Chiral amino ether-controlled catalytic enantioselective arylthiol conjugate additions to α,β-unsaturated esters and ketones: Scope, structural requirements, and mechanistic implications

Article abstract of DOI:10.1021/jo015879v

Asymmetric conjugate addition reaction of 2-trimethylsilylbenzenethiol with enoates and enones is catalyzed by a chiral amino ether-lithium thiolate complex and affords adducts with high enantioselectivity. Both the s-cis conformation and a steric wall at one side of the carbonyl group are structural requirements in substrates yielding adducts with high enantioselectivity. Reactions with tert-butyl enones gave addition products with high enantioselectivity. Construction of two contiguous chiral centers was possible by this addition-protonation sequence. Methyl tiglate was stereoselectively converted to a single syn-adduct of 95% enantiomeric excess (ee) bearing two contiguous chiral centers. Methyl 2-phenyl-2-butenoate was converted to a single syn-adduct of 95% ee, which was desulfurized to methyl 2-phenylbutanoate of 95% ee. These additions generate a transient lithium enolate that is protonated by a thiol anti to the C-S bond, giving the corresponding product having two adjacent stereocenters.

Full text of DOI:10.1021/jo015879v

J . Org. Chem. 2002, 67, 431-434
431
Ch ir a l Am in o Eth er -Con tr olled Ca ta lytic En a n tioselective
Ar ylth iol Con ju ga te Ad d ition s to r,â-Un sa tu r a ted Ester s a n d
Keton es: Scop e, Str u ctu r a l Requ ir em en ts, a n d Mech a n istic
Im p lica tion s
Katsumi Nishimura and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, J apan
tomioka@pharm.kyoto-u.ac.jp
Received J une 29, 2001
Asymmetric conjugate addition reaction of 2-trimethylsilylbenzenethiol with enoates and enones
is catalyzed by a chiral amino ether-lithium thiolate complex and affords adducts with high
enantioselectivity. Both the s-cis conformation and a steric wall at one side of the carbonyl group
are structural requirements in substrates yielding adducts with high enantioselectivity. Reactions
with tert-butyl enones gave addition products with high enantioselectivity. Construction of two
contiguous chiral centers was possible by this addition-protonation sequence. Methyl tiglate was
stereoselectively converted to a single syn-adduct of 95% enantiomeric excess (ee) bearing two
contiguous chiral centers. Methyl 2-phenyl-2-butenoate was converted to a single syn-adduct of
95% ee, which was desulfurized to methyl 2-phenylbutanoate of 95% ee. These additions generate
a transient lithium enolate that is protonated by a thiol anti to the C-S bond, giving the
corresponding product having two adjacent stereocenters.
In tr od u ction
methodology relies on nucleophilicity enhancement of a
thiol through lithiation and subsequent chelate formation
with an external chiral ligand.7 An arylthiol is activated
by way of lithiation-chelate formation with a chiral
amino ether and can be used as a sulfur Michael donor
in a catalytic asymmetric conjugate addition reaction
with cyclic and acyclic enoates.8 2-Substituted ben-
zenethiols were preferred nucleophiles for both their high
reactivity and enantioselectivity, and 2-trimethylsilyl-
benzenethiol reacted with methyl crotonate in toluene-
hexane at -78 °C, affording the corresponding sulfide
with excellent enantioselectivity (up to 97% ee).9 The
conjugate addition chemistry of a thiol was extended to
a catalytic enantioselective protonation reaction of a
transient lithium ester enolate.10,11 A transient lithium
ester enolate was further shown to be trapped with
aldehydes, yielding conjugate addition-aldol tandem
products.12,13 However, the range of enoates and thiols
is not wide and is limited. The current report summarizes
Efficient catalytic asymmetric conjugate addition of
achiral thiols to prochiral, activated olefins has been a
long-standing challenge of asymmetric reactions.1,2,3 Pio-
neering works by Wynberg and Mukaiyama revealed that
some chiral amines were moderate activators as well as
stereocontrollers of a thiol reaction with enones, yielding
conjugate addition products with moderate enantioselec-
tivity.4 The unsatisfactory efficiency of these approaches
is attributable to the imperfect reactivity of thiol acti-
vated by hydrogen bond formation with an amine, which
renders insufficient nucleophilicity to a thiol to allow the
reaction to proceed at lower temperatures. Recently
developed successful methodologies are classified into two
categories: nucleophilic activation of a thiol by metala-
tion5 and electrophilic activation of unsaturated carbonyl
compounds with chirally modified Lewis acids.6 Our
(1) Recent review for metal-catalyzed C-S bond formation: Kondo,
T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205-3220.
