Sequential Wittig olefination-catalytic asymmetric epoxidation with reuse of waste Ph3P(O): Application of α,β-unsaturated N-Acyl pyrroles as ester surrogates

Article abstract of DOI:10.1002/anie.200352509

Waste not, want not: Efficient one-pot access to optically active epoxides with 96 to 99.5% ee from a variety of aldehydes is described. In a sequential process, the Ph3P(O) by-product of a Wittig reaction acts as a modulator for the samarium catalyst in the asymmetric epoxidation of the conjugated N-acyl pyrrole Wittig product (see scheme). The N-acyl pyrrole functionality is key to the high reactivity and selectivity observed. R = alkyl, aryl, vinyl.

Full text of DOI:10.1002/anie.200352509

Communications
Asymmetric Olefination–Epoxidation
Sequential Wittig Olefination–Catalytic
Asymmetric Epoxidation with Reuse of Waste
Ph3P(O): Application of a,b-Unsaturated N-Acyl
Pyrroles as Ester Surrogates**
Tomofumi Kinoshita, Shigemitsu Okada, Sun-
Ryung Park, Shigeki Matsunaga, and
Masakatsu Shibasaki*
The catalytic asymmetric epoxidation of a,b-unsaturated
carbonyl compounds is an important transformation in
organic synthesis.[1] Although we[2] and others[1] have devel-
oped efficient catalytic asymmetric epoxidations of a,b-
unsaturated ketones, there are only limited examples of the
use of a,b-unsaturated esters as substrates with a salen–Mn
complex[3] or a chiral ketone[4] as the catalyst. In both cases,
[*] Prof. Dr. M. Shibasaki, T. Kinoshita, S. Okada, S.-R. Park,
S. Matsunaga
Graduate Schoolof PharmaceuticalSciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by RFTFand a Grant-in-Aid for the
Encouragement of Young Scientists (B) (to S.M.) from the JSPS.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352509
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except for the recent report of Shi and co-workers,[4a] only b-
aryl-substituted a,b-unsaturated esters were used. Although
Shi and co-workers reported excellent results for a few b-
alkyl-substituted substrates, trans-b-alkyl-substituted a,b-
unsaturated esters could not be used, thus leaving room for
improvement in substrate generality. We recently reported
the catalytic asymmetric epoxidation of a,b-unsaturated 4-
phenylcarboxylic acid imidazolides[5,6] and morpholinyl
amides[6] as ester surrogates. Although moderate to high
enantioselectivities were observed for substrates with b-aryl
or b-alkyl substituents (imidazolide: 79–94% ee, amide:
were used, the reaction was complete within 0.5 h and
afforded 2a in 93% yield and with 94% ee (Table 1,
entry 1). The reaction rate was much faster than for a
carboxylic acid imidazolide or a morpholinyl amide, and as
fast as for an enone. The reaction also proceeded smoothly in
the presence of 5 mol% of the catalyst (Table 1, entry 2: 85%
yield, 96% ee). Various binol derivatives were screened in an
attempt to improve the enantioselectivity of the reaction, and
it was found that H8-binol gave the best results. The superior
performance of the H8-binol complex over that of the binol
complex is probably a result of the large bite angle in the
former complex.[12] Compound 2a was formed with 99% ee in
the presence of the novel Sm–(R)-H8-binol complex (Table 1,
entry 3). Ph3P(O) was also an effective additive in the
reaction of substrate 1a[11] (Table 1, entries 4–6). A THF/
toluene solvent mixture led to better results than THF alone,
and 2a was obtained with 96–99% ee, depending on the
amount of Ph3P(O) added (Table 1, entries 7–9). Both the
reaction rate and the selectivity were highest when 100 mol%
of the Ph3P(O) additive was used (Table 1, entry 9). Under
the best conditions (THF/toluene, Ph3P(O) (100 mol%)) the
reaction proceeded smoothly with a low catalyst loading
(1 mol%) to afford 2a in 94% yield and with 99% ee within
0.3 h (Table 1, entry 10). Cumene hydroperoxide (CMHP),
