Asymmetric aldol additions: Use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones

Article abstract of DOI:10.1021/jo001387r

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to >99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.

Full text of DOI:10.1021/jo001387r

894
J . Org. Chem. 2001, 66, 894-902
Asym m etr ic Ald ol Ad d ition s: Use of Tita n iu m Tetr a ch lor id e a n d
(-)-Sp a r tein e for th e Soft En oliza tion of N-Acyl Oxa zolid in on es,
Oxa zolid in eth ion es, a n d Th ia zolid in eth ion es
Michael T. Crimmins,* Bryan W. King, Elie A. Tabet, and Kleem Chaudhary
Venable and Kenan Laboratories of Chemistry, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received September 18, 2000
Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione,
and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-
Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium
tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of
N-methyl-2-pyrrolidinone, selectivities of 97:3 to >99:1 were obtained for the Evans syn aldol
products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-
Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering
the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed
to be a result of switching of mechanistic pathways between chelated and nonchelated transition
states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution.
Iterative aldol sequences with high diastereoselectivity can also be accomplished.
In tr od u ction
amine or tetramethylethylenediamine as the base, but
slightly lower selectivity was observed than with the
dibutylboron enolates.2-5 Also, to achieve good levels of
conversion, excess aldehyde (from 2 to 5 equiv) was
required.4 The nonchelated transition state 1 has been
proposed for the boron enolate (and the titanium enolate)
to give the Evans syn aldol product.8 Yan has investi-
gated chlorotitanium enolates of camphor-derived oxazo-
lidinethiones noting the ability to access the non-Evans
syn aldol adducts. It was proposed that if chloride ion is
lost, the titanium enolate can proceed through transition
state 2 in which both the aldehyde and the auxiliary are
coordinated to titanium and the non-Evans adduct is
produced through reversal of the pi-facial orientation of
the enolate in this chelated transition state.5,6 A highly
organized chelated transition state has also been pro-
posed by Nagao and Fujita to explain the diastereose-
lectivity observed with tin (II) enolates of N-acylthiazo-
lidinethiones.7 The chelated transition state could be a
minor competitive pathway for the titanium enolate of
oxazolidinones thus lowering the diastereoselectivity.
Silks recently reported the preparation of non-Evans syn
aldol adducts from the titanium enolates of N-acylselones,9
and Oppolzer noted a switiching to non-Evans syn
adducts when tin (IV) enolates of N-acyl sultams were
utilized in aldol additions.2c Results from our laboratory
The asymmetric aldol addition mediated by chiral
auxiliaries is one of the most important and general
methods for asymmetric carbon-carbon bond formation.1
The utility of the asymmetric aldol addition has been
amply demonstrated through a multitude of synthetic
applications.2 Dibutylboron enolates of N-acyl oxazolidi-
nones, pioneered by Evans, are the most commonly
utilized enolates and are highly effective for the prepara-
tion of Evans syn products in asymmetric aldol addi-
tions.3 Titanium (IV)4,5,6 enolates of N-acyl oxazolidinones
and oxazolidinethiones, tin (IV)2c enolates of N-acyl
sultams, and tin (II) enolates7 of thiazolidinethiones have
also been shown to be effective in creating well ordered
transition states for aldol reactions. Evans and Yan
reported the use of chlorotitanium enolates for aldol
additions of N-acyl oxazolidinones using diisopropylethyl-
(1) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-947. Ager, D. J .;
Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3-12. Ager, D.
J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
(2) (a) For selected examples see: Evans, D. A.; Kaldor, S. W.; J ones,
T. K.; Clardy, J .; Stout, T. J . J . Am. Chem. Soc. 1990, 112, 7001-
7031. Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc. 1992,
114, 9434-9453. Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem.
Soc. 1993, 115, 11446-11459. Evans, D. A.; Fitch, D. M. J . Org. Chem.
1997, 62, 454-455. Evans, D. A.; Kim, A. S.; Metternich R.; Novack,
V. J . J . Am. Chem. Soc. 1998, 120 5921-5942. Walker, M. A.;
Heathcock, C. H. J . Org. Chem. 1991, 56, 5747-5750. (b) Hsiao, C.;
Liu, L.; Miller, M. J . J . Org. Chem. 1987, 52, 2201-2206. (c) Oppolzer,
W.; Blagg, J .; Rodriguez, I.; Walther, E. J . Am. Chem. Soc. 1990, 112,
2767-2772.
(7) Fujita, E. Nagao, Y. Adv. Heterocycl. Chem. 1989, 45, 1-36.
Nagao, Y.; Inoue, T.; Hashimoto, K.; Hagiwara, Y.; Ochiai, M. Fujita,
E. J . Chem. Soc., Chem. Commun. 1985, 1419-1420. Yamada, S.;
Kumagai, T.; Ochiai, M. Fujita, E. J . Chem. Soc., Chem. Commun.
1985, 1418-1419. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.;
Inoue, T.; Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2391-
2393. Hsiao, C.-N.; Liu, L., Miller, M. J . J . Org. Chem. 1987, 52, 2201-
2206.
(8) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 2, pp 239-275.
(9) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J . D.; Silks,
L. A. P., III. J . Am. Chem. Soc. 2000, 122, 386-387.
(3) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129.
(4) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047-1049.
(5) Nerz-Stormes, M.; Thornton, E. R. J . Org. Chem. 1991, 56, 2489-
2498. Bonner, M. P.; Thornton, E. R. J . Am. Chem. Soc. 1991, 113,
1299-1308.
(6) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J .
Am. Chem. Soc. 1993, 115, 2613-2621 and references therein. Yan,
T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J . Org. Chem.
1995, 60, 3301-3306.
10.1021/jo001387r CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

Asymmetric Aldol Additions
Sch em e 1
J . Org. Chem., Vol. 66, No. 3, 2001 895
Sch em e 2
cous oil (Note: crystallization of the oil would occur after
approximately one month at 0 °C). Preparation of 4 could
also be accomplished with carbon disulfide and triethyl-
amine in THF through a modification of the method
described by Corre;15 however, lower yields were obtained
due to the formation of thiazolidinethione 6 as a minor
byproduct. Oxazolidinethione 4 was readily acylated with
n-butyllithium and propionyl chloride in THF at -78 °C
to provide propionyloxazolidinethione 5 in 90% yield
(Scheme 2). The propionyl oxazolidinethione 5 is highly
crystalline and can be purified by recrystallization from
hexanes to give a pure, white crystalline solid ready for
use in the aldol reactions. The thiazolidinethione 6 was
prepared from (S)-phenylalaninol by heating in the
presence of aqueous potassium hydroxide and carbon
disulfide by a modification of the Corre procedure.15
Acylation of the thiazolidinethione 6 with n-butyllithium
and propionyl chloride was accomplished as for the
oxazolidinethione. The propionylthiazolidinethione is also
crystalline and readily purified by recrystallization. The
N-acyloxazolidinethiones and thiazolidinethiones were
prepared in three steps in 70-85% overall yield.
