Highly Selective Asymmetric Acetate Aldol Reactions of an N-Acetyl Thiazolidinethione Reagent

Article abstract of DOI:10.1021/ol036020y

(Equation presented) A highly diastereoselective acetate aldol reaction that uses a tert-leucine-derived thiazolidinethione auxiliary and dichlorophenylborane has been developed. The reaction proceeds in excellent yields and with high diastereoselectivities (drs range from 9.5:1 to >100:1).

Full text of DOI:10.1021/ol036020y

ORGANIC
LETTERS
2004
Vol. 6, No. 1
23-25
Highly Selective Asymmetric Acetate
Aldol Reactions of an N-Acetyl
Thiazolidinethione Reagent
Yingchao Zhang, Andrew J. Phillips, and Tarek Sammakia*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
sammakia@colorado.edu
Received October 16, 2003
ABSTRACT
A highly diastereoselective acetate aldol reaction that uses a tert-leucine-derived thiazolidinethione auxiliary and dichlorophenylborane has
been developed. The reaction proceeds in excellent yields and with high diastereoselectivities (drs range from 9.5:1 to >100:1).
In 1981, Evans reported a highly diastereoselective asym-
metric aldol reaction using boron enolates of N-acyloxazo-
lidinones.1 Since that time, chiral auxiliary-based aldol bond
constructions have been widely used for accessing single
isomers of â-hydroxy acid derivatives,2 and intensive re-
search has given rise to a large number of chiral auxiliaries
that can produce syn- or anti-propionate aldol units in high
yields and with excellent diastereoselectivities.3 However,
the development of an auxiliary-based stereoselective acetate
aldol reaction has been a more elusive goal. Many of the
auxiliaries that work well for propionate aldol reactions give
minimal diastereoselection for acetate aldol reactions.4
Although successful methods in this area using chiral acetate
enolates of tin (Nagao-Fujita),5 lithium (Braun and Yama-
moto),6 boron (Yan),7 and titanium (Yan, Urpi, and Phillips)8
are known, these methods have some shortcomings, including
the use of expensive reagents and metals, lower levels of
diastereoselectivity with aliphatic aldehydes, or the need for
extremely low reaction temperatures for satisfactory diaste-
reoselectivities. Furthermore, although the diastereoselec-
tivities for many of these processes are useful, they are
(4) For reviews of asymmetric acetate aldol reactions, see: (a) Masamune,
S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985,
24, 1. M. Braun, Angew. Chem., Int. Ed. Engl. 1987, 26, 24. For selected
recent references to other auxiliary-based asymmetric acetate aldol reactions,
see: (b) Oppolzer, W.; Starkemann, C. Tetrahedron Lett. 1992, 33, 2439.
(c) Helmchen, G.; Leikauf, U.; Taufer-Kno¨pfel, I. Angew. Chem., Int. Ed.
Engl. 1985, 24, 874. (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. For
approaches utilizing metal-based chirality, see: (f) Masamune, S.; Sato,
T.; Kim, B. M.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108, 8279. (g)
Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker, M. Angew.
Chem., Int. Ed. Engl. 1989, 28, 495. (h) Corey, E. J.; Imwinkelried, R.;
Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493.
(5) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J.
Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem.
1986, 51, 2391.
(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. (c) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem.,
Int. Ed. 1998, 37, 3378.
(7) Yan, T. H.; Hung, H. C.; Hung, A. W.; Lee, H. C.; Chang, C. S. J.
Org. Chem. 1994, 59, 8187.
(8) (a) Yan, T. H.; Hung, A. W.; Lee, H. C.; Chang, C. S. Liu, W. H. J.
Org. Chem. 1995, 60, 3301. (b) Gonza´lez, AÄ .; Aiguade´, J.; Urp´ı, F.;
Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (c) Guz, N. R.; Phillips, A.
J. Org. Lett. 2002, 4, 2253.
(1) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(2) For selected reviews on the aldol reaction, 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) Machajewski, T. D.; Wong, C. H. Angew. Chem.,
Int. Ed. 2000, 39, 1353. (e) Carreira, E. M. In Modern Carbonyl Chemistry;
Otera, J., Ed., Wiley: New York, 2000.
(3) (a) For selected examples, see: Crmmins, M. T.; King, B. W.; Tabet,
E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894 and references therein.
Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.
Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392. Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow,
J. S. Org. Lett. 2002, 4, 1127. (b) For recent advances in asymmetric
synthesis with chiral imide auxiliaries, see: Evans, D. A.; Shaw, J. T.
Actualite´ Chim. 2003, 35.
10.1021/ol036020y CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/05/2003

