Titanium Enolates of Thiazolidinethione Chiral Auxiliaries: Versatile Tools for Asymmetric Aldol Additions

Article abstract of DOI:10.1021/ol9913901

formula presented Asymmetric aldol additions using chlorotitanium enolates of 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 (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.

Full text of DOI:10.1021/ol9913901

ORGANIC
LETTERS
2000
Vol. 2, No. 6
775-777
Titanium Enolates of Thiazolidinethione
Chiral Auxiliaries: Versatile Tools for
Asymmetric Aldol Additions
Michael T. Crimmins* and Kleem Chaudhary
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received December 22, 1999
ABSTRACT
Asymmetric aldol additions using chlorotitanium enolates of 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 (−)-sparteine as the base, selectivities of
97:3 to >99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was
employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups.
Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.
Chiral auxiliary-mediated asymmetric aldol additions have
been studied extensively and are now an important and
general method for asymmetric carbon-carbon bond forma-
tion.1 In particular, dibutylboron enolates of acyl oxazolidi-
nones, pioneered by Evans, are highly effective for the
preparation of “Evans” syn products in asymmetric aldol
additions.2 Recent studies in our laboratory have shown that
chlorotitanium enolates of oxazolidinethiones provide high
diastereoselectivity as well as the ability to produce either
“Evans” or “non-Evans” syn aldol adducts depending on the
stoichiometry of titanium tetrachloride and nature of the
amine employed.3 However, more easily cleavable auxiliaries
than oxazolidinones or oxazolidinethiones would be advanta-
geous. We now report that the use of chlorotitanium enolates
of acyl thiazolidinethione auxiliaries also results in high
diastereoselectivities in aldol additions. The aldol adducts
of acyl thiazolidinethiones are easily removed and can be
directly converted to aldehydes as well as to other functional
groups.
Synthesis of the thiazolidinethione auxiliaries4 was readily
accomplished by reduction of an amino acid to the corre-
sponding amino alcohol5 followed by conversion of the
amino alcohol to the thiazolidinethione by exposure to carbon
disulfide and 1 M KOH6 (Figure 1). The auxiliary was then
acylated with propionyl chloride in the presence of triethy-
lamine (Figure 2).
Formation of the enolate at 0 °C using titanium tetrachlo-
ride and the appropriate amine base occurred within 20 min;
(1) (a) 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.
(2) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(3) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883-7884.
(4) Nagao, Y.; Yamada, S.; Kumagai, Ochiai, M.; Fujita, E. J. Chem.
Soc., Chem Commun. 1985, 1418-1419.
(5) McKennon, M. J.; Meyer, A. I. J. Org. Chem. 1993, 58, 3568-3571.
(6) Delaunay, D.; Toupet, L.; Le Corre, M.J. Org. Chem. 1995, 60,
6604-6607.
Figure 1. Synthesis of thiazolidinethione auxiliary.
10.1021/ol9913901 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000

Table 2. Selectivities for Propionate Aldol Additions Using
Thiazolidinethione Chiral Auxiliaries with Titanium
Tetrachloride and Diamines (1 Equiv)
auxiliary (2)
R )
aldehyde
(RCHO)
yield
(%)
base
3:4
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
52
74
51
50
62
52
63
79
42
63
64
65
58
45
49
60
52
57
97:3
92:8
>99:1
>99:1
92:8
92:8
92:8
98:2
>99:1
95:5
91:9
93:7
97:3
>99:1
>99:1
98:2
>99:1
98:2
Figure 2. Acylation of thiazolidinethione auxiliary.
Ph
subsequent addition of the aldehyde led to formation of aldol
adducts with excellent diastereoselectivity.7 Interestingly, the
use of diisopropylethylamine (DIEA), TMEDA, or (-)-
sparteine resulted in preferential formation of non-Evans syn
aldol adducts 3 when 1 equiv of titanium tetrachloride and
1 equiv of amine was employed (Tables 1 and 2). However,
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
Ph
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
Table 1. Selectivities for Propionate Aldol Additions Using
Thiazolidinethione Chiral Auxiliaries with Titanium
Tetrachloride and Diisopropylethylamine
Ph
Me2CHCH2
auxiliary (2)
R )
TiCl4
aldehyde11
(RCHO)
yield12
(%)
(equiv)
3:413
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
1
1
1
1
1
1
2
2
2
2
2
2
PhCHdCH
Ph
Me2CH
Me2CHCH2
CH2dCH
MeCHdCH
PhCHdCH
Ph
80
78
77
40
30
53
56
60
75
51
40
44
87:13
91:9
product 4 were realized for all aldehydes studied when 2
equiv of (-)-sparteine was used instead of TMEDA8 (Table
3).9 Isolation of diastereomeric products proceeded very
87:13
84:16
>99:1
>99:1
96:4
90:10
95:5
90:10
>99:1
96:4
Table 3. Selectivities for Propionate Aldol Additions Using
Thiazolidinethione Chiral Auxiliaries with Titanium
Tetrachloride and Diamines (2 Equiv)
Me2CH
Me2CHCH2
CH2dCH
MeCHdCH
auxiliary (2)
R )
aldehyde
(RCHO)
yield
(%)
base
3:4
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
(-)-sparteine
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
75
53
42
57
61
60
80
66
72
84
85
81
66
64
77
75
62
71
2:98
<1:99
<1:99
4:96
6:94
4:96
the use of TMEDA gave excellent selectivities in all cases
for Evans syn product 4 when 2 equiv of base was used.
Higher selectivities and improved yields of Evans syn
Ph
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
(7) Typical Procedure. To a dry round-bottom flask under nitrogen was
added 0.2330 g (1.0 mmol) of the thiazolidinethione in 5 mL of CH2Cl2.
The solution was cooled to 0 °C. Titanium(IV) chloride (0.121 mL, 1.1
mmol) was added dropwise, and the solution was allowed to stir for 5 min.
To the red suspension was added (-)-sparteine (0.572 mL, 2 mmol). The
dark red enolate was stirred for 20 min at 0 °C. Freshly distilled aldehyde
(1.1 mmol) was added dropwise and the resulting mixture stirred for 1 h at
0 °C. The reaction was quenched with half-saturated ammonium chloride,
and the layers were separated. The aqueous layer was re-extracted with
CH2Cl2, and the combined extracts were dried over magnesium sulfate,
filtered, and concentrated. HPLC analysis of the unpurified product revealed
the isomer ratios. Purification by flash column chromatography afforded
the major diastereomer.
4:96
<1:99
<1:99
5:95
8:92
3:97
Ph
Me2CHCH2
PhCHdCH
MeCHdCH
CH2dCH
Me2CH
8:92
<1:99
<1:99
3:97
<1:99
2:98
Ph
(8) Using 1.5 equiv of diamine gave selective formation of the Evans
syn product, but 2 equiv resulted in better selectivity.
(9) For a discussion of effects of amine structure on selectivity in Tin-
(II) enolates, see: Mukaiyama, T.; Iwasawa, N. Chem Lett. 1984, 753-
756.
Me2CHCH2
(10) The configuration of the aldol adducts was verified by correlation
to authentic samples after removal of the auxiliary.
easily. The products were yellow in color, which allowed
for visual chromatography where separation of components
could be seen directly on a silica gel column.
The major aldol addition product formed was the non-
Evans syn adduct when using 1 equiv of DIEA, TMEDA,
(11) Aldehydes were freshly distilled prior to use.
1
(12) All new compounds were characterized by H and 13C NMR and
optical rotation. Yields are for isolated, chromatographically purified
products.
(13) Diasteromeric ratios were determined by HPLC.
776
Org. Lett., Vol. 2, No. 6, 2000

