Two concise enantioselective total syntheses of (-)-glabrescol implicate alternative biosynthetic pathways starting from squalene

Article abstract of DOI:10.1021/ol3016836

The C₂-symmetric (-)-glabrescol was synthesized in two steps from (10S,11R)-dihydroxy-10,11-dihydrosqualene or squalene with 50% or 10% overall yields, respectively. These highly efficient and biomimetic syntheses employed a base-promoted middl

Full text of DOI:10.1021/ol3016836

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Two Concise Enantioselective Total
Syntheses of (ꢀ)-Glabrescol Implicate
Alternative Biosynthetic Pathways
Starting from Squalene
Peng Yang, Pei-Fang Li, Jin Qu,* and Liang-Fu Tang
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin,
300071, China
qujin@nankai.edu.cn
Received June 19, 2012
ABSTRACT
The C2-symmetric (ꢀ)-glabrescol was synthesized in two steps from (10S,11R)-dihydroxy-10,11-dihydrosqualene or squalene with 50% or 10%
overall yields, respectively. These highly efficient and biomimetic syntheses employed a base-promoted middle-to-terminal double epoxide-
opening cascade, which constructs the five tetrahydrofuran rings in glabrescol in one operation.
In recent years, the groups of polyethers containing 2,5-
linked tetrahydrofuran subunits, occurring in both terres-
trial and marine plants, have attracted notable attention
because of their special chemical structures and potential
bioactivities.1 (ꢀ)-Glabrescol, the first reported squalene-
derived penta-tetrahydrofuran polyether, was extracted
from the branches and wood of Spathelia glabrescens in
0.005% yield by Jacobs et al. in 1995.2 It was originally
assigned the Cs-symmetric structure 1 based on the ob-
servation that the optical rotation of this compound was
zero (Scheme 1). In 2000, Corey’s group3a and Kodama’s
group3b separately reported the total syntheses of this
proposed structure but found that the NMR data of their
synthetic compound 1 were different from those of the
isolated natural product. The correct C2-symmetric structure
of (ꢀ)-glabrescol (2) was revealed in the same year through
the enantioselective total synthesis by Morimoto et al.4 They
also reported that the optical rotation of the synthetic (ꢀ)-
glabrescol was ꢀ22.4. Shortly after Morimoto’s total synthe-
sis, Corey and Xiong reported a biomimetic total synthesis
of the revised C2-symmetric (ꢀ)-glabrescol.5 Their six-step
total synthesis relies on the terminal-to-middle double
cyclizations of a tetraol tetraepoxide to construct the key
tetracycle intermediate. Herein, we report two concise
biomimetic total syntheses of (ꢀ)-glabrescol (2) via base-
promoted epoxide-opening cascade reactions.
(1) For reviews, see: (a) Vilotijevic, I.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2009, 48, 5250–5281. (b) Connolly, J. D.; Hill, R. A. Nat. Prod.
Rep. 2003, 20, 640–659. (c) Fernandez, J. J.; Souto, M. L.; Norte, M.
(4) (a) Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc. 2000,
122, 7124–7125. (b) Morimoto, Y.; Kinoshita, T.; Iwai, T. Chirallity
2002, 14, 578–586. (c) Morimoto, Y.; Takaishi, M.; Iwai, T.; Kinoshita,
T.; Jacobs, H. Tetrahedron Lett. 2002, 43, 5849–5852. (d) Morimoto, Y.;
Iwai, T.; Nishikawa, Y.; Kinoshita, T. Tetrahedron: Asymmetry 2002,
13, 2641–2647. (e) Morimoto, Y. Org. Biomol. Chem. 2008, 6, 1709–
1719. (f) Morimoto, Y. Asahi Garasu Zaidan Josei Kenkyu Seika
Hokoku, 2011.
ꢀ
Nat. Prod. Rep. 2000, 17, 235–246.
