Enantioselective Lewis Acid-Catalyzed Mukaiyama-Michael Reactions of Acyclic Enones. Catalysis by allo-Threonine-Derived Oxazaborolidinones

Article abstract of DOI:10.1021/jo035379x

allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2 -oxazaborolidin-5-ones 1g,n catalyze the asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of 2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve high enantioselectivity in these reactions. The effects of the additives are discussed in terms of the retardation of an Si⁺-catalyzed racemic pathway, which seriously deteriorates the enantioselectivity of asymmetric Mukaiyama-Michael reactions. A working model for asymmetric induction is proposed based on correlation between catalyst structures and enantioselectivities.

Full text of DOI:10.1021/jo035379x

En a n tioselective Lew is Acid -Ca ta lyzed Mu k a iya m a -Mich a el
Rea ction s of Acyclic En on es. Ca ta lysis by a llo-Th r eon in e-Der ived
Oxa za bor olid in on es
Xiaowei Wang, Shinya Adachi, Hiroyoshi Iwai, Hiroshi Takatsuki, Katsuhiro Fujita,
Mikako Kubo, Akira Oku, and Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, J apan
harada@chem.kit.ac.jp
Received September 20, 2003
allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2-oxazaborolidin-5-ones 1g,n catalyze the
asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal
in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael
acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of
2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve
high enantioselectivity in these reactions. The effects of the additives are discussed in terms of the
retardation of an Si+-catalyzed racemic pathway, which seriously deteriorates the enantioselectivity
of asymmetric Mukaiyama-Michael reactions. A working model for asymmetric induction is
proposed based on correlation between catalyst structures and enantioselectivities.
The Michael addition reaction stands for the most
straightforward methods for constructing 1,5-dicarbonyl
skeletons and is regarded as a fundamental method in
organic synthesis.1 Recently, much attention has been
focused on the enantioselective version of this reaction.2
Significant advances have been made in direct Michael
reactions involving in situ generation of enolate anions.3,4
To this approach, however, nucleophilic partners of the
reaction are limited to readily enolizable carbonyl com-
pounds such as active methylene compounds.
The Mukaiyama-Michael reaction in which silyl ketene
acetals and enolsilanes are used as nucleophiles is well
recognized to be a powerful and reliable method for the
preparation of various types of 1,5-dicarbonyl com-
pounds.5 In comparison with the great success of the chi-
ral Lewis acid catalysis in mechanistically related asym-
metric Mukaiyama aldol reactions, only limited advances
have been made toward the enantioselective version of
the Mukaiyama-Michael reaction.6,7 Kobayashi et al.
have reported the highly enantioselective reaction for
cyclopent-2-enone by using a BINOLate titanium(IV)
complex.6a Recently, Evans et al. demonstrated the utility
of chiral bis(oxazoline) copper(II) catalysts for the reac-
tion of bidentate Michael acceptors such as alkylidene
malonates and alkenoyl oxazolidinones.6g-k Most recently,
the enantioselective organocatalytic reaction of enals with
siloxy furans has been developed by MacMillan et al.7
Despite these advances, the asymmetric Michael reaction
to simple acyclic enones leading directly to enantiopure
1,5-dicarbonyl compounds remains a challenging issue
in this field.6l
* Corresponding author.
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon Press: Oxford, UK, 1992.
(2) Review: (a) Tomioka, K.; Nagaoka, Y. In Comprehensive Asym-
metric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 3, Chapter 31.1. (b) Kanai, M.;
Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
(6) (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem.
Lett. 1994, 97. (b) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron
Lett. 1996, 37, 8921. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti,
S.; Scolastico, C. Tetrahedron 1997, 53, 13009. (d) Kitajima, H.; Ito,
K.; Katsuki, T. Tetrahedron 1997, 53, 17015. (e) Kitajima, H.; Katsuki,
T. Synlett 1997, 568. (f) Nishikori, H.; Ito, K.; Katsuki, T. Tetrahedron:
Asymmetry 1998, 9, 1165. (g) Evans, D. A.; Rovis, T.; Kozlowski, M.
C.; Tedrow, J . S. J . Am. Chem. Soc. 1999, 121, 1994. (h) Evans, D. A.;
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Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J .
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Zhang, F.-Y.; Corey, E. J . Org. Lett. 2001, 3, 639. (m) Desimoni, G.;
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Ed.; Wiley: New York, 2000;
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Synthesis 2001, 171.
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Hirama, M. J . Org. Chem. 1996, 61, 3520. (b) Harada, S.; Kumagai,
N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J . Am. Chem. Soc.
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10.1021/jo035379x CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003
10046
J . Org. Chem. 2003, 68, 10046-10057

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
SCHEME 1
SCHEME 2
F IGURE 1.
ally related Mukaiyama-aldol reaction.8 It may be more
serious in the asymmetric Michael reaction.
Herein we wish to report that (L)-allo-threonine derived
oxazaborolidinones 1g and 1n are efficient catalysts for
the asymmetric Mukaiyama-Michael reaction of simple
acyclic enones. The use of 2,6-diisopropylphenol and tert-
butyl methyl ether as additives is found to retard the
undesirable Si+-catalyzed racemic pathway efficiently,
leading to enantioselective formation of various γ-ke-
toacid thiol esters.9
Resu lts a n d Discu ssion
Molecu la r Design a n d Syn th esis of a llo-Th r eo-
n in e-Der ived OXB. In the present study, we focused
on a new N-sulfonyl-1,3,2-oxazaborolidin-5-one (OXB)
catalyst10 1 derived from allo-threonine (Figure 1). Previ-
ously reported X-ray11 and calculated12 structures of
related OXBs show that the heterocyclic ring is almost
planar and the SO2-R2 bond is nearly perpendicular to
this plane at the bottom face.13 The rotation around the
C(4)-C(1′) bond is expected to be fixed as depicted in
Figure 1 by the methyl group (C(2′)H3) because of
unfavorable interaction between the sulfonyl oxygen
atom, O(A), and the methyl (or O-acyl) group in an
alternative conformer. Accordingly, the acyloxy group is
anticipated to reside at the top face of the ring. If we
assume a top-face coordination of enones, the chiral
environment around the enones could be optimized by
modifying the structure of the acyl group in OXBs. It is
also anticipated that slight deviation from the planarity
for the bond rotation around the C(1′)-O and the
adjacent O-COR1 bonds would make the acyloxy moiety
Two major difficulties to be overcome are conceivable
in the asymmetric Mukaiyama-Michael reaction of acy-
clic enones. There are four possible coordination modes
of an acyclic enone to a chiral Lewis acid (ML*n) (Scheme
1). Except for the sterically congested s-cis-syn isomer,
three other isomers are all feasible structures for acti-
vated complexes. Since the enantiotopic faces of the
coordinating enone at the olefinic carbons are opposite
between the s-cis and s-trans isomers, the reaction is
required to proceed selectively through one of these
activated complexes. The second problem is a competing
silyl cation-catalyzed racemic pathway that may cause
reduction in enantioselectivity (Scheme 2). Coordination
of an enone by a chiral Lewis acid to form activated
complex A followed by addition of a silyl ketene acetal
gives rise to intermediate B. For the regeneration of the
Lewis acid catalyst ML*n, the silyl group attached to a
carbonyl oxygen atom needs to migrate to a remote
enolate oxygen atom. Alternatively, the silyl group of B
could be transferred to the starting enone to form another
activated complex C, leading to the silyl cation catalyzed
racemic pathway through intermediate D. The pathway
may cause a severe decrease in overall enantioselectivity.
A similar problem has been reported for the mechanistic-
(8) (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35,
4323-4326. (b) Carreira, E. M.; Singer, R. A.; Lee, W. J . Am. Chem.
Soc. 1994, 116, 8837-8838. (c) Hollis, T. K.; Bosnich, B. J . Am. Chem.
Soc. 1995, 117, 4570-4581.
(9) For a preliminary report of the work described here, see: (a)
Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A. Org.
Lett. 2001, 3, 2101. (b) Wang, X.; Harada, T.; Iwai, H.; Oku, A. Chirality
2003, 15, 28.
(10) (a) Takasu, M.; Yamamoto, H. Synlett 1990, 194. (b) Sartor,
D.; Saffrich, J .; Helmchen, G. Synlett 1990, 197. (c) Kiyooka, S.-i.;
Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J . Org. Chem. 1991,
56, 2276. (d) Corey, E. J .; Loh, T.-P. J . Am. Chem. Soc. 1991, 113,
8966. (e) Kinugasa, M.; Harada, T.; Oku, A. J . Org. Chem. 1996, 61,
6772. (f) For leading references, see: Ishihara, K.; Kondo, S.; Yama-
moto, H. J . Org. Chem. 2000, 65, 9125.
(11) Vedejs, E.; Chapman, R. W.; Lin, S.; Muller, M.; Powell, D. R.
J . Am. Chem. Soc. 2000, 122, 3047.
(12) Salvatella, L.; Ruiz-Lo´pez, F. J . Am. Chem. Soc. 1999, 121,
10772 and references therein.
(13) For
a nomenclature of top and bottom faces of OXB, see:
Kaneko, Y.; Kiyooka, S. Kochi Daigaku Rigakubu Kiyo, Kagaku 1994,
15, 9.
J . Org. Chem, Vol. 68, No. 26, 2003 10047

Wang et al.
TABLE 1. OXB-Ca ta lyzed Mich a el Rea ction of
Ben za la ceton e (4a ) w ith Silyl Keten e Aceta l 5a
flexible, allowing the space for the structural change in
the transition state of the Michael reaction.
methoda
yield (%)
ee (%)
A variety of O-acyl-N-sulfonyl-(L)-allo-threonines 3a -k
were prepared starting from (L)-allo-threonine. Except
for 3d ,j,k ,14 these ligands were synthesized by N-tosyl-
ation of the amino acid under Schotten-Baumann condi-
tions and esterification with benzyl alcohol followed by
O-acylation of the resulting monoesters 2 and hydro-
genolysis of the benzyl ester moiety (eq 1). Treatment of
entry
OXB
mol %
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1g
8a
8b
20
10
20
40
100
20
A
A
B
B
B
A
A
A
94
97
79
76
85
88
86
90
7
18
14
32
53
10
8
20
20
<5
a
Method A: a mixture of 4a (0.5 M), 5a (1.5 equiv), and 1a ,g
in CH2Cl2 was stirred for 1 h at -78 °C. Method B: To a solution
of 5a (1.5 equiv, 0.75 M) and 1a in CH2Cl2 at -78 °C was added
a CH2Cl2 solution of 4a (0.25 M) over 4 h.
benzalacetone (4a ) with trimethylsilyl ketene S,O-acetal
5a proceeded smoothly at -78 °C to give enolsilane 6a
as an initial product, which was hydrolyzed under acidic
conditions to give Michael adduct 7a in high yield without
enantioselectivity (eq 3, entry 1 in Table 1). OXB 1a , as
well as O-(2-naphthoyl) derivative 1g, did not give
advantageous results over other conventional OXBs
8a ,b10,15 (entries 7 and 8 vs 1 and 6). Slight improvement
of the enantioselectivity was observed when the reaction
was carried out by slowly adding enone 4a to a mixture
of 5a and 1a (entries 3-5). The observed effect of slow
addition suggests intervention of a Si+-catalyzed racemic
pathway (Scheme 2), which was retarded to some extent
by transformation of enolborate intermediate B (ML*n
) OXB) to the product during slow addition of the enone.
With anticipation that a sterically hindered Lewis base
could act as a silicon shuttle8b to retard the Si+-pathway
(Scheme 3), reactions were carried out in the presence
of pyridine derivatives. In the presence of 2,6-di-tert-
butylpyridine (0.2 equiv), the reaction of 1a and 4a , under
the conditions similar to those of entry 4 (Table 1), gave
7a of 48% ee in 39% yield. The use of less bulky
2,6-lutidine (0.2 equiv) as an additive, on the other hand,
exhibited higher ee of 69% albeit with lower product yield
(20%). When a similar reaction was carried out for 15 h
after accomplishment of the slow addition, 7a was
obtained in higher yield (58%) but with lower enantiose-
lectivity (50% ee). More hindered 2,6-di-tert-butylpyridine
seems to be less efficient in capturing the Si+ species in
comparison with 2,6-lutidine, which, however, may also
ligands 3 with aryldihaloboranes in CH2Cl2 followed by
removal of HX (X ) Cl, Br) and the solvent in vacuo gave
the corresponding OXB 1a -q (eq 2).15 In several cases,
1
clean formation of the complexes was ascertained by H
NMR analysis. A relatively small coupling constant (J
) ca. 2 Hz) observed between H(4) and H(1′) is consistent
with the anticipated structure in Figure 1.
Op tim iza tion of Rea ction Con d ition s. In the pres-
ence of O-benzoyl-OXB 1a (20 mol %), the reaction of
(15) Kinugasa, M.; Harada, T.; Egusa, T.; Fujita, K.; Oku, A. Bull.
Chem. Soc. J pn. 1996, 69, 3639.
(14) For the preparation of 3d ,j,k , see the Experimental Section.
10048 J . Org. Chem., Vol. 68, No. 26, 2003

