Synthesis of a new N-acetyl thiazolidinethione reagent and its application to a highly selective asymmetric acetate aldol reaction

Article abstract of DOI:10.1021/ol048810t

(Chemical Equation Presented) A new N-acetyl thiazolidinethione reagent, which undergoes highly diastereoselective aldol reactions upon enolization with dichlorophenylborane and (-)-sparteine and subsequent treatment with a variety of aldehydes, is descri

Full text of DOI:10.1021/ol048810t

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3139-3141
Synthesis of a New N-Acetyl
Thiazolidinethione Reagent and Its
Application to a Highly Selective
Asymmetric Acetate Aldol Reaction
Yingchao Zhang and Tarek Sammakia*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215.
sammakia@colorado.edu
Received June 22, 2004
ABSTRACT
A new N-acetyl thiazolidinethione reagent, which undergoes highly diastereoselective aldol reactions upon enolization with dichlorophenylborane
and (−)-sparteine and subsequent treatment with a variety of aldehydes, is described. This reagent is pseudoenantiomeric to an L-tert-leucine-
derived reagent recently described by us and is useful because it avoids the prohibitively costly D-tert-leucine.
We recently described a new method for performing dia-
stereoselective acetate aldol reactions1,2 using the chiral
N-acetyl thiazolidinethione reagent 1 (Scheme 1).3 In this
chiral auxiliary for this reagent is derived from L-tert-leucine,
and the reaction benefits from the bulk of the tert-butyl group
as other less bulky groups provide significantly lower
diastereoselectivities. However, this method suffers from the
(2) (a) For reviews of asymmetric acetate aldol reactions, see: Masamune,
S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985,
24, 1. Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. (b) For selected
references of asymmetric acetate aldol reactions, see: Iwasawa, N.;
Mukaiyama, T. Chem. Lett. 1983, 297. Braun, M.; Devant, R. Tetrahedron
Lett. 1984, 25, 5031. Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.;
Fujita, E. J. Chem. Soc., Chem. Commun. 1985, 1418. Nagao, Y.; Hagiwara,
Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org.
Chem. 1986, 51, 2391. Helmchen, G.; Leikauf, U.; Taufer-Kno¨pfel, I.
Angew. Chem., Int. Ed. Engl. 1985, 24, 874. Masamune, S.; Sato, T.; Kim,
B. M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108, 8279. Devant, R.;
Mahler, U.; Braun, M. Chem. Ber. 1988, 121, 397. Duthaler, R. O.; Herold,
P.; Lottenbach, W.; Oertle, K.; Riediker, M. Angew. Chem., Int. Ed. Engl.
1989, 28, 495. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J.
Am. Chem. Soc. 1989, 111, 5493. Oppolzer, W.; Starkemann, C. Tetrahedron
Lett. 1992, 33, 2439; 24, 874. Yan, T. H.; Hung, H. C.; Hung, A. W.; Lee,
H. C.; Chang, C. S. J. Org. Chem. 1994, 59, 8187. Yan, T. H.; Hung, A.
W.; Lee, H. C.; Chang, C. S. Liu, W. H. J. Org. Chem. 1995, 60, 3301.
Gonza´lez, AÄ .; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1996,
37, 8949. Bond, S.; Perlmutter, P. J. Org. Chem. 1997, 62, 6397. Palomo,
C.; Gonzalez, A.; Garcia, J. M.; Landa, C.; Oliarbide, M.; Rodr´ıguez, S.;
Linden, A. Angew. Chem., Int. Ed. 1998, 37, 180. Guz, N. R.; Phillips, A.
J. Org. Lett. 2002, 4, 2253.
Scheme 1
reaction, enolization is accomplished using phenyldichloro-
borane and sparteine, and high yields and excellent selectivi-
ties are observed in additions to a variety of aldehydes. The
(1) (a) For selected reviews on the aldol reaction, see: Evans, D. A.;
Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. Arya, P.; Qin, H.
P. Tetrahedron 2000, 56, 917. Cowden, C. J.; Paterson, I. Org. React. 1997,
51, 1. Machajewski, T. D.; Wong, C. H. Angew. Chem., Int. Ed. 2000, 39,
1353. Carreira, E. M. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley: New York, 2000. (b) For recent advances in asymmetric synthesis
with chiral imide auxiliaries, see: Evans, D. A.; Shaw, J. T. Actualite´
Chimique 2003, 35.
(3) Zhang, Y.; Phillips, A. J.; Sammakia, T. Org Lett. 2004, 6, 23.
10.1021/ol048810t CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004

