Asymmetric synthesis of functionalized cyclopentanones via a multicatalytic secondary amine/N-heterocyclic carbene catalyzed cascade sequence

Article abstract of DOI:10.1021/ja905342e

(Chemical Equation Presented) A one-pot, asymmetric multicatalytic formal [3+2] reaction between 1,3-dicarbonyls and α,β-unsaturated aldehydes is described. The multicatalytic process involves a secondary amine catalyzed Michael addition followed by a N-h

Full text of DOI:10.1021/ja905342e

Published on Web 09/04/2009
Asymmetric Synthesis of Functionalized Cyclopentanones via a Multicatalytic
Secondary Amine/N-Heterocyclic Carbene Catalyzed Cascade Sequence
Stephen P. Lathrop and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received July 6, 2009; E-mail: rovis@lamar.colostate.edu
Increased focus has recently been placed on the development of
organic transformations that allow for the rapid construction of
densely functionalized molecules from simple readily available
starting materials. One approach in which these demands can be
achieved is through the expanding field of cascade catalysis.1
Although a number of examples of asymmetric cascade catalysis
have been developed, most rely on a single catalyst1a,d-g,2 to
perform two sequential operations. More recently, multiple catalyst
systems for cascade reactions have been realized.1b,c,3 Although
these reactions showcase the potential power in this field, relatively
few asymmetric examples exist.4 The major challenge in developing
multiple catalyst systems for cascade catalysis is that each catalyst
must be compatible with all reagents, intermediates, and other
catalysts present from the onset of the reaction. This circumstance
is occasionally avoided by addition of reagents and/or catalysts at
the midpoint of a given reaction.
While both secondary amines and carbenes are inherently basic,
initiation of the sequence by carbene reaction could be detrimental
given the possibility of the carbene-catalyzed benzoin,12 Stetter,13
and redox14,15 pathways. The test reaction involved treatment of
acetylacetone with crotonaldehyde, 3,5-bistrifluoromethyl diphenyl
prolinol TMS ether catalyst 5,16 and triazolium salt 617 (Table 1).
Combining the two catalysts in the absence of exogenous base yields
trace amounts of the desired cyclopentanone (entry 1). However,
1
intermediate 1 is observed by crude H NMR, suggesting that the
Michael addition occurs but the carbene is not being generated under
the reaction conditions. To alleviate this problem, catalytic triethy-
lamine was added to the reaction. In the presence of base, the
desired cyclopentanone 7a is formed in moderate yield and excellent
enantioselectivity (entry 2). A brief screen of the reaction conditions
revealed sodium acetate to be the optimal base, while chloroform
gives the highest level of diastereoselectivity (entries 3-6).
Increasing the concentration in the presence of 2 equiv of dicarbonyl
3 provides optimal yields without loss of enantioselectivity or
diastereoselectivity (entry 7).
Stimulated by the inherent basicity of many common organic
catalysts, most notably secondary amines,5 Cinchona alkaloids,6
and nucleophilic carbenes,7 we speculated that these catalysts could
coexist in a single flask to exert their influence over complementary
bond-forming events without mutual interference. Indeed, we have
already revealed this by utilizing carbene and acyl transfer
cocatalysis in the synthesis of amides.8 To generalize this concept,
we initiated a research program to develop multicatalytic asym-
metric processes.
Table 1. Catalyst and Solvent Screen
At the outset of our studies, we considered the use of active
methylene compounds and R,ꢀ-unsaturated aldehydes as the first
opportunity to test our hypothesis. A number of examples involving
the enantioselective secondary-amine-catalyzed conjugate addition
of malonates and ꢀ-ketoesters to R,ꢀ-unsaturated aldehydes9 and
ketones10 have been described. Reaction between a 1,3-diketone
and an enal generates aldehyde 1 bearing a tethered ketone (eq 1).
We envisioned that this intermediate would undergo an intramo-
lecular crossed benzoin11 reaction in the presence of a carbene
catalyst to afford highly functionalized cyclopentanone 2 via a
formal [3+2] process in a multicatalytic cascade sequence.
c d
,
entrya
solvent
base
yield (%)
drb
ee (%)
1
2
3
4
5
6
7e
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
PhMe
CHCl3
CHCl3
none
Et3N
trace
31
55
<20
53
nd
nd
84
86
70
84
86
86
80:20:<1:<1
80:20:<1:<1
80:20:<1:<1
80:20:<1:<1
85:15:<1:<1
85:15:<1:<1
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
60
93
a All reactions conducted using 20 mol % 5, 10 mol % 6, and 10 mol
% base at 22 °C (0.06 M) unless otherwise stated. b Diastereomeric ratio
determined by GC analysis of unpurified reaction mixture. c Enantio-
meric excess determined by GC analysis on chiral stationary phase.
d Major diastereomer. e 20 mol % 5, 10 mol % 6, 10 mol % NaOAc,
and 2 equiv of 3 (0.2M) at 22 °C.
In all cases, only two of the four possible diastereomers are
observed by GC/MS analysis. The relative configuration of the
major diastereomer was assigned on the basis of NOE studies,
confirmed by analogy to X-ray crystal structures of major and minor
diastereomers (13 and 10d, respectively). The absolute configuration
is based on previous work by Jørgensen and co-workers.9d
A series of R,ꢀ-unsaturated aldehydes with varying substitution
was subjected to the optimized reaction conditions (Table 2). Alkyl
as well as aromatic substitution is tolerated in the reaction (entries
9
13628 J. AM. CHEM. SOC. 2009, 131, 13628–13630
10.1021/ja905342e CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. R,ꢀ-Unsaturated Aldehyde Scope
give both [3.3.0] and [4.3.0] bicyclic systems (entries 6-7). Benzyl
protected nitrogen is tolerated in the cyclic ꢀ-ketoester backbone
to afford the highly functionalized bicyclic structure 10g (entry 5).
Table 3. ꢀ-Ketoester Scope
a-d See Table 2.
To shed light on the observed reactivity, we conducted a
control experiment leaving the azolium catalyst out of the
reaction (eq 2). Prolinol catalyst 5 mediates the asymmetric
Michael reaction furnishing aldehyde 11 in 70% yield. Surpris-
ingly, subjection of this intermediate to the azolium catalyst and
base generates the desired product in only 58% ee again with
diminished yield.18 Experiments aimed at elucidating the source
of this variance revealed that aldehyde 11 undergoes a retro-
Michael in the presence of prolinol 5, thus eroding ee. This
situation is exacerbated in the presence of silica gel.19 The
carbene catalyst serves to shuttle the intermediate aldehyde on
to product thus limiting the prolinol-mediated retro-Michael.
a See footnote e, Table 1. b See Table 1. c Enantiomeric excess deter-
mined by GC or HPLC analysis on a chiral stationary phase. d See
Table 1.
1-5). Protected alcohols and amines participate in the desired
reaction to give products readily amenable to further functional-
ization (entries 6-8). The sterically larger iso-propyl enal 4i
provides reduced yields and diastereoselectivity while maintaining
good levels of enantioselectivity (entry 8).
Next we examined unsymmetrical 1,3-dicarbonyls under the
optimized reaction conditions (Table 3). Methyl, ethyl, tert-butyl,
and benzyl acetoacetate provide the desired products with alkyl
and aromatic enals giving high levels of enantioselectivity (entries
1-4). ꢀ-Ketothioester 8e also gives the desired product with good
selectivity (entry 3). However, these unsymmetrical dicarbonyls
afford all four possible diastereomers with moderate selectivity.
Cyclic ꢀ-ketoesters also react under the optimized conditions to
9
J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009 13629

