Lewis acid activated synthesis of highly substituted cyclopentanes by the n-heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters

Article abstract of DOI:10.1002/anie.201005908

A great team: Cyclopentanes with four contiguous stereogenic centers were assembled with excellent diastereo- and enantioselectivity from simple β,γ-unsaturated α-ketoesters and enals in a reaction catalyzed by an N-heterocyclic carbene (NHC) and mediated

Full text of DOI:10.1002/anie.201005908

Communications
DOI: 10.1002/anie.201005908
Asymmetric Catalysis
Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes
by the N-Heterocyclic Carbene Catalyzed Addition of Homoenolate
Equivalents to Unsaturated Ketoesters**
Daniel T. Cohen, Benoit Cardinal-David, and Karl A. Scheidt*
The stereoselective construction of highly functionalized
small- and medium-sized carbocycles from simple substrates
is an ongoing objective in organic synthesis. One approach to
this goal is the use of small organic molecules that have been
designed as efficient catalysts for selective cascade reac-
tions.[1] Over the last decade, N-heterocyclic carbenes
(NHCs)[2] have provided new opportunities for the develop-
ment of catalytic systems based on polarity reversal or
Umpolung.[3] Notably, the NHC-catalyzed generation of
homoenolate equivalents from enals has emerged as a
powerful tool for the synthesis of hetero- and carbocycles.[4,5]
An important discovery by Nair et al.[6] was the ability of
Scheme 1. NHC/Lewis acid homoenolate strategy.
NHCs to catalyze the addition of homoenolates to unsatu-
rated ketones to yield 3,4-disubstituted cyclopentenes. This
approach was recently extended by the addition of methanol
to afford a highly substituted racemic cyclopentane with a
pendent methyl ester.[5l] Although these processes expanded
the reaction repertoire of carbene catalysis, the coupling
partner with the enal is limited to chalcones and oxobute-
noates,[7] and the products from this reaction typically have
only a single alkene functional group. To advance this
carbene-driven carbocycle synthesis, we envisioned that b,g-
unsaturated a-ketoesters would be a suitable class of homo-
enolate acceptors for the synthesis of compounds with
potentially more functional groups adorning the periphery
of the carbocycle framework.[8] Unfortunately, initial attempts
at NHC catalysis with Lewis base activation were unsuccess-
ful, and addition of the homoenolate intermediate to the b,g-
unsaturated a-ketoester was not observed (Scheme 1). We
have been engaged recently in developing a cooperative
carbene catalysis strategy by employing different Lewis acids
in combination with NHCs.[9] We have shown that a MgII
Lewis acid enhances the reaction rate and yield of the
products in an NHC-catalyzed homoenolate addition to
hydrazones.[9a] A Lewis acid in combination with carbene
catalysis also completely reverses the facial selectivity of an
NHC-bound homoenolate equivalent, presumably as a result
of the multiple coordination sites on the metal.[9b]
Even with these advances, a major challenge in the field of
carbene catalysis is to develop processes that employ new
classes of electrophiles that fail as competent substrates when
only NHCs are used. With this prospect in mind, we turned
our attention to the activation of b,g-unsaturated a-ketoesters
with bidentate Lewis acids: a strategy that has proven
successful in stereoselective Lewis acid catalyzed processes
(Scheme 1).[10] Cooperative carbene catalysis might allow
access to NHC-bound homoenolates in the presence of Lewis
acids that coordinate and activate unsaturated a-ketoesters.
Herein, we report the use of a Lewis acid as an essential
component for an NHC-catalyzed annulation of enals with a
new class of electrophiles. This reaction generates highly
substituted cyclopentanols containing four contiguous stereo-
genic centers.
[*] D. T. Cohen, Dr. B. Cardinal-David, Prof. K. A. Scheidt
Department of Chemistry, Center for Molecular Innovation and
Drug Discovery
We began our studies by combining cinnamaldehyde (1)
with (E)-methyl 2-oxo-4-phenylbut-3-enoate (2) in the pres-
Chemistry of Life Processes Institute
Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
ence of the azolium precatalyst
A (20 mol%), DBU
(40 mol%), and Ti(OiPr)4 (2 equiv). Under these conditions,
cyclopentanol 3 was isolated in 69% yield as a single
diastereomer (Table 1, entry 2). The excellent diastereoselec-
tivity of this conjugate addition prompted us to develop an
enantioselective version of the reaction. Use of the chiral
azolium precatalysts B–D resulted in varying yields and
selectivity levels (Table 1, entries 3–5). The (S,R)-aminoinda-
nol-derived triazolium precatalyst E[9] furnished the desired
cyclopentanol in 68% yield with a 7:1 d.r. and 90% ee
[**] Financial support was generously provided by the NIH (NIGMS
RO1 GM73072), Amgen, AstraZeneca, GlaxoSmithKline, and a
GAANN (Graduate Assistance in Areas of Nation Need) fellowship
to D.T.C. FQRNT (Fonds Quꢀbꢀcois de la Recherche sur la Nature et
les Technologies) is also gratefully acknowledged for a postdoctoral
fellowship to B.C.-D. We thank John M. Roberts (NU) for assistance
with X-ray crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005908.