which is less explosive and less reactive than TBHP, could also
be used. The reaction reached completion in the presence of
this oxidant within 0.2 h with 5 mol% of the catalyst (Table 1,
entry 11: 91% yield, > 99.5% ee).[13]
99% ee), from
a practical viewpoint many problems
remained: a) a catalyst loading of 10 mol% was essential
for good conversion, b) explosive tert-BuOOH (TBHP) was
essential as the oxidant for good reactivity, and c) the
preparation of b-alkyl a,b-unsaturated carboxylic acid imida-
zolides from aldehydes was lengthy. To address these issues,
we report herein the application of a,b-unsaturated N-acyl
pyrroles, which were found to be highly reactive and versatile
substrates, as ester surrogates. Furthermore, these substrates
were used in a one-pot sequential Wittig-olefination–cata-
lytic-asymmetric-epoxidation process in which the Ph3P(O)
formed in the Wittig step was reused in the second step. This
process provided efficient access to optically active pyrrolyl
epoxides from a variety of aldehydes in high yields and with
high enantioselectivities. The versatility of the pyrrolyl
epoxide products was also demonstrated.
Although the potential of N-acyl pyrroles as ester
surrogates was reported two decades ago,[7] it was only
recently that the unique reactivity of N-acyl pyrroles was
recognized and utilized in organic synthesis, for example, in
asymmetric catalysis.[8] A recent report by Evans et al.[9] on
the unique properties of N-acyl pyrroles prompted us to
investigate the use of a,b-unsaturated N-acyl pyrroles as ester
surrogates. As summarized in Table 1, the catalytic asymmet-
ric epoxidation of 1a proceeded smoothly. When the Sm–(R)-
binol complex (10 mol%)[10] and Ph3As(O) (10 mol%)[11]
One reason that a,b-unsaturated N-acyl pyrroles have not
been widely used as acceptors in 1,4-addition reactions,
despite their high reactivity, might be the lackof an efficient
method for their preparation under mild conditions.[14]
A
Wittig reaction of the ylide 3 with aldehydes was examined as
a general synthetic approach to a range of functionalized a,b-
unsaturated N-acyl pyrroles. The ylide 3 was synthesized
efficiently in 98% yield in one step from 1,1’-carbonyldipyr-
role and methylenetriphenylphosphorane.[15] The Wittig reac-
tion of 3 with benzaldehyde (4a)
proceeded smoothly to afford 1a in
97% yield, along with a stoichio-
Table 1: Catalytic asymmetric epoxidation of a,b-unsaturated N-acylpyrroel s.
metric amount of waste Ph3P(O)
(Scheme 1).
Although the functional-group
tolerance of the Wittig reaction is
good because of the mild condi-
tions, this olefination is generally
Entry Ligand (mol%)[a] Additive (mol%) Solvent
Oxidant
t [h] Yield [%][b] ee [%][c]
considered to be somewhat ineffi-
cient as a result of the production
of Ph3P(O) as a by-product. We
hypothesized that the reuse of
waste Ph3P(O) in the epoxidation
reaction as a modulator for the
Sm–H8-binol complex would parti-
ally compensate this disadvantage
of the Wittig reaction. Thus, a
sequential Wittig olefination–cata-
lytic asymmetric epoxidation was
designed in which the Ph3P(O)
produced in the first (Wittig) reac-
1
2
3
4
5
6
7
8
binol(10)
binol(5)
Ph 3As(O) (10)
Ph 3As(O) (5)
Ph 3As(O) (5)
Ph 3P(O) (15)
Ph 3P(O) (50)
Ph 3P(O) (100)
Ph 3P(O) (15)
Ph 3P(O) (50)
Ph 3P(O) (100)
Ph 3P(O) (100)
Ph 3P(O) (100)
THF
THF
THF
THF
THF
THF
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
0.5
0.5
0.5
0.5
0.5
0.5
0.4
0.5
0.2
0.3
0.2
93
85
94
84
88
85
85
92
97
94
91
94
96
99
94
98
97
96
99
99
H8-binol(5)
H8-binol(5)
H8-binol(5)
H8-binol(5)
H8-binol(5)
H8-binol(5)
H8-binol(5)
H8-binol(1)
H8-binol(5)
THF/toluene TBHP
THF/toluene TBHP
THF/toluene TBHP
THF/toluene TBHP
THF/toluene CMHP
9
10
11
99
>99.5
[a] Sm(OiPr)3/ligand 1:1. [b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
phase.
