Metalloporphyrin-catalyzed diastereoselective epoxidation of allyl-substituted alkenes

Article abstract of DOI:10.1021/jo047733c

By using [Mn(2,6-Cl₂TPP)Cl] (1) as a catalyst and Oxone/H ₂O₂ as an oxidant, we have developed an efficient method for erythro-selective epoxidation of acyclic allyl-substituted alkenes, including allylic alcohols, amines, and esters. Up to 9:1 erythro selectivities for terminal allyllic alkenes could be achieved, which are significantly higher than that achieved using m-CPBA as an oxidant. In addition, the synthetic utilities of this epoxidation method were highlighted in stereoselective synthesis of key anti-HIV drug intermediates and epoxidation of glycals.

Full text of DOI:10.1021/jo047733c

Metalloporphyrin-Catalyzed Diastereoselective Epoxidation of
Allyl-Substituted Alkenes
Wing-Kei Chan, Man-Kin Wong,* and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular
Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road,
Hong Kong, China
cmche@hku.hk
Received December 28, 2004
2 2 2
By using [Mn(2,6-Cl TPP)Cl] (1) as a catalyst and Oxone/H O as an oxidant, we have developed
an efficient method for erythro-selective epoxidation of acyclic allyl-substituted alkenes, including
allylic alcohols, amines, and esters. Up to 9:1 erythro selectivities for terminal allyllic alkenes could
be achieved, which are significantly higher than that achieved using m-CPBA as an oxidant. In
addition, the synthetic utilities of this epoxidation method were highlighted in stereoselective
synthesis of key anti-HIV drug intermediates and epoxidation of glycals.
Introduction
phyrin complexes containing a wide variety of bulky/
chiral substitutents can catalyze alkene epoxidations
with excellent regio- and enantioselectivies. In addition,
Epoxides of allyl-substituted alkenes are versatile
synthetic building blocks for organic synthesis and
important structural moieties of biologically active natu-
6
exceptionally high turnover numbers can be achieved
7
with polyhalogenated metalloporhyrins as catalysts.
1
ral products. Diastereoselective alkene epoxidation re-
Recently, we have reported that sterically bulky poly-
mains one of the most efficient methods for stereoselec-
tive synthesis of these epoxides. Through hydrogen-
bonding between oxidizing agents and the syn-directing
group of allyl-substituted alkenes, excellent syn selectiv-
(3) For selected examples on anti-selective epoxidations of cycloalk-
enes, see: (a) Kurihara, M.; Ito, S.; Tsutsumi, N.; Miyata, N. Tetra-
hedron Lett. 1994, 35, 1577. (b) Murray, R. W.; Singh, M.; Williams,
B. L.; Moncrieff, H. M. Tetrahedron Lett. 1995, 36, 2437. (c) Murray,
R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J. Org. Chem. 1996,
61, 1830. (d) Adam, W.; Mitchell, C. M.; Saha-Moller, C. R. Eur. J.
Org. Chem. 1999, 785. (e) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Wong, M.-
K. J. Org. Chem. 1999, 64, 1635. (f) Adam, W.; Corma, A.; Garcia, H.;
Weichold, O. J. Catal. 2000, 196, 339. (g) O’Brien, P.; Childs, A. C.;
Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.;
Rosser, C. M. Org. Lett. 2003, 5, 4955.
2
ity can be achieved. For allyl-substituted alkenes with-
out syn-directing groups, anti-epoxides would be obtained
as the major product due to steric interaction. However,
the anti selectivities are generally low and rarely exceed
3
,4
2
0:1. The key to achieving high anti selectivities is to
develop sterically bulky oxidizing agents possessing
strong steric interaction with the substrates and yet
sufficient reactivity for epoxidation.
Metalloporphyrin-catalyzed alkene epoxidation has
been extensively investigated for decades. Metallopor-
(
4) For selected examples of anti-selective epoxidations of acyclic
alkenes, see: (a) Adam, W.; Brunker, H.-G.; Kumar, A. S.; Peters, E.-
M.; Peters, K.; Schneider, U.; von Schnering, H. G. J. Am. Chem. Soc.
1
996, 118, 1899. (b) Kurihara, M.; Ishii, K.; Kasahara, Y.; Kameda,
M.; Pathak, A. K.; Miyata, N. Chem. Lett. 1997, 1015. (c) Yang, D.;
Jiao, G.-S.; Yip, Y.-C.; Lai, T.-H.; Wong, M.-K. J. Org. Chem. 2001,
5
6
6, 4619.
(
5) (a) Meunier, B. Chem. Rev. 1992, 92, 1411. (b) Dolphin, D.;
(
1) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004,
04, 2857.
2) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
307. (b) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
Traylor, T. G.; Xie, L. Y. Acc. Chem. Res. 1997, 30, 251. (c) McLain, J.
L.; Lee, J.; Groves, J. T. In Biomimetic Oxidations Catalyzed by
Transition Metal Complexes; Meunier, B., Ed.; Imperial College
Press: London, 2000; pp 91-169.
