A strategy for position-selective epoxidation of polyprenols

Article abstract of DOI:10.1021/ja801899v

An effective strategy has been developed for the efficient site-selective epoxidation of poylolefinic isoprenoid alcohols, based on the use of an internal control element for intramolecular reaction. The approach is illustrated by application to a series of polyisoprenoid alcohols (polyprenols) at substrate concentration of 0.5 mM. With polyprenol substrates having the hydroxyl function at one terminus, the internal epoxidation can be directed at the double bond of the polyprenol, which is either four or five away from the terminal hydroxyprenyl subunit.

Full text of DOI:10.1021/ja801899v

Published on Web 05/22/2008
A Strategy for Position-Selective Epoxidation of Polyprenols
Vijay Gnanadesikan and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received March 13, 2008; E-mail: corey@chemistry.harvard.edu
Abstract: An effective strategy has been developed for the efficient site-selective epoxidation of poylolefinic
isoprenoid alcohols, based on the use of an internal control element for intramolecular reaction. The approach
is illustrated by application to a series of polyisoprenoid alcohols (polyprenols) at substrate concentration
of 0.5 mM. With polyprenol substrates having the hydroxyl function at one terminus, the internal epoxidation
can be directed at the double bond of the polyprenol, which is either four or five away from the terminal
hydroxyprenyl subunit.
Introduction
the O-O bond (σ*-orbital) of the internally hydrogen-bonded
peroxycarbonyl group, with the CdC σ plane approximately
The site-selective epoxidation of poly-unsaturated substrates
is a key process in the biosynthesis of several families of natural
products, including steroids and triterpenoids (from 2,3-(S)-
oxidosqualene),1 insect juvenile hormones (farnesoate or ho-
mofarnesoate terminal epoxides),2 and eicosanoids (e.g., leu-
kotriene-A43 or (11R,12S)-oxidoarachidonic acid).4 The selective
introduction of an oxirane unit in polyenes by chemical means
remains a relatively undeveloped area of chemical synthesis.
Only a few examples of such reactions are currently known:
(1) the terminal hydroxybromination of farnesol esters or
squalene (neither of which is highly selective),5 (2) the
bromolactonization of poly-unsaturated fatty acids (e.g., arachi-
donic acid at the ∆5-double bond),6 (3) the internal epoxidation
of peroxyarachidonic acid 1, which generates the 14,15-epoxide
2 with high efficiency,7 and (4) the terminal epoxidation of
geraniol and farnesol esters by OsO4-K3Fe(CN)6 in the presence
of the Noe-Lin,8 Zhang,9 or Huang10 cinchona-based catalyst.
The selective formation of 2 from 1 can be ascribed to the
stereoelectronic constraints for intramolecular oxygen transfer
arising from attack by the CdC π-orbital electrons backside to
perpendicular to the peroxycarbonyl ring, as shown in 3. Such
structures for internal transfer of oxygen to the ∆5-, ∆8-, or
∆11-double bonds in 1 would involve appreciably more ring
strain.11 The present paper describes the application of this
model to the development of a strategy for the position-selective
epoxidation of poly-unsaturated alcohols, specifically polyiso-
prenoid alcohols (polyprenols).
(1) Corey, E. J.; Russey, W. E.; Ortiz de Montellano, P. R. J. Am. Chem.
Soc. 1966, 88, 4750–4751.
(2) Ro¨ller, H.; Dahm, K. H.; Sweeley, C. C.; Trost, B. M. Angew. Chem.,
Int. Ed. 1967, 6, 179–182.
(3) (a) Hammarstro¨m, S.; Samuelsson, B.; Clark, D. A.; Mioskowski, C.;
Corey, E. J. Biochem. Biophys. Res. Commun. 1979, 91, 1266–1272.
(b) Corey, E. J.; Arai, Y.; Mioskowski, C. J. Am. Chem. Soc. 1979,
101, 6748–6749.
Results and Discussion
(4) (a) Node, K.; Huo, Y.; Ruan, X.; Yang, B.; Spiecker, M.; Ley, K.;
Zeldin, D. C.; Liao, J. K. Science 1999, 285, 1276–1279. (b) Corey,
E. J.; Marfat, A.; Falck, J. R.; Albright, J. O. J. Am. Chem. Soc. 1980,
102, 1433–1434. (c) Han, X.; Crane, S. N.; Corey, E. J. Org. Lett.
