Total synthesis of polygalolide A

Article abstract of DOI:10.1021/ol2028256

The total synthesis of polygalolide A was accomplished through intramolecular C-glycosylation of glucal modified with siloxyfuran. The siloxyfuran group and siloxy substituent at the C-3 position played crucial roles in allowing direct access to the highl

Full text of DOI:10.1021/ol2028256

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6532–6535
Total Synthesis of Polygalolide A
Masaatsu Adachi,*,† Hitomi Yamada,† Minoru Isobe,‡ and Toshio Nishikawa†
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences,
Nagoya University, Chikusa, Nagoya 464-8601, Japan, and Department of Chemistry,
National Tsing Hua University, Hsinchu 30013, Taiwan
madachi@agr.nagoya-u.ac.jp
Received October 20, 2011
ABSTRACT
The total synthesis of polygalolide A was accomplished through intramolecular C-glycosylation of glucal modified with siloxyfuran. The
siloxyfuran group and siloxy substituent at the C-3 position played crucial roles in allowing direct access to the highly substituted
oxabicyclo[3.2.1] core skeleton with correct quaternary stereogenic centers.
Polygalolide A (1) and B (2) were isolated from the roots
and stems of the folk medicinal plant Polygala fallax Hemsl.
(Polygalaceae) by Wei and co-workers in 2003 (Figure 1).1
These two molecules represent a new type of phenolic
compound with a distinctive tetracyclic substructure char-
acterizedbya highlysubstitutedoxabicyclo[3.2.1]octanone
core skeleton, contiguous quaternary stereogenic centers
fusedwithaγ-lactone, and a six-membered ether. Although
details of the biological activity of 1 and 2 have not been
reported, their characteristic structures have attracted con-
siderable interest in the fields of organic synthesis and
biology. Studying the structures and synthesis of polyga-
lolides may also help to develop general annulation stra-
tegies for the construction of oxabicycles.2 The first total
synthesis of polygalolides was reported by Hashimoto and
co-workers, who constructed the oxabicyclo[3.2.1]octanone
skeleton using 1,3-dipolar cycloaddition of carbonyl ylide
and determined the absolute configurations.3 Snider and
Hashimoto also reported the formal total synthesis using
[5 þ 2] cycloaddition of oxidopyrylium ylide.4 Here, we
report an alternative total synthesis of polygalolide A (1)
through intramolecular C-glycosylation5 of glucal modi-
fied with siloxyfuran.
Figure 1. Structures of Polygalolide A (1) and B (2).
The retrosynthetic analysis of polygalolide A (1) is
illustrated in Scheme 1. We planned to synthesize 1 from
intermediate 3, a known synthetic precursor of polygalo-
lides, according to the report of Hashimoto.3 In our
† Nagoya University.
‡ National Tsing Hua University.
(1) Ma, W.; Wei, X.; Ling, T.; Xie, H.; Zhou, W. J. Nat. Prod. 2003,
66, 441–443.
(2) For recent reviews on the synthesis of the oxabicyclo scaffold, see:
(a) Harmata, M. Adv. Synth. Catal. 2006, 348, 2297–2306. (b) Battiste,
M. A.; Pelphrey, P. M.; Wright, D. L. Chem.;Eur. J. 2006, 12, 3438–
3447. (c) Lopez, F.; Mascarenas, J. L. Chem.;Eur. J. 2007, 13, 2172–
2178. (d) Singh, V.; Krishna, U. M.; Trivedi, G. K. Tetrahedron 2008, 64,
3405–3428.
(4) Snider, B. B.; Wu, X.; Nakamura, S.; Hashimoto, S. Org. Lett.
2007, 9, 873–874.
ꢀ
~
(5) For recent reviews on C-glycosylation, see: (a) Meo, P.; Osborn,
H. H. I. In Carbohydrate; Osborn, H. M. I., Ed.; Academic Press:
Amsterdam, 2003; pp 337ꢀ384. (b) Nishikawa, T.; Adachi, M.; Isobe,
M. In Glycoscience, 2nd ed.; Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.;
Springer Verlag: Berlin, Heidelberg, 2008; pp 756ꢀ811.
(3) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew.
Chem., Int. Ed. 2006, 45, 6532–6535.
r
10.1021/ol2028256
Published on Web 11/17/2011
2011 American Chemical Society