1
(
1
10.1021/jo047733c CCC: $30.25 © 2005 American Chemical Society
4226
J. Org. Chem. 2005, 70, 4226-4232
Published on Web 04/21/2005

Epoxidation of Allyl-Substituted Alkenes
TABLE 1. Epoxidation of trans-Alkenes 3a-c by Mn-porphyrinsa
E:T epoxide ratiob
entry
alkene
catalyst
% conversionb
% yield b
catalyst
m-CPBAc
1
2
3
4
3a
1
93
100
60
70
62
64
6:1
1.7:1
1.4:1
n.d.
n.d.
5:1
1.6:1
[Mn(F20-TPP)Cl]
[Mn(TTP)Cl]
1
1
[Mn(F20-TPP)Cl]
[Mn(TTP)Cl]
d
3b
3c
91
<5 (58)
1:1
1:1
e
d
5
57
<5 (49)
d
6
7
8
97
51 (15)
d
72
35 (9)
4:1
1
1
49
35
1:1
n.d.
1.4:1
e
9
<5
95
n.d.
86
1
0
[Mn(F20-TPP)Cl]
a
Unless otherwise indicated, all the epoxidation reactions were performed as follows: To a CH3CN/H2O solution of alkene (0.1 mmol),
NH4OAc (0.05 mmol) and catalyst (0.5 µmol) was added Oxone (0.13 mmol) and NH4HCO3 (0.4 mmol) at room temparture (Reaction
b
1
time: 2 h). Conversion and yield were analyzed and quantified by H NMR spectroscopy with 4-bromochlorobenzene or 1,1-
c
diphenylethylene as an internal standard. Epoxidations were conducted in CH2Cl2 with an alkene/m-CPBA/NaHCO3 molar ratio of
e
1
:2:3. d Percent yield of trans-4-phenyl-3-buten-2-one. To a solution of alkene (0.2 mmol), NH4OAc (0.03 mmol), and 1 (2 µmol) in CH3CN
(
4 mL) was added a premixed solution of NH4HCO3 (0.6 mmol), CH3CN (0.5 mL), H2O (0.5 mL), and 35% H2O2 (0.1 mL) at room temperature
reaction time: 2 h).
(
FIGURE 2. Diastereoselective epoxidation with [Mn(2,6-
Cl TPP)Cl] (1) as a catalyst.
2
Results and Discussion
FIGURE 1. Structures of metalloporphyrins.
Diastereoselective Epoxdation of Allyl-Substitut-
ed trans-Alkenes. Recently, we have reported that
highly trans-selective epoxidation of cycloalkenes could
2
halogentated metalloporphyrins [Mn(2,6-Cl TPP)Cl] (1)
2
and [Ru(2,6-Cl TPP)(CO)] (2) (Figure 1) could catalyze
highly diastereoselective epoxidation of allyl-substituted
be attained by using [Mn(2,6-Cl
2
TPP)Cl] (1) as a catalyst
cycloalkenes in good yields (up to 99%) with up to >99:1
and H as a terminal oxidant. It has been reported that
2 2
O
8
trans selectivity. The exceptionally high trans selectivity
Oxone could also be used as a green oxidant for manga-
nese porphyrin-catalyzed epoxidation.5 Thus, apart
a,9
could be attributed to the strong steric interaction
between the substrates and the bulky porphyrin ligands.
As part of our continuing effort to develop efficient
methods for diastereoselective alkene epoxidation under
mild reaction conditions, we have expanded the substrate
scope to acyclic allyl-substituted alkenes including allylic
alcohols, amines, and esters (Figure 2). By using [Mn-
2 2
from H O , Oxone was also employed as the oxidant in
our studies.
At the outset, we studied the epoxidation of allylic ester
3a using 1 as a catalyst and Oxone as an oxidant.
Treatment of a CH
(0.5 µmol) with NH
and NH HCO
3
CN solution of 3a (0.1 mmol) and 1
OAc (0.05 mmol), Oxone (0.13 mmol),
3
(0.4 mmol) afforded epoxide 4a in 70%
4
(
2,6-Cl
2
TPP)Cl] (1) as a catalyst, we achieved erythro
4
selectivities of up to 9:1 for epoxidation of allyl-substi-
tuted terminal alkenes, which are significantly higher
than that achieved using m-CPBA as an oxidant.
yield based on 93% conversion. The erythro:threo ratio
1
of 4a was 6:1 as determined by H NMR analysis (Table
1, entry 1), whereas poor erythro selectivity (1.6:1) was
obtained with m-CPBA.1
0,11
The activities of other Mn-
(
6) (a) Groves, J. T.; Nemo, T. E. J. Am. Chem. Soc. 1983, 105, 5786.
