Exploring substrate scope of Shi-type epoxidations

Article abstract of DOI:10.1055/s-0028-1083545

Enantioselective epoxidations of alkenes (12 examples) were achieved using a Shi-type carbohydrate-derived hydrate and Oxone. The chiral platform provided by the catalyst tolerates a wide range of substituents providing high yields and enantioselectivities (80-95.5% ee). However, styrene derivatives were only converted with poor selectivities (11-26% ee). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083545

2856
LETTER
Exploring Substrate Scope of Shi-Type Epoxidations
E
xploring Substrat
a
e
Scope of
t
Shi-Ty
a
pe Epoxida
l
tions ia Nieto,a Ian J. Munslow,a Héctor Fernández-Pérez,a Anton Vidal-Ferran*a,b
a
Institute of Chemical Research of Catalonia (ICIQ), Avgda. Països Catalans 16, 43007 Tarragona, Spain
Fax +34(977)920228; E-mail: avidal@iciq.es
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08018 Barcelona, Spain
b
Received 21 July 2008
The currently accepted model for epoxidations mediated
by 1 is based on Shi’s analysis of the stereochemistry of
the produced epoxides. A chiral dioxirane derived from
ketone 1 has two diastereomeric oxygens and on the basis
Abstract: Enantioselective epoxidations of alkenes (12 examples)
were achieved using a Shi-type carbohydrate-derived hydrate and
Oxone. The chiral platform provided by the catalyst tolerates a wide
range of substituents providing high yields and enantioselectivities
(80–95.5% ee). However, styrene derivatives were only converted of sterical arguments the equatorial oxygen is likely to be
with poor selectivities (11–26% ee).
the more accessible one for olefin approach, with the ma-
jor enantiomer resulting via a spiro transition state.5
Key words: alkenes, asymmetric catalysis, organocatalysis,
ligands, epoxidations
Singleton and Wang have recently supported this analysis
through the use of experimental kinetic isotope effects
(KIE) and DFT calculations.9 We have recently reported a
study via isotopic labelling studies that further, experi-
mentally, supports this model of dioxirane-mediated ep-
oxidations.10 Our results revealed several key aspects
about the origin of the stereoinduction. Namely, the ep-
oxidation process comprises highly stereoselective attack
Asymmetric alkene epoxidation is a powerful route to
chiral epoxides,1 which are useful synthetic intermediates
for the asymmetric synthesis of complex molecules2 or
chiral catalysts.3 Chiral dioxiranes, generated in situ from
chiral ketones and potassium peroxomonosulfate
(KHSO5), are practically unrivalled in the epoxidation of
unfunctionalised trans and trisubstituted alkenes.1b,d,4 The
development by Shi and co-workers of carbohydrate-de-
rived ketones4a–4c and KHSO5 (Oxone) as the stoichiomet-
ric oxidant is perhaps the most efficient of these
methodologies and the fructose derivative 1 is the most
well known of these catalysts (Figure 1).5
–
of the b face of 2 by HSO5 , oxygen transfer from the di-
oxirane to the alkene proceeds predominately through ap-
proach of the Si-alkene face onto the b face of dioxirane
and that attack of the most hindered face of the dioxirane
by the alkene does not take place to any measurable ex-
tent.
Preliminary epoxidation studies of a model trans alkene
showed that hydrate 3 was at least as useful a chiral cata-
lyst as ketone 1.7 We thus sought to perform an in depth
study of the catalytic properties and substrate scope of hy-
drate 3. Described herein is the application of this com-
pound as a mediator in the asymmetric epoxidation of
unfunctionalised alkenes (Scheme 1 and Table 1).
