A solution to the cyclic aldol problem

Article abstract of DOI:10.1021/ol005525a

(equation presented) A protocol for achieving stereoselective aldol reactions with cyclic ketones is presented. In terms of yield, the process is particularly effective when a quaternary center at the α-carbon of the β-hydroxy ketone product is created. The stereochemical outcome, anti or syn, is achieved by the Lewis acid-mediated ring expansion of stereochemically homogeneous epoxides in a reaction related to the pinacol rearrangement.

Full text of DOI:10.1021/ol005525a

ORGANIC
LETTERS
2
000
Vol. 2, No. 9
193-1196
A Solution to the Cyclic Aldol Problem
1
Steven W. Baldwin,* Ping Chen, Nikola Nikolic, and Daniel C. Weinseimer
Paul M. Gross Chemical Laboratory, Department of Chemistry, Duke UniVersity,
Durham, North Carolina 27708
baldwin@chem.duke.edu
Received January 10, 2000
ABSTRACT
A protocol for achieving stereoselective aldol reactions with cyclic ketones is presented. In terms of yield, the process is particularly effective
when a quaternary center at the r-carbon of the â-hydroxy ketone product is created. The stereochemical outcome, anti or syn, is achieved
by the Lewis acid-mediated ring expansion of stereochemically homogeneous epoxides in a reaction related to the pinacol rearrangement.
One of the more important and vital contributions to synthetic
organic methodology in the past 20-25 years has been the
large body of work detailing the stereochemical outcome of
by incorporating chiral auxiliaries in either reaction partner,
or in both to take advantage of double diastereoselection
processes.
6
1
the aldol and related reactions. In the acyclic aldol conden-
In contrast to the regularity and predictability associated
with the aldol condensations of acyclic carbonyl compounds,
cyclic ketones have often proved to be more fractious. In
general, cyclic aldol reactions run under equilibrating condi-
tions favor the anti (threo) diastereomer as seen for the
thermodynamic reaction of the lithium and zinc chloride
enolates of cyclohexanone with benzaldehyde to give anti/
sation, the reaction between an acyclic carbonyl enolate or
equivalent and an aldehyde, the conventional mnemonic
holds that the relative stereochemistry of the â-hydroxyl
carbonyl product (syn/anti; erythro/threo) is usually the result
2
of a closed transition state (Zimmerman-Traxler) in which
enolate geometry is transferred to the product by minimizing
7
nonbonded interactions. It is interesting that recent work has
syn ratios of 67/33 and 83/17, respectively. As expected
3
focused on the aggregated nature of the enolates as well as
for an enolate constrained in the E configuration, one would
also expect aldol condensations run under kinetic conditions
to favor the formation of the anti product, in accord with
the results of the acyclic aldol reactions summarized above.
In general this is true, although the diastereomeric ratios are
particularly sensitive to the nature of the counterion and
reaction conditions. Representative results for the reaction
between a variety of cyclohexanone enolates and benzalde-
4
the aldol product alkoxides, and the strong indication that
in the usual organic solvents the reaction may actually be
5
occurring within a molecular aggregate. Absolute stereo-
chemistry in acyclic aldol reactions can often be controlled
(1) For comprehensive discussions of the various aspects of the aldol
condensation see: (a) Meckleburger, H. B.; Wilcox, C. S. In ComprehensiVe
Organic Synthesis; Trost B. M., Fleming, I., Eds.; Pergamon Press:
Elmsford, NY, 1991; Vol. 2, pp 99-131. (b) Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Trost B. M., Fleming, I., Eds.; Pergamon
Press: Elmsford, NY, 1991; Vol. 2, pp 133-179. (c) Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Trost B. M., Fleming, I., Eds.; Pergamon
Press: Elmsford, NY, 1991; Vol. 2, pp 181-238. (d) Kim, B. M.; Williams,
S. F.; Masamune, S. In ComprehensiVe Organic Synthesis; Trost B. M.,
Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol. 2, pp 239-
8
hyde show only barely recognizable trends, and even these
results do not extrapolate to other cyclic ketones or carbonyl
(5) (a) Seebach, D.; Amstutz, R.; Dunitz, J. D. HelV. Chim. Acta 1981,
64, 2622. (b) C. H. Heathcock, C. H.; J. Lampe, J. J. Org. Chem. 1983, 48.