Eva n s Syn Ald ol Ad d ition s w ith N-Acyloxa zolid i-
n eth ion es. Titanium enolates of oxazolidinethione 5
were examined in aldol additions with a variety of
aldehydes of differing structural types and at different
temperatures. The diastereoselectivity, percent conver-
sion to product, and the rate of the aldol reaction were
highly dependent on the amine base and the amount of
titanium tetrachloride used to generate the titanium
enolate. The enolates were formed by a two-step pro-
cess: (1) titanium tetrachloride was added to a solution
of oxazolidinethione 5 in methylene chloride at 0 °C to
produce a yellow solution or more commonly a slurry
representative of a TiCl4-carbonyl complex; (2) an amine
base was added to immediately produce a homogeneous
deep red solution characteristic of a titanium enolate 8
(Scheme 3).16 The enolate was then treated with an
aldehyde to afford mixtures of the Evans syn product 10,
the non-Evans syn product 9, and an anti product (not
shown). Titanium tetrachloride was used directly as
received from Aldrich Chemical Co. No purification was
necessary. All diastereomeric ratios were determined by
HPLC (Dynamax-60 A, 1 mL/min, 30% EtOAc/hexanes).
Initial experiments with N-acyloxazolidinethione 5
were performed by generating the enolates with 1.1 equiv
have reported the use of chlorotitanium enolates of both
N-acyloxazolidinethiones10 and N-acylthiazolidineth-
iones11 for the preparation of both Evans and non-Evans
syn aldol adducts. We report here a detailed account of
these investigations together with additional studies and
mechanistic interpretations.
Resu lts a n d Discu ssion
Given the lower selectivity of the aldol additions of
chlorotitanium enolates of N-acyl oxazolidinones reported
by Evans, it was anticipated that a more highly ordered
transition state might improve the selectivity. Also, if a
suitable method for asymmetric aldol reactions with
chlorotitanium enolates of N-acyloxazolidinethiones and
N-acylthiazolidinethiones could be developed, these aldol
reactions might be complimentary to the existing Evans
protocol. Initially, N-acyl oxazolidinethione and thiazo-
lidinethione enolates were investigated since it was
thought that they might proceed through the “chelated”
transition state 2 due to the known higher affinity of
sulfur for titanium, thus creating a more rigid transition
state. Fowles had shown that thioxane prefers to coor-
dinate to titanium through sulfur rather than oxygen.12
In addition, there was a collateral advantage since the
N-acyloxazolidinethiones and thiazolidinethiones are
more easily cleaved; they undergo aminolysis at room
temperature: conditions which do not cleave the corre-
sponding oxazolidinones.13
P r ep a r a tion of N-Acyloxa zolid in eth ion es a n d N-
Acylt h ia zolid in et h ion es. Oxazolidinethione 4 was
readily synthesized in two steps from inexpensive, com-
mercially available (S)-phenylalanine (Scheme 2). Reduc-
tion of (S)-phenylalanine with sodium borohydride and
iodine in THF following the Meyers method provided (S)-
phenylalaninol 3 in 95% yield.14 Cyclization of the ami-
no alcohol 3 with thiophosgene and triethylamine in
CH2Cl2 gave oxazolidinethione 4 in 95% yield as a vis-
(10) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc.
1997, 119, 7883-7884.
(11) Crimmins, M. T. Chaudhary, K. Org. Lett. 2000, 2, 775-777.
(12) Fowles, G. W. A.; Rice, D. A.; Wilkins, J . D. J . Chem. Soc. A
1971, 1920-1923.
(13) Nagao, Y.; Yagi, M.; Ikedo, T.; Fujita, E. Tetrahedron Lett. 1982,
23, 201-204.
(15) Delaunay, D.; Toupet, L.; Corre, M. L. J . Org. Chem. 1995, 60,
6604-6607.
(16) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J . S.; Bilodeau, M.
T. J . Am. Chem. Soc. 1990, 112, 8215-8216.
(14) McMKennon, M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568-
3571.

896 J . Org. Chem., Vol. 66, No. 3, 2001
Crimmins et al.
Ta ble 2. TMP DA-Med ia ted a ,b Ald ol Ad d ition s of 5
Sch em e 3
entry
tempc
aldehyde (RCHO)d
% yielde
10:9:anti
1
2
3
4
5
6
-78 °C
0 °C
Me2CH
Me2CH
Et
62
69
72
85
65
76
96.4:2.7:0.9
92.9:5.1:2.0
97.6:1.6:0.8
94.9:5.1:0.0
93.1:6.6:0.3
96.0:3.0:1.0
0 °C
0 °C
0 °C
0 °C
Ph
MeCHdCH
Me2CHCH2
a
b
TiCl4 was used as obtained from Aldrich Chemical Co. 1.0
equiv of TiCl4 and 2.5 equiv of TMPDA were employed. c Tem-
d
perature at which the aldehyde was added. 1.1 equiv of aldehyde
was employed. e Yields are for the isolated, chromatographically
purified major diastereomer.