The siloxyfuran 5 was first synthesized from D-glucal
(6) through furanone-substituted glucal 13 (Scheme 2).
Silylation of D-glucal (6) was followed by benzylation of
the remaining secondary alcohol to afford glucal 7.
Following the hydration of 7 with triphenylphosphine
hydrobromide in CH2Cl2 and H2O,11 the resulting hemi-
acetal was oxidized with PCC to provide lactone 8.
Introduction of an acetylene unit to 8 was performed
by the addition of lithium trimethylsilylacetylide and de-
hydration of the resulting hemiacetal with TFA to fur-
nish alkynylated glucal 9. After the primary TIPS group
was selectively desilylated using pyridine hydrofluoride
in THF, oxidation with IBX afforded aldehyde 10.
The addition of lithiosiloxyfuran12 to 10 in the presence
of ZnCl2 proceeded in a highly stereoselective manner
with chelation control. Subsequent acid hydrolysis of
the unstable adduct gave lactone 12 as a single dia-
stereomer.13 An acetyl group, a leaving group at the
C-6 position required for Ferrier-type C-glycosylation,
was introduced by deprotection of the TIPS group and
regioselective acetylation using Vedejs’s procedure.14
The resulting glucal 13 was treated with TBSOTf and
triethylamine in Et2O to furnish the siloxyfuran 5 in high
yield.
Scheme 1. Retrosynthetic Analysis of Polygalolide A (1)
proposed synthesis route, tetracyclic intermediate 3 would
be generated via deoxygenation at the C-3 position of
the oxabicyclo[3.2.1]octene skeleton of tricyclic spiro com-
pound 4, followed by oxy-Michael addition and lactoniza-
tion to an enone intermediate. We envisaged that 4 would
be synthesized by intramolecular Ferrier-type C-glycosyla-
tion as a key step from glucal 5 modified with a ketene silyl
acetal and a siloxy substituent at the C-3 position.6,7 For
C-glycosylation,8,9 silicon-basedreagentshave been widely
employed as highly reactive carbon nucleophiles. Here, we
selected stable siloxyfuran8a as an equivalent of the ketene
silyl acetal, with the aim of constructing a quaternary
stereogenic center at the C-2 position of 4 and synthesis
of an oxabicyclooctene ring system. The siloxy substituent
at the C-3 position was expected to control the configura-
tion at the C-2 position as a result of steric hindrance in the
transition state, as discussed later. Furthermore, we antici-
pated that the acetylene moiety of 5 would stabilize an
oxocarbenium cation intermediate generated through
activation to construct a quaternary stereogenic center
at the C-8 position. Precursor 5, possessing all of the
necessary carbon atoms, would be synthesized from a
commercially available D-glucal (6) by introduction of
an acetylene moiety and chelation-controlled addition10
of a siloxyfuran to aldehyde to establish the C-3 stereo-
genic center.
Scheme 2. Synthesis of Siloxyfuran 5, a Precursor for C-Gly-
cosylation
(6) As the methodology for construction of the oxabicyclo[3.2.1]
skeleton includes a CꢀC bond formation at an anomeric position using
an oxocarbenium cation generated from glucal derivative 5, we termed it
intramolecular C-glycosylation.
(7) For intramolecular C-glycosylation via an oxocarbenium ca-
tion by using carbohydrate derivatives and related compounds, see:
(a) Martin, O. R. Tetrahedron Lett. 1985, 26, 2055–2058. (b) Stork, G.;
Krafft, M. E.; Biller, S. A. Tetrahedron Lett. 1987, 28, 1035–1038.
(c) Araki, Y.; Mokubo, E.; Kobayashi, N.; Nagasawa, J.; Ishido, Y.
Tetrahedron Lett. 1989, 30, 1115–1118. (d) Anastasia, M.; Allevi, P.;
Ciuffreda, P.; Fiecchi, A.; Scala, A. Carbohydr. Res. 1990, 208, 264–266.
(e) Craig, D.; Munasinghe, R. N. Tetrahedron Lett. 1992, 33, 663–666.
(f) Sasmal, P. K.; Maier, M. E. Org. Lett. 2002, 4, 1271–1274.
Org. Lett., Vol. 13, No. 24, 2011
6533

