Stereoselective addition of the titanium enolate of N-acetyl (4S)-isopropyl-1,3-thiazolidine-2-thione to five-membered N-acyl iminium ions

Article abstract of DOI:10.1021/jo050188a

Addition of the chlorotitanium enolate of N-acetyl 4-isopropyl-1,3- thiazolidine-2-thione to five-membered, N-Substituted N-acyl iminium ions furnished the corresponding Mannich-type addition products with good diastereoselectivity and in good yields. The

Full text of DOI:10.1021/jo050188a

strated in the addition of nucleophiles to chiral cyclic
imine and iminium ions.4 Enolates derived from chiral
ester surrogates such as N-acyl-oxazolidinones and par-
ticularly N-acyl-thiazolidinethiones have appeared to be
promising nucleophiles for achieving high diastereose-
lection in the addition to prochiral cyclic imine and
iminum ions.5
Stereoselective Addition of the Titanium
Enolate of N-Acetyl
(4S)-Isopropyl-1,3-thiazolidine-2-thione to
Five-Membered N-Acyl Iminium Ions
Efra´ın Barraga´n, Horacio F. Olivo,*
Moise´s Romero-Ortega, and Seth Sarduy
Highly diastereoselective alkylation of the tin(II) eno-
late of N-acetyl isopropyl thiazolidinethione (IPTT) was
observed by Nagao’s group when added to cyclic acyl
imines.5g-k However, a lack of diastereoselectivity was
observed when the same enolate was added to cyclic
N-acyl iminium ions.5c,g,h Similarly to the acetate aldol
reaction, the presence of a removable group on the
N-acetyl group results in high enantioselectivities, albeit
increasing the number of steps in the synthesis.5g,6 Some
diastereoselectivity was observed by Pilli when the
titanium(IV) chloride of chiral N-acetyl oxazolidinone was
alkylated with N-acylpiperidinium ions, but no selectivity
was obtained with the corresponding five-membered
analogues.5c In this paper, we describe our investigations
on the addition of titanium(IV) enolates of N-acetyl IPTT
to five-membered N-acyliminium ions. We are interested
in these addition products because of their potential as
intermediates for the synthesis of several Stemona and
other alkaloids.7
A difference in stereoselectivity between N-acetyl and
N-propionyl groups is observed in chiral auxiliary-based
aldol and Mannich-type reactions. Although excellent dia-
stereoselectivity is observed in propionate aldol reactions
using chiral oxazolidinones, poor diastereoselectivity is
observed in the acetate aldol reactions.8 However, very
good stereoselectivities have been observed in acetate
aldol reactions using chiral oxazolidinethiones and thia-
zolidinethiones.9 Several advantages of thiazolidinethi-
one chiral auxiliaries have also been shown over their
Division of Medicinal and Natural Products Chemistry,
College of Pharmacy, The University of Iowa,
Iowa City, Iowa 52242
horacio-olivo@uiowa.edu
Received January 29, 2005
Addition of the chlorotitanium enolate of N-acetyl 4-isopro-
pyl-1,3-thiazolidine-2-thione to five-membered, N-Substi-
tuted N-acyl iminium ions furnished the corresponding
Mannich-type addition products with good diastereoselec-
tivity and in good yields. The synthetic utility of the addition
product 8 was demonstrated in a chemospecific anti-aldol
reaction with cinnamaldehyde. By using this strategy, we
constructed three contiguous chiral centers with high ste-
reocontrol employing the same chiral auxiliary. X-Ray
crystallographic analysis of addition product 2 and aldol
product 14 revealed their absolute stereochemistry.
â-Aminocarbonyl functionalities are important con-
stituents of many biologically active natural products and
therapeutics. They are also useful building blocks for the
syntheses of heterocyclic natural products and modified
peptides with enhanced in vivo stability.1 The Mannich
reaction is one of the classical methods for the prepara-
tion of â-aminocarbonyl compounds.2 Over the past few
years, the addition of nucleophiles of silyl enol ethers,
silyl keteneacetals, and enamines to preformed iminium
salts has greatly expanded the versatility of this reac-
tion.3 Good diastereofacial selectivity has been demon-
(4) (a) Klitske, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605-
5608. (b) Mukaiyama, T.; Kobayashi, S. Org. React. (NY) 1994, 46,
1-103. (c) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Perga-
mon: Oxford, 1991; Vol. 2, pp 1047-1082. (d) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
(5) Addition of chiral thiazolidinethiones and oxazolidinones to
imines or iminium ions: (a) Ambhaikar, N. B.; Snyder, J. P.; Liotta,
D. C. J. Am. Chem. Soc. 2003, 125, 3690-3691. (b) Ferstl, E. M.;
Venkatesan, H.; Ambhaikar, N. B.; Snyder, J. P.; Liotta, D. C. Synthesis
2002, 14, 2075-2083. (c) Pilli, R. A.; Bo¨ckelmann, M. A.; Alves, C. F.
J. Braz. Chem. Soc. 2001, 12, 634-651. (d) Pilli, R. A.; Alves, C. de F.;
Bo¨ckelmann, M. A.; Mascarenhas, Y. P.; Nery, J. G.; Vencato, I.