O
O
O
O
O
O
O
O
O
OH
OH
O
AcO
O
AcO
O
O
OAc
OAc
The epoxidations (Scheme 1) were carried out under stan-
dard conditions,12 organoaqueous media with 10 mol% of
compound 3 at 0 °C, as this offered a good balance be-
tween conversion and selectivity.7 The pH value was a
key parameter in dioxirane-catalysed epoxidations,5
hence the optimal pH value for epoxidation with 3 was in-
vestigated using trans-stilbene (4a) as a test substrate. The
pH values from 9 to 10 were obtained by simultaneously
adding aqueous K2CO3 and a solution of Oxone in pH 6
buffer (see footnote a in Table 1).13 Lower conversions
were observed at pH 10 (39% yield) than at pH 9 (55%
yield). Conversely, enantioselectivity improved with
higher pH (89% and 95% ee, respectively). The lower sta-
bility of the oxidant at higher pH values may account for
these low conversions. In order to overcome this problem,
the amount of Oxone was doubled while the pH value was
fixed at 10. As expected, a higher conversion was
achieved (63% yield; Table 1, entry 1). The best yield
(95%) and enantioselectivity (95.5% ee) of all the tested
conditions was obtained by switching from catalytic to
1
2
3
Figure 1 Shi’s standard catalyst 1, diester fructose derivative 2 and
hydrate 3
The diester fructose derivative 2 is even more attractive in
terms of robustness and substrate scope in the asymmetric
epoxidation of alkenes: Shi has reported its use in the ep-
oxidation of a,b-unsaturated esters,6 and our group7 has
extended its use to unfunctionalised alkenes using low
catalyst loadings.8 Furthermore, we have developed a se-
lective and efficient preparation method for both diester 2
and its hydrate 3 and recently reported that hydrate 3
shows the same high catalytic activity as its parent com-
pound 2 in epoxidation studies of a model trans alkene.7
SYNLETT 2008, No. 18, pp 2856–2858
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083545; Art ID: G25908ST
© Georg Thieme Verlag Stuttgart · New York
1
4
.1
1
.2
0
0
8

LETTER
Exploring Substrate Scope of Shi-Type Epoxidations
2857
Table 1 Epoxidations Mediated by Hydrate 3 as Precatalyst
R3
O
3 (cat.)
Entry Alkene Reaction conditionsa
Yield ee
KHSO5, K2CO3
R1
R1
R3
R4
(%)b (%)c
R2
R4
CH2(OMe)2
R2
H2O, MeCN, 0 °C
1
2
4a
4a
4b
4b
4c
4d
3 (10 mol%),
Oxone (3.2 equiv), K2CO3 (6.8 equiv)
63 93.5
5a–l
4a–l
(R,R)-5a
95 95.5
3 (30 mol%),
Oxone (3.2 equiv), K2CO3 (6.8 equiv)
Ph
CH2OH
Ph
Ph
Ph
(R,R)-5a
3
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
60 83
4a
4b
4c
4f
(R,R)-5b
83 89
Ph
CH2Cl
Ph
Et
4
3 (30 mol%),
Oxone (3.2 equiv), K2CO3 (6.8 equiv)
Ph2CHO
4e
MeO
(R,R)-5b
4d
4g
5
3 (10 mol%),
Oxone (3.2 equiv), K2CO3 (6.8 equiv)
89 86
(R,R)-5c
80 90
Ph
Ph
6
3 (30 mol%),
Oxone (3.2 equiv), K2CO3 (6.8 equiv)
Ph
OH
Ph
4h
Ph
(R,S)-5d
4i
7
4e11 3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
52 90d
5e
8
4f
4g
4h
4i
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
99 83e
Ph
Ph
5f
OMe
9
3 (30 mol%),
Oxone (1.6 equiv), K2CO3 (7.2 equiv)
n.d.f 80
4j
4k
4l
(R,R)-5g
Scheme 1 Epoxidations mediated by hydrate 3 as the precatalyst
10
11
12
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
52 92
(R)-5h
41 83
substoichiometric amounts of hydrate 3 (30 mol%, entry
2). However, we considered reaction conditions involving
catalytic amounts of 3, lower amounts of Oxone and lower
pH values to be optimal in terms of atom economy (i.e.
amounts of catalyst used and waste generated), hence they
were chosen for the study of the epoxidation of several
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
(R,R)-5i
4j
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
82 92
(R,R)-5j
99 26
alkenes. Though for some difficult cases the pH value, the 13 4k
3 (10 mol%),
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
(R)-5k
amount of catalyst or Oxone were increased. The results
are summarised in Table 1.
14
4l
3 (10 mol%),
99 11g
Oxone (1.6 equiv), K2CO3 (2.4 equiv)
5l
The hydrate-derived species 3 effectively catalysed the
epoxidation of a variety of trans-aryl-disubstituted olefins
(Table 1, entries 1–8), providing ee values ranging from
83% to 95.5%. Species 3 was found to be comparable to
Shi’s diester fructose derivative 2 for a number of alkenes
(4a,c,g,h).7 Olefin substrates with a wide range of groups,
such as aryl or alkyl substituents, benzyloxy ethers, hy-
a Oxone and base were simultaneously added during a period of 2 h.
