In the past two decades, several methods aimed at
circumventing these rules in order to favor the formation of
pyrans have been published. However, most of these ap-
proaches required either the modification of the epoxide
substrate by covalently attached directing groups9 or the use
of transition-metal complexes10 or antibody catalysts.11
Recently, Jamison et al. reported an epoxide-opening
cascade for the construction of ladder polyether marine
natural products.12 Under optimized conditions in water at
pH ) 7.0, a ratio of 11:1 in favor of the pyran product was
accomplished. Though the epoxy alcohols used in this study
are templated toward pyran formation, we were encouraged
to envisage chromanol formation via an epoxide ring opening
as depicted in Scheme 2.
Table 1. Shi Epoxidation of Olefins 5a-ia
entry epoxide
R1
R2
yieldb (%) dec (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
(-)-Camphd TBS
73
62
76
75
78
87
76
81
81
79
66
73
82
85
73
74
91
97
TIPS
TIPS
TIPS
Me
MOM
TBS
TIPS
TIPS
benzyl
Me
(-)-Camphd Anthre
DPS
DPS
Scheme 2.
Proposed Chromanol Ring Constructiona
Me
DPS
a General experimental conditions: 1 equiv of 5, 0.4 equiv of ent-4,
and 5.4 equiv of H2O2 (30% aq) in a buffered (2 M K2CO3/EDTA) mixture
of MeCN/EtOH/CH2Cl2 (1:1:2) at 0 °C for 10 h. b Isolated yields.
c Determined by chiral HPLC. d (-)-Camphanoyl. e 9-Methylanthracenyl.
relation15 between catalyst configuration and product ster-
eochemistry suggested that we could obtain the desired
epoxide 2 using ent-4 rather than the commercially available
4.17 In view of the given structure of our synthetic intermedi-
ate 5, variation of the protecting groups at the hydroquinone
was the only choice to enhance the difference in size of the
substitutents at the trisubstituted double bond.
a In all schemes, figures and tables, R ) (4′R,8′R)-4′,8′,12′-trimethyl-
tridecanyl.
First of all, this strategy requires the asymmetric epoxi-
dation of a trisubstituted, unfunctionalized olefin. The
stereoselective synthesis of epoxides has been extensively
investigated13 including the direct asymmetric epoxidation
of alkenes.14 But most of these methods are substrate
dependent and hence were not considered to be suitable for
our strategy. In 1997, Shi et al. reported the use of a chiral
fructose-derived catalyst in the epoxidation of trans disub-
stituted and trisubstituted olefins15,16 (Scheme 3). The wide
(4) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew.
Chem. 2007, 119, 8824; Angew. Chem., Int. Ed. 2007, 46, 8670.
(5) Netscher, T. In Vitamins and Hormones; Litwack, G., Ed.; Elsevier:
San Diego, 2007; Vol. 76, p 155.
(6) Gru¨tter, C.; Alonso, E.; Chougnet, A.; Woggon, W.-D. Angew. Chem.
2006, 118, 1144; Angew. Chem., Int. Ed. 2006, 45, 1126.
(7) Liu, K.; Chougnet, A.; Woggon, W.-D. Angew. Chem. 2008, 120,
5911; Angew. Chem., Int. Ed. 2008, 47, 5827.
(8) Baldwin, J. J. Chem. Soc., Chem. Commun. 1976, 18, 734.
(9) Many directing groups have been employed. Selected examples: (a)
Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 5330. (b) Gonzalez, I. C.; Forsyth, C. J. J. Am.
Chem. Soc. 2000, 122, 9099. (c) Morimoto, Y.; Nishikawa, Y.; Takaishi,
M. J. Am. Chem. Soc. 2005, 127, 5806. (d) Simpson, G. L.; Heffron, T. P.;
Merino, E.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1056. (e) Morimoto,
Y.; Nishikawa, Y.; Ueba, C.; Tanaka, T. Angew. Chem. 2005, 118, 824;
Angew. Chem., Int. Ed. 2006, 45, 810.
Scheme 3
.
Shi Epoxidation in MeCN Using H2O2 as a
Co-oxidant
(10) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936. (b) Wu, M. H.; Hansen, K. B.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 1999, 38, 2012.
(11) (a) Janda, K. D.; Shevlin, C. G.; Lerner, R. A. Science 1993, 259,
490. (b) Gruber, K.; Zhou, B.; Houk, K. N.; Lerner, R. A.; Shevlin, C. G.;
Wilson, I. A. Biochemistry 1999, 38, 7062.
(12) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.
(13) For a review, see: (a) Besse, P.; Veschambre, H. Tetrahedron 1994,
50, 8885. (b) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV. 1997, 97,
2341.
(14) For a review, see: (a) Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p 103. (b)
Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1. (c) Jacobsen, E. N. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p
159. (d) Katsuki, T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH:
New York, 2000; p 287. (e) Porte, M. J.; Skidmore, J. Chem. Commun.
2000, 1215. (f) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Synth. Org. Chem.
Jpn. 2002, 60, 94.
scope of reactive olefin substrates made it the catalyst of
choice.
Several factors govern the selectivity of this reaction; in
particular, the size of the olefin substituents is significant
such that small R1 and large R3 groups gave the best
enantioselectivities.15 Further, Shi’s mechanism-based cor-
(15) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(16) (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (b) Shu, L.; Shi, Y.
Tetrahedron 2001, 57, 5213.
(17) Zhao, M.-X.; Shi, Y. J. Org. Chem. 2006, 71, 5377.
5124
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