Total syntheses of (S)-(-)-zearalenone and lasiodiplodin reveal superior metathesis activity of ruthenium carbene complexes with imidazol-2-ylidene ligands

Article abstract of DOI:10.1021/jo0009999

Total syntheses of the bioactive orsellinic acid derivatives zearalenone 3 and lasiodiplodin 1 are reported based on a ring-closing metathesis (RCM) reaction of styrene precursors as the key steps. These and closely related macrocyclizations are catalyzed

Full text of DOI:10.1021/jo0009999

7990
J . Org. Chem. 2000, 65, 7990-7995
Tota l Syn th eses of (S)-(-)-Zea r a len on e a n d La siod ip lod in Revea l
Su p er ior Meta th esis Activity of Ru th en iu m Ca r ben e Com p lexes
w ith Im id a zol-2-ylid en e Liga n d s
Alois Fu¨rstner,* Oliver R. Thiel, Nicole Kindler, and Beata Bartkowska
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/ Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received J uly 3, 2000
Total syntheses of the bioactive orsellinic acid derivatives zearalenone 3 and lasiodiplodin 1 are
reported based on a ring-closing metathesis (RCM) reaction of styrene precursors as the key steps.
These and closely related macrocyclizations are catalyzed with high efficiency by the “second
generation” ruthenium carbene catalyst 5 bearing a N-heterocyclic carbene ligand, whereas the
standard Grubbs carbene 4 fails to afford any cyclized product. Only the (E)-isomer of the macrocyclic
cycloalkene is formed in all cases. The substrates for RCM can be obtained either via a Stille cross-
coupling reaction of tributylvinylstannane or, even more efficiently, by Heck reactions of the aryl
triflate precursors with pressurized ethene. Furthermore, the synthesis of 1 via RCM is compared
with an alternative approach employing a low-valent titanium-induced McMurry coupling of
dialdehyde 47 for the formation of the large ring. This direct comparison clearly ends in favor of
metathesis which turned out to be superior in all preparatively relevant respects.
In tr od u ction
sites where RCM proceeds readily in the presence of
catalytic amounts of the Grubbs ruthenium carbene
complex 4.2
As part of our program on the application of ring-
closing metathesis (RCM) to the synthesis of biologically
active natural products1 we have previously reported
efficient entries into various orsellinic acid derivatives
including (R)-(+)-lasiodiplodin 12,3,4 and the animal growth
promoting agent zeranol 2 (Ralgro, Ralabol).2a,5 In both
cases, the macrocyclic rings had to be closed at the allylic
* To whom correspondence should be addressed. Tel: +49 - 208 306
2342. FAX: +49 - 208 306 2994.
(1) Selected references: (a) Fu¨rstner, A.; Langemann, K. J . Am.
Chem. Soc. 1997, 119, 9130. (b) Fu¨rstner, A.; Mu¨ller, T. J . Am. Chem.
Soc. 1999, 121, 7814. (c) Fu¨rstner, A.; Grabowski, J .; Lehmann, C. W.
J . Org. Chem. 1999, 64, 8275. (d) Fu¨rstner, A.; Gastner, T.; Weintritt,
H. J . Org. Chem. 1999, 64, 2361. (e) Fu¨rstner, A.; Thiel, O. R. J . Org.
Chem. 2000, 65, 1738. (f) Fu¨rstner, A.; Langemann, K. J . Org. Chem.
1996, 61, 8746. (g) Fu¨rstner, A.; Mu¨ller, T. J . Org. Chem. 1998, 63,
424. (h) Fu¨rstner, A.; Mu¨ller, T. Synlett 1997, 1010. (i) Fu¨rstner, A.;
Langemann, K. J . Org. Chem. 1996, 61, 3942. (j) Fu¨rstner, A.;
Langemann, K. Synthesis 1997, 792.
(2) (a) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55,
8215. (b) Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005.
(3) Isolation of 1 and its de-O-methyl congener: (a) Aldridge, D. C.;
Galt, S.; Giles, D.; Turner, W. B. J . Chem. Soc. (C) 1971, 1623. (b)
Cambie, R. C.; Lal, A. R.; Rutledge, P. S.; Woodgate, P. D. Phytochem-
istry 1991, 30, 287. (c) Lee, K.-H.; Hayashi, N.; Okano, M.; Hall, I. H.;
Wu, R.-Y.; McPhail, A. T. Phytochemistry 1982, 21, 1119. (d) Xin-Seng,
Y.; Ebizuka, Y.; Noguchi, H.; Kiuchi, F.; Iitaka, Y.; Sankawa, U.; Seto,
H. Tetrahedron Lett. 1983, 24, 2407. (e) For the isolation of new
lasiodiplodin derivatives, see: Matsuura, H.; Nakamori, K.; Omer, E.