Tetrahedron Lett. 1999, 40, 2891-2894. (e) Matsumura, Y.; Kanda,
Y.; Shirai, K.; Onomura, O.; Maki, T. Org. Lett. 1999, 1, 175-178. (f)
Pilli, R. A.; Russowsky, D. J. Org. Chem. 1996, 61, 3187-3190. (g)
Nagao, Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. Tetrahedron 1990, 46,
6361-6380. (h) Nagao, Y.; Dai, W.-M.; Ochiai, M. Tetrahedron Lett.
1988, 29, 6133-6136. (i) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi,
S.; Fujita, E. J. Am. Chem. Soc. 1988, 110, 289-291. (j) Nagao, Y.;
Kumagai, T.; Tamai, S.; Kuramoto, Y.; Taga, T.; Aoyagi, S.; Nagase,
Y.; Ochiai, M.; Inoue, Y.; Fujita, E. J. Am. Chem. Soc. 1986, 108, 4673-
4675. (k) Nagao, Y.; Kumagai, T.; Abe, T.; Ochiai, M.; Taga, T.;
Machida, K.; Inoue, Y. J. Chem. Soc., Chem. Commun. 1986, 602-
603. (l) Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. J. Am. Chem. Soc.
1986, 108, 4675-4676.
(1) â-Aminocarbonyl compounds: (a) Williams, R. M. Synthesis of
Optically Active R-Amino Acids. Pergamon: Oxford, 1989. (b) Cole, D.
C. Tetrahedron 1994, 50, 9517-9582. (c) Juaristi, E.; Quintana, D.;
Escalante, J. Aldrichimica Acta 1994, 27, 3-11.
(2) Mannich reaction: (a) Maryanoff, B. E.; Zhang, H. C.; Cohen, J.
H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431-1628.
(b) Arend, M.; Westermann, B.;. Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044-1070. (c) Tramontini, M.; Angiolini, L. Tetrahedron 1990,
46, 1791-1837. (d) Tramontini, M. Synthesis 1973, 703-775.
(3) Addition of nucleophiles of silyl enol ethers, silyl keteneacetals,
and enamines: (a) Camilo, N. S.; Pilli, R. A. Tetrahedron Lett. 2004,
45, 2821-2823. (b) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M.
D.; Ga´lvez, J. A. Tetrahedron Lett. 2003, 44, 9189-9192. (c) Russowsky,
D.; Petersen, R. Z.; Godoi, M. N.; Pilli, R. A. Tetrahedron Lett. 2000,
41, 9939-9942. (d) Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki,
M. Tetrahedron Lett. 1996, 37, 2809-2812. (e) Hart, D. J.; Ha, D.-C.
Chem. Rev. 1989, 89, 1447-1465. (f) Pilli, R. A.; Russowsky, D. J.
Chem. Soc., Chem. Commun. 1987, 1053-1054.
(6) Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T.
Tetrahedron 2000, 56, 7411-7422.
(7) Vela´zquez, F.; Olivo, H. F. Org. Lett. 2002, 4, 3175-3178.
(8) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39-42.
10.1021/jo050188a CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/09/2005
4214
J. Org. Chem. 2005, 70, 4214-4217

TABLE 1.
entry
TiCl4
base
temp, time
dr (anti:syn)
yield
1
2
3
4
5
6
1 equiv
2 equiv
3 equiv
2 equiv
3 equiv
2 equiv
DIPEA, 1.2 equiv
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 2 h
-78 to 0 °C, 5 h
77:23
74:26
76:24
nd
70:30
80:20
48%
66%
71%
30%
61%
82%
DIPEA, 1.2 equiv
DIPEA, 1.2 equiv
(-)-sparteine, 1.2 equiv
(-)-sparteine, 1.2 equiv
DIPEA, 1.2 equiv
oxazolidinone analogues, e.g., they can be directly re-
duced to aldehydes, easily removed, and displaced by
some nucleophiles.10,11 For these reasons, we are now
interested in expanding their utility in Mannich-type
additions.
A modest yield and good diastereoselectivity was
obtained when the titanium(IV) enolate of N-acetyl
IPTT12 was reacted with N-cinammyl 5-acetoxypyrroli-
dinone,13 employing 1 equiv of Lewis acid and 1 equiv of
Hunig’s base, Table 1. A slight improvement in yield was
observed when the number of equivalents of Lewis acid
was doubled and also when the reaction was allowed to
warm to 0 °C before quenching. The diastereomeric
products were separated on silica gel chromatography,
and the major isomer was obtained as a solid. Single-
crystal X-ray diffraction analysis of the major isomer
revealed the stereochemistry of the newly created ste-
reocenter.14 The stereochemistry of the major diastere-
omer 2 corresponds to the anti product (where the
isopropyl group on the chiral auxiliary and the hetero-
atom are on opposite sides). Interestingly and contrary
to results obtained when employing tin(II) triflate,5g,h
some good diastereoselectivity is observed when employ-
ing the less expensive titanium(IV) chloride.
FIGURE 1. Open transition state.
