Direct and Enantioselective Organocatalytic α-Chlorination of Aldehydes

Article abstract of DOI:10.1021/ja049562z

The first direct enantioselective catalytic α-chlorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective chlorination of aldehydes to generate α-chloro aldehydes, an i

Full text of DOI:10.1021/ja049562z

Published on Web 03/11/2004
Direct and Enantioselective Organocatalytic r-Chlorination of Aldehydes
Michael P. Brochu, Sean P. Brown, and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received January 25, 2004; E-mail: dmacmill@caltech.edu
The enantioselective construction of carbon-halogen stereoge-
quinone 1 was initially less than fruitful (entries 4, 5, and 7, proline,
2% ee, imidazolidinone 4, 42% ee). However, a dramatic increase
in enantioselectivity was achieved using quinone 1 in the presence
of amine catalyst 3 to access (S)-2-chlorooctanal in 92% ee (Table
1, entry 6).
A survey of reaction media for this organocatalytic chlorination
revealed that a variety of solvents may be employed without
significant loss in enantiocontrol (Table 2). Surprisingly, the use
of acetone provided optimal selectivity, reaction rate, and chemical
yield, without halogenation of the bulk medium (entry 6, 93%
conversion, 92% ee). Moreover, product epimerization, formation
of R,R-dichlorooctanal, or octanal aldol dimerization were com-
prehensively suppressed using these conditions. The superior levels
of asymmetric induction and efficiency exhibited by amine salt 3
in acetone at -30 °C to afford (S)-2-chlorooctanal in 92% ee
prompted us to select these catalytic conditions for further explora-
tion.
nicity has become an important objective for practitioners of
1
medicinal chemistry and organic synthesis. Within the realm of
drug design, the stereospecific replacement of C-H or C-Me bonds
with fluorine or chlorine substituents can often endow metabolic
2
stability without loss in substrate binding affinity. Meanwhile, as
a stereodefined electrophile, the R-halocarbonyl substructure rep-
resents a versatile linchpin for organic fragment coupling and the
stereocontrolled construction of C-C, C-N, C-S, or C-O bonds.3
As part of a program aimed at developing broadly useful organic
4
catalysts for enantioselective synthesis, we recently reported the
proline-catalyzed R-oxidation of aldehydes (eq 1).5 In this Com-
munication, we advance this enamine catalysis concept to describe
a highly enantioselective procedure for the R-chlorination of
aldehydes. To our knowledge, this study represents the first example
of a direct formyl R-chlorination that is accomplished with high
levels of asymmetric induction.
,6
Table 1. Effect of Catalyst and Chlorinating Reagent on
R-Chlorination
entry
catalyst
reagent
temp (°C)
time (h)
% conversiona
%eeb
1
2
3
4
5
6
7
L-proline
3
4
L-proline
L-proline
3
4
NCS
NCS
NCS
1
1
1
4
4
4
6
6
6
12
30
8
99
20
60
44
NR
91
2
19
10
2
NA
92
42
4
-30
-30
-30
5
In our aldehyde oxidation studies, the enantioselective step was
1
6
78
proposed to involve a proton-mediated cyclic transition state that
enforces nitrosobenzene activation in the asymmetric environment
of a π-rich enamine. Intrigued by the possibility that such a
mechanistic scenario might be expanded to encompass electrophilic
forms of chlorine, we identified N-chlorosuccinimide (NCS) and
the perchlorinated quinone 1 as reagents that might engage in an
analogous transition state 2 via carbonyl-proton association and
concomitant chlorine activation (eq 2). It is important to note that
the capacity of quinone 1 to function in enantioselective enolate
halogenations has previously been established by the pioneering
studies of Leckta and co-workers.1
a
Conversion determined by GLC analysis of product relative to an
internal standard (benzyl methyl ether). b Enantiomeric excess determined
by chiral GLC analysis (Bodman Γ-TA).
Experiments that probe the scope of the aldehyde substrate are
summarized in Table 3. Considerable variation in the steric demand
of the aldehyde component (entries 1, 3-5, R ) n-Hex, Cy-Hex,
adamantyl, Bn) is possible without loss in efficiency or enantio-
control (71-85% yield, 92-94% ee). Moreover, these mild catalytic
conditions are tolerant of acid sensitive functionality such as acetals
(Table 3, entry 6). It is important to note that these R-chloroalde-
hydes are typically configurationally stable to pH neutral silica
a,b
As revealed in Table 1, exposure of octanal to NCS in the
presence of L-proline, or imidazolidinone catalysts 3 or 4, resulted
in a facile but nonselective aldehyde chlorination (Table 1, entries
7
purification. Indeed, only the R-chlorohydrocinnamaldehyde adduct
was found to significantly diminish in optical purity upon isolation
1
-3). Changing the electrophilic chlorine source to the Leckta
(entry 5, crude 92% ee, isolated 80% ee).
4108
9
J. AM. CHEM. SOC. 2004, 126, 4108-4109
10.1021/ja049562z CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Effect of Solvent on Organocatalyzed R-Chlorination
corresponding syn adduct with high fidelity. These transformations
clearly demonstrate the synthetic advantages of catalyst-enforced
induction versus substrate directed stereocontrol.
entry
solvent
time (h)
% conversiona
%eeb
1
2
3
4
5
6
EtOAc
THF
toluene
CH3CN
CHCl3
acetone
12
18
18
8
8
7
93
56
83
65
91
93
87
89
89
92
92
92
a
Conversion determined by GLC analysis of product relative to an
b
internal standard (benzyl methyl ether). Enantiomeric excess determined
by chiral GLC analysis (Bodman Γ-TA).
Table 3. Enantioselective R-Chlorination: Substrate Scope
In summary, we have described the first direct, enantioselective
R-chlorination of aldehydes. Importantly, the chlorinated quinone
1
and both enantiomers of catalyst 3 are bench stable and
commercially available. Further studies to evaluate the mechanism
of this process, expand the scope, and utilize the R-chloroaldehydes
via in situ functionalization are now underway. Finally, it should
be noted that the imidazolidinone scaffold has revealed itself to be
a broadly useful catalyst for enantioselective synthesis within the
realms of both iminium activation4 and now enamine catalysis.
,8
Acknowledgment. Financial support was provided by kind gifts
from Bristol-Myers Squibb, Eli Lilly, and Merck Research Labo-
ratories. D.W.C.M is grateful for support from the Sloan Foundation
and Research Corporation. Teresa Beeson is thanked for additional
enantioselectivity analysis.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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2
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