Organocatalytic iminium ion/carbene reaction cascade for the formation of optically active 2,4-disubstituted cyclopentenones

Article abstract of DOI:10.1021/ol2018104

An organocatalytic iminium ion/N-heterocyclic carbene (NHC) cascade reaction between β-keto phenyltetrazolesulfones and α,β- unsaturated aldehydes, providing direct access to optically active 2,4-disubstituted cyclopent-2-enones, has been developed. The p

Full text of DOI:10.1021/ol2018104

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4790–4793
Organocatalytic Iminium Ion/Carbene
Reaction Cascade for the Formation of
Optically Active 2,4-Disubstituted
Cyclopentenones
Christian Borch Jacobsen, Kim L. Jensen, Jonas Udmark, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
kaj@chem.au.dk
Received July 6, 2011
ABSTRACT
An organocatalytic iminium ion/N-heterocyclic carbene (NHC) cascade reaction between β-keto phenyltetrazolesulfones and R,β-unsaturated
aldehydes, providing direct access to optically active 2,4-disubstituted cyclopent-2-enones, has been developed. The products are isolated in
good yields with high enantioselectivities.
The utilization of organocatalytic cascade reactions in
the development of complex reaction sequences has been
explored significantly in recent years.1 Combinations of
enamine and iminium ion catalysis are well-studied exam-
ples among these developments.2 Recently, the catalytic
activities of secondary amines and N-heterocyclic carbenes
(NHCs) have been combined in the synthesis of complex
structures.3
The application of easily accessible β-keto hetero-
arylsulfones4,5 as nucleophiles in the enantioselective
organocatalytic introduction of alkenyl and alkynyl
(5) For reviews on sulfones in organocatalysis, see: (a) Nielsen, M.;
~
Jacobsen, C. B.; Holub, N.; Paixao, M.; Jørgensen, K. A. Angew. Chem.,
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Int. Ed. 2010, 49, 2668. (b) Alba, A. N. R.; Companyo, X.; Rios, R.
Chem. Soc. Rev. 2010, 39, 2018.
(6) (a) Nielsen, M.; Jacobsen, C. B.; Paixao, M. W.; Holub, N.;
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Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581. (b) Paixao, M. W.;
€
(1) For recent reviews, see: (a) Enders, D.; Grondal, C.; Huttl,
Holub, N.; Vila, C.; Nielsen, M.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2009, 48, 7338. (c) Jacobsen, C. B.; Lykke, L.; Monge, D.; Nielsen,
M.; Ransborg, L. K.; Jørgensen, K. A. Chem. Commun. 2009, 6554. (d)
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Yu, X.; Wang, W.
Org. Biomol. Chem. 2008, 6, 2037. (c) Zhou, J. Chem. Asian J. 2010, 5,
422. (d) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(2) For selected recent examples, see: (a) Simmons, B.; Walji, A. M.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349. (b)
Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem., Int. Ed. 2009, 48, 7892. (c) Quintard, A.; Alexakis, A.
Chem. Commun. 2011, 47, 7212. (d) Xiang, S.; Zhang, B.; Cui, Y.; Hiao,
N. Chem. Commun. 2011, 47, 5007. (e) Appayee, C.; Brenner-Moyer,
S. E. Org. Lett. 2010, 12, 3356. (f) Hong, B.; Sadani, A. A.; Nimje, R. Y.;
Dange, N. S.; Lee, G. Synthesis 2011, 12, 1887.
(3) For selected recent examples, see: (a) Lathrop, S. P.; Rovis, T.
J. Am. Chem. Soc. 2009, 131, 13628. (b) Enders, D.; Grossmann, A.;
Huang, H.; Raabe, G. Eur. J. Org. Chem. 2011, 4298. (c) Jiang, H.;
Gschwend, B.; Albrecht, L.; Jørgensen, K. A. Org. Lett. 2010, 12, 5052.
(d) Hong, B.; Dange, N. S.; Hsu, C.; Liao, J. Org. Lett. 2010, 12, 4812. (e)
Hong, B.; Dange, N. S.; Hsu, C.; Liao, J.; Lee, G. Org. Lett. 2011, 13,
1338. (f) Ozboya, K. E.; Rovis, T. Chem. Sci. 2011, 2, 1835.
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Holub, N.; Jiang, H.; Paixao, M. W.; Tiberi, C.; Jørgensen, K. A.
Chem.;Eur. J. 2010, 16, 4337. (e) Jacobsen, C. B.; Nielsen, M.; Worgull,
D.; Zweifel, T.; Fisker, E.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
7398.
(7) For reviews on the synthesis of cyclopentenones, see: (a) Gibson,
S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873. (b)
Lee, H.; Kwong, F. Eur. J. Org. Chem. 2010, 789. For recent examples of
enantioselective formations of cyclopentenones illustrating different
approaches, see: (c) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 10296. (d) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 8078.
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(e) Schelwies, M.; Dubon, P.; Helmchen, G. Angew. Chem., Int. Ed. 2006,
45, 2466. (f) Cao, P.; Deng, C.; Zhou, Y.; Sun, X.;Zheng, J.; Xie, Z.; Tang,
Y. Angew. Chem., Int. Ed. 2010, 49, 4463. (g) Schultz-Fademrecht, C.;
Tius, M. A.; Grimme, S.; Wibbeling, B.; Hoppe, D. Angew. Chem., Int.
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r
10.1021/ol2018104
Published on Web 08/19/2011
2011 American Chemical Society

