Asymmetric thio-Michael/nucleophilic addition domino reaction with chiral N-sulfinimines

Article abstract of DOI:10.1021/jo062251h

(Chemical Equation Presented) Optically active N-sulfinimines underwent stereoselective Michael/nucleophilic addition domino reaction triggered by magnesium thiolate to give α-phenylthiomethyl-β-(N-sulfinylamino) esters in high diastereomeric excess. The

Full text of DOI:10.1021/jo062251h

imines. Recently we have developed an alternative stereose-
lective Baylis-Hillman strategy, that is the domino-Michael/
aldol method with a sulfur-centered anion and analogous
conditions.11 With the extension of our method for asymmetric
synthesis of amino compounds, we focused on the use of chiral
sulfinimines which were devised by Davis12 and Ellman.13 In
this paper we report a stereoselective asymmetric Michael/
nucleophilic addition domino reaction, which provided a general
method for the asymmetric aza-Baylis-Hillman-equivalent
reaction for aromatic as well as aliphatic imines.
(S)-Sulfinimines 1 were prepared through the reported method
in >95% ee.14 Exposure of imine 1 to a mixture of magnesium
thiolate and tert-butyl acrylate resulted in the smooth formation
of domino adduct 2 in good yields (Scheme 1). The results are
summarized in Table 1.
Asymmetric Thio-Michael/Nucleophilic Addition
Domino Reaction with Chiral N-Sulfinimines
Akio Kamimura,*,† Hidenori Okawa,‡ Yuki Morisaki,‡
Shingo Ishikawa,† and Hidemitsu Uno§
Department of Applied Molecular Bioscience, Graduate School
of Medicine, Yamaguchi UniVersity, Ube 755-8611, Japan,
Department of Applied Chemistry, Faculty of Engineering,
Yamaguchi UniVersity, Ube 755-8611, Japan, and
Integrated Center for Sciences, Ehime UniVersity,
Matsuyama 790-8577, Japan
ak10@yamaguchi-u.ac.jp
ReceiVed October 31, 2006
Magnesium thiolate was generated from the corresponding
thiol and methyl Grignard reagent. tert-Butyl acrylate and chiral
sulfinimine 1a were added at -50 °C to the mixture. After usual
workup, desired domino adduct 2a was obtained in 99% yield
(entry 1). The adduct 2a contained two diastereomers whose
ratio was 81/19. The major isomer was isolated by the usual
chromatographic purification and recrystallization. The obtained
crystals of major 2a allowed us to perform an X-ray crystal-
lographic analysis that unambiguously indicated that its absolute
configuration was 2R,3R. Use of lithium thiolate also promoted
the reaction but the yield of 2a decreased to 43% although the
level of diastereoselectivity was almost the same (entry 2). Other
sulfinimines 1 also underwent the reaction smoothly to give 2
in good yields (entry 3-8). It should be mentioned that not
only aromatic sulfinimines but also aliphatic sulfinimines gave
the adduct 2 in good yields. The absolute stereochemistry of
major-2e was also confirmed by X-ray crystallographic analysis,
Optically active N-sulfinimines underwent stereoselective
Michael/nucleophilic addition domino reaction triggered by
magnesium thiolate to give R-phenylthiomethyl-â-(N-sulfi-
nylamino) esters in high diastereomeric excess. The adducts
were readily converted into optically active R-methylene-
â-(N-sulfinylamino)esters so that this reaction provides a
useful asymmetric aza-Baylis-Hillman-equivalent method.
(3) (a) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507. (b)
Shi, M.; Chen, L.-H. Chem. Commun. 2003, 1310. (c) Shi, M.; Xu, Y.-M.;
Shi, Y.-L. Chem. Eur. J. 2005, 11, 1794. (d) Shi, M.; Chen, L.-H.; Li,
C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. (e) Shi, M.; Chen, L.-H.; Teng,
W.-D. AdV. Synth. Catal. 2005, 347, 1781. (f) Shi, M.; Li, C.-Q.
Tetrahedron: Asymmetry 2005, 16, 1385. (g) Shi, Y.-L.; Shi, M. Tetrahedron
2006, 62, 461. (g) Liu, Y.-H.; Chen, L.-H.; Shi, M. AdV. Synth. Catal. 2006,
348, 973.
(4) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
(5) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama,
S. Org. Lett. 2003, 5, 3103.
(6) Li, G.; Wei, H.-X.; Whittlesey, B. R.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061.
(7) Aggarwal, V. K.; Castro, A. M. M.; Mereu, A.; Adams, H.
