Enesulfonamides as nucleophiles in catalytic asymmetric reactions

Article abstract of DOI:10.1002/anie.200605054

(Chemical Equation Presented) A biased copper-coin toss: Highly diastereo- and enantioselective copper-catalyzed addition reactions of enesulfonamides to α-keto aldehydes and azodicarboxylates have been developed. Low loadings of the chiral copper catalys

Full text of DOI:10.1002/anie.200605054

Angewandte
Chemie
DOI: 10.1002/anie.200605054
Synthetic Methods
Enesulfonamides as Nucleophiles in Catalytic Asymmetric Reactions**
Ryosuke Matsubara, Takashi Doko, Ryosuke Uetake, and Shu¯ Kobayashi*
Enamines and metalated enamines are useful as nucleophiles
in synthesis because of the resonance-donating property of
the nitrogen atom, which is greater than that of oxygen atoms,
thus they are more reactive than the enols and enolates.[1]
Asymmetric reactions of enamines and metalated enamines
have been reported. Yamada et al. first reported the chiral
nonracemic enamines 1 which were derived from ketones and
secondary amines[2] and subsequently several chiral enamines
such as 2, based on this concept, have been developed and
successfully employed.[3] Recently the research group of
Ellman reported the first use of metalated enamines 3 derived
from chiral N-sulfinylimines in addition reactions to alde-
hydes.[4] Since in this case primary sulfinamide-derived N-
sulfinylimines were employed, the products were b-hydroxy-
N-sulfinylketimines which could be reduced stereoselectively
to afford either the syn- or anti-1,3-amino alcohols.
report the first asymmetric nucleophilic addition reactions of
a wide range of readily prepared enesulfonamides.[7] The
enesulfonamides could be rapidly and efficiently synthesized
from the corresponding ketones and underwent smooth
reactions with a range of electrophiles such as ethyl glyox-
ylate, azodicarboxylate, and phenylglyoxal in stereoselective
fashion. The product sulfonylimines could be readily reduced
to the corresponding sulfonamides, which are important
functional groups in medicinal chemistry.[8]
Enesulfonamides were synthesized from the correspond-
ing ketones via the N-sulfonylimine intermediates
(Scheme 1).[9] Separation of the geometric isomers was
Scheme 1. Synthesis of the enesulfonamides (see the Supporting
Information for experimental procedure).
achieved by column chromatography on silica gel or recrys-
tallization.[10] In contrast to the enecarbamates, which were
synthesized from the corresponding nitriles or a,b-unsatu-
rated carboxylic acids,[6] a wide range of enesulfonamides
could be synthesized directly from the corresponding ketones
and sulfonamides by modification of a previously reported
method.[9]
Although high diastereoselectivity was observed in many
of the above cases, stoichiometric amounts of the chiral
component (as well as stoichiometric amounts of a strong
base to prepare the metalloenamines) were necessary.
Recently we reported the development of highly diastereo-
and enantioselective addition reactions of enecarbamates to
ethyl glyoxylate.[5] These reactions proceeded smoothly with
high selectivity in the presence of a catalytic amount of a
chiral Lewis acid, and was marked by a stereospecific
conversion of a-substituted ketone-derived enecarbamates
into 1,3-imino alcohols. Despite the importance of enecarba-
mates, direct methods of synthesizing enecarbamates from
the corresponding ketones have not been developed to the
same extent as other types of enamines or imines.[6] Herein we
The reaction of enesulfonamides with ethyl glyoxylate,
which was freshly distilled from a commercially available
solution of the polymer in toluene, was performed in the
presence of the complex formed between CuI and diimine
ligand 5. Our investigation began with a survey of the
electronic effect of the sulfonyl group of the enesulfonamide.
The proposed reaction mechanism involves an aza-ene-type
reaction, in which both the acidity of the sulfonamide
hydrogen atom and the electron density of the double bond
should affect the reaction rate. Accordingly, the reaction rates
of (Z)-enesulfonamides 4 with different sulfonyl groups were
measured and it was revealed that the enesulfonamide that
contained a p-methoxybenzenesulfonyl group was the most
reactive, while the reaction in the case of the enesulfonamide
that contained a p-chlorobenzenesulfonyl group was the
slowest. These results indicate that the reactivity of the system
is more strongly influenced by the electron density of the
double bond rather than by the acidity of the sulfonamide
hydrogen. The synthesis of methyl sulfonyl protected enesul-
fonamides failed under the same reaction conditions as were
used in the syntheses of the aryl sulfonyl protected enesulfon-
amides.
[*] R. Matsubara, T. Doko, R. Uetake, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo, The HFRE Division, ERATO
Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: ( +81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Science (JSPS).
We thank the Nissan Chemical Co., Ltd. for providing us with ligand
11.
To determine the diastereo- and enantioselectivity of the
reaction, 6a was hydrolyzed to the corresponding ketone 7a
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3047