porphyrin catalysts for the diastereoselective epoxidation
of 3a were also examined under the same reaction
(
b) Tabushi, I.; Morimitsu, K. J. Am. Chem. Soc. 1984, 106, 6871. (c)
Collman, J. P.; Brauman, J. I.; Meunier, B.; Hayashi, T.; Kodadek, T.;
Raybuck, S. A. J. Am. Chem. Soc. 1985, 107, 2000. (d) Groves, J. T.;
Neumann, R. J. Am. Chem. Soc. 1987, 109, 5045. (e) Collman, J. P.;
Zhang, X.; Hembre, R. T.; Brauman, J. I. J. Am. Chem. Soc. 1990,
(9) (a) de Pooter, B.; Meunier, B. J. Chem. Soc., Perkin Trans. 2
1985, 1735. (b) Robert, A.; Meunier, B. New J. Chem. 1988, 12, 885.
(c) Liu, J.-Y.; Li, X.-F.; Li, Y.-Z.; Chang, W.-B.; Huang, A.-J. J Mol.
Catal. 2002, 187, 163.
(10) Structure of erythro-4a is similar to the epoxide moiety of
crytophycins (cytotoxic macrocyclic depsipeptides). The erythro-epoxide
of crytophycins could be prepared by m-CPBA or dimethyl dioxirane
epoxidation with 2-3:1 erythro selectivity; see: (a) Salamonczyk, G.
M.; Han, K.; Guo, Z.-W.; Sih, C. J. J. Org. Chem. 1996, 61, 6893. (b)
White, J. D.; Hong, J.; Robarge, L. A. J. Org. Chem. 1999, 64, 6206.
(c) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem.
2000, 65, 3143. (d) Buck, S. B.; Huff, J. K.; Himes, R. H.; Gerog, G. I.
J. Med. Chem. 2004, 47, 696.
1
12, 5356. (f) Collman, J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S.
Brauman, J. I. Science 1993, 261, 1404.
7) (a) Che, C.-M.; Liu, C.-J.; Yu, W.-Y.; Li, S.-G. J. Org. Chem. 1998,
3, 7364. (b) Liu, C.-J.; Yu, W.-Y.; Che, C.-M.; Yeung, C.-H. J. Org.
(
6
Chem. 1999, 64, 7365. (c) Che, C.-M.; Yu, X.-Q.; Huang, J.-S.; Yu, W.-
Y. J. Am. Chem. Soc. 2000, 122, 5337. (d) Zhang, R.; Yu, W.-Y.; Wong,
K.-Y.; Che, C.-M. J. Org. Chem. 2001, 66, 8145. (e) Che, C.-M.; Zhang,
J.-L. Org. Lett. 2002, 4, 1911. (f) Zhang, R.; Yu, W.-Y.; Sun, H.-Z.; Liu,
W.-S.; Che, C.-M. Chem. Eur. J. 2002, 8, 2495.
(
8) Chan, W.-K.; Liu, P.; Yu, W.-Y.; Wong, M.-K.; Che, C.-M. Org.
Lett. 2004, 6, 1597.
J. Org. Chem, Vol. 70, No. 11, 2005 4227

Chan et al.
TABLE 2. Epoxidation of trans-Alkenes 3 by
Ru(2,6-Cl2TPP)CO] (2)a
[
FIGURE 3. Oxidation of 3b catalyzed by Mn-porphyrins.
E:T epoxide ratiob
entry alkene % conversionb % yieldb
2
m-CPBAc
conditions. It was found that 1 exhibited the highest
erythro selectivity in the epoxidation of 3a, while [Mn-
1
2
3
4
5
3a
3b
3c
3d
3e
82
28
100
100
100
72
(95)
70
87
85
5:1
1.6:1
1:1
d
(F
20-TPP)Cl] and [Mn(TTP)Cl] provided erythro selectivi-
ties of 1.7:1 and 1.4:1, respectively (Table 1, entries 2 and
).
Then, we proceeded to investigate the epoxidation of
allylic alcohol 3b by using the “1 + Oxone” approach
Table 1). Note that epoxidation of 3b bearing an allylic
2.2:1
1.6:1
2.3:1
1:1
1:1
3
1:1
a
Unless otherwise indicated, all the epoxidation reactions were
carried out at 40 °C for 48 h with a 2/2,6-Cl2pyNO/alkene molar
b
(
ratio of 1:130:100 under a nitrogen atmosphere. Determined by
t
1
c
OSi Bu(CH
yl-3-buten-2-one (58% yield based on 91% conversion)
Figure 3) as the major product with less than 5% yield
of epoxide 4b (Table 1, entry 4). The same enone was
found to be the major product with H as a terminal
oxidant (49% yield based on 57% conversion). Yet, [Mn-
20-TPP)Cl] and [Mn(TTP)Cl] with smaller ortho sub-
stituents on the porphyrin-phenyl group provided epoxide
)
3 2
group unexpectedly afforded trans-4-phen-
H NMR. Epoxidations were performed in CH2Cl2 with an alkene/
d
m-CPBA/NaHCO3 molar ratio of 1:2:3. Percent yield of trans-4-
phenyl-3-buten-2-one.
