Total Synthesis of (+)-zampanolide

Full text of DOI:10.1021/ja012220y

12426
J. Am. Chem. Soc. 2001, 123, 12426-12427
Scheme 1
Total Synthesis of (+)-Zampanolide
Amos B. Smith, III,* Igor G. Safonov, and R. Michael Corbett
Department of Chemistry, UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed September 24, 2001
In 1996 Tanaka and Higa reported the isolation, partial structure
elucidation, and biological activity of (-)-zampanolide, an
architecturally novel macrolide from the Okinawan sponge
Fasciospongia rimosa (Scheme 1).1 Key structural elements
include the highly unsaturated framework and the uncommon
N-acyl hemiaminal side chain.2 Adding to the structural complex-
ity, only the relative stereochemistry between C(11), C(15), and
C(19) had been assigned. Although the extreme scarcity of (-)-
zampanolide precluded a comprehensive evaluation of the bio-
logical profile, the impressive cytotoxicity against P388, HT29,
A549, and MEL28 cell lines (IC50 1-5 ng/mL), in conjunction
with the interesting architecture, prompted us to launch a synthetic
program targeting this metabolite. Herein, we disclose the first
total synthesis and tentative stereochemical assignment of the
nonnaturally occurring antipode, (+)-zampanolide (1).
Scheme 2
Retrosynthetically, disconnections of 1 at the amide, the
macrolide, and the C(2-3), C(8-9), and C(17-18) linkages gave
rise to fragments C(3-8) A, C(9-17) B, C(18-20) C, and C(1′-
6′) D. In the forward direction, we envisioned construction of
the macrolide via Kocienski-Julia olefination3 of aldehyde A with
sulfone B, followed in turn by nucleophilic opening of epoxide
C with a higher-order cuprate4 derived from AB, incorporation
of a C(1-2) acyl phosphonate, and intramolecular Horner-
Emmons macrocyclization.5 Highlights of the closing stage of
the synthesis would then entail installation of the N-acyl hemi-
aminal moiety via a stereospecific Curtius rearrangement6 of
R-alkoxy acid 2 followed by acylation with acid chloride D.
To assemble fragment B we elected the Petasis-Ferrier
rearrangement,7 recently established in our laboratory as a
powerful, stereocontrolled entry to cis-2,6-disubstituted tetrahy-
dropyrans.8 Toward this end, Brown asymmetric allylation9 of
aldehyde 310 (Scheme 2) followed in turn by TES protection of
the hydroxyl and ozonolysis afforded (+)-4, which upon oxida-
tion11 and desilylation led to â-hydroxy acid (-)-5 (57% yield,
five steps). Bis-silylation12 followed by union with (2E)-3-
Scheme 3
(1) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535. (b) For a related
structure see: Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus,
C.; Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.
(2) For other natural products possessing the N-acyl hemiaminal functional-
ity, see: (a) Benz, F.; Knu¨sel, F.; Nu¨esch, J.; Treichler, H.; Voser, W.; Nyfeler,
R.; Keller-Schierlein, W. HelV. Chim. Acta 1974, 57, 2459. (b) Umezawa,
H.; Kondo, S.; Iinuma, H.; Kunimoto, S.; Ikeda, Y.; Iwasawa, H.; Ikeda, D.;
Takeuchi, T. J. Anitibiot. 1981, 34, 1622.
bromobut-2-enal13 promoted by TMSOTf 14 furnished dioxanone
(+)-6 in 82% overall yield [10:1 at C(15)]. Methylenation with
the Petasis-Tebbe reagent15 then furnished the corresponding enol
ethers [72% yield, 6:1 at C(15)], which upon treatment with
Me2AlCl8 underwent the desired Petasis-Ferrier rearrangement7
to deliver cis-pyranone (+)-7 in 59% yield.16 Ketone methylena-
tion, desilylation, incorporation of the thiotetrazole via Mitsunobu
reaction,17 and oxidation18 proceeded smoothly to afford sulfone
(-)-B (62% yield, 4 steps).
(3) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(4) (a) Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J. Organomet. Chem. 1985, 285, 437. (b) Smith, A. B., III;
Friestad, G. K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima, M.; Qiu,
Y.; Spoors, P. G.; Bertounesque, E.; Salvatore, B. A. J. Org. Chem. 1998,
63, 7596.
(5) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem. Soc. 1982,
104, 2030.
(6) (a) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421. (b)
Hoffmann, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34, 7903.
(7) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141.
(8) Smith, A. B., III; Verhoest, P. V.; Minbiole, K. P.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123, 4834 and references therein.
(9) Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem. 1991, 63, 307.
(10) Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H.
J. Am. Chem. Soc. 1987, 109, 7553.
Construction of subunits A and C was achieved as outlined in
Scheme 3.19 Noteworthy is the stereoselective20 installation of
the C(4-5) olefin in subtarget A.
With the requisite subtargets in hand, assembly of the macrolide
began with the Kocienski-modified3 Julia olefination21 of aldehyde
(13) Prepared by oxidation of (2E)-3-bromobut-2-enol with PCC in 79%
yield. For preparation of the latter see: Corey, E. J.; Bock, M. G.; Kozikowski,
A. P.; Rama Rao, A. V.; Floyd, D.; Lipshutz, B. Tetrahedron Lett. 1978, 19,
1051.
(14) Seebach, D.; Imwinkelried, R.; Stucky, G. HelV. Chim. Acta 1987,
70, 448.
