Synthesis of the Putative Structure of Eupomatilone-6

Article abstract of DOI:10.1021/ol035908j

(Matrix presented) The synthesis of eupomatilone-6 (1) has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular Horner-Wadsworth-Emmons reactions. The spectroscopic studies carried out on synthetic eupomatilone-

Full text of DOI:10.1021/ol035908j

ORGANIC
LETTERS
2004
Vol. 6, No. 3
317-319
Synthesis of the Putative Structure of
Eupomatilone-6
Mukund K. Gurjar,* Joseph Cherian, and C. V. Ramana
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
gurjar@dalton.ncl.res.in
Received September 30, 2003
ABSTRACT
The synthesis of eupomatilone-6 (1) has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular
Horner−Wadsworth−Emmons reactions. The spectroscopic studies carried out on synthetic eupomatilone-6 do not agree with those reported
for the natural product, and therefore revision of the assigned structure is warranted.
In 1991, Taylor et al. isolated a series of novel lignans
eupomatilones 1-7 from the shrubs Eupomatia bennettii
F.Muell., and their relative configurations were elucidated
by extensive NMR studies.1,2 Eupomatilones are character-
ized by the biaryl system with a substituted γ-lactone ring
attached to one of the aryl rings. Although they exist as a
mixture of atropisomers, efforts to separate them by HPLC
were unsuccessful. Apart from a recent synthesis of (()-5-
epi-eupomatilone-6, no report has yet appeared on the total
synthesis of any of these natural products.3
The synthesis began with the Suzuki coupling reaction
between 55 and 66 in the presence of Pd(0) to afford the biaryl
aldehyde derivative 77 in 79% yield (Scheme 1). Treatment
of 7 with ethoxycarbonylmethylenetriphenylphosphorane in
CH2Cl2 afforded 8 as a mixture of E/Z-isomers (85:15). In
Scheme 1a
As part of our continuing interest in biaryl-containing
natural products coupled with the structural peculiarity of
eupomatilones, herein we report the total synthesis of eupo-
matilone-6 (1).4 It is pertinent to mention that the synthetic
product did not match spectroscopically with assigned struc-
ture of natural eupomatilone-6, and therefore a revision in
structure is proposed.
a Reagents and conditions: (a) Pd[(PPh3)]4, benezene, ethanol, 2
M Na2CO3, reflux, 24 h, 79%; (b) Ph3PdCHCO2Et, CH2Cl2, rt, 3
h; (c) (DHQD)2PHAL, K2OsO4‚2H2O, MeSO2NH2, K2CO3, tBuOH:
H2O (1:1), 0 °C, 18 h, 80% (for two steps).
10.1021/ol035908j CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004