(2) Harding, W. W.; Lewis, P. A.; Jacobs, H.; McLean, S.; Reynolds,
W. F.; Tay, L.-L.; Yang, J.-P. Tetrahedron Lett. 1995, 36, 9137–9140.
(3) (a) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 4831–
4832. (b) Hioki, H.; Kanehara, C.; Ohnishi, Y.; Umemori, Y.; Sakai, H.;
Yoshio, S.; Matsushita, M.; Kodama, M. Angew. Chem., Int. Ed. 2000,
39, 2552–2554.
(5) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9328–9329.
r
10.1021/ol3016836
XXXX American Chemical Society

Scheme 1. Originally Proposed Cs-Symmetric Glabrescol (1)
and the Correct C2-Symmetric (ꢀ)-Glabrescol (2) and Its
Proposed Biogenesis
Scheme 2. Retrosynthetic Analysis of (ꢀ)-Glabrescol (2) and
(þ)-Glabrescol (ent-2)
It was proposed that (ꢀ)-glabrescol (2) is biosynthesized
in a single step from the meso hexaepoxide (3) derived from
squalene (Scheme 1). The nucleophilic attack of water at
the terminal epoxide of 3 initiates an all-exo left-to-right
unidirectional epoxide-opening cascade and constructs the
five tetrahydrofuran rings in one step.2,4 Mimicking this
biogenetic pathway meets two challenges: (1) the regio-
and stereoselective epoxidation of squalene to generate a
hexaepoxide, in which the configurations of the right three
epoxides are opposite to those of the left three epoxides; (2)
the unidirectional cascade epoxide-opening cyclization
from the correct terminus of the polyepoxide precursor
(the cascade proceeds in the opposite direction giving ent-
glabrescol). The feasibility of this biogenetic pathway has
recently been tested by Morimoto’s group. The unidirec-
tional left-to-right or right-to-left epoxide-opening cas-
cades of meso hexaepoxide 3 proceeded in the presence
of a catalytic amount of TfOH, but as was expected, the
reaction gave (()-glabrescol in 8% yield.4f However, by
applying a bidirectional epoxide-opening strategy, it is
possible to design a cascade utilizing a homochiral poly-
epoxide precursor. Inspired by the previous successful
utilizations of cascade epoxide-opening cyclizations in
the total synthesis of polyether natural products,4ꢀ6 we
considered that the C2-symmetric (ꢀ)-glabrescol was pos-
sibly generated from the cascade epoxide opening of 10,11-
dihydroxypentaepoxide (4a). The two middle hydroxyl
groups of 4a may initiate the middle-to-terminal double
epoxide-opening cascades and produce the penta-THF
structure in one step (Scheme 2). 4a (with all S,S-epoxides)
and 4b (with all R,R-epoxides) could be synthesized from
diol 5a and 5b respectively using the Shi asymmetric
epoxidation.7 Equal amounts of 5a and 5b could be
obtained from the racemic 10,11-oxidosqualene (6) via
hydrolysis and resolution. Therefore, according to this
strategy, both (ꢀ)-glabrescol and ent-glabrescol can be
synthesized from the same starting material 6. It should be
mentioned that both enantiomers of 10,11-oxidosqualene
are natural products and, more specifically, the (10R,11R)-
oxidosqualene was suggested asthe biogenetic precursor of
several natural polyethers.8
This strategy was first tested with the synthesis of
(þ)-glabrescol (ent-2) (Scheme 3). (10R,11S)-Dihydroxy-10,
11-dihydrosqualene (5b) was prepared from the racemic
10,11-oxidosqualene 6 by hydrolysis and resolution using
the reported methods.9 Shi asymmetric epoxidation of 5b
with the ketone 7 derived from the inexpensive D-fructose7
gave a mixture of pentaepoxide 4b, tetraepoxide 8, and a
small amount of other diastereomers in 90% yield. Com-
pounds 4b and 8 were inseparable by flash column chro-
matography, and their ratio varied depending on the silica
gel chromatography and the storage conditions. The ex-
istence of the central THF ring in compound 8 was judged
(6) (a) Xiong, Z.; Busch, R.; Corey, E. J. Org. Lett. 2010, 12, 1512–
1514. (b) Morimoto, Y.; Okita, T.; Kambara, H. Angew. Chem., Int. Ed.
