Synthesis of the carbocyclic core of the cornexistins by ring-closing metathesis

Article abstract of DOI:10.1021/ol027265y

(Matrix presented) An advanced intermediate in the synthesis of the phytotoxins cornexistin and hydroxycornexistin has been synthesized. Sequential palladium-mediated sp²-sp³ fragment coupling and ring-closing diene metathesis have been used to construct the nine-membered carbocyclic core found in the natural products.

Full text of DOI:10.1021/ol027265y

ORGANIC
LETTERS
2
003
Vol. 5, No. 1
9-92
Synthesis of the Carbocyclic Core of
the Cornexistins by Ring-Closing
Metathesis
8
J. Stephen Clark,* Frederic Marlin, Bastien Nay, and Claire Wilson
School of Chemistry, UniVersity of Nottingham, UniVersity Park,
Nottingham, NG7 2RD, UK
j.s.clark@nottingham.ac.uk
Received November 11, 2002
ABSTRACT
An advanced intermediate in the synthesis of the phytotoxins cornexistin and hydroxycornexistin has been synthesized. Sequential palladium-
2
3
mediated sp −sp fragment coupling and ring-closing diene metathesis have been used to construct the nine-membered carbocyclic core
found in the natural products.
Cornexistin and hydroxycornexistin are phytotoxic members
1
of the nonadride family of natural products. The cornexistins
contain a nine-membered carbocycle fused to a cyclic
anhydride and are structurally related to several other natural
2
products such as glaucanic acid, 12-epi-glaucanic acid,
CP-225,917, and CP-263,114.3
Cornexistin was first isolated from a culture of the fungus
Paecilomyces Variotii Bainier (strain SANK 21086) by
researchers at Sankyo Co. in Japan in 1991, and its structure
The related compound hydroxycornexistin was isolated
was elucidated using NMR spectroscopy and X-ray crys-
from the same strain of P. Variotii by workers at DowElanco
tallography.1 This compound has attracted considerable
a
1
b
in the USA. This compound has even greater herbicidal
activity than cornexistin against many broadleaf weeds,
including several very aggressive varieties.
attention in the agrochemical industry because it displays
potent herbicidal activity against many grasses and broadleaf
weeds but is well tolerated by maize plants.
The selective and potent herbicidal activity of cornexistin
and hydroxycornexistin combined with their novel mode of
action makes them important lead compounds in the search
for new herbicides for post-emergence weed control in crop
(
1) (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Sato, S.; Furukawa, Y.;
Furuya, K.; Honma, T.; Kadotani, J.; Kozasa, M.; Haneishi, T. J. Antibiot.
991, 44, 1065. (b) Fields, S. C.; Mireles-Lo, L.; Gerwick, B. C. J. Nat.
Prod. 1996, 59, 698.
2) Barton, D. H. R.; Sutherland, J. K. J. Chem. Soc. 1965, 1769.
3) (a) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jankovich, N.
D.; Kaneko, T.; Li, J.-C.; Lindsey, S.; Moshier, P. M.; Subashi T. A.;
Therrien, M.; Watts, P. C. J. Antibiot. 1997, 50, 1. (b) Dabrah, T. T.; Kaneko,
T.; Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 1594.
1
4
production.
(
(
Our interest in cornexistin and hydroxycornexistin as
synthetic targets was aroused by the synthetic challenges
these compounds present coupled with their potent bioac-
1
0.1021/ol027265y CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/11/2002