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
SCHEME 3a
TABLE 2. Effect of P h en olic Ad d itives in th e
OXB-Ca ta lyzed Rea ction of 4a w ith 5a
entry OXB
phenolic additive
equiv yield (%) ee (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1g
1g
1g
1g
1g
76
52
76
80
61
74
76
89
43
81
77
88
32
5
10a : R ) iPr, R′ ) H
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
3.0
3.0
3.0
10b: R, R′ ) Me
21
50
45
48
24
64
81
74
81
79
10c: R, R′ ) iPr
10d : R, R′ ) sBu
10e: R, R′ ) Ph
10f: R ) tBu, R′ ) Me
10c
10c
10c
10c
10c
10b
11b,c
12b,d
a
BL*3 ) OXB 1, Si ) TMS.
SCHEME 4a
a
Unless otherwise noted, reactions were carried out at -78 °C
by adding a CH2Cl2 solution of 4a (0.5 M) and 10 to a CH2Cl2
solution of OXB 1a ,g (40 mol %, 0.1 M) and 5a (1.5 equiv) over 4
b
h. 3 equiv of 5a were used. c Reaction was carried out at 0.2 M
d
of 1g. OXB 1g (20 mol %) was used.
encumbered 10c reacts with the catalyst in the absence
of enone 4a .
In the presence of diisopropylphenol 10c (1 equiv),
2-naphthoyl OXB 1g exhibited a higher ee of 65% (entry
8). Increasing the amount of the phenol brought about a
further improvement in enantioselectivity albeit with a
significant lowering of the product yield (entry 9). The
GC analysis of the aliquots from the reaction mixture of
this reaction showed consumption of the nucleophile 5a
before the completion of slow addition. A separate experi-
ment in which phenol 10c was treated with 5a (1.5 equiv)
in the presence of 1g (20 mol %) at -78 °C gave tri-
a
BL*3 ) OXB 1, Si ) TMS.
act as a catalyst poison through complexation at the
boron atom. The use of diethyl ether as an additive did
not cause any effect on either the enantioselectivity or
the product yield.
i
methylsilyl phenol 11 (R, R′ ) Pr) quantitatively, in-
dicating that the OXB also catalyzes silylation of the
phenol with the silyl ketene acetal. The lower conversion
observed in entry 9 is most probably due to the competing
consumption of 5a by this reaction. Indeed, full conver-
sion of the enone while keeping the level of enantiose-
lectivity was achieved by using 3 equiv each of 5a and
the phenol (entry 10). The better result of 81% ee was
obtained when the reaction was conducted at higher con-
centration (0.2 M) of the catalyst (entry 11). The reaction
with 20 mol % of the catalyst afforded the comparable
ee as well as the high chemical yield (entry 12).
Effect of Eth er ea l Ad d itive. Although diethyl ether
alone was not effective in retarding the undesirable Si+-
catalyzed racemic pathway (vide supra), the additive was
found to be advantageously used in combination with
phenol 10c especially in the reaction without an excess
amount of the phenol (Table 3). Even 0.4 equiv of diethyl
ether exhibited improved enantioselectivity in the reac-
tion, using OXB-catalyst 1g (20 mol %) with 1.0 equiv of
10c (entry 2 vs 1). The enantioselectivity was improved
by the increase of the amount of the additive, reaching
almost plateau values in the presence of >1.6 equiv of
diethyl ether (entries 2-6). When diethyl ether was used
as a solvent, the reaction became heterogeneous, result-
ing in lower ee and product yield (entry 7).
An alternative approach to the retardation of the Si+
pathway may involve the use of a hydroxyl compound as
an additive (Scheme 4).16 Thus, a phenol as an additive
would react with intermediate 9 to give adduct 7a and
the corresponding silyl phenol 11 with simultaneous
regeneration of catalyst 1. Reactions were carried out by
adding a solution of enone 4a and several phenols (10a -
f) to a solution of OXB catalyst 1a (40 mol %) and 5a
(Table 2, entries 2-7). Of the 2,6-disubstituted phenols
examined, sec-alkyl derivatives 10c,d and phenyl deriva-
tive 10e exhibited improved enantioselectivity of ca. 50%
ee without lowering the product yield. For these reac-
tions, GC analysis of the crude reaction mixture before
acid treatment showed the formation of Michael adduct
7a and the corresponding silyl phenol 11 together with
enolsilane 6a and the starting phenol. Both the sterically
less demanding phenols 10a ,b and the more hindered
phenol 10f, on the other hand, showed reduced enantio-
selectivity. In the later reaction, no silylation of the
phenol was observed in the GC analysis of the crude
reaction mixture, suggesting that Si+-trap was sterically
hampered. Lower enantioselectivity observed for 10a ,b
can be understood if we assume that these phenols react
with OXB 1a competitively to reduce the amount of active
catalyst. No reaction was observed when 4a was added
to a solution of OXB 1a , 5a , and 2,6-diisopropylphenol
(10c). The observation implies that even sterically more
Reactions with several ethereal additives (2 equiv) and
the addition time of 6 h revealed that the effect is
sensitive to their structures (entries 8 and 10-13).
Anisole as an additive gave lower enantioselectivity.
Nonselective reaction was observed when relatively more
basic THF was used (entry 10). Of ethers examined,
tBuOMe exhibited the highest ee of 83% (entry 13). It
(16) Hexafluoro-2-propanol, which has been reported to be an
effective additive for a similar purpose,6d,h did not give us improved
enantioselectivity.
J . Org. Chem, Vol. 68, No. 26, 2003 10049

Wang et al.
SCHEME 5a
TABLE 3. Effect of Eth er ea l Ad d itive in th e
Asym m etr ic Mich a el Rea ction of 4a Ca ta lyzed by
OXB 1ba
entry 1b (mol %) additive (equiv) timeb (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
9d
20
20
20
20
20
20
20
20
10
20
20
20
20
10
4
4
4
4
4
4
4
6
6
6
6
6
6
6
64
71
53
84
86
82
45
87
79
71
73
84
84
91
63
69
72
74
77
74
64
81
76
2
Et2O (0.4)
Et2O (0.8)
Et2O (1.6)
Et2O (2.0)
Et2O (3.2)
Et2Oc
Et2O (2.0)
Et2O (1.0)
THF (2.0)
PhOMe (2.0)
iPr2O (2.0)
tBuOMe (2.0)
tBuOMe (1.0)
a
10
BL*3 ) OXB 1.
11
12
13
14d
70
77
83
80
TABLE 4. Asym m etr ic Mich a el Rea ction of 4a a n d TBS
Keten e Aceta l 5b w ith OXB 1a -qa
entry OXB yield (%) ee (%) entry OXB yield (%) ee (%)
a
Unless otherwise noted, the reactions were carried out at -78
°C by adding a CH2Cl2 solution of 4a (0.5 M) and 10c (1.0 equiv)
to a CH2Cl2 solution of 1b (0.1 M), 5a (1.5 equiv), and an ethereal
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
6
13
36
30
10
23
15
21
20
83
83
82
81
82
83
88
88
89
10
11
12
13
14
15
16
17
1j
1k
1l
1m
1n
1o
1p
1q
27
17
2
19
20
28
19
28
88
77
92
93
94
87
67
51
additive. Time for slow addition. c The reaction was carried out
b
d
in diethyl ether. A CH2Cl2 solution of 4a (1 M) and 10c was
added.
should be noted that, even with a 10 mol % catalyst load,
the reaction in the presence of BuOMe afforded adduct
7a of 80% ee in 91% yield (entry 14). On the other hand,
the use of diethyl ether under similar conditions resulted
in lowering of the ee (entry 9).
t
a
Reactions were carried out at -78 °C by adding a CH2Cl2
solution of 4a (0.25 M) and 10c (1.0 equiv) over 4 h to a CH2Cl2
solution of 5b (1.5 equiv) and 1a -q (40 mol %, 0.2 M).
The way an ethereal additive works is uncertain at this
time. The ineffectiveness of the additive in the absence
of the phenol implies that it is not a simple silicon
shuttle8b but plays a role in the trapping reaction of Me3-
Si+ species by the phenol. Nonselective reaction in the
presence of THF can be rationalized by its coordination
to the catalyst, reducing its effective concentration.
En a n tioselectivity of OXB Ca ta lysts 1 in th e
Rea ction of TBS Keten e Aceta l 5b. In the present
OXB-catalyzed Michael reaction, enantioselectivity is
determined both by the intrinsic selectivity of the catalyst
and by the extent of competing Si+-catalyzed racemic
pathway. This makes it difficult to optimize OXB struc-
tures especially with respect to their enantioselectivities.
The reaction with TBS ketene acetal 5b as a nucleophile
(eq 4) turned out to be very informative for the evaluation
of the intrinsic selectivity.
Taking advantage of the above observation, the enan-
tioselectivity of various OXBs (1a -q) was evaluated by
the reaction with TBS ketene acetal 5b as a nucleophile
(Table 4). The modification of the aryl group attached to
the boron atom of an OXB did not affect the enantiose-
lectivity (entries 1-4 and 7-10). N-Mesyl derivative 1e
exhibited an ee similar to that for the corresponding tosyl
derivative 1a (entry 5 vs 1). On the other hand, the
structure of the O-acyl group (R1CO) was found to be
influential. Thus, in comparison with O-benzoyl OXB 1a ,
O-(2-naphthoyl) OXB 1g of the more extended π-system
exhibited higher enantioselectivity (entry 7 vs 1). 1-Naph-
thoyl and 2-anthracenoly derivatives 1f,k , however, did
not give better results (entries 6 and 11). Introduction of
a substituent at the para position of the benzoyl group
significantly improved the enantioselectivity of the re-
sulting OXB-catalysts 1l-n (entries 12-14). Both electron-
donating (MeO) and electron-withdrawing (CF3) substit-
uents are effective. Of these, p-biphenoyl OXB 1n showed
the highest ee value of 94% ee. 3,5-Dimethoxybenzoyl
OXB 1o also exhibited selectivity higher than that of 1a
(entry 15) but not better than para substituted 1l-n . The
low selectivity observed for O-acetyl OXB 1p and O-tosyl
OXB 1q indicates that planar aroyloxy groups attached
at the 2′ position are essential to the high enantioselec-
tivity of the OXB catalysts.
The reaction of enone 4a with TBS ketene acetal 5b
catalyzed by O-benzoyl OXB derivative 1a (40 mol %)
gave adduct 7a of 83% ee and racemic enolsilane 12 (2%
ee) in 6% and 71% yield, respectively. In this reaction,
intermediate 13 might undergo intermolecular TBS
group transfer to 4a to catalyze a nonselective reaction
(path b) rather than undergoing intramolecular transfer
to the enolate oxygen atom to give 12 (path a, Scheme
5). Therefore, the adduct 7a of high ee might be derived
from boron enolate 14 thus formed, therefore showing
the intrinsic enantioselectivity of OXB 1a .
En a n tioselectivity of OXB Ca ta lysts 1 in th e
Rea ction of TMS Keten e Aceta l 5a . Results obtained
in the reaction of 4a with TMS ketene acetal 5a by using
selected OXB catalysts (10-20 mol %) in the presence of
t
diisopropylphenol and BuOMe are summarized in Table
5. O-Biphenoyl OXB 1n showed the highest ee value of
89% also in the reaction with 5a (entries 6 and 7). If we
assume that the degree of enantioselectivity of the
catalyst is similar to that for the reaction with TBS
10050 J . Org. Chem., Vol. 68, No. 26, 2003

