An improved procedure for asymmetric aldol additions with N-acyl oxazolidinones, oxazolidinethiones and thiazolidinethiones

Article abstract of DOI:10.1055/s-2004-825626

Asymmetric aldol additions using chlorotitanium enolates of N-acyl oxazolidinones, oxazolidinethiones and thiazolidinethiones proceed with high diastereoselectivity for the 'Evans syn' product using one equivalent of titanium tetrachloride, one equivalent

Full text of DOI:10.1055/s-2004-825626

LETTER
1371
An Improved Procedure for Asymmetric Aldol Additions with N-Acyl
Oxazolidinones, Oxazolidinethiones and Thiazolidinethiones
I
mprove
d
Procedure fo
i
r
Asym
c
metric Ald
h
ol
A
dditions
a
with
N
-A
c
e
yl
O
xazolid
l
inones T. Crimmins, Jin She
Department of Chemistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
Fax +1(919)9622388; E-mail: crimmins@email.unc.edu
Received 30 April 2004
Dedicated to Professor Clayton H. Heathcock
improved TiCl4, (–)-sparteine-NMP, method was quite ef-
fective and has found increasingly wider use as an eno-
lization method for asymmetric aldol reactions.10
However, the need for the moderately expensive (–)-
Abstract: Asymmetric aldol additions using chlorotitanium eno-
lates of N-acyl oxazolidinones, oxazolidinethiones and thiazoli-
dinethiones proceed with high diastereoselectivity for the ‘Evans
syn’ product using one equivalent of titanium tetrachloride, one
equivalent of diisopropylethylamine and one equivalent of N-meth- sparteine as the base has been the point of some concern
yl-2-pyrrolidinone. Typical selectivities of 94:6 to >98:2 were ob-
tained using N-propionyl oxazolidinones, oxazolidinethiones and
with the method. Consequently, we recently reinvestigat-
ed the asymmetric aldol reaction with the goal of finding
thiazolidinethiones at 0 °C with stoichiometric amounts of alde-
a set of conditions, which would obviate the need for (–)-
hyde. Glycolate imides also gave high selectivities and high yields
sparteine as the base and perhaps offer improved perfor-
using this procedure.
mance in asymmetric aldol reactions of N-glycolyl oxazo-
Key words: aldol reactions, asymmetric synthesis, titanium eno-
lidinones, oxazolidinethiones or thiazolidinethiones. We
lates, imides, glycolates
report here the results of our findings (Equation 1).
X
O
OH
X
O
The chiral auxiliary mediated asymmetric aldol addition
is one of the most general and widely used methods for
asymmetric carbon-carbon bond formation.1 The utility of
the asymmetric aldol addition has been amply demon-
strated through a multitude of synthetic applications.2 The
Evans protocol using dibutylboron enolates of acyl oxazo-
lidinones is the most commonly utilized method provid-
ing the ‘Evans syn’ product as the major diastereomer.3
Titanium(IV)4–6 and tin(II)7 enolates have also been
shown to be effective in creating well-ordered transition
TiCl4 (1 equiv)
N
Y
R
N
Y
Me
(-)-sparteine (1 equiv)
1-methyl-2-pyrrolidinone (1 equiv)
Bn
Bn
CH2Cl2, RCHO
–78 °C
Evans syn
98% >98:2
X = Y = O
X = Y = S
X = S, Y = O
Equation 1 Diastereoselective aldol additions using TiCl4,
(–)-sparteine, and NMP
states for aldol reactions. Evans and Yan have reported the Our initial attempts to further improve conditions for the
use of chlorotitanium enolates of N-acyloxazolidinones in chlorotitanium enolate aldol reaction focused on finding a
aldol additions, prepared by soft enolization using titani- suitable base to substitute for (–)-sparteine. Tetramethyl-
um tetrachloride and diisopropylethylamine amine.4,6 ethylenediamine (TMEDA), also a diamine, seemed a
However, slightly lower selectivity was observed than logical choice since it had shown some promise in our
with the dibutylboron enolates and excess aldehyde (from original survey of conditions with oxazolidinethiones.8
2–5 equiv) was required to achieve good levels of conver- However, the combination of TiCl4, TMEDA, and NMP
sion.4,6
gave inferior selectivity to the TiCl4, (–)-sparteine, NMP
method and generally gave lower overall conversion. Af-
ter surveying other tertiary amines, the best combination
was found to be 1.05 equivalents of titanium tetrachloride,
1.1 equivalents of diisopropylethylamine and 1.0 equiva-
lent of N-methyl-2-pyrrolidinone. Utilizing these condi-
tions with only 1.1 equivalents of the desired aldehyde
We recently reported a protocol for accessing Evans syn
aldol adducts using 1 equivalent of titanium tetrachloride
and 2.2 equivalents of (–)-sparteine to form the titanium
enolates of N-acyl oxazolidinethiones, thiazolidinethi-
ones, and oxazolidinones.8 Since it was proposed that the
second equivalent of (–)-sparteine was functioning simply
as a ligand for titanium, an improved protocol using 1
equivalent of titanium tetrachloride, 1 equivalent of (–)-
sparteine and 1 equivalent of 1-methyl-2-pyrrolidinone
(NMP), as the ligand for titanium, was investigated.9 The
X
O
OH
X
O
TiCl4 (1.05 equiv)
N
Y
R
N
Y
Me
diisopropylethylamine (1.1 equiv)
Bn
Bn
1a X = Y = O
1b X = S, Y = O
1c X = Y = S
1-methyl-2-pyrrolidinone (1.0 equiv)
CH2Cl2, RCHO
0 °C
Evans syn
SYNLETT 2004, No. 8, pp 1371–1374
0
1.
0
7.
2
0
0
4
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-825626; Art ID: Y02904ST
© Georg Thieme Verlag Stuttgart · New York
Equation 2 Diastereoselective aldol additions using TiCl4,
i-Pr2NEt, and NMP

