Practical and highly selective oxazolidinethione-based asymmetric acetate aldol reactions with aliphatic aldehydes.

Article abstract of DOI:10.1021/ol026108w

[reaction: see text] The utility of a valine-derived oxazolidinethione for auxiliary-based asymmetric acetate aldol reactions is reported. Titanium(IV) chloride, along with (-)-sparteine and N-methylpyrrolidinone, is employed for enolization. Subsequent a

Full text of DOI:10.1021/ol026108w

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2253-2256
Practical and Highly Selective
Oxazolidinethione-Based Asymmetric
Acetate Aldol Reactions with Aliphatic
Aldehydes
Nathan R. Guz and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado at Boulder,
Boulder, Colorado 80309-0215
andrew.phillips@colorado.edu
Received April 30, 2002
ABSTRACT
The utility of a valine-derived oxazolidinethione for auxiliary-based asymmetric acetate aldol reactions is reported. Titanium(IV) chloride, along
with (−)-sparteine and N-methylpyrrolidinone, is employed for enolization. Subsequent aldol reaction with aliphatic aldehydes occurs with
high diastereoselectivity (from 92:8 to 99:1 dr).
During the past 2 decades the asymmetric aldol reaction has
risen to a position of prominence among carbon-carbon
bond forming reactions.1 Although there have been signifi-
cant advances in catalytic asymmetric variants of the aldol
reaction,2 auxiliary-based aldol reactions remain a valuable
and widely employed strategy for the synthesis of the
â-hydroxycarbonyl subunit. Pioneering studies by Evans and
co-workers in 1981 firmly established N-acyloxazolidinones
as the method of choice for the synthesis of syn-propionate
aldol constructs (1, Figure 1),3 while recent work from the
Many of the auxiliaries that work well for propionate aldol
reactions give minimal diastereoselection for the synthe-
sis of acetate aldol adducts (3).5 Among successful methods
two auxiliary systems currently enjoy widespread recognition
as the state of the art for auxiliary-based acetate aldol
reactions: Braun’s (2-hydroxy-1,2,2-triphenylethyl)acetate
(HYTRA) system6 and the Nagao-Fujita 5-ethyloxazolidine-
thione and 5-isopropylthiazolidinethione auxiliaries.7 Despite
levels of diastereoselectivity ranging from 76:24 to 98:2,
these two methods suffer from several potential drawbacks
including extremely low reaction temperatures for satisfac-
tory diastereoselectivity (Braun), an expensive metal source
(1) For selected reviews see: (a) Evans, D. A.; Nelson, J. V.; Taber, T.
R. Top. Stereochem. 1982, 13, 1. (b) Arya, P.; Qin, H. P. Tetrahedron 2000,
56, 917. (c) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. (d) Carreira,
E. M. In Modern Carbonyl Chemistry; Otera, J., Ed., Wiley: New York,
2000.
(2) (a) For a review see: Machajewski, T. D.; Wong, C. H. Angew.
Chem., Int. Ed. 2000, 39, 1353. (b) Carreira, E. M.; Singer, R. A.; Lee, W.
J. Am. Chem. Soc. 1994, 116, 8837. (c) Keck, G. E.; Kishnamurthy, D. J.
Am. Chem. Soc. 1995, 117, 2363. (d) Nelson, S. G.; Peelen, T. J.; Wan, Z.
J. Am. Chem. Soc. 1999, 121, 9742.
Figure 1. â-Hydroxycarbonyl subunits.
(3) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(4) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586.
Masamune and Abiko laboratories has resulted in an excel-
lent method for the synthesis of anti-propionate aldol subunits
(2, Figure 1) using norephedrine-based auxiliaries.4
10.1021/ol026108w CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/30/2002

