A new organocatalyzed Michael-Michael cascade reaction generates highly substituted fused carbocycles

Article abstract of DOI:10.1021/ol9024293

[Chemical Equation Presented] While β-ketoesters are useful Michael donors, they were previously ineffective in Michael-Michael cascade reactions using αβ-unsaturated aldehydes in conjunction with diphenylprolinol silyl ether organocatalysts. However, thr

Full text of DOI:10.1021/ol9024293

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5654-5657
A New Organocatalyzed Michael-
Michael Cascade Reaction Generates
Highly Substituted Fused Carbocycles
Patrick G. McGarraugh and Stacey E. Brenner*
Department of Chemistry, Brooklyn College and the City UniVersity of New York,
2900 Bedford AVenue, Brooklyn, New York 11210
sbrenner@brooklyn.cuny.edu
Received October 21, 2009
ABSTRACT
While ꢀ-ketoesters are useful Michael donors, they were previously ineffective in Michael-Michael cascade reactions using r,ꢀ-unsaturated
aldehydes in conjunction with diphenylprolinol silyl ether organocatalysts. However, through rational modification of substrates and manipulation
of the catalytic cycle, we developed an efficient Michael-Michael cascade reaction using ꢀ-ketoesters of type 9. In this transformation, highly
substituted fused carbocycles are generated in a single step in up to 87% yield and 99% ee.
Organocatalyzed cascade reactions are a powerful synthetic tool
in green chemistry, as environmentally inert catalysts are used
in the formation of multiple bonds and stereocenters in a single
reaction flask.1 Diphenyl prolinol silyl ethers such as 1a
(Scheme 1) have recently emerged as highly effective catalysts
for organocascade reactions. This class of catalysts has been
employed in cascade processes in which the formation of
multiple C-C single bonds generates 3-, 5-, or 6-membered
carbocycles. These include Michael-SN2 alkylation,2
Michael-aldol,3 Michael-Knoevenagel,4 Michael-Mannich,5
Michael-Henry,6 Michael-Wittig,7 and Michael-Michael8
cascade reactions.
donor in only one example8b (reaction 1, Scheme 1), despite
the fact that this type of Michael donor is commonly employed
in organocatalytic conjugate addition reactions.9 However, when
the unsaturation was relocated relative to the ꢀ-dicarbonyl
moiety in an attempt to form substituted cyclohexanes, the
(3) (a) Marigo, M.; Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 5475–5479. (b) Enders, D.; Narine, A. A.;
Benninghaus, T. R.; Raabe, G. Synlett 2007, 1667–1670. (c) Wang, J.; Li,
H.; Xie, H.; Zu, L.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007, 46,
9050–9053. (d) Hong, B.-C.; Nimje, R. Y.; Sadani, A. A.; Liao, J.-H. Org.
Lett. 2008, 10, 2345–2348. (e) Zhao, G.-L.; Dziedzic, P.; Ullah, F.; Eriksson,
L.; Co´rdova, A. Tetrahedron Lett. 2009, 50, 3458–3462. (f) Rueping, M.;
Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699–
3702. (g) Enders, D.; Wang, C.; Bats, J. W. Synlett 2009, 1777–1780.
(4) (a) Hayashi, Y.; Toyoshima, M.; Hiroaki, G.; Ishikawa, H. Org. Lett.
2009, 11, 45–48. (b) Łukaz, A.; Richter, B.; Vila, C.; Krawczyk, H.;
Jørgensen, K. A. Chem.sEur. J. 2009, 15, 3093–3102.
Among the latter class of reactions, of those cascades initiated
by activation of an R,ꢀ-unsaturated aldehyde through iminium
catalysis, a ꢀ-dicarbonyl compound was used as a Michael
(5) Ibrahem, I.; Rios, R.; Vesely, J.; Co´rdova, A. Tetrahedron Lett. 2007,
48, 6252–6257.
(1) For a review, see: Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570–1581.
(6) (a) Hayashi, Y.; Okano, Y.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922–4925. (b) Reyes, E.; Jiang, H.; Milelli, A.; Elsner,
P.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202–
9205.
(2) (a) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 48, 5835–5839. (b) Vesely, J.; Zhao, G.-L.; Bartoszewicz, A.;
Co´rdova, A. Tetrahedron Lett. 2008, 49, 4209–4212. (c) Ibrahem, I.; Zhao,
G.-L.; Rios, R.; Vesely, J.; Sunde´n, H.; Dziedzic, P.; Co´rdova, A.
Chem.sEur. J. 2008, 14, 7867–7879.
(7) Liu, Y.-k.; Ma, C.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Org. Lett.
2009, 11, 2848–2851.
10.1021/ol9024293  2009 American Chemical Society
Published on Web 11/18/2009