Communications
under the conditions reported in Table 1, entry 1.[5] However,
the yield and diastereoselectivity were much lower than those
expected from the kinetic study shown in Figure 1. We
reasoned that isomerization of 6a to 8a might occur during
hydrolysis, thus leading to lower yields and diastereoselectiv-
ity.[11] Further investigation revealed that more concentrated
acidic conditions were necessary to accomplish hydrolysis of
imines without erosion of yield or selectivity (Table 1,
entry 2).
We next examined several enesulfonamides, and the
results are summarized in Table 2. Although an enesulfon-
amide with the p-methoxybenzenesulfonyl group on the
Table 1: Investigation of the conditions for the hydrolysis reaction.[a]
Table 2: Reactions of 4 with ethyl glyoxylate catalyzed by the complex
CuI–5.[a]
Entry Solvent
Acid
t [min] Yield [%][b] syn/
ee [%][d]
anti[c]
Entry
4
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
4
5
6
7
8
(E)-4a
(Z)-4a
(E)-4b
(Z)-4b
(Z)-4c
(E)-4d
(Z)-4d
(E)-4e
(Z)-4e
(Z)-4e
(E)-4 f
(Z)-4 f
(E)-4g
(Z)-4g
(E)-4h
(Z)-4h
4i
49
50
71
93
63
65
68
85
93
89
69
70
50
95
95
96
85
6:64
93:7
8:92
93:7
96:4
26:74
79:21
4:96
93:7
98:2
97
93
99
98
98
87
90
99
98
97
98
88
75
92
98
71
97
1
2
3
EtOH
(3 mL)
EtOH
(0.5 mL)
EtOH
(0.5 mL)
conc. HBr
(0.3 mL)
conc. HBr
(0.5 mL)
conc. HBr
(1 mL)
1.5
2.0
2.0
43
93
58
77:23 97
93:7
96:4
98
98
[a] Addition reactions were performed with ethyl glyoxylate (0.4 mmol)
and enesulfonamide 4 (0.2 mmol) in CH2Cl2 (3.0 mL) at 08C for 24 h in
the presence of the catalyst (5 mol%). Hydrolysis was performed at RT.
[b] Yield of isolated product 7a. [c] Determined by 1H NMR spectroscopy
after hydrolysis of 6a to 7a. [d] ee value of the major diastereomer of 7a
determined by HPLC analysis.
9
10[e]
11
12
13
14
15[g]
16
17
<1:>99[f]
87:13[f]
6:94
86:14
8:92
94:6
13:87
[a] All reactions were performed with ethyl glyoxylate (0.4 mmol) and
enesulfonamide 4 (0.2 mmol) in CH2Cl2 (3.0 mL) at 08C for 24 h in the
presence of the catalyst (5 mol%) unless otherwise stated. In all the
reactions, the pure geometric isomer of 4 was used. [b] Yield of isolated
ketone product 7. [c] Determined by 1H NMR spectroscopy after
hydrolysis of 6 to 7. [d] ee value of the major diastereomer of 7
determined by HPLC analysis. [e] Catalyst (0.2 mol%), CH2Cl2 (1.0 mL).
[f] Diastereomeric ratio of 6. [g] Reaction carried out at À208C.
nitrogen atom was found to be more reactive (Figure 1), it
was important to demonstrate the reactivity of enesulfon-
amides with other sulfonyl groups on the nitrogen atom
because the products obtained after reduction (see below)
retained the sulfonamide group that is often present in
druglike molecules. It was found that enesulfonamides with
sulfonyl groups other than p-methoxybenzenesulfonyl
reacted with ethyl glyoxylate to afford the adducts in good
Figure 1. Kinetic study using enesulfonamides with different sulfonyl
groups (red squares: R3 =p-methoxyphenyl (PMP), blue triangles:
R3 =p-tolyl, black circles: R3 =p-chlorophenyl). All reactions were
performed in CH2Cl2 at 08C in the presence of CuClO4·CH3CN
(5 mol%) and 5 (5.5 mol%) and the yields were determined by
1H NMR spectroscopy.
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yields with high selectivities (Table 2, entries 1–7). The
reactions proceeded stereoselectively: E enesulfonamides
gave anti adducts, whereas Z enesulfonamides gave syn
adducts with high diastereo- and enantioselectivities in most
cases.[12] The reaction was not limited only to aromatic
ketone-derived enesulfonamides (Table 2, entries 1–14) but
also could be effected with enesulfonamides derived from
aliphatic and cyclic ketones (Table 2, entries 15–17). More-
over, the catalyst loading could be reduced to as little as
0.2 mol% without loss of activity (Table 2, entry 11). It is
noteworthy that aliphatic ketone-derived enesulfonamides
could be directly synthesized from the corresponding ketones
in two steps, whereas the synthesis of aliphatic ketone-derived
enecarbamates needed several steps.[6]
high enantioselectivity [Eq. (2); Ar= 3,5-xylyl, Bn = benzyl,
MS = molecular sieves, Tf = trifluoromethanesulfonyl].
The reactions of enesulfonamides are more atom eco-
nomical than those of metal enolates as the initial imine-type
products 6 contain all the atoms that make up both the
substrates (ethyl glyoxylate and enesulfonamide).[13] The
sulfonylimine initially formed could be converted into the
corresponding sulfonamide by reduction. Accordingly, treat-
ment of 6e (synthesized from (Z)-4e) with NaBH4 afforded
the sulfonamide 9 stereoselectively (Scheme 2).
In summary, novel highly diastereo- and enantioselective
Cu-catalyzed addition reactions of enesulfonamides have
been developed. It has been shown that in the addition
reactions to ethyl glyoxylate we obtained high yields as well as
excellent diastereo- and enantioselectivities, even using only
0.2 mol% of the catalyst. In addition, the sulfonylimine thus
obtained could be reduced to the corresponding sulfonamide
diastereoselectively, thus providing access to chiral sulfon-
amides which are biologically important compounds. Phenyl-
glyoxal and azodicarboxylate were also found to be good
electrophiles in the nucleophilic addition of enesulfonamides.
Further investigations on the precise mechanism of this
reaction as well as the application of this methodology to the
synthesis of biologically active compounds are in progress.
Received: December 14, 2006
Published online: March 20, 2007
Keywords: asymmetric catalysis · copper ·
.
nucleophilic addition · sulfonamides · sulfonylimines
Scheme 2. Diastereoselective reduction of the sulfonylimine 6e.
NaBH4 (0.4 mmol) was added to a solution of 6e (0.2 mmol, the
crude product from the Cu-catalyzed addition) in MeOH (2.5 mL) at
À788C.
[1] a) Z. Rappoport, The Chemistry ofEnamines , Wiley, Chichester,
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Landesman, J. Szmuszkovicz, R. Terrell, J. Am. Chem. Soc. 1963,
85, 207.
The enesulfonamides also reacted with electrophiles other
than ethyl glyoxylate. Using the previously described proce-
dure, phenylglyoxal reacted with enesulfonamide 4b in the
presence of the CuI–diimine complex, to afford the 2-
hydroxy-1,4-diketone 10 in good yield with good selectivities
[Eq. (1)]. The amination of enesulfonamide (E)-4b using
[2] S. Yamada, K. Hiroi, K. Achiwa, Tetrahedron Lett. 1969, 10,
4233.
[3] a) J. dꢀAngelo, D. DesmaØle, F. Dumas, A. Guingant, Tetrahe-
dron: Asymmetry 1992, 3, 459, and references therein; b) T.
Schrader, R. Kober, W. Steglich, Synthesis 1986, 372.
[4] a) T. Kochi, J. A. Ellman, J. Am. Chem. Soc. 2004, 126, 15652;
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[6] For the synthesis of enecarbamates from nitriles, see: a) Y. Suen,
A. Horeau, H. B. Kagan, Bull. Soc. Chim. Fr. 1965, 5, 1454; from
a,b-unsaturated carboxylic acid, see: b) T. Mecozzi, M. Petrini,
azodicarboxylate was catalyzed by a CuII–diamine complex[14]
and provided the desired compound 12 in good yield with
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www.angewandte.org 3049