(Sn(OTf)2, Nagao-Fujita), and lower levels of diastereo-
selectivity with aliphatic aldehydes. These drawbacks have
limited the applications of these auxiliaries in the synthesis
of complex polyketide-derived natural products.
desired acetate aldol adduct in excellent yield and with high
diastereoselectivity (Scheme 2).14
In the case of Evans’ oxazolidinones the poor diastereo-
selection for acetate-type aldol reactions can be attributed
in part to the lack of substituents at the R-carbon of the
enolate.8 To compensate for the absence of this control ele-
ment, we have investigated highly hindered oxazolidinones
and oxazolidinethiones9-11 under reaction conditions that are
expected to give highly ordered transition states, and in this
Letter we describe the use of valine-derived N-acetyl
oxazolidinethione 5 to achieve highly selective acetate aldol
reactions with aliphatic aldehydes.12
Scheme 2a
a Conditions: TiCl4 (1 equiv), (-)-sparteine (1 equiv), NMP (1
equiv), CH2Cl2, 0 °C, 30 min, then (CH3)2CHCH2CHO (0.77 equiv),
-78 °C, 1 h, 82%
Oxazolidinethione 5 was synthesized by a three-step
sequence from L-valine methyl ester hydrochloride employ-
ing literature methods (Scheme 1).13 It is noteworthy that
this short sequence can be readily achieved on a 0.3 mol
scale.
Table 1 documents the utility and scope of this system
for aldol reactions with aliphatic aldehydes. When 1.3 equiv
of the enolate (relative to the aldehyde) are employed,
Table 1. Aldol Reactions of Oxazolidinethione 5 with
Representative Aldehydesa
Scheme 1a
a Conditions: (1) PhMgBr (5 equiv), Et2O; (2) CS2, Et3N, THF,
reflux, 42% (over two steps); (3) NaH, THF, AcCl, 96%
entry
aldehyde
dr (6:7)d
yield (%)e
1
2
3
4
5
6
7
8
PhCH2CH2CHO
n-PrCHO
EtCHO
n-BuCHO
(CH3)2CHCH2CHO
i-PrCHO
CH3(CH2)4CHO
trans-CH3CHdCHCHO
PMBOCH2CHO
TBDPSOCH2CH2CHO
PhCHO
95:5
95:5
93:7
95:5
96:4
92:8
95:5
99:1
97:3
99:1
85:15
83
78
90
77
82
83
78
85
55
56
86
Our initial efforts focused on the enolization of 5 under
the conditions reported by Crimmins for related propionate
aldol reactions.9b,d Gratifyingly, treatment of 5 with TiCl4
(1 equiv), followed by (-)-sparteine (1 equiv) and N-
methylpyrrolidinone (1 equiv) in CH2Cl2 at 0 °C, followed
by reaction with isovaleraldehyde at -78 °C, provided the
9b
10c
11
(5) For a review of acetate aldol reactions, see: M. Braun, Angew. Chem.,
Int. Ed. Engl. 1987, 26, 24. For more recent references to other auxiliary-
based asymmetric acetate aldol reactions, see: (a) Oppolzer, W.; Starke-
mann, C. Tetrahedron Lett. 1992, 33, 2439. (b) Helmchen, G.; Leikauf,
U.; Taufer-Kno¨pfel, I. Angew. Chem., Int. Ed. Engl. 1985, 24, 874. (c) Yan,
T. H.; Hung, H. C.; Hung, A. W.; Lee, H. C.; Chang, C. S. J. Org. Chem.
1994, 59, 8187. (d) Bond, S.; Perlmutter, P. J. Org. Chem. 1997, 62, 6397.
(e) Palomo, C.; Gonzalez, A.; Garcia, J. M.; Landa, C.; Oliarbide, M.;
Rodr´ıguez, S.; Linden, A. Angew. Chem., Int. Ed. 1998, 37, 180. (f) Saito,
S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1998,
37, 3378. For approaches utilizing metal-based chirality, see: (g) Masamune,
S.; Sato, T.; Kim, B. M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108,
8279. (h) Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker,
M. Angew. Chem., Int. Ed. Engl. 1989, 28, 495. (i) Corey, E. J.;
Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111,
5493.
(6) (a) Braun, M.; Devant, R. Tetrahedron Lett. 1984, 25, 5031. (b)
Devant, R.; Mahler, U.; Braun, M. Chem. Ber. 1988, 121, 397 and references
therein.
(7) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J. Chem.
Soc., Chem. Commun. 1985, 1418. For reactions of Sn(II) enolates of
5-substituted thiazolidinethiones with R,â-unsaturated aldehydes, see:
Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto,
K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
a For a representative procedure see Supporting Information. b 1.75 equiv
of aldehyde used. c 1.5 equiv of aldehyde used. d Obtained by 1H NMR
spectroscopic analysis of the crude reaction products. e Combined yield of
both diastereoisomers after purification.
straight-chain and R- or â-branched aliphatic aldehydes react
with uniformly high selectivities (dr > 92:8) and in good to
excellent yields (entries 1-7). Sensitive aldehydes, such as
(9) Recent studies from the Yan and Crimmins groups have shown that
oxazolidinethiones are valuable auxiliaries for syn propionate aldol additions,
particularly when employed as their Ti(IV) enolates; see: (a) Yan, T. H.;
Tan, C. W.; Lee, H. C.; Lo, H. C.; Huang, T. Y. J. Am. Chem. Soc. 1993,
115, 2613. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem.
Soc. 1997, 119, 7883. (c) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc.
1998, 120, 9084. (d) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894.
(10) Related heterocycles such as (S)-4-benzyl-5,5-dimethyl-oxazolidin-
2-one (“SuperQuat”) have been studied by Davies in the context of conjugate
additions and alkylation reactions. For a recent paper, see: Bull, S. D.;
Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Tetra-
hedron: Asymmetry 2000, 11, 3475 and references therein.
(8) The dibutylboryl enolate of Evans’ valine-derived oxazolidinone gives
a 52:48 ratio of diastereoisomers with isobutyraldehyde and a 72:28 ratio
with acetaldehyde (see ref 3).
2254
Org. Lett., Vol. 4, No. 13, 2002