or (-)-sparteine regardless of the amount of titanium
tetrachloride added.10 This can be attributed to a proposed
highly ordered chelated transition state (Figure 3). We
Scheme 1. Conversion of Aldol Adduct to Various Products
in efficient conversion to the diol. Conversion to the Weinreb
amide was possible simply by treatment with N,O-dimeth-
ylhydroxylamine hydrochloride and imidazole.14 Conversion
to the amide via substitution using a primary amine also
proceeded cleanly. Most importantly, conversion to the
aldehyde using i-BuAl2H was possible.15 In addition, forma-
tion of esters was effected with an alcohol and imidazole.16
In all cases, liberation of the deacylated auxiliary results.
Because of the relatively high acidity of the thiazolidineth-
ione, it is readily removed from the reaction mixture with a
basic wash using 1 M NaOH and can be recovered by
acidification.17 The ability to separate the auxiliary from the
cleavage products by simple extraction is a distinct advantage
of both the oxazolidinethione and thiazolidinethione auxil-
iaries.
In summary, aldol additions of the chlorotitanium enolates
of acyl thiazolidinethiones deliver highly selective aldol
reactions favoring non-Evans syn products 3 when using 1
equiv of DIEA, TMEDA, or (-)-sparteine as the base and
Evans syn products 4 with 2 equiv of TMEDA or (-)-
sparteine. The products are easily isolated and can be
converted directly to the aldehyde as well as to a variety of
other functionalities. Recovery of the auxiliary is effected
by basic extraction of the product mixture.
Figure 3. Proposed transition states for aldol additions using
titanium enolates of thiazolidinethiones.
previously observed that, with oxazolidinethiones, use of 1
equiv of TiCl4 led to formation of the Evans syn product.
Addition of an additional 1 equiv of TiCl4 led to formation
of non-Evans syn aldol adduct. However, in the case of
thiazolidinethiones, the increased nucleophilicity of the
auxiliary apparently results in formation of the highly ordered
chelated transition state with only 1 equiv of titanium
tetrachloride to yield the non-Evans syn product preferen-
tially. Interestingly, when 2 equiv of TMEDA or (-)-
sparteine was used, a reversal of selectivity was observed to
give the Evans syn aldol adduct in excellent selectivity. The
diamine may participate by coordinating to the titanium,
disfavoring the chelation of the thiocarbonyl to the metal
center (Figure 3).
Acknowledgment. This work was supported by a re-
search grant from the National Institutes of Health (NCI)
(CA63572). Thanks to Matthew Duffey, Steven Taylor, and
Professor James P. Morken for help with structural assign-
ments of the aldol adducts.
The aldol adducts formed can be converted to a variety
of derivatives (Scheme 1). Treatment with NaBH4 resulted
(14) 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.
Supporting Information Available: Spectral data for
Evans syn products 4a-l, non-Evans products 3a-f, and
cleavage products 5-9. This material is available via the
Internet at http://pubs.acs.org.
(15) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama,
S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097-2100.
(16) 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.
(17) This procedure cannot be used in the case of the aldehyde, which
is easily epimerized under basic conditions.
OL9913901
Org. Lett., Vol. 2, No. 6, 2000
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