A pH Study on the Chiral Ketone Catalyzed Asymmetric Epoxidation of Hydroxyalkenes

Article abstract of DOI:10.1021/jo972106r

A detailed study shows that the chiral ketone catalyzed asymmetric epoxidations of hydroxyalkenes are highly pH dependent. The lower enantioselectivity obtained at low pH is attributed to the substantial contribution of the direct epoxidation by Oxone. At high pH the epoxidation mediated by chiral ketone out-competes the racemic epoxidation, leading to higher enantioselectivity. The effective substrates include allylic alcohol, homoallylic alcohol, and bishomoallylic alcohol. In most cases, over 90% ee was obtained.

Full text of DOI:10.1021/jo972106r

J . Org. Chem. 1998, 63, 3099-3104
3099
A p H Stu d y on th e Ch ir a l Keton e Ca ta lyzed Asym m etr ic
Ep oxid a tion of Hyd r oxya lk en es
Zhi-Xian Wang and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received November 17, 1997
A detailed study shows that the chiral ketone catalyzed asymmetric epoxidations of hydroxyalkenes
are highly pH dependent. The lower enantioselectivity obtained at low pH is attributed to the
substantial contribution of the direct epoxidation by Oxone. At high pH the epoxidation mediated
by chiral ketone out-competes the racemic epoxidation, leading to higher enantioselectivity. The
effective substrates include allylic alcohol, homoallylic alcohol, and bishomoallylic alcohol. In most
cases, over 90% ee was obtained.
Sch em e 1
Chiral dioxiranes have displayed remarkable potential
for asymmetric epoxidation.1-3 Recently we reported a
highly enantioselective epoxidation method for trans-
disubstituted and -trisubstituted unfunctionalized olefins
using a fructose-derived ketone 1 as catalyst and Oxone
as oxidant (Scheme 1).4 However, under our initial
reaction conditions, the enantioselectivities for hydroxy-
alkenes were substantially lower.4a For example, the ee’s
for trans-2-hexen-1-ol and trans-3-hexen-1-ol were only
78% and 70%, respectively.4a The unusual behavior
displayed by this class of olefins triggered us to carry out
the investigations further. In this paper, we report our
detailed studies on this subject.
that this 6% difference could result from the pH change.
On the basis of this assumption, a systematic pH study
on the epoxidation of hydroxyalkenes was therefore
carried out.
trans-3-Hexen-1-ol and geraniol were chosen as the test
substrates. The enantioselectivities were indeed depend-
ent on the pH as shown in Figure 1. For trans-3-hexen-
1-ol, the ee increased by 17% from pH ∼7 to ∼10.6
(Figure 1, A). In the case of geraniol, the change of the
enantiomeric excesses with the pH were much more
Resu lts a n d Discu ssion
We were intrigued by an observation that the ee for
the epoxidation of cinnamyl alcohol increased from 84%,
using the initial reaction conditions (pH 7-8),4a to 90%,
using the catalytic conditions (pH ∼10.5).4b We surmised
* To whom correspondence should be addressed. Phone: 970-491-
7424. Fax: 970-491-1801. E-mail: yian@lamar.colostate.edu.
(1) For general leading references on dioxiranes, see: (a) Murray,
R. W. Chem. Rev. 1989, 89, 1187-1201. (b) Adam, W.; Curci, R.;
Edwards, J . O. Acc. Chem. Res. 1989, 22, 205-211. (c) Curci, R.; Dinoi,
A.; Rubino, M. F. Pure Appl. Chem. 1995, 67, 811-822. (d) Adam, W.;
Smerz, A. K. Bull. Soc. Chim. Belg. 1996, 105, 581-599.
(2) For examples of in situ generation of dioxiranes, see: (a)
Edwards, J . O.; Pater, R. H.; Curci, R.; Di Furia, F. Photochem.
Photobiol. 1979, 30, 63-70. (b) Curci, R.; Fiorentino, M.; Troisi, L.;
Edwards, J . O.; Pater, R. H. J . Org. Chem. 1980, 45, 4758-4760. (c)
Gallopo, A. R.; Edwards J . O. J . Org. Chem. 1981, 46, 1684-1688. (d)
Cicala, G.; Curci, R.; Fiorentino, M.; Laricchiuta, O. J . Org. Chem.
1982, 47, 2670-2673. (e) Corey, P. F.; Ward, F. E. J . Org. Chem. 1986,
51, 1925-1926. (f) Yang, D.; Wong, M. K.; Yip, Y. C. J . Org. Chem.
1995, 60, 3887-3889 and references therein. (g) Denmark, S. E.;
Forbes, D. C.; Hays, D. S.; DePue, J . S.; Wilde, R. G. J . Org. Chem.
1995, 60, 1391-1407 and references therein.