crotonaldehyde, p-methoxybenzyloxyacetaldehyde, and 3-(tert-
butyldiphenylsilyloxy)propanal are also excellent substrates
for the reaction (entries 8-10), although oxygenated alde-
hydes currently require an excess of aldehyde for reasonable
yields. Aldol reaction with benzaldehyde (entry 11) gave
lower levels of diastereoselection, and this illustrates a
shortcoming of this method.
From a practical viewpoint it is worth noting that the
diastereoselectivity of the reaction is remarkably consistent
proVided care is taken to ensure that the exact stoichiometry
of reagents is employed.15 Deviation from the correct
stoichiometry of TiCl4 and amine results in inconsistent
diastereoselection.
The stereochemical course of the reaction was determined
by reductive cleavage of the aldol adducts obtained in entries
1 and 6 to give known compounds (S)-5-phenylpentane-1,3-
diol and (R)-4-methyl-pentane-1,3-diol.16 The sense of asym-
metric induction is opposite to that usually observed when
dialkylboryl enolates of oxazolidinones are used.3 Interest-
ingly it is also the opposite of that observed by Crimmins9
for titanium enolates of N-propionyl oxazolidinethiones,
suggesting a mechanistic divergence between the two reac-
tions.
Figure 2. Possible models to account for the observed stereo-
chemistry.
derived from valine without the 5,5-diphenyl substituents
reacts with minimal selectivity (dr values of 1.2-2.5:1 vs
several aldehydes), which suggests that diastereoselection can
be affected by altering the population of rotamers around
the auxiliary-enolate by decreasing the interactions between
the ligands on titanium and the substituents on the oxa-
zoldinethione.20
Alternatively, a dipole-minimized boat structure (Figure
2, structure B) could also give rise to the observed stereo-
chemistry. Boat and twist-boat transition states have been
calculated to lie within (2 kcal/mol of the more commonly
proposed chair transition states,21 and recently Evans has
proposed on the basis of calculated transition state energies
that anti-aldol reactions with thiazolidinethiones proceed via
a boat.22 This model allows for consistency with the facial
selectivity observed by Crimmins under the same reaction
conditions as we employ and could also rationalize the
decreased diastereoselectivity observed with the correspond-
ing oxazolidinone on the basis of differing dipole moments.23
Further studies will be required to unequivocally discriminate
between these two models.
Two models can be considered to account for the observed
stereoselectivity. One possibility is a coordinated chair
structure (Figure 2, structure A).17 This structure minimizes
the steric interactions between the ligands on titanium and
the substituents on the oxazolidinethione ring and is con-
sistent with the following observations: (a) the corresponding
oxazolidinone, which is postulated not to be capable of
coordination to Ti under these conditions,18 reacts with much
lower dr values of 2.0-3.0:1,19 and (b) the oxazolidinethione
(11) For two relevant examples of acetate aldol reactions with titanium
enolates of thiazolidinethiones, see: (a) Gonza´lez, A.; Aiguade´, J.; Urp´ı,
F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (b) Crimmins, M. T.;
Emmitte, K. A. Org. Lett. 1999, 1, 2029.
(12) Seebach has reported the synthesis of the corresponding oxazoli-
dinone. Suprisingly, it exhibited only modest diastereoselectivity for acetate
aldol reactions; see: Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998,
81, 2093.
(13) (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem.
Commun. 1983, 469. (b) Delaunay, D.; Toupet, L. Corre, M. L. J. Org.
Chem. 1995, 60, 6604.
(14) The corresponding Li and B enolates gave poor conversion and
diastereoselectivity.