Scheme 1
.
1a-Catalyzed Cascade Reactions
Table 1. Catalyst Optimizationa
time
%
dr
% ee % ee
entry catalyst solvent (h) conversionb (10:11)b (10a)c (10b)c
1d
2
3
4
5
1a
1a
1a
1b
1c
1d
1e
DCE
DCE
240
168
13
25
61
20
0
78:22
84:16
78:22
85:15
nd
nd
99
99
87
nd
99
87
nd
99
99
99
nd
98
96
EtOH 168
EtOH 168
EtOH 168
EtOH 168
EtOH 216
6
7
66
65
79:21
80:20
a Reaction conditions: 3a (1 equiv), 9a (1 equiv), cat. (20 mol %),
b
1
PhCOOH (20 mol %), solvent (0.3 M), rt. Determined by H NMR of
crude reaction mixture. c Determined by chiral HPLC. d Reaction run without
PhCOOH.
desired transformation (i.e., reaction 4) was surprisingly not
observed. When conjugated ꢀ-ketoesters with terminal, mono-
substituted olefins (5) were used, the initial Michael addition
was instead followed by a Morita-Baylis-Hillman reaction
(reaction 2).10 Alternatively, when conjugated ꢀ-ketoesters with
internal olefins (7) were used, subsequent to the initial Michael
addition, acetal formation occurred in lieu of another Michael
addition (reaction 3).11 Presumably, the second Michael addition
is kinetically slow and/or thermodynamically unfavorable, as
it would disrupt the highly conjugated system.
We reasoned that using conjugated ꢀ-ketoesters of type 9,
in which the olefin is part of a carbocycle, would modulate the
reactivity of these substrates and might enable the desired
Michael-Michael cascade reaction. First, disubstitution at the
1-position of the alkene would preclude the undesired Morita-
Baylis-Hillman pathway. Additionally, the fact that the alkene
is cyclic and is not part of a system with extended conjugation
may alter the kinetic and thermodynamic preference, respec-
tively, for the desired Michael addition pathway relative to the
undesired acetalization pathway. Moreover, substrates of type
9 would produce highly substituted fused carbocycles, with a
chiral catalyst, as well as the thermodynamic preference for the
ring junction, establishing multiple stereocenters.
Using conjugated ꢀ-ketoester 9a, the 1a-catalyzed Michael-
Michael cascade reaction with 3a in DCE did generate 10 and
11, albeit in very low conversion even after 10 days (entry 1,
Table 1). While the initial Michael addition was complete within
12 h, the subsequent Michael addition was exceedingly sluggish.
To promote this second step, a preliminary screen of additives
known to facilitate catalyst turnover (i.e., benzoic acid) or to
enhance enamine formation (i.e., Et3N, NaOAc) was carried
out. While basic additives did not accelerate the reaction (data
not shown), with benzoic acid, enhanced diastereomeric ratios
and excellent ee’s of the major diastereomer, 10b, and its
epimer, 10a, were achieved (entry 2). Although the conversion
was also improved, it was still low after extended reaction times.
As suspected, ethanol, a protic solvent that can participate in
hydrogen bonding interactions with the ꢀ-ketoester moiety,
further accelerated the second Michael addition and greatly
improved conversion (entry 3).
The use of a more electron-rich catalyst, 1b, drastically
slowed both Michael additions in the cascade reaction (entry
4), while the use of a more electron-deficient catalyst, 1c,
completely suppressed the second Michael addition (entry 5).
Catalysts with different silyl groups did not provide both 10a
and 10b in 99% ee, as had catalyst 1a (entries 6 and 7). In all
cases, the ee of the minor diastereomer, 11, was diminished
relative to that of 10a and 10b, ranging from 33% (using 1d)
to 82% (using 1b).
(8) (a) Enders, D.; Hu¨ettl, M. R. M.; Grondal, C.; Raabe, G. Nature
2006, 441, 861–863. (b) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang,
Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732–3734. (c) Carlone,
A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007,
46, 1101–1104. (d) Bor-Cheng, H.; Nimje, R. Y.; Wu, M.-F.; Sadani, A. A.
Eur. J. Org. Chem. 2008, 1449–1457. (e) Penon, O.; Carlone, A.; Mazzanti,
A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.sEur. J.
2008, 14, 4788–4791. (f) Zhao, G.-L.; Ibrahem, I.; Dziedzic, P.; Sun, J.;
Bonneau, C.; Co´rdova, A. Chem.sEur. J. 2008, 14, 10007–10011. (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, 1–5.
(h) Hong, B.-C.; Nimje, R. Y.; Liao, J.-H. Org. Biomol. Chem. 2009, 3095–
3101.
(9) For a review of organocatalyzed conjugate addition reactions,
including those involving ꢀ-dicarbonyl compounds as Michael donors, see
Alma¸si, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18,
299–365.
(10) Cabrera, S.; Alema´n, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2008, 47, 121–125.
(11) Zhu, M.-K.; Wei, Q.; Gong, L.-Z. AdV. Synth. Catal. 2008, 350,
1281–1285.
Org. Lett., Vol. 11, No. 24, 2009
5655