A.; Hatakeyama, C.; Yoshihara, T.; Ichihara, A. Phytochemistry 1998,
49, 579. (f) Barrow, C. J . J . Nat. Prod. 1997, 60, 1023.
(4) Previous syntheses: (a) Gerlach, H.; Thalmann, A. Helv. Chim.
Acta 1977, 60, 2866. (b) Danishefsky, S.; Etheredge, S. J . J . Org. Chem.
1979, 44, 4716. (c) Takahashi, T.; Kasuga, K.; Tsuji, J . Tetrahedron
Lett. 1978, 4917. (d) Braun, M.; Mahler, U.; Houben, S. Liebigs Ann.
1990, 513. (e) J ones, G. B.; Huber, R. S. Synlett 1993, 367. (f) Fink,
M.; Gaier, H.; Gerlach, H. Helv. Chim. Acta 1982, 65, 2563. (g) Solladie´,
G.; Rubio, A.; Carren˜o, M. C.; Garcia Ruano, J . L. Tetrahedron:
Asymmetry 1990, 1, 187. (h) Bracher, F.; Schulte, B. J . Chem. Soc.,
Perkin Trans. 1 1996, 2619.
(5) Reviews: (a) Betina, V. Zearalenone and its Derivatives in
Mycotoxins: Chemical, Biological and Environmental Aspects; Else-
vier: Amsterdam, 1989. (b) Shipchandler, M. T. Heterocycles 1975, 3,
471.
The important anabolic, estrogenic, and antibacterial
macrolide (S)-(-)-zearalenone 3,6,7 however, remained
beyond reach of this approach simply because complex 4
was found totally ineffective for attempted cyclizations
of the required styrenyl precursor.8 We now report that
this situation is easily rectified by using the “second
generation” ruthenium carbene complex 5 bearing a
N-heterocyclic carbene (NHC) ligand for the crucial ring
closure. Moreover, it will be shown that this powerful new
catalyst upgrades the performance of RCM to such an
extent as to make this transformation significantly more
effective, reliable, and economical than the McMurry
coupling which was previously considered a prime tool
for handicapped macrocyclization events.
(6) Isolation and structure: (a) Stob, M.; Baldwin, R. S.; Tuite, J .;
Andrews, F. N.; Gillette, K. G. Nature 1962, 196, 1318. (b) Urry, W.
H.; Wehrmeister, H. L.; Hodge, E. B.; Hidy, P. H. Tetrahedron Lett.
1966, 3109. (c) Cordier, C.; Gruselle, M.; J aouen, G.; Hughes, D. W.;
McGlinchey, M. J . Magn. Res. Chem. 1990, 28, 835.
10.1021/jo0009999 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Total Syntheses of (S)-(-)-Zearalenone
J . Org. Chem., Vol. 65, No. 23, 2000 7991
Sch em e 1a
Resu lts a n d Discu ssion
Mod el Stu d ies a n d Syn th esis of r a c-Zea r a len on e.
Recently it has been shown that the replacement of one
PCy3 group in 49 by strongly electron-donating and
sterically encumbered N,N′-disubstituted 2,3-dihydro-1H-
imidazol-2-ylidene ligands or the fully saturated ana-
logues thereof imparts a significantly improved stability
to the active species in solution and leads to a substan-
tially increased catalytic activity as well.10,11 Advantage
can be taken from this excellent application profile of the
resulting complexes such as 5 in many cases which were
previously difficult to achieve or even impossible. This
includes the formation of tetrasubstituted cycloalk-
enes,10,11 metathetic conversions of acrylates and related
electron poor substrates,12,13 and RCM of conformation-
ally restricted dienes.14 In light of this encouraging
precedent, we were prompted to reinvestigate the mac-
rocyclization of stryrene derivatives related to zearale-
none 3.
a
(a) 9-Decenol, PPh3, DEAD, Et2O, rt, 3 h, 75%; (b) Complex 5
(5 mol %), toluene, 80 °C, 23 h, 75%.