In conclusion, we have described a readily synthesized
oxazolidinethione auxiliary that provides high levels of
(15) Guz, N. R.; Phillips, A. J. Unpublished results. Repeat reactions
with hexanal gave dr values of 95.3:4.7, 95.7:4.3, and 94.6:5.4.
(16) (S)-5-Phenylpentane-1,3-diol: [R]D ) -6.2 (c 0.75, EtOH), lit. -7.2
(c 1.52, EtOH). See: Nunez, M. T.; Martin, V. S. J. Org. Chem. 1990, 55,
1928. (R)-4-Methyl-pentane-1,3-diol: [R]D ) +16.6 (c 0.25, CHCl3), lit.
+12 (c 2.43, CHCl3). See: Harada, T.; Kurokawa, H.; Kagamihara, Y.;
Tanaka, S.; Inoue, A. J. Org. Chem. 1992, 57, 1412.
(17) Models of this type have previously been proposed for Ti enolates
of N-acyloxazolidinones generated by transmetalation from lithium enolates
(Nerz-Stormes, M.; Thronton, E. R. J. Org. Chem. 1991, 56, 2489), for
oxazolidinethiones generated by enolization with TiCl4 and trialkylamine
bases (see ref 9a), and for titanium enolates of thiazolidinethiones generated
with trialkylamine bases (Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000,
2, 775). For related aldol reactions with N-acyl oxazolidineselones that
presumably react via the same transition state, see: (c) Li, Z.; Wu, R.;
Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks, L. A., III J. Am. Chem.
Soc. 2000, 122, 386.
(19) Guz, N. R.; Phillips, A. J. Unpublished results. The observed facial
selectivity is the same as that observed for the oxazolidinethione.
(20) The calculation of transition structures and energies for these
reactions is complicated by uncertainty with respect to the ligand sphere
around titanium. We have chosen to depict B as the tetrachlorotitanium
species on the basis of speculations first advanced by Evans; see (a) Evans,
D. A.; Urp´ı, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem.
Soc. 1990, 112, 8214. (b) Bilodeau, M. T. Ph.D. Thesis, Harvard University,
1994.
(21) (a) Li, Y.; Paddon Row: M. N.; Houk, K. N. J. Org. Chem. 1990,
55, 481. (b) Bernardi, A.; Gennari, C.; Goodman, J. M.; Paterson, I.
Tetrahedron: Asymmetry 1995, 6, 2613.
(22) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.;
Tedrow, J. S. Org. Lett. 2002, 4, 1127.
(23) We have calculated the dipole moments (MP2, 6-31G*) for
oxazolidinone (5.40 D, lit. 5.07 D Lee, C. M.; Kumler, W. D. J. Am. Chem.
Soc. 1961, 83, 4596) and oxazolidinethione (6.86 D). These values suggest
that the rotameric populations around the enolate-auxiliary bond may be
different for each system. Calculations were performed using PC Spartan
Pro, Wavefunction Inc., Irvine, CA.
(18) Crimmins has observed that oxazolidinethiones without substituents
at C5 require a second equivalent of titanium to produce “non-Evans” syn
adducts (ref 9b,d). In contrast, Yan’s camphor-based oxazolidinethiones
and oxazolidinones react with opposite facial selectivity in the presence of
only 1 equiv of titanium (ref 9a).
Org. Lett., Vol. 4, No. 13, 2002
2255

diastereoselection for acetate aldol reactions with aliphatic
aldehydes. This work also further highlights the practical
utility of Crimmins’ combination of titanium(IV) chloride
and (-)-sparteine for enolization of oxazolidinethiones and
subsequent aldol reaction. Mechanistic studies and applica-
tions to the synthesis of natural products are underway in
these laboratories and will be reported in due course.
discussions, and the University of Colorado for support of
this research.
Supporting Information Available: Characterization
data and spectra for all new compounds, procedures for the
synthesis of 4 and 5, and a representative procedure for the
aldol reaction. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We thank Professors Tarek Sam-
makia, Jonathan Morris, and Randall Halcomb for helpful
OL026108W
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Org. Lett., Vol. 4, No. 13, 2002