moderate when compared with the levels attainable for
propionate aldol reactions. These drawbacks have limited
the applications of these auxiliaries in the synthesis of
complex polyketide-derived natural products.
Aldol reaction diastereoselectivity with a chiral enolate
can be considered to be the product of enolate diastereotopic
face selectivity coupled with the relative face selectivity
between the enolate and aldehyde; to obtain high levels of
selectivity in a reaction, both stereocontrol elements must
be operative. Evans’ oxazolidinone auxiliary fails to give
high selectivities in acetate aldol reactions,1,9 and we
speculate that this is due to a loss of the diastereotopic face
selectivity of the enolate but that the integrity of the chair
transition state (and therefore, the relative face selectivity
between the enolate and aldehyde) is maintained. As such,
to achieve high selectivities in acetate aldol reactions, we
wished to study a system that would provide high diaste-
reoface selectivity in the enolate component. Our strategy
is to employ a strongly Lewis acidic metal as the enolate
counterion such that it may coordinate to a Lewis basic site
on the chiral auxiliary and thereby provide a rigid species
with sterically differentiated faces (Scheme 1). Reaction of
Figure 1. Chiral acetate aldol reagent variants.
this reaction provides a 12:1 ratio of diastereomers. We then
synthesized and studied the tert-leucine-derived N-acetylthi-
azolidinethione reagent 3 (Figure 1)12 and were pleased to
find that it also underwent clean enolization using 1.0 equiv
of dichlorophenylborane and 2.0 equiv of sparteine and
proVided an 82:1 ratio of aldol diastereomers upon treatment
with dihydrocinnamaldehyde.13 The valine-derived thiazo-
lidinethione reagent 4 (Figure 1) provides the product in 78%
yield but with significantly reduced diastereoselectivity (6:
1), indicating that the bulky tert-butyl group is required for
high selectivities. Compound 3 was thus chosen for further
studies.
After optimization of this reaction, we settled on a
procedure in which 1.3 equiv of reagent 3 and dichlorophe-
nylborane, 2.6 equiv of sparteine, and 1.0 equiv of the
aldehyde are used (Scheme 2). These conditions are designed
Scheme 1
Scheme 2a
this species with an aldehyde via an open transition state
would provide the needed combination of diastereotopic face
selectivity and relative face selectivity for high levels of
asymmetric induction. In this communication, we describe
an acetate aldol protocol utilizing a thiazolidinethione
auxiliary that is readily prepared and provides excellent yields
and diastereoselectivities in reactions with a variety of
aldehydes.
a Conditions: PhBCl2 (1.3 equiv), (-)-sparteine (2.6 equiv),
CH2Cl2, rt, 30 min; -78 °C, PhCH2CH2CHO (1.0 equiv), 5 h;
slowly warmed to rt within 2 h; then rt 0.5 h, hexane and H2O2,
84% yield.
To study the premise that a more Lewis acidic counterion
would provide higher levels of diastereoselectivity in acetate
aldol reactions, we attempted the preparation of the chlo-
rophenylboryl enolate10 of the Evans N-acetyloxazolidinone
reagent (1, Figure 1). Unfortunately, treatment of 1 with
dichlorophenylborane and a variety of tertiary amine bases
in chloroform failed to provide any of the desired enolate.11
We therefore turned our attention to the more acidic tert-
leucine-derived N-acetyloxazolidinethione reagent 2 (Figure
1) and found that it underwent clean enolization and provided
the desired aldol adduct in 65% yield upon treatment with
dihydrocinnamaldehyde. We were encouraged to find that
to provide maximum utilization of the most valuable species
in the reaction, which, typically, is the aldehyde. We
observed diminished yields when less than 2.6 equiv of
sparteine is used due to incomplete enolization14 and when
less than 1.3 equiv of the reagent is used.
Table 1 documents the utility and scope of this process in
reactions with representative aldehydes. We find that straight-
(12) Auxiliary 3 has been synthesized from tert-leucinol on a 10 g scale
by a modification of a general two-step literature procedure for the synthesis
of thiazolidinethiones. Slightly harsher conditions are required for the
synthesis of 3 than is typically required for other thiazolidinethiones due
to the greater steric bulk of the tert-butyl group. See Supporting Information
for details. (a) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568. (b) Delaunay, D.; Toupet, L.; Corre, M. L. J. Org. Chem. 1995, 60,
6604.
(13) The corresponding trichlorotitanium enolate (prepared from TiCl4
and sparteine) gave lower diastereoselectivities (drs range from 2:1 to 6:1
for a variety of aldehydes). Enolization with other trialkylamine bases
(Hunig’s base or triethylamine) provided lower yields.
(9) 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 1).
(10) For aldol reactions using dichlorophenylborane as the Lewis acid,
see: (a) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 1729.
(b) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871. (c) Evans,
D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454. (d) Luke, G. P.; Morris,
J. J. Org. Chem. 1995, 60, 3013.
(14) Enolization was studied by NMR at room temperature in CDCl3.
We find that a 2:1 ratio of sparteine to compound 3 provides 92% enolization
and that lower ratios of sparteine to 3 provide less enolization (1.5:1, 80%
enolization; 1.2:1, 60% enolization).
1
(11) Enolization was followed by H NMR spectroscopy in CDCl3.
24
Org. Lett., Vol. 6, No. 1, 2004

