Substrate-induced diastereoselectivity in the dimethyldioxirane epoxidation of simple alkenes and dienes

Article abstract of DOI:10.1055/s-2001-18751

Various alkenes and dienes, such as (R)- or (S)-limonene 2, 2-carene 6, 3-carene 8, (R)-α-pinene 10, (S)-α-pinene 12, and endo-dicyclopentadiene 14 were transformed into the corresponding mono- and bis-epoxides by epoxidation with dimethyldioxirane (as an acetone solution). The selectivity observed in these epoxidations is explained by the assumption of hydrogen bonding between bridge protons and the dioxirane.

Full text of DOI:10.1055/s-2001-18751

LETTER
1847
Substrate-Induced Diastereoselectivity in the Dimethyldioxirane Epoxidation
of Simple Alkenes and Dienes
S
ubstrate-Induced
m
D
iastereoselectivity
a
in the
D
im
l
ethyldioxirane
a
E
poxidation Asouti, Lazaros P. Hadjiarapoglou*
Section of Organic Chemistry and Biochemistry,Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Fax +30(651)98799; E-mail: LXATZIAR@cc.uoi.gr
Received 23 July 2001
for the more electron-rich double bond of the molecule.
Abstract: Various alkenes and dienes, such as (R)- or (S)-limonene
Although the diastereoselectivity was poor [ratio R-3/R-
2, 2-carene 6, 3-carene 8, (R)- -pinene 10, (S)- -pinene 12, and
4 = 1:8], it is better than many other oxidation protocols
endo-dicyclopentadiene 14 were transformed into the correspond-
11
involving oxidants such as mCPBA9 or PhIO,10 H2O2
ing mono- and bis-epoxides by epoxidation with dimethyldioxirane
(as an acetone solution). The selectivity observed in these epoxida- and various Fe-porphyrins. The diastereoselectivity was
tions is explained by the assumption of hydrogen bonding between
bridge protons and the dioxirane.
influenced by the co-solvent used in the epoxidation
(Table 1). When acetonitrile or methanol, were used as
Key words: dimethyldioxirane, epoxidation, diasteroselectivity,
regioselectivity
co-solvents (entries 4, 6) the conversion was quantitative
but the diastereoselectivity was low, while in the case of
methanol the formation of bis-epoxide was negligible (
1%). In contrast, when dichloromethane was used (entries
Dimethyldioxirane (DMD, in situ or isolated as solution) 1, 3), the conversion was smaller, the diastereoselectivity
has been established1 as a widely-used oxidant, due to the better, and bis-epoxide R-5 was formed in larger amounts.
convenience of its isolation2 from cheap, commercially The best diastereoselectivity was observed in the case of
available starting materials, its efficiency, and its perfor- petroleum ether (entry 5), where also the lowest conver-
mance under strictly neutral conditions. Its reaction mode sion was obtained.
includes epoxidation3 of alkenes, oxygen insertion4 into
-bonds, and heteroatom oxidation.5 Alkene epoxidation
has found numerous applications6 in the total syntheses of
natural products. However, there are only few impressive
results of regio- and diastereoselective epoxidations with
DMD, i.e. the regioselective epoxidation7 of a disubstitut-
O
O
O
ed double bond over a trisubstituted enol ether moiety,
and the exclusive epoxidation8 at the endocyclic double
bonds of pentafulvenes.
R-2
+
+
CH2Cl2, CH3COCH3
-5 to 0 °C, 4 h, Ar
We thought that this powerful oxidant might be more re-
gio- and diastereoselective than initially assumed. A more
systematic investigation of simple strained alkenes could
lead to interesting observations concerning transition
states of the epoxidation mechanism. Herein, we report
the DMD epoxidations of simple bicyclic alkenes and
dienes yielding often regio- and diastereoselectively the
corresponding mono- and bis-epoxides.
O
R-5
Me
Me
O
O
R-3
R-4
66%
O
34%
1
O
O
S-2
+
+
CH2Cl2, CH3COCH3
-5 to 0 °C, 4 h, Ar
Epoxidation of (R)-(+)-limonene R-2 with dimethyldiox-
irane at –5 °C yields a 65:35 mixture of mono-epoxides
R-3, R-4 (66% yield at 90% conversion) and bis-epoxide
R-5 (34% yield at 90% conversion) (Scheme 1). The mix-
ture of epoxides R-3, R-4 was separated from R-5 by col-
umn chromatography; addition of another equivalent of
dimethyldioxirane led to the isolation of bis-epoxide R-5.
