Catalytic asymmetric epoxidation of α,β-unsaturated amides: Efficient synthesis of β-aryl α-hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation - Pd-catalyzed epoxide opening process

Article abstract of DOI:10.1021/ja028454e

The catalytic asymmetric epoxidation of α,β-unsaturated amides using Sm-BINOL-Ph₃As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding α,β-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of β-aryl α-hydroxy amides, including β-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity. Copyright

Full text of DOI:10.1021/ja028454e

Published on Web 11/13/2002
Catalytic Asymmetric Epoxidation of r,â-Unsaturated Amides: Efficient
Synthesis of â-Aryl r-Hydroxy Amides Using a One-Pot Tandem Catalytic
Asymmetric Epoxidation-Pd-Catalyzed Epoxide Opening Process
Tetsuhiro Nemoto, Hiroyuki Kakei, Vijay Gnanadesikan, Shin-ya Tosaki, Takashi Ohshima, and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received September 7, 2002
Table 1. Catalytic Asymmetric Epoxidation of R,â-Unsaturated
Amides
Catalytic asymmetric epoxidation of R,â-unsaturated amides
provides chiral R,â-epoxy amides that can be converted into useful
chiral building blocks such as R-hydroxy amides and â-hydroxy
amides. To date, catalytic asymmetric epoxidation of enones1 and
R,â-unsaturated esters2 have been intensively studied. There are
no reports, however, of catalytic asymmetric epoxidation of R,â-
unsaturated amides,3 perhaps due to the lower reactivity. We report
a general and highly enantioselective epoxidation of R,â-unsaturated
amides promoted by chiral lanthanide catalysts. In addition, a one-
pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide
opening process was demonstrated. This process leads to the
efficient synthesis of â-aryl R-hydroxy amides.
We previously reported that alkali-metal free lanthanide-BINOL
complexes, in particular La-BINOL-Ph3AsdO complex 1, were
very useful catalysts for the asymmetric epoxidation of enones4a,b
and R,â-unsaturated imidazolides.4c Although catalytic asymmetric
epoxidation of R,â-unsaturated esters proceeded very sluggishly
with the use of 10 mol % of 1, R,â-unsaturated amides were
epoxidized more smoothly under the same conditions.5 This result
prompted us to optimize the reaction conditions.6 The effect of the
central metal and the amount of TBHP were investigated in detail
using 2a. Sm-(S)-BINOL-Ph3AsdO complex 4, generated from
Sm(O-i-Pr)3, (S)-BINOL, and Ph3AsdO in a ratio of 1:1:1, was
found to be the best catalyst for this reaction and 1.2 equiv of TBHP
to 2a gave the best reactivity (condition A). The scope and
limitations using numerous substrates was further examined. As
shown in Table 1, this catalytic system had a broad generality for
epoxidations of various amides 2a-o. When 5-10 mol % of 4
was used, â-alkyl-substituted amides 2a-j, prepared from primary
amines (entries 1, 2, 4-6, 11-13), R-branched primary amines
(entries 7, 8), and secondary amines (entries 9, 10), were smoothly
epoxidized to afford the corresponding R,â-epoxy amides in
excellent yield and in excellent enantiomeric excess. This was also
effective for the epoxidation of â-aryl-substituted amides 2k-o.
In these cases, activation of MS 4A was necessary to improve the
lower reactivity, but there was a slight decrease in enantiomeric
excess (condition B). In addition, Sm-(S)-BINOL-Ph3PdO
complex 5 was found to be also effective, yielding the products
with slightly lower selectivity (entries 3, 16).7,8 To the best of our
knowledge, this is the first example of a general catalytic asym-
metric epoxidation of R,â-unsaturated amides.
a Conditions A: TBHP in decane was used. MS 4A was not dried.
