Total synthesis of (±)-magnofargesin

Article abstract of DOI:10.1021/ol0609053

A convenient method for the preparation of 2,5-dihydrofurans by using the chemistry of alkynyl(phenyl)iodonium salts is reported. Treatment of 3-alkoxy-1-alkynyl(phenyl)iodonium triflates with sodium benzenesulfinate generates an alkylidenecarbene, which

Full text of DOI:10.1021/ol0609053

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3659-3662
Total Synthesis of (±)-Magnofargesin
Duncan J. Wardrop* and Joseph Fritz
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
wardropd@uic.edu
Received April 13, 2006
ABSTRACT
A convenient method for the preparation of 2,5-dihydrofurans by using the chemistry of alkynyl(phenyl)iodonium salts is reported. Treatment
of 3-alkoxy-1-alkynyl(phenyl)iodonium triflates with sodium benzenesulfinate generates an alkylidenecarbene, which undergoes [1,5]-C-H insertion
to form 2-substituted 4-benzenesulfonyl-2,5-dihydrofurans in reasonable yield. These cyclic vinyl sulfones are functionalized in such a way as
to make them useful starting materials for the preparation of lignans. The application of this methodology to the first total synthesis of
(±)-magnofargesin is disclosed.
Substituted 2,5-dihydrofurans have proven to be valuable
building blocks for the preparation of tetrahydrofuran-based
natural products and consequently there is considerable
interest in the development of synthetic routes to this ring
system.1 The activation of carbon-hydrogen bonds, via the
[1,5]-insertion of alkylidenecarbenes 2,2 is notable in this
regard since it offers rapid access to five-membered hetero-
cycles, including 2,5-dihydrofurans 3, and proceeds with
retention of configuration at the site of insertion (Scheme
1).3
glycosides.4b,c In this case, intermediate 2 was generated by
addition of trimethylsilyldiazomethyllithium to oxopropyl
ketones 1.5 While this method of vinylidene formation is
convenient, the requirement that the carbene â substituent
be alkyl-based, to suppress Fritsch-Buttenberg-Wiechell
(FBW) rearrangement of 2,2a places some limitations on the
utility of the insertion products 3.6
In this context, we became interested in the generation
and cyclization of γ-alkoxy alkylidenecarbenes 6 that bear
an arylsulfonyl group at the â position (Scheme 2). Pioneer-
ing work by Stang7a and Ochiai7b and subsequent studies by
Feldman8 have demonstrated that these intermediates are
readily accessible through Michael-type addition of sodium
arylsulfinates to alkynyliodonium salts, are resistant to FBW
rearrangement, and undergo [1,5]-insertion to form syntheti-
cally useful cyclic vinyl sulfones. Herein, we report the
development of the idea outlined in Scheme 2 and its
As part of an ongoing study of the synthesis of five-
membered heterocycles through carbene C-H insertion,4 we
have previously reported the application of the transformation
shown in Scheme 1 to the synthesis of [4.5]spiroketal
(1) For approaches to 2,5-dihydrofurans, see: (a) Berry, C. R.; Hsung,
R. P.; Antoline, J. E.; Petersen, M. E.; Challeppan, R.; Nielson, J. A. J.
Org. Chem. 2005, 70, 4038. (b) Van Veldhuizen, J. J.; Gillingham, D. G.;
Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
12502. (c) Trost, B. M.; Brown, B. S.; McEachern, E. J.; Kuhn, O. Chem.
Eur. J. 2003, 9, 4442. (d) Bravo, F.; Viso, A.; Castillon, S. J. Org. Chem.
2003, 68, 1172. (e) Donohoe, T. J.; Raoof, A.; Freestone, G. C.; Linney, I.
D.; Cowley, A.; Helliwell, M. Org. Lett. 2002, 4, 3059. (f) Duffy, M. G.;
Grayson, D. H. J. Chem. Soc., Perkin Trans. 1 2002, 1555. (g) Gilbertson,
S. R.; Fu, Z. Org. Lett. 2001, 3, 161.
Scheme 1
(2) For reviews of the chemistry of alkylidenecarbenes, see: (a) Knorr,
R. Chem ReV. 2004, 104, 3795. (b) Kirmse, W. Angew. Chem., Int. Ed.
Engl. 1997, 36, 6, 1164. (c) Taber, D. F. In Methods of Organic Chemistry,
4th ed.; Helmchen, G., Ed.; Georg Thieme Verlag: New York, 1995; Vol.
E21, p 1127. (d) Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 274.
10.1021/ol0609053 CCC: $33.50
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Published on Web 07/19/2006