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Angew. Chem. Int. Ed. 2011, 50, 1678 –1682

Table 1: Reaction optimization.
Table 2: Scope of the reaction with respect to the b,g-unsaturated a-
ketoester.[a]
Entry Azolium Ti(OiPr)4 iPrOH Yield [%][a] d.r.[b]
ee [%][c]
Entry
R
Yield [%][b]
d.r.[c]
ee [%][d]
[equiv]
[equiv]
1
2
3
4
5
6
7
8
9
A
A
B
C
D
E
E
E
E
E
–
2
2
2
2
2
2
5
–
–
6
–
–
–
–
–
6
6
6
–
0[d]
69
–
–
–
1
2
3
4
5
6
7
8
9
Ph
84 (3)
69 (4)
72 (5)
82 (6)
82 (7)
68 (8)
52 (9)
77 (10)
85 (11)
20:1
20:1
13:1
20:1
20:1
20:1
12:1
20:1
20:1
95
97
95
96
97
97
97
97
97
>20:1
12:1 70
4-Cl-C6H4
2-Cl-C6H4
4-OMe-C6H4
4-Me-C6H4
3-Me-C6H4
4-pyridyl
2-furyl
76
44
69
68
63
84
10:1 86
20:1 20
7:1 90
18:1 96
20:1 95
0[d]
0[d]
–
–
–
–
2-thienyl
10
10
11
61 (12)
62 (13)
20:1
20:1
99
94
[a] Yield of the isolated product. [b] The diastereomeric ratio was
determined by H NMR spectroscopy (500 MHz). [c] The ee value was
determined by HPLC analysis using a chiral stationary phase. [d] Starting
material was recovered after 48 h. DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene, Mes=mesityl (2,4,6-trimethylphenyl).
1
[a] See the Supporting Information for details. [b] Yield of the isolated
product. [c] The diastereomeric ratio was determined by 1H NMR
spectroscopy (500 MHz) of the unpurified reaction mixture. [d] The
ee value was determined by HPLC analysis using a chiral stationary
phase.
Table 3: Scope of the reaction with respect to the aldehyde substrate.[a]
(Table 1, entry 6).[11] The addition of 2-propanol (6 equiv)
promoted a faster transesterification, and surprisingly, we
observed a small increase in the diastereo- and enantioselec-
tivity to d.r. 18:1 and 96% ee (Table 1, entry 7).[12] A decrease
in the quantity of the Lewis acid used to a substoichiometric
amount resulted in incomplete conversion (results not
shown).[13] An increase in the amount of the Lewis acid
used to 5 equivalents led to an increase in the yield to 84%
(Table 1, entry 8). When this reaction was performed under
our optimized conditions but in the absence of the Lewis acid,
3 was not obtained (Table 1, entries 9 and 10). This result
illustrates the importance of this Lewis acid as a key
component.[14]
Having optimized the reaction conditions, we surveyed
several b,g-unsaturated a-ketoesters with varying substitution
at the g position (Table 2). Electron-withdrawing and elec-
tron-donating substituents on the aromatic ring were well-
accommodated, with only a slight decrease in diastereoselec-
tivity (13:1 d.r.) for the substrate with an ortho-chloro
substituent (Table 2, entry 3). Heterocyclic compounds were
competent substrates in the presence of TiIV; the products
were obtained in moderate to good yields (52–85%) with
good to excellent diastereo- and enantioselectivity (Table 2,
entries 7–9). Finally, g-cyclopropyl and g-alkynyl substitution
was well-tolerated (Table 2, entries 10 and 11), whereas only
modest conversion was observed for substrates with alkyl and
alkenyl groups in the g position (results not shown).
Entry
R
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4-Cl-C6H4
3-Cl-C6H4
2-Cl-C6H4
4-Br-C6H4
4-CO2Me-C6H4
4-Me-C6H4
4-MeO-C6H4
2-MeO-C6H4
1-napthyl
74 (14)
73 (15)
68 (16)
75 (17)
82 (18)
68 (19)
56 (20)
62 (21)
78 (22)
77 (23)
78 (24)
20:1
20:1
10:1
20:1
18:1
20:1
17:1
5:1
97
97
98
96
91
97
96
97
97
96
97
4
5[e,f]
6
7
8
9
12:1
16:1
20:1
10
2-napthyl
4-Cl-C6H4
11[g]
[a] See the Supporting Information for details. [b] Yield of the isolated
product. [c] The diastereomeric ratio was determined by 1H NMR
spectroscopy (500 MHz). [d] The ee value was determined by HPLC
analysis using a chiral stationary phase. [e] The reaction was carried out
with 6 equivalents of Ti(OiPr)4. [f] Transesterification to 4-CO2iPr-C6H4
was observed. [g] (E)-Methyl 4-(4-methoxyphenyl)-2-oxobut-3-enoate
was used.
