Regio- and enantioselective epoxidation of dienes by a chiral dioxirane: Synthesis of optically active vinyl cis-epoxides

Article abstract of DOI:10.1002/anie.200600840

(Chemical Equation Presented) Putting the O into olefins: A highly regio-and enantioselective epoxidation of conjugated dienes was developed using glucose-derived ketone 1 as catalyst and oxone (KHSO₅) as oxidant to form vinyl cis-epoxides (see scheme).

Full text of DOI:10.1002/anie.200600840

Angewandte
Chemie
Asymmetric Epoxidation
DOI: 10.1002/anie.200600840
Regio- and Enantioselective Epoxidation of
Dienes by a Chiral Dioxirane: Synthesis of
Optically Active Vinyl cis-Epoxides**
Christopher P. Burke and Yian Shi*
Optically active vinyl epoxides are very useful synthetic
intermediates,[1] and enantioselective monoepoxidation of
conjugated dienes presents an efficient approach to these
compounds.[2,3] Enantioselective epoxidation of conjugated
dienes using chiral (salen)Mn catalysts has been shown to
proceed predominantly at the cis-olefin with high regioselec-
tivity and high enantioselectivity.[3] In the case of acyclic
dienes, the epoxidation gave optically active vinyl trans-
epoxides as major products.[3a,b,d] Earlier, we reported that
fructose-derived ketone 1 (Scheme 1)is effective for the
regioselective epoxidation of conjugated dienes to provide
vinyl trans- and trisubstituted epoxides with high ee values
[Eq. (1)].[4,5] Nevertheless, an efficient synthesis of chiral vinyl
cis-epoxides is still highly desirable.
[*] C. P. Burke, Prof. Dr. Y. Shi
Department of Chemistry
Colorado State University
Fort Collins, CO 80523 (USA)
Fax: (+1)970-491-1801
E-mail: yian@lamar.colostate.edu
[**] We are grateful to the generous financial support from the General
Medical Sciences of the National Institutes of Health (GM59705-
07).
Supporting information for this article, including the character-
ization of epoxides and the data for the determination of the
enantiomeric excesses of the epoxides, is available on the WWW
under http://www.angewandte.org or from the author.
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The epoxidation of conjugated dienes was carried out with
ketone 2 as catalyst and oxone as oxidant. A variety of dienes
are shown to be effective substrates, giving vinyl cis-epoxides
with high ee values (Table 1).[8] The reactions were generally
clean as judged by the 1H NMR spectra of the crude reaction
mixtures. The reactions were also stereospecific in that cis-
olefins yielded only cis-epoxides, with no isomerization
observed. The low isolated yields compared with the con-
versions in some cases were a result of the high sensitivity of
vinyl epoxides towards flash column chromatography using
silica gel.
Scheme 1. Boc=tert-butyloxycarbonyl.
Some of the reaction trends are highlighted as follows.
Regioselectivity for the epoxidation is dependent on the type
of diene. For cis/trans-dienes, it was found that the cis-olefins
were epoxidized preferentially with high regioselectivity.[9]
The epoxide derived from the trans-olefin was only detected
in one case (Table 1, entry 7). A conjugated triene (Table 1,
entry 9)also proved to be an effective substrate. As expected,
cis/trisubstituted dienes showed competition for epoxidation
between the two olefins. The degree of trisubstituted olefin
epoxidation varied depending on the steric and electronic
properties of the diene. If the trisubstituted olefin was
deactivated electronically and/or sterically, cis-olefin epox-
idation was favored (Table 1, entries 10 and 11).
Recently, we found that oxazolidinone-containing ketone
2 provides high enantiomeric excesses for certain cis-olefins
and styrenes.[6,7] Earlier studies suggest that spiro transition
state A is favored over competing spiro B owing to an
attraction between the Rp group of the olefin and the
oxazolidinone moiety of the ketone catalyst (Scheme 2).[6,7]
In most cases, no further epoxidation of vinyl cis-epoxides
was found, presumably due to the deactivation of the olefin by
the epoxide. For entry 8 in Table 1, bis(epoxide)was detected.
In this case, the ee value of the mono(epoxide)did not change
at different conversions, thus indicating that no significant
kinetic resolution occurred during the reaction. However, for
entry 10 in Table 1, it was found that the ee value of the vinyl
epoxide increased with the conversion, which suggests that
kinetic resolution may be occurring.
Changing the group on the 4-position of the aromatic ring
of the catalyst had an effect on the enantioselectivity, likely
due to additional interactions (possibly hydrophobic in
nature)between this group and the substrate. The hydro-
phobic and hydrophilic nature of the R1 and R3 groups of the
diene (Scheme 3)also have significant effects on the enantio-
selectivity of the epoxidation. Lower ee values were observed
when the R1 group was hydrophobic (Table 1, entry 7),
presumably due to the increased hydrophobic interactions
between the R1 group and the N substituent of the catalyst in
the competing spiro transition state D (Scheme 3). Con-
versely, higher ee values could be expected with more
hydrophilic R1 and/or more hydrophobic R3 groups, thus