tivity. Both compounds possess a nine-membered carbocycle
fused to a highly reactive cyclic anhydride, a combination
of structural features that constitutes a significant obstacle
to conventional methods of ring construction. In addition,
the cornexistins present several problems with regard to
stereocontrol; control of the exocyclic alkene configuration
is especially problematic.
4-phenyloxazole10 at 200 °C resulted in Diels-Alder reac-
tion, and immediate retrocycloaddition to give furan 5. The
11
ketone was then methylenated using Nysted reagent and
1
2
titanium(IV) chloride, and the protecting group was then
removed to deliver alcohol 6. Swern oxidation and Wittig
methylenation of the resulting aldehyde delivered precursor
7 required for the anticipated RCM reaction.
At the outset, we identified ring-closing metathesis (RCM)
as the most promising reaction for construction of the nine-
5
6
membered ring. We had already prepared a variety of
medium-ring ethers using diene RCM reactions promoted
Scheme 2a
7
by the ruthenium complexes 1 and 2, and other workers
had used RCM to prepare medium-sized carbocycles.
However, there were no literature examples involving direct
8
construction of nine-membered carbocycles using RCM.
a
Reagents and conditions: (a) (i) n-BuLi, THF; (ii) n-PrCHO,
THF, -78 °C f rt; (b) TPAP, NMO, CH
c) 4-Phenyloxazole, 200 °C, 70%; (d) Zn(CH
THF, 0 °C f rt, 89%; (e) TBAF, THF, rt, 99%; (f) (COCl)
2 2
Cl , rt, 66% (two steps);
(
2
ZnBr)
2
‚THF, TiCl
4
,
,
2
In our original retrosynthetic analysis of hydroxycorn-
existin, functional group interconversion (FGI) suggested the
tricyclic furan i as a late-stage intermediate (Scheme 1).
Further FGI gave the cyclononene ii, and disconnection of
the alkene revealed the diene iii. Bond disconnection between
the butenolide and furan portions of the diene iii resulted in
lactone iv and the 3,4-dialkylfuran v as intermediates. This
retrosynthetic analysis implies that the synthesis will involve
coupling of fragments corresponding to the chiral lactone iv
and the achiral furan v, followed by RCM of the diene iii
and stereoselective hydroboration of the resulting trisubsti-
tuted alkene. Subsequent reduction of the lactone, adjustment
of oxidation levels and removal of protecting groups would
then deliver hydroxycornexistin.
DMSO, CH Cl , Et N, -60 °C f rt, 91%; (g) Ph PCH , THF, rt,
2
2
3
3
2
2 2
85%; (h) 1 or 2 CH Cl , rt or reflux.
Unfortunately, all attempts to effect ring closure by RCM
failed to deliver the required carbocyclic product 8. The
failure of the reaction was attributed to difficulties in forming
a nine-membered ring and a conjugated trisubstituted alkene
during metathesis. To circumvent these problems, we altered
our retrosynthetic analysis to give key disconnection of the
nine-membered carbocycle at a different position (Scheme
3). In this retrosynthetic analysis, FGI of hydroxycornexistin
suggests the diol vi as a late-stage intermediate. Recognition
that the syn 1,2-diol implies an alkene then leads to
cyclononene vii, and this can be disconnected to give diene
viii. Further disconnection at one of the C-C bonds
connecting the two rings leads to butenolide ix and 3,4-
Scheme 1
(4) (a) Haneishi, T.; Nakajima, M.; Koi, K.; Furuya, K.; Iwado, S.; Sato,
S. U.S. Patent 4 897 104, 1990. (b) Haneishi, T.; Nakajima, M.; Koi, K.;
Furuya, K.; Iwado, S.; Sato, S. U.S. Patent 4 990 178, 1991. (c) Fields, S.
C.; Gerwick, B. C.; Mireles-Lo, L. U.S. Patent 5 424 278, 1995.
(5) For reviews concerning RCM reactions, see: (a) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1997, 371. (d) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413. (e) F u¨ rstner A. Angew. Chem., Int. Ed.
2
000, 39, 3013.
(6) (a) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123. (b)
Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127. (c) Clark, J. S.;
Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321. (d) Clark, J. S.;
Kettle, J. G. Tetrahedron 1999, 55, 8231. (e) Clark, J. S.; Hamelin, O.
Angew. Chem., Int. Ed. 2000, 39, 372.
(7) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(
8) For preparation of a related eight-membered carbocyclic system,
see: Efremov, I.; Paquette, L. A. J. Am. Chem. Soc. 2000, 122, 9324.
9) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
994, 639.
To explore the key RCM reaction, diene 7 was prepared
from TBS-protected 7-octyn-1-ol (3) (Scheme 2). Reaction
of butanal with the lithium acetylide derived from alkyne 3
and immediate oxidation of the resulting alcohol using
(
1
(
29.
10) Whitney, S. E.; Winters, M.; Rickborn, B. J. Org. Chem. 1990, 55,
9
(11) Hutton, J.; Potts, B.; Southern, P. F. Synth. Commun. 1979, 9, 789.
9
catalytic TPAP afforded ketone 4. Subsequent reaction with
(12) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313.
90
Org. Lett., Vol. 5, No. 1, 2003