decrease in diastereo- and enantioselectivity was observed in
some cases (Table 3, entries 3 and 5). The presence of
electron-donating groups led to moderate yields and good
enantioselectivities. However, the diastereoselectivity drop-
ped for methoxy-substituted aryl enals (Table 3, entries 7 and
8). Finally, naphthyl-derived enals furnished the desired
cyclopentanols in good yields with good enantioselectivity
but with slightly decreased diastereoselectivity (Table 3,
entries 9 and 10).[15]
Modification of the aldehyde component was also
explored (Table 3). Electron-withdrawing groups were well-
tolerated at all positions of the aromatic ring, although a slight
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Communications
Our proposed pathway for this reaction is illustrated in
Scheme 2. Initial coordination of the a,b-unsaturated alde-
hyde to the titanium(IV) Lewis acid, followed by the addition
Scheme 3. Synthetic transformations: a) LiAlH4, THF, 0–258C;
b) NaIO4·SiO2, CH2Cl2, 258C; c) NaBH4, THF/MeOH (2:1), 08C;
d) NaIO4·SiO2, CH2Cl2, 258C; e) DMSO/H2O, 1308C. DMSO=di-
methyl sulfoxide.
of the carbonyl units that remain during this novel process
promoted by an NHC and a Lewis acid. These reactions also
enable efficient differentiation of the two esters as well as the
formation of compounds that are challenging to access
otherwise, such as 3,4-cis-substituted cyclopentanones.
In conclusion, we have developed the first NHC-catalyzed
addition of homoenolates to b,g-unsaturated a-ketoesters.
The use of Ti(OiPr)4 as a mild Lewis acid compatible with
NHC catalysis is essential for activation of the electrophile
and promotion of the conjugate addition. This powerful
NHC–Lewis acid combination enables the rapid assembly of
highly substituted and functionalizable cyclopentanols from
simple substrates with excellent levels of diastereo- and
enantioselectivity. Furthermore, derivatization of the prod-
ucts provides enantiomerically enriched cyclopentanones.
The two esters in the products can be differentiated by
directed reduction. The powerful strategy combining Lewis
basic NHC catalysis with Lewis acid activation can provide
innovative ways of incorporating new reaction components
and continues to be a promising area of research. New
directions related to this strategy are under way and will be
reported in due course.
Scheme 2. Proposed reaction pathway.
of the NHC, induces the formation of the extended Breslow
intermediate I, presumably coordinated to the oxophilic
titanium center. The Lewis acid concurrently coordinates to
the b,g-unsaturated a-ketoester to give II, thereby activating
the a-ketoester and promoting the conjugate addition.[16]
À
Following C C bond formation, the bisenolate III undergoes
protonation, tautomerization, and an intramolecular aldol
reaction to afford intermediate IV. Subsequent acylation and
catalyst turnover gives the mixed ester V, which then under-
goes transesterification to furnish 3.[17] Surprisingly, neither
the b-lactone nor the cyclopentene is observed, even though
the metal alkoxide and the acyl azolium moiety are cis in
intermediate IV: an arrangement that could lead to an
intramolecular acylation. Our current proposal is that the
titanium Lewis acid prevents intramolecular acylation of IVas
a result of the stability of the various titanium–oxygen
interactions/ligations, which undergo hydrolysis upon
workup and release of the product.
Experimental Section
The azolium precatalyst E (0.2 equiv) and the g-aryl (E)-a-oxobute-
noic ester (3.0 equiv) were placed in an oven-dried screw-capped vial
equipped with a magnetic stir bar. The vial was capped with a septum
cap, removed from the dry box, and put under positive N2 pressure.
Cinnamaldehyde (32.2 mg, 0.244 mmol), THF (0.5m), Ti(OiPr)4
(5.0 equiv), iPrOH (6.0 equiv), and DBU (0.4 equiv) were added
successively to the vial with a syringe, and the reaction mixture was
stirred at room temperature under a static nitrogen atmosphere.