SnCl in THF. After isolation,9 exposure of these products
to Stang’s reagent (PhI(CN)OTf)10 in CH2Cl2 rapidly gener-
ated the corresponding alkynyliodonium salts 5. Finding the
isolation of these unstable compounds to be troublesome,
we opted to forego purification and instead carry out the
insertion reaction directly. Thus upon addition of a 0.1 M
aqueous solution of sodium benzenesulfinate to 5, insertion
occurred in situ to provide dihydrofurans 7 in moderate
overall yield from 8. As indicated in Table 1, this sequence
Scheme 2
Table 1. Preparation of 3-Phenylsulfonyl-2,5-dihydrofurans 7a
application to the first total synthesis of the lignan natural
product, magnofargesin (9, Scheme 3).
Scheme 3
Our study commenced with the preparation of alkynyl-
stannanes 4a-h from the corresponding propargyl ethers
8a-h, through sequential treatment with n-BuLi and n-Bu3-
(3) For preparation of 2,5-dihydrofurans via alkylidenecarbene insertion,
see: (a) Akiyama, M.; Isoda, Y.; Nishimoto, M.; Kobayashi, A.; Togawa,
D.; Hirao, N.; Kuboki, A.; Ohira, S. Tetrahedron Lett. 2005, 46, 7483. (b)
Hobley, G.; Stuttle, K.; Wills, M. Tetrahedron 2003, 59, 4739 and other
papers in this series. (c) Taber, D. F.; Christos, T. E. Tetrahedron Lett.
1997, 38, 4927. (d) Ohira, S.; Noda, I.; Mizobata, T.; Yamato, M.
Tetrahedron Lett. 1995, 36, 3375. (e) Kunishima, M.; Hioki, K.; Tani, S.;
Kato, A. Tetrahedron Lett. 1994, 35, 7253. (f) Ohira, S.; Okai, K.; Moritani,
T. Chem. Commun. 1992, 721. (g) Baird, M. S.; Baxter, A. G. W.; Hoorfar,
A.; Jefferies, I. J. Chem. Soc., Perkin Trans. 1 1991, 2575. (h) Buxton, S.
R.; Holm, K. H.; Skattebøl, L. Tetrahedron Lett. 1987, 27, 2167. (i) Walsh,
R. A.; Bottini, A. T. J. Org. Chem. 1970, 35, 1086.
a Reagents and conditions: (1) 8, n-BuLi (1.1 equiv), THF, -78 °C,
n-Bu3SnCl (1.0 equiv), -78 °C, 6 h. (2) PhICN(OTf) (1.1 equiv), CH2Cl2,
-42 °C, 45 min, then PhSO2Na (1.1 equiv), H2O, 45 min. b Isolated yield
of 7 over two steps, after purification by flash chromatography.
(4) (a) Wardrop, D. J.; Bowen, E. G. Chem. Commun. 2005, 5106. (b)
Wardrop, D. J.; Zhang, W.; Fritz, J. Org. Lett. 2002, 4, 489. (c) Wardrop,
D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389. (d) Wardrop, D. J.;
Velter, A. I.; Forslund, R. E. Org. Lett. 2001, 3, 2261.
(5) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977,
869. (b) Colvin, E. W.; Hamill, B. J. Chem. Commun. 1973, 151.
(6) Similar restrictions are associated with the use of 1,1-dihalogenoalk-
enes and 1-halogenoalkenes and as alkylidenecarbene precursors: see, refs
3e and 3i, respectively.
(7) (a) Zhdankin, V. V.; Stang, P. J. Tetrahedron 1998, 54, 10927. (b)
Ochiai, M. In HyperValent Iodine Chemistry: Modern DeVelopments In
Organic Synthesis; Wirth T., Ed.; Springer-Verlag: Berlin, Germany, 2003;
Vol. 224, p 5.
of reactions is applicable to a range of substrates, most
notably acetals 8g and 8h which were converted to the
corresponding spiroketals. That there appears to be little
(9) Since alkynylstannanes 8 displayed variable stability toward silica
gel, they were used in the iodonium transfer reaction without further
purification.
(10) Stang, P. J.; Williamson, B. L.; Zhdankin, V. V. J. Am. Chem. Soc.
1991, 113, 5870.
(8) For an account of this work, see: Feldman, K. S. In Strategies and
Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier Academic Press:
London, UK, 2004; Vol. 4, p 133.
3660
Org. Lett., Vol. 8, No. 17, 2006