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
TABLE 5. Asym m etr ic Mich a el Rea ction of 4a a n d TMS
Keten e Aceta l 5a w ith Selected OXBa
tioselectivity (entries 1-11). Ee values of 85-90% could
be achieved by using 10 mol % of 1g or 1n except for
m-fluoro derivative 4e (entry 6). When O-(2-naphthoyl)-
OXB 1g was employed, benzalacetone derivatives 4h ,i
with electron-donating substituents attached on the
benzene ring showed relatively low enantioselectivity
(entries 9 and 11). However, a satisfactory level of the
selectivity could be attained by using O-(biphenoyl)-OXB
1n . For enones 4b-g with electron-withdrawing substit-
uents, on the other hand, both 1g and 1n exhibited a high
enantioselectivity (entries 2-8). Enantioselectivity com-
parable to benzalacetone 4a was obtained in the reaction
of 2-naphthyl and 2-furyl derivatives 4j,l (entries 12 and
14).
entry
OXB
mol %
yield (%)
ee (%)
% OXBb
1
1a
1g
1g
1l
1m
1n
1n
1o
20
20
10
20
20
20
10
20
71
84
90
87
60
88
88
60
79
83
80
82
72
89
89
51
95
94
91
89
77
95
95
59
2
3c
4
5
6
7c
8
a
Unless otherwise noted, reactions were carried out at -78 °C
by adding a CH2Cl2 solution of 4a (0.5 M) and 10c (1.0 equiv) over
6 h to a CH2Cl2 solution of OXB 1 (0.1M), 5a (1.5 equiv), and
b
tBuOMe (2.0 equiv). For definition, see text. c A CH2Cl2 solution
of 4a (1.0 M) and 10c was added. 1.0 Equiv of tBuOMe was used.
The reaction of aliphatic enone 4m was also enantio-
selective (entry 15). Low yield in the reaction of homo-
logous enone 4n represents one of the limitations of the
present reaction (entry 16). More hindered 5-methylhex-
3-en-2-one did not react under these reaction condi-
tions.
ketene acetals 5b, the fraction of the chiral Lewis acid-
catalyzed pathway (% OXB) is assessed to be 95% in
these reactions. While % OXB values are not much
influenced by a catalyst load (entry 2 vs 3 and entry 6 vs
7), they are sensitive to the catalyst structure. For
4-methoxy OXB 1m and 3,5-dimethoxy OXB 1o, the Si+-
catalyzed pathway concurrently took place to a signifi-
cant degree resulting in low enantioselectivity (entries
4, 5, and 8).
The structure of the alkyl group attached to the
carbonyl group is influential to the enantioselectivity
(entries 17-21). Although the reaction of the tert-butyl
and phenyl derivatives 4q,r was nonselective, modest
enantioselectivity was obtained for ethyl and isopropyl
derivatives 4o,p (entry 6). Finally, in sharp contrast to
the high enantioselectivity observed for various acyclic
enones, OXB 1g,n did not show selectivity in the reaction
of cyclic enones such as 4s (entry 22).
Scop e a n d Lim ita tion . Asymmetric Michael reaction
of a variety of enones 4a -s with 5a was examined by
using O-(2-naphthoyl)-OXB 1g and O-(biphenoyl)-OXB
1n as catalysts (Table 6). Reaction of benzalacetone
derivatives 4a -i with substituents on the benzene ring
gave the corresponding products 7a -i with high enan-
The absolute structures of Michael adducts 7a and 7o
were determined after conversion to the known methyl
TABLE 6. Asym m etr ic Mich a el Rea ction of En on es 4a -s a n d TMS Keten e Aceta l 5a Ca ta lyzed by OXB 1g a n d 1n
enone
R1
reaction with 1g
yield (%) ee (%)
reaction with 1n
yield (%) ee (%)
mol % of
catalyst
entry
enone
R2
1
2
4a
4b
4b
4c
4d
4e
4f
4g
4h
4h
4i
4j
4k
4l
4m
4n
4o
4p
4p
4q
4r
Ph
p-ClC6H4
Me
Me
10
10
20
10
10
10
10
10
10
20
10
10
20
10
10
20
10
10
40
40
40
40
90
83
94
82
78
75
77
71
78
c
50
76
90
48
28
34
53
74
71
72
90
74
80
86
85
86
86
74
90
90
74
88
91
86
80
76
67
70
71
75
74
78
59
c
44
75
c
63
52
c
89
85
89
83
90
73
80
89
86
89
85
75
3b
4
5
6
7
8
9
m-ClC6H4
p-FC6H4
m-FC6H4
p-CF3C6H4
m-CF3C6H4
p-MeC6H4
Me
Me
Me
Me
Me
Me
10b
11
12
13b
14
15
16b
17
18
19d
20d
21d
22d
p-MeOC6H4
2-Naph
1-Naph
2-furyl
Me
n-C5H11
Ph
Ph
Me
Me
Me
Me
Me
Me
Et
60
81
41
81
86
64
61
66
81
16
14
9
75
89
59
72
iPr
Ph
Ph
tBu
Ph
c
c
c
4s
2-cyclohexenone
22d
a
Unless otherwise note, reactions were carried out at -78 °C by adding a CH2Cl2 solution of an enone 4 (1 M) and 10c (1.0 equiv) over
t
b
6 h to a CH2Cl2 solution of OXB 1g,n (0.1M), 5a (1.5 equiv), and BuOMe (1.0 equiv). A CH2Cl2 solution of 4a (0.5 M) and 10c was
added. 2.0 equiv of tBuOMe was used. c The reaction was not examined. The reaction was carried out by adding a CH2Cl2 solution of an
d
enone 4 (0.5 M) and 10c (3.0 equiv) over 4 h to a CH2Cl2 solution of OXB 1g (0.2 M) and 5a (3.0 equiv).
J . Org. Chem, Vol. 68, No. 26, 2003 10051

Wang et al.
TABLE 7. Asym m etr ic Mich a el Rea ction of Selected
Ben za la ceton e Der iva tives w ith TBS Keten e Aceta l 5b
Ca ta lyzed by OXB 1g a n d 1n a
reaction with 1g
reaction with 1n
entry enone yield (%) ee (%) % OXB yield (%) ee (%) % OXB
1
2
3
4
5
4a
4b
4c
4h
4i
15
7
7
13
3
88
96
95
89
90
91
90
91
83
67
20
20
12
18
5
94
92
86
95
95
95
92
97
91
89
a
Reactions were carried out under the conditions similar to
those described in footnote a of Table 5.
F IGURE 2.
esters (S)-15a ,b17 by their treatment with silver trifluoro-
modification of the B-aryl group and the N-sulfonyl group
but it is affected by the structure of the O-acyl group
(Table 4). The observation is consistent with the coordi-
nation of enone 4 to the top face of OXB 1 in which the
B-phenyl and N-tosyl group locate at the bottom face. The
boron atom is coordinated by enone 4 in a s-cis-anti
fashion. The C(4)-C(1′) bond rotation might be fixed by
the methyl group (C(2′)H3) such that the O-aroyl moiety
shields the si face of the enone, leading to a selective
attack of the nucleophile on the re face. Nonselective
reactions observed for tert-butyl and phenyl ketones 4q,r
as well as cyclic enones 4s can be understood as a
consequence of low selectivity with respect to the syn and
anti coordination mode. The enantioselectivity of OXB
is determined mainly by the shape of O-acyl groups
rather than their electronic nature (Table 4). Introduction
of either an electron-donating or -withdrawing substitu-
ent to the benzene ring of benzalacetone also does not
affect the intrinsic enantioselectivity of OXB 1g,n (Table
7). These observations suggest that π-π interaction20
between an electron-deficient coordinating enone and the
aromatic ring of the acyl group is not a major factor in
the present reaction.21
1
acetate in methanol (eq 6).18 A method based on H NMR
chemical shift differences developed by Hoye et al.19 was
applied to the absolute structure determination of adduct
7m . Treatment of 7m with (R)-1-(R-naphthyl)ethylamine
and silver trifluoroacetate in THF gave amide 16 (eq 7).18
The 3-methyl protons and CH3CO protons of major
diastereomer (3S,1′R)-16 resonated in the lower and
upper fields, respectively, relative to those of the minor
diastereomer.
The origin of the lower enantioselectivity observed for
4h ,i with electron-rich aryl groups in the reaction
employing O-(2-naphthoyl)-OXB 1g is of interest in
connection with a model catalyst-substrate complex of
the present reaction (vide infra). To gain information on
this issue, reactions of selected benzalacetone derivatives
were carried out with TBS ketene acetal 5b. Results
summarized in Table 7 reveal a high intrinsic enantio-
selectivity of 1g (88-96% ee) and 1n (86-95% ee)
irrespective of the electronic nature of enones. Specifi-
cally, for the reactions of 4h ,i, selectivity comparable to
that for the parent benzalacetone 1a was obtained
irrespective of the use of 1g or 1n (entries 4 and 5). The
result implies that the lower selectivity observed in the
reaction with 1g (Table 6, entries 9 and 11) is the result
of the competing Si+-catalyzed racemic pathway as
suggested by the corresponding % OXB values: 83% for
1h and 67% for 1i. These relatively electron-rich enones
might be less reactive toward the attack of nucleophile
5a ,b. This might be influential to the lowering of % OXB
in the reaction with use of sterically more demanding
catalyst 1g. Similar trends of a smaller % OXB value for
1g than that for 1n were also observed in the reaction of
enones 4a -c, although to a lesser extent (e.g., entries
1-3).
Con clu sion . New OXB catalysts derived from O-acyl-
N-sulfonyl-(L)-allo-threonines have been developed for
enantioselective activation of acyclic enones. The asym-
metric Mukaiyama-Michael reaction of acyclic enones
with a trimethylsilyl ketene S,O-acetal catalyzed by thus
developed O-(2-naphthoyl)- and O-biphenoyl-N-tosyl OXB
1g,n provides an expedient entry into enantioenriched
γ-ketoacid thiol esters. A number of alkenyl methyl
ketones are successfully employed as Michael acceptors
affording ee values of 85-90% by using 10 mol % of the
t
catalyst. The use of 2,6-diisopropylphenol and BuOMe
as additives is essential to achieve high enantioselectivity
in these reactions. A Si+-catalyzed racemic pathway that
seriously deteriorates the enantioselectivity of the asym-
metric Mukaiyama-Michael reaction could be retarded
for the most part (<10%) by the use of these additives.
The structure model for the activated complex (Figure
2), in which the O-aroyl group and the enone moiety face
(17) Enders, D.; Papadopoulos, K. Tetrahedron Lett. 1983, 24, 4967.
(18) (a) Masamune, S.; Kamata, S.; Schilling, W. J . Am. Chem. Soc.
1975, 97, 3515. (b) Booth, P. M.; Fox, C. M. J .; Ley, S. V. J . Chem.
Soc., Perkin Trans. 1 1987, 121.
(19) Hoye, T. R.; Koltun, D. O. J . Am. Chem. Soc. 1998, 120, 4638.
(20) Kim, K. S.; Tarakeshwar, P.; Lee, J . Y. Chem. Rev. 2000, 100,
4145.
Wor k in g Mod el. Our working model for the mode of
enantioface selection is shown in Figure 2. The enantio-
selectivity of OXB catalysts 1 is not sensitive to the
(21) Corey, E. J .; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe,
M. C. J . Am. Chem. Soc. 1992, 114, 8290.
10052 J . Org. Chem., Vol. 68, No. 26, 2003