disubstituted furan x bearing suitable substituents (X and Y)
ester was then reduced with lithium aluminum hydride, and
the resulting allylic alcohol was treated with diethyl chlo-
rophosphate to give allylic phosphate 18. The side chain was
2
3
13
for a metal-mediated sp -sp coupling reaction. This
retrosynthetic plan has the advantage that RCM of a substrate
possessing two terminal alkenes is implicit.
N
installed by copper-catalyzed S 2′ displacement of the allylic
phosphate with n-propylmagnesium chloride, following the
procedure of Yamamoto and co-workers, to give alkene 19.18
Cleavage of the TBS ether and conversion of the resulting
primary alcohol into the corresponding chloride via the
mesylate, using the procedure described by Tanis for the
Scheme 3
19
synthesis of related chlorides, afforded the second coupling
partner 20.
Scheme 5a
The precursors required for implementation of the syn-
thetic plan suggested in Scheme 3 were prepared by the
routes shown in Schemes 4 and 5. The readily available
starting material tetronic acid (9) was first converted into
the vinylogous amide 10 in high yield by reaction with
a
Reagents and conditions: (a) LiAlH , THF, -78 °C f rt; (b)
4
MnO
over three steps); (d) Ph
THF, -78 °C f rt, 98%; (f) P(O)(OEt)
CH Cl , rt; (g) n-PrMgCl, CuCN (10 mol %), LiCl (30 mol %),
THF, -78 °C, 63% (over two steps); (h) TBAF, THF, rt, 82%; (i)
MeSO Cl, LiCl, collidine, DMF, 0 °C, 90%.
2
, CH
2
Cl
2
, rt; (c) TBSCl, imidazole, DMAP, CH
2
Cl
Et, THF, rt, 98%; (e) LiAlH
Cl, pyridine, DMAP,
2
, rt, 73%
(
3
PdCHCO
2
4
,
14
2
pyrrolidine (Scheme 4). Deprotonation with t-butyllithium
and treatment of the resulting anion with allyl bromide then
afforded alkylated product 11.15 Acid-catalyzed hydrolysis
of the compound delivered tetronic acid derivative 12, and
this was then converted into triflate 13. The stannane (14)
2
2
2
2
3
required for the sp -sp coupling reaction was obtained by
the palladium-catalyzed reaction of triflate 13 with hexa-
butylditin.16
The precursor required for the RCM reaction was prepared
by sp -sp coupling of vinylic stannane 14 and chloride 20.
Coupled product 21 was obtained in 60% yield (1:1 mixture
2
3
2 3
of diastereoisomers) upon treatment with Pd (dba) and
2
0
triphenylarsine in THF at reflux (Scheme 6). This com-
pound was then subjected to RCM using ruthenium complex
Scheme 4a
2
in toluene at 80 °C. The reaction was complete in 3 h, and
tricyclic product 22 was obtained as a separable mixture of
diastereoisomers (a and b) in 61% yield. When the RCM
reaction was performed using ruthenium complex 1 in
dichloromethane at reflux, the reaction took 60 h and alkene
2
2a/b was obtained in 70% yield.
(
13) For reviews of the Stille reaction, see: (a) Stille, J. K. Pure Appl.
Chem. 1985, 57, 1771. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986,
5, 508. (c) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction;
Wiley: New York, 1999.
14) Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y. Heterocycles
1988, 27, 1907.
15) For the alkylation of a related tetronic acid derivative, see:
Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P. Tetrahedron Lett. 1988,
a
Reagents and conditions: (a) pyrrolidine, heat, 94%; (b) t-BuLi,
2
CH
1%; (d) Tf
Pd(PPh , THF, reflux, 75%.
2
CHCH
2
Br, THF, -78 °C f rt, 70%; (c) aqueous HCl, 60 °C,
8
2
O, i-Pr NEt, CH Cl , -78 °C, 89%; (e) (Bu Sn) , LiCl,
2
2
2
3
2
(
3 4
)
(
2
9, 1489.
The synthesis of the second coupling partner commenced
from commercially available dimethyl 3,4-furandicarboxylate
(16) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277.
(17) Cook, M. J.; Forbes, E. J. Tetrahedron 1968, 24, 4501.
(15) (Scheme 5). Complete reduction of the diester followed
(
(
(
18) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett 1993, 689.
by selective mono-oxidation of the resulting diol with
19) Tanis, S. P. Tetrahedron Lett. 1982, 23, 3115.
17
manganese dioxide afforded aldehyde 16. Protection of the
remaining hydroxyl group as the TBS ether followed by
Wittig reaction of the aldehyde with methyl (triphenylphos-
phoranylidene)acetate delivered alkene 17 in high yield. The
2
3
20) For examples of related palladium-mediated sp -sp coupling
reactions, see: (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C., Jr.
Tetrahedron Lett. 1988, 29, 5739. (b) Yang, Y.; Wong, H. N. C. Tetrahedron
1994, 50, 9583. (c) Takeda, T.; Kabasawa, Y.; Fujiwara, T. Tetrahedron
1995, 51, 2515.
Org. Lett., Vol. 5, No. 1, 2003
91