correlation between the efficiency of C-H insertion and the
nature of the C-H bond undergoing reaction is likely a
reflection of the highly reactive, undiscriminating nature of
the alkylidenecarbene intermediates generated during this
reaction. Having established the viability of this methodol-
ogy, we turned our attention to its application to natural
product synthesis.
Scheme 4
The dried and pulverized flower buds of Magnolia
fargessi, also known as “shin-i”, have been used for centuries
in China and Japan as materia medica. While traditionally
this material has been indicated for the relief of nasal
congestion and headaches, more recently it has proven to
be a rich source of natural products, including several
biologically active lignans.11 Isolated by Miyazawa and co-
workers in 1995 from “shin-i”, (-)-magnofargesin (9) is an
antagonist of platelet-activating factor (PAF), which reverses
leukotriene D4-induced bronchoconstriction in guinea pigs
with an LD50 of 19 µM (Scheme 3).12 PAF is a potent
phospholipid activator and mediator of many leukocyte
functions, including platelet aggregation, inflammation, and
anaphylaxis. Antagonists of PAF are of potential therapeutic
value for the treatment of asthma and as protective agents
against ischemic injury.13
Retrosynthetically, we envisioned that, after construction
of the target’s furanoid skeleton from 12, via C-H insertion,
both the C-8 hydroxymethyl group and the right-hand C-8′
“arm” of the lignan system could be installed in a one-pot,
three-component coupling operation (Scheme 3). Specifi-
cally, we anticipated that addition of 2-lithio-1,3-dithiane to
12 would proceed from the less hindered face to generate
an R-sulfonyl anion at C-8′.14 Alkylation of this intermediate
with veratraldehyde would then provide â-hydroxysulfone
11 from which the C7′-C8′ alkene could be installed through
reductive elimination.15
Our route to (()-magnofargesin (9) commenced from
3,4,5-trimethoxybenzyl progargyl ether (13), which was
converted to stannane 12, as previously described (Scheme
4). Sequential exposure of 12 to cyanophenyliodonium triflate
and aqueous sodium benzenesulfinate then provided dihy-
drofuran 11 in 59% yield.16 Although treatment of 11 with
2-lithiodithiane in THF, at -78 °C, now resulted in vinyl
sulfone addition, unexpectedly, attempts to trap the resulting
R-sulfonyl anion with a range of aldehydes, including
veratraldehyde, failed. In all cases, a complex, intractable
mixture of products, which included vinyl sulfone 15, the
product resulting from â-elimination of the conjugate base
of 14, was obtained. The instability of the anionic intermedi-
ate was not entirely unanticipated since Knochel has previ-
ously noted that related 3-phenylsulfonyl tetrahydrofurans
also undergo ring opening upon exposure to n-BuLi.17 Guided
by Craig’s observations of these systems,18 we carried out
the metalation-addition process at -100 °C in anticipation
that the R-sulfonyl anion would be stable at this temperature.
While we believe that deprotonation of 16 occurred under
these conditions, the subsequent reaction with veratraldehyde
proved to be impractically slow. As a result, we opted to
intercept the R-sulfonyl anion by protonation and install the
C8′ side chain in a stepwise fashion. Thus, sequential
(11) Jung, K. Y. N.; Kim, D. S.; Oh, S. R.; Park, S. H.; Lee, I. S.; Lee,
J. J.; Shin, D. H.; Lee, H. K. J. Nat. Prod. 1998, 61, 80 and references
therein.
(12) (a) Miyazawa, M.; Hiroyuki, K.; Kameoka, H. Phytochemistry 1996,
42, 531. (b) Miyazawa, M.; Kasahara, H.; Kameoka, H. Nat. Prod. Lett.
1995, 7, 205. (c) Myazawa, M. Lignan derivative and its use as a
bronchodilator; Japanese Kokai Tokkyo Koho JP 06065224, 1994; Chem.
Abstr. 1994, 121, 91784.
(13) Singh, M.; Saraf, M. K. Drug Future 2001, 26, 883.
(14) (a) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986, 86, 903. (b) Fuchs,
P. L.; Braish, T. L.; Saddler, J. C. J. Org. Chem. 1988, 53, 3647.
(15) Kocienski, P. J. Reductive Elimination, Vicinal Deoxygenation and
Vicinal Desilylation. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 6, Chapter 5.2, p
975.
(17) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985,
26, 4455.
(16) This reaction was carried out on scales of up to 8 mmol without
incident.
(18) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron 1999,
55, 13471 and other papers in this series.
Org. Lett., Vol. 8, No. 17, 2006
3661