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
3c (428 mg, 100% yield): mp 135-136 °C (recrystallized from
each other in a parallel arrangement on the top face of
OXB, has been proposed based on the correlation between
catalyst structures and enantioselectivities. The present
investigation demonstrates a potential of (L)-allo-threo-
nine-derived OXB catalysts whose chiral environment
can be readily optimized for specific reactions by the
modification of the O-acyl group.
ether); 1H NMR (500 MHz, CDCl3) δ 1.44 (3H, d, J ) 6.5 Hz),
2.23 (3H, s), 4.45 (1H, dd, J ) 4.6 and 9.2 Hz), 4.5 (1H, br),
5.42 (1H, dq, J ) 3.9 and 6.5 Hz), 5.69 (1H, br d, J ) ca. 9
Hz), 7.15 (2H, m), 7.57 (1H, br t, J ) ca. 7 Hz), 7.62 (1H, br t,
J ) ca. 7 Hz), 7.72 (2H, m), 7.85 (1H, br d, J ) ca. 8 Hz), 7.88
(1H, br d, J ) ca. 8 Hz), 7.96 (2H, m), 8.52 (1H, br s); 13C NMR
(125.8 MHz, CDCl3) δ 15.7, 21.4, 58.5, 70.9, 125.2, 125.9, 126.7,
127.1, 127.7, 128.1, 128.5, 129.5, 129.7, 131.5, 132.3, 135.7,
136.4, 143.9, 165.9, 171.6; IR (KBr disk) 3200 (br), 1740, 1700,
1275, 660 cm-1. Anal. Calcd for C22H21NO6S: C, 61.82; H, 4.95.
Found: C, 61.63; H, 4.91.
Exp er im en ta l Section
The following compounds were prepared according to a
literature procedure: (L)-allo-threonine,22 ArBBr3 (Ar ) p-
chlorophenyl, m-chlorophenyl, 3,4-dichlorophenyl),23 silyl ketene
S,O-acetal 5a ,b,24 and enones 4c-k ,o-q.25
O-Ben zoyl-N-tosyl-(L)-a llo-th r eon in e ben zyl ester : 74%
1
yield; H NMR (300 MHz, CDCl3) δ 1.34 (3H, d, J ) 6.5 Hz),
2.36 (3H, s), 4.29 (1H, dd, J ) 4.5 and 6.5 Hz), 4.92 (1H, d, J
) 12.0 Hz), 4.95 (1H, d, J ) 12.0 Hz), 5.45 (1H, dq, J ) 4.5
and 6.5 Hz), 5.45 (1H, d, J ) 9.7 Hz), 7.15-7.2 (4H, m), 7.25-
7.35 (3H, m), 7.37 (2H, m), 7.54 (1H, m), 7.68 (2H, m), 7.90
N-Tosyl-(L)-a llo-th r eon in e. To a solution of (L)-allo-threo-
nine22 (10.0 g, 83.9 mmol) in 1 N NaOH (150 mL) at room
temperature was added an ether (150 mL) solution of p-
toluenesulfonyl chloride (17.6 g, 92.3 mmol). The mixture was
stirred vigorously at room temperature overnight. The aqueous
layer was separated, washed twice with ether, and acidified
with conc HCl. This was extracted three times with ethyl
acetate. The combined organic layers were dried and concen-
trated in vacuo to give 17.0 g (74%) of the tosyl amide: 1H
NMR (300 MHz, d6-aceteone) δ 1.18 (3H, d, J ) 7.0 Hz), 2.37
(3H, s), 3.83 (1H, dd, J ) 7.0 and 12.8 Hz), 3.96 (1H, quintet,
J ) 7.0 Hz), 6.56 (1H, br d, J ) 13 Hz), 7.41 (2H, m), 7.71
(2H, m).
(2H, m); IR (KBr disk) 3280, 1715, 1280, 1165, 715 cm-1
.
O-Ben zoyl-N-tosyl-(L)-a llo-th r eon in e (3a ): 100% yield;
1
mp 193-202 °C (recrystallized from CH3OH-H2O); H NMR
(500 MHz, acetone-d6) δ 1.42 (3H, d, J ) 6.5 Hz), 2.37 (3H, s),
2.5 (1H, br), 4.42 (1H, dd, J ) 4.6 and 9.4 Hz), 5.39 (1H, dq, J
) 4.6 and 6.5 Hz), 7.05 (1H, br d, J ) 9.4 Hz), 7.3 (2H, m), 7.5
(2H, m), 7.65 (1H, m), 7.74 (2H, m), 7.97 (2H, m); 13C NMR
(125.8 MHz, acetone-d6) δ 15.1, 20.5, 58.8, 70.7, 126.9, 128.3,
129.4, 129.5, 130.1, 133.0, 138.4, 143.0, 165.0, 169.4; IR (KBr)
3300, 3000 (br), 1720, 1275, 710, 670 cm-1
.
N-Tosyl-(L)-a llo-th r eon in e Ben zyl Ester (2). A solution
of N-tosyl-(L)-allo-threonine (5.10 g, 18.7 mmol), benzyl alcohol
(4.04 g, 37.4 mmol), and p-toluenesulfonic acid monohydrate
(356 mg, 1.87 mmol) in toluene (340 mL) was refluxed with a
Dean-Stark trap for 12 h. The mixture was poured into
aqueous NaHCO3 and extracted three times with ether. The
organic layers were dried and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography (20-40% ethyl
acetate in hexane) gave 5.71 g (84%) of 2: mp 95-98 °C
O-(1-Na p h th oyl)-N-tosyl-(L)-a llo-th r eon in e ben zyl es-
ter : 79% yield; 1H NMR (300 MHz, CDCl3) δ 1.39 (3H, d, J )
6.5 Hz), 2.30 (3H, s), 4.42 (1H, dd, J ) 4.6 and 9.6 Hz), 4.96
(2H, s), 5.39 (1H, dq, J ) 4.7 and 6.5 Hz), 5.49 (1H, br d, J )
9.6 Hz), 7.1-7.2 (6H, m), 7.2-7.3 (3H, m), 7.40 (1H, t, J ) 7.7
Hz), 7.5-7.65 (2H, m), 7.7 (2H, m), 7.88 (1H, br d, J ) 7.9
Hz), 8.01 (1H, d, J ) 8.1 Hz), 8.07 (1H, d, J ) 6.5 Hz), 8.91
(1H, d, J ) 8.4 Hz).
O-(1-Na p h th oyl)-N-tosyl-(L)-a llo-th r eon in e (3b): 100%
yield; mp 63-64 °C; 1H NMR (300 MHz, CDCl3) δ 1.44 (3H, d,
J ) 6.5 Hz), 2.21 (3H, s), 4.45 (1H, dd, J ) 4.8 and 9.8 Hz),
5.41 (1H, dq, J ) 4.2 and 6.6 Hz), 5.63 (1H, br d, J ) 9.3 Hz),
7.06 (2H, m), 7.44 (1H, t, J ) 7.6 Hz), 7.5-7.7 (6H, m), 7.87
(1H, br d, J ) 7.8 Hz), 8.01 (1H, d, J ) 8.1 Hz), 8.09 (1H, dd,
J ) 1.0 and 7.3 Hz), 8.87 (1H, d, J ) 8.4 Hz); IR (KBr disk)
1
(recrystallized from ethyl acetate and hexane); H NMR (300
MHz, CDCl3) δ 1.12 (3H, d, J ) 6.4 Hz), 2.30 (1H, br d, J )
8.5 Hz), 2.40 (3H, s), 3.97 (1H, dd, J ) 3.9 and 8.8 Hz), 4.06
(1H, m), 4.95 (2H, m), 5.49 (1H, br d, J ) ca. 9 Hz), 7.17-7.35
(7H, m), 7.71 (2H, m).
O-(2-Na p h th oyl)-N-tosyl-(L)-a llo-th r eon in e Ben zyl Es-
ter . To a solution of the benzyl ester 2 (1.00 g, 2.75 mmol) in
pyridine (5 mL) at 0 °C was added dropwise a solution of
2-naphthoyl chloride (587 mg, 3.08 mmol) in CH2Cl2 (5 mL).
After being stirred at room temperature for 26 h, the mixture
was poured into water and extracted three times with ethyl
acetate. The organic layers were washed successively with 1
N HCl water and aq NaHCO3, dried, and concentrated in
vacuo. Purification of the residue by flash chromatography
(10-20% ethyl acetate in hexane) and recrystallization from
ethyl acetate and hexane gave 1.39 g (96%) of the O-(2-
3560, 3480, 3300, 1735, 1710, 785, 675 cm-1
.
O-(4-Meth oxyben zoyl)-N-tosyl-(L)-a llo-th r eon in e ben -
1
zyl ester : 77% yield; H NMR (300 MHz, CDCl3) δ 1.33 (3H,
d, J ) 6.4 Hz), 2.37 (3H, s), 3.85 (3H, s), 4.29 (1H, dd, J ) 4.5
and 9.8 Hz), 4.93 (2H, m), 5.25 (1H, dq, J ) 4.5 and 6.4 Hz),
5.52 (1H, d, J ) 9.7 Hz), 6.85 (2H, m), 7.15-7.35 (7H, m), 7.68
(2H, m), 7.5 (2H, m).
O-(4-Meth oxyben zoyl)-N-tosyl-(L)-a llo-th r eon in e (3e):
100% yield; mp 132-133 °C (recrystallized from ether); 1H
NMR (300 MHz, CDCl3) δ 1.35 (3H, d, J ) 6.5 Hz), 2.85 (3H,
s), 3.85 (3H, s), 4.32 (2H, m, including dd (1H, J ) 3.4 and 8.9
Hz)), 5.82 (1H, dq, J ) 3.4 and 6.5 Hz), 5.63 (1H, br, J ) 9.3
Hz), 6.85 (2H, m), 7.19 (2H, m), 7.69 (2H, m), 7.88 (2H, m);
13C NMR (125.8 MHz, CDCl3) δ 16.0, 21.7, 55.6, 58.9, 70.7,
113.8, 121.9, 127.3, 129.9, 132.0, 136.7, 144.1, 163.4, 165.7,
1
naphthoyl) derivative: mp 106-107 °C; H NMR (500 MHz,
CDCl3) δ 1.42 (3H, d, J ) 6.5 Hz), 2.31 (3H, s), 4.39 (1H, dd,
J ) 4.8 and 9.8 Hz), 4.98 (2H, s), 5.36 (1H, dq, J ) 4.8 and 6.4
Hz), 5.53 (1H, br d, J ) ca. 10 Hz), 7.18 (4H, m), 7.27 (3H, m),
7.56 (1H, br t, J ) ca. 8 Hz), 7.62 (1H, br t, J ) ca. 8 Hz), 7.72
(2H, m), 7.85 (1H, br d, J ) ca. 8.5 Hz), 7.90 (2H, m), 7.95
(1H, br d, J ) ca. 8.5 Hz), 8.51 (1H, br s).
172.4; IR (KBr) 3250, 3000 (br), 1705, 1605, 1255, 770 cm-1
.
Anal. Calcd for C19H21NO7S: C, 56.01; H, 5.20; N, 3.44.
Found: C, 55.89; H, 5.21; N, 3.67.
O-(2-Na p h th oyl)-N-tosyl-(L)-a llo-th r eon in e (3c). A mix-
ture of the O-(2-naphthoyl) derivative (500 mg, 0.970 mmol)
and Pd/C (10%) (80 mg) in ethyl acetate (20 mL) was vigorously
stirred under hydrogen atmosphere at room temperature for
16 h. The mixture was filtered through a pad of cellulose
powder and the filtrate was concentrated in vacuo to give pure
O-(4-Tr iflu or om et h ylb en zoyl)-N-t osyl-(L)-a llo-t h r eo-
n in e ben zyl ester : 70% yield; 1H NMR (500 MHz, CDCl3) δ
1.35 (3H, d, J ) 6.6 Hz), 2.38 (3H, s), 4.33 (1H, dd, J ) 4.5
and 9.5 Hz), 4.96 (2H, s), 5.31 (1H, m), 5.41 (1H, d, J ) 9.5
Hz), 7.18 (2H, m), 7.21 (2H, m), 7.30 (3H, m), 7.63 (2H, d, J )
8.3 Hz), 7.68 (2H, d, J ) 8.3 Hz), 8.01 (2H, d, J ) 8.1 Hz).
O-(4-Tr iflu or om et h ylb en zoyl)-N-t osyl-(L)-a llo-t h r eo-
n in e (3f): 99% yield; mp 159-160 °C; 1H NMR (500 MHz,
CDCl3) δ 1.41 (3H, d, J ) 6.6 Hz), 2.38 (3H, s), 4.45 (1H, dd,
J ) 3.9 and 9.4 Hz), 5.38 (1H, dq, J ) 3.9 and 6.5 Hz), 5.56
(1H, d, J ) 9.4 Hz), 6.0 (1H, br), 7.25 (2H, m), 7.71 (4H, m),
(22) Elliot, D. F. J . Chem. Soc. 1950, 62-68.
(23) Haubold, W.; Herdtle, J .; Gollinger, W.; Einholz, W. J . Organo-
met. Chem. 1986, 315, 1.
(24) Kita, Y.; Segawa, J .; Haruta, J .; Yasuda, H.; Tamura, Y. J .
Chem. Soc., Perkin Trans. 1 1982, 1099.
(25) Hill, G. A.; Bramann, G. M. Org. Synth. 1941, 1, 77 and 81.
J . Org. Chem, Vol. 68, No. 26, 2003 10053