Scheme 6a
Figure 1. X-ray crystal structure of compound 22b.
a
Reagents and conditions: (a) Pd
2
(dba)
3
, AsPh
3
, THF, reflux,
this is the first example of direct construction of a nine-
membered carbocycle using RCM.
6
0%; (b) 2, PhMe, 80 °C, 3 h, 61% or 1, CH
2
2
Cl , rt, 3 d, 70%.
The preparation of fragments 13 and 20 as single enan-
tiomers and completion of the total syntheses of cornexistin
and hydroxycornexistin are in progress. Results of this work
will be reported in due course.
The more polar diastereoisomer was obtained as a crystal-
line solid, and subsequent recrystallization from dichloro-
methane-petroleum ether gave crystals suitable for X-ray
2
1
analysis. This revealed the more polar isomer to be the
Acknowledgment. We thank the EPSRC (Grant GR/
N63666) for financial support and for the provision of a
Bruker SMART1000 CCD X-ray diffractometer (Grant GR/
M54728). We also thank Dr. John Clough (Syngenta,
Jealott’s Hill Research Station, Bracknell, Berks., UK) for
helpful discussions regarding aspects of this work.
unnatural diastereoisomer 22b (Figure 1).
In summary, we have constructed the core of the corn-
existins by employing a concise 11-step route in which the
novel sequence of palladium-catalyzed sp -sp fragment
coupling followed by RCM is used. This is the first synthesis
of the core of the cornexistins. In addition, we believe that
2
3
Supporting Information Available: Spectroscopic and
other data for compounds 14, 20, 21, 22a, 22b. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
21) Crystallographic data (excluding structure factors) for compound
2
2b have been deposited (CCDC 196700) with the Cambridge Crystal-
lographic Data Centre. Copies of the data can be obtained, free of charge,
upon application to the CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
(fax, +44 (0)1223 336033; e-mail, deposit@ccdc.cam.ac.uk).
OL027265Y
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Org. Lett., Vol. 5, No. 1, 2003