Enantioselective synthesis of cyclopentene carbaldehydes by a direct multicatalytic cascade sequence: Carbocyclization of aldehydes with alkynes

Article abstract of DOI:10.1002/chem.200903405

The reaction of α, βunsaturated aldehydes 1 with alkyne-tethered nucleophiles, such as malononitriles and cyanoacetates, in a highly enantio- and diastereoselective iminium-enamine-Lewis acid catalyzed cascade sequence to produce cyclopentene carbaldehydes of broadhas been reported. A major driving force for the many new developments in cascade, domino, and tandem reactions is the proficiency with which biological systems transform simple compounds into complex molecular frameworks. An ordinary vial under an inert atmosphere, aldehyde has been added to a stirred mixture of nucleophile. The products are obtained in good yields and excellent enantio- and dia-stereoselectivities. A sigmatropic rearrangement was performed, leading to a highly versatile building block for the total synthesis of a fusicoccane diterpenoid analogue.

Full text of DOI:10.1002/chem.200903405

DOI: 10.1002/chem.200903405
Enantioselective Synthesis of Cyclopentene Carbaldehydes by a Direct
Multicatalytic Cascade Sequence: Carbocyclization of Aldehydes with
Alkynes
Kim L. Jensen, Patrick T. Franke, Carlos Arrꢀniz, Sara Kobbelgaard, and
Karl Anker Jørgensen*[a]
A major driving force for the many new developments in
cascade, domino, and tandem reactions is the proficiency
with which biological systems transform simple compounds
into complex molecular frameworks.[1] Recently, asymmetric
organocatalytic processes have become a powerful tool in
the formation of multiple new bonds and stereogenic centers
in a one-pot system without isolation of intermediates.[2]
Secondary amine organocatalysts are capable of controlling
the sequential introduction of a nucleophile and an electro-
phile by an iminium–enamine activation sequence.[3] This
strategy is currently the most employed approach in devel-
oping new organocatalytic, asymmetric cascade reactions.
Many catalytic cascade reactions rely on only one catalyst;
however, an increased focus has recently been placed on the
dual-activation concept, in which two separate catalysts are
combined in one catalytic system.[4]
Over the past few years, a significant number of cascade
reactions, often involving soft transition metals, such as gold
and copper, have been reported. Activation of alkene,
alkyne, and allene functionalities happens under mild condi-
tions and low catalyst loading.[5] More specifically, cycliza-
tion reactions involving Lewis acids have emerged as a pow-
erful strategy to construct complex carbocycles.[6] In recent
years, the idea of combining transition-metal catalysis with
organocatalysis has emerged as a promising strategy for de-
veloping and enabling unprecedented transformations.[7]
It has been shown by the group of Kirsch that gold and
aminocatalysis can be combined in a direct carbocyclization
of aldehydes with alkynes.[6e] Recently, Dixon and co-work-
ers reported a cascade reaction of a,b-unsaturated ketones
with propargylated malonates leading to racemic cyclopen-
tene products by a combination of amino and copper cataly-
sis.[8] This seminal work inspired us to develop this concept
further by the application of other classes of electrophiles
and nucleophiles in an asymmetric fashion.[9]
Herein, we present the reaction of a,b-unsaturated alde-
hydes 1 with alkyne-tethered nucleophiles, such as malono-
nitriles and cyanoacetates 2, in a highly enantio- and diaste-
reoselective iminium–enamine-Lewis acid catalyzed cascade
sequence to produce cyclopentene carbaldehydes of broad
scope (Scheme 1). The present work demonstrates the dual-
activation concept in which an organocatalyst is combined
with a Lewis acid to activate an alkyne towards nucleophilic
attack. Activation of an a,b-unsaturated aldehyde 1 through
iminium-ion formation by using a secondary amine organo-
catalyst induces the Michael addition of the propargylated
nucleophile 2. The intermediate A undergoes a 5-exo-dig
À
cyclization, forming a C C bond in which both the organo-
catalyst and Lewis acid are involved, followed by double-
bond isomerization (Scheme 1). The optically active prod-
ucts formed are key motifs in the synthesis of, for example,
[a] K. L. Jensen, P. T. Franke, C. Arrꢀniz, S. Kobbelgaard,
Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903405.
Scheme 1. Organo- and Lewis acid catalytic approach to cyclopentene
carbaldehydes.
