Enantioselective synthesis of the oxadecalin core of phomactin A via a highly stereoselective Diels-Alder reaction

Article abstract of DOI:10.1021/ol0161357

matrix presented Phomactin A (1) is a selective antagonist of platelet activating factor (PAF). Herein, we report our progress toward the construction of the oxadecalin core of 1. This route is based on the Diels-Alder cycloaddition of an appropriately fu

Full text of DOI:10.1021/ol0161357

ORGANIC
LETTERS
2001
Vol. 3, No. 19
2949-2951
Enantioselective Synthesis of the
Oxadecalin Core of Phomactin A via a
Highly Stereoselective Diels−Alder
Reaction
Sherry R. Chemler, Ulrich Iserloh, and Samuel J. Danishefsky*
Laboratory of Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research,
1275 York AVenue, Box 106, New York, New York 10021, and Department of
Chemistry, Columbia UniVersity, HaVemeyer Hall, New York, New York 10027
s-danishefsky@ski.mskcc.org
Received May 17, 2001
ABSTRACT
Phomactin A (1) is a selective antagonist of platelet activating factor (PAF). Herein, we report our progress toward the construction of the
oxadecalin core of 1. This route is based on the Diels−Alder cycloaddition of an appropriately functionalized vinyl pyran and a complementary
dienophile. A model of this reaction involving 2 and maleic anhydride was conducted. Adduct 3 contains the correct stereochemical arrangements
between functional groups necessary for gaining access to phomactin A.
Phomactin A (1), isolated from the marine fungus Phoma
sp. by Sugano and co-workers in 1991, is a selective
antagonist of platelet activating factor (PAF), 1-O-alkyl-2(R)-
(acetylglyceryl)-3-phosphorylcholine.1 Agent 1 is one of the
most structurally complex members of a class of related
compounds, phomactins A-G.2 PAF-mediated signaling has
been implicated in a variety of biological effects that include
platelet aggregation, hypotension, smooth muscle contraction,
and vascular permeability.3 PAF is also implicated as a
causative factor in septic shock and inflammatory, respira-
tory, and cardiovascular diseases.4
Aside from the biology-driven incentives, a total synthesis
exercise directed at phomactin A offers an attractive testing
ground for exploring and evaluating strategy level initiatives.
Indeed, several groups have reported approaches toward the
synthesis of phomactin A (for the moment in racemic form).
However, a solution to the problem has not yet been
described.5 Approaches toward phomactin D have also been
described, and an enantioselective total synthesis of this
molecule has been achieved.6
Phomactin A contains six stereogenic centers in its
oxadecalin core. An additional ansa-like bridge connects the
(4) (a) Heuer, H. Lipids 1991, 26, 1369-1373. (b) Bazen, N. G.; Squinto,
S. P.; Branquet, P.; Panetta, T.; Marchelselli, V. L. Lipids 1991, 26, 1236-
1242. (c) Uchiyama, S.; Yamazaki, M.; Maruyama, S. Lipids 1991, 26,
1280-1282. (d) Chung, K. F.; Barnes, P. J. Lipids 1991, 26, 1277-1279.
(e) Page, C. P. Lipids 1991, 26, 1280-1282. (f) Godfroid, J. J.; Dive, G.;
Lamotte-Brasseur, J.; Batt, J. P.; Heymans, F. Lipids 1991, 26, 1162-1166.
(g) Lamotte-Brasseur, J.; Heymans, F.; Dive, G.; Lamouri, A.; Batt, J. P.;
Redeuilh, C. Lipids 1991, 26, 1167-1171.
(5) (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) Mi, B.; Maleczka, R. E., Jr. Org. Lett. 2001, 3, 1491-1494. (d) Foote,
K. M.; John, M.; Pattenden, G. Synlett 2001, 3, 365-368.
(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.; 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.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188.
(c) Chu, M.; Patel, M. G.; Gullo, V. P.; Truumees, I.; Puar, M. S.; McPhail,
A. T. J. Org. Chem. 1992, 57, 5817-5818.
(3) (a) Koltai, M.; Braquet, P. G. Clin. ReV. Allergy 1994, 12, 361-
380. (b) Goldstein, R. E.; Feuerstein, G. Z.; Bradley, L. M.; Stambouly, J.
J.; Laurindo, F. R. M.; Davenport, N. J. Lipids 1991, 26, 1250-1256. (c)
Rabinovici, R.; Yue, T.-L.; Feuerstein, G. Lipids 1991, 26, 1369-1373.
10.1021/ol0161357 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