significant limitation that only the L-enantiomer of tert-
leucine is available at reasonable cost. We, therefore, wished
to devise a new reagent that is the functional equivalent of
D-tert-leucine, and in this communication, we describe the
synthesis of such a reagent and its application to diastereo-
selective acetate aldol addition reactions using our previously
described procedure.
In considering the design of reagents which bear steric
bulk, we sought to replace the tert-butyl group with a
protected tertiary alcohol and wished to study the thiazolidine
thione reagent 2 shown in Figure 1. Tertiary alcohols are
of methyllithium to 3 was then studied, and while the reaction
provides good yields, it proceeds with partial racemization
to provide the product in a maximum of 62% enantiomeric
excess under a variety of conditions.6 This is presumably
due to enolization under the reaction conditions, and we
therefore studied the use of the corresponding organocerium
reagent7 (prepared from MeLi and CeCl3). Addition of this
reagent to 3 proceeds in high yields and provides the highly
crystalline 4 with an enantiomeric excess of 94%. A single
recrystallization of 4 from toluene provided material with
an enantiomeric purity of 99.4% in an overall yield of 80%
(after crystallization). This material was protected as the
triethylsilyl ether to provide 5 and then acylated to provide
2. The overall yield of this four-step process is 61% (or 51%
if the thiazolidinethione is prepared using CS2), and we have
prepared 6 g of 2 in a single batch.
With compound 2 in hand, we carried out a survey of the
scope of this reagent in reactions with representative alde-
hydes (Table 1).8 As expected, the results are similar to the
Figure 1. Reagent 2, the pseudoenantiomer of the L-tert-leucine-
derived reagent 1.
Table 1. Aldol Reactions of Thiazolidinethione 3 with
Representative Aldehydesa
readily prepared by nucleophilic additions to esters, and our
synthesis begins with the ethyl ester of cysteine (Scheme
2). Conversion of commercially available cysteine ethyl ester‚
Scheme 2a
entry
aldehyde
dr (6:7)b
yield (%)c
1
2
3
4
5
6
7
8
PhCH2CH2CHO
(CH3)2CHCHO
CH3(CH2)3CHO
(CH3)2CHCH2CHO
BnOCH2CHO
TBSOCH2CH2CHO
PhCHO
trans-PhCHdCHCHO
49:1
57:1
59:1
89:1
59:1
31:1
16.5:1
9.5:1
86
88
91
92
86
80
80
63
a Conditions: compound 2 (1.3 equiv), PhBCl2 (1.3 equiv), (-)-sparteine
(2.6 equiv), CH2Cl2, 0 °C to room temperature, then RCHO, -78 °C to 0
°C. b Ratios were determined by 500 MHz 1H NMR spectroscopic analysis
of the crude reaction mixtures. c Yield of the major diastereomer after
purification.
a Conditions: (1) NEt3 (1 equiv), thiocarbonyldiimidazole (1
equiv), THF, 90%; (1′) NEt3 (1 equiv), CS2 (1.1 equiv), CH2Cl2,
75%. (2) MeLi (3.5 equiv), CeCl3 (4 equiv), THF, -78 °C, then
ester 3 was added at -40 °C, recrystallization from toluene 80%.
(3) TESOTf, (2 equiv), DMAP (2 equiv), CH2Cl2, 0 °C to room
temperature, 95%. (4) n-BuLi (1.2 equiv), -78 °C, then CH3COCl
(1.2 equiv), THF, 90%.
tert-leucine derived N-acetyl thiazolidine thione reagent 1.
Straight-chain and R- or â-branched aliphatic aldehydes react
with high selectivities (diastereomeric ratios range from 49:1
to 89:1) and in excellent yields (86-92%, entries 1-4).
Aldehydes that are oxygenated at the R- or â-position such
as benzyloxyacetaldehyde and 3-(tert-butyldimethylsilyloxy)-
propanal are also excellent substrates for this reaction (entries
HCl to the corresponding thiazolidine thione 3 was ac-
complished in 90% yield by treatment with triethylamine
and thiocarbonyldiimidazole.4 Alternatively, this reaction can
be performed using the less costly reagent combination of
carbondisulfide and triethylamine in 75% yield.5 The addition
(6) Reaction was studied in THF and ether, at temperatures ranging from
-78 °C to room temperature, and using methyl Grignard in THF, ether, or
dichloromethane at the same temperature ranges with no improvement in
the results.
(7) For reviews on organocerium reagents, see: (a) Liu, H. J.; Shia, K.
S.; Shang, X.; Zhu, B. Y. Tetrahedron 1999, 55, 3803. (b) Takeda, N.;
Imamoto, T. Org. Synth. 1999, 76, 228. (c) Imamoto, T. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon Press: Oxford, UK, 1991; Vol. 1, p 231.
(4) Soai, K.; Ishizaki, M. Heterocycles 1984, 22, 2827.
(5) (a) Rufino, A. R.; Biaggio, F. C. Tetrahedron Lett. 2001, 42, 8559.
(b) Nagao, Y.; Ikeda, T.; Inoue, T.; Yagi, M.; Shiro, M.; Fujita, E. J. Org.
Chem 1985, 50, 4072. (c) Hsiao, C. N.; Liu, L.; Miller, M. J. Org. Chem.
1987, 52, 2201.
(8) For experimental details, see Supporting Information.
3140
Org. Lett., Vol. 6, No. 18, 2004