(11) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(12) Harada, T.; Yoshida, T.; Kagamihara, Y.; Oku, A. J. Chem. Soc.,
Chem. Commun. 1993, 1367.
10.1021/ja012220y CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/14/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 49, 2001 12427
Scheme 4
rearrangement. Exposure of (-)-2 in turn to Hu¨nig’s base,
i-BuOCOCl, and aqueous NaN3 a´ la Weinstock,25 followed by
thermal rearrangement and capture of the isocyanate with 2-(tri-
methylsilyl)-ethanol provided carbamate (-)-14 in 75% overall
yield, with complete transfer of the C(20) stereogenicity.6
Acylation26 with acid chloride D27 then afforded (-)-15 in 58%
yield, possessing the complete carbon skeleton of zampanolide.
Iterative removal of the Teoc and TBS moieties,28 and oxidation
of the C(7) hydroxyl gave ketone (+)-16 as a single compound
in 75% yield (three steps). Oxidative removal of the PMB moiety
then produced a mixture (1.3:1) of two polar compounds epimeric
at C(20). After separation, the major, less polar component, (+)-
1, possessed spectral data identical in all respects to natural (-)-
1
zampanolide (e.g., 500 MHz H NMR, 125 MHz 13C NMR,
COSY, HMQC, HRMS, and IR), except for chiroptic properties.
The structure of (+)-17, epimeric only at C(20), was secured via
the NMR, HRMS, and IR data.
Unable to prevent erosion of the stereogenicity at C(20) upon
deprotection of (+)-16 and thereby assign the relative stereo-
chemistry with certainty, we reasoned that PMB reprotection, in
conjunction with spectroscopic correlation with (+)-16 having
known stereogenicity at C(20), would provide a viable solution
to this dilemma. After extensive experimentation, reprotection of
(+)-1 exploiting the Hanessian protocol29 under carefully buffered
conditions afforded (+)-16 and (+)-C(20)-epi-16 with good
stereocontrol (1:7.6). In similar fashion, (+)-17 afforded (+)-16
and (+)-C(20)-epi-16 (3.7:1). With these results, the relative and
absolute stereochemistry of (+)-zampanolide (1) can be tentatively
assigned as 11R, 15R, 19R, and 20R.
In summary, the first total synthesis of (+)-zampanolide (1)
has been achieved. Key elements of the synthesis include efficient
use of the Petasis-Ferrier rearrangement to construct the cis-
2,6-disubstituted tetrahydropyran and a stereospecific Curtius
rearrangement to set the C(20) stereogenicity.
Acknowledgment. Support was provided by the National Institutes
of Health (National Cancer Institute) through Grants CA-19033 and a
postdoctoral fellowship (CA-80337) to R.M.C.
Supporting Information Available: Spectroscopic and analytical data
for compounds A, B, C, AB, ABC, 1, 2, 4-8, 10, 12-17 and selected
experimental procedures (PDF). This information is available free of
charge via the Internet at http://pubs.acs.org.
JA012220Y
(16) The minor trans-pyranone was isolated in 12% yield after chroma-
tography. The gradual decay in the cis/trans ratio [(+)-6f(+)-7] is partially
attributed to harsh reaction conditions.
(17) Mitsunobu, O. Synthesis 1981, 1.
(18) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
(19) For preparation of (-)-9 see: Oizumi, M.; Takahashi, M.; Ogasawara,
K. Synlett 1997, 1111. For preparation of (+)-11 see: Somfai, P.; Olsson, R.
Tetrahedron 1993, 49, 6645.
(20) Corey, E. J.; Katzenellenbogen, J. J. Am. Chem. Soc. 1969, 91, 1851.
(21) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175.
(22) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(23) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(24) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(+)-A (Scheme 4) with sulfone (-)-B to provide vinyl bromide
(-)-AB as the sole C(8-9) olefin isomer (88% yield). Union of
(-)-AB with epoxide (+)-C was then achieved through aegis of
a higher-order cuprate.4 Initially, low yields resulted due to the
extreme sensitivity of the cuprate to adventitious oxygen.
Scrupulous deoxygenation with Oxiclear favorably reflected on
the yield of (-)-ABC. Introduction22 of the C(1-2) acyl phos-
phonate at C(19), selective desilylation (HF‚Pyr) at C(3), and
Dess-Martin oxidation23 then led to (-)-12, substrate for Horner-
Emmons macrocyclization.5 To our delight, the latter proceeded
in 72% yield to furnish (+)-13.
(25) Weinstock, J. J. Org. Chem. 1961, 26, 3511; also see: Overman, L.
E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164.
(26) (a) Roush, W. R.; Pfeifer, L. A. J. Org. Chem. 1998, 63, 2062. (b)
Roush, W. R.; Pfeifer, L. A.; Marron, T. G. J. Org. Chem. 1998, 63, 2064.
(27) Prepared in one step from 2Z,4E-hexa-2,4-dienoic acid. For preparation
of the latter see: Crombie, L.; Crombie, W. M. L. J. Chem. Soc., Perkin
Trans. 1 1994, 1267.
Selective24 removal of the DMB ether (DDQ) and a two-step
oxidation then produced (-)-2, the requisite acid for Curtius
(28) One-pot global desilylation gave a substantially lower yield.
(29) Hanessian, S.; Huynh, H. K. Tetrahedron Lett. 1999, 40, 671.
(15) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.