Organocatalytic Michael addition of aldehydes to γ-keto-α, β-unsaturated esters. an efficient entry to versatile chiral building blocks

Article abstract of DOI:10.1021/ol802354u

(Chemical Equation Presented) The diarylprolinol ether/HOAc-catalyzed Michael addition of aldehydes to γ-keto-α,β-unsaturated esters occurs in a highly regioselective and enantioselective manner. The adducts could easily be converted into synthetically useful cyclohexenones, cyclohexanones, piperidines, and γ-lactones.

Full text of DOI:10.1021/ol802354u

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5425-5428
Organocatalytic Michael Addition of
Aldehydes to γ-Keto-r,ꢀ-unsaturated
Esters. An Efficient Entry to Versatile
Chiral Building Blocks
Jing Wang, Anqi Ma, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@mail.sioc.ac.cn
Received October 11, 2008
ABSTRACT
The diarylprolinol ether/HOAc-catalyzed Michael addition of aldehydes to γ-keto-r,ꢀ-unsaturated esters occurs in a highly regioselective and
enantioselective manner. The adducts could easily be converted into synthetically useful cyclohexenones, cyclohexanones, piperidines, and
γ-lactones.
Organocatalytic Michael addition of aldehydes to electron-
deficient olefins is an attractive approach for organic
synthesis because it can provide versatile chiral building
blocks from conveniently available starting materials in an
efficient manner.1 This transformation normally requires
highly reactive electron-deficient olefins as Michael acceptors
to ensure good conversions.1-6 These olefins include ni-
troalkenes,2 1,1-bis(benzenesulfonyl)ethylene,3 maleimides,4
alkylidenemalontes,5 and R-keto-R,ꢀ-unsaturated esters.6 For
nitroalkenes, great progress has been made in developing
effective catalytic systems and extending the reaction scope.2
However, little attention has been directed to explore the
possibility of using enones as substrates, although their
products are more synthetically useful.7 In 2003, Melchiorre
and Jørgensen reported that chiral amines could catalyze the
direct Michael addition of aldehydes to vinyl ketones.7a
Gellman and co-workers subsequently discovered that diphe-
nylprolinol methyl ether7b and MacMillan imidazolidinone
catalyst7c provided better enantioselectivity. In their studies,
only two enones, methyl vinyl ketone and ethyl vinyl ketone,
gave the adducts with good yields.7 More sterically hindered
(1) For a review, see: Vicario, J. L.; Badı´a, D.; Carrillo, L. Synthesis
2007, 2065.
(2) For recent references, see: (a) Hayashi, Y. T.; Okano, T. S.; Aratake,
S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (b) Zhu, S.; Yu,
S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545. (c) Wiesner, M.; Revell,
J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871. (d) Chi, Y.;
Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608.
(e) Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem.
Soc. 2008, 130, 5610. (f) García-García, P.; Lade´peˆche, A.; Halder, R.;
List, B. Angew. Chem., Int. Ed. 2008, 47, 4719. (g) Hayashi, Y.; Itoh, T.;
(5) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10, 3075. A
hetero-Diels-Alder reaction mechanism is also possible for this reaction.
(6) Zhao, G.-L.; Vesely, J.; Sun, J.; Christensen, K. E.; Bonneau, C.;
Co´rdova, A. AdV. Synth. Catal. 2008, 350, 657.
Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4722
(3) Mosse´, S.; Alexakis, A. Org. Lett. 2005, 7, 4361
(4) Zhao, G.-L.; Xu, Y.; Sunde´n, H.; Eriksson, L.; Sayah, M.; Co´rdova,
.
.
(7) (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151.
(b) Chi, Y.; Gellmann, S. H. Org. Lett. 2005, 7, 4253. (c) Peelen, T. J.;
Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598.
A. Chem. Commun. 2007, 734
.
10.1021/ol802354u CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society