Scheme 2
Figure 1.
C(6) quaternary carbon and the C(2) tertiary ether in a 12-
membered macrocycle. Recently we described a transannular
macrocyclization method that uses the B-alkyl Suzuki-
Miyaura reaction to illustrate a C(sp3)-C(sp2) bond forming
event.7 This method may well find application in the closure
of a seco phomactin A structure, possibly through the C(4′)-
C(5′) bond.
In this letter we describe our efforts directed toward the
formation of the oxadecalin core of phomactin A. We
envisioned a rather direct entry into this system via a Diels-
Alder reaction between an appropriately functionalized diene
of type 4 and an appropriately matched dienophile (cf. 5)
(Scheme 1). Such a cycloaddition could potentially install
Scheme 1
enantiomer of 8 is reported in the literature.10 Oxidation of
pyrone 9 with Pb(OAc)4 in refluxing benzene11 afforded a
chromatographically separable 1:1 mixture of diastereomeric
acetates 10 and 11 where 11 contains the correct relative
configuration (C(3) phomactin A stereocenter). Additional
quantities of 11 were obtained through an epimerization
protocol, whereby acetate 10 was converted to a 1.4:1
mixture of 10 and 11 (cat. DBU, pyridine, CH2Cl2, reflux).
Iodination of 11 afforded vinyl iodide 12. Reduction of the
ketone functionality of 12 under Luche conditions12 afforded
a mixture of acetylated regioisomeric alcohols. Treatment
of this material with K2CO3 in 95% EtOH then afforded diol
13, contaminated with ca. 10% of a diastereomer, presumably
arising from the reduction step. Protection of the less
hindered alcohol of 13 as its TBDPS ether, followed by
reduction of the ester functionality led to 14.
the C(6), C(7) ,and C(8a) stereogenic centers, as well as the
C(5a)-C(8b) endocyclic olefin of phomactin A.8
Synthesis of the oxadecalin core began with the cyclo-
condensation reaction between trans-1-methoxy-3-(trimethyl-
silyloxy)-1,3-butadiene (7) and ethyl pyruvate in the presence
of the catalyst formed from 2,2′-isopropylidenebis[(4S)-4-
tert-butyl-2-oxazoline] (8) and Cu(OTf)2 (Scheme 2).9 As
reported by Jørgensen, this transformation is highly efficient
and enantioselective. To date, we have used the commercially
available ligand 8, which is enantiomeric to that required
for a synthesis of phomactin A. Synthesis of the required
(6) (a) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett.
1996, 37, 7107-7110. (b) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000,
2, 2687-2690.
(7) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695-2698.
(8) It should be noted that our Diels-Alder disconnection is comple-
mentary to Totah’s approach toward the oxadecalin core of phomactin A.
Totah’s Diels-Alder disconnection of the oxadecalin core is based on the
condensation of an electron-deficient pyrone with an electron-rich diene:
ref 5b and (a) Chen, D.; Wang, J.; Totah, N. I. J. Org. Chem. 1999, 64,
1776-1777. (b) Seth, P. P.; Chen, D.; Wang, J.; Gao, X.; Totah, N. I.
Tetrahedron 2000, 56, 10185-10195.
(10) (a) Adger, B. M.; Dyer, U. C.; Lennon, I. C.; Tiffin, P. D.; Ward,
S. E. Tetrahedron Lett. 1997, 38, 2153-2154. (b) Viret, J.; Patzelt, H.; Collet,
A. Tetrahedron Lett. 1986, 27, 5865-5868.
(11) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1995; Vol. 5, pp 2949-2954.
(12) (a) Danishefsky, S. J.; Bednarski, M. Tetrahedron Lett. 1985, 26,
3411-3412. (b) Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101,
5848-5849.
(9) Yao, S.; Johannsen, M.; Audrain, H.; Jørgensen, J. A. J. Am. Chem.
Soc. 1998, 120, 8599-8605.
2950
Org. Lett., Vol. 3, No. 19, 2001

