Intramolecular Formal oxa-[3 + 3] Cycloaddition Approach to the ABD System of Phomactin A

Article abstract of DOI:10.1021/ol030115i

(Equation Presented) The ABD-ring of phomactin A was synthesized using an intramolecular formal oxa-[3 + 3] cycloaddion of an α,β-unsaturated iminium salt tethered to a 1,3-diketone. This represents the first time that the 12-membered ring has been formed

Full text of DOI:10.1021/ol030115i

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4843-4846
Intramolecular Formal oxa-[3 + 3]
Cycloaddition Approach to the ABD
System of Phomactin A
Kevin P. Cole and Richard P. Hsung*
Department of Chemistry, UniVersity of Minnesota, 207 Pleasant St. SE,
Minneapolis, Minnesota 55455-0431
hsung@chem.umn.edu
Received September 26, 2003
ABSTRACT
The ABD-ring of phomactin A was synthesized using an intramolecular formal oxa-[3 + 3] cycloaddion of an r,â-unsaturated iminium salt
tethered to a 1,3-diketone. This represents the first time that the 12-membered ring has been formed simultaneously with the 1-oxadecalin and
should afford a facile route to the challenging structure of phomactin A.
Phomactin A (1a) was isolated in 1991 by Sugano and co-
workers from the culture filtrate of Phoma sp. (SANK
11486), a parasitic fungus harvested off the coast of Japan.1
The phomactins display novel biological activity as platelet
1a), and then Halcomb ((+)-1a) in 2003, reported their
successes.6
activating factor (PAF) aggregation inhibitors (1a: IC50
)
10 µM). PAF is a phospholipid mediator that is alleged to
have a role in asthma and other inflammatory diseases.2 The
phomactins are of current interest due to their novel mode
of action on PAF, as well as their interesting and challenging
molecular architecture.
A number of phomactins have since been isolated,3 but
the first total synthesis of a phomactin (phomactin D, 1b)
was not achieved until 1996.4 Despite the efforts of a number
of groups toward the phomactin core,5 phomactin A did not
succumb to total synthesis until 2002 when Pattenden ((()-
Figure 1. Phomactins A and D.
We have developed a formal oxa-[3 + 3] cycloaddition
method for constructing 1-oxadecalins.7-9 Reactions of
(1) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463-5464.
(2) (a) Sugano, M.; Sato, A.; Saito, K.; Takaishi, S.; Matsushita, Y.;
Iijima, Y. J. Med. Chem. 1996, 39, 5281-5284. (b) Xhu, X.; Mun˜oz, N.
M.; Kim, K. P.; Sano, H.; Cho, W.; Leff, A. R. J. Immunol. 1999, 163,
3423-3429.
(3) (a) Sugano, M.; Sato, A. Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda,
K.; Hata, T. J. Org. Chem. 1994, 59, 564-569. (b) Sugano, M.; Sato, A.;
Iijima, Y.; Furuya, K.; Hata, T.; Kuwano, H. J. Antibiot. 1995, 48, 1188-
1190.
(5) (a) Foote, K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett. 1996,
37, 275-278. Foote, K. M.; John, M.; Pattenden, G. Synlett 2001, 365-
368. (b) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000, 2, 2687-2690.
Mohr, P. J.; Halcomb, R. L. Org. Lett. 2002, 4, 2413-2416. (c) Seth, P.
P.; Totah, N. I. Org. Lett. 2000, 2, 2507-2509. (d) Mi, B.; Maleczka, R.
E. Org. Lett. 2001, 3, 1491-1494. (e) Chemler, S. R.; Iserloh, U.;
Danishefsky, S. J. Org. Lett. 2001, 3, 2949-2951. (f) Houghton, T. J.; Choi,
S.; Rawal, V. H. Org Lett. 2001, 3, 3615-3617. (g) Balnaves, A. S.;
McGowan, G.; Shapland, D. P.; Thomas, E. J. Tetrahedron Lett. 2003, 44,
2713-2716.
(4) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996,
37, 7107-7110.
10.1021/ol030115i CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/19/2003

