Concerning the efficient conversion of epoxy alcohols into epoxy ketones using dioxiranes

Article abstract of DOI:10.1021/jo048816w

Representative epoxy alcohols are cleanly converted into the corresponding epoxy ketones in high yield by selective oxidation using dimethyldioxirane (1a) and its trifluoro analogue (1b) under mild conditions. The oxidation is found to take place leaving the configuration at the epoxy functionality unaffected. The direct oxyfunctionalization of simple cyclic epoxides with the powerful dioxirane 1b provides another attractive method to access epoxy ketones regioselectively.

Full text of DOI:10.1021/jo048816w

CHART 1
Concerning the Efficient Conversion of
Epoxy Alcohols into Epoxy Ketones Using
Dioxiranes
Lucia D’Accolti,† Caterina Fusco,‡ Cosimo Annese,†
Maria R. Rella,§ Joanna S. Turteltaub,§
Paul G. Williard,*,§ and Ruggero Curci*,†,§
Dipartimento Chimica, Universita` di Bari,
CNRsICCOM, v. Amendola 173, I-70126 Bari, Italy, and
Department of Chemistry, Brown University,
Providence, Rhode Island 02912
sponding allylic- or homoallylic alcohols has been the
subject of extensive studies.5-7 Thus, the search for
efficient oxidants that allow this transformation with
high selectivity and yields represents a significant goal,
and especially so in multistep synthetic sequences. For
instance, one of us (P.G.W.), long actively engaged in the
convergent synthesis8 of active 1R,25-dihydroxyvitamin
D3 analogues,9 was faced with the goal of carrying out
the transformation of the CD-ring epoxy alcohol 2 into
the corresponding carbonyl 3 (Chart 1) in the highest
yield achievable.
For this transformation, one obvious choice is to employ
the classic metal-based oxidants.5-7 In fact, the most
efficient method reported to-date involves using pyri-
dinium dichromate (PDC) in CH2Cl2, affording 3 in 65%
yield.10 In our hands other transition-metal oxidants tried
were found to give distinctly inferior yields. For instance,
stoichiometric RuO4 (prepared from RuO2 and NaIO4)5e
provided 3 in 28% yield only; additional complications
in using RuO4 derived from its toxicity and difficulties
in handling. Application of the established Dess-Martin
periodinane oxidant11 afforded the target epoxy ketone
in 53% yield. Alternatively, one may seek to use other
mild nonmetal organic oxidants that mediate efficient
homogeneous oxidations without the need of metal
complexes.12 Indeed, one major benefit of metal-free
csmirc17@area.ba.cnr.it
Received July 13, 2004
Abstract: Representative epoxy alcohols are cleanly con-
verted into the corresponding epoxy ketones in high yield
by selective oxidation using dimethyldioxirane (1a) and its
trifluoro analogue (1b) under mild conditions. The oxidation
is found to take place leaving the configuration at the epoxy
functionality unaffected. The direct oxyfunctionalization of
simple cyclic epoxides with the powerful dioxirane 1b
provides another attractive method to access epoxy ketones
regioselectively.
During the past decade, applications in synthesis of
the currently popular dimethyldioxirane (1a) (DMD)1 and
of methyl(trifluoromethyl)dioxirane (1b) (TFD)2 as effec-
tive oxidants have proliferated to access valuable syn-
thons.3
Racemic and optically active epoxy ketones count
among the most versatile building blocks in organic
synthesis.4 Indeed, both the ketone and epoxide moieties
can be further functionalized to provide interesting
intermediates, useful for the synthesis of natural and
biologically active products.4
Epoxy alcohols represent attractive precursors of epoxy
ketones since they are readily available by epoxidation
of the corresponding unsaturated compounds.5-7 In fact,
the stereoselective synthesis of R,â-epoxy and â,γ-epoxy
alcohols via diastereoselective epoxidation of the corre-
(5) (a) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.;
Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254.
(b) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63.
(c) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 1657.
(d) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(e) Nakata, H. Tetrahedron 1963, 19, 1959.
(6) (a) Prat, D.; Delpech, B.; Lett, P. Tetrahedron Lett. 1986, 27,
711. (b) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51, 13039. (c) Adam,
W.; Mitchell, C. M. Saha-Mo¨ller, C. R. J. Org. Chem. 1999, 64, 3699.
(d) Adam, W.; Stegmann, V. R.; Saha-Mo¨ller, C. R. J. Am. Chem. Soc.
1999, 121, 1879.
