C O M M U N I C A T I O N S
Table 2. Direct Organocatalytic Enantioselective R-Chlorination of
Aldehydes Catalyzed by 3c and 3ia
in high yields (>90%). It was demonstrated that the oxidation
proceeded completely without loss of optical purity by converting
the R-chloro acids 6 into R-chloro methyl esters 7 with TMSCHN2
and checking the optical purity by CSP-GC.
The R-chloro ester 7 was also transformed into the corresponding
azide 8 by treatment with NaN3 in DMF at 60 °C, without loss of
ee as demonstrated for 2-chloro butanoic acid methyl ester 7a.
Hydrogenolysis of the azide with H2 (atm) and Pd/C catalyst
afforded the nonproteinogenic (R)-2-aminobutanoic acid methyl
ester 9 in high yields and enantioselectivity. A similar azide
substitution-hydrogenolysis sequence was performed on the 2-chlo-
ro alcohol 4d to afford optically active 2-amino butanol 11, the
key intermediate in the synthesis of tuberculostatic ethambutol.6
These synthetic transformations show the potential of this novel
organocatalytic direct enantioselective R-chlorination of aldehydes
as the products obtained are highly versatile chiral building blocks.
Today, many of these compounds are obtained by kinetic resolution,
and the present approach affords an attractive alternative to this
procedure.6
In summary, we have developed an organocatalytic R-chlorina-
tion of aldehydes affording optically active R-chloro aldehydes in
excellent yields and enantioselectivities. We are currently investi-
gating the extension of these new findings to a general halogenation
reaction of ketones, as well as to bromination and iodination of
aldehydes. These results and investigations concerning the mech-
anism will be reported shortly.
catalyst 3c
catalyst 3i
entry
aldehyde
yieldb (%)
ee (%)
yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
Me - 1b
2b - 99
2c - 99
2a - 95
75c (R)h
80d (R)j
-
-
Et - 1c
2c - 90
97d (S)j
94d (S)
i-Pr - 1a
87d (R)h 2a - 90
t-Bu - 1d
n-Hexyl - 1e
Allyl - 1f
CH2Ph - 1g
2d - 93g 95d (R)i 2d - 30f 94d (S)
2e - 95
2f - 90
2g - 99
70c (R)k 2e - 99
95c
95d
95e
81
74d
78e
86
2f - 90
2g - 82
2h - 95g
(CH2)2OTBS - 1h 2h - 92
a Reaction conditions: NCS (1.3 equiv.) was added to a mixture of
aldehyde and catalyst at 0 °C and the reaction mixture was allowed to warm
to ambient temperature. b Measured by 1H NMR and confirmed by GC due
to the high volatility of the products. c ee determined by CSP-GC after
oxidation and esterification to the corresponding methyl ester. d ee deter-
mined by CSP-GC. e ee determined by CSP-HPLC after reduction to the
corresponding alcohol. f Due to homo-aldol product formation. g Reaction
conducted at -24 °C for 20 h to avoid homo-aldol condensation. h Absolute
configuration determined by comparison of the optical rotation with literature
values. i Absolute configuration determined by X-ray crystallography after
reduction to the corresponding alcohol. j Absolute configuration determined
by comparison of optical rotation with literature values after transformation
to amino ester 9. k Absolute configuration determined by comparison of
optical rotation with literature values after transformation to epoxide 5.
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation. M.M. thanks
EU: HMPT-CT-2001-00317 for financial support. Thanks are
expressed to Dr. R. G. Hazell for performing X-ray analysis.
Scheme 1. Synthetic Transformations of R-Chloro Aldehydes
Supporting Information Available: Complete experimental pro-
cedures and characterization of novel compounds (PDF). This material
References
(1) See e.g.: ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
(2) For recent examples of catalytic enantioselective electrophilic chlorination
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3i as the catalyst afforded the corresponding optically active
R-bromo aldehyde in up to 80% ee. Under similar conditions the
R-iodination of 3-methylbutanal 1a using NIS proceeded in
quantitative yields and up to 24% ee. Furthermore, we have also
found that ketones can be R-chlorinated using NCS with, for
example, cyclohexanone affording R-chlorocyclohexanone with up
to 76% ee.
This novel enantioselective organocatalytic R-chlorination reac-
tion of aldehydes giving optically active R-chloro aldehydes
provides highly versatile chiral building blocks for a variety of
different synthetic transformations leading to optically active
compounds. Scheme 1 outlines several examples: Direct reduction
of the 2-chloro aldehydes 2 with NaBH4 affords the corresponding
2-chloro alcohols 4 in >90% yield without any decrease in optical
purity.
(3) For R-amination reactions, see: (a) Bøgevig, A.; Juhl. K.; Kumaragu-
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Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
(h) Bøgevig, A.; Sunde´en, H.; Co´rdova, A. Angew. Chem., Int. Ed. 2004,
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Furthermore, the 2-chloro alcohol 4c can be transformed into
the optically active terminal epoxide 5 by treatment with KOH.5
The versatile 2-chloro aldehydes 2 were also easily transformed
into R-chloro acids 6 after a brief (1-10 min) KMnO4 oxidation
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JA049231M
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J. AM. CHEM. SOC. VOL. 126, NO. 15, 2004 4791