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this system is also superior to previous results with carboxylic
acid imidazolides[5,6] and morpholinyl amides,[6] which were
synthesized and purified prior to use.
As summarized in Table 2, the sequential reaction descri-
bed herein has broad substrate generality and affords the
desired epoxides with excellent enantioselectivities (96 to
> 99.5% ee) and in good yields (Table 2, entries 1–13: 72–
96% yield from the corresponding aldehydes). Aromatic
aldehydes with various substituents (Table 2, entries 1–7),
functionalized aliphatic linear and branched aldehydes
(Table 2, entries 8–12), and a,b-unsaturated aldehydes
(Table 2, entry 13) were all suitable substrates. The reaction
proceeded chemoselectively with the aldehyde 4l, which
contains a methyl ketone (Table 2, entry 12). In many
examples, less explosive CMHP was used as the oxidant
instead of TBHP, which demonstrates an additional practical
benefit of this methodology. When the chiral aldehyde 4n was
used, the sequential reaction proceeded in an almost com-
Scheme 1. Synthesis of the ylide 3 and Wittig reaction.
tion was reused as an additive in the second (epoxidation)
reaction. When 4a was subjected to this olefination–epox-
idation sequence, 2a was produced in 96% yield (two steps)
and with 99.8% ee (Scheme 2a). As expected, the selectivity
and reactivity were much lower when the reaction was
performed in two separate steps and no Ph3P(O) was added in
the second step (75.2% ee,
Scheme 2b).
When
Ph3P(O)
Table 2: Sequential Wittig olefination–catalytic asymmetric epoxidation with achiral aldehydes.
(15 mol% or 50 mol%) was
added in the second step after
isolation of intermediate 1a and
removal of the Ph3P(O) by-product
(1 equiv) as waste, 2a was obtained
with 96.8% ee or 98.8% ee, respec-
tively (Scheme 2b). These results
suggested that Ph3P(O) did indeed
function as an effective additive to
improve the yield and enantiose-
lectivity of the epoxidation reac-
tion, but that only 0.5–1 equivalent
of Ph3P(O) was required to pro-
mote high enantioselectivity. The
fact that only one purification step
was required in the one-pot process
(Scheme 2a), in contrast to the two
required in the reaction sequence
in Scheme 2b, clearly shows the
higher total efficiency of the one-
pot sequential process for the syn-
thesis of the epoxide 2a from the
aldehyde 4a. The total efficiency of
Wittig reaction
Epoxidation
t [h]
Entry
R
T [8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
C6H5-
p-Me-C6H4-
p-Cl-C6H4-
p-MeO-C6H4-
o-ClC6H4-
2-naphthyl
1-naphthyl
C6H5CH2CH2-
PMBOCH2CH2-
4a
4b
4c
4d
4e
4 f
4g
4h
4i
100
100
100
110
100
100
100
80
48
48
24
84
24
48
48
24
24
25
72
36
72
0.5
2.5
0.5
0.5
0.5
2
0.5
0.5
0.5
0.5
2
96
92
100
87
83
100
85
84
91
82
75
>99.5
99
99
98
97
99
99
97
97
96
98
96
96
4[c]
5[c]
6
7
8
9
80
=
10
11
12
13[c,d]
CH2 CH(CH2)8-
4j
4k
4l
100
100
80
c-C6H11
CH3C(O)CH2CH2-
trans-CH3(CH2)2CH CH-
0.5
2
93
72
=
4m
100
[a] Yield of the isolated product 2 (from 4). [b] Determined by HPLC analysis on a chiral phase.
