Syn-anti isomerization of aldols by enolization

Article abstract of DOI:10.1021/ol016581u

Figure presented A variety of aldol adducts (i.e., 3-hydroxy ketones) are shown to undergo syn-anti isomerization in the presence of imidazole by an enolization mechanism with negligible retroaldol or elimination products.

Full text of DOI:10.1021/ol016581u

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3671-3673
Syn−Anti Isomerization of Aldols by
Enolization
Dale E. Ward,* Marcelo Sales, and Pradip K. Sasmal
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon SK S7N 5C9, Canada
dale.ward@usask.ca
Received August 15, 2001
ABSTRACT
A variety of aldol adducts (i.e., 3-hydroxy ketones) are shown to undergo syn−anti isomerization in the presence of imidazole by an enolization
mechanism with negligible retroaldol or elimination products.
The aldol reaction can produce up to two new stereogenic
centers, and several stereoisomeric products are generally
possible. The reaction is readily reversible, and when
mediated by weak bases (e.g., hydroxide, alkoxide, amine),
product distribution is generally under thermodynamic
control.1 The advent of modern enolate chemistry and the
use of preformed enol(ate) derivatives facilitated rapid
development of the “directed” aldol reaction.2 In this case,
product formation is typically under kinetic control although
isomerization of metal aldolate intermediates can be facile
under certain conditions.3 The development of methods for
stereoselective aldol reactions has been intensively investi-
gated for more that 20 years.4 Nonetheless, the ability to
produce each of the possible aldol stereoisomers selectively,
especially from chiral substrates, remains a significant
challenge.4c,5 Isomerization of aldol adducts is an alternative
strategy to access aldol stereoisomers. Although there have
been several reports of isomerization of cyclic1,6 and
acyclic3e,7 aldols through a retroaldol mechanism, isomer-
ization of aldols via an enol8 or enolate9 is rare. In this paper
we report that imidazole effectively catalyzes the syn-anti
isomerization of 3-hydroxy ketones by an enolization mech-
anism with negligible retroaldol or elimination products.
Reaction of 1a10 with TBDMS-Cl in the presence of
imidazole11 in CH2Cl2 solution failed to give the desired
TBDMS ether; however, after 5 days ca. 30% of 1s10 was
detected and isolated from the reaction mixture. The isomer-
1
ization of 1a was readily followed by H NMR in CDCl3
(1) Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1-438.
(2) Mukaiyama, T. Org. React. 1982, 28, 203-331.
(5) Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797-800.
(6) (a) Kok, P.; Sinha, N. D.; Sandra, P.; de Clercq, P. J.; Vandewalle,
M. E. Tetrahedron 1982, 38, 2279-2283. (b) Vekgova´, H. Collect. Czech.
Chem. Commun. 1986, 51, 930-936. (c) Hui, A.; Fairbanks, A. J.; Nash,
R. J.; de Q. Lilley, P. M.; Storer, R.; Watkin, D. J.; Fleet, G. W. J.
Tetrahedron Lett. 1994, 47, 8895-8898. (d) Seto, H.; Fujioka, S.; Kamiya,
Y.; Yoshida, S. Heterocycles 1998, 48, 2245-2251. (e) Mukaiyama, T.;
Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.;
Nishimura, K.; Tani, Y.-i.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.
Eur. J. 1999, 5, 121-161. (f) Aurrecoechea, J. M.; Fan˜ana´s, R.; Arrate,
M.; Gorgojo, J. M.; Aurrekoetxea, N. J. Org. Chem. 1999, 64, 1893-1901.
(7) (a) Mahrwald, R.; Costisella, B.; Gu¨ndogan, B. Synthesis 1998, 262-
264. (b) Yang, W.; Digits, C. A.; Hatada, M.; Narula, S.; Rozamus, L. W.;
Huestis, C. M.; Wong, J.; Dalgarno, D.; Holt, D. A. Org. Lett. 1999, 1,
2033-2035.