C O M M U N I C A T I O N S
Supporting Information Available: Experimental procedures,
1
characterization H/13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Figure 1. One-pot cascade reaction monitored by GC analysis utilizing
20 mol % 5, 10 mol % 6, 10 mol % NaOAc, with 1 equiv of acetylacetone
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(18) Addition of 10 mol % sodium acetate to the first step results in similar
yield and enantioselectivity. We also observed that carrying out the reaction
in a stepwise manner led to more complex reaction mixtures.
(19) See Supporting Information.
(20) General Procedure: a 1 dram vial was equipped with a magnetic stir bar
under argon and charged with catalyst 6 (0.024 mmol). CHCl3 (1 mL),
1,3-dicarbonyl (0.448 mmol), and enal (0.224 mmol) were added sequen-
tially followed by catalyst 5 (0.044 mmol) and NaOAc (0.024 mmol) in
one portion. The reaction was allowed to stir at room temperature for 14 h
at which point the reaction mixture was filtered through a short pad of
silica gel, eluted with Et2O (∼10 mL), and then concentrated in vacuo.
The resulting crude product was purified by flash silica gel chromatography.
(21) Reaction of 4a and 8a was conducted on 2.4 mmol scale using 10 mol %
5, 5 mol % 6, and 5 mol % NaOAc to afford 90% yield, 91% ee, and
identical diastereomer ratio of 10a.
In conclusion, we have developed an operationally simple single
step multicatalytic cascade process20,21 for the preparation of R-hy-
droxycyclopentanones containing three contiguous stereocenters.
The highly functionalized products are obtained from cheap, readily
available reagents in high enantioselectivities and moderate dias-
tereoselectivities. We further provide conclusive evidence that both
catalysts are mutually compatible and are operating concurrently.
Experiments aimed at extending the scope of these types of
transformations are currently underway.
Acknowledgment. We thank the NIGMS for support (GM72586).
T.R. thanks the Monfort Family Foundation for a Monfort Profes-
sorship. We thank Derek Dalton and Kevin Oberg (CSU) for solving
the crystal structures of 10d and 13. We thank a reviewer for helpful
suggestions.
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