2009, 48, 2538–2541. (c) Marshall, J. A.; Hann, R. K. J. Org. Chem.
2008, 73, 6753–6757. (d) Morimoto, Y.; Yata, H.; Nishikawa, Y. Angew.
Chem., Int. Ed. 2007, 46, 6481–6484. (e) Morimoto, Y.; Okita, T.;
Takaishi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2007, 46, 1132–1135.
(f) Marshall, J. A.; Mikowski, A. M. Org. Lett. 2006, 8, 4375–4378. (g)
Morimoto, Y.; Nishikawa, Y.; Takaishi, M. J. Am. Chem. Soc. 2005,
127, 5806–5807. (h) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard,
G. S. J. Am. Chem. Soc. 1995, 117, 3448–3467. (i) Lindel, T.; Franck, B.
Tetrahedron Lett. 1995, 36, 9465–9468. (j) Koert, U.; Wagner, H.; Stein,
M. Tetrahedron Lett. 1994, 35, 7629–7632. (k) Dolle, R. E.; Nicolaou,
K. C. J. Am. Chem. Soc. 1985, 107, 1691–1694.
1
from the characteristic signals in the H and 13C NMR
spectra of the mixture of 4b and 8. The peak at 3.87 ppm in
the 1H NMR spectrum (in CDCl3) suggeststhe existence of
a THF structure. There is only one 13C signal at 86.2 ppm
(8) (a) Kigoshi, H.; Ojika, M.; Shizuri, Y.; Niwa, H.; Yamada, K.
Tetrahedron Lett. 1982, 23, 5413–5414. (b) Napoli, L.; De; Fattorusso,
E.; Magno, S.; Mayol, L. Phytochemistry 1982, 21, 782–784.
ꢀ
(7) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224–11235. (b) Zhao, M.-X.; Shi, Y. J. Org.
Chem. 2006, 71, 5377–5379.
(9) (a) Abad, J. L.; Casas, J.; Sanchez-Baeza, F.; Messeguer, A.
J. Org. Chem. 1995, 60, 3648–3656. (b) Abad, J. L.; Camp, F. Tetra-
hedron 2004, 60, 11519–11525.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Epoxide-Opening Cascade Reaction Operated under
Acidic or Basic Conditionsa
Scheme 3. Synthesis of (þ)-Glabrescol (ent-2)
4b, 8 conditions ð þ Þ-Glabresol (ent-2)
f
reagent
(equiv)
temp
time
(h)
yieldb
(%)
entry
solvent
toluene
(°C)
1
2
CSA (0.6)
0
2
44
55
NaOH (16)
H2O/1,4-dioxane
v/v = 1:1
H2O/1,4-dioxane
v/v = 1:2
MeOH
100
0.5
3
KOH (8)
100
1
80
4
K2CO3 (10)
NaOH (10)
NaOH (5)
NaOH (3)
KOH (3)
60
60
60
60
60
60
60
1.5
0.8
2
61
85
87
90
87
65
45
5
MeOH
6
MeOH
7
MeOH
3
8
MeOH
3
9
NaOH (3)
NaOH (3)
EtOH
2
10
H2O
13
which indicated that a C2-symmetric THF ring was
formed, and this judgment was further supported by the fact
that only one signal appeared at 72.9 ppm which belonged
to the carbons of the tertiary alcohol. Compound 8 was
likely formed through the opening of the 14,15-epoxide of
4b by the hydroxyl group at C11. The diastereoselectivity
of the Shi asymmetric epoxidation was very high (dr
value >9:1 and the ee value of the epoxidation of each
double bond >97%).3a,10 Both 4b and 8 could afford ent-2
in the next step, so the mixture of 4b and 8 was used in the
following studies.11 Treatment of the above mixture with
camphor-10-sulfonic acid (CSA)3a,5,6a,12 in toluene at 0 °C
for 2 h provided the desired pentacyclic product ent-2 in
44% isolated yield (entry 1, Table 1).13 The NMR, LRMS
a The reaction was conducted with 0.1 mmol of substrate in the
indicated solvent at the indicated temperature. b Isolated yield.13
was treated with 16 equiv of NaOH in the mixed solvent of
H2O and 1,4-dioxane (v/v = 1:1)14 at reflux temperature,
ent-2 was formed in 55% yield (entry 2, Table 1). The
cascade cyclization was also tested with other bases and
solvent systems. The highest yield (90%, entry 7) of ent-2
was obtained by treating the mixture of 4b and 8 with
3 equiv of NaOH in methanol at 60 °C.
