of this transformation is shown in Table
1. We selected 3(E)-penten-2-one (18) as our initial Michael
acceptor for the tranformation. We were pleased to observe
that enone 20 could be formed by using benzylamine as an
additive in the presence of catalyst 17 (Table 1, entry a).
Our laboratory has developed a proline aryl sulfonamide
derivative (2S)-N-(p-dodecylphenylsulfonyl)-2-pyrrolidine-
carboxamide (17) containing a lipophilic side arm, which
imparts significantly improved solubility in nonpolar solvent
systems.19 Under these conditions, it appears the initial
Mannich addition product (e.g., 19) undergoes rapid elimina-
tion to generate the corresponding enone 20. Benzylamine
is critical to the success of this reaction as no product is
observed in its absence. While benzylamine is potentially
catalytic in this reaction, use of less than 1 equiv led to
been known for some time.8 In 1969, Yamada and Otani
reported a protocol that employed stoichiometric proline
derivative 6 to facilitate the one-pot Robinson annulation of
2-phenylpropanal (5) and methyl vinyl ketone (1) in modest
enantioselectivity (up to 49% ee).9 Despite this encouraging
early report, the concept has laid essentially dormant over
the next four decades,10 likely due to the inability to turn
over the catalyst and the disappointing levels of enantiose-
lectivity.11 One major limitation of this chemistry to date is
the lack of substitution on the ꢀ-position of the enone moiety
(e.g., compound 11).9-12 Bella13 and our laboratory14 have
separately reported examples of successful Michael additions
(15) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 2458–2460. (b) Thayumanavan, R.; Dhevalapally, B.; Sakthivel, K.;
Tanaka, F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817–3820. (c)
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Angew. Chem., Int. Ed. 2004, 43, 1272–1277. (e) Li, P.; Payette, J. N.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534–9435. (f) Wu, L.-Y.;
Bencivenni, G.; Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2009, 48, 7196–7199. (g) Bencivenni, G.; Wu, L.-
Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200–7203. (h) Wang,
H.-F.; Cui, H.-F.; Zhuo, C.; Li, P.; Zheng, C. W.; Yang, Y. Q.; Zhao, G.
Chem.sEur. J. 2009, 15, 13295–13298.
(8) (a) Schuster, D. I.; Rao, J. M. J. Org. Chem. 1981, 46, 1515–1521.
(b) Flaugh, M. E.; Crowell, T. A.; Farlow, D. S. J. Org. Chem. 1980, 45,
5399–5400. (c) Huffman, J. W.; Potnis, S. M.; Satish, A. V. J. Org. Chem.
1985, 50, 4266–4270. (d) Zimmerman, H. E.; Zhu, Z. J. Am. Chem. Soc.
1995, 117, 5245–5262.
(9) (a) Yamada, S.-I.; Otani, G. Tetrahedron Lett. 1969, 4237–4240.
(b) Otani, G.; Yamada, S.-I. Chem. Pharm. Bull. 1973, 21, 2112–2118.
(10) (a) Ramamurthi, N.; Swaminathan, S. Indian J. Chem. Sect. B: Org.
Chem. Incl. Med. Chem. 1990, 29, 401–404. (b) Rajagopal, D.; Narayanan,
R.; Swaminatham, S. Tetrahedron Lett. 2001, 42, 4887–4890.
(11) During the final preparation of a revised version of this manuscript,
Kotsuki and co-workers reported an greatly improved version of Otani’s
reaction involving a one-pot, two-step approach with a duel catalyst system
of 30 mol % of (1R,2R)-1,2-cyclohexanediamine and 30 mol % of (1R,2R)-
1,2-cyclohexanedicarboxylic acid. See: Inokoishi, Y.; Sasakura, N.; Nakano,
K.; Ichikawa, Y.; Kotsuki, H. Org. Lett. 2010, 12, 1616–1619.
(16) (a) Brian, P. W.; McGowan, J. C. Nature 1945, 156, 144–145. (b)
Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053–2061.
(17) (a) Chow, Y.-L.; Erdtman, H. Proc. Chem. Soc., London 1960, 174–
175. (b) Matsumoto, T.; Usui, S.; Kawashima, H.; Mitsuki, M. Bull. Chem.
Soc. Jpn. 1981, 54, 581–584.
(12) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4353–4356
.
(18) (a) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M. J. Am.
Chem. Soc. 1996, 118, 8759–8760.
