Sodium bicarbonate-catalyzed stereoselective isomerizations of electron-deficient propargylic alcohols to (Z)-enones

Article abstract of DOI:10.1021/jo0623944

Redox isomerization is a synthetically important process because it creates two new functional groups in the product, among which is the isomerization of propargylic alcohols to conjugated enones. Although E-enones have been prepared by this approach, Z-e

Full text of DOI:10.1021/jo0623944

TABLE 1. Conversion of 1 to 2 and 3
Sodium Bicarbonate-Catalyzed Stereoselective
Isomerizations of Electron-Deficient Propargylic
Alcohols to (Z)-Enones
John P. Sonye and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh,
219 Parkman AVenue, Pittsburgh, PennsylVania 15260
entry
base
solvents
CDCl3
C6D6
DMSO-d6
DMSO-d6/D2O (8:1)
DMSO-d6/H2O (8:1)
t1/2
2:3
1.2:1
1.0:1
1.6:1
3-d-2 only
2 only
1
2
3
4
5
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
NaHCO3
60
126
12
n.d.
n.d.
koide@pitt.edu
ReceiVed NoVember 21, 2006
important substrates in Diels-Alder cycloadditions17-19 and
potentially in many other cycloaddition reactions. Z- and E-γ-
oxo-R,â-alkenyl esters B and C are interesting electrophiles as
a result of their distinct reactivities, with the greater electro-
philicity of C compared to that of B.20 Presumably because of
such differences, they exhibit distinct biological activities.20
These distinctive chemical reactivities and biological activities
prompted us to develop divergent synthetic methods to prepare
a range of analogs B and C from common intermediates A.
We have recently reported the stereoselective isomerization
of A (and other electron-deficient propargylic alcohols) to C
using catalytic DABCO.21,22 Despite the synthetic and biological
importance of esters B, the only general approach toward B is
the oxidation of 2-alkoxyfurans that are not readily accessible.23
Presumably for this reason, the full synthetic and biological
potential of B has not yet been explored. In this paper, we wish
to describe a convenient and highly stereoselective method to
produce B from readily available A.24,25 This is the first
stereoselective isomerization of electron-deficient propargylic
alcohols to the corresponding Z-enones.
Redox isomerization is a synthetically important process
because it creates two new functional groups in the product,
among which is the isomerization of propargylic alcohols
to conjugated enones. Although E-enones have been prepared
by this approach, Z-enones could not be accessed. We
previously reported DABCO-catalyzed E-selective isomer-
ization of electron-deficient propargylic alcohols to enones
and its mechanism. Based on this mechanism, we have now
developed the first Z-selective redox isomerization of
electron-deficient propargylic alcohol to enone using sodium
bicarbonate as a catalyst.
Diversity-oriented organic synthesis has emerged as a new
paradigm to discover small molecules that perturb biological
processes. In this field, a new and exciting challenge is to
develop synthetic methods to prepare skeletally and stere-
ochemically diverse bioactive small molecules from common
substrates.1 As part of our efforts in this area, we became
interested in Z- and E-γ-oxo-R,â-alkenyl esters (B and C, eq
1) and their derivatives. These moieties are part of biologically
Prior to this work, we attempted the hydrogenation of 4
(Scheme 1); this deceptively straightforward Lindlar catalyst-
(10) Hayashi, M.; Kim, Y. P.; Hiraoka, H.; Natori, M.; Takamatsu, S.;
Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995,
48, 1435-1439.
(11) Takamatsu, S.; Kim, Y. P.; Hayashi, M.; Hiraoka, H.; Natori, M.;
Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95-98.
(12) Goto, S.; Chen, K.-X.; Oda, S.; Hori, H.; Terada, H. J. Am. Chem.
Soc. 1998, 120, 2457-2463.
(13) Zhang, H.; Tomoda, H.; Tabata, N.; Miura, H.; Namikoshi, M.;
Yamaguchi, Y.; Masuma, R.; Omura, S. J. Antibiot. 2001, 54, 635-641.
(14) Evidente, A.; Andolfi, A.; Vurro, M.; Zonno, M. C.; Motta, A.
Phytochemistry 2002, 60, 45-53.
(15) Berg, A.; Notni, J.; Dorfelt, H.; Grafe, U. J. Antibiot. 2002, 55,
660-662.
important natural and unnatural compounds2-16 and are also
(16) Findlay, J. A.; Li, G. Q.; Miller, J. D.; Womiloju, T. O. Can. J.
Chem. 2003, 81, 284-292.
(1) Schreiber, S. L. Science 2000, 287, 1964-1969.
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4677.
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Wenkert, E. J. Org. Chem. 1988, 53, 4325-4328.
(18) Molander, G. A.; Harris, C. R. J. Org. Chem. 1998, 63, 812-816.
(19) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc. 1988, 110, 3693-
3695.
(20) Dal Pozzo, A.; Acquasaliente, M.; Donzelli, G.; DeMaria, P.; Nicoli,
M. C. J. Med. Chem. 1987, 30, 1674-1677.
(21) Sonye, J. P.; Koide, K. Synth. Commun. 2006, 36, 599-602.
(22) Sonye, J. P.; Koide, K. J. Org. Chem. 2006, 71, 6254-6257.
(23) Antonioletti, R.; D’Auria, M.; De Mico, A.; Piancatelli, G.; Scettri,
A. Synthesis 1984, 3, 280-281.
(24) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-
2527.
(3) Aldridge, D. C.; Armstrong, J. J.; Speake, R. N.; Turner, W. B. Chem.
Commun. 1967, 26-27.
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96, 5954-5956.
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45, 28-29.
10.1021/jo0623944 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/02/2007
1846
J. Org. Chem. 2007, 72, 1846-1848

TABLE 2. Scope of Z-Isomerization
SCHEME 1. Model Systems Used in This and Previous
Studies
SCHEME 2. Proposed Mechanism
based hydrogenation of 4 was not Z-selective, providing a
mixture of 2 and 3 in a 1:5 ratio in favor of 3. Therefore, the
lack of a convenient method to prepare 2 prompted us to develop
a new synthetic methodology so that we would be able to
prepare both 2 and 3 stereoselectively from the same precur-
sor 1.
We previously screened various organic bases (DBU, DMAP,
i
DABCO, Et3N, Pr2NEt) in NMR solvents (CDCl3, C6D6,
DMSO-d6, CD3CN) to convert 1 to 3.22 As Table 1 shows, we
discovered that iPr2NEt catalyzed the conversion of 1 to 2 and
3 in CDCl3 (entry 1) and C6D6 (entry 2) and more rapidly in
i
DMSO-d6 (entry 3). In the presence of Pr2NEt, the E:Z ratio
remained the same even after 1 was consumed, excluding the
possibility for isomerization of 2 to 3. Although the stereose-
lectivity was less than desirable at this point, ranging from 1:1
to 1.6:1, we became interested in the mechanism of this
moderately Z-selective transformation. To determine how
hydrogen atoms are transferred in the iPr2NEt-catalyzed isomer-
ization of 1, we subjected 1 to 10 mol % of iPr2NEt in a DMSO-
d6-D2O mixture (8:1) at 23 °C and monitored the reaction in
an NMR tube. To our surprise, this experiment generated
exclusively 3-d-2 (entry 4) and no E-isomer! This high
Z-selectivity is not due to the potential selective degradation of
3 since compound 3 was found to be stable under the reaction
conditions.
The position of the deuterium incorporation indicates that the
mechanism is analogous to the DABCO-catalyzed E-selective
isomerization, except that the final Z to E isomerization does
not take place. In other words, as shown in Scheme 2, iPr2EtN
first abstracts the 4-H to form cumulenoate 5. This intermediate
is then protonated by iPr2EtNH+ to form the allene intermediate
6. It is worthwhile to mention here that iPr2EtNH+ reacts faster
with 6 than with D2O (i.e., no proton exchange with water)
during this process, analogous to our previous studies.26
Intermediate 6 then abstracts a deuterium atom from D2O to
generate 3-d-2. An alternative mechanism has recently been
described for a closely related transformation, in which the
authors proposed a 1,3-hydride shift.27 Their transformation can
also be explained by extending our mechanism presented here
and in our previous communication,26 which does not involve
the 1,3-hydride shift that is known to be antarafacial and thus
requires extremely high temperature.28
With such high Z-selectivity in wet DMSO, we screened other
non-nucleophilic bases and found that NaHCO3 also catalyzed
the conversion of 1 to 2 (entry 5, Table 1). After some
optimization efforts, we found that this transformation was
efficient when 1 was treated with 0.5 equiv of NaHCO3 and
0.1 mol % of hydroquinone (as a possible stabilizer of 1 and 2)
in an 8:1 DMSO-H2O mixture. Under these conditions, 2 was
obtained in 76% yield with trace 3 (∼1%) after 24 h at 23 °C
(Table 2, entry 1).
We then set out to determine the scope of this method. Unless
specifically noted, the following reactions provided exclusively
Z-products. To verify that the optimized conditions can be
applied to other types of esters, the ethyl ester 7 (entry 2) was
treated with NaHCO3 to generate 8 in 55% isolated yield. The
(26) Sonye, J. P.; Koide, K. Org. Lett. 2006, 8, 199-202.
(27) Wang, S.-H.; Tu, Y.-Q.; Wang, M. Tetrahedron Lett. 2006, 47,
8621-8623.
(28) Baldwin, J. E.; Fleming, R. H. J. Am. Chem. Soc. 1972, 94, 2140-
2142.
J. Org. Chem, Vol. 72, No. 5, 2007 1847

TABLE 3. Isomerization of Phosphonate 25
The isomerization of phosphonate 25 under the above
conditions gave a 1:2 mixture of 26 and 27 in 45% combined
yield (Table 3, entry 1). In an attempt to improve the Z-
selectivity, we screened related bases. Because LiHCO3 is not
commercially available, we mixed NaHCO3 with LiBr (1:1) to
test the effect of cations. Interestingly, these modified conditions
increased the E-selectivity (entry 2). With other bases such as
KHCO3 (entry 3) and CsHCO3 (entry 4), we were only able to
improve the E-selectivity. Thus, this challenging transformation
would require further substantial investigation for the Z-olefin
formation.
To demonstrate the viability of our base-dependent isomer-
ization methods in the context of diversity-oriented synthesis,
we subjected compounds 2 and 3 to Diels-Alder reactions with
2,3-dimethyl-1,3-butadiene (10 equiv) in the presence of AlCl3
(0.2 equiv)17,18 for 1.5 h (Scheme 3). From the Z-compound 2,
the corresponding cis Diels-Alder product 28 was generated
in 86% yield without epimerization. The E-substrate 3 afforded
29 in 94% yield. Since a cyclohexyl group has a higher
migratory aptitude than a phenyl group in Baeyer-Villiger
oxidation reactions,29 the benzoyl groups in 28 and 29 could
serve as precursor for benzoyl-protected hydroxy groups.
combined
yield (%)
entry
reagent(s)
NaHCO3
NaHCO3 + LiBr
KHCO3
time (h)
26:27
1
2
3
4
52
52
50
29
1:2
1:>20
1:4
45
50
n.d.
38
CsHCO3 (40 °C)
1:>20
SCHEME 3. Diels-Alder Reactions of Z- and
E-γ-Oxo-r,â-Alkenyl Esters
In conclusion, we have developed the first method to
stereoselectively transform A to B using catalytic NaHCO3 in
DMSO-water. This divergent approach to prepare B and C
from A should allow for the preparation of stereochemically
diverse small molecule libraries.
more electron-deficient trifluoromethyl derivative 9 (entry 3)
and the electron-rich substrate 11 (entry 4) underwent the
isomerizations smoothly, providing the Z-products 10 and 12
in 50% and 58% yields, respectively. The o-bromo derivative
13 (entry 5) was converted to its derivative 14 in 20% yield
after 48 h. We also recovered the starting material 13 in 20%
yield. Similarly to this example, another ortho halo-substituted
compound proved to be a poor substrate: the o-fluoro derivative
15 (entry 6) underwent isomerization to give 16 in 22% yield.
Interestingly, the isomerization of compound 17 (entry 7)
under the above conditions generated a mixture of Z-product
18 and its E-isomer in a 3.5:1 ratio (not shown). However, the
presence of LiBr (0.9 equiv) as an additive allowed for the
exclusive formation of 18 in 57% yield, indicating compatibility
with furans. The cinnamylalcohol derivative 19 (entry 8)
underwent the isomerization more rapidly (7.5 h) than most other
substrates to afford the diene compound 20 in 53% yield. The
aliphatic alkene derivative 21 (entry 9) provided the expected
product 22 in 52% yield, whereby the crude NMR did not
indicate any byproduct formation. This result shows that the
NaHCO3-catalyzed isomerization is not limited to aromatic
compounds. Unfortunately, substrates 23 and 24 (entries 10 and
11) generated intractable mixtures under the reaction conditions.
Experimental Section
General Procedure for the Preparation of Z-Olefins. To a
solution of alkynoate (0.2500 mmol) in 1:8 H2O-DMSO (1.25 mL
total) at 23 °C was added a 0.01 M solution of hydroquinone in
DMSO (25 µL, 2.5 µmol). Subsequently, NaHCO3 (15.8 mg, 50.0
µmol) was added in one portion, and the resulting solution was
stirred at the same temperature for the indicated time. The reaction
was then diluted with water (25 mL) and then acidified to pH 3
with a pH 3 phosphate buffer. The resulting aqueous mixture was
extracted with Et2O (25 mL × 3). The combined organic layers
were then washed with water (25 mL) and brine (25 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(EtOAc in hexanes) to afford the corresponding Z-olefin.
Acknowledgment. Financial support was provided by the
University of Pittsburgh. We thank Dr. Damodaran Krishnan
and Dr. John Williams for assisting with NMR and mass
spectroscopic analyses, respectively.
Supporting Information Available: 1H NMR, 13C NMR, IR,
and HRMS analysis data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(29) Friess, S. L.; Farnham, N. J. Am. Chem. Soc. 1950, 72, 5518-
5521.
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1848 J. Org. Chem., Vol. 72, No. 5, 2007