The optimized reaction protocol of base-promoted cas-
cade epoxide-opening was then applied to the synthesis of
the natural (ꢀ)-glabrescol (Scheme 4). Shi asymmetric
epoxidation of (10S,11R)-dihydroxy-10,11-dihydrosqua-
lene 5a with the ketone 9 derived from L-fructose7 gave
pentaepoxide 4a. Without further purification, the crude
product was subsequently treated with 5 equiv of NaOH in
(EI), and HRMS data match very well with the literature
25
=
data,2,4,5 whereas the optical rotation of ent-2, [R]D
þ21.3 (c = 0.3, CHCl3), is of the opposite sense to that of
25
the synthetic (ꢀ)-glabrescol ([R]D = ꢀ22.4 (c = 1.27,
CHCl3) reported by Morimoto4 or [R]D23 = ꢀ25.2 (c =
0.3, CHCl3) reported by Corey5). The CD spectrum of ent-
2 showed the opposite absorption pattern compared with
(ꢀ)-glabrescol measured by Morimoto’s group. Under
acidic conditions, the epoxide-opening cascade may pro-
ceed at various levels depending on which epoxides in the
polyepoxide precursor have been activated, and thus the
cascade reactions give rather complex products.1a We
envisioned that activation of the hydroxyl group might
impart better control over the progress of the cascade and
make the reaction cleaner. When the mixture of 4b and 8
Scheme 4. Synthesis of (ꢀ)-Glabrescol (2)
(10) In the Shi asymmetric epoxidation of the (S)-(þ)-R-methoxy-
R-(phenyl)-acetate of 4b, the purity of the designed pentaepoxide prod-
uct was >90% determined by 1H NMR, indicating that the dr value
was >9:1 and the ee value of each epoxide formation was >97%; see SI.
(11) The (S)-(þ)-R-methoxy-R-(phenyl)-acetate of 4b could also
afford ent-2 under identical reaction conditions; see SI.
(12) (a) Paterson, I.; Boddy, I.; Mason, I. Tetrahedron Lett. 1987, 28,
5205–5208. (b) Paterson, I.; Boddy, I. Tetrahedron Lett. 1988, 29, 5301–
5304. (c) Paterson, I.; Craw, P. A. TetrahedronLett. 1989, 30, 5799–5802.
(13) The yield was corrected for the diastereomeric purity of 4b and 8
in the starting material. The total purity of 4b and 8 as the products of the
Shi asymmetric epoxidation in different runs ranged from 70% to 90%
determined by 1H NMR.
(14) (a) Hoye, T. R.; Witowski, N. E. J. Am. Chem. Soc. 1992, 114,
7291–7292. (b) Hoye, T. R.; Jenkins, S. A. J. Am. Chem. Soc. 1987, 109,
6196–6198. (c) Hoye, T. R.; Suhadolnik, J. C. Tetrahedron 1986, 42,
2855–2862. (d) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Soc. 1985,
107, 5312–5313.
