Diastereoselective synthesis of the pectenotoxin 2 non-anomeric AB spiroacetal

Article abstract of DOI:10.1021/ol0630447

The reductive cyclization reaction of a cyanoacetal has been used to prepare the pectenotoxin 2 (PTX-2) AB spiroacetal with high diastereoselectively for the first time. The strategy is convergent and makes use of the axial-selective reductive lithiation

Full text of DOI:10.1021/ol0630447

ORGANIC
LETTERS
2007
Vol. 9, No. 4
711-714
Diastereoselective Synthesis of the
Pectenotoxin 2 Non-Anomeric AB
Spiroacetal
Danielle Vellucci and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
IrVine, California, 92697-2025
srychnoV@uci.edu
Received December 16, 2006
ABSTRACT
The reductive cyclization reaction of a cyanoacetal has been used to prepare the pectenotoxin 2 (PTX-2) AB spiroacetal with high
diastereoselectively for the first time. The strategy is convergent and makes use of the axial-selective reductive lithiation of 2-cyano
tetrahydropyran rings to introduce the spiroacetal center with the desired non-anomeric selectivity.
The pectenotoxins are a family of polyether macrolide natural
products originally isolated from the scallop Patinopecten
yessoensis as causative agents for diarrhetic shellfish poison-
ing.1 The dinoflagellate Dinophysis fortii was found to
produce pectenotoxin 2 (PTX-2, Figure 1).2 PTX-2 is
considered the progenitor of PTX-1, PTX-3, and PTX-6,
which would be produced upon metabolism by the scallop.
PTX-2 exhibits nanomolar cytotoxicity against breast, colon,
and lung cancer cell lines.3 PTX-2 and PTX-6 interact with
the actin skeleton at a unique site, effecting depolymeriza-
tion of F-actin.4 Actin damage is believed to be responsible
for triggering apoptosis in p53-deficient tumor cells by
PTX-2.5 The scarcity, structural complexity, and potent
biological activity have made the pectenotoxins priority
targets for synthetic chemists.
Evans completed the first and only syntheses of pecteno-
toxin macrolides, PTX-4 and PTX-8, in 2002.6 Many other
research groups have described approaches to fragments of
pectenotoxin, including Murai,7 Roush,8 Brimble,9 and
Paquette.10 Of particular relevance to the current report, Pihko
reported the synthesis of the AB spiroacetal segment of
PTX-2 by a kinetic cyclization.11 We now describe a
diastereoselective route to the non-anomeric PTX-2 AB
spiroacetal.
Control of configuration of the AB spiroacetal of the
pectenotoxins is a daunting challenge. The more stable AB
spiroacetal with the 7S configuration, found in PTX-4 and
(6) (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.
(7) (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300-1302.
(b) Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733-1736. (c)
Fujiwara, K.; Kobayashi, M.; Yamamoto, F.; Aki, Y.-i.; Kawamura, M.;
Awakura, D.; Amano, S.; Okano, A.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 5067-5069.
(8) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949-1952.
(9) (a) Halim, R.; Brimble, M. A.; Merten, J. Org. Lett. 2005, 7, 2659-
2662. (b) Halim, R.; Brimble, M. A.; Merten, J. Org. Biomol. Chem. 2006,
4, 1387-1399.
(1) (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019-1025. (b) Daiguji, M.; Satake,
M.; James, K. J.; Bishop, A.; Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem.
Lett. 1998, 653-654.
(2) Suzuki, T.; Mitsuya, T.; Matsubara, H.; Yamasaki, M. J. Chromatogr.
A 1998, 815, 155-160.
(3) Spector, I.; Braet, F.; Shochet, N. R.; Bubb, M. R. Microsc. Res.
Tech. 1999, 47, 18-37.
(4) Leira, F.; Cabado, 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.
(10) (a) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937-
940. (b) Peng, X.; Bondar, D.; Paquette, L. A. Tetrahedron 2004, 60, 9589-
9598. (c) Bondar, D.; Liu, J.; Mueller, T.; Paquette, L. A. Org. Lett. 2005,
7, 1813-1816.
(5) Chae, H.-D.; Choi, T.-S.; Kim, B.-M.; Jung, J. H.; Bang, Y.-J.; Shin,
D. Y. Oncogene 2005, 24, 4813-4819.
(11) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849-3852.
10.1021/ol0630447 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/18/2007