(
2
O
2
effect chemoselective desilylation of 3b to provide the
enone in 95% yield based on 28% conversion (entry 2).
For epoxidation of allylic alcohols 3c-e, 2 could afford
erythro selectivity of 2:1, while m-CPBA provided 1:1
mixtures of erythro- and threo-epoxides (entries 3-5).
Diastereoselective Epoxdation of Allylic Termi-
nal Alkenes. It has always been a challenge to attain
high erythro selectivity for epoxidation of allylic terminal
alkenes, and the reason is twofold. In contrast to cyclic
alkenes, acyclic alkenes are conformationally nonrigid.
In addition, the conformation of terminal alkenes is
particularly flexible due to the lack of 1,2- or 1,3-allylic
strains.2a The highly flexible conformation of the allylic
terminal alkenes would lead to additional competing
transition state geometries during the oxygen transfer
process, resulting in poor diastereoselectivity (see later
section).
12
(F
4
4
b as the major product and [Mn(F20-TPP)Cl] provided
b with erythro selectivity of 5:1 in 51% yield, while
[
Mn(TTP)Cl] gave 4b with erythro selectivity of 4:1 in
3
5% yield based on 72% conversion. It should be noted
that only a 1:1 mixture of erythro- and threo-epoxides
with no enone formation was obtained with m-CPBA as
an oxidant.
For allylic alcohol 3c with an OAc group, no enone was
detected either using 1 or [Mn(F20-TPP)Cl] as a catalyst
(
4
entries 8-10). Using the “1 + Oxone” approach, epoxide
c was obtained in 49% yield based on 35% conversion,
whereas less than 5% conversion was observed with H
2 2
O
as an oxidant (entries 8 and 9). [Mn(F20-TPP)Cl] could
provide 4c with erythro selectivity of 1.4:1 with 86% yield
As the sterically bulky metalloporphyrin catalysts have
exhibited high diastereoselectivity in epoxidation of al-
lylic alkenes, we were interested to examine the activity
of 1 in epoxidation of allylic terminal alkenes. Using the
“1 + Oxone” approach, terminal allylic alcohol 5a could
be epoxidized to 6a15 with an erythro selectivity of 5.7:1
(Table 3, entry 1), and higher erythro selectivity (7.8:1)
could be achieved with H O as a terminal oxidant (entry
based on 95% conversion (entry 10).
Despite the importance of -OSi Bu(CH
t
)
3 2
as a versatile
13
protecting group in organic synthesis, there are only
limited methods for its oxidative desilylation.14 As shown
in Table 1, the Mn-porphyrins could achieve oxidative
2 2
desilylation by using H O or Oxone as an oxidant. In
addition, our results indicated that the ratio of epoxides
to enones could be varied by proper choice of Mn-
porphyrins (Figure 3).
2
2
2). For a bulkier allylic alcohol 5b, epoxide 6b could be
obtained with erythro selectivities of 7.1:1 and 9:1 in the
1-catalyzed epoxidations with Oxone and H O as an
oxidant, respectively (entries 3 and 4). Notice that m-
CPBA could only give 1:1 mixtures of erythro-and threo-
epoxides 6a and 6b. To the best of our knowledge, the
erythro selectivities for the 1-catalyzed epoxidations of
Apart from Mn-porphyrins, we also examined the
2
2
catalytic activity of [Ru(2,6-Cl
2
TPP)(CO)] (2). With 2 (1
mol %) as a catalyst, alkene 3a could be epoxidized to
a with erythro selectivity of 5:1 (Table 2, entry 1), which
is similar to that of 1. As depicted in Table 2, 2 could
4
4
b
5
a and 5b are the best results ever achieved.
With these promising findings in hand, we proceeded
(11) For other methods to obtain erythro-epoxides of crytophycins,
see: (a) Hoard, D. W.; Moher, E. D.; Martinelli, M. J.; Norman, B. H.
Org. Lett. 2002, 4, 1813. (b) Al-awar, R. S.; Ray, J. E.; Schultz, R. M.;
Andis, S. L.; Kennedy, J. H.; Moore, R. E.; Liang, J.; Golakoti, T.;
Subbaraju, G. V.; Corbett, T. H. J. Med. Chem. 2003, 46, 2985.
to examine diastereoselective epoxidation reactions of
other classes of terminal alkenes. A search of the
literature revealed that some erythro-amino epoxides are
key building blocks for the synthesis of several FDA-
(
12) Manganese porphyrins were known to catalyze alkane hydroxy-
lation; see ref 5a.
t
16
(
13) For the use of -OSi Bu(CH
3
)
2
as a protecting group, see:
approved anti-HIV drugs. Particularly, phenylalanine-
Protective Group in Organic Synthesis, 3rd ed.; Greene, T. W., Wuts,
derived erythro-amino epoxides have been used as the
P. G. M., Eds.; John Wiley & Sons: New York, 1999; Chapter 3.
(
14) (a) Muzart, J.; N’Ait Ajjou, N. Synlett 1991, 7, 497. (b) Muzart,
J.; Ajjou, A. N. Synth. Commun. 1992, 22, 1993. (c) Firouzabadi, H.;
Shiriny, F. Synth. Commun. 1996, 26, 423. (d) Heravi, M. M.; Ajami,
D.; Tabar-Heydar, K. Synth. Commun. 1999, 29, 1009.