After obtaining siloxyfuran 5, we next investigated a
key intramolecular C-glycosylation for the synthesis of
oxabicyclo[3.2.1]octene 4 (Scheme 3). Upon treatment of
siloxyfuran 5 with a Lewis acid such as SnCl4, TiCl4, or
BF3•OEt2 in CH2Cl2, a complex mixture of products was
obtained. After extensive examination, we determined that
TMSOTf and 2,4,6-collidine in CH2Cl2 at ꢀ20 °C was the
optimal condition for the intramolecular C-glycosylation
to give desired oxabicyclo[3.2.1]octene 4 in 83% yield as a
single product. The structure of 4 was unambiguously con-
firmed by X-ray crystallographic analysis.15
Scheme 4. Total Synthesis of Polygalolide A (1)
Scheme 3. Synthesis of Oxabicyclo[3.2.1]octene 4 and Proposed
Mechanism for the Intramolecular C-Glycosylation
The high stereoselectivity of the intramolecular C-gly-
cosylation, as predicted (Scheme 3), is dictated by the effect
of the siloxy substituent at the C-3 position. Under the
reaction conditions, siloxyfuran 5 would give an oxocar-
benium cation intermediate, which has two possible tran-
sition states (TS-1 and TS-2) in a cyclization step. Con-
sidering allylic 1,3-strain, the C-glycosylation proceeds
through the more stable TS-2 with minimum steric hin-
drance between the two TBS groups to yield product 4
exclusively.
(8) (a) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydr.
Res. 1987, 171, 193–199. (b) Saeeng, R.; Sirion, U.; Sahakitpichan, P.;
Isobe, M. Tetrahedron Lett. 2003, 44, 6211–6215. (c) Isobe,M.;Phoosaha,
W.; Saeeng, R.; Kira, K.; Yenjai, C. Org. Lett. 2003, 5, 4883–4885.
(d) Saeeng, R.; Isobe, M. Org. Lett. 2005, 7, 1585–1588. (e) Saeeng, R.;
Isobe, M. Chem. Lett. 2006, 35, 552–557.
(9) (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993, 34,
5757–5760. (b) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633–5644.
(c) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–2945.
(10) (a) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556–569.
(b) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223.
(11) (a) Koviach, J. L.; Chappell, M. D.; Halcomb, R. L. J. Org.
Chem. 2001, 66, 2318–2326. (b) Bolitt, V.; Mioskowski, C. J. Org. Chem.
1990, 55, 5812–5813.
Next, oxabicyclo[3.2.1]octene 4 was transformed into
tetracyclic lactone 3, as shown in Scheme 4. Hydrolysis of 4
with LiOH gave a hemiacetal, and partial hydrogenation
of the desilylated acetylenic moiety with Lindlar’s catalyst
and subsequent reduction with Et3SiH and BF3•OEt2
˚
in the presence of MS-4 A afforded spirolactone 14. At
this stage, oxygen functionality at the C-3 position was
removed using the BartonꢀMcCombie deoxygenation
protocol.16 Deprotection of the TBS group was followed
(12) Boukouvalas, J.; Marion, O. Synlett 2006, 1511–1514.
(13) Although the stereochemistry of the generated alcohol at the C-3
position was not determined at this stage, the configuration was finally
confirmed to be S by X-ray crystallographic analysis of oxabicyclo-
[3.2.1]octene 4.
(14) (a) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358–
3359. (b) Vedejs, E.; Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras,
M.; Lin, S.; Oliver, P. A.; Peterson, M. J. J. Org. Chem. 1993, 58, 7286–
7288.
(15) CCDC 836367 (4) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(16) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585. (b) Barton, D. H. R.; Crich, D.; Lobberding,
A.; Zard, S. Z. Tetrahedron 1986, 42, 2329–2338.
6534
Org. Lett., Vol. 13, No. 24, 2011

by treatment with n-BuLi, CS2, and MeI to give xanthate
15, which was treated with n-Bu3SnH in the presence of
AIBN at 110 °C to furnish alkene 16. Debenzylation of 16
with FeCl3 and oxidation with MnO2 gave enone 17. Upon
treatment with Cs2CO3 in aqueous THF and MeOH, oxy-
Michael addition of the alcohol intermediate resulted in a
tricyclic compound. Methylation of the carboxylic acid
group with MeI and K2CO3 afforded methyl ester 18. Seq-
uential ozonolysis of the vinyl group and chemoselective
reduction of the resulting aldehyde with LiAlH(O-t-Bu)3 in
the presence of the ketone provided the primary alcohol,
which underwent spontaneous lactonization to yield the
desired tetracyclic lactone 3.3
Finally, according to Hashimoto’s procedure,3 tetracyc-
lic lactone 3 was transformed into polygalolide A (1) by
Mukaiyama aldol-type condensation with dimethyl acetal
19. The spectroscopic data of the synthesized compound
were identical to those of natural polygalolide A (1) with
the exception of optical rotation. The synthetic [R]D value
([R]D26 = ꢀ491 (c = 0.0226, MeOH)) was also consistent
with that of reported data.3
the C-3 position of 5 played crucial roles in allowing direct
access to the highly substituted oxabicyclo[3.2.1] core skel-
eton with correct quaternary stereogenic centers. This
novel and reliable methodology is applicable for the syn-
thesis of polygalolide analogues and natural products con-
taining an oxabicyclo skeleton.
Acknowledgment. This work was financially supported
by Grants-in-Aid for Young Scientists (Start-up and B)
and a Global COE program from the Japan Society
for the Promotion of Science (JSPS), and a SUNBOR
GRANT from the Suntory Institute for Bioorganic Research.
H.Y. is thankful for the Daiko Foundation Scholarship
and Nagoya University Scholarship for outstanding grad-
uate students. We are grateful to Mr. K. Yoza (Bruker
AXS) for the X-ray crystallographic analysis. We grate-
fully acknowledge Prof. S. Hashimoto (Hokkaido University)
and Prof. S. Nakamura (Nagoya City University) for pro-
viding the spectra of tetracyclic compound 3 and poly-
galolide A.
In conclusion, we have accomplished the total synthesis
of polygalolide A (1) starting from D-glucal through intra-
molecular C-glycosylation for the construction of the
oxabicyclo[3.2.1] core skeleton. In our distinctive synthesis
approach, the siloxyfuran group and siloxy substituent at
Supporting Information Available. Experimental proce-
dures, characterization data, copies of 1H and 13C NMR
spectra for all new compounds, and crystallographic data
for 4 (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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