Ta ble 3. (-)-Sp a r tein e-Med ia ted a Ald ol Ad d ition s of 5
entry
tempb
aldehyde (RCHO)c % yieldd
10:9:anti
1e
2e
-78 °C
0 °C
Me2CH
Me2CH
Et
Et
Ph
70
90
69
80
89
89
77
65
94
91
80
98
91
95
89
89
91
98.8:1.0:0.2
97.0:2.5:0.5
97.5:1.0:1.5
97.8:1.7:0.5
98.7:1.3:0.0
97.3:2.2:0.5
97.8:1.3:0.9
97.4:2.3:0.3
97.1:2.2:0.7
97.8:2.2:0.0
98.9:0.0:1.1
99.3:0.7:0
97.8:1.4:0.8
95.2:4.8:0
96.8:3.2:0
99.4:0.6:0
99.0:1.0:0
3e
-78 °C
4e
0 °C
Ta ble 1. DIEA- a n d TMEDA-Med ia ted Ald ol Ad d ition s
of 5
5e
-78 °C
0 °C
6e
Ph
entry basea,b,c aldehyde (RCHO)d % yielde
10:9:anti
7e
-78 °C
MeCHdCH
MeCHdCH
Me2CHCH2
Me2CHCH2
CH2dCH
Me2CH
Et
8e
0 °C
1
2
3
4
5
6
7
DIEAf
Me2CH
Me2CH
Me2CH
Et
86g
87g
58
60
60
85.8:13.9:0.3
33.7:65.9:0.4
98.9:0.6:0.5
93.3:6.3:0.4
97.6:2.4:0.0
98.2:1.3:0.5
100:0.0:0.0
9e
-78 °C
0 °C
DIEAf
10e
11e
12f
13f
14f
15f
16f
17f
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
-78 °C
Ph
MeCHdCH
Me2CHCH2
49
43
Ph
MeCHdCH
Me2CHCH2
CH2dCH
a
b
All reactions performed at -78 °C. TiCl4 was used as
obtained from Aldrich Chemical Co. c 1.0 equiv of TiCl4 and 2.5
d
equiv of amine were employed. 1.1 equiv of aldehyde was em-
a
b
TiCl4 was used as obtained from Aldrich Chemical Co. Tem-
perature at which the aldehyde was added. c 1.1 equiv of aldehyde
ployed. e Yields are for the isolated, chromatographically purified
major diastereomer. f Reaction performed with 1.0 equiv of TiCl4
d
was employed. Yields are for the isolated, chromatographically
g
and 2.5 equiv of DIEA. Total yield of all aldol diastereomers.
purified major diastereomer. e 1.0 equiv of TiCl4 and 2.5 equiv of
(-)-sparteine were employed. f 1.05 equiv of TiCl4, 1.0 equiv of (-)-
sparteine, and 1.0 equiv. of N-methyl-2-pyrrolidinone were em-
ployed.
of titanium tetrachloride and 2.5 equiv of diisopropyl-
ethylamine followed by addition of 1.1 equiv of aldehyde.
The diastereoselectivity of these aldol reactions were
inconsistent and appeared to be very sensitive to small
changes in the Lewis acid stoichiometry. However, when
2.5 equiv of tetramethylethelenediamine (TMEDA) was
employed as the base, consistently high diastereoselec-
tivity (>98:2 Evans:non-Evans 10:9) was observed as
shown in Table 1. Unfortunately, using 1 equiv of
aldehyde, the reactions generally failed to go to comple-
tion even after extended reaction times and isolated
yields were modest (45-60%). Addition of a second
equivalent of aldehyde was beneficial in improving the
yields, but conditions were needed to avoid the use of
greater than 1 equiv of aldehyde if expensive or syntheti-
cally prepared aldehydes were to be employed. A survey
of several amines such as tributylamine, N-ethylpiperi-
dine, DABCO, and DBU provided no significant advan-
tages. Tetramethylpropylenediamine (TMPDA) did im-
prove yields somewhat (Table 2). However, when (-)-
sparteine was used to generate the titanium enolate of
N-propionyl-oxazolidinethione 5, a dramatic rate ac-
celeration was observed in the aldol additions. The aldol
reactions were essentially complete after 30 s to 1 min,
even with 1.1 equiv of aldehyde, and diastereoselectivities
were >98:2 Evans syn 10/non-Evans syn 9 and >99:1
syn/anti (Table 3). Isolated yields with (-)-sparteine were
improved substantially compared to TMEDA and TMP-
DA. Of equal importance was the observation that no
significant reduction in selectivity occurred when the
reactions were conducted at 0 °C as compared to -78 °C.
Isolated yields were typically slightly higher at 0 °C due
to slightly improved conversions. In the case of crotonal-
dehyde, the reduction in yield can be attributed to the
increase in the polymerization rate of crotonaldehyde at
0 °C (Table 3, entry 8). An additional important point is
that TiCl4 and (-)-sparteine were used directly as
received without further purification. The reason for the
dramatic rate acceleration of these aldol reactions in the
presence of 2.5 equiv of (-)-sparteine is not yet clear. Rate
enhancement may be related to a bidentate coordination
of (-)-sparteine to the metal center, although this is
speculative.
Because of the cost of (-)-sparteine, the use of 2.5 equiv
of the chiral base was a potential issue and conditions
were sought to reduce the quantity of (-)-sparteine. If
the base was coordinating to the metal, other good
ligands for titanium might also prove useful. Since excess
aldehyde also seemed to help the reaction rate and the
degree of completion of reaction, it seemed reasonable
that the aldehyde was acting as a ligand for the metal
as well. If so, better Lewis basic carbonyl compounds
might obviate the need for 2.5 equiv of (-)-sparteine or
excess aldehyde. Since the carbonyl oxygen of an amide
is more Lewis basic than an aldehyde carbonyl, the use
of a tertiary amide as an unreactive ligand on the metal
was explored. The use of 1.05 equiv of titanium tetra-
chloride, 1.0 equiv of (-)-sparteine, and 1.0 equiv of
N-methyl-2-pyrrolidinone resulted in reaction rates, level
of completion, and distereoselectivity comparable to the
use of 2.5 equivlents of (-)-sparteine (entries 12-17,

Asymmetric Aldol Additions
Sch em e 4
J . Org. Chem., Vol. 66, No. 3, 2001 897
Ta ble 4. (-)-Sp a r tein e-Med ia ted Ald ol Ad d ition s of 7a
entry
tempc
aldehyde (RCHO)d
% yielde
17:16
1b
2b
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
66
64
77
75
62
71
77
84
84
79
72
74
92:8
>99:1
3b
>99:1
4b
97:3
5b
Ph
>99:1
98:2
98.6:1.4
98.1:1.9
94.2:5.8
98.2:1.8
93.7:6.3
96.1:3.9
6b
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
7f
8f
9f
10f
11f
12f
Ph
Me2CHCH2
a
b
TiCl4 was used as obtained from Aldrich Chemical Co. 1.0
equiv of TiCl4 and 2.5 equiv of (-)-sparteine were employed.
d
c Temperature at which the aldehyde was added. 1.1 equiv of
aldehyde was employed. e Yields are for the isolated, chromato-
graphically purified major diastereomer. f 1.05 equiv of TiCl4, 1.0
equiv of (-)-sparteine, and 1.0 equiv of N-methyl-2-pyrrolidinone
were employed.