further favoring spiro transition state C over D (for example,
see Table 1, entry 8).
Scheme 2.
Up to this point, the Rp group has been primarily limited to
aromatic groups. As part of our continuing efforts to further
understand the interaction and expand the scope of this
epoxidation, we examined the asymmetric epoxidation of
conjugated dienes with ketone 2. This study allows us to
investigate whether alkenes can be effective directing groups
to favor spiro transition state C (Scheme 3)and lead to the
The stereochemistry of the epoxides shown in Table 1 is
assigned on the basis of transition state spiro C. To further
validate this model and the assigned stereochemistry, the
absolute configurations of two representative examples
(Table 1, entries 1 and 11)were determined [Eq. (3)and
(4)] by converting the epoxide into a compound with known
configuration.[10,11] The results in both cases support the initial
assignment based on transition state spiro C.
Scheme 3.
synthesis of optically active vinyl cis-epoxides [Eq. (2)].
Herein, we report our preliminary efforts on this subject.
In summary, we report that a conjugating olefin is an
effective group for the attraction between the oxazolidinone
of the catalyst and the substrate. A variety of conjugated
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Angewandte
Chemie
Table 1: Asymmetric epoxidation of dienes by ketone 2.[a]
observed to give cis-epoxides
exclusively from cis-olefins. The
regio- and enantioselectivity of
the reaction are dependent on
the substitution pattern of the
diene system. With this method-
ology, a variety of enantioenriched
vinyl cis-epoxides are now readily
available.
Entry
Diene
Epoxide
Ketone
Yield (Conv.) [%][b]
ee [%]
1
2b
66 (>95)[c,d]
85[e]
2
3
4
5
6
2c
2d
2d
2d
2b
47 (89)[f–h]
58 (100)[f,i]
64 (85)[f,g,k]
62 (98)[i]
89[e]
92[j]
90[l]
90[l]
94[l]
Experimental Section
Representative procedure for asym-
metric epoxidation (Table 1, entry 6).
Buffer (0.1m K2CO3/AcOH in 4 ”
10À4 m aqueous EDTA, pH 9.3; 5 mL)
and Bu4NHSO4 (0.0075 g, 0.02 mmol)
were added with stirring to a solution
of the diene (0.070 g, 0.50 mmol)and
ketone 2b (0.042 g, 0.125 mmol)in
DME/DMM (3:1, v/v; 7.5 mL). The
mixture was cooled to about À108C
(NaCl–ice bath temperature), and then
a solution of oxone (0.20m; 0.49 g,
0.80 mmol)in aqueous EDTA (4 ”
64 (99)[i]
7
2d
66 (88)[g,i,m,n]
76[l]
8
9
2c
2b
2a
80 (100)[c,f,i,o,p]
74 (99)[i]
89[e]
94[l]
93[l]
10
61 (100)[f,i,q]
10À4 m, 4.0 mL)and
a solution of
K2CO3 (0.84m, 0.46 g, 3.36 mmol)in
aqueous EDTA (4 ” 10À4 m, 4.0 mL)
were added dropwise simultaneously
over a period of 4 h through a syringe
pump. The reaction was then quenched
with the addition of petroleum ether
and extracted with a mixture (1:1, v/v)
of petroleum ether/diethyl ether. The
combined organic layers were washed
with water and brine, dried (Na2SO4),
filtered and concentrated, and the
residue was purified by flash chroma-
tography (the silica gel was buffered
with 1% Et3N in petroleum ether;
petroleum ether/diethyl ether (1:0 to
19:1, v/v)was used as eluent)to give
11
2b
67 (>95)[c,i,r] [3b]
91[s]
[a] All reactions were carried out at À108C with diene (1 equiv), ketone (0.1–0.3 equiv), oxone
(1.6 equiv), and K2CO3 (6.7 equiv) in DME/DMM (3:1, v/v) and buffer (0.1m K2CO3/AcOH in 1”10À4
m
aq. EDTA, pH 9.3) for 4 h, unless otherwise stated. TMS=trimethylsilyl; TBS=tert-butyldimethylsilyl;
Bn=benzyl; DME=1,2-dimethoxyethane; DMM=dimethoxymethane; EDTA=ethylenediaminetetra-
acetic acid. [b] The conversion was determined by GC analysis of the crude reaction mixture. [c] The
conversion was determined by 1H NMR spectroscopy of the crude reaction mixture. [d] 0.10 equiv
catalyst used. [e] Enantioselectivity was determined by chiral HPLC (Chiralcel OJ column). [f] Oxone and
K2CO3 were added over 8 h. [g] 2.4 equiv oxone and 10.1 equiv K2CO3 were used. [h] 0.20 equiv catalyst
used. [i] 0.25 equiv catalyst used. [j] Enantioselectivity was determined by chiral shift 1H NMR
spectroscopy
with
Eu(hfc)3
(hfc=3-(heptafluoropropylhydroxymethylene)-d-camphorate).
[k] 0.30 equiv catalyst used. [l] Enantioselectivity was determined by Chiral GC (Chiraldex B-DM
column). [m] Oxone and K2CO3 were added over 10 h. [n] 12:1 ratio of cis/trans-epoxides (regioselec-
tivity) observed; the yield and ee for the cis-epoxide is given. [o] 0.96 equiv oxone and 4.0 equiv K2CO3
were used. [p] 10:1 ratio of mono/bis(epoxide)s observed; the yield and ee for the mono(epoxide) is
given. [q] 1.8 equiv oxone and 4.0 equiv K2CO3 were used. [r] The isolated product is a mixture of cis-/
trisubstituted epoxides (3.3:1); the ee value is given for the cis-epoxide. [s] Enantioselectivity was
determined by chiral HPLC (Chiralcel OD column).
the cis-epoxide as
a colorless oil
(0.050 g, 64% yield, 94% ee).
Received: March 4, 2006
Published online: June 9, 2006
Keywords: asymmetric synthesis ·
.
dienes · epoxidation ·
synthetic methods
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Angew. Chem. Int. Ed. 2006, 45, 4475 –4478
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Communications
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