Wang et al.
8.08 (2H, m); 13C NMR (125.8 MHz, CDCl3) δ 8, 15.3, 21.5,
58.2, 71.0, 123.5 (q, J ) 273 Hz), 125.4, 127.1, 129.8, 130.2,
132.6, 134.7 (q, J ) 32.8 Hz), 136.3, 144.1, 164.5, 172.4; IR
MHz, DMSO-d6) δ 1.03 (3H, d, J ) 6.2 Hz), 2.30 (3H, s), 3.30
(3H, s), 3.51 (1H, dd, J ) 8.2 and 9.3 Hz), 3.70 (2H, m), 7.38
(2H, m), 7.62 (2H, m), 8.24 (1H, d, J ) 9.4 Hz). Esterification
of the crude N-tosyl-(L)-allo-threonine methyl ester with
2-anthracenoyl chloride by a procedure similar to that de-
scribed above gave the ester in 30% overall yield. 1H NMR
(300 MHz, CDCl3) δ 1.47 (3H, d, J ) 6.5 Hz), 2.27 (3H, s),
3.63 (3H, s), 4.43 (1H, dd, J ) 4.3 and 9.6 Hz), 5.42 (1H, dq,
J ) 4.3 and 6.5 Hz), 5.56 (1H, br d, J ) 9.6 Hz), 7.20 (2H, m),
7.65-7.75 (5H, m), 8.04 (1H, dd, J ) 1.6 and 9.2 Hz), 8.5-8.6
(4H, m), 9.20-9.24 (1H, br s).
(KBr) 3275 (br), 3180 (br), 1730, 1710, 1315, 660 cm-1
.
O-(4-Bip h en oyl)-N-tosyl-(L)-a llo-th r eon in e ben zyl es-
1
ter : 63% yield; H NMR (500 MHz, C6D6) δ 1.41 (3H, d, J )
7.0 Hz), 2.41 (3H, s), 4.28 (1H, dd, J ) 4.5 and 5.0 Hz), 5.33-
5.38 (1H, m), 5.48 (1H, d, J ) 10 Hz), 7.22-7.27 (4H, m), 7.52-
7.53 (2H, m), 7.64-7.67 (4H, m), 7.74-7.76 (2H, m), 8.01-
8.03 (2H, m), 7.81-7.88 (2H, m).
O-(4-Bip h en oyl)-N-tosyl-(L)-a llo-th r eon in e (3 g): 99%
yield; mp 153-154 °C (recrystallized from benzene); 1H NMR
(500 MHz, acetone-d6) δ 1.46 (3H, d, J ) 6.4 Hz), 2.35 (3H, s),
4.45 (1H, dd, J ) 5.4 and 9.4 Hz), 5.44 (1H, dq, J ) 5.4 and
6.4 Hz), 7.07 (1H, br d, J ) 9.4 Hz), 7.31 (2H, m), 7.45 (1H,
m), 7.50 (2H, m), 7.75-7.8 (6H, m), 8.05 (2H, m); 13C NMR
(125.8 MHz, acetone-d6) δ 15.0, 20.5, 58.7, 59.8, 70.7, 126.8,
129.0, 129.1, 130.2, 131.0, 131.4, 132.2, 140.5, 141.7, 145.0,
147.5, 166.9, 171.4; IR (KBr) 3300, 3000 (br), 1715, 1695, 1280,
810, 740 cm-1. Anal. Calcd for C24H23NO6S: C, 63.56; H, 5.11;
N, 3.09. Found: C, 63.37; H, 5.27; N, 3.03.
O-(2-An th r a cen oyl)-N-tosyl-(L)-a llo-th r eon in e (3d ). A
solution of O-(2-anthracenoyl)-N-tosyl-(L)-allo-threonine meth-
yl ester (500 mg, 1.00 mmol) and iodotrimethylsilane (0.8 mL,
5.6 mmol) in CHCl3 (1 mL) was heated at 70 °C for 6 h.
Concentration of the mixture followed by flash chromatogra-
phy (SiO2, CHCl3:methanol:acetic acid; 25:1:1) gave 373 mg
(78% yield) of 3d : mp 142-143 °C 1H NMR (300 MHz, acetone-
d6) δ 1.54 (3H, d, J ) 6.6 Hz), 2.18 (3H, s), 4.58 (1H, dd, J )
4.4 and 9.5 Hz), 5.52 (1H, dq, J ) 4.4 and 6.6 Hz), 7.17 (1H,
d, J ) 9.5 Hz), 7.27 (2H, m), 7.79 (2H, m), 7.85-7.95 (3H, m),
8.12 (1H, dd, J ) 1.5 and 9.2 Hz), 8.55-8.65 (4H, m), 9.19
(1H, br s); IR (KBr disk) 3200 (br), 1720, 1230, 815, 760, 670
O-(3,5-Dim et h oxyb en zoyl)-N-t osyl-(L)-a llo-t h r eon in e
1
ben zyl ester : 87% yield; H NMR (300 MHz, CDCl3) δ 1.33
cm-1
.
(3H, d, J ) 6.5 Hz), 2.37 (3H, m), 4.30 (1H, dd, J ) 4.5 and
9.6 Hz), 5.27 (1H, dq, J ) 4.5 and 6.5 Hz), 5.44 (1H, br d, J )
9.6 Hz), 6.64 (1H, t, J ) 2.4 Hz), 7.1-7.2 (6H, m, including d
(2H, J ) 2.4 Hz)), 7.25-7.35 (3H, m), 7.67 (2H, m).
O-Ben zoyl-N-m eth an esu lfon yl-(L)-a llo-th r eon in e Meth -
yl Ester . Thionyl chloride (1.6 mL, 22 mmol) and (L)-allo-
threonine (5 g, 42 mmol) were added successively to methanol
(42 mL) at 0 °C. After being stirred for 19 h at room
temperature, the mixture was concentrated in vacuo to give
crude (L)-allo-threonine methyl ester hydrochloride (7.1 g).
Triethylamine (17.6 mL, 126 mmol) and methanesulfonyl
chloride (3.6 mL, 46.2 mmol) were added successively to a
suspension of the crude methyl ester hydrochloride in CH2Cl2
(100 mL) at 0 °C. After being stirred for 4 h at room
temperature, the mixture was poured into brine and extracted
with ethyl acetate. Concentration of the dried organic layers
gave 4.39 g (50% yield) of the crude N-methanesulfonyl-allo-
threonine methyl ester: 1H NMR (300 MHz, CDCl3) δ 1.19
(3H, d, J ) 6.6 Hz), 3.0 (1H, br), 3.00 (3H, s), 3.79 (3H, s),
4.20 (2H, m), 5.76 (1H, d, J ) 10.8 Hz). Esterification of the
N-methanesulfonyl-(L)-allo-threonine methyl ester with ben-
zoyl chloride by a procedure similar to that described above
O-(3,5-Dim et h oxyb en zoyl)-N-t osyl-(L)-a llo-t h r eon in e
(3h ): 100% yield; mp 166-167 °C; 1H NMR (300 MHz, CDCl3)
δ 1.36 (3H, d, J ) 6.5 Hz), 2.34 (3H, s), 3.81 (6H, s), 4.33 (1H,
dd, J ) 4.0 and 9.3 Hz), 5.29 (1H, dq, J ) 4.0 and 6.5 Hz),
5.40 (1H, br), 5.68 (1H, br d, J ) 9.3 Hz), 6.63 (1H, t, J ) 2.3
Hz), 7.12 (2H, d, J ) 2.3 Hz), 7.18 (2H, m), 7.68 (2H, m); 13C
NMR (125.8 MHz, CDCl3) δ 15.7, 21.4, 55.5, 58.6, 71.0, 106.0,
107.4, 127.1, 129.7, 131.2, 136.4, 145.0, 160.5, 165.4, 172.1;
IR (KBr disk) 3275, 3200 (br), 1750, 1695, 1595, 1050, 675
cm-1. Anal. Calcd for C20H23NO8S: C, 54.91; H, 5.30; N, 3.20.
Found: C, 54.75; H, 5.40; N, 3.39.
O-(Acetyl)-N-tosyl-(L)-a llo-th r eon in e ben zyl ester : 100%
1
yield; H NMR (300 MHz, CDCl3) δ 1.16 (3H, d, J ) 6.5 Hz),
1.93 (3H, s), 2.40 (3H, s), 4.22 (1H, dd, J ) 4.4 and 9.3 Hz),
4.96 (2H, m), 5.03 (1H, dq, J ) 4.4 and 6.5 Hz), 5.36 (1H, br
d, J ) 9.3 Hz), 7.15-7.3 (4H, m), 7.3-7.4 (3H, m), 7.69 (2H,
m).
1
gave the benzoate in 59% yield. H NMR (300 MHz, CDCl3) δ
1.40 (3H, d, J ) 6.6 Hz), 2.97 (3H, s), 3.84 (3H, s), 4.55 (1H,
dd, J ) 3.6 and 8.7 Hz), 5.39 (1H, br d, J ) 8.4 Hz), 5.43 (1H,
dq, J ) 3.6 and 6.6 Hz), 7.44 (2H, m), 7.57 (1H, m), 8.02 (2H,
m).
O-(Acet yl)-N-t osyl-(L)-a llo-t h r eon in e (3i): 100% yield;
1
mp 119-120 °C; H NMR (300 MHz, CDCl3) δ 1.21 (3H, d, J
) 6.5 Hz), 1.96 (3H, s), 2.40 (3H, s), 4.27 (1H, dd, J ) 4.0 and
9.1 Hz), 5.08 (1H, dq, J ) 4.0 and 6.6 Hz), 5.73 (1H, br d, J )
9.1 Hz), 7.28 (2H, m), 7.74 (2H, m); IR (KBr disk) 3525, 3300,
O-Ben zoyl-N-m eth a n esu lfon yl-(L)-a llo-th r eon in e (3k ).
A solution of O-benzoyl-N-methanesulfonyl-(L)-allo-threonine
methyl ester (1.46 g, 4.64 mmol) and iodotrimethylsilane (1.06
mL, 7.42 mmol) in CHCl3 (1.2 mL) was heated at 50 °C for 10
h. Concentration of the mixture followed by flash chromatog-
raphy (SiO2, CHCl3-MeOH-acetic acid; 25:1:1) gave 424 mg
(30% yield) of 3k : mp 142-143 °C (recrystallized from CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.44 (3H, d, J ) 6.6 Hz), 2.98
(3H, s), 4.60 (1H, dd, J ) 3.6 and 9.0 Hz), 5.48 (1H, dq, J )
3.9 and 6.6 Hz), 5.58 (1H, d, J ) 9.0 Hz), 6.2 (1H, br), 7.44
(2H, m), 7.57 (1H, m), 8.02 (2H, m); IR (KBr disk) 3400 (br),
1725, 1165, 820 cm-1
.
N,O-Ditosyl-(L)-a llo-th r eon in e Ben zyl Ester . Treatment
of N-tosyl-(L)-allo-threonine benzyl ester with p-toluenesulfon-
yl chloride (1.1 equiv) in pyridine in the presence of a catalytic
amount of 4-(N,N-dimethylamino)pyridine gave the ditosylate
in 72% yield: 1H NMR (300 MHz, CDCl3) δ 1.29 (3H, d, J )
6.6 Hz), 2.39 (3H, s), 2.44 (3H, s), 4.02 (1H, dd, J ) 4.0 and
9.4 Hz), 4.77 (1H, dq, J ) 4.1 and 6.5 Hz), 4.89 (1H, d, J )
12.2 Hz), 4.95 (1H, d, J ) 12.2 Hz), 5.24 (1H, br d, J ) 9.4
Hz), 7.15-7.25 (4H, m), 7.3-7.4 (5H, m), 7.63 (2H, m), 7.72
(2H, m).
1755, 1720, 1270, 715 cm-1
.
S-ter t-Bu t yl (S)-5-Oxo-3-p h en ylh exa n et h ioa t e (7a )
(Typ ica l P r oced u r e for Asym m etr ic Mich a el Rea ction ,
Ta ble 5, en tr y 7). To a solution of allo-threonine derivative
3g (45.4 mg, 0.10 mmol) in CH2Cl2 (1 mL) under nitrogen
atmosphere at room temperature was added dichlorophenyl-
borane (13 µL, 0.10 mmol). After being stirred for 1 h, the
mixture was concentrated in vacuo. To a solution of the
resulting OXB 1n and silyl ketene acetal 5a (306 mg, 1.5
mmol) in CH2Cl2 (1 mL) at -78 °C were added a CH2Cl2 (1
mL) solution of enone 4a (146 mg, 1.0 mmol) and 2,6-
diisopropylphenol (178 mg, 1.0 mmol) over 6 h with use of a
syringe pump. After completion of the addition, the mixture
was quenched by the addition of saturated aqueous NaHCO3
N,O-Ditosyl-(L)-a llo-th r eon in e (3j): 100% yield; mp 99-
100 °C; 1H NMR (300 MHz, acetone-d6) δ 1.29 (3H, d, J ) 6.5
Hz), 2.42 (3H, s), 2.49 (3H, s), 4.17 (1H, dd, J ) 4.1 and 9.4
Hz), 4.89 (1H, dq, J ) 4.1 and 6.5 Hz), 6.76 (1H, br d, J ) 9.5
Hz), 7.36 (2H, m), 7.49 (2H, m), 7.72 (2H, m), 7.80 (2H, m); IR
(KBr disk) 3280 (br), 1750, 900, 680 cm-1
.
O-(2-An th r a cen oyl)-N-tosyl-(L)-a llo-th r eon in e Meth yl
Ester . Thionyl chloride (9.2 mL, 126 mmol) and N-tosyl-(L)-
allo-threonine (2.0 g, 7.3 mmol) were added successively to
methanol (10 mL) at 0 °C. After being stirred for 40 h at room
temperature, the mixture was concentrated in vacuo to give
crude N-tosyl-(L)-allo-threonine methyl ester: 1H NMR (300
10054 J . Org. Chem., Vol. 68, No. 26, 2003