TABLE 2. Alkylation of N-Acetyl IPTT with
N-Substituted Cyclic N-Acyliminium Ion
entry
R
dr (anti:syn)
yield
1
2
3
4
5
6
-Ph
(4:9) 73:27
(5:10) 80:20
(6:11) 80:20
(7:12) 78:22
(2:3) 80:20
(8:13) 88:12
80%
58%
77%
75%
82%
84%
p-CH2C6H4Br
-CH2Ph
-(CH2)3CH3
trans-CH2CHdCHPh
trans-CH2CHdCHCH3
The stereochemical outcome of the major diastereomer
can be rationalized as being formed by a transition state
in which the cyclic N-acyl iminium ion approaches the
titanium(IV) enolate on the less hindered side, with the
N-acyl group antiperiplanar to the enolate as illustrated
in Figure 1. This presumed transition state yields
preferentially the anti product 2 (4′S,3R stereochemis-
tries).
Addition of the titanium enolate of N-acetyl IPTT to
other N-substituted 5-acetoxypyrrolidinones under the
optimized reaction conditions is shown in Table 2. N-
Substituents included aromatic, benzylic, allylic, and
alkyl groups. Iminium addition products were obtained
in a similar diastereomeric ratio in 58-84% yields. In
all cases, chromatographic separation of the diastereo-
mers was easy to monitor because of the yellow color of
the addition products.
To test the utility of these iminium addition products,
N-acyl thiazolidinethione 8 was added to cinnamaldehyde
employing the recently disclosed conditions for an anti-
aldol reaction.15 Aldol addition of N-acyl thiazolidine-
thione 8 to cinnamaldehyde in the presence of substoi-
chiometric amounts (10%) of MgBr2-Et2O, TMSCl, and
Et3N in ethyl acetate gave exclusively one stereoisomer
in 81% yield. The structure and stereochemistry of anti-
(9) (a) Nagao, Y.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985,
1418-1419. (b) Nagao, Y.; Fujita, E. J. Org. Chem. 1986, 51, 2391-
2393. (c) Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H.
J. Org. Chem. 1995, 60, 3301-3306. (d) Gonza´lez, A.; Aiguade´, J.; Urp´ı,
F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949-8952. (e) Guz, N.
R.; Phillips, A. J. Org. Lett. 2002, 4, 2253-2256. (f) Zhang, Y.; Phillips,
A. J.; Sammakia, T. Org. Lett. 2004, 6, 23-25. (g) Hodge, M. B.; Olivo,
H. F. Tetrahedron 2004, 60, 9397-9403.
(10) For a review on chiral thiazolidinethiones and oxazolidine-
thiones, see: Vela´zquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6,
303-340.
(11) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-
777. (b) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.;
Carroll, K. A.; van Alphen, S. Org. Lett. 2004, 6, 2317-2320. (c) Wu,
Y.; Sun, Y.-P.; Yang, Y.-Q.; Hu, Q.; Zhang, Q. J. Org. Chem. 2004, 69,
in press.
(12) Andrade, C. K. Z.; Rocha, R. O.; Vercillo, O. E.; Silva, W. A.;
Matos, R. A. F. Synlett 2003, 2351-2352.
(13) Acetoxy N-substituted pryrrolidines were prepared by acety-
lation of the 5-hydroxy N-substituted pyrrolidinone prepared as in:
Guzma´n, A.; Romero, M.; Muchowski, J. M. Can. J. Chem. 1990, 68,
791-794.
(14) ORTEP drawings and crystallographic data of compounds 2 and
14 can be found in Supporting Information.
(15) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org.
Lett. 2002, 4, 1127-1130.
J. Org. Chem, Vol. 70, No. 10, 2005 4215

(CHCl3-ethyl acetate-petroleum ether, 4:2:1); [R]D25 +152.2 (c
1.0, CHCl3); IR 2965, 1686, 1256, 1038, 753 cm-1 1H NMR
SCHEME 1. anti-Aldol Condensation of N-Acyl
Thiazolidinethione 8 with Cinnamaldehyde.
;
(CDCl3) δ 7.41-7.19 (5H, m), 6.52 (1H, d, J ) 15.8 Hz), 6.11
(1H, dd, J ) 15.8, 6.0 Hz), 5.12 (1H, t, J ) 7.0 Hz), 4.30 (1H, dd,
J ) 15.5, 6.3 Hz), 4.15 (1H, m), 3.89 (1H, dd, J ) 15.8, 7.0 Hz),
3.76 (1H, dd, J ) 17.7, 4.1 Hz), 3.48 (1H, dd, J ) 17.7, 8.5 Hz),
3.30 (1H, dd, J ) 11.7, 8.2 Hz), 2.95 (1H, dd, J ) 11.4, 0.6 Hz),
2.63-2.23 (4H, m), 1.79 (1H, m), 1.05 (3H, d, J ) 6.8 Hz), 0.97
(3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 203.1 (C), 175.0 (C),
170.9 (C), 136.5 (C), 132.9 (CH), 128.7 (2CH), 127.9 (CH), 126.5
(2CH), 124.4 (CH), 71.5 (CH), 54.7 (CH), 43.4 (CH2), 42.9 (CH2),
30.9 (CH), 30.3 (CH2), 29.8 (CH2), 25.3 (CH2), 19.2 (CH3), 17.8
(CH3); HRMS (EI) exact mass calcd for C21H26N2O2S2Na [M +
Na]+ 425.1333, found 425.1353.
aldol product 14 were verified by single-crystal X-ray
diffraction analysis.14 Gratifyingly, the aldol reaction pro-
ceeded uneventfully; no retro Mannich was observed, and
the lactam ring was untouched. The free aldol product
15 was obtained in quantitative yield after acidic removal
of the silyl group. By using this synthetic sequence, three
contiguous chiral centers were constructed with high
stereocontrol employing the same chiral auxiliary.In
summary, we have studied the addition of titanium
enolates of N-acetyl IPTT to N-substituted pyrroli-
dinonium formed in situ. Addition products were obtained
in good yields and with good diastereoselectivity. No
significant difference in diastereoselectivity was observed
with different N-substituents in the iminium ion moiety.