(13) Bella, M.; Schietroma, D. M. S.; Cusella, P. P.; Gasperi, T.; Visca,
V. Chem. Commun. 2009, 597–599.
(19) (a) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652. (b)
Yang, H.; Carter, R. G. J. Org. Chem. 2009, 74, 2246–2249. (c) Yang, H.;
Carter, R. G. J. Org. Chem. Submitted for publication.
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(b) Yang, H.; Carter, R. G. Tetrahedron 2010, 66, 4854-4959.
Org. Lett., Vol. 12, No. 13, 2010
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a range of chemical transformations.22 Unfortunately, addi-
tion of 4-fluorobenzoic acid (20 mol %) led to a significant
decrease in enantioselectivity (Table 1, entry c). Use of
several other standard organocatalysts also proved ineffective
for transformation (Table 1, entries d-g). Both proline (3)
and tetrazole 2223 gave reduced chemical yields and lower
enantioselectivities (Table 1, entries d and e). The prolinol
catalyst 23 and its silyl derivative 24 were ineffective at
generating the desired product (Table 1, entries f and g).
Previously, we have shown that chlorinated solvents can be
advantageous to reaction selectivity (Table 1, entry h).19
Interestingly, use of a modified form of the parent aryl
sulfonamide catalyst, namely the p-dodecylester 25, proved
more effective at accomplishing this transformation (Table
1, entry i). This catalyst can be readily prepared from
inexpensive starting materials (Scheme 2). The presence of
Table 1. Optimization of Multicomponent Coupling Reaction
yield
catalyst (%)
er
(dr)
Scheme 2. Synthesis of Sulfonamide Catalyst 25
entry
a
conditions
PhMe, 24 h, rt
17
17
17
3
30
66
60
32
11
77.3:22.7
(>20:1)
90.7:9.3
(>20:1)
76.7:23.3
(>20:1)
84.4:15.6
(>20:1)
62:38
b
c
PhMe, 36 h, rt, mol. sieves
4-F-C6H4CO2H (20 mol %),
PhMe, 20 h, rt, mol sieves
PhMe, 60 h, rt, mol sieves
d
e
PhMe, 60 h, rt, mol sieves
22
(20:1)
f
g
h
PhMe, 60 h, rt, mol sieves
PhMe, 60 h, rt, mol sieves
DCE, 60 h, rt, mol sieves
23
24
17
trace
trace
67
molecular sieves continued to be critical to the enantiose-
lectivity of this transformation (Table 1, entry j). It should
be noted that the sequestering of water by molecular sieves
complicates any mechanism for catalyst turnover, which may
in part explain the observed rate of reaction. Attempts to
accelerate the rate of this transformation using additive ethyl
3,4-dihydroxybenzoate12 proved deleterious to the enanti-
oselectivity of the reaction. The optimized, one-step protocol
(Table 1, entry i) constitutes the first enantioselective
synthesis of compound 20, a natural product that has been
isolated from pine needles by Zhou and co-workers.24 Prior
efforts to access this general scaffold have focused on metal-
catalyzed conjugate addition to desymmetrize an achiral
cyclohexadienone structures25 or palladium-mediated cou-
plings of ꢀ,γ-unsaturated cyclic ketones.26
92.1:7.9
(>20:1)
94.6:5.4
(>20:1)
85.7:14.3
(>20:1)
93.4:6.6
(20:1)
i
DCE, 60 h, rt, mol sieves
DCE, 48 h, rt
25
25
25
75
66
77
j
k
CH2Cl2, 60 h, rt, mol sieves
appreciably slower rates.20 The presence of molecular sieves
in the reaction mixture had a beneficial effect on the reaction
profile, leading to increased chemical yield and enantiose-
lectivity (Table 1, entry b). This result is counter to what is
often observed in organocatalyzed processes where water can
have a beneficial impact on the reaction.14,19,21 We are unsure
as to the exact nature of the difference, but one possibility
may be that water disrupts a presumed hydrogen-bonding
interaction between the catalyst and enamine nucleophile as
shown in tentative and empirically derived model 21. A more
detailed mechanistic discussion can be found in our previous
publications.14 Melchiorre and co-workers have successfully
utilized fluorobenzoic acid additives with organocatalysts in
Initial exploration of the reaction scope for the acyclic
enones is shown in Table 2. A variety of aldehyde compo-
(22) (a) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri,
L.; Bartoli, G.; Melchiorre, P. Chem.sEur. J. 2008, 14, 4788–4791. (b)
See also ref.15g
(23) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558–
560. (b) Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun.
2006, 66–68. (c) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831–1834. (d) Torii, H.; Nakadai, N.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983–1986.
