Asymmetric induction of three consecutive chiral centers by reactions of N-enoylthioamides with aldehydes

Article abstract of DOI:10.1002/anie.200351106

Wrap it up and put on a bow! The reaction of N-cinnamoyl-1,3-oxazoline-2-thione with aromatic aldehydes in the presence of BF₃·Et₂O diastereoselectively gave adducts 1, which contain three consecutive asymmetric centers and a chiral bridgehead bound to four heteroatoms.

Full text of DOI:10.1002/anie.200351106

Angewandte
Chemie
Tandem Michael–Aldol Reaction
Asymmetric Induction of Three Consecutive
Chiral Centers by Reactions of
N-Enoylthioamides with Aldehydes**
Tadashi Kataoka,* Hironori Kinoshita,
Sayaka Kinoshita, Takashi Osamura, Shin-
ichi Watanabe, Tatsunori Iwamura, Osamu Muraoka,
and Genzoh Tanabe
Recently we developed a chalcogenide/TiCl4-mediated reac-
tion, which consists of the Michael addition of a chloride ion
generated from a chalcogenide/TiCl4 complex to an enone,
followed by an aldol reaction with an aldehyde to give an a-
chloromethyl aldol, which can be transformed into an a-
methylene aldol (the Morita–Baylis–Hillman adduct).[1,2] This
reaction is completed much faster than the Morita–Baylis–
Hillman reaction[3] and, therefore, can be utilized advanta-
geously in several reactions which do not give good results
under Morita–Baylis–Hillman reaction conditions.[4–8] We
further studied the tandem Michael–aldol reaction initiated
by the intramolecular Michael cyclization of a chalcogenide
group to an enone moiety.[9–11] Goodman et al. reported a
similar intermolecular example.[12]
While investigating the chalcogenide catalyst, we found
that a thioketone acted as a nucleophile toward an enone[13]
and a thiourea was also useful for the tandem Michael–aldol
reaction.[14] Recently, it was reported that a thiourea moiety
added intramolecularly to an enone moiety to form a thiazine
ring.[15,16] These reports prompted us to examine the tandem
Michael–aldol reaction of N-propenoyl cyclic thioamides with
aldehydes. We now report the asymmetric tandem Michael–
aldol reaction of chiral N-cinnamoyl-1,3-thiazolidine-2-thione
and its 1,3-oxazolidine congener with aldehydes in the
presence of BF3·Et2O.
The reaction of N-cinnamoyl-1,3-thiazolidine-2-thione
(1a) with p-chlorobenzaldehyde (2a) was conducted for the
first time [Eq. (1)]. The results are shown in Table 1. Various
molar ratios of the starting compounds and the Lewis acid
were tested, and the best result was obtained from the
reaction of 1a (2 equiv) with 2a (1 equiv) in the presence of
3 equiv BF3·Et2O (Table 1, entry 1). This reaction was quite
fast and was completed within 15 minutes at room temper-
[*] Prof. T. Kataoka, H. Kinoshita, S. Kinoshita, T. Osamura,
Dr. S. Watanabe, Dr. T. Iwamura
Gifu PharmaceuticalUniversity
6-1 Mitahora-higashi 5-chome, Gifu 502-8585 (Japan)
Fax: (+81)58-237-5979
E-mail: kataoka@gifu-pu.ac.jp
Prof. O. Muraoka, Dr. G. Tanabe
Faculty of Pharmaceutical Sciences
Kinki University
3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan)
[**] This work was supported in part by a Grant-in-Aid (No. 3824) from
the Japan Society for the Promotion of Science.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 2889 – 2891
DOI: 10.1002/anie.200351106
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2889