moieties into organic molecules has recently been described.6
Inspired by the seminal work of Rovis3a and Enders,3b
which affords polysubstituted cyclopentanones (Scheme 1,
top), we envisioned that β-keto phenyltetrazolesulfones
could be employed in an iminium ion/NHC-catalyzed
reaction sequence for the formation of optically active
2,4-disubstituted cyclopent-2-enones (Scheme 1, bottom),7
as the NHC-catalyzed benzoin condensation leads to a
Smiles rearrangement (vide infra).8 The cyclopentenone
motif is present in numerous natural products and bio-
active molecules and serves as a useful intermediate in
synthesis.9 Therefore, enantioselective organocatalytic10
approaches toward these compounds are of interest.
Herein, we wish to disclose the synthesis of optically
active 2,4-disubstituted cyclopent-2-enones by a one-pot
organocatalytic iminium ion/NHC reaction sequence. The
products are formed in high enantioselectivities and iso-
lated in good yields. Moreover, selected transformations
illustrate the synthetic versatility of the products obtained.
We initially focused on having both aminocatalyst 3 and
carbene catalyst precursor 4 (Table 1) present from the
beginning of the reaction; however, we realized that the
NHC-catalyzed step does not occur at the lowered tem-
perature required to obtain satisfying enantiomeric excess
in the initial organocatalytic Michael addition step. Con-
sequently, carbene precursor 4 was added in a sequential
one-pot manner at elevated temperature after the comple-
tion of the addition.
sequence (Table 1). Commencing with an optimization of
the isolated yield of product 5aa, employing the carbene
precursor 4a, we were unable to obtain any conversion
from the Michael-adduct to the desired product (entry 1).
The more electron-withdrawing perfluorinated moiety
in catalyst 4b partly solves the conversion problem, and
5aa was isolated in 27% yield employing 50 mol % of
DIPEA as base (entry 2). Changing the base to the weaker
NaOAc has an advantageous effect on the isolated yield
(entry 3). To obtain the desired product in an acceptable
yield, it is necessary to increase the carbene and base
loadings, and product 5aa was isolated in 60% yield
employing 25 mol % of 4b and 200 mol % of NaOAc
(entry 4). Subsequent investigations showed that the en-
antioselectivity is virtually unaffected by the temperature
employed in the carbene-catalyzed step (entries 5 and 6).
However, theenantioselectivity can beimproved to93% ee
by lowering the aminocatalyst loading in the initial addi-
tion step (entries 6 and 7).
With the optimized reaction conditions for the cascade
sequence in hand, we next investigated the scope of the
reaction (Scheme 2). Commencing with the scope of the
R,β-unsaturated aldehydes 1, it was found that a variety of
aliphatic aldehydes can be employed. The optically active
products 5aaÀ5ca were formed in good yields (61À63%)
and high enantioselectivities (90À96% ee) independent of
the length of the aldehyde substituent. The formation of
the products 5da, 5ea, and 5dd demonstrates that double
Table 1. Optimization of the One-Pot Cascade Sequencea
Scheme 1. Previous Work for the Synthesis of Enantioenriched
Cyclopentanones (Top) and the Present Organocatalytic Ap-
proach toward Optically Active 2,4-Disubstituted Cyclopent-2-
enones (Bottom) (PT = Phenyltetrazole)
carbene
temp (°C),
yieldb
(%)
eec
entry (mol %) base (mol %) step 1/step 2
(%)
1
2
4a (50) DIPEA (50)
4b (13) DIPEA (50)
4b (13) NaOAc (50)
4b (25) NaOAc (200)
4b (25) NaOAc (200)
4b (25) NaOAc (200)
4b (25) NaOAc (200)
rt/40
rt/rt
no conversion
27
37
60
57
57
63
3
rt/rt
4
rt/rt
5
À30/20
À30/40
À30/40
85
86
93
6
7d
a All reactions performed one-pot as follows. Step 1: 1a (0.20 mmol),
2a (0.10 mmol), 3 (10 mol %), and o-NO2-benzoic acid (10 mol %) in
toluene (1.0 mL) at the designated temperature. Step 2: As reported in
the table. b Isolated yield. c Enantiomeric excess determined by CSP-
HPLC. d Performed with 3 (5 mol %) and o-NO2-benzoic acid (10 mol %).
Having established the optimal reaction conditions for
the initial iminium ion catalyzed step,11 we turned our
attention toward developing the entire one-pot cascade
bonds in the aldehyde chain are also tolerated. Moreover,
the presence of a heteroatom is accepted, as illustrated by
(8) Warren, L. A.; Smiles, S. J. Chem. Soc. 1930, 1327.
Org. Lett., Vol. 13, No. 18, 2011
4791