In line with our expectations, the resulting diene 7
readily cyclizes on exposure to catalytic amounts of
complex 5 in toluene at 80 °C. Surprisingly, however, the
14-membered cycloalkene 8 which is isolated in 75% yield
was found to consist of the E-isomer only.17 This gratify-
ing result contrasts to most RCM-based macrocycliza-
tions previously reported in the literature in which
mixtures of both stereoisomers are usually obtained.1,18
Next, we investigated if alkoxy substituents on the
arene ring, which significantly alter the electronic prop-
A suitable model for the core structure of this macrolide
is available by esterification of 2-vinylbenzoic acid 615
with 9-decenol under Mitsunobu conditions (Scheme 1).16
(15) Dale, W. J .; Starr, L.; Strobel, C. W. J . Org. Chem. 1961, 26,
2225.
(16) Mitsunobu, O. Synthesis 1981, 1.
(17) After this paper had been submitted, one example of a macro-
cyclization was published in which the use of the “fully saturated”
analogue of complex 5 affords a much higher E/ Z ratio than the use
of the “standard” Grubbs carbene 4. This result is caused by the ability
of the former catalyst to isomerize the initial product under the reaction
conditions, thereby progressively enriching the mixture in the ther-
modynamically favored E-isomer, cf. Lee, C. W.; Grubbs, R. H. Org.
Lett. 2000, 2, 2145. This increased propensity of 5 to give macrocyclic
E-alkenes is also evident from the following comparison:
(7) For previous syntheses of 3 and related compounds see the
following for leading references: (a) Keinan, E.; Sinha, S. C.; Sinha-
Bagchi, A. J . Chem. Soc., Perkin 1 1991, 3333. (b) Hitchcock, S. A.;
Pattenden, G. J . Chem. Soc., Perkin Trans. 1 1992, 1323. (c) Takahashi,
T.; Nagashima, T.; Ikeda, H.; Tsuji, J . Tetrahedron Lett. 1982, 23, 4361.
(d) Takahashi, T.; Ikeda, H.; Tsuji, J . Tetrahedron Lett. 1981, 22, 1363.
(e) Kalivretenos, A.; Stille, J . K.; Hegedus, L. S. J . Org. Chem. 1991,
56, 2883. (f) Rama Rao, A. V.; Deshmukh, M. N.; Sharma, G. V. M.
Tetrahedron 1987, 43, 779. (g) Takahashi, T.; Kasuga, K.; Takahashi,
M.; Tsuji, J . J . Am. Chem. Soc. 1979, 101, 5072. (h) Solladie´, G.;
Maestro, M. C.; Rubio, A.; Pedregal, C.; Carreno, M. C.; Garcia Ruano,
J . L. J . Org. Chem. 1991, 56, 2317. (i) Taub, D.; Girotra, N. N.;
Hoffsommer, R. D.; Kuo, C. H.; Slates, H. L.; Weber, S.; Wendler, N.
L. Tetrahedron 1968, 24, 2443. (j) Vlattas, I.; Harrison, I. T.; To¨ke´s,
L.; Fried, J . H.; Cross, A. D. J . Org. Chem. 1968, 33, 4176. (k) Windholz,
T. B.; Brown, R. D. J . Org. Chem. 1972, 37, 1647. (l) Hurd, R. N.; Shah,
D. H. J . Org. Chem. 1973, 38, 390. (m) Hurd, R. N.; Shah, D. H. J .
Med. Chem. 1973, 16, 543. (n) Peters, C. A.; Hurd, R. N. J . Med. Chem.
1975, 18, 215. (o) Bass, R. J .; Banks, B. J .; Leeming, M. R. G.; Snarey,
M. J . Chem. Soc., Perkin Trans. 1 1981, 124. (p) Nicolaou, K. C.;
Winssinger, N.; Pastor, J .; Murphy, F. Angew. Chem. Int. Ed. 1998,
37, 2534. (q) Corey, E. J .; Nicolaou, K. C. J . Am. Chem. Soc. 1974, 96,
5614.
(8) Attempts to isomerize the double bond of the RCM product
formed in our previous route to zeranol 2 from the allylic into the
vinylic position have failed, cf. ref 2a. Therefore, no viable entry into
zearalenone itself was found during these investigations.
(9) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1993, 115, 9858. (b) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am.
Chem. Soc. 1996, 118, 100.
