Access to both anomers of pectenotoxin spiroketals by kinetic spiroketalization

Article abstract of DOI:10.1021/ol048321t

A concise synthesis of both AB ring spiroisomers of the pectenotoxins is described. The nonanomeric AB spiroketal ring system of the pectenotoxins-1, -2, -3, and -6 is formed under very mild, kinetic spiroketalization conditions, along with the anomeric i

Full text of DOI:10.1021/ol048321t

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3849-3852
Access to Both Anomers of
Pectenotoxin Spiroketals by Kinetic
Spiroketalization
Petri M. Pihko* and Jatta E. Aho
Laboratory of Organic Chemistry, Helsinki UniVersity of Technology, P.O.B. 6100,
FI-02015 HUT, Finland
petri.pihko@hut.fi
Received August 23, 2004
ABSTRACT
A concise synthesis of both AB ring spiroisomers of the pectenotoxins is described. The nonanomeric AB spiroketal ring system of the
pectenotoxins-1, -2, -3, and -6 is formed under very mild, kinetic spiroketalization conditions, along with the anomeric isomer. Only catalytic
asymmetric transformations were used as the source of chirality in the synthesis route.
The pectenotoxins (PTX) comprise a family of marine natural
products isolated from scallops Patinopecten yessoensis. The
first members of the family were isolated and characterized
by Yasumoto and co-workers in 1985;1 in subsequent studies,
a total of 10 PTX toxin congeners have been found.2 The
compounds have drawn considerable attention as a result of
their significant cytotoxicity against a variety of lung, colon,
and breast cancer cell lines and their still largely unknown
mode of action. PTX-2 and PTX-6 are known to interact
with the actin cytoskeleton at a unique site, effecting
depolymerization of F-actin.3
(Figure 1). Synthetic efforts toward the pectenotoxins have
been reported by the Murai,4 Roush,5 and Paquette6 groups,
Structurally, the pectenotoxins share a common carbon
skeleton, and the different congeners differ from each other
in the C7 spiro geometry and in the oxidation state of C43
(1) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto, G.
K.; Clardy, J. Tetrahedron 1985, 41, 1019-1025.
(2) (a) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998,
63, 2475-2480. (b) Daiguji, M.; Satake, M.; James, K. J.; Bishop, A.;
Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem. Lett. 1998, 7, 653-654.
(3) (a) Spector, I.; Braet, F.; Schochet, N. R.; Bubb, M. R. Microscop.
Res. Technol. 1999, 47, 18-37. (b) Leira, F.; Cabadon, A. G.; Vieytes, M.
R.; Roman, Y.; Alfonso, A.; Botana, L. M.; Yasumoto, T.; Malaguti, C.;
Rossini, G. P. Biochem. Pharmacol. 2002, 63, 1979-1988.
Figure 1. Structures of the pectenotoxins.
10.1021/ol048321t CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/11/2004

culminating in the recent total synthesis of PTX-4 and its
conversion to PTX-8 by Evans and co-workers.7
a highly stereoselective access to the (Z)-allylic alcohol 17
(Scheme 2). In recent studies, we have reported9 an improved
The C7 spiro configuration of PTX-1, PTX-2, PTX-3, and
PTX-6, the major and the most cytotoxic toxins of the
pectenotoxin family, is R, corresponding to a spiroketal with
no anomeric stabilization (Figure 2). To date, studies
Scheme 2
Figure 2. AB spiroketal segments of PTX-1-7.
protocol for (Z)-olefination of alkenes using the Ando
phosphonate10 and a combination of NaH/NaI as the base.
Starting from the known11 aldehyde 15 (prepared in two steps
and 75% overall yield from 1,5-pentanediol), the Horner-
Wadsworth-Emmons olefination using our conditions gave
the (Z)-enoate 16 in 85% yield and 97:3 Z:E selectivity
(Scheme 2). The remaining (E)-isomer was readily removed
by flash chromatography. Subsequent DIBAL-H reduction
gave the pure (Z)-allylic alcohol 17 in 94% yield.
addressing the synthesis of this structurally challenging
subunit have not been reported. Herein, we report an
asymmetric synthesis of the C1-C11 AB spiroketal segment
of the pectenotoxins that provides access to both spiroketal
isomers via a kinetically controlled spiroketalization. Im-
portantly, all stereocenters present in the C1-C11 segment
are created by catalytic asymmetric transformations.
The Katsuki-Sharpless asymmetric epoxidation protocol
gave the epoxide 18 in 60-72% yield and 75-83% ee. Ring
opening of the cis epoxide with higher order cuprate12 and
subsequent cleavage of the 1,2-diol side product13 (ca 25%)
with NaIO4 gave the crystalline diol 19 (Scheme 3).
Retrosynthetically, the C1-C11 spiroketal segment could
be envisioned to arise from the corresponding A ring building
block 13 (Scheme 1) by Grignard addition and asymmetric
Scheme 1. Retrosynthetic Analysis of the AB Ring Segment
Scheme 3
dihydroxylation. For setting up the C2-C3 syn stereochem-
istry, we decided to employ a sequence of Katsuki-Sharpless
asymmetric epoxidation8 and regioselective epoxide ring
opening with a higher order cuprate. This strategy required
Recrystallization afforded the pure diol in 65% overall yield.
The enantiomeric purity of the diol had also improved to
(4) (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300-1302.
(b) Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733-1736.
(5) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949-1952.
(6) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937-940.
(7) (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4569-4573. (b) Evans, D. A.; Rajapakse, H. A.; Chiu,
A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4573-4576.
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976. (b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922-
1925. (c) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
3850
Org. Lett., Vol. 6, No. 21, 2004