The reaction mixture was further stirred at 0 °C for 16 h. The pH val-
ues were increased throughout the addition period from 6 to ca. 9
when K2CO3 (2.4 equiv) was used, and to ca. 10 in the other cases.
b Isolated material.
c Enantiomeric excesses.
droxymethyl or chloromethyl substituents were tolerated. d Unreported epoxide, configuration was assumed to be R,R.
e Configuration was assumed to be R,R.
Under the same experimental conditions, the epoxidation
of diaryl-substituted alkenes proceeded with the highest
f Not determined (5g was distilled together with the solvent during the
workup).
selectivity, followed by arylalkyl-substituted alkenes and,
lastly, dialkyl-substituted alkenes (cf. entries 2, 4 and 9 in
Table 1). Several trisubstituted olefins (Table 1, entries
10–12) were also epoxidised with high selectivity. How-
ever, disappointingly, the epoxidation of styrenes by 3
showed only poor selectivities (entries 13 and 14), though
conversions remained high, under all tested conditions. In
all cases, where known, the absolute configurations of the
obtained products are in agreement with the currently ac-
cepted mechanism of epoxidation by chiral dioxiranes de-
rived from ketone 1.5
g Configuration assumed to be R.
In summary, hydrate 3 has been found to be comparable
to Shi’s diester fructose derivative 2 in epoxidations in-
volving Oxone and we have expanded the substrate scope
catalysed by 3-derived species for a number of structural-
ly varied alkenes. Current efforts are directed towards ex-
ploiting this methodology towards epoxidations of more
difficult substrates, such as styrenes and tetrasubstituted
alkenes.
Synlett 2008, No. 18, 2856–2858 © Thieme Stuttgart · New York

2858
N. Nieto et al.
LETTER
[a]D25 +28.53 (c 0.12, CH2Cl2). IR: 2871–3066, 1599, 1491,
1097, 1037, 855 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.12–7.36 (m, 15 H), 5.36 (s, 1 H), 3.69 (d, 1 H, J = 1.9 Hz),
3.65 (t, 2 H, J = 6.0 Hz), 3.13 (td, J = 5.6, 1.9 Hz), 2.02 (td,
2 H, J = 5.6, 6.0 Hz). 13C NMR: d = 142.3, 142.3, 137.8,
128.6, 128.5, 128.2, 127.6, 127.6, 127.3, 127.1, 127.0,
125.7, 84.0, 65.7, 61.1, 58.8, 33.1. HRMS: m/z calcd for
C23H22O2Na: 353.1517; found: 353.1520. Enantiomeric
excess was determined by HPLC using a chiral stationary
phase (Chiracel OD-H column), eluent: hexane–i-PrOH
(95:5); flow: 0.8 mL/min; l = 216 nm; tR (major) = 10.8 min;
tR (minor) = 11.7 min.
Acknowledgment
We sincerely thank DGI-MCYT (Grant CTQ2005-02193/BQU),
DURSI (Grant 2005SGR225), Consolider Ingenio 2010
(CSD2006-0003), the ICIQ and the ‘Ramón Areces’ Foundations,
and the ‘Programa Torres Quevedo’ for financial support.
References and Notes
(1) (a) Katsuki, T. In Comprehensive Asymmetric Catalysis,
Vol. 2; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Heidelberg, 1999, 621–648. (b) Jacobsen, E. N.;
Wu, M. H. In Comprehensive Asymmetric Catalysis, Vol. 2;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
Heidelberg, 1999, 649–677. (c) Johnson, R. A.; Sharpless,
K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000, 231–285. (d) Katsuki,
T. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000, 287–325.
(12) General Procedure for the Epoxidation of Alkenes: The
corresponding alkene (2.22 mmol) and the required amount
of catalyst 3 (10–30 mol%) were dissolved in MeCN–
dimethoxymethane (44 mL, 1:2). A pH 6 buffer solution (8
mL), tetrabutylammonium hydrogen sulfate (35 mg, 0.10
mmol) was slowly added with stirring and the mixture was
cooled to the desired temperature. The flask was equipped
with two syringe pumps; one of them was filled with a
solution of Oxone (3.62–6.82 mmol) in pH 6 buffer (14 mL)
and the other one with a solution of K2CO3 (5.33–16.06
mmol) in H2O (14 mL). The two solutions were added
dropwise over a 2 h period (syringe pump). The solution was
stirred at 0 °C for the corresponding reaction time. The
mixture was diluted with H2O (40 mL) and extracted with
the appropriate organic solvent [5a and 5h: hexane (4 × 40
mL); 5b–g,i–l: CH2Cl2 (4 × 40 mL)]. The combined organic
fractions were collected and washed with brine (50 mL),
dried over Na2SO4, filtered and the solvents were removed
under reduced pressure. The crude material was purified by
flash chromatography on SiO2·Et3N (2.5%). Enantioselec-
tivity was determined by chiral chromatography and the
configuration of epoxides was established by comparison
with either reported elution order or optical rotation if
reported data was available. For 5a, HPLC; Chiralpak AD.14
For 5b,15 5j,16 and 5k,17 GC: gamma dex. For 5c18 and 5h,19
HPLC; Chiralcel OD. For 5d, HPLC; Chiralcel OD-H.20 For
5f,21 HPLC: Chiralcel AD-H. For 5l GC: gamma dex.