(3) For examples of asymmetric epoxidation mediated by chiral
ketones, see: (a) Curci, R.; Fiorentino, M.; Serio, M. R. J . Chem. Soc.,
Chem. Commun. 1984, 155-156. (b) Curci, R.; D’Accolti, L.; Fiorentino,
M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831-5834. (c) See ref 2g. (d)
Brown, D. S.; Marples, B. A.; Smith, P.; Walton, L Tetrahedron 1995,
51, 3587-3606. (e) Yang, D.; Yip, Y. C.; Tang, M. W.; Wong, M. K.;
Zheng, J . H.; Cheung, K. K. J . Am. Chem. Soc. 1996, 118, 491-492.
(f) Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am.
Chem. Soc. 1996, 118, 11311-11312. (g) Song, C. E.; Kim, Y. H.; Lee,
K. C.; Lee, S. G.; J in, B. W. Tetrahedron: Asymmetry 1997, 8, 2921-
2926.
F igu r e 1. Plot of the enantiomeric excesses of the epoxida-
tions of olefins against pH. The olefins presented are: trans-
3-hexene-1-ol (A), geraniol (6,7-olefin) (B), geraniol (2,3-olefin)
(C), geraniol-TBS ether (6,7-olefin) (D), and geraniol-TBS
ether (2,3-olefin) (E) (for the detailed data and reaction
conditions, see Tables 1-3 in Supporting Information).
(4) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J . Am. Chem. Soc. 1996, 118,
9806-9807. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J . Org. Chem.
1997, 62, 2328-2329. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J .-R.;
Shi, Y. J . Am. Chem. Soc. 1997, 119, 11224-11235.
S0022-3263(97)02106-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/16/1998

3100 J . Org. Chem., Vol. 63, No. 9, 1998
Wang and Shi
Ta ble 1. p H Stu d ies on th e Ep oxid a tion of Ger a n iol a n d Its TBS Eth er Usin g Dioxir a n es a n d Oxon e
entry
substrates
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
oxidant
pH
4.5
7.2
8.8
9.3
10.0
10.9
7-7.5
8.0
9.0
10.0
10.7
11.5
conv. (%)g
ratio (4/5)i
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMDa
17
19
18
20
20
16
33
44
38
30
17
5
<1
41(<1)h
12.3
24
45
58
58
58
5
5.3
4.4
5.2
5.0
4.7
5.2
2.1
2.0
2.3
2.2
2.4
nd
DMDa
DMDa
DMDa
DMDa
DMDa
Oxoneb
Oxonec
Oxonec
Oxonec
Oxonec
Oxonec
Oxoneb
Oxoneb
1/Oxoned
1/Oxonee
1/Oxonee
1/Oxonee
1/Oxonee
1/Oxonee
dioxirane 2f
1/Oxoned
1/Oxonee
1/Oxonee
7-7.5
nd
3a + 3b (1/1)
7-7.5
7-7.5
8.0
2.9j
2.4
3.1
4.6
6.1
5.6
5.9
5.7
4.3
4.4
4.5
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
9.0
10.0
11.0
11.5
7.5
7-7.5
8.0
10.6
5
10
41
a
All reactions were carried out at room temperature with dimethyldioxirane (DMD) (0.25 eq) (for details see the Experimental Section).
The reaction was carried out with substrate (1 eq) in CH3CN-aqueous Na2(EDTA) (4 × 10-4 M) (1.5:1 v/v) by adding a mixture powder
b
of Oxone (0.5 eq) and NaHCO3 (1.55 eq) over 1 h at 0 °C, followed by additional 1 h stirring at 0 °C. c Oxone (0.5 eq) was added as an
aqueous Na2(EDTA) (4 × 10-4 M) solution through a syringe pump at 0 °C over 1.5 h (for the detail control of the pH, see the Experimental
Section). The reactions were carried out with substrate (1 eq) and ketone 1 (1 eq) in CH3CN-aqueous Na2(EDTA) (4 × 10-4 M) (1.5:1
d
v/v) by adding a mixture powder of Oxone (0.5 eq) and NaHCO3 (1.55 eq) over 1 h at 0 °C, followed by additional 1 h of stirring at 0 °C.
e The reactions were carried out with substrate (1 eq) and ketone 1 (0.3 eq). Oxone (0.5 eq) was added as an aqueous Na2(EDTA) (4 × 10-4
M) solution through a syringe pump at 0 °C over 1.5 h (for the detail control of the pH, see the Experimental Section). f For details, see
the Experimental Section. Determined by the 1H NMR. The conversion of geraniol was kept low to minimize the formation of the
g
bisepoxide. The conversion for 3a is 41%, and the conversion for 3b is <1%. Determined by the 1H NMR analysis of the crude reaction
mixtures. For the DMD mediated epoxidation of 3a , no bisepoxide 6a was observed. For others, small amounts of bisepoxides 6a or 6b
were formed in some cases, and the 1H NMR signals of the bisepoxides partially overlapped with the signals of the monoepoxides. Therefore,
h
i
j
the presented ratio is actually the ratio of (4 + 6)/(5 + 6). This ratio is for substrate 3a .