Ta ble 5. TMEDA- a n d (-)-Sp a r tein e-Med ia ted Ald ol
Ad d ition s of 18a ,b
entry
base
aldehyde (RCHO)c % yieldd
21:20
1
2
3
4
5
6
7
8
9
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
75
53
42
57
61
60
80
66
72
84
85
81
98:2
>99:1
>99:1
96:4
94:6
96:4
Table 3). These modified conditions were not only more
cost efficient but also simplified the workup since less
insoluble material was observed at the end of the reaction
and filtration was significantly simplified.
Ph
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
96:4
To determine if the chiral architecture of (-)-sparteine
was influencing the selectivity of the aldol addition,
achiral N-propionyloxazolidinethione 12 was prepared
and aldol additions of its chlorotitanium enolate were
examined. Treatment of 2-amino-1-ethanol with carbon
disulfide and triethylamine in THF provided a 2:1
mixture of oxazolidinethione 11 and the thiazolidineth-
ione (Scheme 4). Acylation of oxazolidinethione 11 with
n-BuLi and propionyl chloride gave, after purification,
acylated oxazolidinethione 12 in 60% yield for two steps.
Addition of isobutyraldehyde to the titanium enolate of
oxazolidinethione 12 generated from 1 equiv of TiCl4 and
2.5 equiv of (-)-sparteine afforded the aldol products 13
in 70% yield with a 98:2 syn/anti ratio. Determination
of the enantioselectivity of the aldol addition by chiral
HPLC was accomplished by reductive removal of the
oxazolidinethione and protection of the resulting diol as
the primary p-toluate 14. Analysis by chiral HPLC
(Chiralcel ODH column) revealed a 1.27:1 ratio of enan-
tiomers 14R,S and 14S,R (the absolute stereochemistry
of the enantiomer formed in slight excess was not
determined). Therefore, any asymmetric induction pro-
vided by (-)-sparteine was minimal. In addition, (-)-
sparteine produced comparable rate enhancements and
very similar diastereoselectivities when either enanti-
omer of the oxazolidinethione auxiliary was employed.
Eva n s Syn Ald ol Ad d ition s w ith N-Acylth ia zo-
lidin eth ion es. The chlorotitanium enolates of N-acylthia-
zolidinethiones were also examined since it was thought
that (1) the thiocarbonyl of the thiazolidinethione could
be a better ligand for titanium and might lead to aldol
additions through the chelated transition state to provide
the non-Evans syn aldol adducts and (2) the thiazolidi-
nethiones are more readily cleaved by nucleophilic attack
than both oxazolidinethiones and oxazolidinones. Forma-
tion of the chlorotitanium enolate of N-acylthiazolidi-
nethione 18 as described for the oxazolidinethione in the
presence of 2.5 equiv of TMEDA followed by addition of
>99:1
>99:1
95:5
92:8
97:3
10
11
12
Ph
Me2CHCH2
a
b
TiCl4 was used as obtained from Aldrich Chemical Co. 1.0
equiv of TiCl4 and 2.5 equiv of diamine were employed. c 1.1 equiv
of aldehyde was employed. Yields are for the isolated, chromato-
d
graphically purified major diastereomer.
1.1 equiv of aldehyde gave excellent selectivities in all
cases for Evans syn product 21. As for the oxazolidineth-
iones, improved conversion (and resulting higher yields)
to Evans syn product 21 were realized for all aldehydes
examined when 2.5 equiv of (-)-sparteine was used
instead of TMEDA17 (Tables 4 and 5).18 High selectiv-
ity and excellent yields were also realized when N-
acylthiazolidinethione 7 was enolized with 1.05 equiv of
titantium tetrachloride and 2.5 equiv of (-)-sparteine.
Similar yields and selectivity were observed for N-
acylthiazolidinethione 7 with 1 equiv of (-)-sparteine and
1 equiv of N-methyl-2-pyrrolidinone as observed with
the N-acyloxazolidinethiones. The diastereomeric prod-
ucts are readily separated by chromatography and can
often be separated by recrystallization. Since the products
were yellow in color, the separation can be observed
visually as the separate components move down the
column.
Eva n s Syn Ald ol Ad d ition s w ith N-Acyloxa zoli-
d in on es. To determine if the soft enolization with
titanium tetrachloride and (-)-sparteine was a general
phenomenon, we investigated the aldol addition reactions
of N-acyloxazolidinones. Enolization of oxazolidinone 22
(17) Use of 1.5 equiv of diamine gave selective formation of the
Evans syn product, but 2.5 equiv resulted in better selectivity.
(18) For a discussion of effects of amine structure on selectivity in
aldol additions of tin(II) enolates see: Mukaiyama, T.; Iwasawa, N.
Chem. Lett. 1984, 753-756

898 J . Org. Chem., Vol. 66, No. 3, 2001
Crimmins et al.
Sch em e 5
Sch em e 6
Ta ble 7. Non -Eva n s Syn Ald ol Ad d ition s w ith
Oxa zolid in eth ion e 5a
Ta ble 6. (-)-Sp a r tein e-Med ia ted Ald ol Ad d ition s of 22a
entry
temperature
aldehyde (RCHO)b
yieldc
25:24
amine
1d
2d
3d
4d
5e
0 °C
0 °C
0 °C
Et
84
89
89
87
98
99:1
97:3
98:2
97:3
98:2
entry (1.1 equiv)b aldehyde (RCHO)c % yieldd
9:10:anti
MeCHdCH
Me2CH
t-Bu
1
2
3
4
5
6
7
8
9
DIEA
DIEA
DIEA
DIEA
DIEA
DIEA
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
Et
80
81
44
87
88
75
72
80
55
79
84
95.7:0.5:3.8
94.7:0.0:5.3
99.3:0.0:0.7
94.9:0.0:5.1
97.6:0.7:1.7
96.7:0.0:3.3
93.6:6.4:0.0
92.9:0.0:7.1
95.3:0.0:4.7
94.1:0.0:5.9
95.5:0.0:4.5
MeCHdCH
CH2)CH
Me2CH
Ph
Me2CHCH2
Et
MeCHdCH
CH2dCH
Me2CH
Me2CHCH2
0 °C
-78 °C
Me2CH
a
b
TiCl4 was used as obtained from Aldrich Chemical Co. 1.1
equiv of aldehyde was employed. c Yields are for the isolated,
d
chromatographically purified major diastereomer. 1.0 equiv of
TiCl4 and 2.5 equiv of (-)-sparteine were employed. e 1.05 equiv
of TiCl4, 1.0 equiv of (-)-sparteine, and 1.0 equiv of N-methyl-2-
pyrrolidinone were employed.
