SCHEME 1
A F a cile Access to Ch ir a l 4-Isop r op yl-,
4-Ben zyl-, a n d 4-P h en yloxa zolid in e-2-th ion e
Yikang Wu,* Yong-Qing Yang, and Qi Hu
State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
carbon disulfide and amino alcohols either with NEt3 in
CH2Cl2 or with an aqueous solution of NaOH or Na2CO3
in a biphasic mixture. A cosolvent such as THF or ethanol
was sometimes added to facilitate the reaction.
yikangwu@mail.sioc.ac.cn
Received February 4, 2004
In general, the CH2Cl2/NEt3 conditions require many
hours of refluxing to drive the reaction to any syntheti-
cally useful extents. As carbon disulfide has a low flash
point (-30 °C) and a low boiling point (46 °C), extended
(and hence likely to be unattended) periods of refluxing
would inevitably create potential danger. Use of aqueous
base can remarkably shorten the reaction time and
consequently improve the safety of the procedure. How-
ever, a thermodynamically favored side product, the
corresponding thiazolidine-2-thione (3, Scheme 1), is often
formed5e,g in substantial quantities regardless of the
amount of the carbon disulfide present in the reaction
system. As a consequence, a tedious chromatographic
separation is unavoidable. To get around these problems,
Crimmins6 and co-workers recently introduced a novel
time-efficient and high-yielding protocol, which used
thiophosgene to replace the CS2. However, because
thiophosgene is highly toxic and expensive, the need for
a facile practical access to 1 still remains.
In an exhaustive literature search we found that in
1997 Li and Ohtani reported7 a unique route to oxazoli-
dine-2-thiones (not related to auxiliaries chemistry),
which utilized H2O2 to convert the intermediate SH
anions into S-S bonds and thus turned the otherwise
sluggish ring-closure into a rapid and irreversible pro-
cess. However, to our knowledge, the potential of this
route in the synthesis of chiral auxiliaries such as 1 has
never been realized.8
Abstr a ct: A highly practical procedure for preparing the
chiral oxazolidine-2-thione auxiliaries using carbon disulfide
and the corresponding chiral amino alcohols as the starting
materials in the presence of potassium carbonate and
hydrogen peroxide is presented.
Chiral 4-monosubstituted oxazolidine-2-thiones are
very useful auxiliaries in enantioselective organic syn-
thesis.1,2 Among them, the 4-isopropyl, 4-benzyl-, or
4-phenyloxazolidine-2-thione (1a -c, and the enantiomer
of 1a ) are particularly valuable, because they can be
prepared from the corresponding amino acids that are
commercially available at low prices. These auxiliaries
can function equally well as the classical oxazolidinone3
(Evans) auxiliaries but enjoy a remarkable advantage of
easier2 removal after completion of the chiral induction.
Such a feature has great merits in the synthesis of
complicated “fragile” molecules containing many different
functionalities.
However, the synthesis of the oxazolidinethione aux-
iliaries themselves remains a substantial barrier to their
broad application in asymmetric synthesis. Unlike their
oxazolidinones counterparts,4 1a -c are still not so readily
accessible. They are usually prepared5 (Scheme 1) from
(1) See, e.g.: (a) Fujita, E.; Nagao, Y. Adv. Heterocyl. Chem. 1989,
45, 1-36. (b) Garcia-Fernandez, J . M.; Ortiz-Mellet, C.; Fuentes, J . J .
Org. Chem. 1993, 58, 5192-5199. (c) Nagao, Y.; Kumagai, T.; Nagase,
Y.; Tamai, S.; Inoue, Y.; Shiro, M. J . Org. Chem. 1992, 57, 4232-4237.
(2) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc.
1997, 119, 7883-7884.
Application of Li and Ohtani’s procedure on 2a led to
the expected 1a smoothly. However, as a potential
industrial synthesis this procedure suffered from at least
two shortcomings: (1) the cost of the base (NEt3) was too
high (compared with inorganic bases) and (2) both the
base and the solvent (MeOH) were remarkably toxic and
thus would raise safety and environment concerns.
