Asymmetric epoxidation of α-substituted acroleins catalyzed by diphenylprolinol silyl ether

Article abstract of DOI:10.1021/ol102269s

Asymmetric epoxidation of α-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether to afford α-substituted-β,β-unsubstituted-α,β-epoxy aldehyde with excellent enantioselectivity and the generation of

Full text of DOI:10.1021/ol102269s

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5434-5437
Asymmetric Epoxidation of
r-Substituted Acroleins Catalyzed by
Diphenylprolinol Silyl Ether
Bojan P. Bondzic, Tatsuya Urushima, Hayato Ishikawa, and Yujiro Hayashi*
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received September 21, 2010
ABSTRACT
Asymmetric epoxidation of r-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether
to afford r-substituted-ꢀ,ꢀ-unsubstituted-r,ꢀ-epoxy aldehyde with excellent enantioselectivity and the generation of a chiral quaternary carbon
center. The method was applied to a short synthesis of (R)-methyl palmoxirate.
Epoxide is a synthetically important functional group, and there
are several methods for preparation of chiral epoxides from the
corresponding alkene via asymmetric epoxidation reactions.1
For instance, Katsuki-Sharpless epoxidation of allyl alcohols2
and manganese-salen complex-mediated epoxidation reported
independently by Jacobsen and Katsuki3 are well-known
methods catalyzed by organometallic reagents.
derived organocatalyst,5 while a pyrrolidine-based catalyst
was utilized by Aggarwal.6 Chiral iminium salt7 and chiral
tripeptide8 were also used as efficient organocatalysts.
Organocatalysts are also effective in nucleophilic epoxidation
reactions. ꢀ-Substituted acrolein is enantioselectively epoxi-
dized by diarylprolinol silyl ether,9 chiral phosphoric amine
salt,10 and diphenylfluoromethylpyrrolidine,11 while the
In recent years, organocatalysis has been developing very
rapidly,4 and several excellent epoxidation reactions cata-
lyzed by organocatalysts have been developed. For electro-
philic epoxidation, Shi developed a reaction using a sugar-
(4) For selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Asymmetric Organocatalysis;
Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005. (c) Hayashi,
Y. J. Synth. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun.
2006, 819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001.
(f) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug
DiscoVery Today 2007, 12, 8. (g) EnantioselectiVe Organocatalysis; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim, 2007. (h) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (i) Walji, A. M.;
MacMillan, D. W. C. Synlett 2007, 1477. (j) MacMillan, D. W. C. Nature
2008, 455, 304. (k) Barbas, C. F. III. Angew. Chem., Int. Ed. 2008, 47, 42.
(l) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (m)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int.
Ed. 2008, 47, 6138. (n) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. ReV.
2009, 38, 2178.
(1) (a) Johnson, R. A.; Sharpless, K. B. Asymmetric methods of
epoxidation in ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 7, pp 389-437. (b)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: New York, 1999. (c) Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley: New York, 2000.
(2) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
For reviews, see: (a) Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 103-158.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
(3) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L.
J. Am. Chem. Soc. 1991, 113, 7063. (b) Irie, R.; Noda, K.; Ito, Y.;
Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345. (c) For a
review, see: Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, 1993; pp 159-202.
(5) (a) Wang, Z.-X.; Tu, W.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224 Review, see. (b) Frohn, M.; Shi, Y. Synthesis
2000, 14, 1979. (c) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(6) Adamo, M. F. A.; Aggarwal, V. A.; Sage, M. A. J. Am. Chem. Soc.
2000, 122, 8317.
10.1021/ol102269s  2010 American Chemical Society
Published on Web 11/04/2010