1372
M. T. Crimmins, J. She
LETTER
provided high levels of conversion and high selectivities
even at 0 °C.11
Bn
N
Bn
OBn
TiCl4, R3N
O
H
H
O
N
OBn
O
All three imide auxiliaries: oxazolidinones, oxazolidine-
thiones and thiazolidinethiones were found to function
well under these conditions to afford the Evans syn prod-
uct as the major diastereomer. It is important to note that
our early studies indicated the use of diisopropylethyl-
amine as base without added NMP gave inconsistent re-
sults with N-propionyloxazolidinethiones,8a and provided
the non-Evans syn adducts with N-propionylthiazolidine-
thiones.8b Table 1 shows the results of a survey of several
aldehydes with each of the three propionyl imides 1a, 1b,
1c (Equation 2). This new protocol provides a cost effec-
tive, operationally simple procedure for the execution of
diastereoselective aldol additions with N-acyl oxazoli-
dinones, oxazolidinethiones and thiazolidinethiones.
O
CH2Cl2
CH2=CHCHO
H
H
O
O
O
HO
O
6
7
i-Pr2NEt
45%; 98:2 d.r.
50%, 98:2 d.r.
2 equiv (–)-sparteine
Equation 3 Previous results with glycolate aldol reactions
example, when the enolate of N-acyloxazolidinone 6 was
prepared with 1 equivalent titanium tetrachloride and di-
isopropylethylamine and then treated with acrolein
(Equation 3), the yield of the aldol adduct was only about
45%. The (–)-sparteine protocol improved the efficiency
slightly, but the yield was still disappointingly low (50%).
When imide 6 was treated with 1 equivalent of titanium
tetrachloride and 2.5 equivalents13 of diisopropylethy-
lamine plus 1 equivalent of NMP, the conversion of the
reaction was substantially improved to 78% with high lev-
els of diastereoselectivity.14 Furthermore, the improved
reaction conditions are general for a variety of N-glycoly-
loxazolidinones as illustrated in Table 2.
The success of the new protocol for the aldol addition with
N-propionylimides prompted an investigation to its appli-
cability to aldol additions of simple and more complex N-
glycolylimides, since we have utilized aldol adducts of N-
glycolylimides in a number of syntheses of complex cy-
clic ethers.12 Using either the standard Evans dibutylboryl
enolates or chlorotitanium enolates through various eno-
lization methods had met with limited success with com-
plex glycolylimides. Typically, levels of conversion were
low compared to N-propionylimide aldol reactions. For
In summary, a new cost effective, operationally simple
protocol for the execution of diastereoselective aldol ad-
ditions with N-acyl oxazolidinones, oxazolidinethiones
Table 1 Aldol Additions with N-Propionyl Oxazolidinones, Oxazolidinethiones and Thiazolidinethiones11
Entry
1
Aldol Substrate
Aldehyde
Product
Yield (%)
99
Diastereoselectivity
97:3
Me2CHCHO
O
S
S
O
O
O
OH
R
N
N
N
O
O
S
N
O
Me
Bn
Bn
2a R = i-Pr
3a R = C5H11–
2
3
4
5
1a
1a
1a
C5H11CHO
75
97
97
93:7
94:6
95:5
C6H5CHO
4a R = C6H5–
C6H5CH=CHCHO
Me2CHCHO
5a R = C6H5CH=CH–
S
98 (–78 °C to 0 °C)
97 (0 °C)
>98:2
97:3
O
OH
O
N
O
R
Me
Bn
Bn
2b R = i-Pr
3b R = C5H11–
6
7
8
9
1b
1b
1b
C5H11CHO
97
95
97
99
94:6
93:7
96:4
98:2
C6H5CHO
4b R = C6H5–
C6H5CH=CHCHO
Me2CHCHO
5b R = C6H5CH=CH–
S
O
OH
O
N
S
R
Me
Bn
Bn
2c R = i-Pr
10
11
12
1c
1c
1c
C5H11CHO
3c R = C5H11–
97
99
98
96:4
96:4
96:4
C6H5CHO
4c R = C6H5–
C6H5CH=CHCHO
5c R = C6H5CH=CH–
Synlett 2004, No. 8, 1371–1374 © Thieme Stuttgart · New York