treatment of 11 with 2-lithiodithiane and camphorsulfonic
acid (CSA) at -100 °C provided 14 as a single diastereomer
in excellent yield. The relative stereochemistry of the C-2
and C-3 stereogenic centers in 14 was confirmed by a
NOESY experiment, which revealed the correlation shown
in Scheme 4.19 Alkylative hydrolysis of the dithiane group
was accomplished under mild conditions (MeI, CaCO3)20 and
the resulting aldehyde immediately reduced with sodium
borohydride to provide the corresponding primary alcohol.
Protection of this functionality as a tert-butyldimethylsiyl
ether then gave compound 16 in excellent overall yield from
14.
With a route to 16 established, we now readdressed the
issue of sulfone alkylation. Although attempts to condense
veratraldehyde with lithiated 16 in THF at -100 °C failed
to provide 17, use of Wicha’s protocol21 proved to be more
fruitful. Thus, metallaton of 16 with n-BuLi as before,
followed by sequential addition of BF3‚Et2O and veratral-
dehyde provided a mixture of unstable â-hydroxysulfones
17 in low yield (<40%).22 In this case, a significant quantity
of starting material 16 was also recovered. While extension
of the deprotonation time failed to increase the degree of
conversion, the use of the Trapp mixture (THF/Et2O/pentane,
4:4:1),23 which unlike THF does not become viscous at low
temperatures, led to a significant improvement in efficiency.
That mixture 17 readily underwent retroaddition upon
exposure to silica gel is most likely a consequence of the
sterically congested nature of these â-hydroxysulfones.24 To
circumvent this problem, 17 was immediately acetylated after
workup to provide 18 as a mixture of diastereomers in good
overall yield. Introduction of the exocyclic olefin was now
accomplished by exposure of mixture 18 to magnesium
amalgam in ethanol.25 Under these conditions, reductive
elimination proceeded efficiently to provide a 10:9 ratio of
E and Z isomers. Unable to separate this mixture by flash
chromatography, the tert-butyldimethylsilyl protecting group
was removed with TBAF to yield a mixture of magnofargesin
(9) and 7′-epi-magnofargesin (19) with high efficiency
(83%). Separation of these products by semipreparative
HPLC then gave a sample of synthetic (()-magnofargesin
(9), whose spectral data (1H and 13C NMR) were in complete
agreement with those reported by Miyazawa for the natural
material.12
In summary, we report a new strategy for the preparation
of 3-phenylsulfonyl-2,5-dihydrofurans 7 involving the [1,5]-
C-H insertion of alkylidenecarbenes generated from readily
accessible alkynyl(phenyl)iodonium triflates 5. This meth-
odology was successfully employed in the first total synthesis
of the natural product magnofargesin (9), which was ac-
complished in 10 steps and in an overall yield of 12%.
Acknowledgment. We gratefully thank the National
Institutes of Health (GM-59157) for financial support of this
work.
Supporting Information Available: Full experimental
procedures and spectral data for compounds7a-h, 8a-h,
11, and 13-19. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) The relative stereochemistry at C-4 could not be unambiguously
assigned, but is presumed to be that shown in Scheme 4.
(20) Fetizon, M.; Jurion, M. Chem. Commun. 1972, 382.
(21) Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankowski,
J.; Wicha, J. Tetrahedron 1988, 44, 4989.
(22) Attempts to purify â-hydroxysulfone 17 by flash chromatography
resulted in its reversion to 16.
(23) (a) Ko¨ebrich, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 41. (b)
Wakefield, B. J. Organolithium Methods; Academic Press: London, UK,
1994; p 8.
OL0609053
(24) The reaction of sterically hindered sulfonyl anions with aldehydes
is known to be reversible: (a) Marko´, I. E.; Murphy, F.; Dolan, S.
Tetrahedron Lett. 1996, 37, 2089. (b) Keck, G. E.; Savin, K. A.; Welgarz,
M. A. J. Org. Chem. 1995, 60, 3194.
(25) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S.
Tetrahedron Lett. 1995, 36, 5607.
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