Enantioselective addition of thioacetic acid to nitroalkenes via N-sulfinyl urea organocatalysis

Article abstract of DOI:10.1021/ja903351a

(Chemical Equation Presented) The highly enantioselective addition of thioacetic acid to nitroalkenes using a new sulfinyl urea organocatalyst is described. The addition of thioacetic acid proceeds in high yields and enantioselectivities for a variety of

Full text of DOI:10.1021/ja903351a

Published on Web 06/04/2009
Enantioselective Addition of Thioacetic Acid to Nitroalkenes via N-Sulfinyl
Urea Organocatalysis
Kyle L. Kimmel, MaryAnn T. Robak, and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received April 25, 2009; E-mail: jellman@uclink.berkeley.edu
Table 1. Optimization of Thioacetic Acid Addition
Asymmetric hydrogen-bonding organocatalysis is a burgeoning
field of exploration in organic chemistry.1 N-Sulfinyl ureas have
recently emerged as a successful new class of hydrogen-bonding
organocatalysts, in which the sulfinyl group can serve as an easily
tunable, chiral acidifying group.2 The sulfinyl moiety offers a
potential advantage over other acidifying groups in achieving
sufficient steric demand while simultaneously introducing chirality
and good catalyst solubility in nonpolar solvents. The utility of
N-sulfinyl urea catalysts has recently been demonstrated for the
aza-Henry reaction with enantioselectivities of 93-96% for a variety
of aryl and alkyl N-Boc imine substrates.2a To expand the scope
of N-sulfinyl urea catalysis, we chose to explore thioacetic acid
additions to nitroalkenes, where the only previous report4a gave
enantioselectivities ranging from 20 to 70% using Takemoto’s
thiourea organocatalyst 9.3-5 Notably, nitroalkene thioacid addition
products are versatile intermediates for the preparation of 1,2-
aminothiol derivatives, which are prevalent in biologically active
compounds such as penicillamine, penicillin, biotin, and sulcona-
zole, a clinically used azole antifungal drug.6 Herein we report that
appropriately substituted N-sulfinyl ureas catalyze the enantiose-
lective addition of thioacetic acid to a variety of nitroalkenes with
selectivities up to 96% ee and further demonstrate application of
the method to the first asymmetric synthesis of sulconazole.
.
mol %
catalyst
concn
(M)
equiv of
thioacid
ratioa
2a:1a:3
eeb
(%)
entry
1
2
3
4
5
6
7
2.0
2.0
2.0
2.0
5.0
0.5
5.0
0.4
0.1
0.4
0.4
0.4
0.4
0.1
2.0
2.0
1.0
5.0
2.0
2.0
2.0
71:0:29
86:4:10
42:55:3
32:0:68
85:0:15
42:25:33
82:12:6
87
90
88
82
87
80
90
a Product ratios were determined by 1H NMR analysis. b Enan-
tiomeric excess was determined by chiral HPLC.
Table 2. Catalyst Screen Under Optimized Conditions
In an initial catalyst screen, the N-trisylsulfinyl urea 4 was
identified as the most selective catalyst, promoting the addition of
thioacetic acid to trans-ꢀ-nitrostyrene (1a) with 87% ee in cyclo-
pentyl methyl ether (CPME) at -78 °C (Table 1, entry 1). At this
temperature no background reaction is observed; however, ∼30%
of byproduct 3 is produced. To minimize the production of 3, which
could arise via a Baylis-Hilman type mechanism, the catalyst
loading, substrate concentration, and equivalents of thioacetic acid
were optimized (Table 1). As expected, byproduct formation was
inhibited by lower reaction concentrations (entry 2), smaller excess
of thioacetic acid (entries 3 and 4), and increased catalyst loading
(entry 5). Under optimized conditions, the desired product was
formed in 82% yield with 90% ee with only 6% of byproduct 3
being produced (entry 7).
entry
catalyst
conva (%)
eeb (%)
1
2
3
4
5
6
7
4
5
6
7
8
9
10
86
89
99
99
99
99
65
90
80c
53
46
50
32c
68
a Conversion was determined by 1H NMR from the ratio of product
to starting material. b Enantiomeric excess was determined by chiral
HPLC. c Opposite enantiomer obtained as the major product.
The thioacetic acid addition reaction was evaluated with a range
of urea catalysts (Table 2, Figure 1). The N-trisylsulfinyl urea
diastereomer 5 (entry 2), the N-trisylsulfonyl urea 6, and both
diastereomers 7 and 8 of the corresponding N-tert-butanesulfinyl
urea resulted in lower selectivities. Sulfinyl urea 4 was then
compared with Takemoto’s catalysts 9 and 10, which contain the