These iminium addition products were shown to be useful
substrates for anti-aldol addition reactions.
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(phenyl)-pyrrolidin-2-one (4): Rf 0.34 (CHCl3-ethyl
25
acetate-petroleum ether, 4:2:1); [R]D +311.5 (c 1.0, CHCl3);
IR 2966, 1694, 1376, 1169, 755 cm-1; 1H NMR (CDCl3) δ 7.43-
7.35 (4H, m), 7.23 (1H, m), 5.03 (1H, t, J ) 7.1 Hz), 4.75 (1H,
m), 3.63 (1H, dd, J ) 17.5, 3.5 Hz), 3.43 (1H, dd, J ) 11.2, 7.9
Hz), 3.35 (1H, dd, J ) 17.5, 9.2 Hz), 2.98 (1H, dd, J ) 11.6, 0.9
Hz), 2.72-2.41 (3H, m), 2.25 (1H, sext, J ) 6.6 Hz), 1.86 (1H,
m), 1.00 (3H, d, J ) 6.8 Hz), 0.92 (3H, d, J ) 7.0 Hz); 13C NMR
(CDCl3) δ 202.3 (C), 174.2 (C), 170.6 (C), 137.1 (C), 129.3 (2CH),
126.4 (CH), 124.6 (2CH), 71.4 (CH), 56.9 (CH), 42.4 (CH2), 30.8
(CH), 30.8 (CH2), 30.4 (CH2), 24.7 (CH2), 19.1 (CH3), 17.6 (CH3);
HRMS (EI) exact mass calcd for C18H23N2O2S2 [M + H]+
363.1201, found 363.1211.
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(p-bromobenzyl)-pyrrolidin-2-one (5): Rf 0.37 (CHCl3-
25
ethyl acetate-petroleum ether, 4:2:1); [R]D +256.7 (c 1.0,
Experimental Section
CHCl3); IR 2965, 1683, 1488, 1258, 1160 cm-1; 1H NMR (CDCl3)
δ 7.44 (2H, d, J ) 8.3 Hz), 7.13 (2H, d, J ) 8.3 Hz), 5.05 (1H, t,
J ) 7.0 Hz), 4.66 (1H, d, J ) 15.4 Hz), 4.22 (1H, d, J ) 15.4 Hz),
4.01 (1H, m), 3.76 (1H, dd, J ) 17.5, 3.5 Hz), 3.46 (1H, dd, J )
11.3, 7.9 Hz), 3.07 (1H, dd, J ) 17.3, 9.4 Hz), 3.00 (1H, d, J )
11.6 Hz), 2.63-2.19 (4H, m), 1.85-1.70 (1H, m), 1.02 (3H, d, J
) 6.8 Hz), 0.93 (3H, d, J ) 7.1 Hz); 13C NMR (CDCl3) δ 203.1
(C), 175.3 (C), 170.3 (C), 136.1 (C), 131.9 (2CH), 129.7 (2CH),
121.5 (C), 71.4 (CH), 54.8 (CH), 44.3 (CH2), 42.2 (CH2), 30.9 (CH),
30.5 (CH2), 29.7 (CH2), 24.6 (CH2), 19.1 (CH3), 17.7 (CH3); HRMS
(EI) exact mass calcd for C19H24BrN2O2S2 [M + H]+ 455.0463,
found 455.0466.
General Procedure for the Titanium Enolate Addition
to Iminium Ions. The 5-acetoxy N-substituted pyrrolidinone
was first prepared from the corresponding 5-hydroxy pyrrolidi-
none. To a solution of 5-hydroxy N-substituted pyrrolidinone (1.1
mmol) in dichloromethane (5 mL) was added acetic anhydride
(0.5 mL, 2 mmol) and triethylamine (0.5 mL, 3.5 mmol). The
reaction was quenched after 10 h by addition of water. The
organic layer was washed with saturated NaHCO3 (3 × 10 mL)
and brine (10 mL), dried over Na2SO4, filtered, evaporated, and
used without any further purification. A solution of TiCl4 (1 M
in CH2Cl2, 2.2 mL, 2.2 mmol) was added to a solution of N-acetyl-
4-isopropylthiazolidinethione (223.6 mg, 1.1 mmol) in CH2Cl2
(5 mL) cooled to -10 °C. The solution was stirred for 5 min and
then cooled to -50 °C. The reaction mixture was treated with a
solution of ethyldiisopropylamine (155 mg, 1.2 mmol) in CH2-
Cl2 (5 mL). The reaction mixture was stirred for 40 min and
cooled to -78 °C. A solution of the 5-acetoxy N-substituted
pyrrolidinone in CH2Cl2 (5 mL) was added to the reaction
mixture. The reaction mixture was stirred and warmed to 0 °C
for 6 h. The reaction was quenched by addition of saturated NH4-
Cl and stirred for 15 min. The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography.
