Palladium catalyzed synthesis of the furanoterpene ircinin-4

Article abstract of DOI:10.1055/s-1999-2534

A flexible entry into 2,4-disubstituted furan derivatives is outlined employing sulfonium salt 1 as a well accessible starting material. Condensation of the sulfur ylide derived from 1 with aldehydes, palladium catalyzed opening of the vinyloxirane thus formed, and a final oxidative cyclization of the furan ring constitute the key steps of this method. Its utility is exemplified by the first total synthesis of the marine natural product ircinin-4 (2).

Full text of DOI:10.1055/s-1999-2534

LETTER
29
Palladium Catalyzed Synthesis of the Furanoterpene Ircinin-4
Alois Fürstner*, Thomas Gastner and Jörg Rust
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany
Fax: +49-208-306-412342; e-mail: fuerstner@mpi-muelheim.mpg.de
Received 16 October 1998
sources (Scheme 2).3,4 Among them, the ircinin family of
furanoterpenes produced by the mediterranean sponges
Ircinia oros and I. fasciculata deserves mentioning due to
issues related to their biosynthesis5 and, more important-
Abstract: A flexible entry into 2,4-disubstituted furan derivatives is
outlined employing sulfonium salt 1 as a well accessible starting
material. Condensation of the sulfur ylide derived from 1 with alde-
hydes, palladium catalyzed opening of the vinyloxirane thus
formed, and a final oxidative cyclization of the furan ring constitute ly, because of the interesting biological effects exerted by
the key steps of this method. Its utility is exemplified by the first to-
tal synthesis of the marine natural product ircinin-4 (2).
these compounds. Specifically, they exhibit high activity
in the brine shrimp assay and one member of this series
turned out to be a selective inhibitor of phospholipase A2.3
Key words: furan, palladium, sulfur ylide, terpene, marine natural
product
The central role of heterocycles in life sciences and natu-
ral product chemistry provides a constant drive for the de-
velopment of even more efficient methods for their
preparation. In this context, we have recently identified
the functionalized sulfonium salt 1 as a valuable building
block for the formation of pyrroles and have demonstrated
its utility by a concise approach to the complex anti-tumor
alkaloid roseophilin.1 Quite obviously, the underlaying
strategy (Scheme 1) may serve as a more general platform
for the formation of different types of heterocycles. The
first total synthesis of ircinin-4 (2) outlined below now ex-
tends this concept to the furan series.
Scheme 2
As part of our program aiming at the synthesis of bio-
active natural products by organometallic means6 we de-
cided to probe the envisaged entry into furans by an
application to this class of secondary metabolites. Since
no preparative studies on ircinin-4 (2) have been reported
so far, we chose this particular compound as our prime
target. As shown in Scheme 3, 2 may be readily assembled
via alkylation of the side chain surrogate 7 with the fura-
nylmethylfuran derivative 6 which itself can be traced
back to substrate 1. If successful, this convergent ap-
Scheme 1
proach can be easily adapted to the synthesis of other fura-
noterpene dervatives as well.
2,4-Disubstituted furan derivatives are particularly diffi-
cult to make by conventional methods.2 This structural
motif, however, is present in various physiologically ac-
tive natural products such as 2-5 isolated from marine
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30
A. Fürstner et al.
LETTER
Exposure of this derivative 12 to MnO and subsequent
2
treatment of the resulting aldehyde with aq. HCl cleanly pro-
vides the desired furanylmethylfuran derivative 6 which was
isolated in 67% yield. The structural integrity of this key
building block was deduced from NMR, MS and IR data as
well as from an X-ray analysis (Figure 1).12,13
Scheme 3
Our synthesis of segment 6 (Scheme 4) starts from 3-furyl-
acetaldehyde 87 which reacts with the sulfur ylide formed
from 1 by deprotonation with tert-BuLi1 to afford the desired
epoxide 9 in 63% yield. Treatment of this compound with
catalytic amounts of Pd(PPh ) selectively activates its vi-
3 4
nyloxirane entity without affecting the adjacent allyl ether
site.8 The alkoxide unit of the resulting functionalized π-al-
lylpalladium complex deprotonates admixed bis(phenylsul-
fonyl)methane which, in turn, attacks the electrophilic
organopalladium species in a regioselective manner at the
terminal C-atom to afford allylic alcohol 109 in very high
yield. Attempts to transform this compound directly into the
desired furanylmethylfuran 6 by oxidation of its secondary
alcohol and subsequent dehydrative cylization resulted in
rather poor yields.10 A viable alternative, however, was
found by reversing the oxidation pattern: thus, temporary
protection of the –OH group of 10 as a THP acetal 1111 fol-
lowed by fluoride induced cleavage of the TBS group sets the
stage for a selective oxidation of the primary allylic alcohol.