Conditions B: TBHP in toluene was used. MS 4A was dried for 3 h at 180
°C under reduced pressure. b Isolated yield. c Determined by HPLC analysis.
d 5 mol % of 4 was used. e Ph3PdO (30 mol %) was used as an additive.
f Dy was used as a central metal. g cHex ) cyclohexyl.
epoxidation-Pd-catalyzed epoxide opening process.9 Key to the
success of this sequential process is whether the second catalysis
is compatible with the conditions of the first epoxidation. Therefore,
we first performed experiments to examine the influence of the
constituents of the first reaction on the second catalysis (Table 2).6
With the use of 5 mol % of Pd-C, an epoxide opening reaction of
3k was investigated as a model reaction. In the absence of additives,
the reaction proceeded smoothly, giving rise to a mixture of three
compounds, 6k, 7k, and 8k in a ratio of 100:6:3. On the other hand,
when the reaction was performed in the presence of 5,10 the
formation of 7k was completely prevented, whereas there was a
significant increase in the formation of 8k. The formation of both
7k and 8k was successfully depressed in the reaction conditions
including all of the reagents for the first epoxidation, affording 6k
with excellent selectivity (100:0:1). This finding suggests that
beneficial modifications of the Pd catalyst are achieved by the
Optically active â-aryl R-hydroxy amides are biologically
important structural units and can be easily synthesized from â-aryl
R,â-epoxy amides. To achieve efficient transformation, we planned
to develop a new method: a one-pot tandem catalytic asymmetric
* To whom correspondence should be addressed. E-mail: mshibasa@
mol.f.u-tokyo.ac.jp.
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J. AM. CHEM. SOC. 2002, 124, 14544-14545
10.1021/ja028454e CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. One-Pot Synthesis of 12a and 12b
Table 2. Preliminary Experiments for the Pd-Catalyzed Epoxide
Opening Reaction of 3k
time yielda
ratiob
selectivity
entry
additives
(min)
(%)
(6k:7k:8k)
(6k/7k + 8k)
1
2
3
4
60
10
90
60
100 100:6:3
100 100:8:2
100 100:0:23
100 100:0:1
11
10
4
MeOHc
(S)-5 (10 mol %)
(S)-5 (10 mol %),
MS 4A, TBHP (0.2 equiv),
MeOHc
100
a Conversion yield. b The ratio was determined by 1H NMR analysis of
the crude sample. c Solvent ratio: THF/MeOH ) 2/1.
b
1
a Determined by HPLC analysis. Determined by H NMR analysis.
Table 3. One-Pot Tandem Catalytic Asymmetric
Epoxidation-Pd-Catalyzed Epoxide Opening Process
In summary, the catalytic asymmetric epoxidation of R,â-
unsaturated amides with broad generality was developed. Moreover,
this reaction was successfully applied to the synthesis of â-aryl
R-hydroxy amides using a novel one-pot tandem process. Further
studies are currently under investigation in our group.
Acknowledgment. Financial support was provided by RFTF
of Japan Society for the Promotion of Sciences. T. Nemoto thanks
the Japan Society for the Promotion of Science (JSPS) for a research
fellowship.
substrate
time (h)
step A step B yield (%) eed (%)
1
2
3
c
entry
R
NR R
1
2
3
4
5
Ph
Ph
Ph
CH3NH
BnNH
(CH3)2N 2m
2k
2l
21
16
11
18
18
2
2
2
2
2
97
91
97
98
89e
90
99e
99
Supporting Information Available: Experimental procedures and
characterization of the products; other detailed results and discussion
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
4-F-C6H4
CH3NH
2n
2o
4-Me-C6H4 CH3NH
82
97
a Conditions: (S)-5 (10 mol %), TBHP in toluene (1.2 equiv), MS 4A
(dried), THF, room temperature. b Conditions: Pd-C (5 mol %), H2 (1
atm), MeOH (solvent ratio: THF/MeOH ) 2/1). c Isolated yield. d Deter-
mined by HPLC analysis. e Yield and ee were determined after converting
into the corresponding triethylsilyl ether.
References
(1) For a recent review, see: Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Synth.
Org. Chem. Jpn. 2002, 60, 94.