Org. Lett., Vol. XX, No. XX, XXXX
C

methanol at 60 °C.15 The above two-step reaction afforded
2 in 50% isolated yield. The 1H and 13C NMR, IR, CD,
25
Scheme 5. Synthesis of (ꢀ)-Glabrescol (2) from Squalene
LRMS (EI), HRMS, and the optical rotation ([R]D
=
ꢀ20.6 (c = 0.3, CHCl3)) of 2 match those of the natural
and synthetic (ꢀ)-glabrescol.2,4,5
Although the middle-to-terminal epoxide-opening cas-
cade of pentaepoxide 4aproceeds withvery highefficiency,
its precursor 5a needs to be synthesized from squalene over
four steps. We further expected that the base-promoted
regioselective hydrolysis of hexaepoxide 10 would lead to
pentaepoxide 4a and the in situ generated 4a would further
cyclize under the same basic condition to give (ꢀ)-glab-
rescol. In homochiral hexaepoxide 10, there are 12 possible
initiating sites for the single hydrolysis reaction and the
attack of OHꢀ at any site would trigger an epoxide-opening
cascade and lead to one penta-tetrahydrofuran polyether
product (Scheme 5). However, we found that theoretically
only four penta-tetrahydrofuran polyethers would be
formed through these 12 possible attacking modes. To test
this hypothesis, the all S,S-hexaepoxide 10 was synthesized
from squalene using the Shi asymmetric epoxidation. The
crude hexaepoxide was then treated with 50 equiv of KOH
in the mixed solvent of H2O and i-PrOH (v/v = 1:16)
at reflux temperature. The reaction rate was relatively
slow, but all of hexaepoxide 10 was consumed in 43 h.
The diastereomeric mixture could be clearly separated
by repeating column chromatography using chloroform/
acetone (v/v = 9:1) as the eluent. Analysis of the reaction
products showed that all four penta-tetrahydrofuran poly-
ethers were formed as was expected (total yield 47%).
The characteristic data of the diastereomer with an
11% yield corresponds to those of the meso polyether 1.
X-ray crystal analysis of this compound revealed that it
adopts an interesting coiled conformation in which the two
terminal hydroxy groups each form two intramolecular
hydrogen bonds with the THF ether oxygen atoms close to
itand next to it.16 The NMR data of polyether 11, obtained
in 13% yield, match very well with those of the reported
penta-tetrahydrofuran polyether derived from (þ)-
omaezakianol.17 The opposite optical rotation value of
polyether 11 confirmed its absolute stereochemistry. Poly-
ether 12 has not been reported before, and its structure was
(ꢀ)-glabrescol prepared via this synthetic route was equal
to that synthesized from pentaepoxide 4a. Although the
regioselectivity of the epoxide-opening cascades is not
good, this synthetic route for (ꢀ)-glabrescol is still very
attractive since it starts from the readily available and
inexpensive squalene.
In conclusion, two concise total syntheses of (ꢀ)-glab-
rescol (2) have been achieved in 50% yield starting from
(10S,11R)-dihydroxy-10,11-dihydrosqualene (2% overall
yield from squalene, the first route) or 10% overall yield
from squalene (the second route) respectively. The key
feature of our synthetic strategy is the base-promoted
middle-to-terminal double epoxide-opening cascade,
which constructs the five tetrahydrofuran rings of the
C2-symmetric glabrescol in one operation. The epoxide-
opening cascade cyclization is generally accepted as the
biogenetic pathway of squalene-derived polyethers. There-
fore these syntheses implicated two possible biogenetic
pathways of (ꢀ)-glabrescol.
1
determined by the combined use of 1Hꢀ H COSY, HSQC,
HMBC, and NOESY spectra. Its relative stereochemistry
was further checked by the middle-to-terminal epoxide-
opening cascade of all R,R-pentaepoxide of 5a, which
was expected to afford ent-12 as the only cyclization
product (see Supporting Information (SI)). The NMR
spectra of the fourth isomer with a 10% yield was deter-
mined to be (ꢀ)-glabrescol (2). The optical purity of
Acknowledgment. This work was financially supported
by the NSFC (21072098), Program for New Century Ex-
cellent Talents in University, and the 111 Project (B06005).
We thank Prof. Wei-Dong Li and Prof. Qi-Lin Zhou at
Nankai University for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds,
crystal structure of 1 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) The reaction was very slow with 3 equiv of NaOH due to the
existence of the unseparated ketone 9.
(16) CCDC number: 876022; see SI. The crystal structure of the bis-p-
bromobenzoate of compound 1 displays a linear conformation since
both of the two terminal hydroxy groups are protected; see ref 3a.
(17) Matsuo, Y.; Suzuki, M.; Masuda, M.; Iwai, T.; Morimoto, Y.
Helv. Chim. Acta 2008, 91, 1261–1266.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX