Catalytic asymmetric synthesis of α,β-epoxy esters, aldehydes, amides, and γ,δ-epoxy β-keto esters: Unique reactivity of α,β-unsaturated carboxylic acid imidazolides [16]

Full text of DOI:10.1021/ja0164879

9474
J. Am. Chem. Soc. 2001, 123, 9474-9475
Scheme 1. Catalytic Asymmetric Epoxidation of Cinnamic
Acid Ester 2 and Imidazolide 4 Using
La-(S)-BINOL-Ph3AsdO Complex 1
Catalytic Asymmetric Synthesis of r,â-Epoxy Esters,
Aldehydes, Amides, and γ,δ-Epoxy â-Keto Esters:
Unique Reactivity of r,â-Unsaturated Carboxylic
Acid Imidazolides
Tetsuhiro Nemoto, Takashi Ohshima, and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, Hongo
Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed June 25, 2001
ReVised Manuscript ReceiVed August 5, 2001
Asymmetric epoxidation of R,â-unsaturated carbonyl com-
pounds remains one of the most important functional group
manipulations in organic synthesis,1 because of the usefulness of
the corresponding enantiomerically enriched R,â-epoxy carbonyl
compounds.2 Although we3 and others1 have achieved efficient
catalytic asymmetric epoxidation of R,â-unsaturated ketones, there
are only a few reports of catalytic asymmetric epoxidation of R,â-
unsaturated esters using a salen-manganese complex4 or an
optically active ketone5 as a catalyst. In both cases, only cinnamic
acid derivatives were utilized as a substrate. Substrates that have
other functional groups, such as a C-C double bond or ketone,
cannot be used for those asymmetric reactions due to poor
chemoselectivity, indicating that there is still room for improve-
ment in terms of substrate generality. We report the first example
of a general catalytic asymmetric epoxidation of R,â-unsaturated
carboxylic acid imidazolides via a 1,4-addition of peroxide to
afford the corresponding R,â-epoxy carboxylic acid imidazolides,
which were spontaneously converted into the R,â-epoxy peroxy-
carboxylic acid tert-butyl esters. In addition, efficient further
transformations of R,â-epoxy peroxycarboxylic acid tert-butyl
esters into R,â-epoxy esters, amides, aldehydes, and γ,δ-epoxy
â-keto esters are reported.
We recently reported a general and practical catalytic asym-
metric epoxidation of R,â-unsaturated ketones using the La-
BINOL-Ph3AsdO complex 1 generated from La(O-i-Pr)3, BINOL,
and Ph3AsdO in a ratio of 1:1:1.3d With this efficient catalyst,
we examined a catalytic asymmetric epoxidation of ethyl (E)-
cinnamate (2). As a result, 20 mol % of 1 promoted the
epoxidation of 2 to afford 3 in 90% ee, even though the yield
was only 5% after 48 h (Scheme 1). To enhance the reactivity of
the substrate, we examined more reactive R,â-unsaturated esters,
such as p-nitrophenyl ester, pentafluorophenyl ester, and so forth,
as substrates. In these cases, however, only transesterification
occurred to afford 7a, which remained unchanged in the reaction
medium. We then used an activated R,â-unsaturated amide as a
substrate. Carboxylic acid imidazolides are widely used in organic
synthesis, mainly as acylation reagents.6 In contrast to the great
success of N-acyloxazolidinones in asymmetric synthesis,7 N-
acylimidazoles (carboxylic acid imidazolides) have not yet been
used in an asymmetric reaction as a substrate, perhaps because
of their high reactivity at the carbonyl carbon toward nucleophiles.
Despite the above-mentioned negative factors, on the basis of
our preliminary molecular orbital calculations, we assumed that
the exchange of alcohol for imidazole would decrease the energy
of the lowest unoccupied molecular orbital (LUMO),8 and a soft
nucleophile might then attack at the â-carbon in preference to
the carbonyl carbon. Thus, we investigated a catalytic asymmetric
epoxidation using cinnamic acid imidazolide (4a) as a representa-
tive starting material. As we expected, the epoxidation of 4a
successfully proceeded by using the La-BINOL-Ph3AsdO
complex 1 (20 mol %, rt, 4 h) to afford 5a in high yield,9 which
was directly converted to 6a (86%, 91% ee) by the addition of
methanol to the reaction, with 7a (5-10%). During the reaction,
8a was not detected on thin-layer chromatography. In addition,
7a was not converted to 5a under the same conditions. These
findings suggest that the epoxidation of 4 proceeded in preference
to the transesterification to afford 8a, which was spontaneously
converted to 5a.
Next, we investigated the effect of different cinnamic acid
amides 4a-h in the reaction, again using 20 mol % of 1 as a
catalyst. As shown in Table 1, 4-phenylimidazolide 4e, which
has a lower LUMO energy than that of imidazolide 4a,10 gave
the best result in terms of reactivity, chemical yield, and
enantiomeric excess (1 h, 91%, 94% ee). In this case, only a trace
amount of 7a was obtained. These results indicated that 4-phen-
ylimidazolide effectively enhanced the reactivity at the â-carbon
toward the soft nucleophile.
Having succeeded in developing an efficient catalytic asym-
metric synthesis of 6a from 4e, we further examined the scope
and limitation of different substrates.11 This newly developed
system had a broad generality for epoxidations of various R,â-
unsaturated carboxylic acid 4-phenylimidazolides to afford the
(1) For a recent review, see: Porter, M. J.; Skidmore, J. Chem. Commun.
2000, 1215.
(2) For recent examples, see: (a) Nemoto, T.; Ohshima, T.; Shibasaki, M.
Tetrahedron Lett. 2000, 41, 9569. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett.