(2) For impressive enantioselective alkylation at the R-position of
sulfur, see: Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J .
Am. Chem. Soc. 2000, 122, 11340-11347. (b) Nakamura, S.; Naka-
gawa, R.; Watanabe, Y.; Toru, T. Angew. Chem., Int. Ed. 2000, 39,
353-355.
(3) Recently reported diastereoselective conjugate addition of thiol:
(a) Argade, A. B.; Haugwitz, R. D.; Devraj, R.; Kozlowski, J .; Fanwick,
P. E.; Cushman, M. J . Org. Chem. 1998, 63, 273-278. (b) Lin, C.-H.;
Yang, K.-S.; Pan, J .-F.; Chen, K. Tetrahedron Lett. 2000, 41, 6815-
6819. (c) Michieletto, I.; Fabris, F.; Lucchi, O. D. Tetrahedron:
Asymmetry 2000, 11, 2835-2841.
(4) (a) Hiemstra, H.; Wynberg, H. J . Am. Chem. Soc. 1981, 103, 417-
430. (b) Suzuki, K.; Ikegawa, A.; Mukaiyama, T. Bull. Chem. Soc. J pn.
1982, 55, 3277-3282. (c) Yamashita, H.; Mukaiyama, T. Chem. Lett.
1985, 363-366.
(5) (a) Manickam, G.; Sundararajan, G. Tetrahedron: Asymmetry
1997, 8, 2271-2278. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M.
J . Am. Chem. Soc. 1998, 120, 4043-4044. (c) Kinetic resolution: Emori,
E.; Iida, T.; Shibasaki, M. J . Org. Chem. 1999, 64, 5318-5320. (d) Node,
M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J . Am. Chem. Soc.
2000, 122, 1927-1936.
(6) (a) Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J . Am. Chem. Soc.
1999, 121, 8675-8676. (b) Saito, M.; Nakajima, M.; Hashimoto, S.
Chem. Commun. 2000, 1851-1852. (c) Saito, M.; Nakajima, M.;
Hashimoto, S. Tetrahedron 2000, 56, 9589-9594.
(7) (a) Tomioka, K. Synthesis 1990, 541-549. (b) Tomioka, K.;
Nagaoka, Y. In Comprehensive Asymmetric Catalysis; J acobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. III,
Chapter 31. (c) Tomioka, K. In Modern Carbonyl Chemistry; Otera,
J ., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 12.
(8) Tomioka, K.; Okuda, M.; Nishimura, K.; Manabe, S.; Kanai, M.;
Nagaoka, Y.; Koga, K. Tetrahedron Lett. 1998, 39, 2141-2144.
(9) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J . Am. Chem.
Soc. 1997, 119, 12974-12975.
(10) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew.
Chem., Int. Ed. Engl. 2001, 40, 440-442.
(11) For reviews on enantioselective protonation, see: (a) Fehr, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-2587. (b) Yanagisawa,
A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
(12) (a) Ono, M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetra-
hedron Lett. 1999, 40, 1509-1512. (b) Ono, M.; Nishimura, K.;
Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 1999, 40, 6979-6982.
10.1021/jo015879v CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/28/2001

432 J . Org. Chem., Vol. 67, No. 2, 2002
Nishimura and Tomioka
Ta ble 1. Asym m etr ic Rea ction w ith E- a n d Z-En oa tes
entry
1
R
temp (°C) time (h) yield (%) ee (%) R/S
F igu r e 1. s-Cis and s-trans conformations of (E)- and (Z)-
methyl crotonate and MM2 energy differences.
1
2
3
4
E
E
Z
Z
i-Bu -60
Bn -60
i-Bu -60/-40
Bn -60/-40
30
30
48/24
48/24
93
98
94
95
57
54
S
S
R
R
Sch em e 1. Asym m etr ic 1,4-Ad d ition s of a Th iol to
Con ju ga ted Ester s a n d En on es w ith F ixed
Con for m a tion sa
48
58a
a
(Z)-1 (R ) Bn) 32% and (E)-1 (R ) Bn) 7% were recovered.
our efforts to address the relationship between enanti-
oselectivity and reaction variables. One goal of the studies
was to define the essential structural features of the R,â-
unsaturated carbonyl compounds required for high enan-
tioselectivity in 1,4-addition of arylthiols.
Resu lts
s-Cis Con for m a tion Is Not th e On ly Requ ir em en t
of En oa tes. The chiral amino ether-lithium thiolate
complex 3-catalyzed asymmetric conjugate addition reac-
tion of 2-trimethylsilylbenzenethiol 2 took place on the
si-face of acyclic E-enoates 1 (R ) i-Bu, Bn) and gave the
corresponding products 4 having the (S) absolute config-
uration in reasonably high enantioselectivity (94 and
95%, Table 1, entries 1 and 2).