Tetrahedron Lett. 2002, 43, 1577.
(8) (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127,
3680. (b) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761. (c) Matsui,
K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry
2006, 17, 578.
(9) Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701.
(10) Gausepohl, R.; Buskens, P.; Kleiner, J.; Bruckmann, A.; Lehmann,
C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45,
3689.
The Baylis-Hillman reaction has been recognized as a
potentially useful organic reaction because it provides one-step
preparation of R-methylene-â-hydroxy carbonyl compounds
from readily available R,â-unsaturated carbonyl compounds and
aldehydes.1 Catalytic asymmetric modification of the reaction
has been of interest among organic chemists and a number of
reports have been published so far.2 Use of imines instead of
aldehydes gives â-amino-R-methylene esters so the aza-variation
of the reaction is also regarded as an important method for
organic synthesis. Recently, Shi,3 Adolfsson,4 Hatakeyama,5 Li,6
Aggarwal,7 Sasai,8 Jacobsen,9 and Leitner10 have reported
various attempts to obtain the asymmetric aza-Baylis-Hillman
adducts; however, use of imines is only limited for aromatic
† Department of Applied Molecular Bioscience, Graduate School of Medicine,
Yamaguchi University.
‡ Department of Applied Chemistry, Faculty of Engineering, Yamaguchi
University.
§ Integrated Center for Sciences, Ehime University.
(1) (a) Drews, S. E.; Roo, G. H. P. Tetrahedron 1988, 44, 4653. (b)
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (c)
Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York,
1997; Vol. 51, p 201. (d) Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049. (e) Iwabuchi, Y.; Hatakeyama, S. J. Synth. Org. Chem. Jpn. 2002,
60, 2. (f) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811.
(2) (a) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun.
1998, 2533. (b) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama,
S. J. Am. Chem. Soc. 1999, 121, 10219. (c) McDougal, N. T.; Schaus,
S. E. J. Am. Chem. Soc. 2003, 125, 12094.
(11) (a) Kamimura, A.; Mitsudera, H.; Asano, S.; Kakehi A.; Noguchi,
M. Chem. Commun. 1998, 1095. (b) Kamimura, A. J. Synth. Org. Chem.
Jpn. 2004, 62, 705.
(12) (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27,
13. (b) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(c) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichim. Acta 2005, 38, 93.
(13) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984.
(14) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
10.1021/jo062251h CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/04/2007
J. Org. Chem. 2007, 72, 3569-3572
3569

SCHEME 1. Michael/Aldol Domino Reaction of 1
SCHEME 2. Conversion to â-Amino-r-methylene Ester 3a
TABLE 1. Michael/Nucleophilic Addition Domino Reaction of 1
entry
Ar
R
2
yield (%)a
syn/antib
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClC6H4
Et
2a
2a
2b
2c
2d
2e
2f
99
43c
100
84
85
75
96
84
79
81/19
81/19
88/12
89/11
95/5
83/17
97/3
89/11
79/21
a Separated through chromatographic treatment.
SCHEME 3. Conversion of 2 to r-Methylene Aminoester 3
Pr
iPr
iBu
C5H11
Ph
2g
2h
o-CH3C6H4
a Isolated yields. b Determined by HPLC analyses (ODS-column, MeOH/
H2O 70:30 or 80:20). c Lithium thiolate (PhSLi) was used instead of
magnesium thiolate.
TABLE 2. Conversion to Aza-Baylis-Hillman Adducts 3
yield (%)a
deb
which unambiguously indicated its configuration was identical
with that of major-2a.15 The HPLC pattern for compounds 2
made from aliphatic imines was the same so that these results
clearly supported that the configurations for all of major-2 were
syn.16 The presence of a substituent at the ortho position of
thiolate sometimes enhanced the stereoselectivity17 so we
examined the magnesium salt of o-thiocresol for the reaction.
Unfortunately, a slight decrease of the diastereoselectivity was
observed (entry 9).
entry
R
3
1
2
3
4
5
6
7
Ph
3a
3b
3c
3d
3e
3f
65
65
69
67
47
58
51
>99
>99
90
94
97
p-ClC6H4
Et
Pr
iPr
iBu
99
98
C5H11
3g
a Isolated yields. b Determined by HPLC analyses (ODS-column, MeOH/
H2O 70:30 or 80:20).
We next examined the conversion of 2a to aza-Baylis-
Hillman adducts through thermal elimination of sulfoxide.