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
and filtered.26 The filtrate was extracted three times with
hexane, dried (Na2SO4), and concentrated in vacuo. The
residue was dissolved in 1 N HCl (4 mL)-THF (20 mL) and
the resulting solution was stirred at room temperature for 30
min. The mixture was poured into aqueous NaHCO3 extracted
three times with ether. The organic layers were dried (Na2-
SO4) and concentrated in vacuo. Purification of the residue by
flash chromatography (SiO2, 5% ethyl acetate in hexane) gave
245 mg, (88%) of adduct (S)-7a (89% ee): 1H NMR (300 MHz,
CDCl3) δ 1.37 (9H, s), 2.04 (3H, s), 2.25 (1H, dd, J ) 7.3 and
15.0 Hz), 2.76 (1H, dd, J ) 6.6 and 15.0 Hz), 2.79 (1H, dd, J
) 7.8 and 16.8 Hz), 2.83 (1H, dd, J ) 6.6 and 16.6 Hz), 3.69
(1H, quintet, J ) 7.2 Hz), 7.16-7.30 (5H, m); 13C NMR (125.8
MHz, CDCl3) δ 29.6, 30.3, 37.9, 48.0, 48.9, 50.3, 126.7, 127.3,
128.5, 142.6, 198.4, 206.6; IR (liquid film) 1725, 1675, 790, 705
cm-1; MS m/z (rel intensity) 278 (M+, 2), 189 (100), 131 (88);
HRMS calcd for C16H22O2S 278.1342, found 278.1346. Anal.
Calcd for C16H22O2S: C, 69.03; H, 7.96. Found: C, 68.78; H,
7.97. Ee determination (HPLC, Daicel Chiralpak AD, 1 mL/
min, 1% 2-PrOH in hexane) (S) t1 ) 16.8 min, (R) t2 ) 14.1
min.
Found: C, 64.41; H, 6.84. Ee determination (HPLC, Daicel
Chiralpak OJ , 1 mL/min, 1% 2-PrOH in hexane) (S) t1 ) 19.7
min, (R) t2 ) 26.4 min. The absolute stereochemistry was
assumed by analogy.
S-ter t-Bu tyl (S)-3-(3-flu or op h en yl)-5-oxoh exa n eth ioa te
1
(7e): H NMR (500 MHz, CDCl3) δ 1.41 (9H, s), 2.09 (3H, s),
2.71 (1H, dd, J ) 7.5 and 14.5 Hz), 2.75-2.85 (2H, m), 2.87
(1H, dd, J ) 6.5 and 16.5 Hz), 3.73 (1H, quintet, J ) 7.0 Hz),
6.91 (2H, m), 7.0 (1H, d, J ) 7.5 Hz), 7.26 (1H, m); 13C NMR
(125.8 MHz, CDCl3) δ 29.6, 30.3, 37.6, 48.2, 48.7, 50.0, 113.7
(d, J ) 21.4 Hz), 114.3 (d, J ) 21.4 Hz), 123.1, 130.0 (d, J )
7.5 Hz), 145.3 (d, J ) 6.3 Hz), 162.8 (d, J ) 245 Hz), 198.2,
206.1; IR (liquid film) 1710, 1685, 785, 700 cm-1; MS m/z (rel
intensity) 296 (M+, 2), 207 (100), 150 (72); HRMS calcd for
C16H21O2SF 296.1247, found 296.1245. Anal. Calcd for C16H21O2-
SF: C, 64.84; H, 7.14. Found: C, 64.65; H, 7.19. Ee determi-
nation (HPLC, Daicel Chiralpak AD, 1 mL/min, 1% 2-PrOH
in hexane) (S) t1 ) 16.3 min, (R) t2 ) 24.2 min. The absolute
stereochemistry was assumed by analogy.
S-ter t-Bu tyl (S)-3-(4-tr iflu or om eth ylp h en yl)-5-oxoh ex-
1
a n eth ioa te (7f): H NMR (500 MHz, CDCl3) δ 1.37 (9H, s),
Oxa za bor olid in on e 1g: 1H NMR (500 MHz, CDCl3) δ 1.73
(3H, d, J ) 6.6 Hz), 2.31 (3H, s), 4.64 (1H, d, J ) 1.9 Hz), 5.72
(1H, br q, J ) ca. 6.5 Hz), 7.07 (2H, br d, J ) ca. 8 Hz), 7.41
(2H, m), 7.50 (1H, m), 7.55-7.6 (3H, m), 7.72 (1H, d, J ) 8.2
Hz), 7.78 (1H, d, J ) 8.3 Hz), 7.8-7.85 (2H, m), 8.11 (2H, br
d, J ) ca. 8 Hz), 8.33 (1H, s).
S-ter t-Bu tyl (S)-3-(4-ch lor op h en yl)-5-oxoh exa n eth io-
a te (7b): 1H NMR (300 MHz, CDCl3) δ 1.37 (9H, s), 2.05 (3H,
s), 2.66 (1H, dd, J ) 7.6 and 14.8 Hz), 2.75 (1H, dd, J ) 7.2
and 14.8 Hz), 2.74 (1H, dd, J ) 8.2 and 17.2 Hz), 2.83 (1H,
dd, J ) 6.4 and 17.2 Hz), 3.68 (1H, quintet, J ) 7.2 Hz), 7.13
(2H, m), 7.25 (2H, m); 13C NMR (125.8 MHz, CDCl3) δ 29.6,
30.3, 37.2, 48.2, 48.8, 50.0, 128.6, 128.8, 132.4, 141.1, 198.2,
206.1; IR (liquid film) 1725, 1680, 730 cm-1; MS m/z (rel
intensity) 312 (M+, 6), 223 (100), 194 (63), 166 (100), 138 (60),
51(47); HRMS calcd for C16H21O2SCl 312.0952, found 312.0957.
Anal. Calcd for C16H21O2SCl: C, 61.43; H, 6.76. Found: C,
61.18; H, 6.60. Ee determination (HPLC, Daicel Chiralpak AD,
2.07 (3H, s), 2.73 (1H, dd, J ) 7.6 and 15.0 Hz), 2.75-2.85
(2H, m), 2.88 (1H, dd, J ) 6.3 and 17.1 Hz), 3.78 (1H, quintet,
J ) 7.3 Hz), 7.33 (2H, m), 7.54 (2H, m); 13C NMR (125.8 MHz,
CDCl3) δ 29.6, 30.3, 37.5, 48.3, 48.6, 49.8, 124.1 (q, J ) 273
Hz), 125.4 (q, J ) 3.8 Hz), 127.9, 129.0 (q, J ) 32.7 Hz), 146.8,
198.0, 205.9; IR (liquid film) 1720, 1680, 730 cm-1; MS m/z
(rel intensity) 346 (M+, 3), 257 (100), 199 (60); HRMS calcd
for C17H21O2F3S 346.1215, found 346.1220. Anal. Calcd for
C
17H21O2F3S: C, 58.94; H, 6.11. Found: C, 59.00; H, 6.08. Ee
determination (HPLC, Daicel Chiralpak AD, 1 mL/min, 1%
2-PrOH in hexane) (S) t1 ) 19.9 min, (R) t2 ) 27.8 min. The
absolute stereochemistry was assumed by analogy.
S-ter t-Bu tyl (S)-3-(3-tr iflu or om eth ylp h en yl)-5-oxoh ex-
1
a n eth ioa te (7g): H NMR (500 MHz, CDCl3) δ 1.39 (9H, s),
2.11 (3H, s), 2.73 (1H, dd, J ) 7.5 and 15.0 Hz), 2.8-2.9 (2H,
m), 2.93 (1H, dd, J ) 6.5 and 17.5 Hz), 3.80 (1H, quintet, J )
7.0 Hz), 7.43 (2H, m), 7.45-7.5 (2H, m); 13C NMR (125.8 MHz,
CDCl3) δ 29.6, 30.3, 37.6, 48.3, 48.6, 49.9, 123.67, 123.70, 124.2,
129.0, 131.1, 143.7, 198.1, 205.9; IR (liquid film) 1720, 1675,
800, 705 cm-1; MS m/z (rel intensity) 346 (M+, 2), 257 (100),
1 mL/min, 2% 2-PrOH in hexane) (S) t1 ) 14.1 min, (R) t2
)
13.2 min. The absolute stereochemistry was assumed by
analogy.
199 (71); HRMS calcd for
C17H21O2F3S 346.1215, found
S-ter t-Bu tyl (S)-3-(3-ch lor op h en yl)-5-oxoh exa n eth io-
a te (7c): 1H NMR (300 MHz, CDCl3) δ 1.38 (9H, s), 2.07 (3H,
s), 2.66 (1H, dd, J ) 7.4 and 14.8 Hz), 2.75 (1H, dd, J ) 7.2
and 14.7 Hz), 2.78 (1H, dd, J ) 7.7 and 17.1 Hz), 2.85 (1H,
dd, J ) 6.6 and 17.1 Hz), 3.68 (1H, quintet, J ) 7.0 Hz), 7.09
(1H, m), 7.17 (3H, m); 13C NMR (125.8 MHz, CDCl3) δ 29.6,
30.3, 37.4, 48.2, 48.5, 49.9, 125.7, 126.9, 127.5, 129.7, 134.2,
346.1220. Anal. Calcd for C17H21O2F3S: C, 58.94; H, 6.11.
Found: C, 58.50; H, 6.09. Ee determination (HPLC, Daicel
Chiralpak AD, 1 mL/min, 1% 2-PrOH in hexane) (S) t1 ) 10.7
min, (R) t2 ) 11.7 min. The absolute stereochemistry was
assumed by analogy.
S-ter t-Bu tyl (S)-3-(4-Meth ylp h en yl)-5-oxoh exa n eth io-
a te (7h ): 1H NMR (300 MHz, CDCl3) δ 1.39 (9H, s), 2.03 (3H,
s), 2.29 (3H, s), 2.64-2.87 (4H, m), 3.66 (1H, quintet, J ) 7.5
Hz), 7.07 (4H, m); 13C NMR (125.8 MHz, CDCl3) δ 21.0, 29.6,
30.3, 37.6, 48.0, 49.0, 50.5, 127.1, 129.2, 136.2, 139.6, 199.5,
144.7, 198.1, 206.0; IR (liquid film) 1725, 1680, 735, 690 cm-1
;
MS m/z (rel intensity) 312 (M+, 5), 223 (100), 166 (77), 138
(15), 51(12); HRMS calcd for C16H21O2SCl 312.0952, found
312.0957. Anal. Calcd for C16H21O2SCl: C, 61.43; H, 6.77.
Found: C, 60.98; H, 6.74. Ee determination (HPLC, Daicel
206.7; IR (liquid film) 2960, 2920, 1725, 1675, 725, 700 cm-1
;
MS m/z (rel intensity) 292 (M+, 1), 203 (99), 145 (100), 118
(12), 57 (11); HRMS calcd for C17H24O2S 292.1498, found
292.1497. Anal. Calcd for C17H24O2S: C, 69.82; H, 8.27.
Found: C, 69.51; H, 8.42. Ee determination (HPLC, Daicel
Chiralpak AD, 1 mL/min, 1% 2-PrOH in hexane) (S) t1 ) 16.7
min, (R) t2 ) 14.4 min. The absolute stereochemistry was
assumed by analogy.
Chiralpak ADH, 1 mL/min, 1% 2-PrOH in hexane) (S) t1
15.7 min, (R) t2 ) 16.8 min. The absolute stereochemistry was
assumed by analogy.
)
S-ter t-Bu tyl (S)-3-(4-flu or op h en yl)-5-oxoh exa n eth ioa te
1
(7d ): H NMR (500 MHz, CDCl3) δ 1.36 (9H, s), 2.04 (3H, s),
2.66 (1H, dd, J ) 7.5 and 14.5 Hz), 2.70-2.85 (3H, m), 3.69
(1H, quintet, J ) 7.5 Hz), 6.95 (2H, m), 7.16 (2H, m); 13C NMR
(125.8 MHz, CDCl3) δ 29.6, 30.3, 37.2, 48.1, 49.0, 50.3, 115.3
(d, J ) 21.4 Hz), 128.9 (d, J ) 7.5 Hz), 138.3 (d, J ) 3.8 Hz),
161.5 (d, J ) 244 Hz), 198.3, 206.4; IR (liquid film) 1720, 1685,
835 cm-1; MS m/z (rel intensity) 296 (M+, 4), 207 (100), 150
(58), 122 (28), 51(11); HRMS calcd for C16H21O2SF 296.1247,
found 296.1241. Anal. Calcd for C16H21O2SF: C, 64.83; H, 7.14.
S-ter t-Bu tyl (S)-3-(4-m eth oxyp h en yl)-5-oxoh exa n eth -
ioa te (7i): 1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.04 (3H,
s), 2.65-2.85 (4H, m), 3.65 (1H, quintet, J ) 7.3 Hz), 3.77 (3H,
s), 6.82 (2H, m), 7.11 (2H, m); 13C NMR (125.8 MHz, CDCl3) δ
29.6, 30.4, 37.3, 48.0, 49.2, 50.6, 55.2, 113.9, 128.3, 134.6, 158.3,
198.6, 206.9; IR (liquid film) 1720, 1675, 870, 760 cm-1; MS
m/z (rel intensity) 308 (M+, 14), 190 (100), 177 (56); HRMS
calcd for C17H24O3S 308.1447, found 308.1442. Anal. Calcd for
(26) allo-Threonine derivative 3g was separated by filtration as its
sodium salt. The sodium salts of 3g obtained from several runs were
combined and extracted with ethyl acetate after acidification with 1
N HCl. A pure ligand could be recovered by concentration of the dried
organic extracts and recrystallization from benzene.
C
17H24O3S: C, 66.20; H, 7.84. Found: C, 65.84; H, 7.56. Ee
determination (HPLC, Daicel Chiralcel OJ , 1 mL/min, 1%
2-PrOH in hexane) (S) t1 ) 28.1 min, (R) t2 ) 31.8 min. The
absolute stereochemistry was assumed by analogy.
J . Org. Chem, Vol. 68, No. 26, 2003 10055