epoxidation of R,ꢀ-unsaturated ketone is catalyzed by
diphenylprolinol,12 amino alcohol,13 and guanidine-based
catalysts.14
Table 1. Effects of Organocatalysts and Solvents in Epoxidation
Reactionsa
Among the epoxides, R-substituted-ꢀ,ꢀ-unsubstituted-R,ꢀ-
epoxyaldehyde is a synthetically useful chiral building block
possessing a quaternary carbon center because ꢀ,ꢀ-unsub-
stituted epoxide reacts readily with several nucleophiles in
a regio- and stereocontrolled manner. One of the most
straightforward methods for its preparation is asymmetric
epoxidation of R-substituted acroleins. In contrast to the
several successful epoxidation reactions of ꢀ-substituted
acroleins catalyzed by organocatalysts, asymmetric epoxi-
dation of R-substituted acroleins is a synthetic challenge.
Moreover, the asymmetric reaction of R-acroleins via orga-
nocatalyst is a difficult reaction.15
Diarylprolinol silyl ether, developed independently by our
group16 and Jørgensen’s group,17 is an effective organocata-
lyst,18 while Jørgensen and co-workers developed the ep-
oxidation of ꢀ-substituted acroleins catalyzed by diarylpro-
linol silyl ether substituted with trifluoromethyl groups.9a,b
Pihko and co-workers applied the same catalyst to epoxi-
dation of R-benzylacrolein and observed no reaction.19
However, our continuous interest in diphenylprolinol silyl
ether led us to the successful asymmetric epoxidation reaction
of R-substituted acroleins, which will be described in this
communication. While this manuscript was in preparation,
List and co-workers reported an excellent asymmetric
epoxidation of R-substituted acroleins with a wide generality,
in which a cinchona alkaloid-derived primary ammonium
salt in combination with a chiral phosphoric acid counterion
is an effective catalyst.20
entry
catalyst
solvent
conv/%b
yield/%c
ee/%d
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
4
4
4
4
4
4
4
4
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
CH3CN
Et2O
MeOH
toluene
hexane
neat
2
55
53
53
26
<10
36
58
21
<10
57
nd
35
32
34
23
nd
32
55
nd
nd
45
37
44
65
70
72
nd
67
76
80
40
nd
78
87
nd
nd
84
80
86
94
88
94
9
10
11
12
13
14
15e
16f
47
63
85
90
hexane
>90
a Reaction conditions: 2-methylenenonanal (0.5 mmol), H2O2 (30% in
water, 1.5 mmol), catalyst (0.05 mmol), and solvent (0.5 mL) at room
temperature for 48 h. See the Supporting Information for details. nd ) not
determined. b Determined by 1H NMR spectroscopy. c Isolated yield after
column chromatography. d ee was determined by chiral phase HPLC analysis.
e Reaction run without organic solvent. f The catalyst 4 was employed in 20
mol % and the reaction time is 6 h. Product is isolated as aldehyde.
When trimethylsilyl ether was employed, moderate enanti-
oselectivity (67% ee) was obtained (entry 2). The presence
of bulkier tert-butyldimethylsilyl (TBS) ether in catalyst 3
led to greater enantioselectivity, while similar reactivity was
maintained. Further increasing the bulkiness of the silyl ether
moiety increased the enantioselectivity, and good selectivity
was obtained when diphenylmethylsilyl ether catalyst 4 was
employed.21 In contrast to silyl ethers, methyl ether gave
low enantioselectivity (entry 5). Trifluoromethyl-substituted
diarylprolinol trimethylsilyl ether gave good enantioselec-
We chose 2-methylenenonanal as a model R-substituted
acrolein and investigated the reaction in the presence of 10
mol % of various organocatalysts (Figure 1) using aqueous
(11) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew.
Chem., Int. Ed. 2009, 48, 3065.
(12) (a) Lattanzi, A. Org. Lett. 2005, 7, 2579. (b) Lattanzi, A. Chem
Commun. 2009, 1452. (c) Russo, A.; Lattanzi, A. Synthesis 2009, 9, 1551.
(13) Lu, J.; Xu, Y.-H.; Liu, F.; Loh, T.-P. Tetrahedron Lett. 2008, 49,
6007.
Figure 1. Organocatalysts examined in this study.
(14) Tanaka, S.; Nagasawa, K. Synthesis 2009, 4, 667.
(15) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
(b) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930. (c)
Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7892.
H2O2 (30%) as an oxidant (Table 1). Although diphenyl-
prolinol 1 and diarylprolinol 6 did not promote the reaction
(entries 1 and 6), their silyl ethers showed catalytic activity.
(16) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 4212.
(7) (a) Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett. 2004, 6,
1543. (b) Page, P. C. B.; Buckley, B. R.; Farah, M. M.; Blacker, A. J. Eur.
J. Org. Chem. 2009, 3413.
(17) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Marigo, M.; Fielenbach, D.;
Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005,
44, 3703.
(8) Peris, G. C. E.; Jakobsche, S.; Miller, J. J. Am. Chem. Soc. 2007,
129, 8710.
(18) For reviews, see: (a) Palomo, C.; Mielgo, A. Angew. Chem., Int.
Ed 2006, 45, 7876. (b) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3,
922.
(9) (a) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Zhuang, W.; Marigo, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 3883. (c) Sunden, H.;
Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2006, 47, 99. (d) Zhao, G.-L.;
Ibrahem, I.; Sunden, H.; Cordova, A. AdV. Synth. Catal. 2007, 349, 1210.
(10) Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119.
(19) Erkkila, A.; Pihko, P. M.; Clarke, M.-R. AdV. Synth. Catal. 2007,
349, 802.
(20) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010,
132, 10227.
Org. Lett., Vol. 12, No. 23, 2010
5435