diketones 2 with R,â-unsaturated iminium salts 3 proceed
through a Knoevenagel condensation followed by a 6π-
electron electrocyclic ring closure of 1-oxatrienes 4 to give
1-oxadecalins 5 (Scheme 1). Despite our efforts and those
Scheme 1
Figure 2. Possible regioisomers of cyclization.
molecular cyclization (see Figure 2). The desired mode of
cyclization involves formation of the 12-membered D-ring,
while the undesired modes create 10-membered rings. The
success of this reaction would provide a novel approach
toward phomactin in which the 12-membered D-ring is
assembled at the onset, instead of being constructed near
the end.4-6 We decided to test the possibility experimentally.
Our first approach to enal 7 is shown in Scheme 3.
Attempting to take advantage of oxygenation built into the
of others,10 this formal oxa-[3 + 3] cycloaddition reaction
has never been employed in an intramolecular manner. We
wish to communicate here our preliminary success in
developing an intramolecular formal oxa-[3 + 3] cyclo-
addition approach toward the synthesis of the ABD portion
of phomactin A.
Our basic approach to the synthesis of phomactin A is
shown in Scheme 2. We were initially uncertain as to the
Scheme 3
Scheme 2
feasibility of applying the oxa-[3 + 3] to 1a given the
possibility that cyclization could potentially occur onto either
oxygen of the diketone. Upon evaluation of the system, it
became evident that there can be three products of intra-
system, vinylogous ester (()-106a was an attractive retron,
provided that it could be alkylated with an electrophile such
as iodide 11 (prepared in eight steps). Unfortunately, in our
hands this alkylation proved to be problematic in two
important aspects: (1) the yield was unreproduceable and
low and (2) the diastereoselectivity was a disappointing
2.3:1, favoring the desired cis isomer with respect to the C4-
and C5-methyl substituents. Furthermore, these diastereomers
were extremely difficult to separate chromatographically.
The mixture was elaborated over three steps to the enals
7. The cyclization of enals 7 (olefin geometry scrambled
(6) (a) Goldring, W. P. D.; Pattenden, G. Chem. Commun. 2002, 1736-
1737. (b) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712-
1713.
(7) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen,
S. J.; Yao, L. J. Org. Chem. 1999, 64, 690-691. (b) Shen, H. C.; Wang,
J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.; Hsung,
R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Wei, L.-L.;
Sklenicka, H. M.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68,
1729-1735.
(8) For recent applications of the formal oxa-[3 + 3] cycloaddition in
natural product synthesis, see: (a) Kurdyumov, A. V.; Hsung, R. P.; Ihlen,
K.; Wang, J. Org. Lett. 2003, 5, 3935-3938. (b) Hsung, R. P.; Cole, K. P.;
Zehnder, L. R.; Wang, J.; Wei, L.-L.; Yang, X.-F.; Coverdale, H. A.
Tetrahedron 2003, 59, 311-324.
(9) For a review on stepwise hetero-[3 + 3] formal cycloadditions, see:
Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.; McLaughlin, M.
J.; Zehnder, L. R. In Trends in Heterocyclic Chemistry; Research Trends:
Trivandrum, India, 2001; Vol. 7, pp 1-24.
(10) (a) Stevenson, R.; Weber, J. J. Nat. Prod. 1988, 51, 1215. (b)
Schuda, P. F.; Price, W. A. J. Org. Chem. 1987, 52, 1972. (c) de March,
P.; Moreno-Man˜as, M.; Casado, J.; Pleixats, R.; Roca, J. L. J. Heterocycl.
Chem. 1984, 21, 85. (d) Tietze, L. F.; Kiedrowski, G.; Berger, B. Synthesis
1982, 683. (e) de Groot, A.; Jansen, B. J. M. Tetrahedron Lett. 1975, 16,
3407. (f) Malerich, J. P.; Trauner, D. J. J. Am. Chem. Soc. 2003, 125, 9554.
4844
Org. Lett., Vol. 5, No. 25, 2003