2000, 2, 3437–3438.
The tetra-unsaturated acid 7a was synthesized from all-E-
tetraprenol 4 (geranylgeraniol) by the following sequence: (1)
mono coupling with 1 equiv of di-tert-butyldibromosilane
(imidazole catalyst in DMF at 45 °C); (2) further coupling of
the monobromosilyl ether 5 with the potassium salt of methyl
3,5-dibromo-4-hydroxybenzoate to form methyl ester 6 (DMF,
(5) Van Tamelen, E. E.; Curphey, T. J. Tetrahedron Lett. 1962, 3, 121–
124.
(6) Corey, E. J.; Albright, J. O.; Barton, A. E.; Hashimoto, S. J. Am. Chem.
Soc. 1980, 102, 1435–1436.
(7) Corey, E. J.; Niwa, H.; Falck, J. R. J. Am. Chem. Soc. 1979, 101,
1586–1587.
(8) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741–
8744.
(11) Structural oxygen transfer in poly-unsaturated peroxy acid is also
somewhat more facile when the intervening double bonds have Z rather
than E geometry, see: Liau, B. B.; Gnanadesikan, V.; Corey, E. J.
Org. Lett. 2008, 10, 1055–1057.
(9) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211–3214.
(10) Huang, J.; Corey, E. J. Org. Lett. 2003, 5, 3455–3458.
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 8089–8093 8089

A R T I C L E S
Gnanadesikan and Corey
Scheme 1
The nona-unsaturated peracid 10 (Scheme 2) was prepared
from all-E-nonaprenol (solanesol) under the same conditions
as used for 7b (Scheme 1), with essentially identical yields.
The peracid solution of 10 in CH2Cl2 (0.5 mM concentration)
was maintained at -20 °C for 48 h and then treated with excess
Me2S. The resulting carboxylic acid product was methylated
with CH2N2. For analytical purposes, a small quantity of epoxy
silyl methyl ester 11 was subjected to the following sequence:
(1) desilylation with HF-Py in THF and (2) oxirane cleavage
with H5IO6-Bu4NIO4 in a CH2Cl2-H2O mixture. The oxidative
cleavage products were isolated by extraction, filtration through
a small pad of flash silica gel, and removal of solvent. The
cleavage products, produced by the process oxirane f 1,2-diol
f methyl ketone + aldehyde, were then subjected to GC-MS
analysis, which revealed the formation of three methyl ketones
arising from C-C cleavage at bonds 14-15 (92%), 18-19
(5%), and 10-11 (3%), leading to the distribution of oxirane
products shown in formula 10 in Scheme 2. Preparative isolation
of the methyl ester 11 was readily accomplished by column
chromatography of the bulk of the reaction product on flash
silica gel impregnated with AgNO3. Desilylation of 11 provided
the 14,15-epoxide of nonaprenol, 12 (Scheme 2).
The above results with the 4-silyloxybenzoic acid controller
in the substrates 7b and 10 demonstrate that this controller
effectively directs internal epoxidation to the double bond of
the fourth prenyl unit from the prenyl-OH subunit (∆14). This
same mode of selectivity also operates with an isoprenoid
substrate that does not have all the prenyl groups arranged head-
to-tail, as shown for the 1-hydroxylated squalene derivative 13.15
The peroxy acid 13 underwent internal epoxidation mainly at
the double bond four removed from the controller (∆14). A small
amount of epoxidation occurred at the double bond five away
from the controller (∆18, ca. 10%), but none could be observed
at the more proximate or remote olefinic units.16
23 °C, 7 h, 73% overall yield); and (3) demethylation of 6 with
Me3SiOK in ether (Scheme 1).12
We have also designed a spacer/controller for the selective
internal delivery of oxygen to the double bond five removed
from the controller of a polyprenol (∆18). The pentanoic acid
18 was synthesized from all-E-pentaprenol 14 (geranylfarne-
sol)17 by the following sequence: (1) mono coupling with 1
equiv of di-tert-butyldibromosilane, using imidazole catalyst in
DMF at 45 °C for 8 h to give 15; (2) a second coupling of 15
with the dinitro phenol 16, DMAP (2 equiv), and imidazole (2
equiv) in dry DMF at 45 °C for 8 h, leading to 74% overall
yield of 17; and (3) demethylation of 17 with excess Me3SnOH
in refluxing dichloroethane (DCE), as shown in Scheme 3.18
The pentaprenol peroxyacid 19 (see below for more detail) was
The acid 7a was transformed into the peroxy acid 7b by
sequential reaction with carbonyldiimidazole in CH2Cl2 at 23
°C to form the corresponding N-acylimidazole and with a dry
solution of H2O2 in Et2O-EtOAc at -60 °C.7 When a solution
of 7b (0.5 mM concentration) was brought to -20 °C and
maintained there, internal epoxidation occurred to form the
terminal epoxide 8 with >20:1 selectiVity . Methyl esterification
of 8 and desilylation (HF-Py in THF at 23 °C)13 gave solely
the terminal epoxide 9 of all-E-tetraprenol, identical in all
respects with the known compound.14 We determined experi-
mentally that the internal epoxidation competes very favorably
with intermolecular epoxidation at an initial substrate concentra-
tion of 0.5 mM, and this protocol was employed in all the
experiments described herein.