tivity but was slightly less reactive compared with diphe-
nylprolinol catalysts (entry 7).
Table 2. Generality of the Asymmetric Epoxidation Reaction of
R-Substituted Acroleinsa
Next, the effect of the solvent was investigated, and the
results are summarized in Table 1. In polar aprotic solvents
such as THF and CH3CN, the reaction scarcely proceeded
even though the reaction is homogeneous. In other solvents
such as CH2Cl2, CHCl3, MeOH, and toluene, the reaction
proceeded in all cases, affording the desired epoxide with
good enantioselectivity, although yields were dependent on
the solvent. Among the solvents examined, the best selectiv-
ity was obtained when the reaction was performed in hexane,
a highly nonpolar solvent, affording the product in 65% yield
and 94% ee (entry 14). The reaction proceeds in neat
conditions as well, but a slight decrease in enantioselectivity
was observed (entry 15). When 20 mol % of catalyst 4 was
employed, the reaction was completed within 6 h, and a good
yield (72%) was obtained with excellent enantioselectivity.
The reaction proceeds in a two-phase system. The R,ꢀ-
unsaturated iminium ion, which possesses both hydrophilic
and hydrophobic properties, would exist on the interface of
organic and water phases, where it reacts with H2O2
efficiently to afford the product in good yield.
The effect of additives was also tested, as additives can
beneficially influence rate, selectivity, and yield in some
diarylprolinol-catalyzed reactions.22 However, we could not
observe any positive effect of either acid or base additives
such as PhCO2H, p-NO2PhCO2H, ClCH2CO2H, p-NO2PhOH,
and NaHCO3.
After determining the best reaction conditions, the general-
ity of the reaction was investigated, and the results are
summarized in Table 2. In addition to 2-methylenenonanal,
2-methylenehexadecanal is also an effective substrate to
afford the epoxide with good yield and excellent enantiose-
lectivity (entries 1 and 2). R-Benzyl and R-(3-phenylpropyl)
acroleins react with H2O2 to provide the epoxide in 86 and
87% ee, respectively (entries 3 and 4). Acroleins with alkynyl
substituents at the R-position are also suitable substrates,
affording the product with excellent enantioselectivity, in
which the base-sensitive trimethylsilyl acetylene moiety
remains intact under the present reaction conditions (entries
5 and 6). When substrates possessing two alkenes, such as
one substituted with the formyl group and the other with
the terminal or internal double bond, are employed, the
reaction only proceeds efficiently with the formyl-substituted
alkene, providing the R,ꢀ-epoxy aldehyde with excellent
enantioselectivity (entries 7 and 8). For substrates possessing
both R-substituted acrolein and R,ꢀ-unsaturated ester moi-
eties, only the former moiety reacts to afford the monoep-
oxide with good enantioselectivity (entry 9).
a Unless otherwise shown, reaction conditions: R-substituted acrolein
(0.5 mmol), H2O2 (30% in water, 1.5 mmol), catalyst 4 (0.1 mmol), hexane
(0.5 mL) at room temperature for a designated time. b Isolated yield of the
product. c ee was determined by chiral phase HPLC analysis. See the
Supporting Information for details. d Isolated as alcohol after NaBH4
reduction (2 steps). e The determination of the absolute configuration. See
the Supporting Information. f Catalyst 4 was employed in 10 mol %.
Scheme 1. Enantioselective Synthesis of (R)-Methyl Palmoxirate
The present epoxidation was applied to enantioselective
synthesis of (R)-methyl palmoxirate (Scheme 1), a potent
oral hypoglycemic and antiketogenic agent in mammals
(21) Groselj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck,
A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. HelV. Chim. Acta
2009, 92, 1225.
including humans.23,24 2-Methylenehexadecanal was treated
with H2O2 in the presence of (R)-diphenylprolinol silyl ether
ent-4, derived from unnatural D-proline, to afford the desired
(22) See for instance: (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2007, 9, 5307. (b) Hayashi, Y.; Okano, T.; Itoh, T.; Urushima, T.;
Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed. 2008, 47, 9053. (c)
Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854.
5436
Org. Lett., Vol. 12, No. 23, 2010