95% ee upon recrystallization.14 Monosilylation of the diol
with TBDPS chloride (98%) and reductive debenzylation
(89%) cleanly afforded the diol 20. Finally, oxidation of 20
with PCC gave the A ring lactone 21 in 58% yield.
Treatment of lactone 21 with 4-butenylmagnesium bro-
mide (Scheme 4) afforded 22 in a total yield of 60% after
Scheme 4
Figure 3. Diagnostic NOESY cross-peaks observed for the
spiroketalization products.
treatment with an excess of PMB alcohol and PPTS in
CH2Cl2.
Dihydroxylation of the ketal 23 using the Sharpless ligand
(DHQ)2PYR, the ligand typically recommended for dihy-
droxylation of terminal alkenes,16 cleanly afforded the diol
product in 70:30 diastereoselection. To prevent the formation
of the more stable but undesired [6,6]-spiroketal, the crude
diol was immediately protected as the monopivalate (PivCl,
pyridine), yielding a mixture of 25a and 25b in 62% over
two steps.
two recycles of the starting material.15 Acid-catalyzed
methanolysis of keto alcohol 22 gave an unstable product
that readily decomposed to give a mixture of elimination
products. Replacement of MeOH with i-BuOH did not
improve the stability of the resulting mixed ketal; however,
the benzyl and especially the p-methoxybenzyl (PMB) ketals
were stable enough to be carried over the subsequent steps.
The PMB ketal 23 was obtained in 83% yield from 22 by
Different acid promoters spanning a pKa range from <-2
to 5 were screened (Table 1) for the key spiroketalization
reaction. The use of a strong acid (p-TsOH) led to the rapid
formation of a mixture of spiroketals. The less polar products
were identified as the two anomerically stabilized spiroketals
12 and 26; the minor product 26 corresponded to the C10
epimer. The more polar product 11 was only observed in
the initial stages of the reaction. Further equilibration
afforded the spiroketals 12 and 26 almost exclusively (entry
3). Thus, the spiroketal 11 appears to be a kinetic product.
(9) Pihko, P. M.; Salo, T. M. Tetrahedron Lett. 2003, 44, 4361-4364.
(10) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105-4108. (b) Ando,
K. J. Org. Chem. 1997, 63, 11934-1939. (c) Ando, K. J. Org. Chem. 2000,
65, 4745-4749.
(11) Bo¨rjesson, L.; Cso¨regh, I.; Welch, C. J. J. Org. Chem. 1995, 60,
2989-2999. We found the following procedure to be very convenient on
large-scale benzylation of 1,5-pentanediol: Kiddle, J. J.; Green, D. L. C.;
Thompson, C. M. Tetrahedron 1995, 51, 2851-2864.
(12) Lipshutz, B. H.; Kozlowski, J. Wilhelm, R. S. J. Am. Chem. Soc.
1982, 104, 2305-2307.
(13) White and co-workers have employed this very robust protocol in
a manner very similar to our study: White, J. D.; Blakemore, P. R.; Green,
N. J.; Hauser, E. B.; Holoboski, M. A.; Keown, L. E.; Nylund Kolz, C. S.;
Phillips, B. W. J. Org. Chem. 2002, 67, 7750-7760.
(14) Enantiomeric purity of 19 was determined, after its conversion to
20, by chiral HPLC (see Supporting Information).
The use of weaker acids as promoters afforded progres-
sively larger amounts of the more polar spiroketal isomer
11. Several diagnostic NOESY cross-peaks clearly identified
11 as the nonanomeric spiroketal isomer, with an equatorial
C-O bridge (Figure 3).17 The configurations of the other
spiroketal isomers were also assigned by NOESY experi-
ments.
Chloroacetic acid was found to be the optimal acid catalyst
for the kinetic spiroketalization, affording the nonanomeric
(15) In a model system, we had previously utilized a simpler lactone I
that readily afforded the desired hydroxy ketone II upon treatment with
4-butenylmagnesium bromide in 51% yield (85% based on recovered starting
material): Pihko, P. M.; Rissa, T. K. Unpublished work.
(16) (a) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu,
D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785-3786. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-
2547. (c) The use of the corresponding (DHQ)2AQN ligand (see: Becker,
H.; Sharpless. K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448-451) did
not improve the selectivity.
(17) Consistent with our assignment, the 13C NMR chemical shift of the
C7 spiro carbon was also shifted downfield relative to 12 and 26 (109.4
ppm in 11 vs 107.2 in 12 and 107.3 in 26). For comparative data in the
[6,6]-spiroketal series, see: Pothier, N.; Goldstein, S.; Deslongchamps, P.
HelV. Chim. Acta. 1992, 75, 604-620. A similar trend is also seen in the
pectenotoxins; see ref 2a).
Org. Lett., Vol. 6, No. 21, 2004
3851