Communications
Table 1: Representative results for the screening of reaction conditions for the diastereoselective tandem Michael–aldol reactions of N-cinnamoyl-1,3-
thiazolidine-2-thiones 1a,b with aldehydes 2a,b.
Entry
Enone (equiv)
Aldehyde (equiv)
BF3·Et2O [equiv]
T
Products[a] (% yield)
1
2
3
4
5
1a (2)
1a (2)
1a (1)
1b (2)
1b (2)
2a (1)
2a (1)
2a (2)
2a (1)
2b (1)
3
2
3
3
3
RT
RT
RT
08C
08C
3a (58), 4a (31)
3a (50), 4a (33)
3a (48), 4a (30)
5a (54), 6a (28), 7a (4)
5b (43), 6b (41), 7b (4)
[a] Minor products 7a and 7b have the same molecular weights and composition formulas, C22H22ClNO2S2 and C22H22N2O4S2, as 5a, 6a and 5b, 6b,
respectively, but the amounts of 7a and 7b are so small that their stereostructures could not yet be determined.
ature. The structures of products 3a and 4a were determined
1
by comparing the their H and 13C NMR data with those of
5a, whose structure was elucidated by X-ray analysis (vide
infra).
We obtained the three diastereomeric products 5–7 from
the reactions of chiral thioamide 1b, which has a 4S
configuration, with aldehydes 2a,b. X-ray analysis revealed
that the major product 5a (R1 = iPr, R2 = Cl) has a tricyclic
ring system, in which a chiral bridgehead carbon is bound to
four heteroatoms (Figure 1). The configuration of the four
chiral centers is 1R,4S,7R,8S,11R.[17] The structure of product
6a, in which the ClC6H4 group is on the same side as H-11, was
1
determined by comparing its H and 13C NMR spectra with
those of 5a. The absolute configuration of the 8-position is
8R, opposite to that of 5a.
Palomo et al. reported that a chiral thioamide can
undergo an asymmetric Michael addition to an intramolec-
ular enone moiety with high diastereoselectivity.[16] Based on
their findings and ours, we anticipated that the stereoselective
formation of the four chiral centers involving three consec-
utive chiral carbons could be achieved if the aldol reaction of
an enolate with an aldehyde could be stereocontrolled.
Hence, we selected 4,5-disubstituted
Figure 1. X-ray crystalstructure of 5a (ORTEP drawing).
oxazolidine-2-thione as a chiral auxil-
iary and carried out reactions of N-
cinnamoyl-4S-methyl-5R-phenyloxa-
zolidinethione (1c) with various alde-
hydes [Eq. (2)] (Table 2).
The best molar ratio of enone 1
and aldehyde 2 from Table 1 was
applied to the reaction of 1c and 2b,
and the reaction temperature and time were examined. The
reaction at À788C for 25 h gave 8b in 27% yield (Table 2,
entry 1). When the reaction was conducted at À408C, the
chemical yield increased but a small amount of diastereomer
9b formed (entry 2). The best result was obtained for the
reaction at À408C for 24 h (entry 3). The stereostructure of
2890
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2889 – 2891