10
11
a
b
with 1.1 equiv of titanium tetrachloride and 2.5 equiv of
(-)-sparteine followed by addition of 1.1 equiv of the
appropriate aldehyde at 0 °C produced the Evans syn
adduct 25 as the major diastereomer in high yield with
excellent diastereocontrol. The isolated yields of the
major diastereomer after chromatography were 84-89%.
This method is operationally simple, and the cost is lower
than aldol additions with dibutylboron triflate. The use
of 1.05 equiv of titanium tetrachloride, 1.0 equiv of (-)-
sparteine, and 1.0 equiv of N-methyl-2-pyrrolidinone
(NMP) also proved highly efficient and selective as with
the N-acyloxazolidinethiones and N-acylthiazolidineth-
iones (Table 6, entry 5). The advantage of the use of
TiCl4-(-)-sparteine-NMP for the enolization of N-
acyloxazolidinones is that the reagents can be used as
purchased, the reaction proceeds well even at 0 °C, and
no oxidative workup is required. The relative cost is
approximately 35-40% relative to the dibutylborontri-
flate procedure.
TiCl4 was used as obtained from Aldrich Chemical Co. 2.0
equiv of TiCl4 and 1.1 equiv of amine were employed. c 1.1 equiv
d
of aldehyde was employed. Yields are for the isolated, chromato-
graphically purified major diastereomer.
use of (-)-sparteine resulted in somewhat cleaner reac-
tions in most cases than was observed with DIEA.
Non -Eva n s Syn Ald ol Rea ction s w ith N-Acylth i-
a zolid in eth ion es. Interestingly, the major aldol addi-
tion product was the non-Evans syn adduct with N-
acylthiazolidinethiones regardless of the titanium tet-
rachloride stoichiometry (1 or 2 equiv) when only 1 equiv
of amine was utilized. Thus, DIEA, TMEDA, or (-)-
sparteine provide the non-Evans syn adducts 16 and 20
as the major products (Tables 8-10). The thiazolidineth-
iones allow access to either Evans syn or non-Evans syn
simply by changing the base stoichiometry to 2 or 1 equiv,
respectively, without the need for changing the Lewis
acid stoichiometry.
Non -Eva n s Syn Ald ol Rea ction s w ith N-Acylox-
a zolid in eth ion es. Because of the noticeable sensitivity
of the diastereoselectivity of the oxazolidinethione aldol
reactions to small changes in the Lewis acid stoichiom-
etry, a survey of effects of various amines, their stoichi-
ometry, and the stoichiometry of the titanium tetrachlo-
ride was undertaken. After further investigation, it was
observed that employing 2 equiv of TiCl4 and 1 equiv of
i-Pr2EtN gave excellent selectivity for the non-Evans syn
aldol product 9 (Scheme 3). Selectivities were generally
>95:5 for syn/anti and >99:1 for non-Evans syn/Evans
syn (isolated yields generally 80-85%). The major aldol
addition product formed was the non-Evans syn adduct
when using 1 equiv of DIEA, TMEDA, or (-)-sparteine
when 2 equiv of titanium tetrachloride were added. The
Mech a n istic Im p lica tion s. N-Acyloxazolidinones, N-
acyloxazolidinethiones, and N-acylthiazolidinethiones all
produce Evans syn aldol adducts when their chlorotita-
nium enolates are formed in the presence of 2 equiv of
(-)-sparteine. In these instances, the nonchelated transi-
tion state 1 is operative possibly due to coordination of
the second equivalent of diamine to the metal center, thus
preventing coordination of the imide or thioimide carbo-
nyl to the metal. The same factors that govern the boron
enolate transition states would then be operative result-
ing in the Evans syn product. The second equivalent of
diamine may also play a role in avoiding the need for
excess aldehyde, since if the diamine is bound to tita-
nium, no vacant coordination sites would be available for
coordination of a second equivalent of aldehyde. Evidence

Asymmetric Aldol Additions
J . Org. Chem., Vol. 66, No. 3, 2001 899
Ta ble 8. DIEA-Med ia ted Ald ol Ad d ition s of 18a
Sch em e 7
b
auxiliary equiv TiCl4
aldehyde (RCHO)c % yieldd
20:21
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
R ) iBu
1
1
1
1
1
1
2
2
2
2
2
2
PhCHdCH
Ph
Me2CH
Me2CHCH2
CH2)CH
MeCHdCH
PhCHdCH
Ph
80
78
77
40
30
53
56
60
75
51
40
44
87:13
91:9
87:13
84:16
>99:1
>99:1
96:4
90:10
95:5
90:10
>99:1
96:4
Me2CH
Me2CHCH2
CH2dCH
MeCHdCH
a
1.1 equiv of amine was employed. b TiCl4 was used as obtained
from Aldrich Chemical Co. c 1.1 equiv of aldehyde was employed.
Yields are for the isolated, chromatographically purified major
d
diastereomer.
Ta ble 9. Non -Eva n s Syn Ald ol Ad d ition s w ith TMEDA
a n d (-)-Sp a r tein e w ith 18a
auxiliary
baseb
aldehyde (RCHO)c % yieldd 20:21
ably coordinating to the titanium disfavoring the chela-
tion of the thiocarbonyl to the metal center (Scheme 7).
Oxazolidinethiones provide the Evans syn adducts with
1 equiv of titanium tetrachloride and the non-Evans syn
products upon addition of a second equivalent of TiCl4.
Heathcock has reported a similar approach to the prepa-
ration of the non-Evans syn aldol products by adding
additional Lewis acids to boron enolates and has proposed
an acyclic transition state with 1 equiv of Lewis acid
activating the aldehyde.19 In the case of oxazolidineth-
iones, we propose the chelated transition state, originally
proposed by Nagao and Fujita,7 for the formation of the
non-Evans syn adducts. Oppolzer had previously pro-
posed a switching from the standard Zimmerman-Traxler
model to the Nagao chelated model to explain the change
in selectivity observed with tin (IV) enolates of N-acyl
sultams.2c While the oxazolidinethione carbonyl is not
sufficiently nucleophilic to displace chloride ion and
coordinate to the metal center of the chlorotitanium
enolate, upon addition of a second equivalent of titanium
tetrachloride, chloride ion is abstracted from the metal
center opening a coordination site on the metal.20 NMR
experiments support this hypothesis. A single enolate
species was observed when the enolate was prepared with
1.0 equiv of titanium tetrachloride and diisopropylethyl-
amine. Addition of a second equivalent of titanium tetra-
chloride produced a single new species distinct from the
original. The species produced with 2 equiv of titanium
tetrachloride was also produced when the enolate was
prepared with 1.0 equiv of titanium tetrachloride and
diisopropylethylamine followed by addition of 1.0 equiv
of silver hexafluoroantimonate. Abstraction of chloride
ion to form either a neutral trigonal bipyramidal titanium
species or a chloro bridged octahedral dimeric species is
possible.21 Either of these could react with aldehyde to
produce the chelated transition state 2 (Scheme 7).