(3) (a) Dubois, J. E.; Fellmann, P. C. R. Acad. Sci., Ser. C 1972, 274,
1307-1309. (b) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead,
H. D. J. Am. Chem. Soc. 1973, 95, 3310-3324. (c) Heathcock, C. H.; Buse,
C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org.
Chem. 1980, 45, 1066-1081. (d) Heathcock, C. H.; Lampe, J. J. Org. Chem.
1983, 48, 4330-4337. (e) Swiss, K. A.; Choi, W.-B.; Liotta, D. C.; Abdel-
Magid, A. F.; Maryanoff, C. A. J. Org. Chem. 1991, 56, 5978-5980. (f)
Carlier, P. R.; Lo, C. W.-S.; Lo, M. M.-C.; Wan, N. C.; Williams, I. D.
Org. Lett. 2000, 2, 2443-2445.
(4) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
13, 1-115. (b) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J.
D., Ed.; Academic Press: New York, 1984; Vol. 3, pp 111-212. (c)
Heathcock, C. H. Aldrichim. Acta 1990, 23 (4), 99-111. (d) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 357-389. (e) Arya, P.; Qin, H. Tetrahedron
2000, 56, 917-947. (f) Machajewski, T. D.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2000, 39, 1352-1374.
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2817-2820. (b) Yan, T.-H.; Chu, V.-V.; Lin, T.-C.; Tseng, W.-H.; Cheng,
T.-W. Tetrahedron Lett. 1991, 32, 5563-5566.
10.1021/ol016581u CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/20/2001

with 10 equiv of imidazole. After ca. 4 days, a 1.5:1
equilibrium mixture of 1s and 1a, respectively, resulted.
Equilibrium was confirmed by obtaining the same mixture
starting from 1s. These solutions were stable for several
weeks with negligible (<5%) retroaldol (as judged by the
absence of 4) or elimination products being detected.
Subjecting 5a12 or 5s12 to the same conditions resulted in a
1.8:1 equilibrium mixture of 5s and 5a, respectively. In
principle, aldol adducts can isomerize by retroaldol and/or
enolization mechanisms (Scheme 1). Whereas all possible
Table 1. Imidazole-Catalyzed Syn-Anti Isomerization of
Aldols 1 and 5-10a
Scheme 1
starting
aldol
aldols at equilibriumb
(ratio at equilibrium)c
entry
solvent
CDCl3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1s
1a
1s
1a
1a
1a
5a
5s
5s
5s
5s
5s
1s:1a (1.5:1)
1s:1a (1.5:1)
1s:1a (1.6:1)
1s:1a (1.6:1)
1s:1a (2.0:1)
1s:1a (1.4:1)
1s:1a (1.7:1)
5s:5a (1.8:1)
5s:5a (1.8:1)
5s:5a (1.9:1)
5s:5a (1.6:1)
5s:5a (1.5:1)
5s:5a (2.0:1)
5s:5a (2.1:1)
6a :6s (1.1:1)
6a :6s (1.1:1)
7s:7a (1.5:1)
8a :8s (1.6:1)
9a :9s (2.0:1)
10a :10sf (1.1:1)f
CDCl3
CH2Cl2
CH2Cl2
acetone-d6
C6D6
CH3OH
CDCl3
CDCl3
CH2Cl2
acetone-d6
C6D6
CH3OH
DMF-d7
CDCl3
CDCl3
CDCl3
CDCl3
5s
6a
6s
7s
stereoisomers can result from a retroaldol-aldol pathway,
keto-enol tautomerism can interconvert only two stereo-
isomers. We conclude that the above isomerizations of 1 and
5 proceed via imidazole-catalyzed enolization13,14 because:
(i) 5 was not detected in the isomerization of 1 and vice
versa, and (ii) imidazole does not catalyze an aldol reaction
between 2 and 4.
8a
9a
10sd
CDCl3
e
C6D6
a Imidazole (0.2-0.4 M, ca. 10 equiv) at room temperature. b Equilibrium
reached in 4-7 days (monitored by !H NMR). Aldols recovered in >95%
yield after aqueous workup. c Ratios determined by 1H NMR (relative error
estimated at (10%). d A 9:1 mixture of 10s:10a was used. e Reaction at
60 °C for 13 days. f Approximately 6% of benzaldehyde was present.