On the other hand, the reaction with the corresponding
Z-enoates 1 proceeded more slowly and gave (R)-4 of the
opposite absolute configuration in diminished enantiose-
lectivity (57 and 54%, entries 3 and 4). Although the
degree of enantioselectivity was not equivalent, the
direction of the facial selectivity was the same regardless
of which geometrical isomer was used. The thiolate
attacks E- and Z-enoates 1 on the same face, giving the
two enantiomers. This suggested that CdC and CdO
double bonds of the enoates retain the same geometrical
and positional relationships when the reaction takes
place. The diminished enantioselectivity of the Z-enoate
reaction is partially attributable to concomitant isomer-
ization of the starting Z-1 to the more stable E-1 and its
subsequent asymmetric conjugate addition. The isomer-
ized E-enoate was isolated in 7% yield along with 32%
recovery of the starting Z-enoate (entry 4). Regardless
of the geometry of 1, the same sense of enantiofacial
selectivity suggested involvement of the same reaction
mechanism. There are two possible conformations of
acyclic enoate 1 with regard to rotational preference of a
sigma bond connecting the CdC and CdO double bonds:
the s-cis and s-trans forms (Figure 1). Molecular mechan-
ics calculations on E- and Z-methyl crotonates indicated
a preference for the s-trans over the s-cis conformation.
Since the s-trans conformation of E- as well as Z-
enoates is generally more stable than the s-cis form, the
a
In the reactions with E-9, E-11, and E-13, small amounts (less
than 10%) of the diastereomers were formed.
present asymmetric reaction might be expected to pro-
ceed through the s-trans conformation. Chamberlin and
Reich provided a precedent and successfully demon-
strated that hydride reduction of enones resulted in
stereoselective enolate formation with retention of the
conformational preference of the starting s-cis and s-trans
forms of enones.14 Since the Curtin-Hammet principle
is operative here,15 it is important to examine reactions
with enoates and enones having fixed s-trans and s-cis
conformations.
The reaction of 2-TMS-benzenethiol 2 with 5H-furan-
2-one 5 and 6,6-dimethylcyclohex-2-enone 7 of fixed
s-trans conformation proceeded quite smoothly at -78
°C, but gave the adducts 6 and 8 with low enantioselec-
tivities (7 and 23%, respectively; Scheme 1). These
selectivities were lower than those of (Z)-1 and (Z)-2,2-
dimethylhex-4-en-3-one. The reaction of 4-tert-butylben-
(13) Related studies recently reported by other groups: (a) Ka-
mimura, A.; Mitsudera, H.; Asano, S.; Kidera, S.; Kakehi, A. J . Org.
Chem. 1999, 64, 6353-6360. (b) Dinon, F.; Richards, E.; Murphy, P.
J .; Hibbs, D. E.; Hursthouse, M. B.; Abdul Malik, K. M. Tetrahedron
Lett. 1999, 40, 3279-3282. (c) Mitsudera, H.; Kakehi, A.; Kamimura,
A. Tetrahedron Lett. 1999, 40, 7389-7392. (d) Yang, X.-F.; Hou, X.-L.;
Dai, L.-X. Tetrahedron Lett. 2000, 41, 4431-4434. (e) J auch, J . J . Org.
Chem. 2001, 66, 609-611.
(14) Chamberlin, A. R.; Reich, S. H. J . Am. Chem. Soc. 1985, 107,
1440-1441.
(15) Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S.
H., Mander, L. N., Eds.; Wiley-Interscience: New York, 1994; Chapter
10-5, pp 647-655.

Enantioselective Arylthiol Conjugate Additions
J . Org. Chem., Vol. 67, No. 2, 2002 433
zenethiol with 7 proceeded under the same conditions
and gave the adduct 8 (Ar ) 4-t-BuC6H4) in a slightly
better 40% ee. The reaction with cyclohex-2-enone was
not efficient and afforded the addition product of low ee.
The poor selectivity indicated that the more selective
asymmetric 1,4-addition might proceed through the s-cis
and not the s-trans conformation.
However, it was surprising to find that the reaction of
3-(E)-ethylidenedihydrofuran-2-one, the fixed s-cis com-
pound 9, gave the expected syn-product 10 in 90% yield,
but in only 30% ee. Another fixed s-cis compound, 2-(E)-
butylidene-3,4-dihydro-2H-naphthalen-1-one 11, was con-
verted to the syn-product 12 in 89% yield and 59% ee.