Treatment of 2a (dr ) 81/19) with 1 equiv of m-CPBA at 0 °C
gave the corresponding sulfoxide, which afforded the desired
aza-Baylis-Hillman adduct 3a in 65% yield by treatment at
110 °C in toluene. 1H and 13C NMR spectra and HPLC analysis
supported that obtained 3a was diastereomerically pure so that
these results suggested that both of the diastereomers of 2a might
have the same R configuration at the C3 carbon (Scheme 2).
To confirm the absolute configuration of the minor isomer of
2a, we performed a further experiment. The minor isomer of
2a was purified by very careful chromatographic operation, and
treated under similar oxidation/thermal elimination conditions.
This operation also gave diastereomerically pure 3a, which
showed the same positive optical rotation as well as the identical
NMR spectra to the product obtained from syn-2a. These results
clearly supported that minor-2a also contained the same R
configuration at C3. Thus, the diastereomeric difference between
the two isomers of 2a came from the difference of configuration
at C2 so that the stereochemistry of minor-2a has clearly
determined to be 2S,3R anti. It should be mentioned that the
level of diastereoselectivity at C3, which was derived from the
chiral sulfinimine unit, was almost 100%.
Other adducts of 2 were also converted into R-methylene
derivatives 3 in good yields (Scheme 3).18 The results are
summarized in Table 2. This transformation was useful for not
only aromatic-imine adducts 2a and 2b, but also aliphatic-imines
adducts 2c to 2g (entry 3-7). It should be noted that the
temperature of the thermal elimination of sulfoxide was crucial
to avoid partial epimerization at the C3 carbon. For example,
when the elimination of the sulfoxide from 2d was performed
under vigorously refluxing conditions (bath temperature was
about 150 °C), 3d was obtained in 54% yield but became a
mixture of two diastereomers, the ratio of which was 68:32.
After an extensive search for optimized elimination conditions
we found the best elimination conditions, 110 °C for the oil
bath temperature for 1 h, and under these conditions we
succeeded in suppressing the undesired epimerization to less
than the 5% level. Thus, the present method provides the first
general method for the preparation of the optically active aza-
Baylis-Hillman adducts of aliphatic imines.
(15) Due to the sequential rule, adducts syn-2a, syn-2b, and syn-2h from
aromatic imines are assigned to be 2R,3R, while adducts syn-2c to syn-2g
from aliphatic imines are assigned to be 2R,3S, but all of them have the
same absolute stereochemistry as shown in Scheme 1.
(16) In HPLC analyses performed by usual ODS column (4.6 mm id ×
150 mm length), syn-2 was eluted earlier than anti-2. For example, tR for
syn-2f was 60.7 min, while tR for anti-2f was 70.8 min (flow rate ) 0.7
mL/min, MeOH:H2O ) 70:30).
(17) For example: Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K.
J. Am. Chem. Soc. 1997, 119, 12974.
(18) Due to the sequential rule, assignment at C3 is S in all of compounds
3 but the absolute stereochemistry at C3 is maintained during the conversion
from 2 to 3.
3570 J. Org. Chem., Vol. 72, No. 9, 2007

further transformation. The N-sulfinyl group was removed by
acidic treatment.21 The adducts of the present reaction were
potentially useful for the conversion to the aza-Baylis-Hillman
adducts. Further application of the reaction is now underway
in our laboratory.
Experimental Section
Preparation of Thio-Michael/Nucleophilic Addition Domino
Adducts 2: Preparation of (2R,3R)-tert-Butyl 3-phenyl-2-(phe-
nylthio)methyl- 3-(N-p-toluenesulfinyl)aminopropionate [2a]
(syn-2a). To a solution of thiophenol (0.102 mL, 1 mmol) in CH2-
Cl2 (2 mL) was added methylmagnesium bromide (0.86 mL, 1.2
mmol, 1.4 M in toluene/tetrahydrofuran (75:25)) at -50 °C. After
the solution was stirred for 10 min, tert-butyl acrylate (0.146 mL,
1 mmol) and (S)-benzalsulfinimine 1a (0.243 g, 1 mmol) were
added to the mixture at -50 °C and the mixture was allowed to
stir for 6 h at -50 °C. The reaction was quenched by adding
saturated NH4Cl (30 mL) and the mixture was allowed to warm to
0 °C. The mixture was extracted with EtOAc (3 × 30 mL) and the
combined organic phase was washed with brine (1 × 10 mL) and
dried over Na2SO4. After filtration, crude product was obtained by
concentration. Purification by flash column chromatography (silica
gel, hexane:EtOAc ) 7:1) afforded 2a in 99% yield (0.477 g, syn/
anti ) 81/19). White solid; mp 102-103 °C; [R]D +79.8 (CHCl3,
FIGURE 1. Plausible transition state of the reaction.