Table 2. Optimization of Reaction Conditionsa
Scheme 2. Proposed Catalytic Cycle
mol
% of
%
dr
time conver- (10:
(h) sionb 11)b (10a)c (10b)c
ee
ee
entry 1a additive solvent
1
2
20 PhCO2H toluene
20 PhCO2H Et2O
168
168
168
168
2
5
<1
0
80:20 nd
nd
nd
nd
99
nd
99
99
99
99
99
99
nd
nd
nd
99
3
20 PhCO2H THF
nd
4
20 PhCO2H MeCN
20 PhCO2H CF3CH2OH
20 PhCO2H CF3CH2OH 41
32
12
17
85
87
80
25
76
93:7
5
89:11 nd
91:9
6
99
7
20
10
5
CF3CH2OH 17
CF3CH2OH 17
CF3CH2OH 17
CF3CH2OH 88
CF3CH2OH 46
90:10 99
8
91:9
91:9
99
99
9
10
1
88:12 99
92:8 99
11d
5
a Reaction conditions: 3a (1 equiv), 9a (1 equiv), 1a, additive (20 mol
%), solvent (0.3 M), rt. b Determined by 1H NMR of crude reaction mixture.
c Determined by chiral HPLC. d Reaction run at 0 °C.
14 can react with 1a to re-enter the catalytic cycle and go on to
product, as rapidly occurs in the absence of 3a. However, for
reasons explained above, in trifluoroethanol and benzoic acid,
there would be a substantial amount of 3a in solution, which
evidently competes for the catalyst. Together, this accounts for
the presence of 14 after 41 h and for the plateau in conversion
to 10 (entry 6, Table 2).
With optimal catalyst 1a in hand, optimization of other
reaction conditions ensued. Both nonpolar solvents and polar
aprotic solvents led to substantially reduced conversions relative
to reactions run in ethanol (entries 1-4, Table 2). Switching to
trifluoroethanol, a solvent that is a stronger hydrogen bond donor
than ethanol, gave surprising results.
After only 2 h, product formation was detected (entry 5).
Additionally, the ratio of 10a:10b was 1:29, whereas in all
previous experiments the ratios of 10a:10b ranged from 1:1.4
to 1.7:1. After 41 h, there was little improvement in conversion,
but the ratio of 10a:10b was 1:5 (entry 6). Moreover, the first
Michael addition had not gone to completion under these
conditions; the single Michael adduct along with substantial
amounts of 3a and 9a were present after 41 h. As the
diastereomeric ratio and ee’s were both excellent in this solvent,
we sought to improve the conversion. Consideration of these,
and other, observations with respect to the proposed mechanism
of this transformation (Scheme 2) provided insight as to how
to accomplish this.
First, the observation that the initial Michael addition had
not gone to completion indicated that either the “catalyst release
1” pathway of iminium 12 competes with the Michael addition
to 12 or that 14 can revert back to starting materials. Subjecting
single Michael adduct 14 to catalyst 1a and benzoic acid in
trifluoroethanol resulted in rapid conversion to 10 only, revealing
that the formation of 14 is not reversible. Thus, the “catalyst
release 1” pathway appears to be favored in the presence of
benzoic acid in trifluoroethanol more so than in other solvents.
When the initial Michael addition does occur to provide 13,
if pathway A is followed, the second Michael addition occurs.
In trifluoroethanol, this second Michael addition is rapid, as
evidenced by the conversion to 10 within 2 h. However, in this
solvent, as in other solvents, 13 prefers the “catalyst release 2”
pathway, which provides single Michael adduct 14. Compound
Finally, since epimerization of 10a and 10b occurs in the
presence of benzoic acid and 1a, but not benzoic acid alone,
we speculated that it proceeds via an enamine intermediate (16),
and not via a keto-enol equilibrium. The fact that the
conversion to 10a and 10b did not change dramatically over
the course of 39 h under these conditions, while the ratio of
10a to 10b did, suggests that 10b formed first and was slowly
converted to, and reaching equilibrium with, 10a. It would
therefore appear that in the presence of benzoic acid in
trifluoroethanol, “catalyst release 3” predominates over forma-
tion of enamine 16 either from 15 prior to catalyst release or
from 10b (via 15) after its ejection from the catalytic cycle.
Thus, whereas in other solvents a sluggish second Michael
addition hampered conversion, these observations collectively
implied that under these conditions, catalyst release (i.e.,
turnover) was the culprit. Impeding catalyst release from 12
and from 13 should enable a rapid, efficient, and highly selective
Michael-Michael cascade reaction. We therefore ran the
reaction in the absence of benzoic acid, which, as mentioned
earlier, is known to facilitate catalyst turnover. Gratifyingly, this
led to 85% conversion, 9:1 dr, and 99% ee of 10a and 10b
(present in a 1:1.1 ratio) in only 17 h (entry 7, Table 2)!
Lowering the catalyst loading to 10 mol % slightly improved
both conversion and diastereoselectivity (entry 8). A catalyst
loading of 5 mol % led to a slight decrease in conversion but
maintained the high selectivity of the reaction (entry 9). Further
lowering of the catalyst loading to 1 mol % resulted in reduced
conversion and a slight erosion of diastereoselectivity (entry
5656
Org. Lett., Vol. 11, No. 24, 2009