1
The intermediate diol 14 was converted to the silylene
acetal 15 by treatment with a premixed solution of (i-Pr)2Si-
(OTf)2 and 2,6-lutidine. This protecting group was specifi-
cally chosen to enforce a rigid conformation about the pyran
ring wherein the trans-fused ring junction would force the
OTBDPS and the Me groups to adopt axial positions. We
hoped that such a conformer would bias the face selectivity
of the subsequent Diels-Alder reaction. Diene 2 was
fashioned from 15 via Stille coupling13 with vinylstannane
16 followed by protection of the resulting terminal alcohol
as its TBS ether.
selectivity (no other isomer observed by H NMR analysis
at 400 MHz). This result can be rationalized via transition
state 20.16
Some literature precedent existed for the thermal Diels-
Alder reactions between pyran-based alkoxy-dienes and
various dienophiles.12,14 In these reactions, endo addition is
highly favored with substrates such as maleic anhydride.
Additionally, facial selectivity is highly influenced by the
configuration of the C(3) alkoxy group. In these cycloaddi-
tions, the product distribution is consistent with approach
of the dienophile from the face opposite to that group. For
instance, Hayashi and co-workers have reported the reaction
of 17 with maleic anhydride, where adduct 18 is favored
over 19 (5:1).13
The stereochemistry of 3 was assigned by two-dimensional
1H NMR analysis (NOESY). It will be noted that adduct 3
codes for a 1,3-syn relationship between the future C(8a)
hydrogen and the C(2) methyl substitutents of phomactin
A.
We are now well positioned to explore more advanced
diene substrates in conjunction with dienophiles that are more
appropriately functionalized for reaching phomactin A. Our
progress along these lines will be reported.
Acknowledgment. NIH Postdoctoral Fellowship support
is gratefully acknowledged by S.R.C. (AI10439-01) and U.I.
(CA88478-01AI). This work was also supported by NIH
grants to S.J.D. (AI16943 and CA28824).
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0161357
The origin of the strong biasing effect of the C(3)
substituent is thought to be stereoelectronic in nature.
Presumably, the alkoxy group adopts a pseudoaxial position
on the pyran ring in the Diels-Alder transition state.
HoweVer, no examples of Diels-Alder reactions with dienes
fully substituted at C(5) haVe been reported.15
(15) It should be noted that the Diels-Alder reaction of 21 with maleic
anhydride is unselective, thus indicating that conformational constraint is
necessary for achieving facial selectivity.
In the event, Diels-Alder reaction between 2 and maleic
anhydride took place at 23 °C and with complete stereo-
(13) Hayashi, M.; Tsukada, K.; Kawabata, H.; Lamberth, C. Tetrahedron
1999, 55, 12287-12294.
(14) (a) Sun, K. M.; Fraser-Reid, B. J. Am. Chem. Soc. 1982, 104, 367-
369. (b) Sun, K. M.; Giuliano, R. M.; Fraser-Reid, B. J. Org. Chem. 1985,
50, 4774-4780. (c) Giuliano, R. M.; Buzby, J. H. Carbohydr. Res. 1986,
158, C1-C4. (d) Lopez, J. C.; Lameignere, E.; Lukacs, G. J. Chem. Soc.,
Chem. Commun. 1988, 706-707. (e) Lipshutz, B. H.; Nguyen, S. L.;
Elworthy, T. R. Tetrahedron 1988, 44, 3355-3364. (f) Burnouf, C.; Lopez,
J. C.; Calvo-Flores, F. G.; de los Angeles Laborde, M.; Olesker, A.; Lukacs,
G. J. Chem. Soc., Chem. Commun. 1990, 823-825. (g) Giuliano, R. M.;
Jordan, A. D., Jr.; Gauthier, A. D.; Hoogsteen, K. J. Org. Chem. 1993, 58,
5979-5988.
1
(16) By H NMR analysis, the conversion of 2 to 3 is very clean. We
suspect the moderate isolated yield may be the result of partial decomposi-
tion of 3 during chromatography on SiO2, perhaps due to the sensitive
anhydride moiety.
Org. Lett., Vol. 3, No. 19, 2001
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