Table 1. Relative Proportions of the Spiroketal Products with Different Acid Promotersa
entry
acid promoter
pKa H2O (DMSO)
reaction time
12 (%)
26 (%)
11 (+27) (%)
1
2
3
4
5
6
7
PPTS (20 mol %)
TsOH (20 mol %)
TsOH (20 mol %)
ClCH2CO2H (80 m ol %)
HCOOH (40 mol %)
AcOH (200 mol %)d
AcOH (3300 mol %)
5.21 (3.4)
-1.3
-1.3
2.86
3.77
10 min
10 min
90 min
4 h
4 h
6 h
53
51
70
29
29
34
65
18
21
30
22
28
26
35
29b
28
<2
49c
43
4.76 (12.3)
4.76 (12.3)
40
<2
21 h
a For entries 2, 3, 5, and 6, the relative proportions were determined by HPTLC analysis after the reaction had reached >90% conversion. For entries 1,
4, and 7, the ratios represent isolated yields of the products. b Including 10% 27. c Including 5% 27. d With 20 or 40 mol % AcOH, the reaction failed to go
to completion within 24 h.
spiroketal 11 as the major product in 49% yield.18 Interest-
ingly, under these conditions, less than 5% of the minor C10
epimer 27 was formed. Spiroketal 12 corresponds to the C1-
C11 AB spiroketal segment of PTX-4 and PTX-7, and
spiroketal 11 corresponds to the identical C1-C11 AB
segment present in PTX-1-3 and PTX-6.
The formation of the anomerically nonstabilized spiroketal
isomers under kinetic control was first demonstrated by
Deslongchamps and co-workers in the [6,6]-spiroketal se-
ries.19 They suggest that the formation of the less stable
spiroketal isomers can be conveniently explained by assum-
ing an early transition state for the spirocyclization. Kitch-
ing20 has reported similar observations with [6,6]-spiroketals;
however, to the best of our knowledge, ours is the first
documented example of a kinetically controlled spiroketal-
ization in the [6,5]-series.
(PTX-1-3 and PTX-4-6), since the remaining pectenotoxins
(PTX-8-10) can readily be obtained by acid-catalyzed
isomerization.21
In summary, we have developed a novel entry into the
AB spiroketal portion of the pectenotoxins. Importantly, as
a result of kinetic control in the spiroketalization reaction,
our route could be applied to the synthesis of all members
of the pectenotoxin family, including the thus far elusive
members bearing the nonanomeric spiroketal.
Acknowledgment. We thank Helsinki University of
Technology (Outstanding Junior Research Group Award),
TEKES, and the Academy of Finland for support. J.E.A. is
the recipient of an Undergraduate Stipend from the Elina,
Sofia and Yrjo¨ Arffman Fund of the Finnish Cultural
Foundation. We also thank Dr. Juho Helaja and Dr. Jari
Koivisto for NMR assistance and Ms. Terhi Rissa for early
contributions.
Access to the nonanomeric spiroketal 11 provides, for the
first time, a direct avenue to all isomers of the pectenotoxins
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Less strong acids such as acetic, formic, and chloroacetic acid clearly
afforded higher yields of the nonanomeric product 11. It should be noted
that the pKa values in DMSO were much more reliable guides to reactivity
than those measured in H2O, presumably because the spirocyclizations were
performed in an aprotic solvent (CH2Cl2). Thus, PPTS is effectively a
stronger acid than any of the carboxylic acids in such a medium.
(19) A late transition state would be expected to suffer from significant
stereoelectronic strain during the cyclization, since the TS would then
become more and more twist-boat-like. An early TS would suffer only from
small bias. For a thorough discussion, including illustrations of the different
possible transition states, see ref 17.
OL048321T
(21) Acid-catalyzed isomerization of PTX-4 bearing an anomerically
stabilized spiroketal afforded a mixture of PTX-8 (79%), PTX-1 (10%),
and PTX-4 (11%) (ref 7b). While all isomers of the pectenotoxins might
be obtainable through these isomerization reactions, isomerization appears
to favor products with anomeric stabilization.
(20) Chen, J.; Fletcher, M. T.; Kitching, W. Tetrahedron: Asymmetry
1995, 6, 967-972.
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Org. Lett., Vol. 6, No. 21, 2004