The corresponding 8,9-epoxide was not detected in the
crude reaction mixture, a fact that indicates the electro-
philic character of dimethyldioxirane and its preference
O
S-5
S-3
S-4
79%
12%
Scheme 1
It seems that the diastereoselectivity increases with the
electric dipole moment of the solvent; except in the case
of methanol where an extra hydrogen bonding of the sol-
vent with dimethyldioxirane prior to addition could occur.
The variation of temperature seems to have an effect only
in the conversion (entries 7, 8), even if in the case of pe-
troleum ether the regioselectivity decreases slightly.
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1847,1850,ftx,en;G15501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1848
A. Asouti, L. P. Hadjiarapoglou
LETTER
Table 1 Epoxidation of (R)-(+)-Limonene R-2 with Dimethyldioxirane
Entry
1
DMD (equiv) Temp (°C)
Time (min) Solvents
Conversion (%) Yield (%)
Ratio
R-3–R-4
R-3
R-4
R-5
2
–5
240
CH3COCH3–
87
49
27
24
1.8:1
CH2Cl2, 6:1
2
3
1
1
0
0
60
60
CH3COCH3
84
74
48
56
32
26
20
18
1.5:1
2.2:1
CH3COCH3–
CH2Cl2, 1:9
4
5
6
7
8
1
1
1
1
1
0
0
60
60
60
60
60
CH3COCH3–
CH3CN, 1:9
99
71
44
68
58
55
55
38
26
41
25
37
18
6
1.2:1
2.6:1
1.4:1
2.2:1
1.5:1
CH3COCH3–
C6H14, 1:9
0
CH3COCH3–
CH3OH, 1:9
100
48
1
–78
–78
CH3COCH3–
C6H14, 1:9
20
8
CH3COCH3–
CH3OH, 1:9
100
Similarly, epoxidation of (S)-(–)-limonene S-2 with dim- trisubstituted double bond from the same side with the
ethyldioxirane at –5 °C yields a 55:45 mixture of mono- proton of the 4-position.
epoxides S-3, S-4 (79% yield at 90% conversion) and bis-
Dimethyldioxirane epoxidation of 2-carene 6 or 3-carene
epoxide S-5 (12% yield at 90% conversion) (Scheme 1).
8 or (1R)-(+)- -pinene 10 or (1S)-(–)- -pinene 12 at –5 °C
The mixture of epoxides S-3, S-4 was separated from S-5
yields12 the corresponding anti-epoxides 7, 9, 11, and 13
by column chromatography; treatment of the mixture S-3,
in ca. 100%, ca. 100%, 92% and 95%, respectively
(Scheme 2). The other possible syn-epoxides were not de-
S-4 with another equivalent of dimethyldioxirane led to
the quantitative formation of bis-epoxide S-5. Again, the
tected. Elucidation of structures of 7, 9, 11, 13 came from
corresponding 8,9-epoxide was not detected. Although
extended NMR studies where the oxiranyl methyl group
the diastereoselectivity is smaller than for the correspond-
showed a ROESY effect with the signals of the cyclopro-
ing R-limonene, in both cases the anti-epoxide is prefera-
pyl methyl or the gem-dimethyl groups, a fact that provid-
bly formed. That means that the dioxirane attacks the
ed convincing evidence that all the methyl groups are on
H
O
O
H
8
10
H
CH2Cl2,CH3COCH3
CH2Cl2,CH3COCH3
-5 to 0 °C, 1 h, Ar
ca. 100%
-5 to 0 °C, 2 h, Ar
H
11
92%
Me
Me
9
O
O
1
H
H
6
O
O
12
CH2Cl2,CH3COCH3
CH2Cl2,CH3COCH3
H
-5 to 0 °C, 1 h, Ar
-5 to 0 °C, 2 h, Ar
95%
ca. 100%
H
13
7
Scheme 2
Synlett 2001, No. 12, 1847–1850 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Substrate-Induced Diastereoselectivity in the Dimethyldioxirane Epoxidation
1849
the same side, while the oxiranyl moiety resides on the op-
posite side. This indicates that the dimethyldioxirane ap-
proaches the double bond anti to the gem-dimethyl group
or syn to the cyclopropyl (bridge) protons.