β-Citronellol 13 serves as an obvious starting material for the
preparation of the required side chain 7 (Scheme 5). For this
purpose, 13 was converted into aldehyde 14 by two routine
steps14 in excellent yield on a multigram scale; the latter was
then subjected to the modified Wittig reaction for the prepa-
ration of trisubstituted olefins.15 Thus, reaction of 14 with
ethylidenetriphenylphosphorane followed by treatment of
the resulting betaine with n-BuLi at –78°C forms a deeply
red colored β-oxido phosphonium ylide which was quenched
Scheme 4
Scheme 5
Synlett 1999, No. 1, 29–32 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium Catalyzed Synthesis of the Furanoterpene Ircinin-4
31
with excess paraformaldehyde to deliver (Z)-configurated al-
lyl alcohol 15 as a single isomer. Although the chemical
yield was moderate, the preparative ease and the stereospe-
cific course render this transformation sufficiently attractive
for our purposes. 15 was then converted into bromide 7 under
standard conditions.12,16
References and Notes
(1) (a) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120,
2817-2825. (b) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc.
1997, 119, 2944-2945.
(2) For a timely and comprehensive review see: Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S.
Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955-2020.
(3) Ircinins: (a) Cimino, G.; De Stefano, S.; Minale, L. Tetrahe-
dron 1972, 28, 5983-5991. (b) Cimino, G.; De Stefano, S.;
Minale, L.; Fattorusso, E. Tetrahedron 1972, 28, 333-341. (c)
De Giulio, A.; De Rosa, S.; Di Vincenzo, G.; Strazzullo, G.;
Zavodnik, N. J. Nat. Prod. 1990, 53, 1503-1507. (d) De Rosa,
S.; Milone, A.; De Guilio, A.; Crispino, A.; Iodice, C. Nat.
Prod. Lett. 1996, 8, 245-251. (e) See also: Capon, R. J.; Dar-
gaville, T. R.; Davis, R. Nat. Prod. Lett. 1994, 4, 51-56. (f)
Cholbi, R.; Ferrándiz, M. L.; Terencio, M. C.; De Rosa, S.; Al-
caraz, M. J.; Payá, M. Naunyn-Schmiedeberg‘s Arch. Phar-
macol. 1996, 354, 677-683.
(4) (a) Hippospongins: Rochfort, S. J.; Atkin, D.; Hobbs, L.; Ca-
pon, R. J. J. Nat. Prod. 1996, 59, 1024-1028. (b) Spongionel-
lins: Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.
Chem. Lett. 1985, 1521-1524.
(5) Note that ircinin-4 (2) contains 21 (!) C-atoms. This raises the
question whether its biosynthesis proceeds by degradation of
a sesterterpene or by addition of a C-1 unit to a diterpenoid
precursor. Arguments in favor of the former possibility are
launched in: Minale, L.; Cimino, G.; De Stefano, S.; Sodano,
G. Fortschritte der Chemie Organischer Naturstoffe 1976, 33,
1-72.
Reductive metalation of bis-sulfone
6 with lithium
naphthalenide17 followed by addition of the allylic bromide 7
provides the desired coupling product 16; despite consider-
able experimentation, however, the yield did not exceed 46%
(Scheme 6). The remaining sulfone group was then removed
with Na(Hg) (6% w/w) in buffered MeOH as the reaction me-
dium (16→17)18 and the silyl ether was cleaved with TBAF
in aqueous THF. Due to the inherent lability of the furan
rings towards oxidation, the conversion of the resulting alco-
hol 1812 to the target must be carried out under carefully con-
trolled conditions and was best achieved by a two step
19
protocol comprising treatment with PDC in CH2Cl2 fol-
lowed by oxidation of the resulting crude aldehyde with
AgNO3 in ethanolic KOH solution.20 The analytical and
spectroscopic data of ircinin-4 (2) thus formed are in full
agreement with those reported in the literature.12,3a
(6) See i. a.: (a) Fürstner, A.; Szillat, H., Gabor, B.; Mynott, R. J.