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(3-phenylprop-2-enyl)-pyrrolidin-2-one (2): Rf 0.35
(CHCl3-ethyl acetate-petroleum ether, 4:2:1); mp 94-95 °C;
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-benzyl-pyrrolidin-2-one (6): Rf 0.37 (CHCl3-ethyl ace-
25
tate-petroleum ether, 4:2:1); [R]D +320.1 (c 1.0, CHCl3); IR
2967, 1681, 1167, 1093, 1039, cm-1 1H NMR (CDCl3) δ 7.40-
;
7.18 (5H, m), 5.04 (1H, ddd, J ) 7.1, 6.1, 0.9 Hz), 4.79 (1H, d, J
) 15.3 Hz), 4.21 (1H, d, J ) 15.3 Hz), 4.02 (1H, m), 3.77 (1H,
dd, J ) 17.4, 3.4 Hz), 3.44 (1H, dd, J ) 11.5, 8.1 Hz), 3.09 (1H,
dd, J ) 17.3, 9.4 Hz), 2.99 (1H, dd, J ) 11.5, 0.9 Hz), 2.61-2.19
(4H, m), 1.82-1.68 (1H, m), 1.02 (3H, d, J ) 6.9 Hz), 0.92 (3H,
d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 202.9 (C), 175.2 (C), 170.5
(C), 136.8 (C), 128.7 (2CH), 127.9 (2CH), 127.5 (CH), 71.4 (CH),
54.6 (CH), 44.7 (CH2), 42.1 (CH2), 30.9 (CH), 30.5 (CH2), 29.8
(CH2), 24.7 (CH2), 19.1 (CH3), 17.7 (CH3); HRMS (EI) exact mass
calcd for C19H25N2O2S2 [M + H]+ 377.1357, found 377.1358.
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-butyl-pyrrolidin-2-one (7): Rf 0.33 (CHCl3-ethyl acetate-
25
[R]D25 +290.7 (c 1.0, CHCl3); IR 2965, 1685, 1373, 1161, 756 cm-1
;
petroleum ether, 4:2:1); [R]D +268.5 (c 1.0, CHCl3); IR 2962,
2873, 1685, 1373, 1168, 1040 cm-1; 1H NMR (CDCl3) δ 5.16 (1H,
t, J ) 7.1 Hz), 4.15 (1H, m), 3.89 (1H, dd, J ) 17.1, 3.4 Hz), 3.61
(1H, m), 3.55 (1H, dd, J ) 11.6, 8.0 Hz), 3.09 (1H, dd, J ) 17.1,
9.9 Hz), 3.07 (1H, dd, J ) 11.5, 0.9 Hz), 2.92 (1H, dd, J ) 11.6,
1.1 Hz), 2.52-2.21 (4H, m), 1.79-1.67 (1H, m), 1.63-1.40 (2H,
m), 1.40-1.21 (2H, m), 1.08 (3H, d, J ) 7.0 Hz), 0.99 (3H, d, J
) 7.0 Hz), 0.93 (3H, t, J ) 7.2 Hz); 13C NMR (CDCl3) δ 203.1
(C), 174.7 (C), 170.7 (C), 71.5 (CH), 54.4 (CH), 42.0 (CH2), 40.4
(CH2), 30.9 (CH), 30.6 (CH2), 29.8 (CH2), 29.6 (CH2), 24.6 (CH2),
20.1 (CH2), 19.1 (CH3), 17.7 (CH3), 13.8 (CH3); HRMS (EI) exact
mass calcd for C16H27N2O2S2 [M + H+] 343.1514, found 343.1514.
5R-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(but-2-enyl)-pyrrolidin-2-one (8): Rf 0.32 (CHCl3-ethyl
1H NMR (CDCl3) δ 7.40-7.21 (5H, m), 6.56 (1H, d, J ) 16.0
Hz), 6.14 (1H, ddd, J ) 16.0, 7.0, 6.0 Hz), 5.11 (1H, ddd, J )
8.0, 6.0, 1.1 Hz), 4.32 (1H, ddd, J ) 15.5, 5.8, 1.4 Hz), 4.18 (1H,
m), 3.95 (1H, dd, J ) 17.5, 3.3 Hz), 3.88 (1H, dd, J ) 15.5, 7.0
Hz), 3.38 (1H, dd, J ) 11.5, 8.0 Hz), 3.20 (1H, dd, J ) 17.4, 9.5
Hz), 2.99 (1H, dd, J ) 11.6, 1.1 Hz), 2.61-2.26 (4H, m), 1.78
(1H, m), 1.04 (3H, d, J ) 6.9 Hz), 0.96 (3H, d, J ) 7.0 Hz); 13C
NMR (CDCl3) δ 202.9 (C), 174.6 (C), 170.3 (C), 136.2 (C), 132.8
(CH), 128.4 (2CH), 127.6 (CH), 126.3 (2CH), 124.0 (CH), 71.3
(CH), 54.7 (CH), 43.0 (CH2), 42.1 (CH2), 30.7 (CH), 30.2 (CH2),
29.6 (CH2), 24.4 (CH2), 18.9 (CH3), 17.5 (CH3); HRMS (EI) exact
mass calcd for C21H27N2O2S2 [M + H]+ 403.1514, found 403.1526.