(13) Higher pH values were not considered since the background
reaction could be significant. See: Kurihara, M.; Ito, S.;
Tsutsumi, N.; Miyata, N. Tetrahedron Lett. 1994, 35, 1577.
(14) Roberts, S. M.; Poignant, G. Catalysis for Fine Chemical
Synthesis: Hydrolysis, Oxidation and Reduction, 1st ed.;
John Wiley & Sons: Chichester, 2002, 94–98.
(2) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K.,
Ed.; Wiley-VCH: Weinheim, 2006.
(3) See, for example: (a) Pericàs, M. A.; Puigjaner, C.; Riera,
A.; Vidal-Ferran, A.; Gómez, M.; Jimenez, F.; Muller, G.;
Rocamora, M. Chem. Eur. J. 2002, 8, 4164. (b) Popa, D.;
Puigjaner, C.; Gómez, M.; Benet-Buchholz, J.; Vidal-
Ferran, A.; Pericàs, M. A. Adv. Synth. Catal. 2007, 349,
2265; and references cited therein.
(4) For leading references on this transformation, see:
(a) Frohn, M.; Shi, Y. Synthesis 2000, 1979. (b) Shi, Y.
Acc. Chem. Res. 2004, 37, 488. (c) Hickey, M.; Goeddel,
D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5794. (d) Yang, D. Acc. Chem. Res. 2004, 37, 497.
(e) Xia, Q. H.; Ge, H. Q.; Ye, C. P.; Liu, Z. M.; Su, K. X.
Chem. Rev. 2005, 105, 1603.
(5) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224; and references cited therein.
(6) Wu, X. Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124,
8792.
(7) Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A.
J. Org. Chem. 2005, 70, 10143.
(8) Diacetate 2 is a very effective as epoxidation catalyst using
10 mol% of catalyst loading. Loading for Shi’s catalysts
usually ranges from 20 mol% to 30 mol%. See refs. 4a–c.
(9) Singleton, D. A.; Wang, Z. J. Am. Chem. Soc. 2005, 127,
6679.
(10) Nieto, N.; Munslow, I. J.; Barr, J.; Benet-Buchholz, J.;
Vidal-Ferran, A. Org. Biomol. Chem. 2008, 6, 2276.
(11) Compound 4e (0.37 g, 46% yield) was obtained as a
colourless oil. 1H NMR (400 MHz, CDCl3): d = 7.27–7.40
(m, 15 H), 6.48 (dt, 1 H, J = 16.0, 1.3 Hz), 6.28 (dt, 1 H, J =
16.0, 6.9 Hz), 5.42 (s, 1 H), 3.62 (t, 2 H, J = 6.9 Hz), 2.60
(qd, 2 H, J = 6.9, 1.3 Hz). 13C NMR: d = 142.4, 137.7, 131.6,
128.5, 128.4, 127.4, 127.3, 127.2, 127.0, 126.0, 83.7, 68.7,
33.6.
(15) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224.
(16) Katsuki, T. J. Mol. Catal. A: Chem. 1996, 113, 87.
(17) Archelas, A.; Furstoss, R. J. Org. Chem. 1999, 64, 6112.
(18) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.
(19) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59,
4378.
(20) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622.
(21) Kin Tse, M.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao,
H.; Döbler, C.; Spannenberg, A.; Mägerlein, W.; Hugl, H.;
Beller, M. Chem. Eur. J. 2006, 12, 1855.
The asymmetric epoxidation of alkene 4e to give (+)-5e was
carried out by the general procedure (see ref. 12).
Compound 5e (0.15 g, 52% yield); white solid; mp 56 °C;
Synlett 2008, No. 18, 2856–2858 © Thieme Stuttgart · New York

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