Highly diastereoselective epoxidation of allyl-substituted cycloalkenes catalyzed by metalloporphyrins

Article abstract of DOI:10.1021/ol0496475

Highly diastereoselective epoxidations of allyl-substituted cycloalkenes including allylic alcohols, esters, and amines using sterically bulky metalloporphyrins [Mn(TDCPP)Cl] (1) and [Ru(TDCPP)CO] (2) as catalysts have been achieved. The "1 + H₂O₂" and "2 + 2,6-Cl₂pyNO" protocols afforded trans-epoxides selectively in good yields (up to 99%) with up to >99:1 trans-selectivity.

Full text of DOI:10.1021/ol0496475

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1597-1599
Highly Diastereoselective Epoxidation of
Allyl-Substituted Cycloalkenes Catalyzed
by Metalloporphyrins
Wing-Kei Chan, Peng Liu, Wing-Yiu Yu, 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 February 27, 2004
ABSTRACT
Highly diastereoselective epoxidations of allyl-substituted cycloalkenes including allylic alcohols, esters, and amines using sterically bulky
metalloporphyrins [Mn(TDCPP)Cl] (1) and [Ru(TDCPP)CO] (2) as catalysts have been achieved. The “1 + H O ” and “2 + 2,6-Cl2pyNO” protocols
2
2
afforded trans-epoxides selectively in good yields (up to 99%) with up to >99:1 trans-selectivity.
Epoxides of allylic cycloalkenes are versatile building blocks
for organic synthesis and construction of biologically active
natural products. Significant advances have been achieved
in cis-selective epoxidation of cyclic allylic alcohols through
hydrogen bonding between their syn-directing hydroxyl
group and oxidants.1 For epoxidation of cycloalkenes without
syn-directing groups, trans-epoxides would be obtained as
major products due to steric interaction. However, the trans-
selectivities are generally low and rarely exceed 20:1.2,3 Thus,
development of new protocols for highly diastereoselective
epoxidation of substituted cyclohexenes poses an important
challenge in organic synthesis.
Metalloporphyrin-catalyzed alkene epoxidation has been
a subject of extensive investigation.4 By virtue of the
structural diversity of the macrocyclic ligand, steric and
electronic properties of metalloporphyrin catalysts can be
fine-tuned for stereo- and enantioselective alkene epoxida-
tions.5 In addition, polyhalogenated metalloporphyrins are
robust and recyclable catalysts for alkene epoxidations with
exceptionally high turnover numbers.6 Here, we report that
[Mn(TDCPP)Cl] (1) and [Ru(TDCPP)CO] (2) can effect
highly diastereoselective catalytic epoxidation of allyl-
substituted cycloalkenes with up to >99:1 trans-selectivity.7
(1) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(2) For selected examples on trans-selective epoxidations, see: (a)
Kurihara, M.; Ito, S.; Tsutsumi, N.; Miyata, N. Tetrahedron 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.
(3) For other methods on the synthesis of trans-R,â-epoxy alcohols,
see: (a) Dubey, S. K.; Kumar, S. J. Org. Chem. 1986, 51, 3407. (b)
Ravikumar, K. S.; Chandrasekaran, S. Tetrahedron 1996, 52, 9137 and
references therein.
(4) (a) Meunier, B. Chem. ReV. 1992, 92, 1411. (b) Dolphin, D.; 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.
(5) (a) Groves, J. T.; Nemo, T. E. J. Am. Chem. Soc. 1983, 105, 5786.
(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, 112, 5356. (f)
Collman, J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S. Brauman, J. I. Science
1993, 261, 1404.
10.1021/ol0496475 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/10/2004

Table 2. Diastereoselective Epoxidation of 3c Catalyzed by
Mn Porphyrinsa
% yield
trans-:cis-
entry
catalyst
% conv.b of epoxidec epoxide ratiod
1
2
3
4
[Mn(TDCPP)Cl] (1)
[Mn(TMP)Cl]
[Mn(TFPP)Cl]
[Mn(TTP)Cl]
100
16
28
88
56
61
n.d.
33:1
22:1
12:1
n.d.