5 and 6). Aldolization with benzaldehyde provided the
products in good yield, but with slightly diminished selectiv-
ity (16.5:1, entry 7), and the use of trans-cinnamaldehyde
provided diminished, but useful, yields and selectivities (63%
yield, 9.5:1 selectivity, entry 8).
The stereochemistry of the products was determined by
reductive cleavage of the aldol adducts obtained in entries 1
and 5 of Table 1 to produce the known compounds (S)-5-
phenylpentane-1,3-diol and (R)-1-O-benzyl-1,2,4-butane-
triol.9 All other entries were assigned by analogy. The sense
of asymmetric induction is as expected and consistent with
our prior studies using the L-tert-leucine-derived auxiliary
1. Thus, the pseudoenantiomeric reagents 1 and 2 provide
the enantiomeric aldol adducts and diols upon reductive
cleavage of the auxiliary (Scheme 3).
diastereoselection in acetate aldol reactions with a variety
of aldehydes in excellent yields. This, together with the L-tert-
leucine-derived thiazolidinethione reagent, affords a powerful
method for the synthesis of either isomeric acetate aldol
adduct in high enantiomeric purity and excellent yield. This
work also further highlights the practical utility of phenyl-
dichloroborane and (-)-sparteine for the enolization of
N-acyl thiazolidinethione reagents and their subsequent
highly selective acetate aldol reactions. Furthermore, the
strategy behind the synthesis of this auxiliary should prove
to be useful for the synthesis of analogues of other L-tert-
leucine-derived reagents and catalysts. The application of
this reagent to the synthesis of natural products is underway
and will be reported in due course.
Acknowledgment. We wish to thank Professor Andrew
Phillips for insightful discussions. This work was supported
by the National Institutes of Health (GM48498) and Array
Biopharma. NMR instrumentation used in this work was
supported in part by the National Science Foundation CRIF
program (CHE-0131003).
Scheme 3
Supporting Information Available: Experimental pro-
cedures for the synthesis of reagent 2, a representative
procedure for conducting the aldol reaction, and spectral data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048810T
(8) (S)-5-Phenylpentane-1,3-diol: [R]D ) -12.8 (c 1.96, EtOH), lit. [R]D
) -7.2 (c 1.52, EtOH). See: Nunez, M. T.; Martin, V. S. J. Org. Chem.
1990, 55, 1928. (R)-1-O-Benzyl-1,2,4-butanetriol: [R]D ) +9.64 (c 0.85,
MeOH), lit. [R]D ) +7.9 (c 7.56, MeOH). See: Takano, S.; Hirama, M.;
Seya, K.; Ogasawara, K. Tetrahedron Lett. 1983, 24, 4233.
In conclusion, we have developed a readily synthesized
thiazolidinethione auxiliary that provides high levels of
Org. Lett., Vol. 6, No. 18, 2004
3141