J. Am. Chem. Soc. 2000, 122, 4831-4832
4831
Scheme 1a
Simple Total Synthesis of the Pentacyclic
Cs-Symmetric Structure Attributed to the Squalenoid
Glabrescol and Three Cs-Symmetric Diastereomers
Compel Structural Revision
Zhaoming Xiong and E. J. Corey*
Department of Chemistry and Chemical Biology
HarVard UniVersity
Cambridge, Massachusetts 02138
ReceiVed March 8, 2000
The hexaisoprenoid squalene occupies a unique place in
chemistry and biology because of its extraordinary versatility as
the biosynthetic parent of a huge number of steroids and triter-
penoids. Recently, yet another class of squalenoids, the polycyclic
oxasqualenoids, has emerged as natural offspring of squalene
which are produced by new types of cascade polycyclization. An
especially intriguing member of this class is glabrescol, a novel
squalenoid which has been isolated from the Caribbean plant
Spathelia glabrescens (0.005% yield) and assigned the penta-
oxacyclic structure 1 on the basis of physicochemical and
spectroscopic data, including HMQC, COSY, NOESY, and
HMBC NMR analysis.1 A central plane of symmetry in the
structure of glabrescol was indicated by the absence of optical
activity, the occurrence of only 15 signals in the 13C NMR
a (a) Oxone, 3, MeCN-DMM-H2O (pH 10.5), 0 °C, 1.5 h. (b) CSA,
toluene, 0 °C, 1 h, 31% (two steps).
Scheme 2a
1
spectrum, and a 2-fold simplification in the H NMR spectrum.
Described herein is a stereoselective synthesis of structure 1 in
just two steps (Scheme 1) from the known (R)-2,3-dihydroxy-
2,3-dihydrosqualene (2), which is available by Sharpless enan-
tioselective dihydroxylation of squalene using the Noe-Lin catalyst
(16/1 enantioselectivity).2
Epoxidation of each of the trisubstituted double bonds could
be achieved with remarkable enantioselection using the Shi chiral-
dioxirane derived from ketone 33 in pH 10.5 H2O-CH3CN-
(CH3O)2CH2 (DMM) which produced the pentaepoxide 4 (80%
estimated purity by 1H NMR analysis) along with several minor
diastereomers that together totaled ∼20% of the total reaction
product.4 The chromatographic separation of the diastereomeric
mixture was difficult but catalyst 3 could be separated from the
mixture by column chromatography on silica gel (3 was eluted
before 4 and recovered in good yield for reuse). Treatment of 4
and diastereomers with a 3 mM solution of camphor-10-sulfonic
acid (CSA) in toluene at 0 °C for 1 h and subsequent purification
by column chromatography on silica gel using 25-50% ethyl
acetate in hexane for elution provided pure 1 in 31% overall yield
from 2. The spectroscopic and physicochemical data were
distinctly different from reported data1 and from measurements
performed in these laboratories with a small sample ( ∼0.5 mg)
of authentic glabrescol.5 The structure of this synthetic product,
predicted to be 1 on the basis that the conversion of 4 to 1 involves
inversion of configuration during each of the five epoxide
displacements which lead to formation of the five tetrahydrofuran
rings of 1, was confirmed independently. Reaction of synthetic 1
with excess p-bromobenzoyl chloride and 4-(dimethylamino)-
pyridine in CH2Cl2 at 23 °C for 60 h produced a crystalline bis-
p-bromobenzoate derivative, mp 142-143 °C, which was shown
by single-crystal X-ray diffraction to correspond to 1.6 Thus, if
a (a) HClO4, THF-H2O, 0 °C. (b) 3, Oxone, as for 4. (c) CSA, C7H8,
0 °C.
the tetrahydrofuran rings of structure 1 are designated as ABCB′A′
(reading 1 from left to right), the H and methyl substituents at
carbons 2 and 5 are A(cis), B(cis) and C(cis). Since the proposal
of structure 1 for glabrescol1 is untenable, we embarked on the
synthesis of the three other possible meso diastereomers of 1 that
could result from the pentacyclization of various 2,3-dihydroxy-
6,7-, 10,11-, 14,15-, 18,19-, 22,23-pentaepoxides of all E-
squalene. The structures of these three Cs-symmetric (meso)
diastereomers of 1 are expressed by formulas 5, 6, and 7 in
Schemes 2-4.
The synthesis of 5, the A(trans), B(cis), C(cis) pentacycle, is
outlined in Scheme 2. The (S,S)-epoxide 8 is available from E,E-
farnesyl acetate by the sequence: (1) enantioselective dihydroxy-
lation of the terminal double bond using the Noe-Lin catalyst,2
(2) reaction with MeSO2Cl-C5H5N to form the secondary
mesylate, (3) treatment with K2CO3-MeOH to form (S)-10,11-
epoxyfarnesol, (4) primary mesylate formation with MeSO2Cl-
Et3N and in situ conversion to (S)-10,11-epoxyfarnesyl bromide
(1) Harding, W. W.; Lewis, P. A.; Jacobs, H.; McLean, S.; Reynolds, W.
F.; Tay, L.-L.; Yang, J.-P. Tetrahedron Lett. 1995, 36, 9137.
(2) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741.
(3) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(4) The enantioselectivity of the epoxidation of each double bond in the
conversion of 2 to 4 can be estimated as >20:1.
(5) Generously provided by Dr. Helen Jacobs, University of the West Indies.
(6) Detailed X-ray crystallographic data are available from the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.
10.1021/ja000842y CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/26/2000