[c] tBuOOH was used as the oxidant. [d] Catalyst: 10 mol%.
Scheme 2. Wittig olefination–catalytic asymmetric epoxidation as a) a one-pot sequential process and b) a stepwise process with isolation of the
Wittig product and addition of externalPh 3P(O).
4682
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pletely catalyst-controlled manner (Scheme 3 and Table 3).
The epoxide was obtained in a 2n/2o ratio of > 99:1 with the
R-configured catalyst (matched pair, Table 3, entry 1) and in a
2n/2o ratio of 1:36 with the S-configured catalyst (mis-
matched pair, Table 3, entry 3). When achiral epoxidation
systems were used, much lower selectivity was observed (d.r.
54:46).[16]
In summary, we have developed a sequential Wittig-
olefination–catalytic-asymmetric-epoxidation process, which
utilizes N-acyl pyrroles as ester surrogates and provides
efficient one-pot access to optically active epoxides. Good
yields and excellent enantioselectivities were observed for a
broad range of aldehyde substrates. The Ph3P(O) produced in
the first step is used to modulate the second step, and CMHP,
which is less explosive and thus more practical than TBHP,
can be used as the oxidant. The reaction of the ylide 3 with
aldehydes proved to be an efficient method for the synthesis
of a variety of functionalized a,b-unsaturated N-acyl pyrroles,
which should also be suitable substrates for asymmetric 1,4-
addition reactions.
Experimental Section
Benzaldehyde (4a; 50.8 mL, 0.5 mmol) was added to a stirred
Scheme 3. Sequential Wittig olefination–catalytic asymmetric epoxida-
tion with the chiraladl ehyde 4n.
suspension of the ylide
3 (139.1 mg, 0.65 mmol) in toluene
(1.25 mL) at 258C. The mixture was stirred for a further 36 h at
1008C, then cooled to 258C. Toluene (1.25 mL) and a suspension of
the catalyst prepared from Sm(OiPr)3 (125 mL, 0.025 mmol, 0.2m in
THF), (R)-H8-binol (7.4 mg, 0.025 mmol), CMHP (231 mL,
0.75 mmol, 3.25m in toluene), and molecular sieves (4 Š) were
added to the reaction mixture at 258C. The mixture was stirred for a
further 0.5 h at 258C, then the reaction was quenched with aqueous
citric acid (2.5%), and the mixture was filtered through celite. The
filtrate was extracted three times with ethyl acetate, and the
combined organic layers were washed with saturated, aqueous
NaHCO3, then brine, and dried over MgSO4. The solvent was
evaporated, and the resulting crude residue was purified by flash
column chromatography (silica gel, ethyl acetate/hexane 1:20) to
afford 2a (102.4 mg, 96% yield, > 99.5% ee).
Table 3: Sequential Wittig olefination–catalytic asymmetric epoxidation
with the chiraladl ehyde 4n.
Entry
Ligand
t [h]
Oxidant
Yield [%][a]
d.r.[b] (2n/2o)
1
2
3
(R)-H8-binol0.7
(S)-H8-binol0.9
(S)-H8-binol0.7
CMHP
CMHP
TBHP
80
60
78
>99:1
1:56
1:36
[a] Yield of the isolated product 2n (from 4n). [b] Determined by HPLC
analysis.
Received: July 29, 2003 [Z52509]
Published Online: September 11, 2003
The versatility of the pyrrolyl epoxide products was
demonstrated by transformations of 2 into compounds 5–9
(Scheme 4). The addition of various carbon nucleophiles
followed by treatment with DBU afforded 5–7 in good
yields.[17] The epoxy alcohol 8 was obtained by the stepwise
reduction of 2h with LiBH4 and NaBH4. After the epoxide
opening of 2n, EtSLi in EtOH was determined to be a
suitable reagent for the conversion of the N-acyl pyrrole into
the corresponding ethyl ester 9 in high yield at room
temperature.