(10) These complexes have been independently and almost simul-
taneously reported by three different research groups, cf: (a) Huang,
J .; Stevens, E. D.; Nolan, S. P.; Petersen, J . L. J . Am. Chem. Soc. 1999,
121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (c) Ackermann, L.; Fu¨rstner, A.;
Weskamp, T.; Kohl, F. J .; Herrmann, W. A. Tetrahedron Lett. 1999,
40, 4787. (d) Weskamp, T.; Kohl, F. J .; Hieringer, W.; Gleich, D.;
Herrmann, W. A. Angew. Chem., Int. Ed. 1999, 38, 2416.
(11) For closely related complexes with fully “saturated” NHC-
ligands, see: (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999,
1, 1751.
(12) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J .; Nolan,
S. P. J . Org. Chem. 2000, 65, 2204.
(13) Chatterjee, A. K.; Morgan, J . P.; Scholl, M.; Grubbs, R. H. J .
Am. Chem. Soc. 2000, 122, 3783.
(14) Ackermann, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron 2000, 56,
2195.
Therefore a similar explanation may apply to the examples reported
in this paper. The question, however, why all styrenyl substrates
described herein exclusively afford the macrocyclic E-cycloalkenes is
not yet solved.
(18) Reviews: (a) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140;
Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Fu¨rstner, A. Top. Catal. 1997, 4, 285.
(d) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036. (e) Fu¨rstner, A. Top. Organomet. Chem. 1998, 1, 37. (f) Ivin, K.
J .; Mol, J . C. Olefin Metathesis and Methathesis Polymerization, 2nd
ed.; Academic Press: New York, 1997.

7992 J . Org. Chem., Vol. 65, No. 23, 2000
Fu¨rstner et al.
Sch em e 2a
Sch em e 3a
a
(a) 9-Decenol, PPh3, DEAD, Et2O, rt, 3 h, 67%; (b) Tf2O,
pyridine, CH2Cl2, 3 h, 90%; (c) (i) tributylvinylstannane, LiCl,
PdCl2(PPh3)2 (5 mol %), DMF, rt, 14 h, 82%; or (ii) ethylene (50
bar), LiCl, triethylamine, PdCl2(PPh3)2 (5 mol %), DMF, 90 °C, 20
h, 88%; (d) Complex 5 (5 mol %), toluene, 80 °C, 15 h, 93%.
erties of the cyclization precursor, have any influence on
the outcome of RCM (Scheme 2). Esterification of the
readily accessible salicylic acid 92a with 9-decenol, con-
version of the resulting product 10 into the aryl triflate
11, and a subsequent Stille cross coupling with tribut-
ylvinylstannane affords an appropriate model com-
pound.19 This diene cyclizes even more readily in the
presence of ruthenium complex 5 than compound 7.
Product 13 thus obtained was isolated in 93% yield in
stereomerically pure form as the (E)-isomer. It is also
worth mentioning that a Heck reaction20 of triflate 11
with ethylene (50 bar) affords an even higher yield of the
required diene 12 and therefore constitutes an attractive,
inexpensive, and nontoxic alternative to the Stille cou-
pling outlined above.
a
(a) 4-Pentenylmagnesium bromide, Et2O, THF, -78 °C f rt,
77%; (b) acid 9, PPh3, DEAD, Et2O, rt, 3 h, 64%; (c) Tf2O, pyridine,
CH2Cl2, 3 h, 92%; (d) (i) tributylvinylstannane, LiCl, PdCl2(PPh3)2
(5 mol %), DMF, rt, 14 h, 83%; or (ii) ethylene (55 bar), LiCl,
triethylamine, PdCl2(PPh3)2 (5 mol %), DMF, 90 °C, 20 h, 93%;
(e) Complex 5 (5 mol %), toluene, 80 °C, 15 h, 91%.
Sch em e 4
This sequence is readily adapted to the synthesis of
zearalenone itself (Scheme 3). Reaction of commercially
available lactone 14 with 4-pentenylmagnesium bromide
at low temperature provides hydroxyketone 15 in good
yield. Esterification of this compound with acid 9 and
formation of the corresponding triflate 17 followed by
Heck reaction with ethylene (55 bar) and ring closure of
the resulting diene 18 in the presence of ruthenium
complex 5 delivers zearalenone dimethyl ether 19 which
can be deprotected to the natural product with BCl3/BBr3
according to a literature procedure.7a The efficiency of the
Heck coupling as well as of the RCM cyclization step
account for the remarkable overall yield of this sequence.
