A convergent total synthesis of the macrolactone disaccharide toxin (- )-polycavernoside A

Full text of DOI:10.1021/ja990384x

4542
J. Am. Chem. Soc. 1999, 121, 4542-4543
triethylsilane in the presence of SnCl4 to give 3 (Scheme 1). This
methodology served to orient the allyl substituent equatorially in
a highly diastereoselective manner. Once the conversion of 3 to
4 was achieved, the iodide was formed10 and subjected to
displacement with lithiated methyl phenyl sulfone to deliver 5.
Attention was simultaneously directed toward elaborating 66
into the companion electrophilic partner. Reduction with lithium
borohydride generated the related diol, which was pivaloylated
as in 7 and subsequently converted efficiently into aldehyde 8.
Wittig olefination of this intermediate followed by asymmetric
dihydroxylation of the terminal olefin11 expectedly set the
appropriate C15 stereochemistry in 9 under reagent control. The
next transformation required was the fully regioselective introduc-
tion of two different silyl-protecting groups. Once 10 was in hand,
the pivaloyl functionality was reductively cleaved with Dibal-H
to deliver a primary alcohol whose perruthenate oxidation12
afforded the desired fully elaborated aldehyde 11. Condensation
of the lithium salt of 5 with 11 in THF at -78 °C gave rise to an
alcohol which was directly oxidized with the Dess-Martin
periodinane reagent13 to provide 12.
At this stage, the key question centered around the timing of
the steps that would lead most efficaciously to 1. Although many
pitfalls were uncovered,14 it did prove practical to deprotect the
C15 hydroxyl in advance of cleavage of the allylic double bond
(Scheme 2). This two-step sequence furnished 13, making possible
chemoselective oxidation of the aldehyde with buffered sodium
chlorite15 and macrocyclization under modified Yamaguchi condi-
tions.16 Interestingly, the macrolactone 14 was produced as a
single diastereomer at C9 as a consequence of concomitant enolate
equilibration. Subsequent exposure of 14 to the HF‚pyridine
reagent served to unmask the primary hydroxyl and enable the
advanced aldehyde 15 to be generated. When this compound was
added to an excess of the Takai reagent,18 stereoselective
iodovinylation as in 16 was achieved without detectable epimer-
ization at C15. This newly introduced functionality proved to be
adequately robust to withstand the conditions needed for the
oxidative desulfonylation19 of 16 to deliver the requisite R-dike-
tone intermediate, as well as the DDQ oxidation20 that made
possible the arrival at 17. The five-membered cyclic acetal was
produced exclusively within the usual limits of spectroscopic
detection. The stereochemical assignment to C10 in 17 was
advanced on the basis of the strong NOE interaction illustrated
which parallels that found in 1.
A Convergent Total Synthesis of the Macrolactone
Disaccharide Toxin (-)-Polycavernoside A
Leo A. Paquette,* Louis Barriault, and Dmitri Pissarnitski
EVans Chemical Laboratories
The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed February 8, 1999
Polycavernoside A (1) was isolated in 19931 from a frequently
ingested red alga that had suddenly developed seasonally de-
pendent lethal properties.2 Identification of the gross structural
features of the causative toxin as a macrolide disaccharide was
accomplished through recourse to detailed NMR analysis.1 Arrival
at its absolute stereochemistry awaited the independent synthesis
of the D-fucose-L-xylose subunit by the Murai3 and Paquette
groups4 and additional preliminary synthetic efforts in both
laboratories.5,6 Reinforcement was derived by the application of
the Celmer model of macrolide stereostructure7 to the unraveled
form of the macrolactone.6 The recently disclosed total synthesis
of 1 by Murai8 demonstrated the previous deductions to be correct.
We describe herein our independent successful development of
a stereoselective protocol for the expeditious construction of this
structurally unique substance.
Our retrosynthetic analysis of polycavernoside A took early
cognizance of the acyloxy triene unit in the northeastern quadrant.
This undoubtedly sensitive functionality was destined therefore
to be introduced late in the synthesis via an appropriate coupling
reaction at the indicated site. Beyond reliance on the cyclization
of a fully elaborated seco acid and stereoselective glycosidation,
the critical C9-C10 bond that interlinks a selectively masked
R-diketone would require early assembly under conditions that
would not promote â-elimination with cleavage of the tetrahy-
dropyran ring. We had previously determined that 1,3-dithiane
technology cannot be satisfactorily applied here,6 and recourse
to a sulfonyl anion alternative was therefore projected.
Completion of the synthesis involved the NBS-promoted
glycosidation21 with the activated disaccharide 18.22 The protocol
(10) Garegg, P. G.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(11) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(12) Ley, S. V.; Norman, J.; Griffith, W. P. Marsden, S. P. Synthesis 1994,
639.
To this end, lactone 2, which is readily available from L-malic
acid,9 was treated with 3 equiv of allylmagnesium bromide at
-78 °C, and the resulting lactol was directly reduced with
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland, R. E.;
Liu, L. B. J. Org. Chem. 1993, 58, 2899.
(14) The unsuccessful approaches examined include oxidative desulfony-
lation in advance of macrolactonization and oxidative desulfonylation after
cyclization but prior to glycosidation and introduction of the trienyl side chain.
These instructive findings will be detailed in the full paper.
(15) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(16) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Tone, H.; Horita, K.;
Yonemitsu, O. Tetrahedron 1990, 46, 4613.
(1) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 1147.