(2) (a) Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E. Tetrahedron
1994, 50, 4323. (b) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998,
621. (c) Soladie´-Cavallo, A.; Boue´rat, L. Org. Lett. 2000, 2, 3531. (d)
Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792.
(3) Recently, asymmetric synthesis of R,â-epoxy amides using a highly
enantioselective Darzens reaction of a camphor-derived sulfonium amide
was reported, see: Aggarwal, V. K.; Hynd, G.; Picoul, W.; Vasse, J.-L.
J. Am. Chem. Soc. 2002, 124, 9964.
constituents of the first epoxidation, producing a more suitable
catalyst for the second epoxide opening reaction.
One-pot tandem reactions were further examined using 2k-o
as substrates (Table 3). After completion of the epoxidation, both
5 mol % of Pd-C and MeOH were directly added to the reaction
mixture and the resulting mixture was stirred under a hydrogen
atmosphere. As expected, the sequential process functioned ef-
ficiently, affording the corresponding 6k-o in excellent overall
yield and in enentiomeric excess. The fact that 6k was obtained in
97% ee indicates that no racemization occurred in this tandem
process.
(4) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1997, 119, 2329. (b) Nemoto, T.; Ohshima, T.;
Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725, and
references therein. (c) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9474.
(5) Preliminary experiments suggested that unfavorable complexation between
the catalyst and R,â-unsaturated ester might occur, resulting in decreased
in the catalyst activity. See Supporting Information for the data.
(6) See Supporting Information for details.
(7) Daikai, M.; Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39, 7321.
(8) Absolute configurations of 3a-b, 3f, and 3j-m were determined to be
2R,3S. For the detailed data, see the Supporting Information.
(9) For recent examples of tandem catalytic processes, see: (a) Jeong, N.;
Seo, S.-D.; Shin, J.-Y. J. Am. Chem. Soc. 2000, 122, 10220. (b) Yamasaki,
S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256. (c) Evans,
P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609. (d) Louie, J.;
Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312.
(e) Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. Angew.
Chem., Int. Ed. 2001, 40, 4620. (f) Bandini, M.; Cozzi, P. G.; Giacomini,
M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67,
3700.
(10) Addition of Ph3AsdO retarded the epoxide opening reaction.
(11) (a) Grimmelikhuijzen, C. J. P.; Rinehart, K. L.; Jacob, E.; Graff, D.;
Reinscheid, H.-P.; Staley, A. L. Proc. Natl. Acad. Sci. U.S.A. 1990, 87,
5410. (b) Ishida, K.; Okita, Y.; Matsuda, H.; Okino, T.; Murakami, M.
Tetrahedron 1999, 55, 10971.
â-Aryllactyl-Leu sequences are found in various biologically
active peptides.11 The developed process can be utilized for the
construction of these dipeptide fragments. Unfortunately, catalytic
asymmetric epoxidation of N-cinnamoyl L-leucine methyl ester 9
did not proceed at all. However, tandem catalytic asymmetric
epoxidation of the R,â-unsaturated imidazolides-peptide coupling-
Pd-catalyzed epoxide opening process made these fragments easily
accessible in a single pot reaction. After completion of the first
epoxidation of 10 using (S)- or (R)-La-BINOL-Ph3PdO complex
11, 1.5 equiv of L-leucine methyl ester was added and the reaction
was stirred for 48 h in the presence of hexafluoroacetone.12 Finally,
a Pd-catalyzed epoxide opening reaction was performed sequentially
to provide the desired fragments 12a and 12b in optically pure
forms, which can be utilized for the synthesis of a neuropeptide,
Antho-RNamide 13 (Scheme 1).11a
(12) Even with use of 3 equiv of L-leucine methyl ester, the peptide coupling
reaction did not complete in 8 d in the absence of hexafluoroacetone. For
the detailed data and discussion, see the Supporting Information.
JA028454E
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J. AM. CHEM. SOC. VOL. 124, NO. 49, 2002 14545