Am. Chem. Soc. 1998, 120, 8305-8314. (b) Fürstner, A.; Hup-
perts, A. J. Am. Chem. Soc. 1995, 117, 4468-4475. (c) Fürst-
ner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem.
1994, 59, 5215-5229. (d) Fürstner, A.; Ernst, A.; Krause, H.;
Ptock, A. Tetrahedron 1996, 52, 7329-7344. (e) Fürstner, A.,
Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60, 6637-
6641. (f) Fürstner, A.; Ernst, A. Tetrahedron 1995, 51, 773-
786.
(7) Uenishi, J.; Kawahama, R.; Tanio, A.; Wakabayashi, S.; Yo-
nemitsu, O. Tetrahedron 1997, 53, 2439-2448.
(8) For leading references on Pd(0) catalyzed reactions of vinylo-
xiranes see: (a) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahe-
dron Lett. 1981, 22, 2575-2578. (b) Trost, B. M.; Molander,
G. A. J. Am. Chem. Soc. 1981, 103, 5969-5972. (c) Trost, B.
M.; Warner, R. W. J. Am. Chem. Soc. 1983, 105, 5940-5942.
(d) Review: Tsuji, J. Palladium Reagents and Catalysts, Wi-
ley, New York, 1995.
(9) Compounds 9-12 are obtained as mixtures of stereoisomers.
Since all of them converge into product 6, the synthesis depic-
ted in Scheme 4 was carried out with these mixtures and no at-
tempts were made to isolate the individual compounds.
(10) For related furan syntheses see: (a) Cyclization of γ-hydroxy-
α,β-unsaturated aldehydes formed in situ by reduction of γ-
hydroxy-α,β-unsaturated nitriles: Mandai, T.; Hashio, S.; Go-
to, J.; Kawada, M. Tetrahedron Lett. 1981, 22, 2187-2190. (b)
Oxidation of 2-butene-1,4-diol derivatives: Nishiyama, H.;
Sasaki, M.; Itoh, K. Chem. Lett. 1981, 1363-1366.
Scheme 6
Further studies on the scope of this new approach to furan
derivatives are in progress and will be reported in due
course.
(11) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem.
1977, 42, 3772-3774.
Acknowledgement
Financial support by the Fonds der Chemischen Industrie is ack-
nowledged with gratitude.
(12) Selected analytical and spectroscopic data of key compounds:
6: 1H NMR (300 MHz, CDCl3): δ 7.90-7.83 (m, 4H), 7.68-
7.59 (m, 2H), 7.54-7.45 (m, 4H), 7.35 (t, J = 1.7 Hz, 1H), 7.22
(m, 1H), 6.90 (m, 1H), 6.23 (m, 1H), 5.61 (m, 1H), 4.54 (t, J
= 5.4 Hz, 1H), 3.60 (s, 2H), 3.28 (d, J = 5.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 154.7, 142.9, 139.7, 139.2, 138.1, 134.5,
129.4, 129.0, 120.7, 120.3, 111.1, 106.3, 84.1, 23.9, 21.7. MS:
m/z (rel intensity) 456 (19), 316 (16), 315 (74), 314 (19), 252
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32
A. Fürstner et al.
LETTER
CDCl3): δ 178.4, 154.6, 142.9, 139.7, 137.4, 135.3, 125.9,
(14), 251 (71), 174 (10), 173 (15), 172 (10), 170 (12), 169
(87), 168 (100), 141 (31), 125 (23), 117 (16), 116 (10), 115
(30), 91 (18), 81 (60), 78 (11), 77 (62), 53 (11), 51 (14). IR:
3108, 3065, 2921, 1614, 1584, 1551, 1501, 1482, 1450, 1433,
1380, 1340, 1313, 1238, 1199, 1186, 1155, 1142, 1109, 1080,
1022, 979, 950, 929, 873, 832, 818, 791, 764, 726, 692, 654,
617, 604, 558, 532, 508 cm-1. HR-MS (C23H20O6S2): calcd.
456.07013; found 456.06868. Anal. calcd. for C23H20O6S2: C,
60.51; H, 4.42; found: C, 60.38; H, 4.46.