4330. (c) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109, 5539.
(d) Wei, Y.; Bakthavatchalam, R. Tetrahedron Lett. 1991, 32, 1535.
(6) (a) See, for example: Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am.
Chem Soc. 1981, 103, 2127. (b) For a review of double diastereoselection
in organic synthesis, see: Masamune, S. Ang. Chem., Int. Ed. Engl. 1985,
24, 1.
2
75.
(2) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
3) (a) Jackman, L. M.; Lange, B. C. Tetrahedron 1977, 33, 2737. (b)
(
Jackman, L. M.; Smith, B. D. J. Am. Chem. Soc. 1988, 110, 3829.
4) An excellent summary of pertinent literature and definitive physical
(
organic studies of the aldol reaction can be found in: Arnett, E. M.; Fisher,
F. J.; Nichols, M. A.; Ribiero, A. A. J. Am. Chem. Soc. 1990, 112, 801.
(7) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J.
Am. Chem. Soc. 1985, 95, 3310 and references therein.
1
0.1021/ol005525a CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/04/2000

9
10
electrophiles. Results become even less predictable when the
cyclic enolate is fully substituted so that the aldol reaction
would generate a quaternary center as in the formation of
aldol product 2 from 2-methylcyclohexanone (1). It is this
problem that is of particular concern in the context of this
work. Furthermore, the problem of absolute stereochemistry
in these reactions has not been adequately solved. The good
facial selectivities that have been observed in the alkylation
reactions of chiral imine and hydrazone-derived cyclic
enolates do not transfer to the hydroxyl-bearing carbons of
their aldol condensation counterparts.
While considering possible alternative solutions to the
cyclic aldol problem, it became clear that epoxides such as
to work by Julia as well as Johnson and Goldsmith.
Formally related to the pinacol rearrangement,11 it was
expected that the reaction would proceed with inversion of
configuration at the migration terminus. More recent indirect
precedent for the stereochemical integrity of the rearrange-
1
2
ment, including an acyclic aldol-equivalent process, is
13
encouraging. Otherwise there has been no systematic study
of this reaction. The results of our studies to better define
its scope and stereochemical parameters are presented here.
Preparation of the initial test substrates 6E and 6Z was
accomplished by the addition of the vinyllithium reagents
derived from the E and Z isomers of commercially available
2-bromo-2-butene to cyclopentanone (∼7/1 mixture of
isomers) followed by epoxidation with mCPBA (Scheme 1).
1
5
possess all of the stereochemical information on the target
aldol products provided that a Lewis acid-mediated rear-
rangement/ring expansion could be effected under controlled
conditions (Figure 1). In a relative sense the stereochemistry
Scheme 1a
a
Reagents and conditions: (a) TMS-imidazole, CH
‚OEt (2 equiv), CH Cl , -78 °C, 2.5 h; (c) Ac
DMAP, EtOAc, 14 h; (d) mCPBA, CH Cl , 20 °C, 40 h; (e) LiAlH
THF, 20 °C, 6 h; (f) BzCl, DMAP, CHCl , 20 °C, 16 h; (g) MsCl,
DMAP, CH Cl , 0 °C, 14 h; (h) Triton B/CH OH, THF, -23 °C,
5 min; (i) SnCl (1 equiv), CH Cl , -78 °C, 2.5 h.
2
Cl
2
, 20 °C,
1
2 h; (b) BF
3
2
2
2
2
O,
2
2
4
,
3
2
2
3
1
4
2
2
Separation of the individual isomers could be accomplished
at either the allylic alcohol or epoxide stage. Verification of
the stereochemical assignments for the epoxides was based
Figure 1. Alternative routes to cyclic aldol products.
of the ring-expanded products would be established by
employing an allylic alcohol with specified alkene geometry
13
on C NMR chemical shift data for the indicated carbons
associated with the epoxide group, as has been observed in
(4E or 4Z) as precursor to the rearrangement substrate
14
similar systems. Particularly diagnostic were the resonances
epoxides (5E or 5Z). Because the stereospecific preparation
of alkenes is well established and alkene epoxidations are
stereospecific processes, a high degree of overall stereo-
chemical control would be possible if the rearrangement
could be accomplished in a synchronous fashion. The
opportunity for absolute stereochemical control also exists
because of a variety of possibilities for enantioselective
epoxidation of the prochiral allylic alcohols, e.g., 4.