(15) 1-Hydroxysqualene was prepared by SeO2 oxidation of squalene with
TBHP in CH2Cl2, see: Sen, S. E.; Prestwich, G. D. J. Med. Chem.
1989, 32, 2152–2158.
(16) The analysis of the internal epoxidation product from 13 and 22 was
carried out by GC-MS measurements of the products of oxirane
cleavage as described above for the products from 10 and 11.
(17) McDonald, B. F.; Neiwert, F. T.; Hardcastle, K. I. Org. Lett. 2004, 6,
4487–4489.
(12) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831–
5834.
(13) For details, see Supporting Information.
(14) Corey, E. J.; Luo, G.; Lin, S. L. J. Am. Chem. Soc. 1997, 119, 9927–
(18) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
Angew. Chem., Int. Ed. 2005, 44, 1378–1382.
9928.
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Position-Selective Epoxidation of Polyprenols
A R T I C L E S
Scheme 2
Scheme 4
Scheme 5
Scheme 3
from the controller, forming the 18,19-epoxide 23 after methy-
lation (67% yield). The structure of 23 was proven by oxidative
cleavage to methyl ketone 24 (Scheme 5). A minor amount of
epoxidation occurred at the double bond four away (6%, ∆14)
and that six away (5%, ∆22) from the controller, but no other
epoxides could be detected.16
The results described above show that it is possible to achieve
site-selective internal epoxidation of a double bond in a poly-
unsaturated substrate by the application of an appropriate spacer/
controller group that also serves as the peroxy acid component.
More specifically, the data support the stereomechanistic model
for internal epoxidation in which the peroxy acid function
approaches the reacting double bond in accord with the
following constraints on the transition-state geometry: (1)
oxygen is delivered in a synchronous fashion to both olefinic
carbons, (2) the midpoint of the CdC π-bond aligns with the
O-O σ*-orbital (behind the O-O bond being broken in the
synthesized from 18 and allowed it to transfer oxygen internally
in 0.5 mM solution in CH2Cl2 at -20 °C. The product was a
single epoxide (81% yield) arising from the delivery of oxygen
selectively to the terminal olefinic unit (fifth from the controller,
as anticipated). Again the product was transformed to the methyl
ester 20 and analyzed by GC-MS after oxidative cleavage of
the oxirane subunit to form silyloxy aldehyde 21 and acetone
(see Scheme 4).