auxiliary (Figure 2, structure A). However, we cannot rule
Table 1. Aldol Reactions of Thiazolidinethione 3 with
Representative Aldehydesa
entry
aldehyde
dr (5:6)b
yield
1
2
3
4
5
6
7
8
PhCH2CH2CHO
(CH3)2CHCHO
CH3(CH2)3CHO
(CH3)2CHCH2CHO
BnOCH2CHO
TBSOCH2CH2CHO
PhCHO
E-PhCHdCHCHO
82:1
43:1
47:1
84
90
84
92
81
85
78
65
>100:1
24:1
45:1
23:1
9.5:1
Figure 2. Possible models to account for the observed stereose-
lectivity.
a For a representative procedure, see Supporting Information. b Ratios
were determined by 500 MHz 1H NMR spectroscopic analysis of the crude
reaction mixtures. c Yield of the major diastereoisomer after purification.
out reaction via a closed transition state (Figure 2, structure
B). The closed transition state minimizes the dipole interac-
tions between the thiocarbonyl group of the auxiliary and
the carbonyl group of the aldehyde and the developing
carbonyl of the aldolate. Evans has convincingly shown that
dipole effects are not important in propionate aldol reactions
using his auxiliary; however, thiazolidinethiones likely have
a greater dipole moment than oxazolidinones, and dipole
minimization considerations could be more important with
these reagents.17
Thiazolidinethione auxiliaries are known to offer certain
advantages over oxazolidinone auxiliaries, including greater
ease of cleavage of the auxiliary from the products.5,18
However, this ease of cleavage can be problematic during
the workup of the reaction if it is conducted under overly
basic conditions. The procedure described in Supporting
Information was optimized to minimize any undesired
cleavage of the auxiliary and should be closely followed in
order to achieve reproducible results.
In conclusion, we have developed a readily synthesized
thiazolidinethione auxiliary that provides high levels of
diastereoselection in acetate aldol reactions with a variety
of aldehydes in excellent yields. The use of phenyldichlo-
roborane for enolization of the reagent is required in order
to achieve high diastereomeric ratios. Further mechanistic
studies and applications to the synthesis of natural products
are underway and will be reported in due course.
chain and R- or â-branched aliphatic aldehydes react with
uniformly high selectivities (drs range from 43:1 to >100:
1) and in excellent yields (84-92%, entries 1-4). Sensitive
R- or â-oxygenated aldehydes such as benzyloxyacetaldehyde
and 3-(tert-butyldimethylsilyloxy)propanal, are also excellent
substrates for the reaction (entries 5 and 6). Aldolization with
conjugated aldehydes such as benzaldehyde or trans-cinna-
maldehyde also gave good yields and selectivities,15 though
the results with cinnamaldehyde are not as good (entries 7
and 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 (R)-5-
phenylpentane-1,3-diol and (S)-1-O-benzyl-1,2,4-butanetri-
ol.16 All other entries in the table were determined by
analogy. The sense of asymmetric induction is the same as
that observed in propionate aldol reactions using dibutyl
boron enolates of Evans’ oxazolidinone auxiliaries.2 Interest-
ingly, it is opposite to that observed by Nagao and Fujita
with tin enolates of their thiazolidinethione auxiliary5 and
opposite to that observed by Urpi8b and Phillips8c with
titanium enolates of thiazolidinethione or oxazolidinethione
auxiliaries.
This reaction was designed to operate via an open
transition state with coordination of the boron to the chiral
Acknowledgment. This work was supported by the
National Institutes of Health (GM48498 to T.S.) and Array
Biopharma. We thank Great Lakes Fine Chemicals for a
generous gift of tert-leucine. NMR instrumentation used in
this work was supported in part by the National Science
Foundation CRIF program (CHE-0131003).
(15) Use of neutral silica gel (we used Mallinckrodt Silica Silica Gel
150, 60-200 mesh (75-250 µm), pH of a 5% slurry ) 7.0) is crucial to
the success of the purification procedure. Other typical “flash” silica gels
we used provide cleavage of the auxiliary and lower yields. The addition
of triethylamine to the solvent system is not beneficial and leads to cleavage
of the auxiliary.
(16) R)-5-Phenylpentane-1,3-diol: [a]D ) +16.9 (c 1.91, EtOH), lit. [a]D
) +9.6 (c 2.3, EtOH). (S)-1-O-Benzyl-1,2,4-butanetriol: [a]D ) -8.32 (c
0.2, MeOH), lit. [a]D ) -8.4 (c 3.6, MeOH). See: Nelson, S. G.; Spencer,
K. L. J. Org. Chem. 2000, 65, 1227.
(17) Evans, D. A. In Proceedings of The Robert A. Welch Foundation
Conferences on Chemical Research. XXXVII. Stereospecificity in Chemistry
and Biochemistry; Nov. 7-9, 1983, Houston, TX; p 13.
(18) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Cosp, A.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42,
4629.
Supporting Information Available: Experimental pro-
cedures for the synthesis of the thiazolidinethione reagent,
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.
OL036020Y
Org. Lett., Vol. 6, No. 1, 2004
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