The higher enantioselectivity observed in the latter
reaction is attributable to the steric bulk around the
carbonyl oxygen atom, especially at the side opposite to
the olefin moiety. The greater steric hindrance of a
methyl group in 13 instead of a proton in 11 markedly
improved the enantioselectivity. Thus, the reaction of
2-(E)-butylidene-3,4-dihydro-8-methyl-2H-naphthalen-1-
one 13 proceeded smoothly at -78 °C and gave the
expected syn-product 14 of 94% ee in 99% yield. Simi-
larly, the reaction of 6-(E)-ethylidene-2,2-dimethylcyclo-
hexanone 15 bearing steric bulk at one side of the
carbonyl group gave the syn-product 16 of 83% ee in 99%
yield. The similar steric bulk in the s-trans enone 7 was
not effective for increasing the enantioselectivity.
The dependence of enantioselectivity on the steric bulk
of the s-cis R′-substituent indicated that the more selec-
tive asymmetric reaction proceeds through the s-cis
conformation. Furthermore, steric hindrance around the
carbonyl oxygen, especially at the side opposite to the
reacting olefin moiety, is a critical requirement for high
enantioselectivity. Lone pair-differentiating coordination
of the carbonyl oxygen with the lithium cation of the
reacting thiolate at the syn-site of the olefin is a mecha-
nistic implication for high enantioselectivity. A methyl
group locked in this position may provide such a steric
wall for the carbonyl oxygen of crotonic methyl esters
(Figure 1).16
Asym m etr ic Rea ction w ith Acyclic En on es. The
asymmetric addition reaction of 2-substituted benzeneth-
iol with acyclic enones was examined as a touchstone to
clarify the steric requirements for high enantioselectivity
as described above. Four enones 17-20 bearing methyl,
phenyl, trityl, and tert-butyl terminal groups attached
at the carbonyl function were examined as substrates
(Figure 2). Molecular mechanics calculations indicated
that the s-trans form is more stable than the s-cis form
by a factor of 0.43 kcal/mol in the case of 17, while both
forms were equally stable for 18 bearing a phenyl group.
It is reasonable that the bulky trityl and tert-butyl
substituents of 19 and 20 favored the s-cis conformation
by over 1.4 kcal/mol because of steric repulsion of these
groups with the â-vinylic proton. The analysis suggested
that the tert-butyl enone 20 would be the best substrate
for a highly enantioselective 1,4-addition because of the
tendency to adopt the s-cis conformation and the effective
blocking of one coordination site of the carbonyl oxygen
lone pairs.
F igu r e 2. MM2 energy differences of enones and asymmetric
addition of 2 to enones.
F igu r e 3. Asymmetric addition of 2 with enones.
the corresponding ketones quantitatively. The enanti-
oselectivity varied in the range from 68 to 92%. The
highest ee was obtained with tert-butyl enone 20, as
expected. In contrast, the trityl enone 19 showed the
lowest (68%) selectivity, possibly because of the unfavor-
able steric hindrance by the large phenyl substituents
to enantiofacial selection. The s-cis conformation, lone
pair-differentiating coordination of the carbonyl oxygen,
and appropriate bulkiness of the substituent attached to
the carbonyl group emerged as crucial factors for high
enantioselectivity in these 1,4-additions.
High selectivity of the tert-butyl enone 22 was also
observed (90% ee) as compared with 77% ee for the
phenyl enone 21 (Figure 3). However, the Z-enone 23
gave an adduct of only 31% ee, antipodal to the product
obtained from 22. The (R) absolute configuration of the
product, (+)-(R)-26, obtained from enone 20 was cor-
related with the analogous 1,4-adduct (+)-24 of methyl
cinnamate.
Deter m in a tion of th e Absolu te Ster eoch em istr y
of ter t-Bu tyl Keton e. Reports on the synthesis and
biological activity of carbonyl compounds bearing a C-S
bond at the â position are widespread and testify to the
increasing value of these subunits in organic synthesis.17
The TMS grouping of (+)-24, obtained by reaction of 2
with methyl cinnamate in the presence of 8 mol % of 3,
was protodesilylated with triflic acid to give the product
in 98% yield (Scheme 2). Treatment with ethanol-
hydrochloric acid converted the methyl ester to the ethyl
ester (+)-R-25, the absolute configuration of which has
already been established.18 The ester function of (+)-R-
24 was then reduced with DIBALH in toluene to an
The reactions of 2-TMS-benzenethiol 2 with the four
enones 17-20 proceeded smoothly at -78 °C and gave
(17) Chiral benzothiazepin such as diltiazem is a typical example
of biologic potency: Kugita, H.; Inoue, H.; Ikezaki, M.; Takeo, S. Chem.