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COMMUNICATION
Table 2. Scope of the multicatalytic cascade reaction.[a]
the biologically important iridoids and fusicoccane diterpe-
noids.[10]
At the outset of our studies, we examined different
alkyne-tethered nucleophiles derived from malonate (R2,
R3 =CO2Me) and a 1,3-diketone (R2, R3 =COMe). Screen-
ing of different solvents, catalysts, and additives, such as
Brønsted acids and bases, showed no reactivity after several
days. We then modified the nucleophile to the more reactive
propargylated malononitrile 2a and examined the cascade
reaction by treating it with hexenal 1a, in the presence of
Entry
R
Metal Product Yield [%][b] ee [%][c]
(S)-2-{bis
ACHTUNGTRENNUNG
methyl}pyrrolidine 3 as the organocatalyst and CuAHCTUNGTRENNUNG
(OTf=trifluoromethanesulfonate) as the Lewis acid
(Table 1).
1
2
3
4
5
6
7
8
Pr (1a)
Et (1b)
hexyl (1c)
iPr (1d)
C
C
C
C
C
C
C
C
C
C
A
A
A
B
B
B
B
B
B
B
B
4a
4b
4c
4d
4e
4 f
4g
4h
4i
88
89
66
96
62
50
80
69
61
72
97
92
61
80
72
91
66
53
55
64
49
95[d]
90[d]
95[d]
96[d]
89[d]
95
(Z)-3-hexenyl (1e)
Bn[e] (1 f)
Table 1. Optimization of the cascade reaction.[a]
Ph (1g)
93
95
93
85
p-CF3-C6H4 (1h)
p-OMe-C6H4 (1i)
o-OMe-C6H4 (1j)
Pr (1a)
iPr (1d)
Ph (1g)
Pr (1a)
hexyl (1c)
iPr (1d)
(Z)-3-hexenyl (1e)
p-CF3-C6H4 (1h)
o-OMe-C6H4 (1j)
p-Br-C6H4 (1k)
naphthyl (1l)
9
10
11
12
13
14
15
16
17
18
19
20
21
4j
4a
4d
4g
4a
4c
4d
4e
4h
4j
99[d]
96[d]
92
99[d]
99[d]
99[d]
90[d]
97
Entry Solvent Metal T [8C] Conversion to 4a [%][b] ee [%][c]
99
99
97
1
2
3
4
5
6
7
toluene
CH2Cl2
CHCl3
MeOH
toluene
toluene
toluene
A
A
A
A
B
B
C
RT
RT
RT
RT
RT
4
100
61
100
57
100
100
100
96
n.d.
80
n.d.
94
99
4k
4l
[a] See the Supporting Information. [b] Isolated by flash chromatography.
[c] Determined by chiral stationary phase HPLC. [d] Determined from
the corresponding alcohol 5. [e] Bn=benzyl.
RT
95
[a] See the Supporting Information. TMS=trimethylsilyl. [b] Determined
by 1H NMR spectroscopy. [c] Determined by chiral stationary phase
HPLC; n.d.=not determined.
and nonconjugated unsaturated substituents, 1a–1 f, the
products were obtained in good to excellent yields (50–
96%) and with excellent enantioselectivities (89–96% ee).
Aromatic aldehydes 1g–1j also provided the products in
good yields (61–80%) and excellent enantioselectivities (85–
95% ee), although, the aromatic a,b-unsaturated aldehydes
reacted more slowly. The reaction was also investigated with
copper salts as the Lewis acid catalyst. By applying CuII
salts, the products were obtained in good yields and excel-
lent selectivities (Table 2, entries 11–13); however, the reac-
tions with CuI as the Lewis acid were generally faster and
provided almost enantiopure products (Table 2, entries 14–
21).
As revealed in the Table, full conversion and excellent
enantioselectivity of the product 5a was obtained in non-
dried toluene (Table 1, entry 1). Screening of other solvents
gave relatively lower conversions and selectivities (Table 1,
entries 2–4). It is believed that CuII is reduced to CuI in the
presence of excess Ph3P. [11] We then examined a CuI species
and 5a was obtained with excellent enantiomeric excess (ee)
(Table 1, entries 5 and 6). Lowering the temperature in-
creased the enantioselectivity from 94 to 99% ee. Finally,
the reaction also worked with a AuI source (Table 1,
entry 7). The reaction with gold is generally slower, but the
advantage of gold compared with copper is that no addition-
al phosphine is needed and the reaction can be performed
in air. It should be pointed out that benzoic acid is impor-
tant to achieve full conversion in the addition step.