<5
a Unless otherwise indicated, all epoxidation reactions were conducted
at room temperature: To a solution of 0.25 mmol of alkene and 0.003 mmol
of 1 in 4 mL of CH3CN was added a premixed solution of 0.5 mL of 0.8
M aqueous NH4HCO3, 0.5 mL of CH3CN, and 0.125 mL of 35% H2O2.
b Determined by GC with internal standard. c Isolated yield based on
substrate conversion, and a trace amount of enone was observed by 1H
NMR. d Determined by GC.
Our working hypothesis for the highly diastereoselective
epoxidation is based on strong steric interaction between the
substrate and the bulky porphyrin ligand. At the outset, we
studied the epoxidation of SitBu(CH3)2-protected cyclohexen-
1-ol 3c using 1 as catalyst and H2O2 as oxidant.8,9 Treatment
of a CH3CN solution of 3c and 1 (1.2 mol %) with a solution
of 35% H2O2 in aqueous NH4HCO3/CH3CN10 afforded trans-
and cis-epoxides 4c in 88% isolated yield.11 On the basis of
capillary GC analysis, the trans-selectivity (i.e., trans-/cis-
epoxide ratio) was determined to be 33:1 (Table 1, entry 3).
The activities of other manganese porphyrin catalysts for
the diastereoselective epoxidation of 3c were examined under
the same reaction conditions (Table 2). It was found that
[Mn(TDCPP)Cl] (1) exhibits the best catalytic activity (88%
epoxide yield) and trans-selectivity (33:1). With [Mn(TMP)-
Cl] as catalyst, lower epoxide yield (56% yield based on
16% conversion) and trans-selectivity (22:1) were observed.
While [Mn(TTP)Cl] was found to exhibit poor catalytic
activity (<5% conversion), the perfluorinated analogue (i.e.,
[Mn(TFPP)Cl]) gave modest catalytic activity (61% yield
based on 25% conversion) and trans-selectivity (12:1).
Table 1. Diastereoselective Epoxidation of Substituted
a
Cycloalkenes 3a-n by 1 Using H2O2
(6) (a) Che, C.-M.; Liu, C.-J.; Yu, W.-Y.; Li, S.-G. J. Org. Chem. 1998,
63, 7364. (b) Liu, C.-J.; Yu, W.-Y.; Che, C.-M.; Yeung, C.-H. J. Org. 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.
(7) For selected examples on the synthetic utilities of trans-epoxides of
cycloalkenes in organic synthesis, see: (a) Tanaka, H.; Yamada, H.;
Matsuda, A.; Takahashi, T. Synlett 1997, 381. (b) Crotti, P.; Di Bussolo,
V.; Favero, L.; Macchia, F.; Pineschi, M. Eur. J. Org. Chem. 1998, 1675.
(c) Hutchison, T. L.; Saeed, A.; Wolkowicz, P. E.; McMillin, J. B.;
Brouillette, W. J. Bioorg. Med. Chem. 1999, 7, 1505. (d) Demay, S.;
Kotschy, A.; Knochel, P. Synthesis 2001, 863. (e) Tachihara, T.; Kitahara,
T. Tetrahedron 2003, 59, 1773. (f) Ahn, D.-R.; Mosimann, M.; Leumann,
C. J. J. Org. Chem. 2003, 68, 7693.
(8) Manganese porphyrins are known to be effective catalysts for
epoxidation of simple alkenes using H2O2; see for examples: (a) Battioni,
P.; Renaud, J. P.; Bartoli, J. F.; Reina-Artiles, M.; Fort, M.; Mansuy, D. J.
Am. Chem. Soc. 1988, 110, 8462. (b) Battioni, P.; Mansuy, D. J. Chem.
Soc., Chem, Commun. 1994, 1035. (c) Poriel, C.; Ferrand, Y.; Le Maux,
P.; Rault-Berthelot, J.; Simonneaux, G. Tetrahedron Lett. 2003, 44, 1759.
See also ref 4b.