Finally, it is emphasized that neither styrene 7 nor 12
or 18 give any cyclized material if the “standard” Grubbs
carbene 4 is used instead of 5 as the catalyst for the RCM
reactions.
enantiomerically pure alcohol 15 suffers from rapid loss
of optical activity. This behavior has been recognized
earlier7i and is caused by the fast and reversible intramo-
lecular hydride shift depicted in Scheme 4. Therefore we
were forced to develop alternative entries avoiding this
scrambling process.
Two independent routes have been pursued toward this
end. The first one (Scheme 5) starts from commercial
1-cyano-4-pentene 20 which reacts with 4-pentenylmag-
nesium bromide in refluxing Et2O to provide the sym-
metrical ketone 21 after aqueous workup. Protection of
the carbonyl group as dioxolane followed by reaction with
m-chloroperbenzoic acid delivers monoepoxide (()-22 in
41% yield. Resolution of this compound according to
J acobsen’s excellent procedure turned out to be very
practical, delivering the required epoxide (S)-22 in opti-
cally pure form (ee > 99%).21 Its reaction with LiBEt3H
affords the required (R)-configured alcohol 23 ready for
esterification with salicylic acid 9 under Mitsunobu
conditions.
(S)-(-)-Zea r a len on e. The approach to (()-3 depicted
in Scheme 3, however, cannot be adapted to the synthesis
of enantiomerically pure zearalenone due to the fact that
(19) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J . Org. React. 1997, 50, 1.
(c) Mitchell, T. N. In Metal-Catalyzed Cross Coupling Reactions;
Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998; p 167.
(20) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Bra¨se, S.; de
Meijere, A. In Metal-Catalyzed Cross Coupling Reactions; Diederich,
F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998; p 99.
The attractive stereochemical outcome of this ap-
proach, however, is somewhat compromised by the rather
poor yield of the mono-epoxidation step. Therefore we

Total Syntheses of (S)-(-)-Zearalenone
J . Org. Chem., Vol. 65, No. 23, 2000 7993
Sch em e 5a
Sch em e 7a
a
(a) 4-Pentenylmagnesium bromide, Et2O, reflux, 3 h, 70%; (b)
ethylene glycol, pyridinium p-toluenesulfonate cat., toluene, reflux,
4 h, 98%; (c) m-CPBA (1.5 equiv), CH2Cl2, 16 h, 41%; (d) (S,S)-
N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
CoIII acetate (2.5 mol %)21, H2O (2 equiv), THF, 67 h, 41%, ee g
99%; (e) LiBEt3H, THF, 1 h, 95%.
Sch em e 6a
a
(a) PPh3, DEAD, Et2O, rt, 3 h, 88%; (b) Tf2O, pyridine, CH2Cl2,
3 h, 89%; (c) ethylene (40 bar), LiCl, triethylamine, PdCl2(PPh3)2
(5 mol %), DMF, 90 °C, 82%; (d) complex 5 (5 mol %), toluene, 80
°C, 4 h, 91%; (e) ref 7a.
out to be straightforward and highly satisfactory. Esteri-
fication of (R)-23 with 9 under Mitsunobu conditions
delivers ester (S)-29 in 88% yield, which is converted into
aryl triflate 30 under standard conditions. Heck-reaction
of this substrate with ethylene (40 bar) catalyzed by
PdCl2(PPh3)2 (5 mol %) in the presence of LiCl and Et3N
proceeds with excellent yield and sets the stage for the
crucial ring closure. Thus, exposure of the resulting
styrene derivative 31 to catalytic amounts of complex 5
in toluene at 80 °C affords (E)-32 as the only product in
91% isolated yield.17 The deprotection of this compound
can be carried out as described in the literature. The
nearly quantitative cyclization effected by the NHC-
complex 5 is in striking contrast to the complete failure
if the standard carbene 4 is employed as the catalyst.