125.0, 121.3, 111.2, 107.3, 41.1, 36.9, 31.4, 29.9, 28.2, 25.2,
24.8, 24.1, 23.3, 19.5. MS: m/z (rel intensity) 344 (23), 229
(12), 175 (25), 163 (12), 162 (100), 81 (24). HR-MS
(C21H28O4): calcd. 344.19876; found 344.19637.
(13) Crystal structure analysis of compound 6: colorless crystals
grown from EtOAc; C23H20O6S2; Mr = 456.51 g.mol-1; crystal
size 0.63 x 053 x 0.42 mm; a = 12.0473(7), b = 15.7355(10),
c = 12.0565(6) Å, V = 2141.1(2) Å3; β = 110.480(5)°; T = 293
K; dcal = 1.416Mg.m-3; Z = 4, space group: monoclinic, P21/n
(No. 14); θ range for data collection: 2.06 to 27.41°; 5106 col-
lected reflections, 4882 unique reflections, refinement
method: full matrix least squares on F2; final R indices: R(F)
= 0.039, wR2 = 0.143. The complete set of data has been de-
posited at the Cambridge Crystallographic Data Center,
Cambridge, U.K., under the deposition number CCDC
103522.
7: 1H NMR (300 MHz, CDCl3): δ 5.35 (dt, J = 7.4, 1.3Hz, 1H),
3.96 (s, 2H), 3.69-3.55 (m, 2H), 2.16-1.94 (m, 2H), 1.84-1.77
(m, 3H), 1.63-1.13 (m, 5H), 0.90-0.84 (m, 12H), 0.03 (s, 6H).
13C NMR (75 MHz, CDCl3): δ 132.0, 131.3, 61.3, 39.8, 36.6,
32.3, 29.1, 26.0, 25.5, 21.8, 19.5, 18.3, -5.3. MS: m/z (rel in-
tensity) 137 (30), 95 (39), 81 (100), 75 (18), 73 (18), 69 (24),
67 (12), 57 (25), 55 (12). IR: 3030, 2956, 2928, 2857, 1733,
1662, 1472, 1463, 1380, 1361, 1256, 1205, 1099, 1034, 1006,
939, 897, 836, 810, 775, 731, 639 cm-1. Anal. calcd. for
C16H33BrOSi: C, 55.00; H, 9.52; found: C, 55.11; H, 9.39.
18: 1H NMR (300 MHz, CD2Cl2): δ 7.38 (m, 1H), 7.30 (m,
1H), 7.11 (m, 1H), 6.34 (m, 1H), 5.94 (m, 1H), 5.13 (t, J = 7.2
Hz, 1H), 3.73 (bs, 2H), 3.70-3.55 (m, 2H), 2.40-2.30 (m, 2H),
2.10-1.85 (m, 4H), 1.67 (m, 3H), 1.67-1.46 (m, 4 H), 1.42-
1.08 (m, 4 H), 0.88 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CD2Cl2): δ 154.2, 143.0, 139.8, 137.5, 134.9, 126.2, 125.7,
121.7, 111.3, 107.3, 61.0, 40.1, 37.6, 31.4, 29.4, 28.4, 25.3,
24.9, 24.1, 23.1, 19.4. MS: m/z (rel intensity) 330 (25), 229
(13), 175 (25), 174 (10), 163 (12), 162 (100), 81 (31), 55 (13),
41 (18). HR-MS (C21H30O3): calcd. 330.21950; found
330.22000.
(14) Thomas, E. J.; Whitehead, J. W. F. J. Chem. Soc. Perkin
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4339-4342.
(17) Yu, J.; Cho, H.-S.; Chandrasekhar, S.; Falck, J. R., Mioskow-
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2: 1H NMR (300 MHz, CDCl3): δ 7.34 (t, J = 1.6 Hz, 1H), 7.27
(m, 1H), 7.08 (m, 1H), 6.30 (m, 1H), 5.88 (m, 1H), 5.09 (t, J
= 7.1 Hz, 1H), 3.71 (bs, 2H), 2.37-2.25 (m, 2H), 2.18-1.84 (m,
6H), 1.65 (d, J = 1.1 Hz, 3H), 1.64-1.49 (m, 2 H), 1.42-1.13
(m, 3 H), 0.94 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
Synlett 1999, No. 1, 29–32 ISSN 0936-5214 © Thieme Stuttgart · New York