(9) (a) Martin, V. A.; Murray, D. H.; Pratt, N. E.; Zhao, Y.; Albizati, K.
F. J. Am. Chem. Soc. 1990, 112, 6965-6978. (b) Woodward, R. B.;
Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward, D. E.; Au-Yeung, B.-W.;
Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C. H.; Cheˆnevert, R. B.;
Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.; Heggie,
W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.; Jacobi, P.
A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert,
T.; Malchenko, S.; Martens, J.; Matthews, S. R.; Ong, B. S.; Press, J. B.;
RajanBabu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.;
Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella,
A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong, H. N.-C.
J. Am. Chem. Soc. 1981, 103, 3210-3213.
Imidazole-catalyzed isomerizations of 1 and 5 were
conducted in several solvents (Table 1). Equilibrium was
typically reached in 4-7 days using 10 equiv of imidazole
(ca. 0.2-0.4 M) without any indication of retroaldol or
elimination products. In all cases the syn aldol diastereomer
(1s or 5s) was favored. Less polar solvents (e.g., benzene)
led to a relatively greater proportion of the anti aldol
diastereomer (1a or 5a) at equilibrium compared to that from
more polar solvents (e.g., methanol), although this effect was
quite small.
(10) Ward, D. E.; Man, C. C.; Guo, C. Tetrahedron Lett. 1997, 38, 2201-
2202.
(11) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-
6191.
To test the generality of syn-anti isomerization of aldols
via enolization 6,12 7,12 8,10 9,10 and 103c were treated with
imidazole in CDCl3 solution (Table 1). As with 1 and 5, the
products from isomerizations of 6 and 7 were mutually
exclusive and incongruent with a retroaldol pathway. The
simple aldols 8 and 9, derived from reactions of benzalde-
(12) See Supporting Information for preparation and determination of
relative stereochemical configurations.
(13) For a review on the mechanism of enolization of ketones, see: Keefe,
J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley:
New York, 1990; Chapter 7, pp 399-480.
(14) For imidazole catalyzed enolization, see: (a) Mel’nichenko, I. V.;
Yasnikov, A. A. Ukr. Khim. Zh. 1964, 30, 723-728. (b) Breslow, R.; Graff,
A. J. Am. Chem. Soc. 1993, 115, 10988-10989.
3672
Org. Lett., Vol. 3, No. 23, 2001

hyde with tetrahydrothiopyran-4-one and cyclohexanone,
respectively, readily equilibrated in the presence of imidazole
to give a slight excess of the anti diastereomer, as expected.3b,c
Isomerization of the acyclic aldol 10s was very slow at room
temperature; however, heating a benzene15 solution of 10s
and imidazole at 60 °C for 13 days produced 1.1:1 mixture
of 10a and 10s, respectively.16 Despite these much harsher
conditions, elimination was negligible and only a small
amount of retroaldol occurred (as indicated by the presence
of benzaldehyde, 6%).
Table 3. Rate of Isomerization of 5s in CDCl3 at Room
Temperaturea
entry
base
[base] (M)
[5]b (M)
t1/2 (h)c
d
1
2
3
4
5
6
7
8
9
pyridine
Et3N
DMAP
0.22
0.40
0.22
0.10
0.20
0.20
0.40
0.40
0.40
0.80
0.036
0.016
0.016
0.016
0.016
0.016
0.030
0.030
0.060
0.120
0.030
0.018
110
14
imidazole
49
19
21
8.9
8.4
8.9
3.4
e
We also examined the imidazole-catalyzed isomerization
of the bisaldols 1117 (Table 2). Reactions of 11aa or 11sa in
10
11
Ti(OiPr)4
Table 2. Imidazole-Catalyzed Isomerization of Bisaldols 11a
a Monitored by 1H NMR by integration of HC-1′ for 5s and 5a. At
equilibrium, a 1.8:1 ratio of 5s:5a was obtained. b Initial concentration of
5s. c The half-life for equilibration: t1/2 ) ln(2)/kobs where kobs is determined
from the slope of the line obtained by plotting ln([5s]equilibrium - [5s]t) vs t
(g8 data points over 2 half-lives; R2 > 0.99). Relative error estimated at
(10%. d No isomerization after 200 h. e Reaction in CH2Cl2 at 0 °C gave
elimination only (cf. ref 7).