epoxide in 78% yield with excellent enantioselectivity (92%
ee). Kraus oxidation followed by treatment with TMSCHN2
gave (R)-methyl palmoxirate in 81% yield over two steps.
The absolute configuration can be explained by the
following reaction mechanism (Figure 2). There are two
of pyrrolidine. Nucleophilic attack by H2O2 occurs from the
less hindered face of the iminium ion to generate C and D.
The ring-closing reaction for formation of the epoxide
proceeds from D to afford the desired epoxide.
Another possible explanation is as follows. There would
be an equilibrium between s-cis (C) and s-trans (D)
conformers of enamine, and conformer D would be more
stable than C. The ring-closing reaction for the formation of
epoxide proceeds from D to afford the desired epoxide.
The enantio-differential step for the formation of chiral
epoxide is the transformation from intermediates C and D
to the epoxide. There is no clear evidence at this stage
whether kinetically generated D or thermodynamically stable
D would be converted into the epoxide.
In summary, an asymmetric epoxidation of R-substituted
acroleins was catalyzed by diphenylprolinol silyl ether 4
using H2O2 as an oxidant. There are several noteworthy
features in this epoxidation: (1) This is the first successful
application of a secondary amine catalyst for epoxidation of
R-substituted acroleins; (2) excellent enantioselectivity has
been realized; and (3) chiral quaternary carbon centers can
be constructed with excellent enantioselectivity. As R-sub-
stituted-ꢀ,ꢀ-unsubstituted-R,ꢀ-epoxyaldehyde is a very valu-
able chiral building block, the present method would be
synthetically useful for asymmetric synthesis, and an ap-
plication was shown in the short-step synthesis of (R)-methyl
palmoxirate.
Supporting Information Available: Detailed experimen-
tal procedures, full characterization, copies of 1H, 13C NMR,
and IR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102269S
Figure 2
acroleins.
. Reaction mechanism of epoxidation of R-substituted
(23) (a) Tutwiler, G. F.; Kirsch, T.; Mohrbacher, R. J.; Ho, W.
Metabolism 1978, 27, 1539. (b) Verhagen, J.; Leempoels, J.; Brugmans,
J.; Tutwiler, G. F. Diabetes Suppl. 1 1984, 33, 688. (c) Mandarino, L.;
Tsalikian, E.; Bartold, S.; Marsh, H.; Carney, A.; Buerklin, E.; Tutwiler,
G.; Haymond, M.; Rizza, R. J. Clin. Endocrinol. Metab. 1984, 59, 658.
(24) For the enantioselective synthesis of methyl palmoxirate, see: (a)
Ho, W.; Tarhan, O.; Kiorpes, T. C.; Tutwiler, G. F.; Mohrbacher, R. J.
J. Med. Chem. 1987, 30, 1094. (b) Garcia, R. J. L.; Martin, C. A. M.;
Rodriguez, J. H. J. Org. Chem. 1994, 59, 533. (c) Jimenez, O.; Bosch,
M. P.; Guerrero, A. J. Org. Chem. 1997, 62, 3496.
conformers, A and B, in the imine generated from R-sub-
stituted acrolein and catalyst 4. Conformer B would be more
stable than conformer A because of steric repulsion between
the vinylidene C-H and methylene C-H at the 5-position
Org. Lett., Vol. 12, No. 23, 2010
5437