achiral N-3,5-bis(trifluoromethyl)phenyl group and have proven to
be very effective catalysts for a number of transformations.5,7
Thiourea 9 resulted in a dramatic decrease in selectivity, and urea
10 resulted in only moderate enantioselectivity and poor conversion.
Sulfinyl catalyst 4 appears to possess the ideal steric demand,
acidity, and stereochemistry, whereas all other catalysts surveyed
lack at least one of these essential characteristics.
Figure 1. Catalysts tested in nitroalkene addition.
The scope of the reaction was then explored for both aromatic
and aliphatic nitroalkenes (Table 3). Electronic variation via para
substitution shows that more electron-deficient nitroalkenes (entries
2 and 3) provide a higher yield, while electron-rich derivatives
provide higher enantioselectivities (entries 4 and 5). Ortho substitu-
9
8754 J. AM. CHEM. SOC. 2009, 131, 8754–8755
10.1021/ja903351a CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Enantioselective Synthesis of (R)-Sulconazole
tion also results in an increase in enantioselectivity (entry 6).
Significantly, o,p-dichloro-trans-ꢀ-nitrostyrene, which can be con-
verted to sulconazole (vide infra), provides both high yield and
enantioselectivity (entry 2). Aliphatic nitroalkenes also undergo the
addition reaction in good yield for both linear (entries 7 and 8)
and branched (entry 9) substrates, although with somewhat reduced
enantioselectivity relative to the aryl substrates. The role of the
configuration of the N-sulfinyl stereocenter in the urea catalyst is
clearly complex because N-sulfinyl catalyst 5 provided the cyclo-
hexyl product 2i with higher selectivity (84% ee) than N-sulfinyl
catalyst 4 (70% ee), which was the preferred catalyst for all other
substrates (entries 1-8).
Table 3. Catalytic Enantioselective Addition of Thioacetic Acid to
Aromatic and Aliphatic Nitroalkenes
aminothiols in compounds of pharmaceutical interest, as demon-
strated by the expedient synthesis of R-sulconazole in 96% ee and
good overall yield.
Acknowledgment. This work was supported by the NSF (CHE-
0742565). M.T.R. thanks Eli Lilly for a graduate fellowship.
entry
R
product
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
73
84
88
65
65
63
64
82
95
90
96
85
91
93
94
78
80
84
Supporting Information Available: Complete experimental pro-
cedures, product characterization, and HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
o,p-Cl2C6H3
p-CF3C6H4
p-MeC6H4
p-MeOC6H4
o-MeC6H4
Me
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a Reactions were run with 5.0 mol % catalyst loading at 0.1 M
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asymmetric induction in sulfinyl urea catalysis, including the acidity,
steric size, electronics, solubility, and stereochemistry of the catalyst.
Based on mechanistic work by Takemoto and Jacobsen with similar
organocatalytic systems, the reaction presumably proceeds with
bifunctional organocatalysis, where the urea hydrogens activate the
nitroalkene via hydrogen bonding while the pendant amine depro-
tonates thioacetic acid.4a,5,7,8
The utility of the method was next demonstrated by the first
asymmetric synthesis of sulconazole from addition product 2b in
only four steps (Scheme 1). Reduction of the 1,2-nitrothiolate was
unprecedented in the literature and is complicated by thiol poisoning
of typical transition metal catalysts employed in nitro reduction.
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chloric acid, reduction of 2b was achieved with concomitant acyl
transfer to the amine, providing thiol amide 11 in 74% yield.
Alkylation of the unmasked thiol in 11 with benzyl bromide 12
followed by quantitative amide hydrolysis gave free amine 13 in
71% overall yield. Final condensation of amine 13 with glyoxal
and formaldehyde9 afforded R-sulconazole in 74% yield. The drug
was synthesized in 96% ee and 32% overall yield for the five steps
from ꢀ-nitrostyrene 1b.
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In conclusion, we have demonstrated that a sulfinyl urea
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of thioacetic acid to aromatic and aliphatic nitroalkenes. This
reaction can serve as a general method for preparing chiral 1,2-
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