SCHEME 4. Removal of N- and O-Protection and
Conversion to â-Lactam
1
c 0.88); H NMR (CDCl3) δ 1.25 (s, 9 H), 2.42 (s, 3 H), 2.81-
2.99 (m, 2 H), 3.08 (dd, 1 H, J ) 4.5, 12.9 Hz), 4.74 (t, 1 H, J )
6.0 Hz), 4.84 (d, 1 H, J ) 4.9 Hz), 7.16-7.36 (m, 12 H), 7.57 (d,
2 H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 21.3, 27.8, 32.7, 52.4, 58.9,
82.0, 125.3, 126.5, 128.1, 128.2, 128.5, 129.0, 129.7, 129.8, 135.3,
139.0, 141.6, 142.3, 172.1; IR (KBr) ν 3200, 2990, 1740, 1170,
1100, 1040, 690 cm-1. Anal. Calcd for C27H31NO3S2: C, 67.33;
H, 6.49; N, 2.91. Found: C, 67.15; H, 6.60; N, 2.94.
The mechanistic origin for the present selectivity remains
unclear. However, we assume that the reaction should proceed
in a similar mechanism to what Davis proposed.19 The mag-
nesium cation should coordinate to both the oxygen atom of
the sulfoxide and the nitrogen atom of the imine to fix a
chelating structure that activates the imine unit toward the
domino reaction as well as offer sufficient steric bias to achieve
the present high diastereoselectivity in the C-nucleophilic attack
on the CdN double bond (Figure 1). The syn/anti selectivity
of the reaction, which should have depended on the E/Z
formation of the enolate, ranged around 8:2 to 9:1, which was
close to the syn/anti selectivity of the Michael/aldol domino
reaction by lithium thiolate.20
The conversion of 2 to â-lactam was also examined. The
sulfinyl group of the adduct was readily removed by acidic
treatment. For example, treatment of 2e with commercially
available HCl solution in dioxane resulted in the smooth removal
of both the N-sulfinyl group and the O-tert-butyl group to give
4, which underwent cyclization to give cis-â-lactam 5 as a single
isomer. The syn-configuration of 5 was supported by 5.5% of
the NOE observed between Hi and H3′ (Scheme 4).
(2S,3R)-tert-Butyl 3-phenyl-2-(phenylthio)methyl-3-(N-p-tolu-
enesulfinyl)aminopropionate [2a] (anti-2a). Yellow oil;
1
[R]D + 31.0 (CHCl3, c 0.51); H NMR (CDCl3) δ 1.29 (s, 9 H),
2.42 (s, 3 H), 2.76-2.84 (m, 1 H), 3.04 (dd, 1 H, J ) 5.9, 13.5
Hz), 3.16 (dd, 1 H, J ) 8.4, 13.4 Hz), 4.72 (t, 1 H, J ) 6.4 Hz),
5.41 (d, 1 H, J ) 6.4 Hz), 7.15-7.45 (m, 12 H), 7.57 (d, 2 H, J )
8.4 Hz); 13C NMR (CDCl3) δ 22.1, 27.9, 33.9, 52.0, 59.0, 82.2,
12.54, 126.5, 127.1, 127.8, 128.5, 129.0, 129.6, 129.8, 135.2, 140.3,
141.4, 142.2, 171.8.