Communications
Synlett 2000, 73; c) A. M. Kanazawa, J.-N. Denis, A. E. Greene,
J. Org. Chem. 1994, 59, 1238.
much more crystalline than the other. See the Supporting
Information for details.
[11] Enesulfonamide 8a is partially hydrolyzed under the acidic
conditions, which caused both the yield and selectivity to
decrease once 8a is formed.
[12] Diastereoselectivity observed in this reaction can be explained
by the same transition-state model as in the reaction with
enecarbamates. See the Supporting Information.
[13] In a strict sense, a stoichiometric amount of titanium chloride
and potassium tert-butoxide were necessary to prepare the
enesulfonamides. An investigation of the synthesis of enesulfon-
amides using no or a catalytic amount of a metal reagent is
underway.
[7] For the non-asymmetric nucleophilic addition reactions of
enesulfonamides, see: a) T. J. Harrison, B. O. Patrick, G. R.
Drake, Org. Lett. 2007, 9, 367; b) T. J. Harrison, G. R. Drake,
Org. Lett. 2004, 6, 5023.
[8] For examples, see: a) J. Holenz et al., J. Med. Chem. 2005, 48,
1781; b) S. Joshi, N. Khosla, P. Tiwari, Bioorg. Med. Chem. 2004,
12, 571; c) T. Owa, A. Yokoi, K. Yamazaki, K. Yoshimatsu, T.
Yamori, T. Nagasu, J. Med. Chem. 2002, 45, 4913.
[9] S. Kato, S. Igami, JP 63250303A2 19881018, 1988 [Chem. Abstr.
1988, 111, 96854].
[10] In most cases, geometric isomers are separated by preparative
HPLC. Recrystallization is also effective when one isomer is
[14] R. Matsubara, S. Kobayashi, Angew. Chem. 2006, 118, 8161;
Angew. Chem. Int. Ed. 2006, 45, 7993.
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