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(3-phenylprop-2-enyl)-pyrrolidin-2-one (3): Rf 0.41
25
acetate-petroleum ether, 4:2:1); [R]D +298.4 (c 1.0, CHCl3);
4216 J. Org. Chem., Vol. 70, No. 10, 2005

IR (film) 2965, 1733, 1687, 1374, 1375, 1257 cm-1
;
1H NMR
(1H, ddd, J ) 17.6, 9.3, 1.1 Hz), 3.05 (1H, d, J ) 11.6 Hz), 2.55-
2.23 (4H, m), 1.82-1.72 (4H, m), 1.07 (3H, d, J ) 6.8 Hz), 0.98
(3H, d, J ) 6.8 Hz); 13C NMR (CDCl3) δ 203.0 (C), 174.7 (C),
171.0 (C), 129.1 (CH), 125.6 (CH), 71.4 (CH), 54.5 (CH), 42.9
(CH2), 42.4 (CH2), 30.9 (CH), 30.5 (CH2), 29.8 (CH2), 25.0 (CH2),
19.2 (CH3), 17.8 (2CH3); HRMS (EI) exact mass calcd for
(CDCl3) δ 5.64 (1H, m), 5.36 (1H, m), 5.14 (1H, t, J ) 6.8 Hz),
4.12 (2H, m), 3.88 (1H, dd, J ) 17.5, 3.3 Hz), 3.57 (1H, dd, J )
15.2, 7.2 Hz), 3.53 (1H, dd, J ) 11.6, 8.1 Hz), 3.10 (1H, dd, J )
17.5, 9.8 Hz), 3.05 (1H, dd, J ) 11.6, 0.8 Hz), 2.51-2.22 (4H,
m), 1.76-1.65 (4H, m), 1.07 (3H, d, J ) 6.9 Hz), 0.97 (3H, d, J
) 6.9 Hz); 13C NMR (CDCl3) δ 203.1 (C), 174.8 (C), 170.9 (C),
129.5 (CH), 125.5 (CH), 71.5 (CH), 54.7 (CH), 43.0 (CH2), 42.3
(CH2), 31.0 (CH), 30.7 (CH2), 29.9 (CH2), 24.8 (CH2), 19.2 (CH3),
17.9 (2CH3); HRMS (EI) exact mass calcd for C16H25N2O2S2 [M
+ H]+ 341.1357, found 341.1373.
C
16H25N2O2S2 [M]+ 341.1357, found 341.1374.
1-(4(S)-Isopropyl-2-thioxo-thiazolidin-3-yl)-3(R)-trimeth-
ylsilanyloxy-2(R)-(1-but-2-enyl-5-oxo-pyrrolidin-2(S)-yl)-5-
phenyl-pent-4-en-1-one (14). To a solution of the addition
product 8 (340.5 mg, 1 mmol) in EtOAc (2.5 mL) was added
MgBr2‚OEt2 (26 mg, 0.1 mmol), followed by cinnamaldehyde (140
µL, 1.1 mmol), Et3N (0.280 µl, 2.0 mmol), and freshly distilled
TMSCl (0.190 µL, 1.5 mmol). The reaction mixture was stirred
at room temperature for 24 h. The resulting suspension was
filtered through a small plug of silica gel (2 × 2 cm) eluting the
TMS ether 14 with Et2O: 440 mg (81% yield); Rf 0.23 (ethyl
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-phenyl-pyrrolidin-2-one (9): Rf 0.41 (CHCl3-ethyl ace-
25
tate-petroleum ether, 4:2:1); [R]D +170.4 (c 1.0, CHCl3); IR
2968, 1693, 1597, 1497, 1372, 1168 cm-1 1H NMR (CDCl3) δ
;
7.42-7.32 (4H, m), 7.23 (1H, m), 4.93 (1H, ddd, J ) 7.6, 6.2, 1.0
Hz), 4.71 (1H, m), 3.55 (2H, m), 3.33 (1H, dd, J ) 11.6, 7.9 Hz),
2.94 (1H, dd, J ) 11.5, 1.0 Hz), 2.76-2.46 (3H, m), 2.27 (1H,
sext, J ) 6.7 Hz), 1.93 (1H, m), 1.01 (3H, d, J ) 6.8 Hz), 0.93
(3H, d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 203.0 (C), 174.3 (C),
170.9 (C), 137.2 (C), 129.3 (2CH), 126.6 (CH), 125.0 (2CH), 71.4
(CH), 57.2 (CH), 42.2 (CH2), 30.9 (CH2), 30.8 (CH), 30.5 (CH2),
25.0 (CH2), 19.1 (CH3), 17.8 (CH3); HRMS (EI) exact mass calcd
for C18H23N2O2S2 [M]+ 363.1201, found 363.1195.