drastic. For the epoxide distal to the OH group, the ee
increased from 19% to 77% when the pH was changed
from ∼7 to ∼11 (Figure 1, B). For the epoxide proximal
to the OH group, the ee change was even greater, from
<5% to 79% when the pH was changed from ∼7 to ∼11
(Figure 1, C). The effect of pH on the epoxidation of the
geraniol TBS ether was studied for comparison. As
shown in Figure 1 (D and E), the ee change with the pH
was much smaller for the TBS ether than for that of
geraniol. The slightly lower enantioselectivity at lower
pH could be due to the epoxidation catalyzed by the
acetone, resulting from the decomposition of ketone 1
since the ketone catalyst decomposes faster at lower pH.4b
These results strongly suggested that the variation of the
enantioselectivity with pH was directly related to the OH
group.
diastereoselectivities of the epoxidations.5 To explore the
possibility of this hydrogen-bonding effect on the enan-
tioselectivity, the following experiment was carried out.
An excess of ketone 1 was treated with Oxone in H2O-
CH3CN at pH 7-7.5 to preform dioxirane 2. After a short
time, the bulk of the aqueous layer was removed by a
cold pipet, and geraniol was added to the remaining
solution.6 Enough epoxides were obtained to determine
the ee’s, although a low conversion (5%) was observed.
The ee’s for both epoxides (70% ee for 6,7-epoxide 4a , 50%
ee for 2,3-epoxide 5a ) were substantially higher than the
ee’s obtained by usual in situ epoxidation (Figure 1, B
and C), even though the pH was the same in both cases
(7-7.5). The results suggested that the hydrogen bond-
ing between the OH group of the olefin and the dioxirane
was not the major factor for the lower ee obtained at low
pH, since the hydrogen bonding in both cases was
expected to be very similar.
It has been established that the hydroxyl group can
hydrogen bond with the dioxirane to affect the regio- and
Furthermore, the pH is expected to have little effect
on the hydrogen bonding over the currently tested range
(pH 7-11.5), since the pKa for the alcohol is usually
greater than 14. To further support this notion, the
epoxidation of geraniol with dimethyldioxirane (DMD) at
(5) For the leading references on the epoxidation of hydroxyalkenes
by dioxiranes, see: (a) Cicala, G.; Curci, R.; Fiorentino, M.; Laricchiuta,
O. J . Org. Chem. 1982, 47, 2670-2673. (b) Murray, R. W.; Singh, M.;
Williams, B. L.; Moncrieff, H. M. Tetrahedron Lett. 1995, 36, 2437-
2440. (c) Adam, W.; Smerz, A. K. Tetrahedron 1995, 51, 13039-13044.
(d) Adam, W.; Smerz, A. K. J . Org. Chem. 1995, 61, 3506-3510. (e)
Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J . Org.
Chem. 1996, 61, 1830-1841. (f) See ref 1d. (g) Adam, W.; Mitchell, C.
M.; Paredes, R.; Smerz, A. K. Veloza, A. Liebigs Ann./ Rec. 1997, 1365-
1369.
(6) It should be noted that dioxirane 2 was very short-lived. It has
been extremely difficult to isolate this species. In this case, it was hoped
that some dioxirane would remain within a short time.

Asymmetric Epoxidation of Hydroxyalkenes
J . Org. Chem., Vol. 63, No. 9, 1998 3101
Sch em e 2
different pH values was then carried out (Table 1, entries
1-6). It has been known that the ratio of the two
epoxides (4a /5a ) will vary if the hydrogen bonding
between the dioxirane and the hydroxyl group is affected
by changing the reaction conditions (e.g., changing the
solvent).5 As shown in Table 1, the ratios (4a /5a ) indeed
remained similar over the tested range (4.5-10.9), which
clearly demonstrated that the pH change did not affect
the hydrogen bonding, if such hydrogen bonding existed
in this case. Therefore, the variation of the enantiose-
lectivity with the pH is highly unlikely to be due to the
alteration of any hydrogen bonding between the hydroxyl
group and dioxirane 2.
A more likely explanation is that the observed low
enantioselectivity at low pH could be due to a substantial
amount of the racemic epoxidation produced by Oxone
itself (pathway b in Scheme 2).7 To further illustrate this
possibility, the epoxidations of geraniol and its TBS ether
were carried out in the absence of ketone 1 (Table 1). A
substantial amount of the geraniol was epoxidized in the
absence of the ketone catalyst (Table 1, entries 7-12).