(24) Zhou, W.; Jiang, Z.; Song, Q. Linchan Huaxue Yu Gongye 1995,
15, 51–56.
(20) The use of (R)- or (S)-R-methylbenzylamine was ineffective in the
transformation, leading to no observed product. See: Pfau, M.; Revial, G.;
J. d’Angelo, A. G. J. Am. Chem. Soc. 1985, 107, 273–274.
(25) (a) Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Aoe, K.; Hiramatsu,
H.; Iwata, C. Tetrahedron 1996, 52, 14177–14188. (b) Imbos, R.; Minnaard,
A. J.; Feringa, B. L. Tetrahedron 2001, 57, 2485–2489.
(26) Hyde, A. M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
177–180.
(21) (a) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891–
1896. (b) Li, X.-J.; Zhang, G.-W.; Wang, L.; Hu, M.-Q.; Ma, J.-A. Synlett
2008, 1255–1259
.
3110
Org. Lett., Vol. 12, No. 13, 2010

Table 2. Initial Exploration of Reaction Scope
Scheme 3. Further Exploration of Reaction Scope
entry enone aldehyde time (h) yield (%)
er (dr)
a
b
c
18
18
18
30
30
30
31
32
33
34
5
60
60
56
54
52
84
76
68
0
94.4:5.6 (>20:1)
R1 ) Me, R2 ) Me
93.6:6.4 (>20:1)
R1 ) Me, R2 ) Br
93.6:6.4 (>20:1)
R1 ) Me, R2 ) Cl
95.7:4.3 (>20:1)
R1 ) Bu, R2 ) H
91.5:8.5 (>20:1)
R1 ) Bu, R2 ) Me
95.9:4.1 (>20:1)
R1 ) Br, R2 ) Br
60
d
e
f
72
72
72
60
32
33
5
g
R1 ) i-Pr, R2 ) H
nents can be utilized in this transformation. X-ray crystal-
lographic analysis of product 35b allowed for the establish-
ment of absolute configuration. Interestingly, 3-octen-2-one
appears to be generally more effective than 3-penten-2-one
in the transformation. This result may in part be due to the
comparable purity of the commercial 30. One limitation was
isopropyl-substituted enone 31, which was unreactive under
the reaction conditions (Table 1, entry g).
A range of alternate subsituents on the ꢀ-position of the
enone were also explored (Scheme 3). Aromatic moieties
appeared to be tolerated, providing the desired products 38
and 39 in good to excellent enantioselectivity. A variety of
aliphatic subsituents can be accommodated as shown with
enones 40-43, 48-52, and 58-59. In the majority of cases,
good chemical yields and high stereoselectivities were
observed. One limitation appears to be the use of propyl
halides subsituents on the enone, compounds 44 and 45;
however, use of the corresponding tosylate 42 led to
improved levels of enantioselectivity. Alkenes, sulfones, silyl
and benzyl ethers, as well as phthamide nitrogens were all
tolerated under the reaction conditions. Interestingly, the
annulation reaction to form cyclohexenone 55 was performed
in the dark to suppress an unwanted intramolecular [3 + 2]
cycloaddition, which consumed enone 50.
a This reaction was run using catalyst 17. Use of catalyst 25 gave lower
levels of enantioselectivity (80:20 er). b This reaction was performed in
the absence of light.
produced: 60%). A range of substituents is tolerated on both
the aldehyde and enone components. A novel sulfonamide
catalyst 25 has also been developed for use in these
organocatalyzed processes. Further applications of this
technology will be reported in due course.
Acknowledgment. Financial support was provided by the
Oregon State University (OSU) Venture Fund. The National
Science Foundation (CHE-0722319) and the Murdock
Charitable Trust (2005265) are acknowledged for their
support of the NMR facility. We thank Dr. Lev N. Zakharov
(OSU and University of Oregon) for X-ray crystallographic
analysis of compounds 35b and 39 and Professor Max
Deinzer and Dr. Jeff Morre´ (OSU) for mass spectra data.
Finally, we are grateful to Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) and Dr. Paul Ha-Yeon Cheong (OSU) for
their helpful discussions.
In summary, a rapid, multicomponent coupling method
has been developed for accessing two contiguous stereogenic
centers on a cyclohexenone scaffold including an all-carbon
quaternary center in a highly enantio- and diastereoselective
fashion (up to 98.8:1.2 er and >20:1 dr) in generally good
chemical yield (average chemical yield for the 20 products
Supporting Information Available: Complete experi-
mental procedures are provided, including 1H and 13C spectra,
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1011955
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