Upon consumption of the aldehyde and transesterification (all
reactions were complete within 48 h), the reaction mixture was
filtered through a short plug of SiO2 and washed with EtOAc. The
solution was concentrated under reduced pressure and purified by
flash chromatography (silica gel, 9% EtOAc/hexanes) to afford the
The synthetic utility of this annulation reaction was
initially demonstrated by further elaboration of the product
cyclopentanols. The treatment of bisester 22 with lithium
aluminum hydride followed by silica-gel-supported sodium
periodate resulted in the formation of b-hydroxyketone 26
(Scheme 3).[18] Additionally, reduction of the bisester 22 with
sodium borohydride in a THF/methanol mixture at 08C was
regioselective (> 20:1) in favor of the 1,2-diol (the 1,3-diol
was not observed), which was isolated in 71% yield.
Subsequent oxidative cleavage under the aforementioned
conditions, followed by decarboxylation in DMSO/H2O at
1308C, afforded the 3,4-cis-disubstituted cyclopentanone
28.[19] Overall, these transformations demonstrate the utility
~
corresponding cyclopentanol. Analytical data for 3: IR (film): n =
3502, 3058, 3030, 2981, 2920, 2851, 1737, 1679, 1604, 1498, 1455, 1375,
1321, 1263, 1241, 1182, 1107, 1067, 911, 742, 699 cmÀ1 1H NMR
;
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Angew. Chem. Int. Ed. 2011, 50, 1678 –1682

(500 MHz, CDCl3): d = 7.06–6.97 (m, 6H), 6.97–6.90 (m, 4H), 5.26
(sept, J = 6.3 Hz, 1H), 4.97 (sept, J = 6.2 Hz, 1H), 4.26 (dd, J = 9.5,
9.5 Hz, 1H), 4.05 (ddd, J = 9.8, 7.3, 7.3 Hz, 1H), 3.99 (s, 1H), 3.85 (d,
J = 9.2 Hz, 1H), 2.80 (dd, J = 13.4, 10.1 Hz, 1H), 2.36 (dd, J = 13.5,
7.2 Hz, 1H), 1.45 (d, J = 6.3 Hz, 3H), 1.43 (d, J = 6.3 Hz, 3H), 1.17 (d,
J = 6.2 Hz, 3H), 1.10 ppm (d, J = 6.3 Hz, 3H); 13C NMR (125 mhz,
CDCl3): d = 174.8, 170.2, 140.9, 140.7, 128.7 (2C), 128.5 (2C), 127.8
(2C), 127.7 (2C), 126.1, 126.0, 81.5, 70.7, 68.5, 59.0, 50.1, 47.9, 44.3,
22.0 (2C), 21.9 ppm (2C); MS (ESI): m/z calcd for C25H31O5: 411
[M+H]+; found: 411. The enantiomeric ratio was measured by chiral-
[6] V. Nair, S. Vellalath, M. Poonoth, E. Suresh, J. Am. Chem. Soc.
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[7] For an enantioselective variant of the NHC reaction described
by Nair et al., see: P.-C. Chiang, J. Kaeobamrung, J. W. Bode, J.
Am. Chem. Soc. 2007, 129, 3520.
[8] For NHC–homoenolate additions to 1,2-dicarbonyl compounds,
see: V. Nair, S. Vellalath, M. Poonoth, R. Mohan, E. Suresh, Org.
Lett. 2006, 8, 507.
[9] a) D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt,
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Nemoto, T. Fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47,
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phase HPLC (Chiralcel OD-H, 5% IPA/hexanes, 0.50 mLminÀ1
,
210 nm): Rt (major) = 13.2 min, Rt (minor) = 18.7 min; 95% ee.
Received: September 20, 2010
Revised: December 2, 2010
Published online: January 14, 2011
Keywords: asymmetric catalysis · asymmetric synthesis ·
homoenolates · Lewis acids · N-heterocyclic carbenes
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[11] The absolute and relative configuration were determined by X-
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the others were assigned by analogy (see the Supporting
Information). The relative configuration of the minor diaste-
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were assigned by analogy (see the Supporting Information).
CCDC 793381 (4) and 793382 (29) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[13] A decrease in the catalyst loading (to 5 and 10 mol%) resulted in
incomplete conversion (50 and 80%, respectively) after 48 h.
[14] In NMR spectroscopic experiments (1H 500 MHz, 13C 125 MHz)
in which the azolium precatalyst E, the base DBU, and a-
ketoester 2 were combined in [D8]THF, no detectable differ-
ences were observed in the signals relative to those in the spectra
of the starting material. Efforts are currently under way to
understand the full role of the Lewis acid in these cooperative
carbene catalytic processes.
[15] At present, the use of achiral carbene A and chiral TiIV
complexes does not provide the desired cyclopentane products.
Further investigations in this area are ongoing.
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Angew. Chem. Int. Ed. 2011, 50, 1678 –1682
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
[17] The transesterification reaction can be monitored by thin-layer
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1
chromatography or by H NMR spectroscopy (500 MHz). The
mixed ester can be isolated by flash chromatography.
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Angew. Chem. Int. Ed. 2011, 50, 1678 –1682