Synthesis of the ABC fragment of the pectenotoxins

Article abstract of DOI:10.1021/ol0507975

(Chemical Equation Presented) A highly stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing fragment 5 of PTX7 (4) has been achieved. Appendage of the C ring to the AB fragment involved Wittig reaction of spiroacetal aldehyde 8 with a stabi

Full text of DOI:10.1021/ol0507975

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2659-2662
Synthesis of the ABC Fragment of the
Pectenotoxins
Rosliana Halim, Margaret A. Brimble,* and Jo1rn Merten
Department of Chemistry, The UniVersity of Auckland, 23 Symonds Street,
Auckland, New Zealand
m.brimble@auckland.ac.nz
Received April 13, 2005
ABSTRACT
A highly stereocontrolled synthesis of the C1−C16 ABC spiroacetal-containing fragment 5 of PTX7 (4) has been achieved. Appendage of the
C ring to the AB fragment involved Wittig reaction of spiroacetal aldehyde 8 with a stabilized ylide 9 followed by displacement of allylic iodide
27 with a lithium acetylide to afford enyne 7. Fructose-derived chiral dioxirane and dihydroxylation were then used to introduce the correct
functionality in the tetrahydrofuran C ring.
The pectenotoxins (PTXs) are a family of complex mac-
rolides1 that were first isolated in 1985 by Yasumoto and
co-workers.1a PTX2 (1) (Figure 1) is produced by the
The potent biological activity of these molecules together
with their exquisitely complex structure has attracted the
attention of several research groups,5-8 notably Evans et al.9
who have reported the only total synthesis of PTX4 (2) and
PTX8 to date. We herein describe our synthesis of the C1-
C16 ABC fragment of PTXs (Scheme 1) by appendage of
the C ring to an AB spiroacetal unit.
Our approach to the synthesis of PTX7 (4) adopts a highly
convergent strategy based on the sequential addition of the
(1) (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, G. K.; Matsumoto,
J. Tetrahedron 1985, 41, 1019. (b) Murata, M.; Sano, M.; Iwashita, T.;
Naoki, H.; Yasumoto, T. Agric. Biol. Chem. 1986, 50, 2693. (c) Sasaki,
K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998, 63, 2475. (d) Suzuki,
T.; Beuzenberg, V.; Mackenzie, L.; Quilliam, M. A. J. Chromatogr. A 2003,
992, 141. (e) Miles, C. O.; Wilkins, A. L.; Samdal, I. A.; Sandvik, M.;
Petersen, D.; Quilliam, M. A.; Naustvoll, L. J.; Rundberget, T.; Torgesen,
T.; Hovgaard, P.; Jensen, D. J.; Cooney, J. M. Chem. Res. Toxicol. 2004,
17, 1423.
(2) Lee, J.-S.; Murata, M.; Yasumoto, T. Mycotoxins and Phycotoxins;
Elsevier: Tokyo, Japan, 1988; p 337.
(3) Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722.
(4) (a) Spector, I.; Braet, F.; Shochet, N. R.; Bubb, M. R. Microscop.
Res. Technol. 1999, 47, 18. (b) Leira, F.; Cabado, A. G.; Vieytes, M. R.;
Roman, Y.; Alfonso, A.; Botana, L. M.; Yasumoto, T.; Malaguti, C.; Rossini,
G. P. Biochem. Pharm. 2002, 63, 1979.
(5) (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300. (b)
Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733.
(6) (a) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937.
(b) Peng, X.; Bondar, D.; Paquette, L. A. Tetrahedron 2004, 60, 9589.
(7) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949.
(8) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849.
Figure 1. Structure of PTXs and the principal disconnections used
for the synthesis of PTXs.
dinoflagellate Dinophysis fortii and is the parent compound
of this family of toxins.2 PTX2 (1) exhibited selective and
potent cytotoxicity against several cancer cell lines at the
nanomolar level.3 PTX2 (1) and PTX6 (3) have also been
shown to interact with the actin cytoskeleton at a unique
site,4 thus providing an important research tool for the study
of basic cellular behavior.
(9) (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4569. (b) Evans, D. A.; Rajapakse, H. A.; Chiu, A.;
Stenkamp, D. Angew. Chem., Int. Ed. Engl. 2002, 41, 4573.
10.1021/ol0507975 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/02/2005