(9) General Procedure for 1-Catalyzed Epoxidation Reactions (Table
1, Entry 3). To a round-bottom flask containing [Mn(TDCPP)Cl] (1) (3.0
mg, 0.003 mmol) and 3c (53.0 mg, 0.25 mmol) in CH3CN (4 mL) was
added a premixed solution of 35% H2O2 (0.125 mL), aqueous NH4HCO3
(0.8 M, 0.5 mL), and CH3CN (0.5 mL) via a syringe pump for 1.5 h at
room temperature. After being stirred for 1 h, the reaction mixture was
diluted with saturated aqueous Na2S2O3 (1 mL) and extracted with n-hexane
(4 × 20 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered through a short pad of silica gel, and concentrated under
reduced pressure. The ratio of trans-4c to cis-4c was determined to be 33:1
by capillary GC analysis. The residue was purified by flash column
chromatography (5% EtOAc in n-hexane) to provide a mixture of epoxides
trans-4c and cis-4c (49 mg, 88% yield based on complete alkene conversion)
as a colorless oil.
(10) For MnSO4 salt catalyzed alkene epoxidation using bicarbonate-
activated H2O2, see: (a) Burgess, K.; Lane, B. S. J. Am. Chem. Soc. 2001,
123, 2933. (b) Lane, B. S.; Vogt, M.; DeRose, V. J.; Burgess, K. J. Am.
Chem. Soc. 2002, 124, 11946.
(11) In control experiments, no epoxidation of 3c was observed either
in the absence of NH4HCO3 or 1. The H2O2/NH4HCO3 mixture alone (i.e.,
without catalyst 1) did not effect epoxidation of 3c.
a Unless otherwise indicated, all the epoxidation reactions were performed
as follows: To a solution of alkene (0.25 mmol) and 1 (3 µmol) in CH3CN
(4 mL) was added a premixed solution of 0.8 M aqueous NH4HCO3 (0.5
mL), CH3CN (0.5 mL), and 35% H2O2 (0.125 mL) at room temperature.
b Isolated yield based on complete alkene consumption, and <5% of enone
1
1
was formed on the basis of H NMR analysis. c Determined by H NMR.
d Epoxidations were carried out in CH2Cl2 for 3 h with an alkene/m-CPBA/
NaHCO3 molar ratio of 1:1.5:3. e Determined by GC. f 7-15% of enone
was formed on the basis of 1H NMR analysis. g 10% of 3-methyl-2-
cyclohexenone was detected by 1H NMR. h Isolated yield based on 87%
alkene conversion. i Isolated yield based on 84% alkene conversion. j No
epoxide was detected.
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Org. Lett., Vol. 6, No. 10, 2004

With these data in hand, other substrates have been
examined by using 1 as catalyst. The catalytic oxidation of
3g (R1 ) OSitBu(CH3)2, R2 ) CH3) proceeded with 80%
epoxide formation and trans-selectiVity >99:1 (Table 1, entry
7). It is known that m-CPBA and dioxiranes are common
oxidants for alkene epoxidation. We found that 3c and 3g
reacted with m-CPBA to give trans-4c and trans-4g with
trans-selectivities of 5:1 and 8:1, respectively. According to
the literature, the trans-selectivities obtained in dioxirane
mediated epoxidation of 3c and 3g are 13:12a and 20:1,2e
respectively. To our knowledge, the trans-selectivity for the
1-catalyzed epoxidation of 3c and 3g are the best results ever
achieved.
Table 3. Diastereoselective Epoxidation of Substituted
Cycloalkenes by 2 Using 2,6-Dichloropyridine N-Oxidea
The trans-selectivity was found to be dependent upon the
size of the substituents R1 and R2. Noting that the 1-catalyzed
epoxidaiton of 3c (R1 ) OSitBu(CH3)2, R2 ) H) proceeded
with excellent trans-selectivity (trans/cis ) 33:1), the related
reactions with 3a (R1 ) OH, R2 ) H) and 3b (R1 ) OAc,
R2 ) H) were found to exhibit lower diastereoselectivity
(trans/cis ∼ 5:1). When 3d (R1 ) OSitBu(Ph)2, R2 ) H)
was employed as substrate, the 1-catalyzed reaction attained
a lower diastereoselectivity (16:1) compared to the value for
the related reaction of 3c. Similar dependence on substituent
was also encountered for the catalytic epoxidation of 3e-h.