We have also examined the application of the biphenyl spacer
16 to the selective internal epoxidation of nonaprenol. The nona-
unsaturated biphenyl-linked peroxy acid 22 was prepared from
all-E-nonaprenol by applying the methodology described above
for 18 (61% overall yield from nonaprenol to the carboxylic
acid corresponding to 22, Scheme 3). The peracid solution 22
in CH2Cl2 (0.5 mM concentration, -20 °C) also underwent
internal epoxidation mainly at the double bond five removed
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A R T I C L E S
Gnanadesikan and Corey
Scheme 6
ketone was readily transformed into all-E-hexaprenol (farne-
sylfarnesol, 26) in four high-yielding steps with an overall yield
of 75%, as shown in Scheme 6.19,20
This study has concentrated on the use of the R-disubstituted
4-silyloxybenzoic and 4′-silyloxybiphenic acid spacers/control-
lers. These have the advantage of leading to highly reactive
peroxy acids that possess the appropriate length for selective
targeted internal epoxidation, axial symmetry (which reduces
the conformational flexibility of the cyclic transition state), and
also synthetic availability. The hydroxybiphenic ester 16,
required in the synthesis of peracids 19 and 22, was made
starting from 4-iodoanisole by the following sequence: (1)
conversion to 4-lithioanisole (1 equiv of BuLi, THF, -78 °C,
30 min); (2) addition of 1 equiv of a solution of anhydrous ZnCl2
in THF; (3) slow addition of this solution over 8 h to a solution
of (PPh3)4Pd and methyl 4-chloro-3,5-dinitrobenzoate in THF
at 45 °C; and (4) isolation and demethylation of 27 with 3 equiv
of BBr3 in CH2Cl2 at -40 °C.
Figure 1. Approximate depiction of the internal epoxidation reaction of
the peroxy acid 7b derivative of tetraprenol that delivers oxygen selectively
to the terminal isopropylidene group.
The di-tert-butylsilyl group was chosen for the controller since
the required precursor t-Bu2SiBr2 is readily available (from
t-BuSiH2 and Br2) and very suitable for successive coupling
with the polyprenol and phenolic ester components. In addition,
the di-tert-butylsilyloxy subunit is stable to isolation by extrac-
tion and chromatography on silica gel. An additional advantage
of using the t-Bu2Si subunit in the linker is that it serves to
orient the aromatic peroxy group moiety and the polyprenol
part in proximity to one another because of its steric bulk.
Figure 2. Representation of the internal epoxidation reaction of pentaprenol,
showing the geometry for oxygen transfer from the peroxy acid function
of the pentaprenol derivative 19 to the terminal isopropylidene unit, which
is the farthest removed of the five double bonds.
transition state), and (3) the plane of the internally H-bonded
peroxy group is approximately orthogonal to the σ-plane of the
olefinic partner.
The ball-and-stick model displayed in Figure 1 illustrates this
geometrically favorable transition-state geometry for the internal
epoxidation of tetraprenol (geranylgeraniol) using the 4-tert-
butylsilyoxy peroxybenzoic acid spacer that delivers oxygen to
the terminal isopropylidene group of 7b.
Similarly, Figure 2 shows the favorable geometry that leads
from the pentaprenol peroxy acid derivative 19 to the terminal
epoxy acid corresponding to the methyl ester 20.
The availability of various epoxy polyprenols by the routes
described above provides access to a range of interesting
polyprenoids. For instance, the 14,15-epoxide 11 derived from
the peroxy acid 10 affords the methyl ketone 25 by oxidative
cleavage with H5IO6-Bu4NIO4 in a CH2Cl2-H2O mixture. This
Conclusions
The research described herein shows the feasibility of
applying internal epoxidation quite generally to the selective
oxidation of a single, double bond in a polyene. Even when the
olefinic units have the same intrinsic reactivity, the transition-
state model shown as 3 above provides a reliable guide for the
design of suitable controller/linker groups for the realization of
useful site selectivity in epoxidation.
(19) For precedent, see: Chen, K. M.; Semple, J. E.; Joullie, M. M. J. Org.
Chem. 1985, 50, 3997–4005.
(20) For a different approach to the synthesis of such oligoprenols, see:
Radetich, B.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 2430–2432.
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Position-Selective Epoxidation of Polyprenols
A R T I C L E S
Acknowledgment. We thank Dr. L. Ku¨rti and Dr. B. Czako´
for help with the modeling studies.
The entropy of activation of the internal epoxidation
reactions can be expected to be quite negative, which clearly
will diminish the rate of the reaction. However, with the
reactions described above, the use of a highly reactive peroxy
acid at concentrations of ca. 0.5 mM in CH2Cl2 can lead to
a favorable rate of intramolecular epoxidation relative to
intermolecular reaction and overcome the unfavorable en-
tropic factor.
Supporting Information Available: Experimental procedures
for the reactions described herein and characterization data of
reaction products. This material is available free of charge via
the Internet at http://pubs.acs.org.
JA801899V
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