In contrast, the epoxidation of the TBS ether was
negligible under the current reaction conditions (Table
1, entry 13). When both the alcohol and the TBS ether
were present in the reaction mixture, only the alcohol
was epoxidized (Table 1, entry 14). This result strongly
suggested that the epoxidation by Oxone was facilitated
by the hydroxyl group in the substrate. The hydroxyl
group could form a hydrogen bond with Oxone to achieve
epoxidation in an intramolecular fashion,8 and/or the
hydroxyl group could enhance the water solubility of the
substrate, consequently facilitating the reaction between
the olefin and Oxone.
(Table 1, entries 1-6, 21). When the epoxidation was
carried out in an in situ fashion using ketone 1 as
catalyst, the ratio (4a /5a ) increased from 2.4 to around
6 when the pH was changed from about 7 to >10 (Table
1, entries 15-20), indicating that the epoxidation by
Oxone (pathway b) dominated at low pH and the epoxi-
dation by the dioxirane dominated at high pH (pathway
a ).
The enantioselectivities obtained for both test sub-
strates (trans-3-hexene-1-ol and geraniol) at high pH
(about 10.5) were quite high. The ee’s were further
improved by changing solvents (for details, see Support-
ing Information) and lowering the reaction temperature.
Encouraged by these results, we investigated the asym-
metric epoxidation of a variety of hydroxyalkenes under
the optimized conditions. The olefins included allylic
alcohols, homoallylic alcohols, and bishomoallylic alco-
hols.9 As shown in Table 2, high enantiomeric excesses
were obtained in many cases.
In summary, we found that the asymmetric epoxida-
tion of hydroxyalkenes is highly pH dependent. At low
pH, the hydroxyl group facilitated epoxidation by Oxone
is dominant, resulting in lower enantiomeric excesses.
As the pH is increased, it appears the Oxone is more
likely to react with the chiral ketone to form the corre-
sponding dioxirane which subsequently reacts with the
olefin, yielding a higher enantioselectivity. The effective
substrates include allylic alcohols, homoallylic alcohols,
and bishomoallylic alcohols. The resulting chiral ep-
oxides should be synthetically useful. The current study
allows us to further understand the factors involved in
the dioxirane mediated epoxidation and to further expand
the synthetic scope of the current asymmetric epoxidation
method.
Studies showed that the epoxidation efficiency by
Oxone was slightly affected by the pH but not substan-
tially (Table 1, entries 7-12). The higher enantioselec-
tivity obtained at high pH could largely be due to an
enhanced nucleophilicity of Oxone toward ketone catalyst
1, increasing the formation of dioxirane 2, which out-
competes the direct epoxidation by Oxone. The competi-
tion between the two pathways (a and b) was also clearly
reflected by the ratio of the two epoxides (4a /5a ) (distal
epoxide vs proximal epoxide). The ratio of two epoxides
(4a /5a ) was around 2 for the direct epoxidation by Oxone
(Table 1, entries 7-11). However, this ratio was higher
(5-6) when the olefins were epoxidized by dioxiranes
Exp er im en ta l Section
For detailed information regarding general methods, see ref
4c. For detailed GC and HPLC conditions, see Supporting
Information.
P r ep a r a tion a n d Ch a r a cter iza tion of th e Olefin Su b-
str a tes. tr a n s-4-P h en yl-2-bu ten -1-ol (Ta ble 2, En tr y 2).
Treatment of (carbethoxymethylene) triphenylphosphorane
with phenylacetaldehyde in dry benzene at room temperature
gave a mixture of trans- and cis-olefins which were separated
by flash chromatography (hexanes-ether, 10:1 v/v): ethyl
trans-4-phenyl-2-butenoate (89% yield) as a colorless oil, Rf )
0.31 (hexanes-ether, 10:1 v/v). DIBAL-H reduction of ethyl
(7) For the leading references on the epoxidation of olefins by Oxone,
see: (a) Bloch, R.; Abecassis, J .; Hassan, D. J . Org. Chem. 1985, 50,
1544-1545. (b) Zhu, W.; Ford, W. T. J . Org. Chem. 1991, 56, 7022-
7026. (c) See ref 5g.
(8) Such hydrogen bonding is likely to enhance the epoxidation
reactivity of Oxone by dispersing the negative charge of Oxone (see
ref 5g).
(9) For highly enantioselective epoxidation of allylic alcohols, see:
(a) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.1. (b) Katsuki, T.;
Martin, V. S. Org. React. 1996, 48, 1-299.
(10) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.