described a complementary epoxide cyclization strategy for
the preparation of non-anomeric [5,5]-spiroacetals.14 The
occurrence and synthesis of non-anomeric spiroacetals has
recently been reviewed.15
The synthetic strategy is outlined in Scheme 1. The non-
anomeric AB spiroacetal 1 will be prepared by reductive
Scheme 1. Retrosynthetic Disconnection of the PTX-2
Non-Anomeric Spiroacetal
lithiation of the 2-cyano tetrahydropyran 2. Reductive
lithiation will generate the axial alkyllithium reagent, which
will then cyclize with retention of configuration onto the
primary alkyl chloride. The cyano acetal 2 can be further
disconnected into the diol 3 and the dihydropyran 4. The
two stereocenters in dihydropyran 4 will arise from an Evans’
aldol adduct. Late stage coupling of the diol 3 and dihydro-
pyran 4 makes the strategy convergent.
Figure 1. Structures of selected pectenotoxins.
PTX-7, has two anomeric interactions. The less stable AB
spiroacetal with the 7R configuration has only one anomeric
interaction and is found in PTX-1, PTX-2, PTX-3, and
PTX-6 (Figure 1). The most active of the pectenotoxins,
PTX-2 and PTX-6, both have the non-anomeric 7R config-
uration. Because of constraints in the macrocyclic ring, both
spiroacetals epimers in pectenotoxin structure have similar
stabilities. With the exception of Pihko’s approach, all of
the routes to the pectenotoxins described to date rely on a
late stage equilibration of the spiroacetal or have not
addressed the issue.
Synthesis of the dihydropyran 4 is outlined in Scheme 2.
Reaction of the boron enolate from 5 with 5-hexenal gave
Scheme 2. Synthesis of the Dihydropyran 4
Evans reported the equilibration of synthetic PTX-4 to
PTX-8 (a [5,5]-spiroacetal that may be an isolation artifact)
and 11% of PTX-1, the spiroacetal epimer. This experi-
ment stands in contrast to Sasaki’s equilibration of natural
PTX-1, which returned 29% of PTX-1 along with PTX-4.
Presumably one or the other of these mixtures did not reach
equilibrium. If Evans’ equilibration study represents a true
equilibrium, then the prognosis for a late-stage equilibration
leading to the 7R pectenotoxins is poor.
Our approach to the pectenotoxin non-anomeric AB
spiroacetal is designed around a reductive lithiation and
cyclization of 2-cyanotetrahydropyrans. This strategy has
been used to prepare non-anomeric [5,4]- and [5,5]-spiro-
acetals with excellent selectivity12 and was recently applied
to the synthesis of the core of spirofungin B.13 Tan recently
the aldol adduct 6 in 73% yield with a 97:3 dr.6a Hydrolysis
and reduction with LAH produced the expected diol in 70%
yield. Selective protection with TIPSCl led to the secondary
alcohol 7. Ozonolysis of 7 generated the lactol as a 1.5:1
(14) (a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc.
2005, 127, 13796-13797. (b) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S.
J. Am. Chem. Soc. 2006, 128, 1792-1793.
(15) (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. ReV. 2005, 105,
4406-4440. For general reviews of spiroacetals, see: (b) Perron, F.;
Albizati, K. F. Chem. ReV. 1989, 89, 1617. (c) Mead, K. T.; Brewer, B. N.
Curr. Org. Chem. 2003, 7, 227-256. (d) Brimble, M. A.; Furkert, D. P.
Curr. Org. Chem. 2003, 7, 1461-1484.
(12) Takaoka, L. R.; Buckmelter, A. J.; La Cruz, T. E.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2005, 127, 528-529.
(13) La Cruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873-
1875.
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Org. Lett., Vol. 9, No. 4, 2007