25
acetate-petroleum ether, 3:7); mp 92-93 °C; [R]D +270.7 (c
1.0, CHCl3); IR 3355, 2964, 2356, 2336, 1682, 1252, 1165 cm-1
;
1H NMR (CDCl3) δ 7.42-7.19 (5H, m), 6.54 (1H, d, J ) 15.9
Hz), 6.09 (1H, dd, J ) 15.9, 7.1 Hz), 5.65 (1H, m), 5.41 (1H, m),
5.33 (1H, dd, J ) 7.4, 4.4 Hz), 4.94 (1H, t, J ) 6.8 Hz), 4.69 (1H,
t, J ) 7.3 Hz), 4.26-4.18 (2H, m), 3.40 (1H, dd, J ) 15.3, 7.1
Hz), 3.32 (1H, dd, J ) 11.4, 7.6 Hz), 2.99 (1H, dd, J ) 11.4, 0.6
Hz), 2.57-2.29 (4H, m), 2.19-2.04 (1H, m), 1.66 (3H, dd, J )
6.4, 1.0 Hz), 1.07 (3H, d, J ) 6.7 Hz), 0.99 (3H, d, J ) 7.0 Hz),
0.12 (9H, s); 13C NMR (CDCl3) δ 204.0 (C), 175.2 (C), 172.8 (C),
136.3 (C), 131.7 (CH), 129.7 (CH), 129.2 (CH), 128.9 (2CH), 128.2
(CH), 126.7 (2CH), 125.4 (CH), 73.3 (CH), 72.6 (CH), 56.2 (CH),
51.4 (CH), 43.0 (CH2), 31.4 (CH2), 31.2 (CH), 30.5 (CH2), 20.8
(CH2), 19.3 (CH3), 18.1 (CH3), 17.9 (CH3), 0.66 (3CH3).
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-(p-bromobenzyl)-pyrrolidin-2-one (10): Rf 0.46 (CHCl3-
25
ethyl acetate-petroleum ether, 4:2:1); [R]D +112.8 (c 1.0,
CHCl3); IR 2965, 1683, 1488, 1172, 1038 cm-1; 1H NMR (CDCl3)
δ 7.44 (2H, d, J ) 8.2 Hz), 7.09 (2H, d, J ) 8.2 Hz), 5.02 (1H, t,
J ) 6.9 Hz), 4.62 (1H, d, J ) 15.0 Hz), 4.25 (1H, d, J ) 15.5 Hz),
4.00 (1H, m), 3.61 (1H, dd, J ) 17.6, 4.5 Hz), 3.39 (1H, dd, J )
11.7, 8.1 Hz), 3.34 (1H, dd, J ) 17.6, 8.1 Hz), 2.98 (1H, d, J )
11.5 Hz), 2.62-2.21 (4H, m), 1.81 (1H, m), 1.02 (3H, d, J ) 6.8
Hz), 0.93 (3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 203.1 (C), 175.5
(C), 170.6 (C), 136.2 (C), 131.9 (2CH), 129.5 (2CH), 121.5 (C),
71.4 (CH), 54.7 (CH), 44.6 (CH2), 42.9 (CH2), 31.0 (CH), 30.4
(CH2), 29.8 (CH2), 25.3 (CH2), 19.2 (CH3), 17.8 (CH3); HRMS (EI)
exact mass calcd for C19H24BrN2O2S2 [M + H]+ 455.0463, found
455.0447.
1-(4(S)-Isopropyl-2-thioxo-thiazolidin-3-yl)-3(R)-hydroxy-
2(R)-(1-but-2-enyl-5-oxo-pyrrolidin-2(S)-yl)-5-phenyl-pent-
4-en-1-one (15). The free alcohol was obtained by treating the
TMS ether 14 in THF (20 mL) with 1 N HCl solution (4 mL) for
1 h. The reaction mixture was diluted with Et2O and water. The
organic layer was washed with saturated NaHCO3 and brine.
The aldol product 15 was purified by silica gel column chroma-
tography eluting with ethyl acetate-petroleum ether (7:3): 382
mg (quantitative yield); Rf 0.4 (ethyl acetate-petroleum ether,
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-benzyl-pyrrolidin-2-one (11): Rf 0.42 (CHCl3-ethyl
25
7:3); [R]D +239.8 (c 1.0, CHCl3); IR 3019, 2969, 1674, 1215,
25
1166 cm-1; 1H NMR (CDCl3) δ 7.41-7.23 (5H, m), 6.62 (1H, dd,
J ) 16.0, 1.9 Hz), 6.16 (1H, dd, J ) 16.0, 3.9 Hz), 6.16 (1H, dd,
J ) 16.0, 3.9 Hz), 5.68 (1H, m), 5.43 (1H, m), 5.20 (1H, dd, J )
6.6, 3.3 Hz), 4.88 (1H, ddd, J ) 7.3, 6.2, 0.9 Hz), 4.63 (1H, m),
4.41 (1H, ddd, J ) 9.0, 6.6, 2.8 Hz), 4.24 (1H, ddt, J ) 15.2, 6.1,
1.2 Hz), 3.49 (1H, dd, J ) 15.1, 6.4 Hz), 3.28 (1H, m), 2.95 (1H,
dd, J ) 11.5, 7.7 Hz), 2.83 (1H, dd, J ) 11.5, 1.0 Hz), 2.70 (1H,
dd, J ) 16.9, 8.8 Hz), 2.44-2.10 (3H, m), 1.71 (3H, dd, J ) 6.4,
1.3 Hz), 1.62 (1H, bs), 1.02 (3H, d, J ) 6.8 Hz), 0.96 (3H, d, J )
7.0 Hz); 13C NMR (CDCl3) δ 204.1 (C), 175.7 (C), 174.3 (C), 136.2
(C), 130.0 (CH), 129.8 (CH), 129.5 (CH), 129.0 (2CH), 128.2 (CH),
126.5 (2CH), 125.3 (CH), 72.1 (CH), 70.5 (CH), 57.2 (CH), 49.4
(CH), 43.2 (CH2), 31.1 (CH), 31.0 (CH2), 30.2 (CH2), 21.9 (CH2),
19.3 (CH3), 18.0 (CH3), 17.9 (CH3); HRMS (EI) exact mass calcd
for C25H33N2O3S2 [M + H]+ 473.1933, found 473.1936.