Wang et al.
S-ter t-Bu tyl (S)-3-(2-n aph th yl)-5-oxoh exan eth ioate (7j):
1H NMR (500 MHz, CDCl3) δ 1.22 (9H, s), 1.91 (3H, s), 2.65-
2.8 (4H, m), 3.75 (1H, quintet, J ) 7.1 Hz), 7.20 (1H, dd, J )
1.7 and 7.6 Hz), 7.25-7.35 (2H, m), 7.50 (1H, br s), 7.6-7.7
(3H, m); 13C NMR (125.8 MHz, CDCl3) δ 29.7, 30.4, 38.1, 48.2,
49.0, 50.4, 125.6 (2c), 126.1 (2c), 127.6, 127.7, 128.4, 132.4,
Chiralpak AD, 0.5 mL/min, 1% 2-PrOH in hexane) (S) t1
29.1 min, (R) t2 ) 24.3 min.
)
S-ter t-Bu tyl (S)-6-m eth yl-5-oxo-3-p h en ylh ep ta n eth io-
1
a te (7p ): H NMR (300 MHz, CDCl3) δ 0.94 (3H, d, J ) 6.9
Hz), 1.00 (3H, d, J ) 6.9 Hz), 1.36 (9H, s), 2.46 (1H, septet, J
) 6.9 Hz), 2.69 (1H, dd, J ) 7.4 and 14.7 Hz), 2.80 (1H, dd, J
) 7.4 and 14.7 Hz), 2.82 (2H, m), 3.71 (1H, quintet, J ) 7.0
Hz), 7.14-7.29 (4H, m); 13C NMR (125.8 MHz, CDCl3) δ 17.8,
29.6, 37.8, 41.0, 45.8, 47.9, 50.1, 126.6, 127.3, 128.4, 142.8,
198.4, 212.2; IR (liquid film) 2970, 2925, 1720, 1680, 735, 700
cm-1; MS m/z (rel intensity) 306 (M+), 217 (100), 188, 131 (49),
71(17); HRMS calcd for C18H26O2S 306.1655, found 306.1656.
Anal. Calcd for C18H26O2S: C, 70.54; H, 8.55. Found: C, 70.18;
H, 8.51. Ee determination (HPLC, Daicel Chiralpak AD, 1 mL/
min, 1% 2-PrOH in hexane) (S) t1 ) 11.4 min, (R) t2 ) 10.4
min. The absolute stereochemistry was assumed by analogy.
S-ter t-Bu tyl (S)-6,6′-d im eth yl-5-oxo-3-p h en ylh ep ta n e-
th ioa te (7q): 1H NMR (300 MHz, CDCl3) δ 1.03 (9H, s), 1.38
(9H, s), 2.68-2.98 (4H, m), 3.74 (1H, quintet, J ) 7.2 Hz),
7.16-7.32 (5H, m); 13C NMR (125.8 MHz, CDCl3) δ 26.0, 29.6,
37.7, 45.3, 44.0, 47.9, 50.0, 126.5, 127.5, 128.3, 143.1, 198.5,
213.3. Ee determination (HPLC, Daicel Chiralpak AD, 1 mL/
min, 1% 2-PrOH in hexane) (S) t1 ) 8.3 min, (R) t2 ) 9.0 min.
The absolute stereochemistry was assumed by analogy.
S-ter t-Bu tyl 5-oxo-3,5-d ip h en ylp en ta n eth ioa te (7r ): 1H
NMR (300 MHz, CDCl3) δ 1.38 (9H, s), 2.80 (1H, dd, J ) 7.4
and 14.8 Hz), 2.90 (1H, dd, J ) 7.4 and 14.8 Hz), 3.34 (1H,
dd, J ) 7.4 and 16.8 Hz), 3.39 (1H, dd, J ) 6.7 and 16.8 Hz),
3.90 (1H, quintet, J ) 7.2 Hz), 7.35-7.5 (5H, m), 7.4-7.6 (3H,
m), 7.90 (2H, m).
133.4, 140.1, 198.3, 206.7; IR (liquid film) 1720, 1680, 745 cm-1
;
MS m/z (rel intensity) 328 (M+, 27), 272 (2), 210 (89), 181 (100),
156 (24), 128(8), 51(7); HRMS calcd for C20H24O2S 328.1498,
found 328.1500. Anal. Calcd for C20H24O2S: C, 73.13; H, 7.36.
Found: C, 72.92; H, 7.21. Ee determination (HPLC, Daicel
Chiralpak AD, 1 mL/min, 1% 2-PrOH in hexane) (S) t1 ) 21.2
min, (R) t2 ) 27.4 min. The absolute stereochemistry was
assumed by analogy.
S-ter t-Bu tyl (S)-3-(1-n aph th yl)-5-oxoh exan eth ioate (7k):
1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.10 (3H, s), 2.85-
3.1 (4H, m), 4.65 (1H, quintet, J ) 7.0 Hz), 7.35 (1H, br d, J
) ca. 7 Hz), 7.45 (1H, t, J ) ca. 9 Hz), 7.51 (1H, t, J ) ca. 8
Hz), 7.59 (1H, t, J ) ca. 7.5 Hz), 7.75 (1H, br d, J ) ca. 8.5
Hz), 7.87 (1H, br d, J ) ca. 8 Hz), 8.24 (1H, br d, J ) ca. 8.5
Hz); 13C NMR (125.8 MHz, CDCl3) δ 29.6 (2c), 30.2, 48.2, 48.6,
50.0, 123.0, 124.4, 125.3, 125.6, 126.3, 127.4, 128.9, 131.1,
134.0, 138.9, 198.7, 206.6; IR (liquid film) 1715, 1680, 795, 780
cm-1; MS m/z (rel intensity) 328 (M+, 13), 239 (14), 181 (100),
153 (76); HRMS calcd for C20H24O2S 328.1498, found 328.1495.
Anal. Calcd for C20H24O2S: C, 73.13; H, 7.36. Found: C, 72.92;
H, 7.25. Ee determination (HPLC, Daicel Chiralcel OD, 1 mL/
min, 0.4% 2-PrOH in hexane) (S) t1 ) 40.5 min, (R) t2 ) 46.6
min. The absolute stereochemistry was assumed by analogy.
S-ter t-Bu tyl (S)-3-(2-fu r a n yl)-5-oxoh exa n eth ioa te (7l):
1H NMR (500 MHz, CDCl3) δ 1.43 (9H, s), 2.12 (3H, s), 2.75-
2.85 (4H, m), 3.82 (1H, quintet, J ) 7.0 Hz), 6.05 (1H, d, J )
3.5 Hz), 6.27 (1H, dd, J ) 2.0 and 3.5 Hz), 7.31 (1H, d, J ) 2.0
Hz); 13C NMR (125.8 MHz, CDCl3) δ 29.7, 30.1, 31.4, 46.3, 47.5,
48.2, 105.5, 110.1, 141.3, 155.4, 198.2, 206.4; IR (liquid film)
1720, 1680, 730 cm-1; MS m/z (rel intensity) 268 (M+, 13), 179
(49), 152 (100); HRMS calcd for C14H20O3S 268.1134, found
268.1136. Anal. Calcd for C14H20O3S: C, 62.66; H, 7.51.
Found: C, 61.93; H, 7.50. Ee determination (HPLC, Daicel
S-ter t-Bu tyl 2-(3-oxocycloh exyl)eth a n eth ioa te (7s): 1H
NMR (300 MHz, CDCl3) δ 1.3-1.5 (10H, including s (9H) at
1.44), 1.68 (1H, m), 1.93 (1H, m), 2.0-2,1 (2H, m), 2.2-2.5 (6H,
m).
S-ter t-Bu tyl 5-(ter t-bu tyld im eth ylsiloxy)-3-p h en yl-4-
2-(3-oxocycloh exyl)eth a n eth ioa te (12): 1H NMR (300 MHz,
CDCl3) δ 0.10 (3H, s), 0.16 (3H, s), 0.97 (9H, s), 1.37 (9H, s),
1.78 (3H, s), 2.65-2.85 (2H, m), 4.28 (br q, J ) ca. 8 Hz), 4.6
(1H, br d, J ) ca. 9 Hz), 7.1-7.3 (5H, m) [a minor geometric
isomer resonated at 3.93 (1H, m) and 4.78 (1H, br d, J ) ca.
10 Hz)].
Chiralpak OD, 1 mL/min, 0.7% 2-PrOH in hexane) (S) t1
12.1 min, (R) t2 ) 13.0 min. The absolute stereochemistry was
assumed by analogy.
)
Meth yl (S)-5-Oxo-3-p h en ylh exa n eth ioa te (15a ). To a
solution of 7a (61.6 mg, 0.220 mmol, 79% ee) in ether (1 mL)
at room temperature was added silver trifluoroacetate (88.0
mg, 0.40 mmol). The resulting suspension was stirred at room
temperature for 4 h. Methanol (40 µL, 1.0 mmol) was added
to this mixture. After being stirred for 36 h at room temper-
ature, the mixture was filtered through a pad of cellulose
powder and the filtrate was concentrated in vacuo. Purification
of the residue by flash chromatography (5% ethyl acetate in
hexane) gave 24.4 mg (55% yield) of 13a : [R]24D -16.9 (c 1.22,
S-ter t-Bu tyl (S)-3-m eth yl-5-oxoh exa n eth ioa te (7m ): 1H
NMR (300 MHz, CDCl3) δ 0.96 (3H, d, J ) 6.5 Hz), 1.44 (9H,
s), 2.13 (3H, s), 2.25-2.56 (5H, m); 13C NMR (125.8 MHz,
CDCl3) δ 19.6, 27.0, 29.6, 30.21, 47.9, 49.7, 50.5, 199.3, 207.0;
IR (liquid film) 2960, 2925, 1725, 1675, 730 cm-1; MS m/z (rel
intensity) 217 (M+, 13), 169 (6), 127 (100), 99 (4), 69(2); HRMS
calcd for C11H20O2S 217.1263, found 217.1268. Anal. Calcd for
C
11H20O2S: C, 61.07; H, 9.32. Found: C, 60.73; H, 8.96. Ee
determination (HPLC, Daicel Chiralpak AD, 1 mL/min, 2%
2-PrOH in hexane) (S) t1 ) 6.2 min, (R) t2 ) 6.0 min.
benzene) [lit.17 (for R-enantiomer) [R]24 22.4 (benzene)]; 1H
D
S-ter t-Bu tyl (S)- 5-oxo-3-p en tylh exa n eth ioa te (7n ): 1H
NMR (300 MHz, CDCl3) δ 0.87 (3H, t, J ) 7.2 Hz), 1.2-1.35
(8H, m), 1.45 (9H, s), 2.14 (3H, s), 2.35-2.55 (5H, m); 13C NMR
(125.8 MHz, CDCl3) δ 14.0, 22.5, 26.3, 29.7, 30.3, 31.78, 31.81,
33.9, 47.7, 48.0, 48.2, 199.8, 208.1; IR (liquid film) 2940, 1720,
1680; MS (CI) m/z (rel intensity) 273 (MH+, 100), 255 (42),
183 (42); HRMS (CI) calcd for C15H29O2S (MH+) 273.1888,
found 273.1887. Ee determination (HPLC, Daicel Chiralpak
AD, 1 mL/min, 1% 2-PrOH in hexane) (S) t1 ) 6.4 min, (R) t2
) 7.0 min.
NMR (300 MHz, CDCl3) δ 2.06 (3H, s), 2.60 (1H, dd, J ) 7.6
and 15.3 Hz), 2.69 (1H, dd, J ) 7.2 and 15.3 Hz), 2.79 (1H,
dd, J ) 7.4 and 16.7 Hz), 2.86 (1H, dd, J ) 7.0 and 16.7 Hz),
3.58 (3H, s), 3.68 (1H, quintet, J ) ca. 7.5 Hz), 7.17-7.24 (3H,
m), 7.26-7.33 (2H, m).
Met h yl (S)-5-Oxo-3-p h en ylh ep t a n et h ioa t e (15b ). The
compound was obtained in 47% yield from 7o (61% ee) by a
procedure similar to that described above; [R]24D -24.1 (c 0.150,
benzene) [lit.17 (for R-enantiomer) [R]24 35.3 (benzene)]; 1H
D
NMR (300 MHz, CDCl3) δ 0.96 (3H, t, J ) 7.3 Hz), 2.32 (2H,
m), 2.69 (1H, dd, J ) 7.7 and 15.3 Hz), 2.69 (1H, dd, J ) 7.2
and 15.3 Hz), 2.76 (1H, dd, J ) 7.3 and 16.5 Hz), 2.82 (1H,
dd, J ) 7.0 and 16.5 Hz), 3.58 (3H, s), 3.69 (1H, quintet, J )
ca. 7.5 Hz), 7.16-7.32 (5H, m).
S-ter t-Bu tyl (S)-5-oxo-3-p h en ylh ep ta n eth ioa te (7o): 1H
NMR (300 MHz, CDCl3) δ 0.95 (3H, t, J ) 7.3 Hz), 1.37 (9H,
s), 2.22-2,42 (2H, m), 2.67-2.86 (4H, m), 3.71 (1H, quintet, J
) 7.2 Hz), 7.15-7.31 (4H, m); 13C NMR (125.8 MHz, CDCl3) δ
7.5, 29.6, 36.3, 38.0, 47.7, 48.0, 50.3, 126.7, 127.3, 128.4, 142.7,
198.5, 209.2; IR (liquid film) 2950, 2920, 1710, 1675, 780, 700
cm-1; MS m/z (rel intensity) 292 (M+), 236, 203 (100), 131 (5),
104 (15), 57; HRMS calcd for C17H24O2S 292.1498, found
292.1491. Anal. Calcd for C17H24O2S: C, 69.82; H, 8.27.
Found: C, 69.53; H, 7.93. Ee determination (HPLC, Daicel
(3S,1′R)-N-(1′-(R-Na p h t h yl)et h yl)-3-m et h yl-5-oxoh ex-
a n ea m id e (16). To a solution of 7m (46.5 mg, 0.22 mmol) and
(R)-(+)-R-naphthylethylamine (71 µL, 0.44 mmol) in THF (2.2
mL) at room temperature was added the silver trifluoroacetate
(97 mg, 0.44 mmol). After being stirred for 1 day at room
temperature, the mixture was quenched by the addition of 1
10056 J . Org. Chem., Vol. 68, No. 26, 2003