LETTER
Improved Procedure for Asymmetric Aldol Additions with N-Acyl Oxazolidinones
1373
Table 2 Aldol Additions with N-Glycolyl Oxazolidinones14
Entry
1
Aldol Substrate
Aldehyde
Product
Yield (%)
72
Diastereoselectivity
CH2=CHCHO
97:3
Bn
Bn
OBn
O
N
OBn
O
O
H
H
O
H
N
R
H
O
O
O
HO
O
6
7 R = CH=CH2
8 R = C12H25–
2
3
4
5
6
6
6
6
6
C12H25CHO
74
76
79
93
77
95:5
96:4
95:5
96:4
95:5
TIPSO(CH2)3CHO
TMSC≡CCHO
TIPSC≡CCHO
CH2=CHCHO
9 R = TIPSO(CH2)3–
10 R = TMSC≡C–
11 R = TIPSC≡C–
Bn
BnO
BnO
O
O
N
O
C10H21
C10H21
O
O
H
H
N
O
12
O
OH
Bn
O
13
7
CH2=CHCHO
83
96:4
Bn
Bn
O
N
OBn
OBn
O
O
H
H
H
O
O
N
R
O
H
14
O
HO
O
15 R = CH2=CH–
8
9
14
C6H5CHO
16 R = CH2=CHCH2CH2–
84
84
96:4
91:9
CH2=CHCHO
Bn
OBn
O
H
O
N
BnO
O
N
OH
Bn
O
O
O
17
18
and thiazolidinethiones has been developed and should References
significantly improve the utility of this important reaction.
(1) (a) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747. (b) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917.
(c) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta
1997, 30, 3. (d) Velazquez, F.; Olivo, H. F. Curr. Org.
Chem. 2002, 6, 303. (e) Evans, D. A.; Shaw, J. T. Actualité
Chimique 2003, 35.
(2) For selected examples see: (a) Evans, D. A.; Kaldor, S. W.;
Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990,
112, 7001. (b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J.
Am. Chem. Soc. 1992, 114, 9434. (c) Evans, D. A.; Ng, H.
P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115, 11446.
(d) Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454.
(e) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J.
J. Am. Chem. Soc. 1998, 120, 5921. (f) Crimmins, M. T.;
King, B. W. J. Am. Chem. Soc. 1998, 120, 9084.
(g) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61,
4192. (h) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.;
Allwein, S. P.; MacAtee, L. F. J. Am. Chem. Soc. 2002, 124,
5661.
Additionally, the successful implementation of the aldol
reaction of chlorotitanium enolates of highly substituted
and stereochemically complex N-glycolyloxazolidinones
should lead to many useful applications in the synthesis of
complex advanced intermediates for synthesis of cyclic
ethers and related substances. These applications are cur-
rently in progress and will be reported in due course.
Acknowledgment
We thank the National Institutes of Health (NIGMS, GM60567) for
generous financial support.
(3) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127.
Synlett 2004, No. 8, 1371–1374 © Thieme Stuttgart · New York