acetate-petroleum ether, 4:2:1); [R]D +119.0 (c 1.0, CHCl3);
IR 3017, 2969, 1685, 1216, 1174 cm-1; 1H NMR (CDCl3) δ 7.40-
7.18 (5H, m), 5.04 (1H, t, J ) 7.0 Hz), 4.74 (1H, d, J ) 15.4 Hz),
4.27 (1H, d, J ) 15.4 Hz), 4.02 (1H, m), 3.59 (1H, dd, J ) 17.9,
4.4 Hz), 3.41 (1H, dd, J ) 11.6, 8.1 Hz), 3.38 (1H, dd, J ) 17.9,
8.4 Hz), 2.97 (1H, d, J ) 11.6 Hz), 2.65-2.21 (4H, m), 1.82 (1H,
m), 1.04 (3H, d, J ) 6.9 Hz), 0.95 (3H, d, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 202.9 (C), 175.4 (C), 170.7 (C), 136.9 (C), 128.8 (2CH),
127.7 (2CH), 127.6 (CH), 71.4 (CH), 54.6 (CH), 45.0 (CH2), 42.7
(CH2), 30.9 (CH), 30.4 (CH2), 29.9 (CH2), 25.3 (CH2), 19.2 (CH3),
17.8 (CH3); HRMS (EI) exact mass calcd for C19H25N2O2S2 [M +
H]+ 377.1357, found 377.1349.
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
yl]-1-butyl-pyrrolidin-2-one (12): Rf 0.33 (CHCl3-ethyl ace-
25
tate-petroleum ether, 4:2:1); [R]D +132.5 (c 1.0, CHCl3); IR
2962, 2873, 1686, 1372, 1256, 1167 cm-1 1H NMR (CDCl3) δ
;
5.19 (1H, ddd, J ) 7.7, 6.3, 1.1 Hz), 4.07 (1H, m), 3.65 (1H, dd,
J ) 17.5, 3.6 Hz), 3.56 (1H, m), 3.53 (1H, dd, J ) 11.5, 2.1 Hz),
3.45 (1H, dd, J ) 17.5, 9.3 Hz), 3.06 (1H, dd, J ) 11.6, 1.2 Hz),
2.87 (1H, m), 2.57-2.25 (4H, m), 1.78 (1H, m), 1.61-1.20 (4H,
m), 1.08 (3H, d, J ) 7.0 Hz), 0.99 (3H, d, J ) 7.0 Hz), 0.92 (3H,
t, J ) 7.2 Hz); 13C NMR (CDCl3) δ 203.1 (C), 174.8 (C), 171.0
(C), 71.5 (CH), 54.4 (CH), 42.2 (CH2), 40.5 (CH2), 30.9 (CH), 30.5
(CH2), 29.9 (CH2), 29.7 (CH2), 25.1 (CH2), 20.2 (CH2), 19.2 (CH3),
17.9 (CH3), 13.9 (CH3); HRMS (EI) exact mass calcd for
Acknowledgment. This research was supported by
the National Science Foundation (CHE-011292) and the
National Institutes of Health (R03-HD41948). We thank
Dr. Dale Swenson for obtaining the X-ray structures of
compounds 2 and 14. We are indebted to Dr. Blake
Watkins (University of Mississippi) for obtaining all the
HRMS.
C
16H27N2O2S2 [M + H]+ 343.1514, found 343.1528.
Supporting Information Available: Copies of 1H and 13
C
5S-[2-(4S-Isopropyl-2-thioxo-thiazolidin-3-yl)-2-oxo-eth-
NMR spectra for compounds 2-14, ORTEP drawings for
compounds 2 and 14, and crystallographic data in CIF format
for compounds 2 and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
yl]-1-(but-2-enyl)-pyrrolidin-2-one (13): Rf 0.42 (CHCl3-ethyl
25
acetate-petroleum ether, 4:2:1); [R]D +168.2 (c 1.0, CHCl3);
1
IR 2964, 2876, 1682, 1373, 1039 cm-1; H NMR (CDCl3) δ 5.61
(1H, m), 5.36 (1H, m), 5.19 (1H, t, J ) 7.2 Hz), 4.07 (2H, m),
3.66 (1H, ddd, J ) 17.6, 3.7, 1.2 Hz), 3.60-3.49 (2H, m), 3.44
JO050188A
J. Org. Chem, Vol. 70, No. 10, 2005 4217