(15) Hindupur, R. M.; Panicker, B.; Valluri, M.; Avery, M. A.
Tetrahedron Lett. 2001, 42, 7341.
(16) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis, 2001, 2203.
4228 J. Org. Chem., Vol. 70, No. 11, 2005

Epoxidation of Allyl-Substituted Alkenes
TABLE 3. Epoxidation of Allyic Terminal Alkenes 5 by
As illustrated in Table 3, the “1 + Oxone” oxidation
system could achieve erythro-selective epoxidation of
phthalimide-protected allylic amines 5c-e and Boc-
a
Mn-porphyrins
protected allylic amine 5f in high yields. For epoxidation
of 5c bearing a benzyl group, epoxide 6c1
8a,c
could be
achieved with erythro selectivity of 3.4:1 in 96% isolated
yield based on 88% conversion, while m-CPBA provided
major product threo-epoxide 6c with a selectivity of 1:3.
It should be noted that this is the first example in which
major product erythro 6c was obtained via direct epoxi-
dation of 5c. By conducting the epoxidation at 0 °C,
erythro selectivity of 3.6:1 could be attained (Table 3,
entry 6). With [Mn(F20-TPP)Cl] as the catalyst, erythro
selectivity of 1.3:1 was obtained (entry 7). For epoxidation
of 5d with an isopropyl group, an increase in erythro
selectivity to 5:1 was observed (entry 8), indicating that
this epoxidation is sensitive to the steric bulkiness of the
R-substituent. For 5e and Boc-protected 5f, erythro
selectivities of 1.8:1 and 1.4:1 were observed, respectively
(
entries 9 and 10). It should be noted that m-CPBA gave
threo-epoxides as major products in the epoxidation of
d (1:3), 5e (1:4), and 5f (1:13). For epoxidation of allylic
esters 5g and 5h using 1 as a catalyst, 1:1 mixtures of
5
2
1
epoxides were observed (entries 11 and 12) in 1 h.
Stereoselective Epoxidation of Glycals. Glycal
epoxides have been shown to be important intermediates
for oligosaccharide synthesis and could be prepared by
2
2
dimethyl dioxirane-mediated glycal epoxidation. How-
ever, the isolation and large-scale preparation of dimethyl
dioxirane would be tedious. In addition, poor facial
a
Unless otherwise indicated, all the epoxidation reactions were
selectivity resulted in epoxidation of glycals bearing small
performed as follows: To a CH3CN/H2O solution of alkene (0.1
mmol), NH4OAc (0.05 mmol) and catalyst (0.5 µmol) was added
Oxone (0.13 mmol) and NH4HCO3 (0.4 mmol) at room temperature
22a,23
substituents such as tri-O-acetylglycal 7.
In this
regard, we were interested to examine the activity of 1
in epoxidation of 7.24 To minimize the possibility of
b
1
c
(
Reaction time: 1 h). Determined by H NMR. Epoxidations
were carried out in CH2Cl2 with an alkene/m-CPBA/NaHCO3
2 2
epoxide hydrolysis by water, urea-H O was used as the
molar ratio of 1:2:3. d To a solution of alkene (0.2 mmol), NH4OAc
(
0.03 mmol), and 1 (2 µmol) in CH3CN (4 mL) was added a
(17) (a) Rotella, D. P. Tetrahedron Lett. 1995, 36, 5453. (b) Albeck,
A.; Estreicher, G. I. Tetrahedron 1997, 53, 5325. (c) Kim, B. M.; Bae,
S. J.; So, S. M.; Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang, J. Org. Lett.
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Kronenthal, D.; Huang, M.-H.; Nugent, W. A. J. Org. Chem. 2004, 69,
premixed solution of NH4HCO3 (0.6 mmol), CH3CN (0.5 mL), H2O
(
0.5 mL), and 35% H2O2 (0.1 mL) at room temperature (Reaction
time: 2 h). Isolated yield based on 88% conversion. f At 0 °C for
e
g
5
h. Mn(F20-TPP)Cl was used instead of 1.
1
629.
18) For other methods, see: (a) Parkes, K. E. B.; Bushnell, D. J.;
(
Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins,
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3
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N. Tetrahedron Lett. 1999, 40, 3183.
(
19) Using m-CPBA as the oxidant, mixtures of erythro- and threo-
epoxides were obtained, see: (a) Luly, J. R.; Dellaria, J. F.; Plattner,
J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987, 52, 1487. (b) Roush,
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5
9, 1139. (g) Romeo, S.; Rich, D. H. Tetrahedron Lett. 1994, 35, 4939.