Enantioselective Mukaiyama-Michael Reactions of Acyclic Enones
N HCl and extracted twice with ethyl acetate. The organic
layers were washed successively with NaHCO3 and water,
Ack n ow led gm en t. Financial support from the Min-
istry of Education, Science, Sports and Culture of the
J apanese Government [Grant-in-Aid for Scientific Re-
search (Priority Areas, No. 412)] is gratefully acknowl-
edged.
dried, and concentrated in vacuo. Purification of the residue
by flash chromatography (20-50% ethyl acetate in hexane)
gave 24.4 mg (38% yield) of 14: 1H NMR (500 MHz, CDCl3) δ
0.99 (3H, d, J ) 6.6 Hz), 1.69 (3H, d, J ) 6.5 Hz), 2.08 (3H, s),
2.12 (1H, dd, J ) 7.0 and 13.8 Hz), 2.20 (1H, dd, J ) 6.8 and
13.8 Hz), 2.30 (1H, dd, J ) 6.8 and 16.3 Hz), 2.45 (1H, sextet,
J ) 6.6 Hz), 2.54 (1H, dd, J ) 6.1 and 16.3 Hz), 5.95-6.0 (2H,
m), 7.45-7.6 (4H, m), 7.82 (1H, d, J ) ca. 8 Hz), 7.89 (1H, d,
J ) ca. 8 Hz), 8.12 (1H, d, J ) ca. 8 Hz) [a minor diastereomer
resonated at δ 0.98 (3H, d, J ) 6.6 Hz) and 2.09 (3H, s)].
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1g, 2, 3a ,b,d ,f,i-k , 7n ,q-s, 12, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O035379X
J . Org. Chem, Vol. 68, No. 26, 2003 10057