Scheme 2. Scope of the Organocatalytic Formation of 2,4-
Disubstituted Cyclopent-2-enones 5a
Scheme 3. Transformation of the Obtained Products 5a
a See Supporting Information for detailed reaction conditions.
Scheme 4. Proposed Mechanism for the NHC-Catalyzed Ben-
zoin Condensation and Subsequent Smiles Rearangement
a All reactions performed one-pot as follows. Step 1: 1 (0.40 mmol), 2
(0.20 mmol), 3 (5 mol %), and o-NO2-benzoic acid (10 mol %) in toluene
(2 mL) À30 °C. Step 2: 4b (25 mol %) and NaOAc (200 mol %) added
at 40 °C. Isolated yields by FC. Enantiomeric excess determined by
CSP-HPLC. b With 3 (10 mol %) and o-NO2-benzoic acid (20 mol %)
employed. c Enantiomeric excess determined after methyl cuprate addi-
tion (see Supporting Information for details). d Performed on 0.10 mmol
scale.
the employment of aldehyde 1f containing an TBDMS-
protected alcohol substituent, thereby providing another
site for functionalization. This entry shows also that more
sterically demanding substituents are tolerated in the
aldehyde side chain.12
(9) For selected reviews on the bioactivity of molecules containingthe
cyclopentenone moiety, see: (a) Rossi, A.; Kapahi, P.; Natoli, G.;
Takahashi, T.; Chen, Y.; Karin, M.; Santoro, M. G. Nature 2000, 403,
103. (b) Straus, D. S.; Glass, C. K. Med. Res. Rev. 2001, 21, 185. (c)
Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem. Soc., Perkin Trans.
1 2002, 1735. (d) Conti, M. Expert Opin. Drug Discovery 2007, 2, 1153.
(e) Conti, M. Anti-Cancer Drugs 2006, 17, 1017. For a recent review
on the synthesis of cyclopentenone prostaglandins, see: (f) Das, S.;
Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286.
See also: (g) Roche, S. P.; Aitken, D. J. Eur. J. Org. Chem. 2010, 5339. (h)
Next, the scope of the nucleophiles 2 was examined.
Nucleophiles with both electron-withdrawing and elec-
tron-donating substituents on the aromatic moiety can
be employed, as demonstrated by the formation of pro-
ducts 5dd and 5ac in 51 and 55% yields and 92 and 93% ee,
respectively. Moreover, substituents can be placed in either
the para- or meta-positions, as shown by the synthesis of
products 5ab and 5ac. A meta-chloro-substituted nucleo-
phile 2 was also attempted, resulting in a low yield of 33%
and moderate enantioselectivity of 43% ee (not shown).
Finally, nucleophiles bearing larger ring systems are also
viable substrates for the developed catalytic sequence, as
illustrated by the employment of 2-naphthyl-substituted
ꢁ
Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.;
Verdaguer, X.; Riera, A. Org. Biomol. Chem. 2008, 6, 4649.
(10) For recent reviews on the use of secondary amines and NHCs in
organocatalysis, see: (a) Chem. Rev. 2007, 107, 5413 Special issue on
organocatalysis. (b) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638. (c) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009,
38, 2178. (d) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.;
Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632. (e)
ꢁ
Marion, N.; Dıes-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed.
2007, 46, 2988.
(11) The initial addition step was performed as described in ref 6a
with o-NO2-benzoic acid as cocatalyst.
(12) Aromatic and heteroaromatic aldehydes were found to be un-
reactive in the initial addition step.
(13) The absolute configuration was assumed to be R by analogy to
previous published results (see ref 6a).
4792
Org. Lett., Vol. 13, No. 18, 2011