Besides, involvement of NEt3 in the reaction also com-
plicated the workup and product isolation. To circumvent
these problems, we conducted the investigation sum-
marized in Table 1.
(3) See, e.g.: (a) Evans, D. A. Scinece 1988, 240, 420-426. (b) Evans,
D. A.; Bartoli, J .; Shih, T. L. J . Am. Chem. Soc. 1981, 103, 2127-2129.
(c) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J . J . Am. Chem.
Soc. 1998, 120, 5921-5942. (d) Evans, D. A.; Gage, J . R.; Leighton, J .
L. J . Am. Chem. Soc. 1992, 114, 9434-9453. (e) Crimmins, M. T.; Choy,
A. L. J . Am. Chem. Soc. 1999, 121, 5653-5660. (f) Nicolaou, K. C.;
Gaulfield, T.; Kataoka, H.; Kumazawa, T. J . Am. Chem. Soc. 1988,
110, 7910-7912.
(4) For a high-yielding low-cost access to chiral 4-monosubstituted
oxazolidinones auxiliaries, see: Wu, Y.-K.; Shen, X. Tetrahedron:
Asymmetry 2000, 11, 4359-4363.
(5) (a) Nagao, Y.; Kumagai, T.; Yamada, S.; Fujita, E. J . Chem. Soc.,
Perkin Trans. 1 1985, 2361-2367. (b) Cuzzupe, A. N.; Hutton, C. A.;
Lilly, M. J .; Mann, R. K.; McRae, K. J .; Zammit, S. C.; Rizzacasa, M.
A. J . Org. Chem. 2001, 66, 2382-2393. (c) Isobe, T.; Ishikawa, T. J .
Org. Chem. 1999, 64, 6989-6992. (d) Moreno-Manas, M.; Padros, I. J .
Heterocycl. Chem. 1993, 30, 1235-1239. (e) Delaunay, D.; Toupet, L.;
Le Corre, M. J . Org. Chem. 1995, 60, 6604-6607. (f) Holmes, A. B.;
Nadin, A.; O’Hanlon, P. J .; Pearson, N. D. Tetrahedron: Asymmetry
1992, 3, 1289-1302. (g) Aitken, R. A.; Armstrong, D. P.; Galt, R. H.;
Mesher, S. T. E. J . Chem. Soc., Perkin Trans. 1 1997, 2139-2145. (h)
Roth, H. J .; Schlump, H. Arch. Pharm. (Weinheim) 1963, 296, 213-
217. (i) Kitoh, S.-i.; Kunimoto, K.-K.; Funaki, N.; Senda, H.; Kuwae,
A.; Hanai, K. J . Chem. Crystallogr. 2002, 32, 547-553.
(6) Crimmins, M. T.; King, B. W.; Tabet, E. A. Chaudhary, K. J .
Org. Chem. 2001, 66, 894-902. However, it should be noted that
chromatographic separation is still needed if one wishes to isolate the
pure auxiliary (although the crude product often can be used directly).
(7) (a) Li, G.; Ohtani, T. Heterocycles 1997, 45, 2471-2474. (b) Li,
G.; Tajima, H.; Ohtani, T. J . Org. Chem. 1997, 62, 4539-4540.
(8) That work of Li’s has already been cited several times in the
literature, including those papers reporting on the synthesis of other
oxazolidinethione auxiliaries. See, e.g.: (a) Ortiz, A.; Quintero, J .;
Hernandez, H.; Maldoado, S.; Mendoza, G.; Bernes, S. Tetrahedron
Lett. 2003, 44, 1129-1132. (b) Ortiz, A.; Quintero, L.; Mendoza, G.;
Bernes, S. Tetrahedron Lett. 2003, 44, 5053-5055.
10.1021/jo049799d CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004
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J . Org. Chem. 2004, 69, 3990-3992