Efficient assembly of the phomactin core via two different macrocyclization protocols.

Article abstract of DOI:10.1021/ol0163833

[reaction--see text] The core structure of phomactins C and D was assembled by an efficient strategy starting from 3,4-dimethylcyclohexen-2-one. Key reactions include (1) a high yielding and highly diastereoselective Michael addition of a mixed cuprate, (

Full text of DOI:10.1021/ol0163833

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3615-3617
Efficient Assembly of the Phomactin
Core via Two Different Macrocyclization
Protocols
Tom J. Houghton, Soongyu Choi, and Viresh H. Rawal*
Chemistry Department, UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received July 3, 2001
ABSTRACT
The core structure of phomactins C and D was assembled by an efficient strategy starting from 3,4-dimethylcyclohexen-2-one. Key reactions
include (1) a high yielding and highly diastereoselective Michael addition of a mixed cuprate, (2) a carbonylative alkyne−enoltriflate coupling
or an intramolecular addition of an acetylide onto an aldehyde to form the macrocycle, (3) chemoselective Michael addition of a cuprate to an
enynone, to give the carbon framework of desformyl phomactin C or D, and finally (4) regioselective addition of a thia-nucleophile to the more
reactive â-position of the resulting dienone.
Phomactins A, C, and D, discovered in the early 1990s, are
structurally related platelet activating factor (PAF) antago-
nists produced by the marine fungus Phoma sp.1 In addition
to inducing human platelet aggregation, PAF has been
implicated as having a role in causing asthma and other
inflammatory diseases.2 Hence PAF antagonists have definite
potential as lead compounds for pharmaceutical drugs. The
biological activity and unusual carbon skeleton of the
phomactins have prompted much interest among organic
chemists but have as yet resulted in only one total synthesis
of a phomactin.3 Several years ago, we began to investigate
an efficient and general strategy to these compounds.4 Recent
publications from other groups prompt us to disclose here
our strategy and progress towards the total syntheses of
phomactins C and D.5
Our synthetic plan3 for the construction of the phomactins
is shown in Scheme 1. The strategy is expected to be quite
general and has already led to the synthesis of an advanced
intermediate lacking just one carbon of the phomactin
(1) (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463-5464. (b)
Chu, M.; Patel, M. G.; Gullo, V. P.; Trumees, I.; Puar, M. S.; McPhail, A.
T. J. Org. Chem. 1992, 57, 5817-5818. (c) Chu, M.; Trumees, I.;
Gunnarsson, I.; Bishop, W. R.; Kreutner, W.; Horan, A. C.; Patel, M. G.;
Gullo, V. P.; Puar, M. S. J. Antibiot. 1993, 46, 554-563. (d) Sugano, M.;
Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J. Org.
Chem. 1994, 59, 564-569. (e) Sugano, M.; Sato, A.; Iijima, Y.; T.; Furuya,
K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188-1190. (f) Sugano,
M.; Sato, A.; Saito, K.; Takaishi, S.; Matsushita, Y.; Iijima, Y. J. Med.
Chem. 1996, 39, 5281-5284.
(4) Choi, S.; Rawal, V. H. Studies Directed Toward the Synthesis of
Phomactin D, presented at the 30th Great Lakes Regional Meeting of the
American Chemical Society, May 28-30, 1997, Chicago, IL, Abstract 133.
(5) Synthetic studies: (a) Foote, K. M.; Hayes, C. J.; Pattenden, G.
Tetrahedron Lett. 1996, 37, 275-278. (b) Seth, P. P.; Totah, N. I. Org.
Lett. 2000, 2, 2507-2509. (c) Seth, P. P.; Chen, D.; Wang, J.; Gao, X.;
Totah, N. I. Tetrahedron. 2000, 56, 10185-10195. (d) Kallan, N. C.;
Halcomb, R. L. Org. Lett. 2000, 2, 2687-2690. (e) Chemler, S. R.;
Danishefsky, S. J. Org. Lett. 2000, 2, 2695-2698. (f) Foote, K. M.; John,
M.; Pattenden, G. Synlett 2001, 365-368. (g) Mi, B.; Maleczka, R. E., Jr.
Org. Lett. 2001, 3, 1491-1494. (h) Chemler, S. R.; Iserloh, U.; Danishefsky,
S. J. Org. Lett. 2001, 3, 2949-2951 (ref 5h added in proof).
(2) Zhu, X.; Mun˜oz, N. M.; Kim, K. P.; Sano, H.; Cho, W.; Leff, A. R.
J. Immunol. 1999, 163, 3423-3429.
(3) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996,
37, 7107-7110.
10.1021/ol0163833 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