Interestingly, the trans-selectivities obtained in the epoxi-
dation of 3e-h with R2 ) CH3 were significantly higher
than that of 3a-d with R2 ) H. It should be noted that in
all cases trans-epoxides were obtained selectively in moder-
ate to good yields with much better trans-selectivity than
the m-CPBA-mediated reactions.
With 1 as catalyst, we also studied the catalytic epoxidation
of allylic esters and amines. As shown in Table 1, trans-
selectivity of 35:1 was attained for the epoxidation of 3k
(R1 ) COOCH(Ph)2, R2 ) H). However, with m-CPBA as
oxidant, only equimolar mixtures of trans-/cis-epoxides were
obtained for the oxidation of 3i-k. Amine 3l (R1 ) N(Boc)2,
R2 ) H) can be readily converted to its trans-epoxide
selectively (trans/cis ) 30:1) under the 1-catalyzed condi-
tions. For 1-catalyzed epoxidation of cyclopenten-1-ols 3m
(R1 ) OSitBu(CH3)2) and 3n (R1 ) OCH2Ph), trans-
selectivities of 18:1 and 10:1 were attained, respectively.
We also examined the catalytic activity of [Ru(TDCPP)-
CO] (2) for cyclohexene epoxidation (Table 3).12 The
2-catalyzed epoxidation of 3a furnished cis-epoxide as major
product (trans/cis ) 1:5). Assuming a metal-oxo intermedi-
a All the epoxidation reactions were carried out in CH2Cl2 at 40 °C for
48 h with a 2/2,6-Cl2pyNO/alkene molar ratio of 1:150:100 under nitrogen
1
atmosphere. b Determined by H NMR with internal standard.
ate, the observed cis-selectivity is probably due to the
hydrogen-bonding effect of the syn-directing OH group in
CH2Cl2.13 Compared to 1, 2 was found to afford much higher
trans-selectivities in the catalytic epoxidation of 3c (>99:
1), 3i (8:1), and 3m (71:1). Interestingly, under the 2-cata-
lyzed epoxidation conditions, enone 3o was converted to
trans-epoxide exclusively, while the analogous reaction of
enone 3p gave the corresponding trans-epoxide as major
product (trans/cis ) 44:1).
In summary, we have developed general and efficient
methods for highly diastereoselective epoxidation of allyli-
cally substituted cycloalkenes by sterically bulky Mn- and
Ru-porphyrin catalysts. Our protocols offer an easy assess
to a diversity of synthetically useful trans-epoxides of
cycloalkenes. Application of the diastereoselective epoxida-
tion methods for natural product synthesis and kinetic
resolution of the substituted cycloalkenes using chiral metal
catalysts are under investigation.
Acknowledgment. This work was supported by The
University of Hong Kong (University Development Fund),
the Hong Kong Research Grants Council (HKU7384/02P),
and the Areas of Excellence Scheme (AoE/P-10-01) estab-
lished under the University Grants Council (HKSAR).
Supporting Information Available: Characterization
1
data of 3 and 4; GC and H NMR determinations of the
trans-/cis-epoxide ratios; 1H and 13C NMR spectra of 3h,j,k
and 4h,j-l. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) General Procedure for 2-Catalyzed Epoxidation Reactions
(Table 3, Entry 2). To a dried CH2Cl2 solution (4 mL) containing 3c (53.0
mg, 0.25 mmol) were added [Ru(TDCPP)(CO)(MeOH)] (2) (2.6 mg, 0.0025
mmol) and 2,6-Cl2pyNO (61.5 mg, 0.38 mmol) under an nitrogen
atmosphere. After being stirred at 40 °C for 48 h, the reaction mixture was
concentrated under reduced pressure. The residue was added 4-bromochlo-
robenzene as an internal standard, and the organic products were then
OL0496475
1
analyzed and quantified by H NMR spectroscopy. The ratio of trans-4c/
(13) For highly threo selective epoxidation of allylic alcohols via syn-
directing hydrogen bonding effect, see: Adam, W.; Stegmann, V. R.; Saha-
Moller, C. R. J. Am. Chem. Soc. 1999, 121, 1879.
cis-4c was determined to be >99:1 by 1H NMR. The yield of epoxides
trans-4c and cis-4c was 85% based on complete alkene conversion.
Org. Lett., Vol. 6, No. 10, 2004
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