(
9) Julia, S.; Julia, M.; Linares, H.; Blondel, J.-C. Bull. Soc. Chim. Fr.
1962, 1952.
(10) (a) Johnson, C. R.; Cheer, C. J.; Goldsmith, D. J. J. Org. Chem.
1
964, 29, 3320. (b) Cheer, C. J.; Johnson, C. R. J. Org. Chem. 1967, 32,
428.
(
11) (a) Rickborn, B. In ComprehensiVe Organic Synthesis; Trost B. M.,
Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol. 3, pp 721-
7
32. (b) Rickborn, B. In ComprehensiVe Organic Synthesis; Trost B. M.,
Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol. 3, pp 733-
7
75. (c) Coveney, D. J. In ComprehensiVe Organic Synthesis; Trost B. M.,
The literature on this kind of ring expansion is interesting,
although rather sparse, and dates back more than 30 years
Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol. 3, pp 777-
801.
(12) (a) Hwang, C.; Reusch, W. Heterocycles 1987, 25, 589. (b) Hwang,
(
8) (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
C.; Ward, D. L.; Reusch, W. J. Org. Chem. 1989, 54, 4318.
(13) An acyclic version of the epoxy alcohol rearrangement described
above, and thus another solution to the acyclic aldol problem, has been
described: (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.;
Shimazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827. (b)
Suzuki, K.; Miyazawa, M.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28,
3515. (c) Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron
Lett. 1987, 28, 5891. (d) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem.
Soc. 1989, 111, 6431.
Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066. (b) Maruoka, K.;
Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nazaki, H. J. Am. Chem.
Soc. 1977, 99, 7705. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099. (d) T. Mukaiyama, T.; K. Banno, K.; K.
Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503. (e) Y. Yamamoto, Y.;
Maruyama, K. Tetrahedron Lett. 1980, 4607. (f) S. Murata, S.; M. Suzuki,
M.; R. Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248. (g) Gennari, C.;
Cardani, S.; Colombo, L.; Scolastico, C. Tetrahedron Lett. 1984, 25, 2283.
1194
Org. Lett., Vol. 2, No. 9, 2000

for the quaternary methyl carbons which were observed at
δ 13.9 and δ 20.3 for 6E and 6Z, respectively. Similarly,
the alcohol-bearing ring carbons for these two isomers were
observed at δ 82.9 and δ 81.0. It is worth noting that for the
pairs of trisubstituted epoxide isomers examined in this study,
epoxide ring in these two compounds were seen at δ 32.5
and δ 38.5, in accord with the trend described previously.
Independent verification was obtained by the alternative
synthesis of 7anti outlined in Scheme 2. Starting with known
1
3
such C NMR chemical shift comparisons provide a
convenient handle for assigning epoxide stereochemistry. In
Scheme 2a
13
particular, it was found that the C NMR chemical shifts of
the carbons attached to the disubstituted end of the epoxide
are sensitive to their spacial relationship to the methyl group
on the monosubstituted epoxide carbon. Specifically, the
resonance for the carbon that is cis to the secondary methyl
group occurs upfield relative to the corresponding resonance
for its stereoisomer (Scheme 1).