(7) (a) Adam, W.; Alsters, P. L.; Neumann, R.; Saha-Mo¨ller, C. R.;
Sloboda-Rozner, D.; Zhang, R. J. Org. Chem. 2003, 68, 1721. (b) Adam,
W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703 and references therein.
(8) (a) Zhu G. D.; Okamura, W. H. Chem Rev. 1995, 95, 1877. (b)
Dai, H.; Posner, G. H. Synthesis 1994, 1383. (c) Lythgoe, B. Chem.
Soc. Rev. 1981, 10, 449. (d) Baggiolini E. G.; Jacobelli, J A.; Hennessy,
B. M.; Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. J Org. Chem.
1986, 51, 3098. (e) Uskokovic, M. R.; Studzinski, G. P.; Gardner, J. P.;
Reddy, S. G.; Campbell, M. J.; Koeffler, H. P. Curr. Pharm. Des. 1997,
3, 99. (f) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. Rev.
1995, 16, 200.
* Corresponding author: Fax: +39-080-5442924. Phone: +39-080-
5442070.
† Universita` di Bari.
‡ CNRsIstituto di Chimica dei Composti Organometallici (ICCOM),
Bari Section, Italy.
§ Brown University.
(1) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(b) Cassidei, L.; Fiorentino, M.; Mello, R.; Sciacovelli, O.; Curci, R. J.
Org. Chem. 1987, 52, 699. (c) Murray, R. W.; Singh, M. Org. Synth.
1996, 74, 91.
(2) (a) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org.
Chem. 1988, 53, 3890. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci,
R. J. Am. Chem. Soc. 1989, 111, 6749. (c) D’Accolti, L.; Fusco, C.; Rella,
M. R.; Curci, R. Synth. Commun. 2003, 33, 3009.
(3) For reviews, see: (a) Curci, R.; Dinoi, A.; Rubino, M. F. Pure
Appl. Chem. 1995, 67, 811. (b) Adam, W.; Hadjiarapoglou, L. P.; Curci,
R.; Mello, R. In Organic Peroxides; Ando, W., Ed.; Wiley: New York,
1992; Chapter 4, pp 195-219. (c) Curci, R. In Advances in Oxygenated
Processes; Baumstark, A. L., Ed.; JAI: Greenwich, CT, 1990; Vol 2,
Chapter I, pp 1-59. (d) Murray, R. W. Chem. Rev. 1989, 89, 1187. (e)
Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205. (f)
Denmark, S. E.; Wu, Z. Synlett 1999, S1, 847.
(9) Nancy E. Lee, N. E.; Reddy, G. S.; Brown, A. J.; Williard, P. G.
Biochemistry 1997, 36, 9429. See also previous articles of the series.
(10) Daniewski, A. R.; Kiegiel, J. J. Org. Chem. 1988, 53, 5534.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph 186;
American Chemical Society: Washington, DC, 1990. See also refer-
ences therein.
(4) For a review, see: Lauret, C. Tetrahedron: Asymmetry 2001, 12,
2359 and references therein.
(12) Adam, W.; Saha-Mo¨ller, C. R.; Ganeshpure, P. A. Chem. Rev.
2001, 101, 3499 and references therein.
10.1021/jo048816w CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/26/2004
8510
J. Org. Chem. 2004, 69, 8510-8513

TABLE 1. Selective Oxidation of Epoxy Alcohols into Epoxy Ketones Employing Dimethyldioxrane or
Methyl(trifluoromethyl)Dioxiranea
a Unless noted otherwise, all reactions were routinely run at 0 °C; solvent composition was ca. 10:1 CH2Cl2/1,1,1-trifluoropropanone
(TFP) for oxidations with 1b and ca. 8:2 CH2Cl2/acetone for oxidations with 1a. b Molar ratio of dioxirane oxidant to substrate. c As
determined ((3%) by GC (ZB-1, 0.25 µm film thickness, 30 m × 0.25 mm i.d., capillary column), Freon A112 internal standard. d Isolated
yield ((5%). e [R]D +24.3° (c 1.6, CHCl3) [lit.11 [R]D +24.8° (c 1.4, CHCl3)]. f Enantiomeric excess determined by chiral stationary phase
GC (Astec, Beta-DM); [R]D +42.1° (c 0.9, CHCl3) [lit.11 [R]D +42.7° (c 1.0, CHCl3)]. g Ref 13. h As determined by GC and integrated 1H
NMR spectra. i [R]D +1.9° (c 1.1, CHCl3); major diastereoisomer: (2S,4S)-4,5-epoxy-2-pentanol. j (4S)-4,5-Epoxy-2-pentanone; [R]D -0.12°
(c 4.2, CHCl3); enantiomeric excess determined as in footnote f. k Racemic mixture 50:50.
organic oxidants consists of their better environmental
acceptance with respect to transition-metal catalysts.