Syn th etic Ma n ip u la tion of Ald ol Ad d u cts. The
aldol adducts of both N-acyloxazolidinethiones and N-
R ) iBu TMEDA
PhCHdCH
MeCHdCH
CH2)CH
Me2CH
52
74
51
50
62
52
63
79
42
63
64
65
97:3
92:8
>99:1
>99:1
92:8
92:8
92:8
98:2
>99:1
95:5
91:9
93:7
R ) iBu TMEDA
R ) iBu TMEDA
R ) iBu TMEDA
R ) iBu TMEDA
Ph
R ) iBu TMEDA
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
R ) iBu (-)-sparteine
R ) iBu (-)-sparteine
R ) iBu (-)-sparteine
R ) iBu (-)-sparteine
R ) iBu (-)-sparteine
R ) iBu (-)-sparteine
Ph
Me2CHCH2
a
TiCl4 was used as obtained from Aldrich Chemical Co. 1.1
b
equiv of TiCl4 was employed. 1.0 equiv of amine was employed.
c 1.1 equiv of aldehyde was employed. Yields are for the isolated,
d
chromatographically purified major diastereomer.
Ta ble 10. Non -Eva n s Syn Ald ol Ad d ition s w ith
(-)-Sp a r tein e w ith 7a
auxiliary
baseb
aldehyde (RCHO)c yieldd 16:17
R ) CH2Ph (-)-sparteine
R ) CH2Ph (-)-sparteine
R ) CH2Ph (-)-sparteine
R ) CH2Ph (-)-sparteine
R ) CH2Ph (-)-sparteine
R ) CH2Ph (-)-sparteine
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
58
45
49
60
52
57
97:3
>99:1
>99:1
98:2
>99:1
98:2
Ph
Me2CHCH2
a
TiCl4 was used as obtained from Aldrich Chemical Co. 1.1
b
equiv of TiCl4 were employed. 1.0 equiv of amine were employed.
c 1.1 equiv of aldehyde was employed. Yields are for the isolated,
d
chromatographically purified major diastereomer.
for coordination of 1 equiv of diamine to the metal center
is particularly strong in the case of the thiazolidineth-
iones where the facial selectivity of the aldol is reversed
upon addition of a second equivalent of diamine without
the addition of a second equivalent of titanium tetra-
chloride.
The fact that thiazolidinethiones produce non-Evans
syn aldol adducts with 1 equiv of (-)-sparteine and 1
equiv of titanium tetrachloride can be attributed to a
highly ordered chelated transition-state (Scheme 7). The
thiocarbonyl of thiazolidinethiones is more nucleophilic
than the oxazolidinone carbonyl or the oxazolidinethione
carbonyl, thus the non-Evans product apparently results
from formation of the highly ordered chelated transition-
state with only 1 equiv of titanium tetrachloride. When
2 equiv of TMEDA or (-)-sparteine were used, a reversal
of selectivity was observed to give the Evans syn aldol
adduct in excellent selectivity. The diamine is presum-
(19) Walker, M. A.; Heathcock, C. H. J . Org. Chem. 1991, 56, 5747-
5750.
(20) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238-1256. Castellino, S.; Dwight, W. J . J . Am. Chem. Soc.
1993, 115, 2986-2987.
(21) For a discussion of the structural features of complexes of
titanium tetrachloride with carbonyl functionality see: Cozzi, P. G.;
Solari, E.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Chem. Ber. 1996,
129, 1361-1368.

900 J . Org. Chem., Vol. 66, No. 3, 2001
Crimmins et al.
Sch em e 8
Sch em e 10
Sch em e 9
Sch em e 11
acylthiazolidinethiones can be readily converted to other
functional groups. Both the oxazolidinethiones and thia-
zolidinethiones are cleaved under milder conditions than
the oxazolidinones. As illustrated in Schemes 8 and 9,
the oxazolidinethiones such as 10b can be reductively
removed with either lithium borohydride or the less ex-
pensive sodium borohydride to produce the diols such as
26. Yields are typically somewhat higher with lithium
borohydride, however. A major practical advantage that
was discovered during the total synthesis of (-)-callys-
tatin A22 was the ability to recover the oxazolidinethione
auxiliary in high yield by simple base extraction with
aqueous NaOH. For example, treatment of intermediate
10b with lithium borohydride in Et2O and methanol
followed by base extraction with aqueous 14% NaOH
provided alcohol 263 in 90% yield (Scheme 9). Neutraliza-
tion of the water layer with aqueous 10% HCl and
subsequent extraction with methylene chloride and con-
centration gave 90% recovery of oxazolidinethione 4. The
facile reductive removal of the oxazolidinethione auxiliary
of 10b is noteworthy given the difficulty often encoun-
tered in the reductive cleavage of oxazolidinone auxilia-
ries in hindered systems.
The N-acylthiazolidinethione aldol adducts are also
reductively cleaved with either lithium borohydride or
sodium borohydride as with the oxazolidinethiones
(Scheme 11). Most importantly, direct conversion to the
aldehyde using iBu2AlH was possible (Scheme 11).25
Conversion to the secondary amide via substitution using
a primary amine or the Weinreb’s amide with N-
MeOMe-HCl and imidazole also proceeded cleanly in
dichloromethane (Scheme 10). In addition, formation of
esters can be achieved with an alcohol and imidazole
(Scheme 10).26 In all cases, liberation of the deacylated
auxiliary results. As with the oxazolidinethiones, because
of the relatively high acidity of the thiazolidinethione, it
is readily removed from the reaction mixture with a basic
wash using 1M NaOH and can be easily recovered by
acidification.27 The ability to separate the auxiliary from
the cleavage products by simple extraction is a distinct
advantage of both the oxazolidinethione and thiazolidi-
nethione auxiliaries.