20) For the use of a polymer-supported ruthenium porphyrin
catalyst to synthesize threo-6f, see ref 7c.
FIGURE 4. Synthetic utilities of erythro-allyic amino ep-
(
oxides.
(
21) For a selected example on the synthetic utility of erythro-6g,
see: Chung, S. J.; Chung, S.; Lee, H. S.; Kim, E.-J.; Oh, K. S.; Choi,
key synthetic intermediates for the construction of
Saquinavir and Amprenavir (Figure 4). Currently, these
H. S.; Kim, K. S.; Kim, Y. J.; Hahn, J. H.; Kim, D. H. J. Org. Chem.
2
001, 66, 6462. Note that with m-CPBA as the oxidant, epoxidations
erythro-epoxides have been obtained by ring-closure
of 5g and 5h required a few days for complete conversion.
reactions of â-halohydrins.1
7,18
(22) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
11, 6661. (b) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem. Int.
However, m-CPBA epoxi-
1
dation could only afford threo-epoxides as major prod-
Ed. Engl. 1996, 35, 1380.
19,20
(23) Kim, H. M.; Kim, I. J.; Danishefsky, S. J. J. Am. Chem. Soc.
ucts.
Up to now, there is no direct epoxidation method
2
001, 123, 35.
available to access these erythro-amino epoxide major
products.
(
24) For the use of a ruthenium porphyrin catalyst in R-selective
epoxidation of glycal, see ref 7a.
J. Org. Chem, Vol. 70, No. 11, 2005 4229

Chan et al.
SCHEME 1
oxygen source, and imidazole was used as an axial ligand
instead of hydroscopic ammonium acetate.25 Reaction of
7
(0.1 mmol) with 1 (2 mol %), imidazole (0.04 mmol),
and urea-H (3 equiv) in CH CN/MeOH afforded the
2
O
2
3
corresponding glycal epoxide, which underwent subse-
quent methanolysis (with an inversion of configuration)
to give methyl 3,4,6-tri-O-acetyl-â-D-glucopyranoside in
1
8
4% yield based on 53% conversion. On the basis of H
NMR analysis, the facial selectivity (R:â) of this glycal
epoxidation was found to be 12:1 (Scheme 1).
Proposed Transition State Models for 1-Cata-
lyzed Diastereoselective Epoxidation of Cyclohexen-
1
-ols. Previously, we have reported that 1 could catalyze
highly diastereoselective epoxidation of allyl-substituted
8
cycloalkenes with up to >99:1 trans selectivity, and the
results are summarized in Figures 5 and 6. Three
FIGURE 6. Diastereoselective epoxidation of 9c with Mn-
porphyrins.
decreased (Figure 6, entries 1-3). (3) The trans selectivi-
2
ties of 9e-h with R ) CH
3
are much higher than that
2
of 9a-d with R ) H (Figure 5, entries 1 vs 5, 2 vs 6, 3
vs 7, and 4 vs 8). On the basis of the experimental
findings, here we propose transition-state models for the
1
-catalyzed diastereoselective epoxidation of cyclohexen-
-ols.
1
Trend 1. The side-on approach was employed to
explain the stereoselectivity obtained in metallopor-
6
a,26
phyrin-catalyzed epoxidation of cis-alkenes.
This
model has gained a widespread acceptance in the oxida-
tion chemistry of metalloporphyrins and has been suc-
cessfully applied to explain the enantioselectivity of the
chiral Mn(salen)-catalyzed asymmetric epoxidation of
unfunctionalized alkenes.27
On the basis of the side-on approach, 1 can transfer
an oxygen atom to the CdC double bond of the cyclo-
hexenes from both faces, and hence two possible transi-
tion states are discernible (Figure 7). In the favored
transition state (TS) leading to trans-epoxides, there is
little or no steric interactions between the X group of 1
1
and the R group of cyclohexenes. However, severe steric
interaction between the X group of 1 and the R group of
FIGURE 5. Diastereoselective epoxidation of cyclohexen-1-
ols 9a-h with 1.
1
cyclohexenes are anticipated in the disfavored TS, leading
to cis-epoxides. The energy difference between the
favored and disfavored TS determines the diastereo-
selectivity. As a result, trans-epoxides are obtained as
the major diastereoisomers in 1-catalyzed epoxidation of
all the substrates tested.
interesting trends were observed: (1) The trans selectivi-
ties increased as the steric size of the cyclohexene
1
t
substituent (R ) increased from OH to OAc to OSi Bu-
1
t
(CH
3
)
2
2
and decreased when R ) OSi Bu(Ph) (Figure 5,
entries 1-4 and 5-8). (2) The trans selectivities de-
creased as the steric size of the ortho substituents X (Cl,
1
According to Figure 7, as the steric size of the R group
of cyclohexenes increases, more severe steric interactions
3
CH , and F) on the phenyl group of porphyrin rings
between the X and R1 groups are expected in the
(
25) Using an axial ligand as a cocatalyst for manganese porphyrin-
catalyzed oxidation reaction, see: (a) Battioni, P.; Renaud, J. P.;
Bartoli, J. F.; Reina-Artiles, M.; Fort, M.; Mansuy, D. J. Am. Chem.