Scheme 1
Scheme 2a
backbone. The epoxide group in the desired targets can be
installed at a late stage in the synthesis from the correspond-
ing dienone by taking advantage of peripheral epoxidation
to set the relative stereochemistry of this moiety.6 Examina-
tion of molecular models of potential intermediates suggested
that of the two enone double bonds the required one would
be more reactive to a nucleophilic epoxidizing agent due to
its greater degree of conjugation with the ketone carbonyl.
Two methods were conceived for the synthesis of the
macrocycle. In one case, intramolecular acetylide addition
to the unsaturated aldehyde of intermediate 5,7 formed
regioselectively via the kinetic enolate of ketone 6, would
produce the required 12-membered ring. Conjugate addition
of the cuprate of enyne 88 to known enone 79 was predicted
to give ketone 6 (X ) H) with good diastereoselectivity.
For the real system, the expectation was that the enolate
formed upon cuprate addition would be intercepted by a
suitable electrophile (cf. 6, X ) CH2OP) to introduce the
one-carbon unit required for the natural products.10 In the
second case, ketone 6 would again be a key intermediate,
but the ring closure would be achieved by a carbonylative
coupling reaction (vide infra). The goal of the initial study3
was to validate the overall strategy through the synthesis of
a compound bearing the desformylphomactin carbon skel-
eton.
a (a) AlMe3, Cp2ZrCl2, Cl(C2H4)Cl; then I2; (b) TBSCl, DMAP,
imidazole, CH2Cl2; (c) n-BuLi, TMSCl, THF; (d) 2M HCl; (e) PPh3,
imidazole, I2, CH2Cl2; (f) 10, Rieke zinc, THF; 9, Pd(PPh3)4; (g)
H2O, AcOH, THF; (h) t-BuLi, Et2O; Cu(C5H7), PBu3; add 7; (i)
LDA, THF; Comins’ triflimide; (j) TBAF, THF; (k) n-BuLi, Et2O;
Me3SnCl; (l) PdCl2dppf‚CH2Cl2, LiCl, CO, DMF.
mmol scale in high overall yield. Hydrolysis of the TBS ether
followed by conversion of the hydroxyl to an iodide produced
8 in 67% overall yield from 9. Iodine-lithium exchange
followed by addition of a solution of copper pentynylide12
gave a mixed cuprate that was treated with 7 at -78 °C.
The solution was then allowed to warm gradually to -25
°C and upon workup afforded the desired addition product,
ketone 13, in 88% yield as a 13:1 mixture of diastereomers.
This reaction is noteworthy in that the cuprate derived from
iodide 8 was not used in excess, as is often the case, but
was used in a 1:1 ratio with enone 7. Kinetic deprotonation
followed by trapping of the regioselectively formed enolate
with Comins’ reagent afforded enol triflate 14 (ca. 9:1 ratio),
poised for assembling the macrocyclic ring.13
A direct route from triflate 14 to the phomactin macrocycle
was through a carbonylative cyclization.14,15 To that end, the
trimethylsilyl group was exchanged for a trimethylstannyl
under standard conditions.16 We were gratified to find that
stannyl triflate 16 underwent the desired transformation upon
heating in a Fischer-Porter bottle under a CO atmosphere
in the presence of a Pd catalyst. Although the yield of this
reaction must be optimized further, it represents a powerful
strategic construct for the phomactin skeleton, accomplishing
As shown in Scheme 2, iodide 8 was prepared from two
butyn-1-ol-derived units using a slight modification of
Negishi’s method. Upon treatment with Rieke zinc,11 iodide
10 was converted to the corresponding organozinc, which
was coupled with vinyl iodide 9 using Pd catalysis. This
coupling protocol has been carried out reliably on a >20
(6) This concept was elegantly demonstrated in the synthesis of peripl-
anone B: Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493-2495.
(7) (a) Danishefsky, S. J.; Mantlo, N. B.; Yamashita, B. S. J. Am. Chem.
Soc. 1988, 110, 6890-6891. (b) Kende, A. S.; Smith, C. A. Tetrahedron
Lett. 1988, 34, 4217-4220.
(8) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. I. J. Org.
Chem. 1981, 46, 4093-4096.
(9) Compound 7 was prepared according to the general method of Braude
et al.: Braude, E. A.; Webb, A. A.; Sultanbawa, M. U. S. J. Chem. Soc.
1958, 3328-3336.
(12) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210-
7211.
(13) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
(14) (a) Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 7500-7506. (b) Gyorkos, A. C.; Stille, J. K.; Hegedus, L. S. J. Am.
Chem. Soc. 1990, 112, 8465-8472.
(10) A recent report clearly supports the feasibility of such a transforma-
tion: Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org. Chem. 2000,
65, 3551-3554.
(11) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56,
1445-1453.
3616
Org. Lett., Vol. 3, No. 23, 2001