Transamination to the Weinreb’s amide occurs by
exposure of the N-acyloxazolidinethione to N,O-dimeth-
ylhydroxylamine hydrochloride and imidazole in dichlo-
romethane (Scheme 8).23 Trimethylaluminum is not
required. A typical procedure involves the sequential
addition of 3 equiv of imidazole and 1 equiv of N,O-
dimethylhydroxylamine hydrochloride to a methylene
chloride solution of an oxazolidinethione substrate such
as 10b (1 equiv). Base extraction allows for the separation
of the oxazolidinethione auxiliary from the amide without
chromatographic separation. These reactions are believed
to proceed by initial displacement of the oxazolidineth-
ione by imidazole followed by further substitution of the
imidazole by the hydroxylamine. It is critical that the
hydroxyl group be unprotected for successful execution
of these transaminations.24
Iter a tive Ald ol Ad d ition s. Certainly one of the most
advantageous aspects of the aldol reactions described
above is the ability to switch from Evans to non-Evans
(24) Evans, D. A.; Gage, J . R.; Leighton, J . C. J . Am. Chem. Soc.
1992, 114, 9434-9453.
(25) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruya-
ma, S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097-2100.
(26) With oxazolidinethione auxiliaries, this product can also be
obtained but the use of DMAP is required, see: Su, D.; Wang, Y.; Yan,
T. Tetrahedron Lett. 1999, 40, 4197-4198.
(22) Crimmins, M. T.; King, Bryan W. J . Am. Chem. Soc. 1998, 120,
9084-9085.
(23) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1997,
4171-4174. Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989-993.
(27) This procedure cannot be used in the case of the aldehyde,
which is easily epimerized under basic conditions.

Asymmetric Aldol Additions
J . Org. Chem., Vol. 66, No. 3, 2001 901
Sch em e 12
syn aldol adducts by simply changing the reaction
conditions, thus nullifying the need for the auxiliary of
the opposite chirality. To demonstrate the utility of the
N-acyloxazolidinethione auxiliaries in this context, an
iterative aldol sequence with both possible syn-syn
tetrads was carried out. Aldol adduct en t-10b from
N-acyloxazolidinethiones en t-5 and isobutyraldehyde was
protected as its triethylsilyl ether 34, and then the
auxiliary was reductively removed with lithium borohy-
dride to give the primary alcohol 35. Dess-Martin
oxidation of the alcohol provided the aldehyde 36 which
was exposed to both the Evans syn conditions [1 equiv
of TiCl4, 2.5 equiv (-)-sparteine] and the non-Evans syn
conditions [2 equiv of TiCl4, 1.0 equiv (-)-sparteine] to
provide the syn-syn-syn adduct 37 and the syn-anti-
syn adduct 38, respectively. Both adducts were formed
in high yield with excellent diastereoselectivity demon-
strating the ability to access either syn tetrad depending
on the reaction conditions. The formation of a syn-syn
tetrad by iterative aldol additions of N-acyloxazolidineth-
iones was utilized in a recent synthesis of (-)-callystatin
A22 and has been exploited by Sulikowski in an approach
to a fragment of apoptolidin.28
chromatography to provide 4.98 g (95%) of oxazolidinethione
415 as a viscous oil (crystallization of the oil would slowly occur
after approximately one month at 0 °C) but was generally
carried to the acylation step without purification: [R]24D -95.4°
(c ) 1.1, CH2Cl2); IR (neat) 3450, 3050 br, 1485, 1325, 1260,
Su m m a r y
Aldol addition reactions of the titanium enolates of
N-acyloxazolidinethiones and N-acylthiazolidinethiones
have been executed with extremely high selectivities and
yields with readily available and easily handled reagents
and with 1.1 equiv of aldehyde. Either enantiomeric syn
aldol product (after removal of the auxiliary) may be
obtained from the same N-acyloxazolidinethione or thia-
zolidinethione by simply changing the reaction condi-
tions. A variety of aldehyde structural types, including
unsaturated aldehydes, are tolerated. The combination
of 1.0 equiv of TiCl4 and 2.5 equiv of (-)-sparteine [or 1
equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrro-
lidinone] has provided excellent selectivity for the Evans
syn aldol product and has shown a dramatic rate en-
hancement. Outstanding selectivity for the non-Evans
syn aldol product was obtained with 2 equiv of TiCl4 and
1.1 equiv of (-)-sparteine for the oxazolidinethiones and
1 equiv of TiCl4 and 1.1 equiv of (-)-sparteine for the
thiazolidinethiones. In addition, the thione auxiliaries are
more easily removed than the corresponding oxazolidi-
nones and can be recovered by simple base extraction of
the crude reaction mixtures. These points exemplify the
practicality of the oxazolidinethione and the thiazolidi-
nethione mediated aldol methodology. The titanium tet-
rachloride-(-)-sparteine-N-methyl-2-pyrrolidinone method
also holds practical advantages in the asymmetric aldol
additions with N-acyloxazolidinones.
1
1220, 1205, 1175 cm-1; H NMR (CDCl3, 200 MHz) δ 7.40-
7.10 (m, 5H), 7.06 (br s, 1H), 4.71 (t, J ) 8.9 Hz, 1H), 4.45-
4.18 (m, 2H), 3.01-2.79 (m, 2H); 13C NMR (CDCl3, 75.5 MHz)
δ 189.3, 135.1, 129.0, 128.9, 127.3, 74.6, 57.6, 40.2.
(S )-3-(1-Oxop r op yl)-4-b e n zyl-1,3-oxa zolid in e -2-t h i-
on e (5). To a cooled solution (-78 °C) of 12.86 g (66.54 mmol)
of oxazolidinethione 4 in 300 mL of THF was added dropwise
41.6 mL (66.54 mmol) of n-butyllithium (1.6 M in hexanes).
After stirring the lithiated oxazolidinethione for 15-20 min,
6.94 mL (7.39 g, 79.85 mmol) of propionyl chloride was added.
The reaction was allowed to stir at -78 °C for 15 min prior to
warming to room temperature and stirring for 30 min. The
reaction was quenched with aqueous 10% K2CO3, and the
volatiles were removed. The aqueous layer was extracted with
CH2Cl2 (2×) and the organic layer concentrated. Purification
of the residue by column chromatography afforded 14.93 g
(90%) of N-acyloxazolidinethione 5 as a white solid: [R]24
D
+127.3° (c ) 0.49, CH2Cl2); IR (neat) 1695, 1400, 1360, 1310,
1
1190 cm-1; H NMR (CDCl3, 200 MHz) δ 1.21 (t, J ) 7.2 Hz,
3H), 2.75 (dd, J ) 13.1, 9.5 Hz, 1H), 3.11-3.51 (m, 3H), 4.20-
4.38 (m, 2H), 4.91 (m, 1H), 7.15-7.39 (m, 5H); 13C NMR
(CDCl3, 50 MHz) δ 185.3, 174.8, 135.2, 129.3, 128.9, 127.3,
70.21, 59.88, 37.55, 31.29, 8.45. Anal. Calcd for C13H1 5NO2S:
C, 62.63; H, 6.06; N, 5.62. Found: C, 62.59; H, 6.04; N, 5.58.