3102 J . Org. Chem., Vol. 63, No. 9, 1998
Wang and Shi
Ta ble 2. Asym m etr ic Ep oxid a tion of Rep r esen ta tive Hyd r oxya lk en es Ca ta lyzed by Keton e 1 a n d en t-1a
a
All reactions were carried out with substrate (1 eq), ketone 1 (0.3 eq), Oxone (1.38 eq), and K2CO3 (5.8 eq) in DMM-CH3CN-aqueous
b
K2CO3/AcOH (prepared by adding 0.5 mL of AcOH to 100 mL of 0.1 M aqueous K2CO3, pH 9.3) (2:1:2 v/v) unless otherwise noted. DME
was used instead of DMM-CH3CN as solvent. c Isolated yield. Enantioselectivity was determined by chiral HPLC (Chiralcel OD column).
d
e Enantioselectivity was determined by the 1H NMR shift analysis of derived acetate with Eu(hfc)3. f Enantioselectivity was determined
by chiral GC (Chiraldex B-TA column). g After recrystallization. The absolute configuration was determined by comparing the measured
h
i
optical rotations with the reported ones. The absolute configuration was tentatively assumed by analogy based on the spiro reaction
mode.
trans-4-phenyl-2-butenoate in dry ether afforded trans-4-
phenyl-2-buten-1-ol (96% yield) as a lightly yellow oil.11b
3,3-Dip h en yl-2-p r op en -1-ol (Ta ble 2, en tr y 4): prepared
by the DIBAL-H reduction (90% yield) of the corresponding
ester obtained by the Wittig reaction (93% yield) of triethyl
phosphonoacetate and benzophenone;15 white crystals, mp 55-
57 °C (recrystallized from hexanes-ether); IR (KBr) 3327, 1628
1
cm-1; H NMR δ 7.45-7.1 (m, 10H), 6.26 (t, J ) 6.6 Hz, 1H),
4.23 (d, J ) 6.6 Hz, 2H), 1.6 (s, 1H); 13C NMR δ 144.4, 142.0,
139.2, 129.9, 128.4, 128.37, 127.82, 127.8, 127.77, 127.7, 60.89.
1-Cycloh exen ylm eth a n ol10 (Ta ble 2, en tr y 5): prepared
by the DIBAL-H reduction of the corresponding methyl cyclo-
hexene-1-carbonate obtained by esterification of cyclohexene-
1-carbonic acid (72% yield for two steps).
(11) (a) Takano, S.; Iwabuchi, Y.; Ogasawara, K. Synlett 1991, 548-
550. (b) Lentz, N. L.; Peet, N. P. Tetrahedron Lett. 1990, 31, 811-814.
(12) Tanner, D.; He, H. M. Tetrahedron 1989, 45, 4309-4316.
(13) (a) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J . Am. Chem.
Soc. 1981, 103, 464-465. (b) Shimizu, I.; Hayashi, K.; Ide, N.; Oshima,
M. Tetrahedron 1991, 47, 2991-2998.
(14) Rossiter, B. E.; Sharpless, K. B. J . Org. Chem. 1984, 49, 3707-
3711.
(15) Sabol, J . S.; Gregge, R. J . Tetrahedron Lett. 1990, 31, 27-30.

Asymmetric Epoxidation of Hydroxyalkenes
J . Org. Chem., Vol. 63, No. 9, 1998 3103
tr a n s-2-Meth yl-2-p en ten -1-ol13a (Ta ble 2, en tr y 6): pre-
pared by the DIBAL-H reduction of trans-2-methyl-2-penten-
1-al in THF with 90% yield.
tr a n s-4-P h en yl-3-bu ten -1-ol (Ta ble 2, en tr y 9): pre-
pared by the LiAlH4 reduction of trans-styrylacetic acid in THF
with 86% yield; IR (KBr) 3357, 1657 cm-1; 1H NMR δ 7.4-7.1
(m, 5H), 6.48 (d, J ) 15.9 Hz, 1H), 6.19 (dt, J ) 15.9, 7.2 Hz,
1H), 3.72 (t, J ) 6.3 Hz, 2H), 2.46 (dt, J ) 7.2, 6.3 Hz, 2H),
2.0 (br s, 1H); 13C NMR δ 137.4, 132.8, 128.7, 127.4, 126.6,
126.2, 62.13, 36.52.
tr a n s-3-Decen -1-ol (Ta ble 2, en tr y 10): prepared by the
LiAlH4 reduction of trans-3-decenoic acid in THF with 90%
yield; colorless oil; IR (KBr) 3329, 1653 cm-1; 1H NMR δ 5.56
(dt, J ) 15.3, 6.6 Hz, 1H), 5.37 (dtt, J ) 15.3, 6.6, 1.2 Hz, 1H),
3.63 (t, J ) 6.3 Hz, 2H), 2.27 (dt, J ) 6.6, 6.3 Hz, 2H), 2.02 (q,
J ) 6.6 Hz, 2H), 1.45 (br s, 1H), 1.4-1.2 (m, 8H), 0.89 (t, J )
6.6 Hz, 3H); 13C NMR δ 134.7, 125.9, 62.22, 36.19, 32.89, 31.92,
29.63, 29.07, 22.83, 14.3.