2b.13 Nucleophiles bearing an aliphatic ketone substituent
were found to be inapplicable, presumably because they
form a stable pyranose intermediate.4a
To demonstrate the potential of the obtained products5,
selected transformations forming more complex structures
were performed (Scheme 3). Methyl cuprate addition
furnishes the products 6a,b as single diastereomers in good
yields, while maintaining the high enantioselectivities. An
L-selectride reduction of product 6a afforded 7 containing
four adjacent stereocenters and isolated in 62% yield as a
single diastereomer.14
The proposed mechanism for the benzoin condensation
initiated Smiles rearrangement is outlined in Scheme 4.
Following the initial iminium ion-catalyzed Michael addi-
tion of nucleophiles 2 to R,β-unsaturated aldehydes 1
forming intermediate A, the carbene adds to the aldehyde
moiety, forming the Breslow intermediate B. This sets the
stageforthecrucial step, namely, the intramolecular attack
on the aromatic ketone. The resultant five-membered ring
C must have the alkoxide and sulfone moiety positioned in
a syn-relationship to facilitate the Smiles rearrangement.
Should anti-C be formed, thus placing the substituents
too far from each other to react, equilibration back to
the Breslow intermediate might furnish the correct dia-
stereomer. Both epimers of A exist in a ca. 1:1 ratio due
to rapid equilibration of the stereocenter carrying the
sulfone moiety; however, it is assumed that syn-C is
formed in large excess from the most reactive epimer
of B.3b
In conclusion, we have presented an organocatalytic
enantioselective iminium ion/NHC-catalyzed reaction se-
quence affording optically active 2,4-disubstituted cyclo-
pent-2-enones. The products are formed in good yields and
high enantioselectivities. Moreover, selected transforma-
tions leading to more complex structures illustrate the
synthetic usefulness of this new reaction concept.
Acknowledgment. This work was made possible by
grants from OChem School, FNU, and the Carlsberg
Foundation.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) The relative configuration was assigned by a selective 1D
NOESY experiment on 7 (see Supporting Information).
Org. Lett., Vol. 13, No. 18, 2011
4793