We then investigated cyanoacetates with
a terminal
alkyne group as these would provide products with an addi-
tional stereogenic center; one of them being quaternary
(Scheme 2). Methyl and isopropyl esters, 2b and 2c, respec-
tively, provided the desired products 5m–5p in good yields
and excellent enantioselectivities. Notably, when aromatic
a,b-unsaturated aldehydes were treated with 2c, highly dia-
stereo- (diastereomeric ratio (dr)>20:1) and enantioen-
riched (99% ee) products 5n–5p were formed. Propargylat-
ed b-ketoesters were also examined, but unfortunately no
reaction was observed. This suggests that at least one cyano
The generality of the reaction was studied for a series of
a,b-unsaturated aldehydes 1 in the presence of three differ-
ent Lewis acids. The reaction with AuI as Lewis acid pro-
ceeded well for both aliphatic and aromatic aldehydes
(Table 2, entries 1–10). For aldehydes with linear, branched,
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K. A. Jørgensen et al.
since it was shown that an amine catalyst is required for cy-
clization.[6e]
The absolute configuration of the product was assigned by
single-crystal analysis of 5k as shown in Figure 1.[13] The ste-
reochemistry formed indicates that addition takes place,
from below, to the Re face of the iminium ion.
Scheme 2. Reaction of a,b-unsaturated aldehydes with cyanoacetates.
group is required in the nucleophile for this cascade se-
quence under the present reaction conditions.
The surprisingly high diastereocontrol in the reactions in-
volving aromatic aldehydes led us to investigate this further.
We, therefore, performed the reaction of cinnamaldehyde
1g with nucleophile 2c without the copper catalyst to deter-
mine the diastereoselectivity in the addition step. This led to
a 1:1 mixture of diastereoisomers indicating no diastereo-
control in the addition step.[12] Since highly diastereoen-
riched products are formed in the cascade reaction this sug-
gests a dual activation of organocatalyst and copper in the
addition step.
Figure 1. X-ray crystal structure of compound 5k; C=gray, H=white,
O=red, N=blue, Br=burgundy.
The cyclopentenyl alcohol motif is important in the total
synthesis of, for example, fusicoccane diterpenoids.[10e] Opti-
cally active allylic alcohol 5d was set up for a Claisen rear-
rangement by the Johnson orthoester protocol as outlined in
Scheme 4. The sigmatropic process gave the product 7, con-
taining a newly formed quaternary stereogenic center, in
high yield and stereoselectivity under unoptimized condi-
tions. The transformation nicely demonstrates how cascade
catalysis has emerged as a powerful tool for forming com-
plex molecular structures.
An additional control experiment, leaving out the Lewis
acid catalyst in the cyclization, was conducted to shed light
on the mechanism (Scheme 3).
Scheme 4. Claisen rearrangement of cyclopentenyl alcohol 5d.
In conclusion, we have developed an enantioselective imi-
nium–enamine-Lewis acid catalyzed cascade sequence for
the synthesis of cyclopentene carbaldehydes.[14] The products
are obtained in good yields and excellent enantio- and dia-
stereoselectivities. A sigmatropic rearrangement was per-
formed, leading to a highly versatile building block for the
total synthesis of a fusicoccane diterpenoid analogue.
Scheme 3. Mechanistic study on the effects of the organocatalyst and
Lewis acid in the cyclization reaction.
Acyclic aldehyde 6 was formed in 73% yield and with
90% ee in the absence of the Lewis acid. Subjecting 6 to
normal reaction conditions gave the product 4d in 69%
yield and 99% ee. However, no cyclization took place in the
absence of organocatalyst 3, indicating a dual-activation
mode in the cyclization step; that is, enamine and Lewis
acid activation. Furthermore, the lower overall yield ob-
tained for 4d from the stepwise approach (50 versus 91%)
suggests that both catalysts function more efficiently when
combined, compared with the separate catalytic approach.
A similar mechanistic study for AuI was not performed,
Experimental Section
In an ordinary vial under an inert atmosphere, aldehyde 1 (0.26 mmol)
was added to a stirred mixture of nucleophile 2 (0.20 mmol), catalyst 3
(0.02 mmol), PhCO2H (0.02 mmol), (CuOTf)2·PhCH3 (0.005 mmol), and
PPh3 (0.04 mmol) in toluene (0.4 mL for aliphatic aldehyde, 0.2 mL for
aromatic aldehyde) at 48C. The mixture was stirred for 16 h at 48C. The
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Enantioselective Synthesis of Cyclopentene Carbaldehydes
COMMUNICATION
crude mixture was subjected to flash chromatography on silica affording
the pure products (see the Supporting Information for more details).
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Acknowledgements
This research was funded by a grant from The Danish National Research
Foundation, OChemSchool, and the Carlsberg Foundation. C.A. thanks
the Ministerio de Educaciꢀn y Ciencia of Spain for a predoctoral fellow-
ship. We are grateful to Dr. Jacob Overgaard for X-ray crystallographic
analysis of 5k.
Keywords: aldehydes · cascade reactions · cyclopentenes ·
Lewis acids · organocatalysis
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Please note: Minor changes have been made to this publication in
Chemistry–A European Journal Early View. The Editor.
Published online: January 14, 2010
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