tr a n s-6-P h en yl-4-h exen -1-ol (Ta ble 2, en tr y 11): pre-
pared by the DIBAL-H reduction of methyl trans-6-phenyl-4-
hexenoate4b with 92% yield; colorless oil; IR (KBr) 3350, 1660
cm-1; 1H NMR δ 7.4-7.15 (m, 5H), 5.66 (dt, J ) 15.3, 6.6, 1H),
5.54 (dt, 15.3, 6.3 Hz, 1H), 3.66 (t, J ) 6.6 Hz, 2H), 3.37 (d, J
) 6.3 Hz, 2H), 2.15 (dt, J ) 7.5, 6.6 Hz, 2H), 1.85 (br s, 1H),
1.68 (tt, J ) 7.5, 6.6 Hz, 2H); 13C NMR δ 141, 131.2, 129.7,
128.6, 128.5, 126.1, 62.51, 39.16, 32.46, 28.93.
Gen er a l P r oced u r e for p H Stu d y. To a mixture of
geraniol (0.154 g, 1 mmol) and tetrabutylammonium hydrogen
sulfate (0.015 g, 0.04 mmol) in acetonitrile (10 mL) and
aqueous K2CO3/AcOH (7 mL) (prepared by adding 0.5 mL of
glacial AcOH to 100 mL of 0.1 M aqueous K2CO3) (the pH of
the reaction solution was adjusted with 1 M aqueous AcOH
for 8-10, and with 1 M aqueous K2CO3 for 10-11.5) was added
ketone 1 (0.0774 g, 0.3 mmol). After the reaction mixture was
cooled with an ice bath, a solution of Oxone (0.31 g, 0.5 mmol)
in aqueous Na2(EDTA) (4 × 10-4 M) (5 mL) was added through
a syringe pump over 1.5 h. The reaction pH was monitored
with a Corning 320 pH meter with a Corning “3 in 1” pH
combination electrode and was maintained by adding aqueous
K2CO3. After completion of the addition of Oxone, the reaction
was immediately quenched with CH2Cl2 (20 mL), and the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The
combined extracts were washed with brine and dried (Na2SO4).
Upon the removal of the solvent, the conversion and ratio were
determined by the 1H NMR analysis of the crude products.
Separation by flash chromatography [the silica gel was buf-
fered with 1% triethylamine solution in hexanes-ether (2:1
v/v); hexanes-ether (2:1 to 1:1 v/v) was used as the eluent]
gave 2,3-epoxygeraniol and 6,7-epoxygeraniol.
p H St u d y on t h e E p oxid a t ion of Ger a n iol b y DMD.
The dimethyldioxirane (DMD) acetone solution (0.05 M) was
freshly prepared by Murray’s method,16 and DMD solution
(0.05 M in acetone, 2.5 mL, 0.125 mmol) was added at room
temperature to a mixture of geraniol (0.077 g, 0.5 mmol) in
acetonitrile (7 mL) and aqueous K2CO3/AcOH (5 mL) (prepared
by adding 0.5 mL of AcOH to 100 mL of 0.1 M aqueous K2-
CO3). (The pH of the reaction solution was adjusted with 1 M
aqueous AcOH.) After the addition of the DMD solution the
pH was monitored with a Corning 320 pH meter with a
Corning “3 in 1” pH combination electrode. Having been
stirred at room temperature for 30 min, the reaction mixture
was extracted with CH2Cl2 (3 × 20 mL), washed with brine,
dried (Na2SO4), and concentrated. The conversion and ratio
were determined by the 1H NMR analysis of the crude
products.
Gen er a l Ep oxid a tion P r oced u r e for Ta ble 2. trans-
Cinnamyl alcohol (0.136 g, 1 mmol), ketone 1 (0.0774 g, 0.3
mmol), and tetrabutylammonium hydrogen sulfate (0.015 g,
0.016 mmol) were dissolved in DMM/CH3CN (2:1 v/v) (10 mL).
An aqueous K2CO3/HOAc solution (7 mL) (prepared by mixing
100 mL of 0.1 M aqueous K2CO3 with 0.5 mL of acetic acid
(pH 9.3)) was added with stirring, and the mixture was cooled
to about -10 °C (inside; outside is about -10 °C to -15 °C)
via a NaCl-ice bath. A solution of Oxone (0.85 g, 1.38 mmol)
in aqueous Na2(EDTA) (4 × 10-4 M) (5 mL) and a solution of
K2CO3 (0.8 g, 5.8 mmol) in water (5 mL) were added dropwise
separately via a syringe pump over a period of 3 h. The
reaction was immediately quenched with CH2Cl2 (20 mL) and
water. The aqueous layer was extracted with CH2Cl2 (3 × 20
mL), washed with brine, dried over Na2SO4, concentrated, and
purified by flash chromatography [the silica gel was buffered
with 1% Et3N in hexanes-ether (2:1 v/v); hexanes-ether (2:1
to 1:1 v/v) was used as eluent] to afford (R,R)-3-phenylox-
iranemethanol as white crystals (0.128 g, 85%; 94% ee).