Although direct rearrangement of the epoxy alcohols gave
satisfactory results, the derived TMS ethers (TMS imidazole)
proved to be more reliable substrates, both in terms of yield
and diastereomeric ratios. Furthermore, although a wide
range of Lewis acids could be used to effect the rearrange-
ment, no single promoter system was consistently superior.
a
Reagents and conditions: (a) NaBH
N, CH Cl , 20 °C, 24 h; (c)Mg, CH
(d) LiAlH , Et O, 0 °C, 3 h; (e) PDC, CH Cl , 20 °C, 24 h; (f)
4 3
, CH OH, 0 °C, 1 h; (b)
20
MsCl, Et
3
2
2
3
OH, 20 °C, 1 h;
4
2
2
2
NH
2
OH‚HCl, NaHCO
3
, H
2
O, 20 °C, 1 h; (g) NaOCl, H
2 2 2
O, CH Cl ,
2
0 °C, 30h; (h) Raney Ni, CH
3
OH, HOAc, 20 °C, 3 h.
In general, however, the best promoters were SnCl
4
, BF
3
‚
ester 10 with secure alkene geometry,17 aldehyde 11 was
prepared in five unenventful steps. Conversion to the oxime
15
2 3
OEt , and ClTi(OiPr) .
Thus, rearrangement of the TMS
ether of 6E afforded an 88% yield of keto alcohols 7anti
and 7syn in a 94/6 ratio, from which pure 7anti was isolated
in 81% yield after chromatography. The diastereomeric ratio
from the rearrangement of the free alcohol 6E was only 68/
followed by oxidation with NaOCl then afforded isoxazoline
18
1
3 through the intermediacy of the nitrile oxide 12. Raney
nickel hydrogenolysis of 13 and hydrolysis according to the
19
protocol of Curran then yielded 7anti, identical with the
3
2. Similarly, rearrangement of the TMS ether of 6Z yielded
the same two products in a <1/99 ratio, the major isomer
syn being isolated in 89% yield after chromatography.
same material derived from the epoxide rearrangement of
6
1
E. As expected for the substitution pattern of compound
2, the yield of the nitrile oxide cycloaddition reaction was
7
Again, the ratio from rearrangement of the free alcohol was
only 20/80. Similar results were obtained for the analogous
ring expansion processes beginning with cyclobutanone,
cyclohexanone, cycloheptanone, and cyclodocecanone, where
the rearrangements (1.3 equiv SnCl /CH Cl /-78 °C) of the
4 2 2
trimethylsilyl ethers of the four sets of E and Z dimethyl
low (∼10%). It did, however, provide unambiguous confir-
mation of our previous stereochemical assignments. There
was no indication of the formation of a second isomer in
the nitrile oxide cycloaddition reaction; rather the remaining
material appeared to be largely the result of nitrile oxide
dimerization.
In an effort to determine the importance of the nature of
the substituent at the migration terminus, two additional
rearrangement substrate types were studied (Scheme 3). Thus,
epoxides proceeded in high yield (>85%) and with high
16
diastereostereoselectivities (>95/5). These details of these
results will be reported in due course.
Because the rearrangement products 7anti and 7syn had
not been previously characterized and because definitive
stereochemical assignments based on spectral comparisons
were difficult, compounds 7anti and 7syn were converted
to the stereoisomeric epoxides 8 and 9 by the reactions
outlined in Scheme 1. As was the case for the original
rearrangement substrates 6E and 6Z, unambiguous stereo-
chemical assignments were made on the basis of the indicated
Scheme 3
1
3
C NMR chemical shifts, in accord with literature prece-
1
4
dent. Specifically, the quaternary methyl carbons of ep-
oxides 8 and 10 were observed at δ 22.1 and δ 14.1,
respectively, while the methylene carbons adjacent to the
rearrangement of phenyl-substituted epoxides 14E and 14Z,
prepared as before by epoxidation of the parent alkenes,21
(
14) (a) Havesi, L.; Nagy, J. B.; Krief, A.; Derouane, E. G. Org. Magn.
Res. 1977, 10, 14. (b) Pri-Bar, I.; Pearlman, P. S.; Stille, J. K. J. Org. Chem.
983, 48, 4629. (c) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem.
Soc. 1988, 110, 2506.