(2) Haddock, R. L.; Cruz, O. L. T. Lancet 1991, 338, 195.
(3) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 191.
(4) Johnston, J. N.; Paquette, L. A. Tetrahedron Lett. 1995, 36, 4341.
(5) (a) Hayashi, N.; Mine, T.; Fujiwara, K.; Murai, A. Chem. Lett. 1994,
2143. (b) Fujiwara, K.; Amano, S.; Oka, T.; Murai, A. Chem. Lett. 1994,
2147. (c) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 855.
(6) (a) Paquette, L. A.; Pissarnitski, D.; Barriault, L. J. Org. Chem. 1998,
63, 7389. (b) Johnston, J. N. Ph.D. Dissertation, The Ohio State University,
1998.
(17) Williams, D. R.; Robinson, L. A.; Amato, G. S.; Osterhout, M. H. J.
Org. Chem. 1992, 57, 3740.
(18) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(19) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.;
Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.
(20) Lee-Ruff, E.; Ablenas, F. J. Can. J. Chem. 1989, 67, 699.
(21) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430.
(7) Celmer, W. D. Pure Appl. Chem. 1971, 28, 413.
(8) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am.
Chem. Soc. 1998, 120, 10770.
(9) Fukui, M.; Okamoto, S.; Sano, T.; Nakata, T.; Oishi, T. Chem. Pharm.
Bull. 1990, 38, 2890.
(22) Prepared by TBS f PMB exchange of the previously described sugar.4
10.1021/ja990384x CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/27/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4543
Scheme 1a
a CH2dCHCH2MgBr, THF, -78 °C. b Et3SiH, SnCl4, CH2Cl2, -78 °C f 20 °C. c NaH, BnBr, NaI, THF, reflux. d TBAF, THF. e Ph3P, I2, imid,
C6H6. f LiCH2SO2Ph, THF, HMPA, rt. g LiBH4, ether, CH3OH. h PvCl, py, CH2Cl2. i 4-CH3OC6H4CH2OC(dNH)CCl3, (TfOH), ether. j Swern. k Ph3PdCH2,
THF. l OsO4, (DHQ)2PYR, K3Fe(CN)6, K2CO3, tert-BuOH, H2O, 0 °C. m TBDPSCl, imid, THF. n TESCl, imid, DMAP, DMF. o (i-Bu)2AlH, THF, -30
°C. p TPAP, NMO, 4 Å MS, CH2Cl2. q n-BuLi, 5, THF, -78 °C. r Dess-Martin periodinane, CH2Cl2.
Scheme 2a
a (TsOH), CH3OH, CH2Cl2. b OsO4, NMO, THF, H2O; NalO4. c NaClO2, NaH2PO4, 2-methyl-2-butene, tert-BuOH, H2O, 0 °C. d 2,4,6-Cl3C6H2COCl,
Et3N, THF, 25 °C. e DMAP, toluene, 110 °C. f Hf‚py, THF, py. g Dess-Martin periodinane, CH2Cl2. h CrCl2, CHl3, THF. i KO-tert-Bu, Davis oxaziridine,
THF, 0 °C. j DDQ (excess), CH2Cl2, H2O. k NBS, 4 Å MS, 18, CH3CN, -20 °C f 0 °C. l PdCl2(CH3CN)2, 19, DMF, rt, 4 h.
delivered exclusively the â-anomer in 49% yield at 50% conver-
sion. Deprotection of the glycoside with DDQ proceeded unevent-
fully. Recourse was made to Stille coupling23 in order to complete
the synthesis. The first indications that this step would be more
difficult than usual came from the lack of success realized in
promoting carbon-carbon formation to dienylstannane 1924 with
a negative optical rotation, [R]25D -34.5 (c 0.06, CH3CN), in close
accord with the reported value was recorded.28 Finally, we call
attention to the fact that the late-stage conjoining of 17, 18, and
19 might well be exploited to prepare new analogues of 1 for
biological evaluation.
Acknowledgment. This contribution is dedicated to the memory of
Donald L. Fields, a true scientific innovator and loyal friend. This research
was made possible by financial support from Eli Lilly and Company.
L.B. is the recipient of a postdoctoral fellowship from the Ministe`re de
l′Enseignement Supe´rieure et de la Science (FCAR, Que´bec, Canada).
Pd2(dba)3/AsPh3 or various Cu(I) salts.26 However, when
25
recourse was made to bis(acetonitrile)dichloropalladium(II) in
DMF at 25 °C,27 the target 1 was obtained exclusively in 80%
yield. The fully synthetic material was identified by direct
1
comparison of its 500 MHz H and 125 MHz 13C NMR spectra
Supporting Information Available: Spectroscopic data for the
advanced intermediates 5, 11-17 and 1, procedural details for the
macrocyclization, glycosidation, and Stille coupling steps, and copies of
the 1H and 13C NMR spectra of synthetic and natural (-)-1 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
in CD3CN to those of authentic polycavernoside A. In addition,
(23) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(24) Prepared by halogen-metal exchange of the iodide8 with tert-
butyllithium and condensation with tri-n-butylchlorostannane.
(25) Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.;
Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237.
(26) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(27) Nicolaou, K. C.; He, Y.; Roschangar, F.; King, N. P.; Vourloumis,
D.; Li, T. Angew. Chem., Int. Ed. 1998, 37, 84.
JA990384X
(28) The [R]D of natural 1 has been reported as -59 (c 0.012, CH3CN) at
22 °C.