Actually, in recent years several nonmetal organic oxi-
dants have been introduced that were widely employed
in selective oxidations.12 Among them the dioxiranes 1
rank high because of their remarkable efficiency, superior
versatility, and ease of operations. These nonmetal
electrophilic oxygen-transfer agents are easily prepared
from suitable ketones and the low-cost potassium per-
oxymonosulfate KHSO5 (Oxone, Caroate) under buffered
conditions (pH 7-7.5). Reactions performed with diox-
iranes 1 in isolated form (as solutions in the parent
ketones)1-4 appear to be best suited for stoichiometric
oxidations under strictly neutral conditions of numerous
acid- or base-sensitive substrates, as well as of hydro-
lytically labile oxyfunctionalized products.4 Ensuing our
pioneering studies on dioxirane oxidations of alcohols,13
this class of novel oxidants has been widely employed for
the conversion of alcohols into carbonyls;12 however, their
application in the selective oxidation of epoxy alcohols
appears to have been only marginally explored.13 We
present herein our data concerning the utilization of
dioxiranes for the selective oxidation of representative
epoxy alcohols under mild conditions. Typical results and
reaction conditions are collected in Table 1.
Tricyclic 2 and several open-chain and cyclic epoxy
alcohols were screened as starting materials; they were
obtained by following published procedures. The Vitamin
D3 CD-synthon 2 was prepared starting with Hajos
dione.14 The â-epoxy alcohols 8, 10, and 14 were easily
obtained by DMD epoxidation of the corresponding
(13) Mello, R.; Cassidei, L.; Fiorentino, M.; Fusco, C.; Hu¨mmer, W.;
Ja¨ger, V.; Curci, R. J. Am. Chem. Soc. 1991, 113, 2205.
J. Org. Chem, Vol. 69, No. 24, 2004 8511

homoallylic alcohols.15 The latter in turn were prepared
starting with the corresponding 1,3-dienes upon selective
monoepoxidation using DMD, followed by reductive ep-
oxide ring cleavage (LiAlH4/Et2O). By the same proce-
dure, the bicyclic syn-γ-epoxy alcohol 16 could be syn-
thesized starting with 1,5-cyclooctadiene. Allylic bromi-
nation (NBS) of cis-cyclooctene, followed by hydrolysis
(H2O, NaHCO3) and DMD epoxidation, afforded anti-
epoxy alcohol 12 in >95% overall yield.
were carried out employing excess TFD (1b) at the
conditions shown in eqs 1 and 2.
DMD (1a) and TFD (1b) solutions that were 0.08-0.1
M in acetone and 0.7-0.8 M in 1,1,1-trifluoropropanone
(TFP), respectively, were prepared as already reported
in detail.1-3 The simple oxidation procedure involved the
addition of an aliquot (usually from 0.5 to 25 mL) of
standardized cold solution of 1a or of 1b to a stirred
solution of the epoxy alcohol (15-500 mg) in CH2Cl2 or
acetone (10-30 mL). The reactions were monitored by
GC, GC/MS, and/or TLC, and product isolation simply
entailed removal of solvent in vacuo; yields of isolated
product were >90% in most of the cases (Table 1). The
epoxy ketone products were identified by 1H and 13C
NMR, FTIR, and mass spectrometry in comparison with
literature data.
Data in Table 1 reveal that both dioxiranes 1a and 1b
can be successfully applied to carry out the transforma-
tion at hand. In fact, both open-chain and cyclic epoxy
alcohols could be neatly transformed into the correspond-
ing epoxy ketones with high conversions and yields using
just 1.1-1.6 equiv of the oxidant. However, reaction times
were much shorter (cf. entries 3-9) using the powerful
methyl(trifluoromethyl)dioxirane (1b). In all of the cases
examined, complete chemoselectivity is achieved in that
just the alcohol functionality is oxidized while the epoxide
moiety remains untouched. Also, the conversion of opti-
cally active substrates (entries 1, 2, and 4) into epoxy
ketones occurs selectively, leaving the configuration at
the chiral center(s) at the oxirane ring practically unaf-
fected.