O
H
H
15
+
When endo-dicyclopentadiene 14 was treated with dime-
thyldioxirane (1 equiv) at 0 °C, epoxides 15, 16 and bis-
epoxide 17 were produced13 in 39:41:20 ratio respectively
(Scheme 3). When excess of endo-dicyclopentadiene 14
was employed, then a mixture (49:51) of epoxides 15, 16
were produced. With excess of dimethyldioxirane, bis-ep-
oxide 17 was quantitatively produced. Treatment of mono
epoxide 15 or 16 with a new equivalent of dimethyldiox-
irane yields quantitatively bis-epoxide 17. These epoxides
are single diastereomers, and were separated by column
chromatography, which permitted their structure elucida-
tion.
Me
Me
O
O
(1 eq.)
H
H
H
H
O
CH3COCH3, CH2Cl2
0 °C, Ar, 5h, 75%
14
16
+
H
H
O
O
17
Scheme 3
The regioselectivity of this reaction, was influenced by
the co-solvent used for the epoxidation (Table 2). When
acetonitrile or methanol was used as co-solvents (entries
4, 6), the conversion was nearly quantitative and the ratio
of 15 to 16 was 0.7 and 1.1 respectively. In contrast, when
pure acetone or petroleum ether were used (entries 2, 5),
the conversion is smaller while the ratio becomes 1.2 and
1.4, respectively.
have no polar substituents but still solvent effects are ob-
served. We anticipate, that in all cases examined, a hydro-
gen bonding is formed16 between the incoming dioxirane
and the suitable bridge protons leading to an improved re-
gio- and diastereoselectivity. Thus, in the limonene series,
a hydrogen bonding between the proton of the C-4 posi-
tion and the dioxirane could be developed in the transition
state (Figure), leading to favored syn-addition (towards C-
4 proton). On the other hand, the mono-epoxidation (4
possible isomers) of endo-dicyclopentadiene could occur
either at the 4,5- or the 8,9-double bond. Hydrogen bond-
ing of the dioxirane with the protons at C-2, C-6 favors the
formation of epoxide 16, while the hydrogen bonding
with the C-10 proton favors epoxide 15.
It is generally accepted that DMD epoxidation proceeds
mainly via a spiro transition state. Solvent effects ob-
served in the DMD epoxidation of allylic alcohols,14 inter-
preted as a mix of several factors including electrostatic,15
substituent size,14 association14 of dioxirane with the adja-
cent hydroxy functionality in the transition state through
hydrogen bonding, and dipole-dipole interactions.14 Nev-
ertheless, in the examples reported here, the substrates
Table 2 Epoxidation of endo-Dicyclopentadiene 14 with Dimethyldioxirane
Entry
DMD (equiv)
Temp (°C)
Time (h)
Solvents
Conversions (%)
73
Yield (%)
Ratio
15–16
0.9:1
15
16
17
20
1
1
–10
18
CH3COCH3–
CH2Cl2, 2:1
39
41
2
3
1
1
0
0
2
2
CH3COCH3
80
71
55
48
45
52
0
0
1.2:1
0.9:1
CH3COCH3–
CH2Cl2, 1:9
4
5
6
7
8
1
0
0
0
0
0
2
2
CH3COCH3–
CH3CN, 1:9
97
77
53
59
43
0
47
41
57
0
0
0
1.1:1
1.4:1
0.7:1
1
CH3COCH3–
C6H14, 1:9
1
2
CH3COCH3–
CH3OH, 1:9
97
0
2.5
0.4
14
18
CH3COCH3–
CH2Cl2, 6:1
100
74
100
0
CH3COCH3–
CH2Cl2, 4:1
49
51
1:1
Synlett 2001, No. 12, 1847–1850 ISSN 0936-5214 © Thieme Stuttgart · New York

1850
A. Asouti, L. P. Hadjiarapoglou
LETTER
(5) (a) Murray, R. W.; Jeyaraman, R.; Pillay, M. K. J. Org.