Typ ica l P r oced u r e for TiCl4 (2 equ iv), i-P r 2NEt, or (-)-
Sp a r tein e (1.1 equ iv). To a dry round-bottom flask under
nitrogen was added 0.25 g (1.00 mmol) of the oxazolidinethione
in 6 mL of CH2Cl2. The solution was cooled to 0 °C. Titanium
(IV) chloride (2.00 mmol, 0.22 mL) was added dropwise and
the solution allowed to stir for 5 min. To the yellow slurry or
suspension was added diisopropylethylamine or (-)-sparteine
(1.10 mmol). The dark red titanium enolate was stirred for 20
min at 0 °C, then was cooled to -78 °C. Freshly distilled
aldehyde (1.10 mmol) was added dropwise. The resulting
mixture was stirred for 1 h at -78 °C and then was warmed
to 0 °C. The reaction was quenched with half-saturated
ammonium chloride (6 mL), and the layers were separated.
The organic layer was dried over sodium sulfate, filtered, and
concentrated. HPLC analysis of the crude revealed the isomer
ratios. Purification by column chromatography of the crude
material afforded the major diastereomer.
Exp er im en ta l Section
(S)-4-Ben zyl-1,3-oxa zolid in e-2-th ion e (4)15. To a solution
of 4.11 g (27.18 mmol) of l-phenylalaninol and 9.47 mL (6.88
g, 67.95 mmol) of triethylamine in 100 mL of CH2Cl2 at 0 °C
was added a solution of 2.07 mL (3.13 g, 27.18 mmol) of
thiophosgene in 2 mL of CH2Cl2. After the mixture was stirred
for 30 min at 0 °C, the reaction was quenched with 10%
NaHSO4. The layers were separated, and the organic layer was
washed with 1 M NH4OH, dried over Na2SO4, decanted, and
concentrated. The crude material could be purified by column
Typ ica l P r oced u r e for TiCl4 (1 equ iv), Dia m in e (2.5
equ iv). To a dry round-bottom under nitrogen was added 1.00
mmol of the N-propionyloxazolidinone, oxazolidinethione, or
(28) Sulikowski, G. A.; Lee, W.-M.; J in, B.; Wu, B. Org. Lett. 2000,
2, 1439-1442.

902 J . Org. Chem., Vol. 66, No. 3, 2001
Crimmins et al.
thiazolidinethione in 6 mL of CH2Cl2. The solution was cooled
to 0 °C. Titanium (IV) chloride (1.05 mmol, 0.115 mL) was
added dropwise and the solution allowed to stir for 5 min. To
the yellow slurry or suspension was added the diamine
[TMEDA or (-)-sparteine, 2.5 mmol]. The dark red enolate
was stirred for 20 min at 0 °C. Freshly distilled aldehyde (1.1
mmol) was added dropwise and the reaction stirred for 1 h at
0 °C. Workup and procedure was the same as above.
Typ ica l P r oced u r e for TiCl4 (1 equ iv), (-)-Sp a r tein e
(1 equ iv), N-Meth yl-2-p yr r olid in on e (1 equ iv). A solution
of the N-acyloxazolidinethione, N-acyloxazolidinone, or N-
acylthiazolidinethione (1.23 mmol) in 10 mL of CH2Cl2 was
cooled to 0 °C. TiCl4 (0.14 mL, 1.29 mmol) was added, and the
mixture was stirred for 5 min. (-)-Sparteine (0.28 mL, 1.23
mmol) was added dropwise slowly. After complete addition,
the mixture was stirred at 0 °C for 20 min. The mixture was
cooled to -78 °C, and 1-methyl-2-pyrrolidinone (0.12 mL, 1.23
mmol) was added. The mixture was stirred for 10 min followed
by addition of freshly distilled isobutyraldehyde (0.12 mL, 1.35
mmol) dropwise. The mixture was stirred for 1 h at -78 °C,
gradually warmed to 0 °C, and stirred for 1h. The reaction
was quenched with half-saturated NH4Cl and warmed to 25
°C. The layers were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography afforded
0.389 g of alcohol (98%).
The solution was cooled to 0 °C. Titanium (IV) chloride (1.00
mmol, 0.11 mL) was added dropwise, and the solution allowed
to stir for 5 min. To the yellow slurry or suspension was added
diisopropylethylamine or (-)-sparteine (1.00 mmol). The dark
red titanium enolate was stirred for 20 min at 0 °C, then was
cooled to -78 °C. Freshly distilled aldehyde (1.10 mmol) was
added dropwise. The resulting mixture stirred for 1 h at -78
°C and then was warmed to 0 °C. The reaction was quenched
with half-saturated ammonium chloride (6 mL) and the layers
separated. The organic layer was dried over sodium sulfate,
filtered, and concentrated. HPLC analysis of the crude re-
vealed the isomer ratios. Purification by column chromatog-
raphy of the crude material afforded the major diastereomer.
Ack n ow led gm en t . We thank Professor J ames P.
Morken and for helpful discussions. Financial support
of our programs by the NIH and the NSF is acknowl-
edged with thanks. Thanks are also due to the Wellcome
Foundation for a fellowship to B.W.K and E.A.T. and
to Organic Reactions for sponsoring a Division of
Organic Chemistry Fellowship for B.W.K.
Su p p or tin g In for m a tion Ava ila ble: Su p p or tin g In -
for m a tion Ava ila ble: Spectral data (1H, 13C NMR, IR, and
optical rotations) for compounds 7, 9a -f, 10a -f, 20a -f, 21a -
f, 26-38 are available. This information is available free of
charge via the Internet at http://pubs.acs.org.
Typ ica l P r oced u r e for TiCl4 (1 equ iv), (-)-Sp a r tein e
(1 equ iv). To a dry round-bottom flask under nitrogen was
added the thiazolidinethione (1.00 mmol) in 6 mL of CH2Cl2.
J O001387R