Aldehyde 11 was prepared starting with a modified11
Evans aldol reaction between propanoyloxazolidinone 1312
and known aldehyde 1413 to set up the required syn
stereochemistry (Scheme 2). Enolization of 13 with titanium
Scheme 1. Retrosynthetic Analysis of ABC Fragment 5
Scheme 2. Synthesis of C1-C7 Containing Aldehyde 11
C, D, and E rings to an initial AB spiroacetal ring system
followed by introduction of the FG fragment via Wittig
olefination before the final macrolactonization step (Figure
1).
tetrachloride followed by condensation with aldehyde 14 in
the presence of (-)-sparteine afforded the syn adduct 15 in
90% yield as a single isomer. Reductive removal of the chiral
auxiliary provided diol 16, the primary alcohol of which was
selectively protected as a TBDPS ether 17. The secondary
alcohol was then silylated to give 18. These steps proceeded
smoothly in good yield over three steps. Hydrogenolysis of
the benzyl group followed by PCC oxidation of the resulting
alcohol afforded the desired aldehyde 11 in 98% yield.
Sulfone 12 was prepared starting from (R)-(+)-benzyl-
glycidol 1914 (Scheme 3). Treatment of methyl phenyl
sulfone with n-BuLi in a mixture of THF and hexameth-
ylphosphoramide (HMPA)15 followed by addition of glycidol
19 effected regioselective ring opening of the epoxide. The
resulting alkoxide was then trapped directly with a premixed
solution of tert-butyldimethylsilyl trifluoromethanesulfonate
and 2,6-lutidine in THF to afford the required sulfone 12 in
97% yield.
Our retrosynthetic analysis of the key spiroacetal-contain-
ing ABC tricyclic fragment 5 is depicted in Scheme 1. The
ABC fragment 5 is constructed via a 5-exo-tet cyclization
of epoxy-diol 6, in which all the necessary stereogenic centers
of the C ring are already installed. Epoxy-diol 6 in turn is
obtained from enyne 7 by asymmetric epoxidation followed
by semihydrogenation and dihydroxylation. Enyne 7 is
prepared from spiroacetal aldehyde 8, stabilized ylide 9, and
acetylene 10. Finally, spiroacetal 8 is derived from the union
of aldehyde 11 with sulfone 12.
The synthesis of PTX2 (1) requires establishment of the
(7R)-configuration of the spirocenter. However, the (7S)-
configuration as present in PTX4 (2) and PTX7 (4) is
stabilized by the anomeric effect and is in fact the thermo-
dynamically favored stereochemistry when the spiroacetal
ring is not embedded in the macrocyclic structure. It was
therefore planned to obtain the natural (7R)-isomer of PTX2
(1) at a later stage in the synthesis after assembly of the
macrolide ring based on the precedent reported by Sasaki
and co-workers10 for PTX4 (2). Our initial attention was
therefore directed toward the synthesis of spiroacetal 8 with
(7S)-configuration as present in PTX7 (4).
With sulfone 12 in hand, the next step was to effect its
union with aldehyde 11 (Scheme 3). R-Deprotonation of
sulfone 12 with n-BuLi followed by addition of aldehyde
(11) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894.
(12) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(13) Bo¨rjesson, L.; Cso¨regh, I.; Welch, C. J. J. Org. Chem. 1995, 60,
2989.
(10) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998, 63,
2475.
(14) Lai, M.; Oh, E.; Shih, Y.; Liu, H. J. Org. Chem. 1992, 57, 2471.
(15) Craig, D.; Smith, A. M. Tetrahedron Lett. 1990, 31, 2631.
2660
Org. Lett., Vol. 7, No. 13, 2005