1374
M. T. Crimmins, J. She
LETTER
allowed to stir for 1–2 h followed by addition of half-sat.
(4) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047.
(5) (a) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991,
56, 2489. (b) Bonner, M. P.; Thornton, E. R. J. Am. Chem.
Soc. 1991, 113, 1299.
(6) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang,
T.-Y. J. Am. Chem. Soc. 1993, 115, 2613; and references
therein. (b) Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-
S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301.
(7) (a) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.;
Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51,
2391. (b) Hsiao, C.-N.; Liu, L.; Miller, M. J. J. Org. Chem.
1987, 52, 2201.
NH4Cl. The organic layer was separated and the aqueous
layer extracted twice with CH2Cl2. The combined organic
layers were dried over Na2SO4, filtered and concentrated.
The initial product mixture was analyzed by 1H NMR
followed by purification by column chromatography.
(12) (a) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62,
7548. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc.
1999, 121, 5663. (c) Crimmins, M. T.; Tabet, E. A. J. Am.
Chem. Soc. 2000, 122, 5473. (d) Crimmins, M. T.; King, B.
W.; Zuercher, W. J.; Choy, A. L. J. Org. Chem. 2000, 65,
8499. (e) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L.
Tetrahedron 2002, 58, 1817.
(8) (a) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998,
120, 9084. (b) Crimmins, M. T.; Chaudhary, K. Org. Lett.
2000, 2, 775.
(9) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem. 2001, 66, 894.
(13) The use of 2.5 equiv of diisopropylethylamine for N-
glycolylimides (compared to the use of 1.1 equiv of
diisopropylethylamine forN-propionyl imides) improved the
levels of conversion in the aldol reaction.
(14) Typical Procedure for Formation of Evans syn Adducts
from N-Glycolylimides. To a dry round-bottom flask under
argon was added 1.00 mmol of the appropriate N-
(10) (a) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org.
Chem. 2004, 69, 2569. (b) Crimmins, M. T.; McDougall, P.
J. Org. Lett. 2003, 5, 591. (c) Ambhaikar, N. B.; Snyder, J.
P.; Liotta, D. C. J. Am. Chem. Soc. 2003, 125, 3690.
(d) Guz, N. R.; Phillips, A. J. Org. Lett. 2002, 4, 2253.
(11) Typical Procedure for Formation of Evans syn Adducts
from N-Propionylimides 1a, 1b, and 1c. To a dry round-
bottom flask under argon was added 1.00 mmol of the
appropriate N-acyloxazolidinone, N-acyloxazolidinethione,
or N-propionylthiazolidinethione, and 10 mL CH2Cl2. After
cooling to 0 °C, TiCl4 (0.115 mL, 1.05 mmol) was added
dropwise and the solution was allowed to stir for 15 min.
Diisopropylethylamine (0.191 mL, 1.10 mmol) was added
dropwise to the mixture and the solution was allowed to stir
for 40 min. 1-Methyl-2-pyrrolidinone (0.096 mL, 1.00 mmol
for N-acyloxazolidinone and N-acyloxazolidinethione;
0.192 mL, 2.00 mmol for N-propionylthiazolidinethione)
was added at 0 °C and the mixture was stirred for an
additional 10 min. Freshly distilled aldehyde (1.10 mmol)
was then added directly to the enolate. The reaction was
acyloxazolidone, N-acyloxazolidinethione, or N-
propionylthiazolidinethione, and 10 mL CH2Cl2. After
cooling to –78 °C, TiCl4 (0.115 mL, 1.05 mmol) was added
dropwise and the solution was allowed to stir for 15 min.
Diisopropylethylamine (0.434 mL, 2.50 mmol) was added
dropwise to the mixture and the solution was allowed to stir
for 1–2 h. 1-Methyl-2-pyrrolidinone (0.096 mL, 1.00 mmol)
was added at –78 °C and the mixture was stirred for an
additional 10 min. Freshly distilled aldehyde (2.00–4.00
mmol) was then added directly to the enolate. The reaction
was allowed to stir for 1–2 h at –78 °C and then warmed to
–40 °C for 1–2 h followed by addition of half-sat. NH4Cl.
The organic layer was separated and the aqueous layer
extracted twice with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered and concentrated. The
initial product mixture was analyzed by 1H NMR followed
by purification by column chromatography.
Synlett 2004, No. 8, 1371–1374 © Thieme Stuttgart · New York