Therefore, this and the other examples reported herein
illustrate the superior reactivity of 5 and further sub-
stantiate the notion that NHC-containing ruthenium
complexes will likely set new standards in the field of
olefin metathesis.10-14
La siod ip lod in : Com p a r ison of RCM a n d Mc-
Mu r r y Cou p lin g. The very same sequence of reactions
using acid 9 and alcohol 33 also gives access to lasio-
diplodin 1 and its naturally occurring de-O-methyl
congener.3,4 These macrolides are efficient inhibitors of
prostaglandin biosynthesis and exhibit reasonably high
anticancer activity.24 As can be seen from Scheme 8, all
individual steps proceed well, including the key cycliza-
tion of styrene 36 which affords (E)-37 as the only product
in 69% yield. The selective deprotection of this compound
to 1 was previously described.4d,g
a
(a) Vinylmagnesium bromide, CuCl(COD) (10 mol %), THF,
-78 °C f rt; (b) TBSCl, imidazole, DMF, 16 h, 63% (over both
steps); (b) (i) Cp2ZrHCl, CH2Cl2, 2 h; (ii) t-BuNC, 2 h; (iii) I2,
benzene, 30 min, 77%; (d) 4-pentenylmagnesium bromide, Et2O,
reflux, 4 h, 68%; (e) ethylene glycol, pTsOH‚H2O cat., benzene,
reflux, 12 h, 73%; (f) n-Bu4NF, THF, 89%.
pursued an alternative route to the same alcohol employ-
ing (R)-propenoxide 24 as the starting material which is
commercially available or can again be prepared on a
large scale using the J acobsen method21 (Scheme 6). Ring
opening with vinylmagnesium bromide in the presence
of catalytic amounts of CuCl(COD) (COD ) cyclooctadi-
ene)22 gives alcohol 25 which is immediately protected
as TBS-ether 26 under standard conditions. Hydrozir-
conation of its double bond followed by reaction with
t-BuNC and I2 as described by Buchwald et al.23 delivers
nitrile 27 in 77% yield. Treatment of 27 with 4-penten-
ylmagnesium bromide then affords ketone 28 which is
converted into (R)-23 by two routine protecting group
manipulations.
Having secured good access to this key building block,
the completion of the total synthesis of (S)-(-)-3 turned
(21) (a) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936. (b) Furrow, M. E.; Schaus, S. E.; J acobsen, E.
N. J . Org. Chem. 1998, 63, 6776.
(22) Previous natural product syntheses from our laboratory em-
ploying a CuCl(COD)-catalyzed propenoxide ring opening reaction: (a)
Fu¨rstner, A.; Konetzki, I. J . Org. Chem. 1998, 63, 3072. (b) Fu¨rstner,
A.; Konetzki, I. Tetrahedron 1996, 52, 15071.
Although this result is slightly inferior to our previous
approach to lasiodiplodin,2 in which the macrocyclic ring
has been formed by RCM in essentially quantitative yield
(24) Detailed in vitro cytotoxicity data of a lasiodiplodin derivative
are reported in ref 2a.
(23) Buchwald, S. L.; LaMaire, S. J . Tetrahedron Lett. 1987, 28, 295.

7994 J . Org. Chem., Vol. 65, No. 23, 2000
Fu¨rstner et al.
Sch em e 8a
Sch em e 10a
a
(a) Acid 9, PPh3, DEAD, Et2O, rt, 3 h, 63%; (b) Tf2O, pyridine,
CH2Cl2, 3 h, 92%; (c) (i) tributylvinylstannane, LiCl, PdCl2(PPh3)2
(5 mol %), DMF, rt, 14 h, 78%; or (ii) ethylene (40 bar), LiCl,
triethylamine, PdCl2(PPh3)2 (5 mol %), DMF, 90 °C, 20 h, 92%;
(d) complex 5 (5 mol %), toluene, 80 °C, 15 h, 69%.
Sch em e 9
at the allylic rather than the vinylic site, a comparison
with an entirely different approach to this target is more
revealing. It is well established in the literature that the
reductive coupling of carbonyl compounds mediated by
low-valent titanium [Ti] (“McMurry coupling”) constitutes
a fairly general and efficient entry into medium and
macrocyclic rings, even if high enthalpic barriers have
to be overcome during cyclization.25 The formal resem-
blance of carbonyl coupling and RCM (Scheme 9) as well
as the fact that a direct comparison of these mechanisti-
cally unrelated olefin forming reactions has not yet been
carried out so far prompted us to pursue a McMurry
approach to lasiodiplodin as well.