O
O
Me
Chem. 1987, 52, 746. (b) Colonna, S.; Gaggero, N.
Tetrahedron Lett. 1989, 30, 6233. (c) Callopo, A. R.;
Edwards, J. O. J. Org. Chem. 1981, 46, 1684. (d) Murray,
R. W.; Jeyaraman, R.; Mohan, L. Tetrahedron Lett. 1986,
27, 2355. (e) Murray, R. W.; Rajadhyska, S. N.; Mohan, L.
J. Org. Chem. 1989, 54, 5783.
H
Me
O
H
H
1
O
O
Me
Me
Me
Me
O
8
H
4
A
B
(6) Recent examples: (a) Schkeryantz, J. M.; Woo, J. C. G.;
Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J. J. Am.
Chem. Soc. 1999, 121, 11964. (b) Crimmins, M. T.; Pace, J.
M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.;
Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc. 1999,
121, 10249. (c) White, J. D.; Sundermann, K. F.; Carter, R.
G. Org. Lett. 1999, 1, 1431. (d) Kocienski, P. J.; Raubo, P.;
Smith, C.; Boyle, F. T. Synthesis 1999, 2087. (e) Barrett, A.
G. M.; Head, J.; Smith, M. L.; Stock, N. S. Chem. Commun.
1999, 133. (f) Barrett, A. G. M.; Head, J.; Smith, M. L.;
Stock, N. S.; White, A. J. P.; Williams, D. J. J. Org. Chem.
1999, 64, 6005.
Figure Hydrogen Bonding between the dioxirane and the substrate
in the transitions states of the epoxidation of limonene (A) and endo-
dicyclopentadiene (B)
In conclusion, the above results indicate that a possible
hydrogen bonding16 between dioxirane and a suitable pro-
ton of the substrate results in selective epoxidations. Fur-
ther research on the extension of this useful selectivity is
currently under way in our laboratory.
(7) Nicolaou, K. C.; Prasad, C. V. C.; Ogilvie, W. W. J. Am.
Chem. Soc. 1990, 112, 4988.
(8) Adam, W.; Hadjiarapoglou, L.; Meffert, A. Tetrahedron
Lett. 1991, 32, 6697.
Acknowledgement
The generous support provided by Prof. Dr. Waldemar Adam, Uni-
versity of Wuerzburg is greatly acknowledged.
(9) Cane, D. E.; Yang, G.; Coates, R. M.; Pyun, H.-J.; Hohn, T.
M. J. Org. Chem. 1992, 57, 3454.
(10) (a) Groves, J. T.; Nemo, T. E. J. Am. Chem. Soc. 1993, 105,
5786. (b) Battioni, P.; Renaud, J. P.; Bartoli, J. F.; Reina-
Artilis, M.; Fort, M.; Mansuy, D. J. Am. Chem. Soc. 1998,
110, 8462.
(11) (a) Majetich, G.; Hicks, R.; Sun, G.-R.; McGill, P. J. Org.
Chem. 1998, 63, 2564. (b) Bösing, M.; Nöh, A.; Loose, I.;
Krebs, B. J. Am. Chem.Soc. 1998, 120, 7252. (c) de Villa,
P. A. L.; Sels, B. F.; De Yos, D. E.; Jacobs, P. A. J. Org.
Chem. 1999, 64, 7267.
(12) Representative Experimental Procedure. Synthesis of 7:
A 0.062 M solution of dimethyldioxirane in acetone (32 mL;
2 mmol) was added into a cooled (–5 °C) solution of 2-
carene (0.16 mL; 1 mmol) in dry CH2Cl2 (5 mL) under Ar
atmosphere. The resulting solution was stirred at –5 °C for 1
h. The solvents were removed under reduced pressure to
give epoxide 7 (150 mg; ca. 100% yield) as a colorless oil.
IR (neat): = 2735 cm–1, 1430, 1350, 1300, 1260, 1230,
1190, 1160, 1140, 1115, 1085, 1065, 1020, 965, 950, 880,
850, 790, 765, 710, 680. 1H NMR (250 MHz, CDCl3):
= 0.59–0.66 (m, 1 H), 1.03 (brs, 4 H), 1.04 (s, 3 H), 1.22 (s,
3 H), 1.45–1.57 (m, 1 H), 1.61–1.66 (m, 2 H), 1.80–1.94 (m,
1 H), 2.98 (d, J = 1.5 Hz, 1 H). 13C NMR (63 MHz, CDCl3):
= 16.4 (d), 20.7 (t), 21.0 (d), 21.8 (d)23.7 (d), 27.1 (t), 28.1
(d), 57.9 (d), 58.2 (s).