Angewandte
Chemie
[2] T. Kataoka, H. Kinoshita, T.
Table 2: Diastereoselective tandem Michael–aldol reactions of N-cinnamoyl-1,3-oxazolidine-2-thione 1c
with aldehydes 2a–e.
Iwama, S. Tsujiyama, T. Iwamura,
S. Watanabe, O. Muraoka, G.
Tanabe, Tetrahedron 2000, 56,
4725 – 4731.
Entry
Aldehyde (R3)
Conditions
Yield [%][a]
8:9:10[b]
1
2
3
4
5
6
7
2b (p-NO2C6H4)
2b (p-NO2C6H4)
2b (p-NO2C6H4)
2c (m-NO2C6H4)
2a (p-ClC6H4)
2d (Ph)
À788C, 25 h
À408C, 5 h
À408C, 24 h
À408C, 24 h
À408C, 24 h
08C, 1 h
27
77
93
85
71
69
59
100:0:0
94:6:0
95:5:0
95:5:0
86:7:7
69:3:28
92:0:8
[3] For reviews of the Morita–Baylis–
Hillman reaction: a) S. E. Drewes,
G. H. P. Roos, Tetrahedron 1988,
44, 4653 – 4670; b) D. Basavaiah,
P. D. Rao, R. S. Hyma, Tetrahe-
dron 1996, 52, 8001 – 8062; c) E.
Ciganek in Organic Reactions,
Vol. 51 (Ed.: L. A. Paquette),
Wiley, New York, 1997, pp. 201 –
350; d) P. Langer, Angew. Chem.
2000, 112, 3177 – 3180; Angew.
2e (p-MeC6H4)
08C, 1 h
[a] Mixture of diastereoisomers. [b] HRMS data indicate that products 9 and 10 have the same molecular
formulas as product 8, but their sterostructures could not be determined because of the small amounts.
Chem. Int. Ed. 2000, 39, 3049 – 3052; e) D. Basavaiah, A. J.
Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811 – 891.
[4] a) T. Kataoka, T. Iwama, H. Kinoshita, S. Tsujiyama, Y.
Tsurukami, T. Iwamura, S. Watanabe, Synlett 1999, 197 – 198;
b) T. Kataoka, T. Iwama, H. Kinoshita, Y. Tsurukami, S.
Tsujiyama, M. Fujita, E. Honda, T. Iwamura, S. Watanabe, J.
Organomet. Chem. 2000, 611, 455 – 462.
[5] D. Basavaiah, K. Muthukumaran, B. Sreenivasulu, Synlett 1999,
1249 – 1250.
[6] T. Bauer, J. Tarasiuk, Tetrahedron: Asymmetry 2001, 12, 1741 –
1745.
[7] R. Pathak, A. K. Shaw, A. P. Bhaduri, Tetrahedron 2002, 58,
3535 – 3541.
[8] T. Kataoka, H. Kinoshita, S. Kinoshita, T. Iwamura, S. Watanabe,
Angew. Chem. 2000, 112, 2448 – 2450; Angew. Chem. Int. Ed.
2000, 39, 2358 – 2360.
[9] T. Kataoka, S. Kinoshita, H. Kinoshita, M. Fujita, T. Iwamura, S.
Watanabe, Chem. Commun. 2001, 1958 – 1959.
[10] T. Kataoka, H. Kinoshita, S. Kinoshita, T. Iwamura, J. Chem.
Soc. Perkin Trans. 1 2002, 2043 – 2045.
the major product 8b corresponds to that of 6b, which has a 4-
isopropylthiazolidine moiety. Diastereomer ratios of the
products were determined from 1H NMR spectra of the
crude products. Reactions with p-chloro- (2a) and m-nitro-
benzaldehyde (2c) were conducted similarly and gave prod-
ucts 8a and 8c in good yields together with isomers 9a,c and
10a (entries 4 and 5). The reaction with benzaldehyde was
slow and was conducted at 08C, but the diasteromer ratio was
decreased (entry 6). Reaction with p-tolualdehyde (2e) gave
the products in a moderate chemical yield (entry 7). The
reaction with o-nitrobenzaldehyde was very slow because of
the steric hindrance, and the reaction with dihydrocinnamal-
dehyde gave a mixture of products with a low diastereomer
ratio.
In conclusion, we have developed a novel tandem
Michael–aldol reaction of chiral thioamide-enones with
aldehydes, which induces four chiral centers simultaneously.
This method is easy to use and gives unusual heterotricyclic
compounds with three consecutive chiral centers and a chiral
carbon center bound to four heteroatoms. If the products can
be converted into polyfunctionalized chiral carboxylic acids,
aldehydes, amides or alcohols, they can be widely utilized for
organic synthesis. This is the subject of current investigation.
[11] T. Kataoka, H. Kinoshita, S. Kinoshita, T. Iwamura, Tetrahedron
Lett. 2002, 43, 7039 – 7041.
[12] L. M. Walsh, C. L. Winn, J. M. Goodman, Tetrahedron Lett.
2002, 43, 8219 – 8222.
[13] T. Iwama, H. Kinoshita, T. Kataoka, Tetrahedron Lett. 1999, 40,
3741 – 3744.
[14] S. Kinoshita, H. Kinoshita, T. Iwamura, S. Watanabe, T. Kataoka,
Chem. Eur. J. 2003, 9, 1496 – 1502.
[15] A. Hari, B. L. Miller, Org. Lett. 2000, 2, 3667 – 3670.
[16] a) C. Palomo, M. Oiarbide, F. Dias, A. Ortiz, A. Linden, J. Am.
Chem. Soc. 2001, 123, 5602 – 5603; b) A. Ortiz, L. Quintero, H.
Hernµndez, S. Maldonado, G. Mendoza, S. Bern›s, Tetrahedron
Lett. 2003, 44, 1129 – 1132.
Experimental Section
General procedure: To a stirred solution of (4S,5R)-4-methyl-5-
phenyl-3-[(E)-3-phenylprop-2-enoyl]-1,3-oxazolidine-2-thione
(1c)(323 mg, 1.0 mmol) and p-nitrobenzaldehyde (2b)(76 mg,
0.5 mmol) in dry CH2Cl2 (1.6 mL) was added dropwise a solution of
BF3·Et2O (190 mL, 1.5 mmol) at À408C. The mixture was stirred at
the same temperature for 24 h, poured into NaHCO3 solution, and
extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by recycling preparative HPLC, eluting with chloroform to
give 8b and 9b.
[17] Crystal structure data for 5a: C22H22ClNO2S2, Mr = 431.99,
prismatic, space group P212121, a = 11.636(2), b = 18.035(2), c =
9.947(2) Š, V= 2087.4(5) Š3, T= 296 K, Z = 4, 1calcd
=
1.375 gcmÀ3
,
m(MoKa) = 4.01 cmÀ1
,
R = 0.0243, Rw = 0.061.
CCDC-200264 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
Received: February 5, 2003 [Z51106]
Keywords: aldol reactions · asymmetric synthesis ·
.
C–C coupling · Michael addition · thiocarbonyl compounds
[1] a) T. Kataoka, T. Iwama, S. Tsujiyama, Chem. Commun. 1998,
197 – 198; b) T. Kataoka, T. Iwama, S. Tsujiyama, T. Iwamura, S.
Watanabe, Tetrahedron 1998, 54, 11813 – 11824.
Angew. Chem. Int. Ed. 2003, 42, 2889 – 2891
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2891