The required cyclization precursor, i.e., dialdehyde 47
is assembled as depicted in Scheme 10. Dimethylation
of 3,5-dihydroxytoluene followed by regioselective bro-
mination of the resulting product 41 leads to compound
42, which is converted into orsellinic acid dimethyl ether
43 by metal/halogen exchange with n-BuLi at low tem-
perature and quenching of the aryllithium species thus
formed.4d The aliphatic fragment is conveniently obtained
by ozonolysis of cycloheptene 38 under Schreiber’s condi-
tions26 followed by reaction of the monoprotected dialde-
hyde 39 with MeLi. Compounds 40 and 43 are then
a
(a) (i) O3, MeOH, CH2Cl2, -78 °C f rt, (ii) Me2S, NaHCO3, rt,
16 h, 82%; (b) MeMgCl, Et2O, 0 °C, 20 h, 95%; (c) NBS, CHCl3,
0 °C, 1.5 h, 97%; (d) (i) n-BuLi, THF, -78 °C; (ii) CO2 (solid), -78
°C f rt, 86%; (e) (i) oxalyl chloride, toluene, reflux, 16 h; (ii) alcohol
40, pyridine, DMAP cat., CH2Cl2, rt, 26 h, 86%; (f) (i) LDA (3
equiv), THF, -78 °C, 10 min; (ii) PhSSPh (2 equiv), -78 °C f rt,
5 h, 96%; (g) NBS, lutidine, aq acetone, 0 °C f rt, 40 min, 82%;
(h) Amberlyst-15 (H-form), aq acetone, 24 h, 75%; (i) Ti-graphite,
DME, rt, 24 h, 60-82%, (j) Pd/C (5% w/w), EtOH, EtOAc, rt, 20 h,
93%; (k) ref 4d,g.
esterified, and the resulting product 44 is converted into
bis(phenylthio)acetal 45 by double deprotonation of its
benzylic CH3 group and trapping of the organometallic
intermediate with diphenyl disulfide.27 While attempted
deprotection of this dithioacetal with Hg(II) failed, the
use of NBS in the presence of 2,6-lutidine effected the
cleavage with formation of aldehyde 46 in 79% yield.28
(25) Reviews: (a) Fu¨rstner, A.; Bogdanovic, B. Angew. Chem. 1996,
108, 2582; Angew. Chem., Int. Ed. Engl. 1996, 35, 2442. (b) McMurry,
J . E. Chem. Rev. 1989, 89, 1513. (c) Lectka, T. In Active Metals.
Preparation, Characterization, Applications; Fu¨rstner, A., Ed.; VCH:
Weinheim, 1996; p 85.
(26) Schreiber, S. L.; Kelly, S. E.; Porco, J . A.; Sammakia, T.; Suh,
E. M. J . Am. Chem. Soc. 1988, 110, 6210.
(27) Hauser, F. E.; Rhee, R. P.; Prasanna, S. Synthesis 1980, 72.
(28) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553.

Total Syntheses of (S)-(-)-Zearalenone
J . Org. Chem., Vol. 65, No. 23, 2000 7995
The subsequent liberation of the aliphatic aldehyde group
was best achieved with Amberlyst-15 in aqueous ac-
etone29 which sets the stage for the formation of the 12-
membered ring by reductive carbonyl coupling.
Despite our experience with low-valent titanium [Ti]
chemistry,30 this key transformation turned out to be
fairly problematic. We noticed that a large excess of [Ti]
and rather high dilution conditions (syringe pump) are
necessary to achieve good yields. The best results were
achieved with titanium-graphite formed from TiCl3 and
2 equiv of C8K31 in DME at ambient temperature.32,33
Even under these optimized conditions, however, the
yield remained somewhat variable, ranging between 60-
82%.34 In all cases variable amounts of pinacol 49 and
phthalide 50 were formed as byproducts. In contrast to
RCM, the McMurry coupling delivers alkene 37 as a
mixture of both stereoisomers (E:Z ≈ 3.5:1). For the
stuctures of these alkenes in the solid-state, consult the
Supporting Information.
any cyclized product.35 Successful preparations of several
other macrocycles as well as a straightforward synthesis
of the cytotoxic natural product lasiodiplodin 1 show the
generality and scope of this transformation. Furthermore,
the RCM-based approach to 1 is compared with a
synthesis of the same lactone via McMurry coupling of a
dialdehyde precursor. This direct comparison unequivo-
cally ends in favor of metathesis which is superior in all
relevant preparative aspects including the overall yield,
accessibility of substrates, total number of steps, stability
of intermediates, stereoselectivity, atom economy, repro-
ducibility, flexibility, and ease of handling of the re-
agents.36 Further applications meant to illustrate the
superb features of metathesis in general are underway
and will be reported in due course.