Keywords: asymmetric catalysis · epoxidation · samarium ·
.
synthetic methods · Wittig reactions
[1] For recent reviews, see: a) M. J. Porter, J. Skidmore, Chem.
Commun. 2000, 1215; b) T. Nemoto, T. Ohshima, M. Shibasaki,
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Am. Chem. Soc. 1997, 119, 2329; for the effects of Ph3As(O) and
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Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 2001, 123, 2725;
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[3] E. N. Jacobsen, L. Deng, Y. Furukawa, L. E. Martinez, Tetrahe-
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Scheme 4. Various transformations of the pyrrolyl epoxides 2. a) PhLi,
THF; then DBU, CH2Cl2, 88%; b) BuLi, 1-pentyne, THF; then DBU,
CH2Cl2, 84%; c) tert-butylacetate, LDA, THF; then DBU, CH 2Cl2, 74%;
d) LiBH4, THF; then NaBH4, 72%; e) (PhSe)2, NaBH4, EtOH/AcOH,
94%; f) EtSLi, EtOH, 92%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
LDA=lithium diisopropylamide.
[4] a) X.-Y. Wu, X. She, Y. Shi, J. Am. Chem. Soc. 2002, 124, 8792;
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Communications
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[12] For a review on the use of H8-binol in asymmetric catalysis, see:
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[6] S. Tosaki, T. Nemoto, T. Ohshima, M. Shibasaki, Org. Lett. 2003,
5, 495.
[13] With less reactive CMHP as the oxidant, the reaction of the
corresponding 4-phenylcarboxylic acid imidazolide resulted in a
low chemical yield (18 h, 47% yield with 10 mol% of the
catalyst); see reference [5b].
[14] The preparation of a,b-unsaturated N-acyl pyrroles from the
corresponding a,b-unsaturated amides was reported by Evans
et al.; see reference [9] and references therein. The reaction of
lithiated pyrrole with an acyl halide did not proceed cleanly,
although the equivalent reaction of 2-substituted pyrroles has
been described; see reference [8c].
[15] For the preparation and reactivity of 1,1’-carbonyldipyrrole, see
reference [9]. For related reactions of N-acyl imidazoles with
methylenetriphenylphosphorane to afford alkanoyl triphenyl-
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[7] S.-D. Lee, M. A. Brook, T.-H. Chan, Tetrahedron Lett. 1983, 24,
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Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem.
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3320; Angew. Chem. Int. Ed. 2002, 41, 3188.
[10] Among the lanthanide metals screened (La, Pr, Nd, Sm, Gd, Er,
and Yb), Sm showed the best reactivity and selectivity. The use
of La, Pr, Nd, Gd, and Er complexes also afforded 2a with
> 90% ee and in > 80% yield. Yb was not suitable for this
reaction with 1a.
[11] Standard conditions for asymmetric epoxidations with lantha-
nide complexes: Ln(OiPr)3/binol/Ph3As(O) 1:1:1 and Ln(OiPr)3/
binol/Ph3P(O) 1:1:3; see references [2], [5], and [6]. When an
imidazolide or an amide was the substrate, a catalyst loading of
10 mol% was essential for the reaction to reach completion.
[16] Use of the system Et2Zn/o-methoxyphenol/tBuOOH led to the
epoxide in 76% yield in 18 h at 258C with low selectivity (d.r.
54:46). Other conditions, such as H2O2–urea with a base,
mCPBA, or aqueous NaClO with a phase-transfer catalyst
either resulted in the decomposition of the enone or afforded the
product in low yield (< 20%).
[17] For reactions of the N-acyl pyrrole unit, see reference [9] and
references therein.
4684
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