enolates. These methods often rely on the use of reagents
and metals that are expensive or difficult to handle and often
suffer from narrow substrate scopes and modest diastereo-
selectivities, further limiting the utility of the asymmetric
acetate aldol addition in synthetic applications. The highly
hindered auxiliaries recently advanced by Phillips10c and
Sammakia9b,c provide the most consistent high levels of
diastereoselectivity to date.
The diminished diastereoselectivity of the acetate aldol
additions in comparison to the high level of diastereoselec-
tivity attainable for propionate aldol additions has been
attributed to the lack of substitution at the R-carbon of the
enolate, which is believed to function as an important
stereocontrol element. In an attempt to overcome this issue,
we have investigated more sterically encumbered chiral
auxiliaries to improve the selectivity in acetate aldol additions
of chlorotitanium enolates of N-acetylthiazolidinethiones.
Mesityl-substituted oxazolidinethione and thiazolidinethiones
were chosen due to the restricted rotational freedom about
the bond between the aromatic ring and the benzylic carbon.11
We herein report the synthesis of mesityl-substituted N-
acetyloxazolidinethione and N-acetylthiazolidinethiones and
the use of their chlorotitanium enolates in acetate aldol
additions.
alcohol. Concomitant acid-catalyzed removal of the sulfinyl
and PMB groups provided amino alcohol 3. Finally, forma-
tion of the auxiliary followed by acylation yielded (R)-N-
acetyloxazolidinethione 4.14
Treatment of 4 with TiCl4 (2 equiv) and diisopropylethyl-
amine (2 equiv) in CH2Cl2 at -78 °C, followed by addition
of the aldehyde (1.2 equiv), resulted in a highly diastereo-
selective acetate aldol addition, utilizing a series of aldehydes
(Table 1).15 This protocol is amenable to aliphatic, aromatic,
Table 1. Aldol Additions of Oxazolidinethione 4
entry
aldehyde
yield (%)a
dr (5/6)b
1
2
3
4
5
6
PhCHdCHCHO
(CH3)2CHCH2CHO
PrCHO
(CH3)2CHCHO
EtCHO
72
84
85
88
78
89
93:7
96:4
95:5
94:6
95:5
96:4
Initial efforts focused on the development of mesityl-
substituted N-acetyloxazolidinethione 4. Oxazolidinethione
4 was synthesized using t-butylsulfinamide methodology
developed by Ellman (Scheme 1).12 Imine 2 was prepared
PhCHO
a Combined yield of diastereomers after purification. b Obtained by HPLC
analysis of crude reaction mixtures.
Scheme 1
and R,â-unsaturated aldehydes. The stereochemistry of the
addition was determined by reductive cleavage of the adduct
obtained in entry 4 to afford (S)-4-methyl-pentane-1,3-diol.16
Efforts then shifted toward the formation of mesityl-
substituted N-acetylthiazolidinethione 9 (Scheme 2). A major
advantage of using thiazolidinethiones over oxazolidineth-
iones lies in the ease with which thiazolidinethiones can be
directly converted to a variety of functional groups, such as
aldehydes, amides, â-ketophosphonates, and â-ketoesters,
whereas conversions of oxazolidinethiones are limited.17,4b
All attempts, however, to convert amino alcohol 3 into a
(14) (S)-N-Acetyloxazolidinethione can be accessed from the same
sequence of steps, starting from (S)-(-)-2-methyl-2-propanesulfinamide.
(15) Typical aldol procedure using N-acetyloxazolidinethione 4: To
a dry 25 mL round-bottom flask, under argon, was added N-acetyloxazo-
lidinethione (0.263 g, 1.00 mmol) and 5 mL of CH2Cl2 (0.2 M). The flask
was cooled to -40 °C. Titanium tetrachloride (neat, 0.22 mL, 2.00 mmol)
was added, and the reaction mixture was stirred for 5 min. Diisopropyl-
ethylamine (0.35 mL, 2.00 mmol) was then added. The solution was stirred
for 2 h at -40 °C and was then cooled to -78 °C, whereupon the freshly
distilled aldehyde (neat, 1.2 mmol) was added. The mixture was stirred for
4 h at -78 °C, then quenched with half saturated ammonium chloride and
warmed to room temperature. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2×). The combined organic layers were
dried over NaSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (20% EtOAc/
Hex). Yields and diastereoselectivities are listed in Table 1.
via the CuSO4-mediated condensation of (R)-(+)-2-methyl-
2-propanesulfinamide (1)13 and (4-methoxybenzyloxy)-ac-
etaldehyde. Addition of mesitylmagnesium bromide to imine
2 afforded a single diastereomer of the protected amino
(11) (a) Medina, E.; Moyano, A.; Pericas, M. A.; Riera, A. HelV. Chim.
Acta 2000, 83, 972. (b) Bandini, M.; Cozzi, P. G.; Gazzano, M.; Umani-
Ronchi, A. Eur. J. Org. Chem. 2001, 10, 1937.
(12) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (b) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem.
2001, 66, 8772. (c) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Org. Chem.
1997, 119, 9913.
(13) (R)-(+)-2-Methyl-2-propanesulfinamide and (S)-(-)-2-methyl-2-
propanesulfinamide are commercially available but can also be synthesized
via Ellman’s procedure: Weix, D. J.; Ellman, J. A. Org. Synth. 2005, 82,
157.
(16) (S)-4-Methyl-pentane-1,3-diol: [R]D ) -17.0° (c ) 0.25, CHCl3).
For the lit. value of (R)-4-methyl-pentane-1,3-diol, see: (a) ref 10c. (b)
Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.; Inoue, A. J. Org.
Chem. 1992, 57, 1412.
(17) Izawa, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979, 52, 555.
150
Org. Lett., Vol. 9, No. 1, 2007