Preparation of â-(N-p-toluenesulfinyl)amino-R-metyleneester
3: Preparation of (3S)-tert-Butyl 2-methylene-3-phenyl-3-(N-
p-toluenesulfinyl)aminopropionate [3a]. To a solution of 2a (0.481
g, 1 mmol, syn/anti ) 81/19) in CH2Cl2 (10 mL) at 0 °C was added
m-CPBA (80 wt %, 0.173 g, 1 mmol), and the reaction mixture
was allowed to stir at the same temperature for 30 min. The reaction
was monitored by TLC analysis. After disappearance of 2a, the
reaction mixture was diluted with EtOAc and washed with saturated
NaHCO3 (1 × 20 mL) and dried over Na2SO4. Filtration followed
by concentration in vacuo gave crude sulfoxide, which was solved
in toluene (10 mL) and allowed to heat at 110 °C for 1 h. The
progress of the reaction was carefully monitored by TLC. The
mixture was concentrated in vacuo and residue was purified through
flash chromatography (silica gel, hexane/ethyl acetate ) 10:1 v/v)
to give 3a in 65% yield (0.241 g). White solid; mp 125-126 °C;
Thus, the present method represents a useful synthesis of
multifunctionalized â-aminoester derivatives from readily avail-
able chiral sulfinimines. The domino reaction formed a new
carbon-carbon bond in a highly stereoselective manner, and
installed the thio-functional group that should be useful for
1
[R]D +111.8 (CHCl3, c 1.00); H NMR (CDCl3) δ 1.30 (s, 9 H),
2.41 (s, 3 H), 4.80 (d, 1 H, J ) 7.0 Hz), 5.39 (d, 1 H, J ) 7.0 Hz),
5.67 (s, 1 H), 6.21 (s, 1 H), 7.24-7.61 (m, 9 H); 13C NMR (CDCl3)
δ 21.4, 27.8, 58.0, 81.5, 125.7, 125.9, 127.5, 127.6, 128.5, 129.5,
140.0, 141.4, 141.7, 142.3, 164.6; IR (KBr) ν 3150, 2990, 1720,
1150, 1090 cm-1. Anal. Calcd. for C21H25NO3S: C, 67.89; H, 6.78;
N, 3.77. Found: C, 67.94; H,6.71; N, 3.74.
(19) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398.
(20) Kamimura, A.; Mitsudera, H.; Asano, S.; Kidera, S.; Kakehi, A.
J. Org. Chem. 1999, 64, 6353.
(21) Davis reported the N-sulfinyl group was removed by acidic treatment
and we have also succeeded in removing it from 3. The optimized condition
is now under investigation in our laboratory.
The same treatment of anti-2a gave 3a. [R]D +116.3 (CHCl3, c
1
0.99); H NMR and 13C NMR were identical with 3a.
Preparation of (4S,3R)-4-Isopropyl-3-phenylthiomethyl-2-
azetidinone [5]. Compound 2e (0.4370 g, 0.977 mmol) was
J. Org. Chem, Vol. 72, No. 9, 2007 3571

dissolved in HCl-dioxane (4 M, 25 mL) at room temperature. The
reaction mixture was allowed to stir for 6 h and disappearance of
2e was monitored by TLC. After the reaction was completed,
solvent was removed to give 4 as the residue. The residue was
added to a solution of EDCI (0.7860 g, 4 mmol), Et3N (0.75 mL),
and DMAP (0.01 g) in CH2Cl2 (100 mL) and the resulting solution
was allowed to stir for 72 h. The reaction mixture was poured into
dilute HCl (40 mL) and the mixture was extracted with EtOAc (3
× 50 mL). The organic phases were combined, washed with
NaHCO3 aq (30 mL), and dried over Na2SO4. After filtration, the
organic solution was concentrated in vacuo. The residue was
purified through flash chromatography (silica gel, hexane-EtOAc
10:1, 5:1, then 3:1 v/v) and the desired â-lactam 5 was isolated in
30% yield (69.5 mg). White solid; mp 104-105 °C; [R]D +16.8
6.9, 13.3 Hz), 3.31-3.48 (m, 3 H), 6.00 (s, 1 H), 7.18-7.41 (m, 5
H); 13C NMR (CDCl3) δ 19.7, 19.8, 28.6, 29.0, 52.0, 59.1, 126.5,
129.1, 129.7, 135.6, 169.4. Anal. Calcd for C13H17NOS: C, 66.34;
H, 7.28; N, 5.95. Found: C, 66.23; H, 7.22; N, 6.12.
Supporting Information Available: Preparation of aliphatic
chiral sulfinimine 1, physical data for compounds syn-2b, syn-2c,
syn-2d, syn-2e, syn-2f, syn-2g, syn-2h, 3b, 3c, 3d, 3e, 3e, 3f, and
1
3g, H NMR and 13C NMR spectra for compounds syn-2a, anti-
2a, syn-2b, syn-2c, syn-2d, syn-2e, syn-2f, syn-2g, syn-2h, 3a, 3b,
3c, 3d, 3e, 3e, 3f, 3g, and 5, and X-ray crystallographic data for
compounds syn-2a and syn-2e. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
(CHCl3, c 0.25); H NMR (CDCl3) δ 0.97 (d, 3 H, J ) 6.4 Hz),
1.03 (d, 3 H, J ) 6.5 Hz), 1.78-1.92 (m 1 H), 3.16 (dd, 1 H, J )
JO062251H
3572 J. Org. Chem., Vol. 72, No. 9, 2007