Pharm. Bull. 1970, 18, 2028-2037.
(18) Dike, S. Y.; Ner, D. H.; Kumar, A. Bioorg. Med. Chem. Lett.
1991, 1, 383-386.
(16) Shambayati, S.; Schreiber, S. L. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 1, Chapter 1.10, pp 283-324.

434 J . Org. Chem., Vol. 67, No. 2, 2002
Nishimura and Tomioka
THF to an alcohol of established stereochemistry.19
Similarly, reaction with 27b quantitatively gave 29b of
95% ee, after 33 h at -78 °C. Desulfurization20 of 29b
gave methyl (S)-2-phenylbutanoate 3021 in 95% ee and
88% yield. The relative configuration of 29b was deter-
mined by oxidation and subsequent thermal elimination
of the sulfoxide.22 Desulfurization of 14 gave ketone 31
of 88% ee, the absolute configuration of which was
established by circular dichroism.
Sch em e 2. Deter m in a tion of th e Absolu te
Con figu r a tion by Ch em ica l Cor r ela tion
Thiolate addition to 27 produced the transient lithium
enolate 28, which was protonated by thiol 2 in a mode
anti to the C-S bond giving 29.23 The anti-protonation
is mainly governed by the conformation 28 of the enolate,
not by the chiral amino ether ligand.22,24 In the absence
of the chiral ligand at -60 °C in THF, 27b was converted
to racemic 29b as the sole product in 94% yield. The sense
of asymmetric induction in the protonation step was
predicted to proceed anti to the newly generated C-SAr
bond of the stable conformation 28.
Sch em e 3. Asym m etr ic 1,4-Ad d ition Rea ction
Con clu sion
Asymmetric conjugate addition reactions of thiols with
an activated olefin are catalyzed by a chiral amino ether-
lithium thiolate to afford the corresponding adducts with
high enantioselectivity. A lone pair-differentiating coor-
dination has emerged as an important mechanistic
consideration on the basis of conformational and steric
requirements of the activated olefin.
Ack n ow led gm en t. This research was supported by
a Grant-in-Aid for Scientific Research on Priority Areas
(A) “Exploitation of Multi-Element Cyclic Molecules”
from the Ministry of Education, Culture, Sports, Science
and Technology, J apan. K.N. was supported by a fel-
lowship from the J SPS and a research grant from
Ajinomoto Co., Ltd.
aldehyde, which was then tert-butylated with tert-butyl-
magnesium chloride in THF to afford a mixture of two
diastereomeric alcohols. Oxidation with DMSO-oxalyl
chloride gave a ketone (+)-26 without any loss of enan-
tioselectivity. The asymmetric 1,4-addition of 2-TMS-
benzenethiol 2 to enone 20 gave (+)-26 of 92% ee, the
absolute configuration of which was thus correlated with
the ester (+)-R-25. The absolute configurations of the
other esters and ketones were analogously assigned.
Asym m et r ic 1,4-Ad d it ion s t o R,â-Disu b st it u t ed
En oa tes. The chiral ligand-lithium thiolate complex
3-catalyzed 1,4-addition of thiol 2 to enones E-13 and 15
enantio- and diastereoselectively produced 14 and 16
bearing two contiguous chiral carbons (Scheme 1). A high
level of stereocontrol is operative in this addition-
protonation sequence not only for cyclic enones but also
for acyclic enoates. Thus, reaction with methyl tiglate 27a
proceeded at -20 °C giving 29a of 95% ee as the sole
product and in quantitative yield after 20 h (Scheme 3).
The absolute and relative configurations were con-
firmed by reduction with lithium aluminum hydride in
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure and spectroscopic and analytical data for the
products. This material is available free of charge via the
Internet at http://pubs.acs.org/.
J O015879V
(19) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T. Tetrahedron
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(20) Node, M.; Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, H.;
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(21) Sato, T.; Otera, J .; Nozaki, H. J . Org. Chem. 1992, 57, 2166-
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(22) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.; Date, T.;
Okamura, K.; Inagaki, S. J . Org. Chem. 1991, 56, 6556-6564.
(23) An allylic strain model for diastereofacial differentiation in the
alkylation of enolates: Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga,
K. J . Am. Chem. Soc. 1988, 110, 3597-3601.
(24) Mohrig, J . R.; Rosenberg, R. E.; Apostol, J . W.; Bastienaansen,
M.; Evans, J . W.; Franklin, S. J .; Frisbie, C. D.; Fu, S. S.; Hamm, M.
L.; Hirose, C. B.; Hunstad, D. A.; J ames, T. L.; King, R. W.; Larson, C.
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