vinyl ketones and ꢀ-substituted enones were found as poor
substrates, although they exhibited good reactivity in some
intramolecular Michael addition.8 Thus, it is highly desired
to discover an alternative way to overcome this drawback.
In connection with our interest in development of orga-
nocatalytic reactions,2b,6 we found that γ-keto-R,ꢀ-unsatur-
ated esters 3, the enones with a ꢀ-carboxylate ester, could
easily react with aldehydes to give Michael adducts 4
(Scheme 1) with good yields and diastereoselectivity and
excellent enantioselectivity. Upon simple treatments, these
adducts could be converted into substituted cyclohexenones,
cyclohexanones, piperidines, and γ-lactones that are useful
chiral building blocks for assembly of some complex natural
products. Herein we wish to detail our results.
Table 1. Synthesis of Substituted γ-Keto Esters 5a
Scheme 1
The required enones 3 can easily be prepared by a simple
Wittig reaction of ethyl glyoxylate with ketone derived ylides
or by ng Nozaki’s method.9 Initially, the reaction of benzyl
4-oxopent-2-enoate 3a with n-pentanal was explored as a
model transformation. As indicated in Table 1, it was found
that Michael addition gave adduct 4a (entry 1) under our
previous conditions (10 mol % of catalyst 1, 50 mol % of
PhCO2H, water as the solvent).2b However, both yield and
diastereoselectivity were unsatisfactory. Reducing the cata-
lytic loading gave a slight improvement (entry 2). A better
result was obtained by changing the solvent to methanol
(entry 3). Further improvement was achieved when the
additive was switched to acetic acid (entry 4). It is note-
worthy that epimerization occurred rapidly during the
purification of the crude adduct 4a; therefore, it was
converted into the silyl ether 5a for both NMR and chiral
HPLC analysis.
Using this three-step transformation as a benchmark, we
examined a series of aldehydes and enones in order to
establish the scope and limits of this Michael addition.
Generally, the adducts were obtained in good yield and
diastereoselectivity and excellent enantioselectivity (entries
5-9). Besides the simple alkyl substituents, benzoxy- and
olefin-embodied substrates were compatible with these
conditions, giving more functionalized products (entries 9,
11, and 12). The size of the aldehydes seemed to have a
slight influence on both enantioselectivity and diastereose-
a Reaction conditions for cycloaddition: 1 (0.0125 mmol), aldehyde 2
(0.5 mmol), enone 3 (0.25 mmol), HOAc (or PhCO2H for entries 1-3,
0.0125 mmol), MeOH (0.5 mL), 0 °C to rt. Determined by H NMR of
the crude adducts. c Isolated yield for three steps, d Determined by chiral-
phase HPLC analysis. e 10 mol % of 1 and 50 mol % of PhCO2H were
used. f Isolated yield for reduction products, while water was used as the
solvent.
b
1
lectivity being evident from the fact that relatively low
stereoselectivity was observed when using propionaldehyde
as a Michael donor (entries 8 and 10).
This encouraging result prompted us to explore the
synthetic applications of the Michael adducts. As shown in
Scheme 2, DBU-mediated intramolecular aldol reaction of
the adducts followed by treatment with mesyl chloride and
triethylamine produced 4,5-disubstituted cyclohexenones. In
the case of n-pentanal, both trans-isomer 6a and cis-isomer
7a were isolated in a ratio of 3:1. The low diastereoselectivity
should result from epimerization of the aldehyde under aldol
reaction conditions. However, starting from 3-methylbutanal,
only trans-isomer 6b was obtained with 67% yield and 99%
ee, indicating that steric hindrance has an important effect
on the diastereo-selectivity during the aldol reaction. Pos-
sibly, enone 6b can be employed for the synthesis of natural
(8) (a) Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43,
3958. (b) Yang, J. W.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc. 2005,
127, 15036. (c) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui,
R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028. (d) Vo, N. T.; Pace,
R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 404.
(9) Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134.
5426
Org. Lett., Vol. 10, No. 23, 2008