References
(1) (a) Murray, R. W. Chem. Rev. 1989, 89, 1187. (b) Adam,
W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22,
205. (c) Curci, R. In Advances in Oxygenated Processes,
Vol. 2; Baumstark, A. L., Ed.; JAI Press: Greenwich, 1980,
Chap. 1, 1. (d) Adam, W.; Hadjiarapoglou, L.; Curci, R.;
Mello, R. In Organic Peroxides; Ando, W., Ed.; J. Wiley and
Sons: New York, 1992, 195. (e) Adam, W.;
Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45.
(f) Clennan, E. L. Trends Org. Chem. 1995, 5, 231.
(g) Murray, R. W.; Sing, M. In Comprehensive Heterocyclic
Chemistry II, Vol. 1a; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996, 429. (h) Adam,
W.; Smerz, K. Bull. Soc. Chim. Belg. 1996, 105, 581.
(i) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (j) Crandall,
W. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1998, 2061.
(2) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
(3) (a) Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett.
1987, 28, 3311. (b) Baumstark, A. L.; Vasquez, P. C. J. Org.
Chem. 1988, 53, 3437. (c) Adam, W.; Hadjiarapoglou, L.;
Jager, V.; Klicic, J.; Seidel, B.; Wang, X. Chem. Ber. 1991,
124, 2361. (d) Adam, W.; Hadjiarapoglou, L.; Nestler, B.
Tetrahedron Lett. 1990, 31, 331. (e) Adam, W.;
(13) Asouti, A.; Hadjiarapoglou, L. P. Tetrahedron Lett. 2000,
41, 539.
Hadjiarapoglou, L. Chem. Ber. 1990, 123, 2077. (f) Adam,
W.; Hadjiarapoglou, L.; Smerz, A. Chem. Ber. 1991, 124,
227. (g) Adam, W.; Golsch, D.; Hadjiarapoglou, L.;
Patonay, T. J. Org. Chem. 1991, 56, 7292. (h) Adam, W.;
Hadjiarapoglou, L.; Peters, K.; Sauter, M. J. Am. Chem. Soc.
1993, 115, 8603.
(14) (a) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51, 13039.
(b) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H.
M. J. Org. Chem. 1996, 61, 1830. (c) Yang, D.; Jiao, G. S.;
Yip, Y.-C.; Wong, M.-K. J. Org. Chem. 1999, 64, 1635.
(d) Yang, D.; Yip, Y.-C.; Chen, J.; Cheung, K.-K. J. Am.
Chem. Soc. 1998, 120, 7659. (e) Freccero, M.; Gandolfi, R.;
Sarzi-Amade, M. Tetrahedron 1999, 55, 11309.
(15) (a) Fehr, C. Angew. Chem. Int. Ed. 1998, 37, 2407. (b) Wu,
J. D.; Li, Y.; Na, K. N.; Houk, K. N. J. Org. Chem. 1993, 58,
4625.
(4) (a) Murray, R. W.; Jeyaraman, R.; Mohan, L. J. Am. Chem.
Soc. 1986, 108, 2470. (b) Mello, R.; Fiorentino, M.; Fusco,
C.; Curci, R. J. Am. Chem. Soc. 1989, 111, 6749. (c) Mello,
R.; Cassidei, L.; Fiorentino, M.; Fusco, C.; Curci, R.
Tetrahedron Lett. 1990, 31, 3067. (d) Curci, R.; D’Accolti,
L.; Fiorentino, M.; Fusco, C.; Adam, W.; Gonzalez-Nunez,
M. E.; Mello, R. Tetrahedron Lett. 1992, 33, 4225.
(16) Kasyanm, L. I. Russ. Chem. Rev. 1998, 67, 263.
Synlett 2001, No. 12, 1847–1850 ISSN 0936-5214 © Thieme Stuttgart · New York