Con clu sion s. A concise synthesis of the macrolide (S)-
(-)-zearalenone 3 is described which is based on the
formation of the macrocyclic ring by RCM of a styrene
derivative. The use of the second generation metathesis
catalyst 5 bearing an NHC-ligand is key to success since
the classical Grubbs ruthenium carbene 4 fails to afford
Ack n ow led gm en t. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz pro-
gram) and the Fonds der Chemischen Industrie is
gratefully acknowledged.
(29) Copolla, G. M. Synthesis 1984, 1021.
(30) For selected references, see: (a) Fu¨rstner, A.; Hupperts, A.;
Seidel, G. Org. Synth. 1999, 76, 142. (b) Fu¨rstner, A.; Hupperts, A. J .
Am. Chem. Soc. 1995, 117, 4468. (c) Fu¨rstner, A.; J umbam, D. N.
Tetrahedron 1992, 48, 5991. (d) Fu¨rstner, A.; Ernst, A. Tetrahedron
1995, 51, 773. (e) Fu¨rstner, A.; Hupperts, A.; Weintritt, H. J . Org.
Chem. 1995, 60, 6637. (f) Fu¨rstner, A.; Ernst, A.; Krause, H.; Ptock,
A. Tetrahedron 1996, 52, 7329. (g) Fu¨rstner, A.; Ptock, A.; Weintritt,
H.; Goddard, R.; Kru¨ger, C. Angew. Chem. 1995, 107, 725; Angew.
Chem., Int. Ed. Engl. 1995, 34, 678. (h) Fu¨rstner, A.; Seidel, G.; Gabor,
B.; Kopiske, C.; Kru¨ger, C.; Mynott, R. Tetrahedron 1995, 51, 8875. (i)
Fu¨rstner, A.; Seidel, G. Synthesis 1995, 63. (j) Fu¨rstner, A.; Seidel,
G.; Kopiske, C.; Kru¨ger, C.; Mynott, R. Liebigs Ann. 1996, 655.
(31) Review: Fu¨rstner, A. Angew. Chem. 1993, 105, 171; Angew.
Chem., Int. Ed. Engl. 1993, 32, 164.
(32) Clive, D. L. J .; Zhang, C.; Murthy, K. S. K.; Hayward, W. D.;
Daigneault, S. J . Org. Chem. 1991, 56, 6447.
(33) (a) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; J anssen, E. J . Org.
Chem. 1994, 59, 5215. (b) Fu¨rstner, A.; Csuk, R.; Rohrer, C.; Weidmann,
H. J . Chem. Soc., Perkin Trans. 1 1988, 1729. (c) Fu¨rstner, A.;
Weidmann, H. Synthesis 1987, 1071.
Su p p or tin g In for m a tion Ava ila ble: The entire Experi-
mental Section including adequate characterization of all new
compounds and the X-ray structures of compounds (E)-37 and
(Z)-37. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0009999
(35) Scattered reports on successful RCM or ROM/CM reactions of
styrene derivatives catalyzed by complex 4 can be found in the
literature; most of them, however, relate to the kinetically favored
synthesis of chromenes and closely related products, cf.: (a) Chang,
S.; Grubbs, R. H. J . Org. Chem. 1998, 63, 864. (b) Harrity, J . P. A.;
Visser, M. S.; Gleason, J . D.; Hoveyda, A. H. J . Am. Chem. Soc. 1997,
119, 1488. (c) Harrity, J . P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.;
Hoveyda, A. H. J . Am. Chem. Soc. 1998, 120, 2343. (d) Fu¨rstner, A.;
Hill, A. F.; Liebl, M.; Wilton-Ely, J . D. E. T. Chem. Commun. 1999,
601. (e) Wipf, P.; Weiner, W. S. J . Org. Chem. 1999, 64, 5321.
(34) Coupling under optimized conditions [TiCl3(DME)1.5/Zn] recom-
mended by McMurry et al. led to similar problems with the reproduc-
ibility; McMurry, J . E.; Lectka, T.; Rico, J . G. J . Org. Chem. 1989, 54,
3748.
(36) For
a discussion of strategic goals in total synthesis, see:
Fu¨rstner, A. Synlett 1999, 1523.