1999, 1, 1287. (c) Carde, L.; Davies, H.; Geller, T. P.; Roberts, S. M.
Tetrahedron Lett. 1999, 40, 5421.
(3) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1997, 119, 2329. (b) Watanabe, S.; Kobayashi, Y.; Arai, T.;
Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7353.
(c) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. J. Org.
Chem. 1998, 63, 8090. (d) Nemoto, T.; Ohshima, T.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725.
(4) Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E. Tetrahedron
1994, 50, 4323.
(5) (a) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621. (b) Wang,
Z. X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 1999, 64, 6443.
(c) Solladie´-Cavallo, A.; Boue´rat, L. Org. Lett. 2000, 2, 3531.
(6) For an example, see: Page, P. C. B.; Gareh, M. T.; Porter, R. A.
Tetrahedron Lett. 1993, 34, 5159 and references therein.
(7) For a review, see: Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica
Acta 1997, 30, 3.
(8) Using semiempirical molecular orbital calculation (AM1), the energy
of LUMO of 2 is calculated to be -0.64902 eV, whereas that of 4a and 4h
is 8.9 and 5.0 kcal/mol lower, respectively.
(9) The peroxy ester 5a can be isolated in 86% yield, which is stable for
at least one month under air at room temperature.
(10) The energy of LUMO of the 4-phenylimidazolide4e is calculated to
be 0.9 kcal/mol lower than that of the imidazolide 4a.
(11) When 10 mol % of 1 was used, decane solution of TBHP gave a
better result (Table 2, entry 1) than toluene solution (3.5 h, 90%, 89% ee) in
terms of selectivity. Thus, decane solution of TBHP was used for further
examinations.
10.1021/ja0164879 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/28/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9475
Table 1. Catalytic Asymmetric Epoxidation of Various Cinnamic
Acid Amides 4a-h Using La-(S)-BINOL-Ph3AsdO Complex 1
Table 2. Catalytic Asymmetric Epoxidation of Various
R,â-Unsaturated Carboxylic Acid 4-Phenylimidazolides
a Isolated yield. b Determined by HPLC analysis. c 5 mol % of the
catalyst was used. d 4-Methylimidazolide was used due to the low
solubility of the corresponding 4-phenylimidazolide. e Isolated yield of
the corresponding peroxycarboxylic acid tert-butyl ester. Addition of
methanol to the reaction gave the corresponding methyl ester in similar
yield. f ee was determined after conversion to the corresponding
4-methoxybenzyl ester.
a Isolated yield. b Determined by HPLC analysis.
corresponding epoxides 6a,i-q (Table 2). When 10 mol % of 1
was used at room temperature, all reactions proceeded to
completion in reasonable reaction times (1-6 h). In the case of
4e, even 5 mol % of 1 promoted the reaction efficiently to give
6a (yield 73%, 85% ee, entry 2). Other cinnamic acid derivatives,
which have an electron-withdrawing group (entry 3, 4) or an
electron-donating group (entry 5) on the aromatic ring, were
smoothly epoxidized to afford 6i,j or 6k in good enantiomeric
excesses (89-93% ee). The epoxide 6k is a key intermediate for
one of the most potent calcium antagonists: diltiazem (Her-
besser).12 This asymmetric catalyst system was also effective for
the â-alkyl-substituted R,â-unsaturated carboxylic acid-type sub-
strates with higher reactivity than the cinnamic acid-type substrates
(entry 6-11). Both primary (entry 6-10) and secondary (entry
11) alkyl-substituted substrates gave the products in high yields
(72-93%) with good enantiomeric excesses (79-88% ee).
Particularly noteworthy is that this reaction was applicable to
substrates that were functionalized with a C-C double bond (entry
7-9) or a ketone (entry 10), without any overoxidation. To the
best of our knowledge, this is the first example of a general
catalytic asymmetric epoxidation of R,â-unsaturated carboxylic
acid derivatives.
Finally, the usefulness of the intermediate 5 was further
demonstrated (Scheme 2). The isolated peroxy ester 5a9 was
converted not only to the R,â-epoxy ester 6a (89%) but also to
the R,â-epoxy amide 9 (92%), the aldehyde 10 (70%), and the
γ,δ-epoxy â-keto ester 11 (77%) by addition of lithium methoxide,
lithium amide, Red-Al, and lithium ester enolate, respectively,
without any epoxide ring-opening reactions.13
In conclusion, we developed the first catalytic enantioselective
synthesis of R,â-unsaturated carboxylic acid derivatives with
broad generality via a 1,4-addition of peroxide using the R,â-
unsaturated carboxylic acid 4-phenylimidazolide as a substrate
Scheme 2. Conversion of 5a to R,â-Epoxy Ester 6a, Amide
9, Aldehyde 10, and γ,δ-Epoxy â-Keto Ester 11
and the novel La-BINOL-Ph3AsdO complex 1 as a catalyst.
The intermediates: the R,â-epoxy peroxycarboxylic acid tert-
butyl esters 5 were efficiently converted to the chiral R,â-epoxy
esters, the amide, the aldehyde, and the γ,δ-epoxy â-keto ester.
The described method renders functionalized enantiomerically
enriched R,â-epoxy carboxylic acid derivatives readily available.
Further investigation concerning the development of a catalyst
with higher activity, the clarification of the reaction mechanism,
and applications to a catalytic asymmetric synthesis of biologically
active compounds is ongoing.
Acknowledgment. Financial support was provided by CREST, The
Japan Science and Technology Corporation (JST), and RFTF of Japan
Society for the Promotion of Science.
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) For a recent example, see: Imashiro, R.; Kuroda, T. Tetrahedron Lett.
2001, 42, 1313 and references therein.
(13) Isolation of 5 is essential for the synthesis of 9, 10, and 11.
JA0164879