upon treatment with H2SO4) was found to occur under very
mild conditions, affording a complex mixture of products.
Several of the reaction products could be attributed to
dimerization/oligomerization of the starting material (as
evidenced by the crude LC/MS), and there appeared to be
peaks in the H NMR assignable to desired product. How-
ever, the mixture contained signals resulting from C5-methyl
diastereomers as well.
alcohol (Scheme 5). In this case, the use of Cy2BH was
preferable, as 9-BBN seemed to promote an undesired side
reduction.
1
Scheme 5
In short, this experiment encouraged us in that the key
cyclization appeared to be feasible, but absolute certainty
as to the identity of the products could only be obtained if
a single diastereomer was subjected to the reaction condi-
tions. Additionally, the paramount cyclization should be
performed under conditions of high dilution to ensure that
only the intramolecular reaction occurs.
We decided to sacrifice brevity and chose a route that
would allow for isolation of a single isomer of 7 using
chemistry that could potentially produce large quantities of
material. As shown in Scheme 4, conjugate addition/
With 20 in hand, the necessary oxygenation was installed
through a six-step procedure (Scheme 6). Removal of the
PMB ether under standard DDQ conditions occurred readily;
TPAP oxidation then afforded the ketone in good yield.
Oxidation to enone 21, however, proved to be problematic;
unidentified byproducts were isolated after the initial sel-
enation step, the olefins of which appeared to have suffered
electrophilic attack. Nucleophilic epoxidation of 21 pro-
ceeded smoothly and with high selectivity to afford the
R-epoxide 22 (assigned by 1H NOE experiments) as the only
observed diastereomer. To open the epoxide, SmI2 reduction
at low temperature was the only protocol surveyed that
reliably opened the epoxy-ketone in a completely regio-
selective manner.16
Scheme 4
Scheme 6
trapping11 of enone 1312 afforded, after distillation, ketone
(()-14 as an 11:1 mixture of diastereomers. Due to the
incompatibility of an ethylene ketal with AlMe3, the ketone
was reduced and protected as its PMB ether. The alkene was
subjected to hydroboration/oxidation followed by Swern
oxidation to afford aldehyde 15. Corey-Fuchs homologa-
tion13 proceeded smoothly to afford alkyne 16, the structure
of which was unambiguously assigned via single-crystal
X-ray analysis. Last, Negishi carboalumination followed by
an iodine quench14 provided vinyl iodide 17.
We had hoped to use the Noyori method to simply
isomerize the R,â-epoxy ketone directly to the 1,3-diketone.17
Unfortunately, under numerous conditions, the reaction was
complicated by both poor conversion and competing reduc-
tion, which afforded mixtures of 23 and the same â-hydroxy
ketone produced from SmI2 reduction.
The terpene side chain was completed using a B-alkyl
Suzuki coupling6b,15 of iodide 17 with the borane derived
from diene 19, which was rapidly assembled from prenyl
(11) Coelho, F.; Diaz, G. Tetrahedron 2002, 58, 1647-1656.
(12) Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. IV, p 162-166.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3792.
(14) Negishi, E.; Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985, 107,
6639-6647.
(16) Molander, G.; Hahn, G. J. Org. Chem. 1986, 51, 2596-2599.
(17) Suzuki, M.; Watanabe, A.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 2095-2096.
(15) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
Org. Lett., Vol. 5, No. 25, 2003
4845

The sensitive 1,3-diketone in 23 was protected as its
vinylogous methyl ester (Scheme 7). The two possible
Scheme 8
Scheme 7
In summary, we have described here an approach to the
ABD-ring of phomactin A, featuring an intramolecular
formal oxa-[3 + 3] cycloaddition as the key step to
simultaneously form the 12-membered D-ring with the
1-oxadecalin. Further optimization of the synthetic route to
enal 7, including an enantioselective approach, as well as
studies directed toward the completion of the total synthesis
of phomactin A, are underway.
regioisomers of the esterification were observed in a 1:1 ratio
and were easily separated. Subsequent reactions showed that
regioisomer 25 was much more resistant to hydrolysis than
24; thus, only 24 was carried forward, while its isomer was
recycled (KOH, THF/MeOH/H2O, 78%). Deprotection of the
silyl ether and periodinane oxidation led to a single isomer
of the enal. Hydrolysis of the methyl ester again scrambled
the olefin geometry but proceeded in high yield, providing
the desired diketone 7.
Acknowledgment. The authors would like thank the
National Institutes of Health [NS38049] and the donors of
the Petroleum Research Fund [Type-G], administered by the
American Chemical Society, for financial support. We also
thank Dr. Victor G. Young and Mr. William W. Brennessel
for solving the X-ray structure. R.P.H. thanks the University
of Minnesota for a McKnight New Faculty Award and
Camille Dreyfus Foundation for a Teacher-Scholar Award.
K.P.C. thanks the American Chemical Society for an Organic
Division Fellowship sponsored by Schering-Plough Research
Institute.
At last, with pure enal 7 in hand, we attempted the key
oxa-[3 + 3] cycloaddition (Scheme 8). Using conditions of
high dilution (5 mL/mg), we were pleased to discover all
three potential intramolecular products (6:(8 + 9) ) 1:2.5).
While isomers 8 and 9 existed as an unassignable and
inseparable 4:1 mixture, the desired cycloadduct (()-6 was
easily separated and its structure confirmed using 1H NOE,
Supporting Information Available: Spectroscopic data
for all new compounds along with detailed experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1H-1H COSY, and H-13C HMBC experiments.
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