products such as cytotoxic marine diterpenes eleutherobin
8,10 (+)-vigulariol 9,11 and polyanthellin A 10,12 calcium
channel antagonist oxo-T-cadinol 11,13 cytotoxic sesquiter-
penoid pulioplopanone A 12,14 and the immunomodulator
13.15 The diterpenes 8-10 belong to a growing family of
nontaxane-based microtubule stabilizers that have received
great attention for synthetic and SAR studies during the past
decade.16 Many successful protocols rely on using natural
(+)-carvone10b-d or (-)-cryptone12b as the starting material.
Our easy assess to both enantiomers of 6b will open a new
avenue to access these biologically important molecules.
of water is helpful to avoid racemization during the Aldol
for a slight decrease in ee values was observed if dry
methylene chloride was used. Similarly, ketones 14b-d were
prepared from the corresponding enones and aldehydes. The
stereochemistry of the present products was established by
NOESY studies of the ketone 14c, which can be explained
using a chairlike transition state model. These compounds
may also be useful building blocks for the assembly of
natural products. From the enantiomer of 14b, for example,
antipyretic alkaloid dendrobine 1517 and sesquiterpene
cladioxazole 1618 could be elaborated, while an analogue of
14d has been used for synthesis of perhydrohistrionicotoxin
17.19
Scheme 2
Scheme 3
We then explored the possibility of preparing heterocycles
from our Michael adducts, and were pleased to observe that
direct reductive amination of the adduct of enone 3a and
n-pentanal with benzylamine and NaBH(OAc)3 provided
1,2,4,5-tetrasubstituted piperidine 18a with 74% yield and
97% ee. Variation at the 2,4 and 5 positions is possible as
indicated by formation of piperidines20 18b-e. In these cases
other minor isomers were isolated in less than 20% yield
and the stereochemistry of these major isomers was estab-
lished by NOESY studies of 18a. The stereoselectivity in
the reductive amination step can be rationalized by a
stereoelectronic control model as indicated in Scheme 4.
Scheme 5 illustrates our effort toward the construction of
γ-lactones. Reduction of the Michael adduct of 4-benzox-
ybutanal with 3a at -78 °C gave rise to semiacetal 19 in
80% yield, which was treated with TsOH in benzene to afford
lactone 20 in excellent yield. Importantly, cis-3,4-disubsti-
The aldol reaction of our Michael adducts has the potential
to give more functionalized cyclohexanones by changing the
substituents of the enone part. Accordingly, the Michael
adduct of 3-methylbutanal and enone 3d was treated with
DBU in methylene chloride (Scheme 3). It was gratifying
to observe that under these reaction conditions 2,3,4,5-
tetrasubstituted cyclohexanone 14a was isolated as a single
isomer with 62% yield and 99% ee. It was found that a trace
(10) Isolation: (a) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.;
Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119,
8744. Synthesis: (b) Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft,
F. L.; Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am. Chem.
Soc. 1998, 120, 8674. (c) Chen, X.; Zhou, B.; Bhattacharya, S. K.;
Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 789. (d) Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon,
O.; Costa, A. M.; Gennari, C. Chem.sEur. J. 2006, 12, 51.
(11) Isolation: (a) Su, J.-H.; Huang, H.-C.; Chao, C.-H.; Yan, L.-Y.;
Wu, Y.-C.; Sheu, J.-H. Bull. Chem. Soc. Jpn. 2005, 78, 877. Synthesis: (b)
Becker, J.; Bergander, K.; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int. Ed.
2008, 47, 1654.
(12) Isolation: (a) Ospina, C. A.; Rodrigueza, A. D.; Ortega-Barria, E.;
Capson, T. L. J. Nat. Prod. 2003, 66, 357. Synthesis: (b) Kim, H.; Lee, H.;
Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2006, 128, 15851.
(13) Taber, D. F.; Christos, T. E. J. Org. Chem. 1996, 61, 2081.
(14) Triana, J.; Lo´pez, M.; Pe´rez, F. J.; Gonza´lez-Platas, J.; Quintana,
J.; Este´vez, F.; Leo´n, F.; Bermejo, J. J. Nat. Prod. 2005, 68, 523.
(15) Zhao, W.; Ye, Q.; Tan, X.; Jiang, H.; Li, X.; Chen, K.; Kinghorn,
A. D. J. Nat. Prod. 2001, 64, 1196.
(17) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.;
Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130.
(18) Ata, A.; Ackerman, J.; Radhika, P. Tetrahedron Lett. 2003, 44,
6951.
(19) Ibuka, T.; Mitsui, Y.; Hayashi, K.; Taga, T.; Inubushi, Y.
Tetrahedron Lett. 1981, 22, 4425.
(20) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953.
(16) Busch, T.; Kirschning, A. Nat. Prod. Rep. 2008, 25, 318.
Org. Lett., Vol. 10, No. 23, 2008
5427

which was treated under acidic conditions to produce 23 in
63% yield, together with its 6-epimer in 26% yield. The
NMR data were identical to those reported in the literature,
and the optical rotation ([R]25D -30 (c 1.3 CHCl3)) was close
Scheme 4
to the reported value ([R]25 -31 (c 1.595 CHCl3)). Thus,
D
this synthesis also confirmed the stereochemistry of the
present adducts which was originally proposed by analyzing
the enamine transition state.23
Scheme 6
tuted-γ-lactone was selectively formed, which is not easily
obtained using ordinary methods like stereocontrolled alky-
lation.
In conclusion, we have found that γ-keto-R,ꢀ-unsaturated
esters are very reactive Michael acceptors toward organo-
catalytic Michael addition with aldehydes. The reaction took
place in a highly regioselective and enantioselective manner
to give adducts which could easily be converted into some
useful chiral building blocks such as 4,5-disubstituted
cyclohexenones, polysubstituted cyclohexanones, and cis-
3,4-disubstituted γ-lactones. Our results will stimulate further
exploration of new Michael acceptors for organocatalytic
reactions. The synthetic usefulness of the present method
has been demonstrated by the synthesis of (-)-acaranoic acid
methyl ester and will be applied in the total synthesis of other
complex natural products. Further investigations on this novel
synthetic process are actively pursued in our laboratory and
will be reported in due course.
Scheme 5
(-)-Acaranoic acid is a natural δ-lactone that was isolated
from lichen Acarospora chlorophana.21 Its structure was
revised by chemical transformation studies22 but has not been
synthesized from commercially available compounds. Using
the present method, we developed a simple route to its methyl
ester. As outlined in Scheme 6, Michael addition of propi-
onaldehyde to enone 3g proceeded smoothly to afford crude
adduct, which was oxidized to give acid 22 and its 2-epimer
in a ratio of 4:1. After recrystallization, the acid 22 was
obtained with 37% overall yield and about 95% purity.
Reduction of 22 with NaBH4 at -20 °C delivered an alcohol,
Acknowledgment. We are grateful to National Natural
Science Foundation of China (Grant No. 20621062) for their
financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectrum for
all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802354U
(21) (a) Zopf, W. Liebigs Ann. Chem. 1895, 284, 107. (b) Santesson, J.
Acta Chem. Scand. 1967, 21, 1993.
(23) For a review, see: Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed.
2006, 45, 7876.
(22) Huneck, S.; Ho¨fle, G. Phytochemistry 1980, 19, 2713.
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Org. Lett., Vol. 10, No. 23, 2008