tr a n s-3-P h en yloxir a n em eth a n ol (Ta ble 2, en tr y 1):
white crystals, mp 47-49 °C (recrystallized from hexanes-
25
ether); [R]D ) +50.0° (c 1.2, CHCl3) (recrystallized from
hexanes-ether); [R]D23 ) -48.6° (c 1.11, CHCl3) (en t-1) [Lit.10
25
mp 51.5-53 °C; [R]D ) -49.6° (c 2.4, CHCl3) for (S,S)-form].
(R,R)-3-(P h en ylm eth yl)oxir a n em eth a n ol (Ta ble 2, en -
tr y 2): colorless oil; [R]D23 ) +34.1° (c 1.27, CHCl3) [lit.11a [R]D
) -34.4° (c 0.99, CHCl3) for (S,S)-form.]
26
(R,R)-3-P r op yloxir a n em eth a n ol (Ta ble 2, en tr y 3):
23
25
colorless oil; [R]D ) +45.4° (c 1.07, CHCl3) [lit.10 [R]D
)
-46.3° (c 3.87, CHCl3) for (S,S)-form].
(R)-3,3-Dip h en yloxir a n em eth a n ol (Ta ble 2, en tr y 4):
25
colorless oil; [R]D ) +33.8° (c 0.42, CHCl3); IR (KBr) 3392,
3060, 3029, 1602, 1496, 1448, 1273, 1077, 1035, 764, 754, 699
cm-1; 1H NMR δ 7.45-7.25 (m, 10H), 3.73-3.62 (m, 2H), 3.45
(m, 1H), 1.9 (br s, 1H); 13C NMR δ 140.3, 137.0, 128.6, 128.55,
128.2, 128.2, 128.0, 127.0, 66.39, 65.92, 62.3. Anal. Calcd for
2,3-Ep oxyger a n iol: colorless oil; Rf ) 0.13 (hexanes-
23
ether, 1:1 v/v); [R]D ) +4.6° (c 0.7, CHCl3) (79% ee, deter-
mined by chiral GC, G-TA column) (Figure 1, pH 11) [lit.10
25
[R]D ) -5.3° (c 3.0, CHCl3) for (S,S)-form (91% ee)].
C
15H14O2: C, 79.62; H, 6.24. Found: C, 79.48; H, 6.13.
6,7-Ep oxyger a n iol:5a colorless oil; Rf ) 0.08 (hexanes-
(R,R)-7-Oxa bicyclo[4.1.0]h ep ta n e-1-m eth a n ol (Ta ble 2,
23
ether, 1:1 v/v); [R]D ) +9.7° (c 1.1, CHCl3) (77% ee, deter-
25
en tr y 5): colorless oil; [R]D ) +22.7° (c 0.55, CHCl3) (-10
mined by chiral GC, B-TA column) (Figure 1, pH 11).
E p oxid a t ion of Ger a n iol b y P r efor m ed Dioxir a n e 2
(Ta ble 1, En tr y 21). To a cold (0 to -5 °C, ice-salt bath)
mixture of ketone 1 (0.52 g, 2 mmol) and NaHCO3 (0.24 g, 2.9
mmol) in acetonitrile (10 mL) and aqueous Na2(EDTA) (4 ×
10-4 M) (7 mL) was added a solution of Oxone (0.55 g, 0.9
mmol) in aqueous Na2(EDTA) (4 × 10-4 M) (3 mL) over 5 min.
After the mixture was stirred at this temperature for another
5 min, most of the aqueous layer (about two-thirds) was
removed by a cold pipet, and a cold solution of geraniol (0.154
g, 1 mmol) in acetonitrile (3 mL) was added. Upon being
stirred at -5 °C for 15 min, the reaction was quenched with
CH2Cl2 (20 mL). The aqueous layer was extracted with CH2-
Cl2 (3 × 20 mL), washed with brine, and dried over Na2SO4.
The conversion and ratio were determined by the 1H NMR
analysis of the crude products. Separation via flash chroma-
tography [the silica gel was buffered with 1% triethylamine
solution in hexanes-ether (2:1 v/v); hexanes-ether (2:1 to 1:1
v/v) was used as the eluent] gave 2,3-epoxygeraniol (50% ee)
and 6,7-epoxygeraniol (70% ee).
23
25
°C); [R]D ) +23.7° (c 1.0, CHCl3) (-15 °C) [lit.10 [R]D
)
-22.8° (c 2.6, CHCl3) for (S,S)-form (93% ee)].