mixture of diastereomers. Dehydration of the lactol with
POCl3 in hot pyridine produced the unsubstituted dihydro-
pyran.16 Introduction of the 2-thiophenyl substituent required
optimization. Initial experiments using t-BuLi gave modest
yields, accompanied by recovered enol ether. Schlosser’s
base led to better results. Deprotonation at -78 °C in THF,
followed by addition of diphenyl disulfide, gave the 2-thio-
phenyl dihydropyran 4. The mixture was contaminated with
diphenyl disulfide, which was not easily separated by chro-
matography. Addition of methyllithium to the crude reaction
mixture converted it to thioanisole and thiophenol, which
were removed under high vacuum. Purification of the product
gave 76% of 2-thiophenyl dihydropyran 4 and 16% of the
unreacted starting material. Compound 4 was prepared in 7
steps and 24% overall yield.
8 is relatively unhindered compared with most previous
cases, which may account for the low selectivity in the
orthoester cleavage. This lack of selectivity may account for
minor cyanoacetal isomers observed but not characterized
in previous cases.12,13 After silyl protection, the reductive
cyclization reaction was carried out by slow addition of
freshly prepared LiDBB in THF at -78 °C. The non-
anomeric spiroacetal 1 was isolated in 76% yield as a single
diastereomer.
The other regioisomer 10 was not silylated efficiently with
TBSCl and imidazole, but it could be silylated with TBSOTf
(Scheme 4). Reductive cyclization led to the expected [5,5]
non-anomeric spiroacetal 12 in modest, unoptimized yield.
The synthesis was completed as shown in Scheme 3. Diol
3 was prepared by the previously described procedure from
Scheme 4. Cyclization of the Minor Cyanoacetal Isomer
Scheme 3. Synthesis of the Pectenotoxin 2 AB Spiroacetal 1
That compound 1 has the non-anomeric configuration at
the spiroacetal was confirmed by the characteristic 108.0 ppm
13C NMR peak for the [4,5]-spiroacetal center. Treatment
of compound 1 with CSA in CH2Cl2 (Scheme 5) led to
Scheme 5. Equilibration of the Pectenotoxin 2 AB Spiroacetal
1
commercially available material.17 Preparation of the ortho-
ester 8 required that both the dihydropyran 4 and the diol
be scrupulously dried over 4 Å molecular sieves. Treatment
with benzenesulfinic acid gave the orthoester in 74% yield
as a 1:1 mixture of diastereomers. In previous cases we have
observed primary selective cleavage of orthoesters with
TMSCN and BF3‚OEt2,18 but in this case two regioisomers
were produced with the preferred regioisomer 9 formed in
50% yield.19 The secondary orthoester oxygen in compound
complete isomerization to the more stable anomeric spiro-
acetal with a 13C NMR peak at 106.9 ppm. These chemical
shifts are consistent with those observed for the pectenotoxin
spiroacetals.20
The non-anomeric AB spiroacetal of pectenotoxin 2 was
prepared by a reductive cyclization strategy. This route is
the first highly diastereoselective approach to the less stable
spiroacetal in the pectenotoxins and lays the ground work
for a diastereoselective approach to the more active pec-
tenotoxin natural products.
(16) Crimmins, M. T.; Katz, J. D.; McAtee, L. C.; Tabet, E. A.; Kirincich,
S. J. Org. Lett. 2001, 3, 949-952.
(17) Diol 3 was prepared as described for the enantiomer in ref 12.
Commercially available (S)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol was
treated with MsCl and LiCl in DMF, followed by hydrolysis with Dowex
and methanol.
(18) Utimoto, K.; Wakabayashi, Y.; Shishiyama, Y.; Inoue, M.; Nozaki,
H. Tetrahedron Lett. 1981, 22, 4279-4280.
(19) We first observed this lack of regioselectivity in another case. The
structures of 9 and 10 were demonstrated by oxidation to an aldehyde and
a ketone, respectively. See Supporting Information for details.
(20) Non-anomeric PTX-1 and PTX-6 show the acetal carbon at 107.5
ppm. Anomeric PTX-4 has the acetal carbon shifted to 106.3 ppm.
Org. Lett., Vol. 9, No. 4, 2007
713

Acknowledgment. Insightful analysis by Thomas La
Cruz (UC Irvine) and Viengkham Malathong (UC Irvine)
was important in this project. This work was supported by
the National Institute of General Medical Sciences (GM-
65338) and by a generous donation from the Schering Plough
Research Institute.
Supporting Information Available: Preparation and
characterization of the described compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
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