Using 10 mol % 1a and trifluoroethanol as solvent at rt, an
investigation of substrate scope was undertaken (Table 3). The
1a-catalyzed Michael-Michael cascade reaction afforded prod-
ucts in high yields and high selectivity using R,ꢀ-unsaturated
aromatic aldehydes with electron-withdrawing, electron-releas-
ing, and electronically neutral substitution at either the meta-
or para-position (entries 1-4). However, ortho (nitro) substitu-
tion was not tolerated. In addition, R,ꢀ-unsaturated aldehydes
with heteroaromatic and nonaromatic substitutents afforded
products in slightly reduced yields, but in 98% ee and 97:3 dr
(entries 5 and 6). Finally, different ester substituents (entry 7)
and, notably, heteroatom substitution in the cyclopentane ring
(entry 8) were well-tolerated in this reaction, leading to rapid
and highly selective product formation. A ketoester with a
cyclohexane (i.e., 9 where X ) (CH2)2) formed additional
diastereomers in this reaction (data not shown).
Table 3. Substrate Scopea
A model for the stereochemical outcome of this reaction is
depicted in Scheme 2. The stereochemistry at C3 was assigned
by analogy with other 1a-catalyzed conjugate additions and is
assumed to arise from the initial Michael addition occurring
from the face opposite the bulky group in iminium 12. The
remaining stereochemistries were established by X-ray crys-
tallograpy (see the Supporting Information). They are consistent
with the intramolecular Michael addition of 13 occurring with
the Michael acceptor approaching the enamine from the face
opposite, and the proton at C3 projected out toward, the bulky
group. Additionally, we established that 10a and 10b were
epimers by subjecting pure 10a to benzoic acid in the presence
of 1a, which produced a mixture of 10a and 10b.
In conclusion, through rational modification of substrates and
manipulation of the catalytic cycle, we developed a new,
efficient 1a-catalyzed Michael-Michael cascade reaction. This
transformation generates highly substituted, fused carbocycles
with dr’s g91:9 and ee’s g96%. Further investigations into
this and other novel, 1a-catalyzed cascade reaction(s) are
presently underway.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (1SC2GM082360). The authors
gratefully acknowledge Dr. Cliff Soll and Dr. Louis Todaro
(both at the City University of New York at Hunter College)
for their assistance with high-resolution mass spectrometry and
X-ray crystallography, respectively. The authors also wish to
thank Prof. Gary Molander (University of Pennsylvania) for
thoughtful discussions.
Supporting Information Available: General experimental
conditions and full characterization data for compounds 9b,9c,
10a, 10b, 11, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a,
21b, 22a, 22b, 23a, 23b, 24a and 24b, including an X-ray
crystal structure of 10a. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions: 3 (1 equiv), 9 (1 equiv), 1a (10 mol %),
CF3CH2OH (0.3 M), rt. b Isolated yield. c Determined by 1H NMR of isolated
products. d Determined by chiral HPLC.
10). Finally, running the reaction at 0 °C led to a more sluggish
reaction with a nominal improvement in diastereoselectivity
(entry 11).
OL9024293
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5657