Scheme 2a
a Reagents and conditions: (a) DMP, CH2Cl2, p-TSA, rt, 94%; (b) LiAlH4, THF, 0 °C, 2 h, 78%; (c) TsCl, Et3N, CH2Cl2, 0 °C, 6 h, 90%;
(d) MeOH, HCl, rt, 1 h, 88%; (e) K2CO3, MeOH, 30 min, rt, 75%; (f) MEMCl, DIPEA, CH2Cl2, rt, 8 h, 83%; (g) LiAlH4, THF, 0 °C, 3
t
h, 94%; (h) PDC, CH2Cl2, 4 Å molecular sieves, 4 h, 67%; (i) PPTS, BuOH, 80 °C, 12 h, 75%; (j) (EtO)2P(O)-CH(Me)-COCl (14),
DIPEA, CH2Cl2, 0 °C, 3 h 70%; (k) NaH, THF, 0 °C, 30 min., 87%; (l) Rh/Al2O3, H2, 60 psi, 20 h, 60%.
1
the H NMR spectrum of 8, the olefinic protons of the
E-isomer appeared at δ 6.26 and 7.48 as doublets (J ) 16.2
Hz), whereas the Z-isomer revealed olefinic protons at δ 5.80
and 6.61 as doublets (J ) 12.2 Hz). Asymmetric dihydroxy-
lation of 8E using (DHQD)2PHAL, K3Fe(CN)6, K2CO3,
MeSO2NH2, and K2OsO4‚2H2O in tBuOH:H2O (1:1) at 0 °C
for 18 h gave the dihydroxy derivative 9 in 80% yield.8
The presence of two atropisomers of the dihydroxyl
derivative 9 was indicated by the 1H NMR spectrum in which
H-3 proton revealed two signals at δ 4.84 (J ) 7.3 Hz) and
δ 4.86 (J ) 7.3 Hz). Attempted separation of these
atropisomers at this stage using chiral HPLC was not
successful. The chromatogram showed only a single peak
with various chiral columns (Chiralcel OD, Chiralpak
AD-H, Cyclobond, Chiralcel OJ columns) used in this pro-
tocol. This study did suggest that compound 9 had been
obtained with excellent ee. Protection of 9 as an isopropy-
lidene derivative (Scheme 2) followed by reduction of the
COOEt group with LiAlH4 gave the alcohol 10. Following
a sequence of reactions such as (a) tosylation of primary
hydroxyl group, (b) deprotection of isopropylidene group,
(c) cyclization to the epoxide derivative, and (d) protection
of free hydroxyl group as the MEM ether, 10 was converted
into 11 in 49% overall yield. Reductive ring opening of the
epoxide ring present in 11 with LiAlH4 in THF at 0 °C
formed 12.
Oxidation of 12 with PDC gave the keto derivative, which
was treated with PPTS in tBuOH at 80 °C to cleave the MEM
group and afford the R-hydroxyketone derivative 13. Com-
pound 13 was reacted with the acid chloride 14 in the
presence of DIPEA-CH2Cl2 to afford the phosphonate 15
(Scheme 2). The intramolecular Horner-Wadsworth-Em-
mons reaction of 15 was carried out by using NaH in DME
at 0 °C.9-11 The resulting unsaturated-γ-lactone 16 (80% 5S,
20% 5R) was hydrogenated in the presence of Rh/Al2O3 in
EtOAc at 60 psi to give 1 and its (3R,4S,5R)-isomer.12 To
obtain analytical data, a small portion of this mixture was
chromatographed on chiral HPLC (for 1, tR ) 14.75, and
for (3R,4S,5R)-isomer, tR ) 17.99; Chiralcel-OD 4.6 × 25,
λ ) 254 nm, hexane/2-propanol 78/12, 0.5 mL/min) and pure
1 was isolated.
1
Interestingly, the H NMR spectrum of synthetic 1 did
not match that of either the natural product1 or the 5-epi-
eupomatilone-63 isomer. The observed NOEs between the
H-3, H-4, and H-5 in the NOESY spectrum of 1 clearly
(1) Taylor, W. C.; Carroll, A. R. Aust. J. Chem. 1991, 44, 1615-1626.
(2) (a) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43-74. (b) Macrae, W.
D.; Towers, G. H. N. Phytochemistry 1984, 23, 1207-1220.
(3) Hong, S.; McIntosh, M. C. Org. Lett. 2002, 4, 19-21.
(4) Rao, A. V. R.; Gurjar, M. K.; Ramana, D. V.; Chheda, A. K.
Heterocycles 1996, 43, 1-6.
(9) For a review of butenolide synthesis, see: Rao, Y. S. Chem. ReV.
1976, 76, 625-694.
(5) Li, J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Collins, J.
T.; Garland, D. J.; Gregory, S. A.; Huang, H.-C.; Isakson, P. C.; Koboldt,
C. M.; Logusch, E. W.; Norton, M. B.; Perkins, W. E.; Reinhardt, E. J.;
Seibert, K.; Veenhuizen, A. W.; Zhang, Y.; Reitzt, D. B. J. Med. Chem.
1995, 38, 4570-4578.
(6) Ziegler, F. E.; Chliwner, I.; Fowler, K. W.; Kanfer, S. J.; Kuo, S. J.;
Sinha, N. D. J. Am. Chem. Soc. 1980, 102, 790-798.
(7) Ni(0) catalyst-mediated Negishi coupling had been used for the
preparation of 7: Larson, E. R.; Raphael, R. A. J. Chem. Soc., Perkin Trans.
1 1982, 521-525.
(8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(10) (a) Katsumura, S.; Kimura, A.; Isoe, S. Tetrahedron 1989, 45, 1337-
1346. (b) Nangia, A.; Prasuna, G. Tetrahedron 1996, 52, 3435-3450. (c)
Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfield, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-2186.
(11) We have noticed that the epimerization happens mainly during the
conversion of 13 to 15. For analytical purposes, we have synthesized (()-
16 from 8E by following the same sequence of reactions but with an achiral
dihydroxylation step and showed it to be a 1:1 racemic mixture by
performing HPLC analysis on a Chiralcel-OD column using 5% 2-propanol
in hexane.
(12) Matsubara, J.; Nakao, K.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1992, 33, 4187-4190.
318
Org. Lett., Vol. 6, No. 3, 2004

Table 1.
indicated a cis relationship between these protons. Addition-
ally, the presence of NOE between 3-Me and 4-Me and the
absence of NOE between H-5 and any Me group substanti-
ated this assignment. A careful examination (Table 1) of the
chemical shifts and coupling constants of the aliphatic
protons of six eupomatilones indicated that the data of
synthetic 1, eupomatilone-4 (3), and eupomatilone-7 (4) were
similar, whereas the data of natural eupomatilone-6 were
close to that of eupomatilone-3 (2) except the J3,4 value. This
clearly indicates that the assigned relative stereochemistry
of three aliphatic protons of eupomatilone-6 deserve revision
and suggests either a 3R,4â,5â-configuration (like in eupoma-
tilone-3) or a 3R,4â,5R-configuration.
In summary, the previously assigned structure of eupoma-
tilone-6 has been synthesized and warrants revision. Efforts
to synthesize eupomatilone-6 and other eupomatilones are
in progress.
Acknowledgment. We thank Dr. S. R. Bhide for HPLC
analyses, and J.C. thanks CSIR (New Delhi) for financial
assistance in the form of a research fellowship.
Supporting Information Available: 1H and 13C NMR
spectra of 1 and 16. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL035908J
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