We briefly examined the effect of other bases and reaction
conditions on the rate of equilibration of 5s in CDCl3 (Table
3). Catalysis by DMAP was at least as effective as imidazole
although Et3N was considerably less efficacious, and pyridine
did not catalyze isomerization of 5s. As expected, the rate
of equilibration was dependent on the molar concentration
of imidazole (compare entries 7, 8, and 9) but not on the
stoichiometry (compare entries 4, 6, and 8). The data
obtained suggest a reaction order in imidazole of 1.320
implying a complex mechanism.13
In summary, we have demonstrated that imidazole is an
effective catalyst for syn-anti isomerization of aldols via
an enolization mechanism. Isomerizations are high yielding
and occur with little or none of the usual byproducts arising
from competing elimination or retroaldol reactions. The
process can provide access to diastereomers unavailable by
other methods, and although stereoselectivity under these
conditions is typically modest, useful amounts of material
can be obtained by recycling if necessary.
starting
bisaldol
aldols at equilibriumb
(ratio at equilibrium)c
entry
solvent
CDCl3
CDCl3
CH2Cl2
C6D6
1
2
3
4
5
6
11sa
11a a
11a a
11a a
11a a
11a a
11sa :11ss:11a a (3.4:1.3:1)
11sa :11ss:11a a (3.4:1.3:1)
11sa :11ss:11a a (4.8:1.4:1)
11sa :11ss:11a a (5.4:2.4:1)
11sa :11ss:11a a (9.6:3.8:1)
11sa (65%),d 11ss (25%),d
11a a (7%)d
acetone-d6
acetone
a Imidazole (0.4-1.0 M) at room temperature. b Equilibrium reached in
6-10 days (monitored by !H NMR). Aldols recovered in >95% yield after
aqueous workup. c Ratios determined by 1H NMR (relative error estimated
at (10%). d Isolated yield.
all cases led to a mixture of the same three aldols, clearly
indicating isomerization by an enolization mechanism.18
Interestingly, although the ratio of the CS symmetrical aldols
(11ss, 11aa) at equilibrium was solvent-dependent (1.3-3.8:
1), the unsymmetrical bisaldol 11sa consistently comprised
60-65% of the mixture. As with previous examples, the
isomerizations proceeded without giving significant amounts
of elimination or retroaldol products.19
Acknowledgment. Financial support from the Natural
Sciences and Engineering Research Council (Canada) and
the University of Saskatchewan is gratefully acknowledged.
Supporting Information Available: Preparation, spec-
troscopic data, and determination of relative configurations
of 5-7. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Chloroform solutions were not stable to prolonged heating.
(16) Holt et al. (ref 7b) obtained a 5:4 mixture of 10a and 10s by
isomerization of 10 in the presence of Ti(Oi-Pr)4 (retroaldol mechanism).
(17) Ward, D. E.; Guo, C.; Sasmal, P. K.; Man, C. C.; Sales, M. Org.
Lett. 2000, 2, 1325-1328.
(18) There are 20 diastereomers possible for 11. In principle, all
diastereomers could be produced from 11aa or 11sa via a retroaldol-aldol
mechanism, whereas enolization can only interconvert the three diastere-
omers shown.
OL016581U
(19) In some experiments, a small amount (1-3%) of aldehyde 4 was
detected after prolonged reaction.
(20) The slope of the line obtained by plotting ln(kobs) vs ln([imidazole])
for entries 4, 6, 7, and 10. Regression analysis on these four data points
yields a slope of 1.28 ( 0.13 (95% confidence interval).
Org. Lett., Vol. 3, No. 23, 2001
3673