Soc. 1988, 110, 8462. (b) Thellend, A.; Battioni, P.; Mansuy, D. J. Chem.
Soc., Chem. Commun. 1994, 1035.
(26) Groves, J. T.; Myers, R. S. J. Am. Chem. Soc. 1983, 105, 5791.
(27) Jacobsen, E. N. In Comprehensive Organometallic Chemistry
II; Wilkinson, G. W., Stone, F. G. A., Abel, E. W., Hegedus, L. S., Eds.;
Pergamon: New York, 1995; Vol. 12, Chapter 11.1.
4230 J. Org. Chem., Vol. 70, No. 11, 2005

Epoxidation of Allyl-Substituted Alkenes
FIGURE 7. Transition-state geometries for epoxidation of cyclohexen-1-ols 9a-d with 1.
FIGURE 8. Transition-state geometries for epoxidation of cyclohexen-1-ols 9e-h with 1.
disfavored TS, which lead to an increase in trans selec-
tivity. This notion is supported by the fact that 9c bearing
t
an OSi Bu(CH
3
)
2
group has a higher trans selectivity than
1
1
9
a (R ) OH) and 9b (R ) OAc). However, when the
size of R continues to increase and up to a certain size
i.e., from OSi Bu(CH
selectivity was observed, indicating that OSi Bu(CH )
1
t
t
(
3 2 2
) to OSi Bu(Ph) ), lower trans
t
3 2
would be the optimum substituent for achieving high
selectivity.
Trend 2. As depicted in Figure 7, when the X group
of the porphyrins becomes smaller (i.e., X changes from
Cl to CH
3
to F), less unfavorable steric interactions were
FIGURE 9. Conformers A and B of substrate 5a.
1
found between the X group and the R group in the
disfavored TS. In this regard, lower trans selectivities
were obtained.
Trend 3. Due to the steric bulkiness of trisubstituted
alkenes 9e-h, the head-on approach (instead of the side-
on approach) was employed to rationalize the 1-catalyzed
7
b
epoxidation. As shown in Figure 8, 9e-h would ap-
proach the metal center from the top of the porphyrin
ring. In the favored TS, there is little or no steric
interaction between the Cl group of the porphyrin and
FIGURE 10. Transition-state geometries for epoxidation of
5
a with 1.
1
the R group of the cyclohexenes, leading to trans-
discernible with comparable free energies (Figure 9). As
depicted in Figure 9, erythro-epoxide would be the major
product from conformer A, while threo-epoxide from
conformer B. As conformers A and B are interchangeable,
equimolar mixtures of erythro- and threo-epoxides would
be resulted. Therefore, to achieve diastereoselective ep-
oxidation of terminal alkenes, the oxidants must be able
to distinguish the conformers A and B.
On the basis of the side-on approach, 1 would transfer
an oxygen atom to 5a anti to the bulky silyl group, and
two possible transition states are proposed (Figure 10).
For conformer A, the sterically bulky silyl group of 5a
positions itself away from the porphyrin ring, leading to
erythro-epoxide. In contrast, for conformer B, severe
epoxides. However, severe steric interaction between the
1
Cl group of porphyrins and the R group of cyclohexenes
are expected in the disfavored TS, giving rise to cis-
1
epoxides. Note that in the disfavored TS, the R group
has two unfavorable steric clashes with the Cl groups of
the porphyrin. The extra one steric clash may account
for the higher trans selectivity observed in the epoxida-
tion of 9e-h compared with 9a-d (Figure 5, entries 1
vs 5, 2 vs 6, 3 vs 7, and 4 vs 8).
Proposed Transition State Models for 1-Cata-
lyzed Diastereoselective Epoxidation of Terminal
Alkene 5a. Due to the lack of 1,2- or 1,3-allylic strains
of 5a, the two most stable conformations A and B are
J. Org. Chem, Vol. 70, No. 11, 2005 4231

Chan et al.
steric interactions are found between the silyl group of
stirring for an additional 1 h, the reaction mixture was diluted
2 2 3
with saturated aqueous Na S O solution (2 mL) and extracted
5
a and the porphyrin ring. As a result, erythro-epoxide,
with n-hexane (4 × 20 mL). The combined organic layers were
coming from the epoxidation of conformer A, is obtained
dried over anhydrous Na SO , filtered, and concentrated under
2
4
as the major diastereoisomer.
reduced pressure. To the residue was added 1,1-diphenyl
ethylene as an internal standard, and the organic products
1
Conclusion
were analyzed and quantified by H NMR spectroscopy. The
yield of trans-4-phenyl-3-buten-2-one was determined to be
Furthering our previous work on metalloporphyrin-
catalyzed diastereoselective epoxidation, we have suc-
cessfully extended this method toward erythro-selective
epoxidation of acyclic allyl-substituted alkenes using
4
9% on the basis of 57% alkene conversion.