not only the necessary one carbon homologation and two
C-C bonds but also the attendant macrocyclization. The
longest linear sequence to 17 by this route is only 11 steps
from butyn-1-ol.
the crude reaction product was treated with a solution of
iodine to yield alkenyl iodide 19 in 85% overall yield.
Iodine-lithium exchange followed by quenching with DMF
and acidic workup produced aldehyde 20, a potential
macrocyclization precursor.19 As the CsF-mediated direct
desilation/cyclization protocol proved unsuccessful for this
substrate, the silyl group was first removed in 91% yield
using KF‚2H2O. A THF solution of the alkyne-aldehyde
(21) was added by syringe pump over ca. 100 min to a 0.036
M THF solution of NaHMDS at -10 °C, which triggered
the desired macrocyclization to afford, upon workup, a
mixture of diastereomeric alcohols in 54% yield. Treatment
of the alcohols with manganese dioxide provided the alkynyl
enone 17, identical to that obtained by the carbonylative
cyclization procedure.
An alternate route to the critical large ring was via a ring-
forming acetylide addition to an aldehyde (Scheme 3).17 The
Scheme 3a
Completion of the desformyl-phomactin skeleton neces-
sitated the introduction of a methyl group to enynone 17.
This process required not only that a conjugate addition be
chemoselectivesto the alkyne rather than the alkenesbut
also that it be stereoselective. In the event, treatment of the
ketone with excess lithium dimethylcuprate gave exclusively
products resulting from the expected conjugate addition to
the alkyne, albeit as a ∼2.5:1 mixture of Z and E isomers,
favoring the undesired Z compound (by GOESY NMR
experiments).20 Photoequilibration of the mixture21 failed to
increase the proportion of the E isomer. Treatment of 22
with a large excess of lithium thiophenolate produced in high
yield a single crystalline product. It had been anticipated that
addition to the cyclohexenyl double bond would be favored
for steric reasons and that the remaining enone double bond
might be isomerized via addition-elimination.22 X-ray
crystallography, however, firmly established the product to
be 23, wherein the thiophenyl group had added to the double
bond in the macrocycle. This result supports our initial
assertion that the macrocyclic enone should be more elec-
trophilic than the cyclohexenyl enone.
Compound 23 bears the full carbon skeleton of desformyl
phomactin C. It and several other compounds shown in
Scheme 3 are currently undergoing preliminary biological
testing to evaluate their PAF antagonist properties. Further
developments on the synthesis of the phomactins will be
reported in due course.
Acknowledgment. Partial financial support from Pfizer
Inc. is gratefully acknowledged. We thank Dr. Ian M. Steele
for the X-ray structure determination.
a (a) Pd(PPh3)4, (SnMe3)2, Li2CO3, LiCl, THF; (b) I2, CH2Cl2;
(c) n-BuLi, Et2O; DMF; NH4Cl; (d) KF‚2H2O, EtOH; (e) NaHMDS,
THF; (f) MnO2, CH2Cl2; (g) LiCuMe2, THF; (h) LiSPh, THF.
1
Supporting Information Available: H and 13C spectra
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Wulff reaction18 converted triflate 14 to the corresponding
trimethylstannane (18), a compound that was prone to proto-
destannylation during chromatographic purification. As such,
OL0163833
(18) 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, 279-280.
(15) The optimum route to the desired macrocycle was through the
carbonylative coupling of alkynyl-enoltriflate 15, a process that has
precedence in the work of Ortar and co-workers: Ciattini, P. G.; Morera,
E.; Ortar, G. Tetrahedron Lett. 1991, 32, 6449-6452. Unfortunately, the
direct macrocyclization of alkyne 15 proved unsuccessful.
(16) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138-
2152.
(17) For use of this type of ring closure on intermediates containing an
enolizable aldehyde, see: (a) Tius, M. A.; Cullingham, J. M. Tetrahedron
Lett. 1989, 29, 3749-3752. (b) Kobayashi, S.; Reddy, R. S.; Sugiura, Y.;
Sasaki, D.; Miyagawa, N.; Hirama, M. J. Am. Chem. Soc. 2001, 123, 2887-
2888.
(19) (a) Wender, P. A.; Beckham, S.; Mohler, D. L. Tetrahedron Lett.
1995, 36, 209-212. (b) Mastalerz, H.; Doyle, T.; Kadow, J.; Leung, K.;
Vyas, D. Tetrahedron Lett. 1995, 36, 4927-4930.
(20) Please see Supporting Information for NMR spectra.
(21) Photoequilibration of a conjugated alkene proved very useful in
syntheses of hydroxyjatrophones A and B: Smith, A. B., III; Lupo, A. T.,
Jr.; Ohba, M.; Chen, K. J. Am. Chem. Soc. 1989, 111, 6648-6656.
(22) (a) Marshall, J. A.; Crooks, S. L.; DeHoff, B. S. J. Org. Chem.
1988, 53, 1616-1623. (b) Marshall, J. A.; Andersen, M. W. J. Org. Chem.
1992, 57, 2766-2768.
Org. Lett., Vol. 3, No. 23, 2001
3617