On the basis of kinetic data and the application of
reaction probes already reported,13 the selectivities moni-
tored herein should be ascribed to a substantially con-
certed O-insertion by the dioxirane into the C-H bond
“R” to the OH functionality generating a gem-diol C(OH)2,
hence the carbonyl. Be the mechanistic details as they
may, the results above suggest that dioxirane oxidation
of epoxy alcohols provides a simple, mild, and efficient
method to access epoxy ketones useful in synthesis.
As a corollary to this feat, it is worthy of notice that
our initial survey points out that certain epoxy ketones
might become available by the direct oxyfunctionalization
of the corresponding epoxides. The powerful methyl-
(trifluoromethyl)dioxirane (1b) should be the reagent of
choice for carrying out these difficult transformations
amounting to O-insertion into “unactivated” C-H bonds.3
The examples provided by the oxyfunctionalization of
cyclohexene oxide 18 and of cyclooctene oxide 19 serve
to call attention to this alternate route. The oxidations
It is seen that in both cases the oxirane moiety again
remains intact; furthermore, remarkable regioselectivity
is attained. In fact, oxidation of epoxide 18 results in
â-epoxy ketone 11 in high yield. In the oxidation of
cyclooctene oxide 19, the â-epoxy ketone 15 is ac-
companied by the γ-epoxy ketone as the major product.
In both cases, oxidation at the methylene CH2 R to the
epoxide ring is practically bypassed. Thus, opposite to
what was found with the cyclopropyl moiety in similar
systems, the oxiranyl ring produces a deactivating effect
on proximal R-CH2 toward dioxirane oxidations.16 This
may be ascribed to the electron-withdrawing effect
exercised by the oxirane oxygen on the electron density
at proximal C-H bonds submitted to electrophilic O-
insertions by the dioxirane.3,16 However, the marked
prevalence for oxyfunctionalization at CH2 in the γ-posi-
tion (δ with respect to the oxirane oxygen) recorded in
the oxidation of the larger ring bicyclic epoxide 19
suggests that complex stereochemical and/or stereoelec-
tronic factors come into play. This is also advocated by a
recent study wherein high regioselectivity at the remote
bridgehead C7-H and C5-H was reported for the TFD
oxyfunctionalization of the structurally rigid methylene-
adamantane oxide.17 The scenario might bear some
resemblance to the regioselectivities observed in TFD
oxyfunctionalization at distant C-H bonds of open-chain
or cyclic compounds bearing electron-withdrawing func-
tionalities such as benzoate or benzenesulfonic esters.18
In that case, hyperconjugative and steric interactions
were invoked in order to rationalize the results.18 Clearly,
precise mechanistic studies are in order to unravel the
subtle effects leading to remote oxyfunctionalization here.
Results reported herein show promise of practical value
in organic synthesis because of the efficiency and simplic-
ity. It constitutes yet another useful entry into either
structurally simple or complex epoxy ketones that are
important building blocks in the synthesis of natural
products and fine chemicals.
Experimental Section
The following procedures are representative for oxidations of
substrates herein using dioxiranes.
(16) (a) D’Accolti, L.; Dinoi, A.; Fusco, C.; Russo, A.; Curci, R. J.
Org. Chem. 2003, 68, 7806. (b) D’Accolti, L.; Fusco, C.; Lucchini, V.;
Carpenter, G. B.; Curci, R. J. Org. Chem. 2001, 66, 9063 and references
therein.
(14) (a) Hajos, Z. G., Parish, D. R. Organic Synthesis; Wiley: New
York, 1990; Collect. Vol. VII, p 363. (b) Ro¨hrig, S.; Hennig, L.;
Findeisen, M.; Welzel, P.; Mu¨ller, D. Tetrahedron 1998, 54, 3439.
(15) For instance, see: (a) D’Accolti, L.; Fiorentino, M.; Fusco, C.;
Rosa, A. M.; Curci, R. Tetrahedron Lett. 1999, 40, 8023. (b) Adam, W.;
Mitchell, C. M.; Saha-Mo¨ller, C. R. J. Org. Chem. 1999, 64, 3699 and
references therein.
(17) D’Accolti, L.; Kang, P.; Khan, S.; Curci, R.; Foote, C. S.
Tetrahedron Lett. 2002, 43, 4649.
(18) Asensio, G.; Castellano, G.; Mello, R.; Gonzale`z-Nun˜ez, M. E.