General Procedure for [Ru(2,6-Cl
Catalyzed Epoxidation (Table 2, Entry 1). To a dried CH2-
Cl solution (3 mL) containing 3a (0.2 mmol) were added
Ru(2,6-Cl TPP)(CO)] (2) (2 µmol) and 2,6-Cl pyNO (0.26
mmol) under a nitrogen atmosphere. After being stirred at 40
C for 48 h, the reaction mixture was concentrated under
2
TPP)(CO)] (2)-
2
[
2
2
2 2
Oxone/H O as oxidants. Up to 9:1 erythro selectivities
could be achieved for terminal allyl-substituted alkenes,
which are much higher than that achieved using m-
CPBA. This epoxidation method provides a convenient
assess to synthetically useful epoxides including erythro-
amino epoxides (important anti-HIV drug intermediates)
and R-glycal epoxide major products. Future work will
be directed toward the application of this method to
natural product synthesis.
°
reduced pressure. The residue was added 1,1-diphenyl ethyl-
ene as an internal standard, and the organic products were
1
analyzed and quantified by H NMR spectroscopy. The ratio
of epoxides erythro-4a/threo-4a was determined to be 5:1 by
1
H NMR. The combined yield of erythro-4a and threo-4a was
72% on the basis of 82% alkene conversion.
Procedure for 1-Catalyzed Epoxidation of Glycal 7. To
3
a solution of dried CH CN (2 mL) and MeOH (1 mL) containing
glycal 7 (0.1 mmol) and imidazole (0.04 mmol) were added 1
2 µmol) and urea-H (0.3 mmol) under a nitrogen atmo-
Experimental Section
(
2 2
O
sphere. After being stirred at room temperature for 5 h, the
reaction mixture was concentrated under reduced pressure.
The residue was diluted with ether (50 mL) and filtered
through a short pad of silica gel. The filtrate was concentrated
under reduced pressure, and 4-bromochlorobenzene was added
as an internal standard. The yield of methyl 3,4,6-tri-O-acetyl-
â-D-glucopyranoside was determined to be 84% on the basis
General Procedure for “[Mn(2,6-Cl
one”-Catalyzed Epoxidation of trans-Alkene (Table 1,
Entry 1). To a round-bottom flask containing [Mn(2,6-Cl TPP)-
Cl] (1) (0.5 µmol), 3a (0.1 mmol), and ammonium acetate (0.05
mmol) in a solution of CH CN (3 mL) and H O (2 mL) was
added a mixture of Oxone (0.13 mmol) and ammonium
bicarbonate (0.4 mmol). After stirring at room temperature
for 2 h, the reaction mixture was diluted with saturated
2
TPP)Cl] (1) + Ox-
2
3
2
1
of 53% conversion by H NMR. The ratio of epoxides R-8/â-8
was determined to be 12:1.
aqueous Na
4 × 20 mL). The combined organic layers were dried over
anhydrous Na SO , filtered, and concentrated under reduced
2 2 3
S O solution (1 mL) and extracted with n-hexane
(
Acknowledgment. This work was supported by The
University of Hong Kong (University Development
Fund), the Hong Kong Research Grants Council (HKU-
7384/02P), and the Area of Excellence Scheme (AoE/P-
2
4
pressure. To the residue was added 1,1-diphenyl ethylene as
an internal standard, and the organic products were analyzed
1
and quantified by H NMR spectroscopy. The ratio of epoxides
1
erythro-4a/threo-4a was determined to be 6:1 by H NMR. The
1
0-01) established under the University Grants Council
combined yield of erythro-4a and threo-4a was 70% on the basis
(
HKSAR).
of 93% alkene conversion.
2 2 2
General Procedure for “[Mn(2,6-Cl TPP)Cl] (1) + H O ”-
Supporting Information Available: Characterization
Catalyzed Epoxidation (Table 1, Entry 5). To a round-
bottom flask containing [Mn(2,6-Cl TPP)Cl] (1) (2 µmol), 3b
0.2 mmol), and ammonium acetate (0.03 mmol) in CH CN (4
mL) was added a premixed solution of 35% H (0.1 mL),
CN (0.5 mL), and H
0.5 mL) in 3 portions for 1 h at room temperature. After
1
data of 4 and 6; H NMR determinations of the erythro-/threo-
2
1
13
epoxide ratio; and H and C NMR spectra of 4a-e, 6b, and
d. This material is available free of charge via the Internet
(
3
6
2
O
2
at http://pubs.acs.org.
ammonium bicarbonate (0.6 mmol), CH
(
3
2
O
JO047733C
4232 J. Org. Chem., Vol. 70, No. 11, 2005