15) The rearrangements were carried out in the presence of 0.3-1.5
1
(16) The ratios of the diastereoisomers were determined by a combination
1
of capillary gas chromatography and H NMR spectroscopy. In the latter
(
analyses, the quartet for the proton on the hydroxyl-bearing carbon was
diagnostic, occurring between 0.1 and 0.2 ppm downfield in the syn isomers
as compared to the anti isomers (e.g., δ 4.08 and δ 3.98 for 7syn and 7anti,
respectively).
equiv of Lewis acid, the indicated amounts being the best for the particular
experiment in question. Other Lewis acids surveyed include TiCl4, ZnCl2,
and TMSOTf, although the diastereomeric ratios with these promoters were
generally lower.
(17) Snider, B. B.; Patricia, J. J. J. Org. Chem. 1989, 54, 38.
Org. Lett., Vol. 2, No. 9, 2000
1195

was accomplished by exposure to SnCl
4
in CH
2
Cl
2
(1.2
17anti and 17syn in a ratio of 99/1, although again in 50-
60% yield. The identity of 17syn and 17anti as the major
products of these two reactions was confirmed by comparison
equiv, -78 °C, 2 h). Epoxide 14E afforded the two
â-hydroxy cyclohexanone products in 87% yield, the ratio
of 15syn and 15anti being <2/98. Similar treatment of 14Z
yielded the same two products (88% yield) in a 95/5 ratio.
As before, rearrangement of the free alcohols afforded lower
diasteroisomeric ratios as well as significant amounts of
chlorohydrin byproducts.
The final rearrangement substrates for these initial studies
were epoxides 16Z and 16E in which the rearrangement
1
migration terminus is unsubstituted (R dH). Prepared by
1
of the H NMR spectrum with that reported for authentic
material. Specifically, the quartet for the proton on the
hydroxyl-bearing carbon of 17syn was observed at δ 3.95,
in agreement with the literature value of δ 3.94 for authentic
18
material. The corresponding proton for the anti isomer was
observed at δ 4.26 as compared with the literature value δ
4
.27.
In summary, the epoxide ring expansion protocol described
epoxidation of the alkene derived from low temperature
addition of (E)- and (Z)-1-lithio-1-propene to cyclopentanone,
this substrate was intended to determine whether a fully
substituted migration terminus is required for successful
here provides a reasonable method for achieving â-hydroxy
cycloalkanone (cyclic aldol) products in good yields and with
high levels of diastereoselection, particularly in those cases
in which the R carbon is fully substituted. Further develop-
ments and applications of this work will be reported
subsequently, including protocols for achieving enantiomeri-
cally enriched epoxide rearrangement subtrates.22
reaction. In the event, rearrangement of 16E with SnCl
4
at
-
40 °C afforded the cyclohexanone products 17anti and
17syn in a ratio of 3/97, although the yield was only 50-
60%. The remaining material was largely chlorohydrin. Other
Lewis acid promoters produced either decomposition of
starting material (BF ‚OEt ) or no reaction (AlEt , TiCl-
OiPr) , Ti(OiPr) ). Similar rearrangement of 16Z afforded
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this work (26532-AC1). We
also gratefully acknowledge NSF (CHE 95 22580) for
financial assistance in the purchase of the 400 MHz NMR
instrument used in support of this work.
3
2
3
(
3
4
(
18) For a discussion of intramolecular nitrile oxide/alkene cycloaddition
INOC) reactions, see: Wade, P. A. In ComprehensiVe Organic Synthesis;
Trost B. M., Fleming, I., Eds.; Pergamon Press: Elmsford, NY, 1991; Vol.
(
4
, pp 1124-1134.
(
19) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826.
(
20) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett.
OL005525A
1
987, 28, 5287.
21) The phenyl-substituted allylic alcohol precursors to epoxides 14 were
(
prepared by lithiation of (Z)-1-bromo-1-phenylpropene followed by addition
to cyclopentanone. At -78 °C the Z/E ratio of the stereoisomeric products
was ∼4/1; at -22 °C the ratio was ∼1/4. Krop, P. J.; Crawford, S. D. J.
Org. Chem. 1994, 59, 3102.
(22) The structures of all new compounds reported in this work were
1
13
confirmed by H and C NMR analysis and IR where appropriate. Suitably
purified samples also exhibited consistent combustion analyses and/or high-
resolution mass spectral data.
1196
Org. Lett., Vol. 2, No. 9, 2000