(R,R)-2-Meth yl-3-eth yloxir a n em eth a n ol (Ta ble 2, en -
23
tr y 6): colorless oil; [R]D ) +18.0° (c 0.85, CHCl3) (-10 °C),
[R]D ) +18.4° (c 0.9, CHCl3) (-15 °C) [lit.13b [R]D ) -21.3°
(c 1.78, CHCl3) for (S,S)-form].
23
24
(R,R)-2-Meth yl-3-p h en yloxir a n em eth a n ol (Ta ble 2, en -
25
tr y 7): colorless oil; [R]D23 ) +13.0° (c 0.87, CHCl3) [lit.10 [R]D
) -16.9° (c 2.0, CHCl3) for (S,S)-form (>98% ee)].
(R,R)-3-Eth yloxir a n eeth a n ol (Ta ble 2, en tr y 8): color-
less oil; [R]D ) +45.2° (c 1.07, EtOH) [lit.14 [R]D ) +17.69°
(c 1.73, EtOH) (41% ee)].
23
25
(R,R)-3-P h en yloxir a n eeth a n ol (Ta ble 2, en tr y 9): color-
25
less oil; [R]D ) +48.2° (c 0.42, CHCl3); IR (KBr) 3416, 2947,
1604, 1497, 1460, 1052, 1027, 878, 762, 749, 698 cm-1; 1H NMR
δ 7.4-7.2 (m, 5H), 3.86 (t, J ) 6.0 Hz, 2H), 3.73 (d, J ) 2.1
(16) Murray, R. W.; J eyaraman, R. J . Org. Chem. 1985, 50, 2847-
2853.

3104 J . Org. Chem., Vol. 63, No. 9, 1998
Wang and Shi
Hz, 1H), 3.15 (ddd, J ) 6.3, 4.2, 2.1 Hz, 1H), 2.1 (dtd, J )
14.7, 6.0, 4.2 Hz, 1H), 1.99 (br s, 1H), 1.86 (ddt, J ) 14.7, 6.3,
6.0 Hz, 1H); 13C NMR δ 137.5, 128.7, 128.4, 125.8, 61.16, 60.0,
58.3, 34.79. Anal. Calcd for C10H12O2: C, 73.15; H, 7.37.
Found: C, 73.12; H, 7.31.
(R,R)-3-Hexyloxir a n eeth a n ol (Ta ble 2, en tr y 10): color-
less oil; [R]D23 ) +39.0° (c 0.82, CHCl3) (-10 °C); IR (KBr) 3434,
2929, 1468, 1378, 1053, 893, 724 cm-1; 1H NMR δ 3.78 (dd, J
) 6.0, 5.7 Hz, 2H), 2.86 (ddd, J ) 6.6, 4.2, 2.4 Hz, 1H), 2.79
(td, J ) 5.4, 2.4 Hz, 1H), 2.04 (br s, 1H), 1.97 (dddd, J ) 14.7,
6.9, 6.0, 4.2 Hz, 1H), 1.69 (dddd, J ) 14.7, 6.6, 5.7, 5.4 Hz,
1H), 1.6-1.2 (m, 10H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR δ
60.25, 58.51, 57.08, 34.39, 32.15, 31.93, 29.28, 26.1, 22.74,
14.25. Anal. Calcd for C10H20O2: C, 69.72; H, 11.70. Found:
C, 69.59; H, 11.58.
28.64. Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found:
C, 74.60, H, 8.28.
Ack n ow led gm en t. We are grateful for the generous
financial support from Colorado State University, the
General Medical Sciences of the National Institutes of
Health (GM55704-01), the Beckman Young Investigator
Award Program, the Camille and Henry Dreyfus New
Faculty Awards Program, and Hoechst Celanese. We
would like to thank Michael Frohn, J on Lorenz, Yong
Tu, and Yuanming Zhu for their helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: The NMR spectral,
GC and HPLC data for the determination of the enantiomeric
excess of the formed epoxides along with the detailed data of
the pH and solvent studies (12 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
tr a n s-3-(P h en ylm eth yl)oxir a n ep r op a n ol (Ta ble 2, en -
25
25
tr y 11): colorless oil; [R]D ) +23.4° (c 0.72, CHCl3); [R]D
)
-22.4° (c 0.68, CHCl3) (en t-1); IR (KBr) 3414, 2939, 1600,
1496, 1454, 1186, 1058, 934, 747, 700 cm-1; 1H NMR δ 7.35-
7.15 (m, 5H), 3.62 (t, J ) 5.9 Hz, 2H), 2.97-2.75 (m, 4H), 1.87
(br s, 1H), 1.8-1.6 (m, 3H), 1.57-1.45 (m, 1H); 13C NMR δ
137.4, 129.1, 128.7, 126.8, 62.43, 59.16, 58.73, 38.56, 29.18,
J O972106R