groups in the presence of the TBDPS group was achieved
by heating ketone 22 under reflux with p-toluenesulfonic acid
in toluene, resulting in clean cyclization of the resultant diol
to give the 5,6-spiroacetal 23 as a single isomer in 84% yield.
Debenzylation of 23 in the presence of Raney nickel followed
by oxidation of the resulting alcohol afforded the desired
AB spiroacetal fragment 8 in 78% yield over two steps. The
stereochemistry of the spirocenter was determined to be 7S
on the basis of NOE studies (Figure 2).
Scheme 3. Synthesis of AB Spiroketal Moiety 8
Figure 2. NOE correlations of spiroacetal 8.
The assembly of the ABC tricyclic ring system 5 com-
menced with Wittig olefination of spiroacetal aldehyde 8 with
ylide 9 (Scheme 4) in CH2Cl2 affording the desired (E)-olefin
25 (E:Z ) 100:1 by 1H NMR analysis) in quantitative yield.
Reduction of ester 25 using diisobutylaluminum hydride
(DIBAL-H) afforded allylic alcohol 26 in 91% yield.
Conversion of 26 to the iodide 27 in preparation for coupling
with acetylene 1017 was achieved via the intermediacy of
the mesylate. The unstable iodide 27 was directly coupled
with the lithium acetylide derived from 10 to afford (E)-
enyne 7 in 56% yield from alcohol 26. The undesired (Z)-
isomer was also obtained in 18% and was easily separated
from (E)-enyne 7 by flash chromatography.
11 afforded the coupled product as an inseparable mixture
of four diastereomers in 99% yield. Oxidation of the resulting
alcohols 20 to the corresponding ketones was then effected
using Dess-Martin reagent16 buffered with pyridine. Treat-
ment of the sulfone diastereomers 21 with sodium mercury
amalgam in methanol then afforded ketone 22 as a single
isomer in 88% yield. Selective deprotection of the TBDMS
Scheme 4. Completion of ABC Spiroacetal 5
Org. Lett., Vol. 7, No. 13, 2005
2661

Finally having assembled the C1-C16 carbon skeleton
7, the next step was the stereoselective introduction of the
appropriate functionality to the enyne system in order to
generate the required epoxy diol 6, which could then be
transformed into the target ABC ring fragment 5. The C11/
C12 stereogenic centers were introduced via asymmetric
epoxidation, adopting the method reported by Shi and co-
workers18 using the chiral dioxirane formed from ketone 28
and Oxone (Scheme 4) to afford the desired syn-epoxide 29.
Semireduction of the alkyne 29 over Lindlar catalyst fol-
lowed by dihydroxylation of the resulting (Z)-olefin with
osmium tetroxide afforded diol 6, which cyclized directly
to form the target ABC spiroacetal fragment 5 in 70% overall
yield.
NOE correlations observed for fragment 5 showed a
correlation between 12-Me and H-15 (Figure 3), establishing
the formation of the desired cis-tetrahydrofuran C ring.
In summary, the ABC spiroacetal fragment 5 of PTX7
(4) has been synthesized in a highly stereocontrolled manner
(19 steps, 5% overall yield from 13). The key strategy in
Figure 3. NOE correlation between 12-Me and H-15 in fragment
5.
the synthesis involved generation of the (E)-geometry across
the C11/C12 bond via Wittig olefination. The (E)-alkene was
later converted to a syn-epoxide using a Shi asymmetric
epoxidation. Dihydroxylation generated the C14/C15 diol that
immediately cyclized to afford the tricyclic ABC fragment
5 of PTX7 (4).
Acknowledgment. M. Brimble acknowledges the award
of a James Cook Research Fellowship from the Royal Society
of New Zealand.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(17) Sammelson, R. E.; Millar, R. B.; Kurth, M. J. J. Org. Chem. 2000,
65, 2225.
(18) Wang, Z.-X.; Tu, T.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(19) (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
(b) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc.
1994, 116, 1278. (c) This ligand is preferred for AD reactions using 1,2-
disubsituted cis-olefins.
Supporting Information Available: Experimental details
and spectroscopic data for compounds 24, 26, 7, and 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0507975
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Org. Lett., Vol. 7, No. 13, 2005