J. Org. Chem. 1996, 61, 5564.
8512 J. Org. Chem., Vol. 69, No. 24, 2004

Oxidation of (1S,3aR,4R,5S,7aS)-4,5-Epoxy-7a-meth-
yloctahydro-1H-inden-1-ol (2) with Dimethyldioxirane
(1a). A standardized solution of DMD (1a) in acetone (1.8 mL,
0.07 M, 0.12 mmol) was added in one portion to a stirred solution
of the epoxy alcohol (2) (14 mg, 0.083 mmol) in acetone (0.6 mL)
at 20 °C. The reaction progress was monitored by TLC. After
2.5 h of reaction time (conversion ) 98%), removal of the volatile
solvent in vacuo afforded >98% pure (GC) (3aR,4R,5S,7aS)-
4,5-Epoxy-7a-methyloctahydro-1H-inden-1-one (3) (13 mg,
0.078 mmol, yield 98%): oil, [R]D ) +42.1° (c 0.9, CHCl3),
practically identical with reported literature data;10 GC/MS (70
eV) m/z (r.i.) 166 (M+), 151 (M+ - 15, 0.9), 123 (16), 110 (19), 95
(47), 67 (48), 42 (42), 41 (100); 13C NMR (CDCl3, 125 MHz) δ
218.5 (CdO), 55.5 (C-O), 50.6 (C-O), 47.4, 44.7, 35.4, 27.0, 24.5,
21.8 (CH2), 15.1 (CH3); FTIR and 1H NMR in excellent agree-
ment with literature.10
Oxidation of (2S,4S)-4,5-Epoxy-2-pentanol (6a) with
Methyl(trifluoromethyl)dioxirane (1b). To a stirred solution
of 6a (500 mg, 4.9 mmol) in CH2Cl2 (15 mL) at 0 °C was added
a solution of 1b in 1,1,1-trifluoropropanone (TFP) (9 mL, 0.65
M, 5.8 mmol) in one portion. The reaction was monitored by GC
(Freon A112 internal standard). After 20 min (conversion )
98%), removal of solvent in vacuo afforded pure (>99%, GC)
(4S)-4,5-epoxy-2-pentanone (7a) (440 mg, 4.41 mmol, yield
90%): colorless liquid, bp 83-85°C; [R]D ) -0.12° (c 4.2, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 3.25 (m, 1H), 2.85 (m, 2H, J1 ) 5,
J2 ) 4 Hz), 2.50 (m, 2H, J ) 5 Hz), 2.42 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 206.0 (CdO), 47.5 (C-O), 46.5 (C-O), 46.5 (CH2),
30.3 (CH3); IR (neat) 3057, 3003, 2927, 1714 (CdO), 1425, 1398,
1362, 1262, 1169, 931, 859 cm-1; GC/MS (70 eV) m/z (r.i.) 100
(M+), 85 (M+ - 15, 0.2), 71 (0.3), 58 (4), 57 (5), 55 (1), 44 (3), 43
(100); HRMS calcd for C5H8O2 100.052430, found 100.052374.
Using chiral column GC (100 °C, 1.1 mL/min, He c.g.; Astec
â-DM column, 30 m × 0.25 mm i.d., 0.25 µm film thickness),
the ee was determined to be 40%.
substrate (493 mg, 3.91 mmol) in acetone (20 mL) kept at 0 °C
was added a standardized solution of dioxirane 1b in TFP (25
mL,0.65 M, 16 mmol) in one portion. The reaction was monitored
by GC and GC/MS. After 2 h (conversion ) 70%), removal of
the solvent in vacuo and subambient (2-5 °C) column chroma-
tography (silanized SiO2) afforded pure (>98%, GC) 9-oxa-
bicyclo[6.1.0]nonan-4-one (17)19,20 (383 mg, 274 mmol, yield
70%; colorless solid, mp 78-80 °C, [lit.21 78-80 °C]; spectral data
in agreement with literature19,21) and byproduct 9-oxa-bicyclo-
[6.1.0]nonan-3-one (15) (54 mg, 0.39 mmol, yield 10%; colorless
solid, mp 65-68 °C [lit.22 67-68 °C]; spectral data identical with
literature21,22).
Acknowledgment. Partial support of this work by
the Ministry of University and Scientific and Research
of Italy (COFIN National Project) and the National
Research Council of Italy (CNR) is gratefully acknowl-
edged. The work at Brown University was supported
in part by PHS Grant GM-35982 and NSF Grant
0213381 to P.G.W.
Supporting Information Available: Experimental de-
tails and supplemental characterization data for substrates
and products and chiral-column GC data for the determination
of the enantiomeric excess of the epoxy ketone 7a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048816W
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J. Org. Chem, Vol. 69, No. 24, 2004 8513