A novel approach to the CDE ring system of pectenotoxin-4 triggered by VO(acac)2-induced epoxy-acetalization

Article abstract of DOI:10.1021/ol8025457

(Chemical Equation Presented) A novel approach to the CDE fragment of pectenotoxin-4 is described wherein the bicyclic acetal is constructed via a cascade cyclization induced by VO(acac)₂ epoxidation of a homoallylic alcohol.

Full text of DOI:10.1021/ol8025457

ORGANIC
LETTERS
2009
Vol. 11, No. 3
563-566
A Novel Approach to the CDE Ring
System of Pectenotoxin-4 Triggered by
VO(acac)2-Induced Epoxy-Acetalization
Sarah Carley and Margaret A. Brimble*
Department of Chemistry, The UniVersity of Auckland,
23 Symonds Street, Auckland, New Zealand
m.brimble@auckland.ac.nz
Received November 4, 2008
ABSTRACT
A novel approach to the CDE fragment of pectenotoxin-4 is described wherein the bicyclic acetal is constructed via a cascade cyclization
induced by VO(acac)2 epoxidation of a homoallylic alcohol.
The pectenotoxins (PTXs) are a family of 20+ polyether
macrolactones which were first isolated in 1985 by Yasumoto
et al.1 and named after the Japanese scallop (Patinopecten
yessoensis) from which they were extracted. These toxins
have since been isolated from microalgae and bivalve
molluscs located worldwide.2 PTX-2 is a cytotoxic agent
which depolymerizes actin filaments,3 and an X-ray structure
of PTX-2 bound to actin provides valuable insight into the
pathway of actin disassembly by the PTX family.4 PTX-2
also initiates cell death in p-53-deficient tumors, and it has
been proposed that PTX-2 results in the depolymerization
of actin, followed by the activation of cell death regulating
proteins Bim and Bax.5
Over the past decade, many groups have been attracted to
the synthetic challenge posed by the PTX family. In spite
of this, only one total synthesis of PTX-4 and PTX-8 has
been reported.6 The considerable synthetic effort directed
toward the various fragments7 of the PTXs have mainly
focused on construction of the spiroacetal ring system,7a-f
the FG rings,7g-k and the substituted tetrahydrofuran C7l-n
and E7n,o rings. The limited methodology reported for
assembly of the bicyclic acetal containing CD unit of PTX-2
has focused on intramolecular ketalization of a ketone
generated via ozonolysis of an olefin7q and intramolecular
cyclization of a keto diol,7p while Paquette et al.7k reported
their thwarted attempts to effect construction of the bicyclic
D ring via transannular cyclization.
(1) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto, G. K.;
Clardy, J. Tetrahedron 1985, 41, 1019.
(2) (a) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998,
63, 2475. (b) Miles, C. O.; Wilkins, A. L.; Hawkes, A. D.; Jensen, D. J.;
Selwood, A. I.; Beuzenberg, V.; MacKenzie, A. L.; Cooney, J. M.; Holland,
P. T. Toxicon 2006, 48, 152, and references are cited therein.
(3) (a) Spector, I.; Braet, F.; Schochet, N. R.; Bubb, M. R. Microsc.
Res. Tech. 1999, 47, 18. (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. (c) Miles, C. O. Phycotoxins
2007, 159.
(5) Chae, H.-D.; Choi, T.-S.; Kim, B.-M.; Jung, J. H.; Bang, Y.-J.; Shin,
D. Y. Oncogene 2005, 24, 4813.
(6) (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. 2002, 41, 4573.
(4) Allingham, J. S.; Miles, C. O.; Rayment, I. J. Mol. Biol. 2007, 371,
959.
10.1021/ol8025457 CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society

Based on the retrosynthetic strategy outlined (Figure 1),
our synthetic efforts toward PTX-4 (1) have resulted in the
Scheme 1. Synthesis of the E Ring Fragment 4
Figure 1. Retrosynthetic analysis of PTX-4 (1).
successful synthesis of the ABC rings7d 2 and the FG rings7r
3 prompting us to next examine methodology for construction
of the highly substituted E ring and the bicyclic acetal D
rings. We herein report our synthesis of the E ring fragment
4 of PTX-4 (1) and subsequent novel VO(acac)2 epoxide
induced tandem cyclization of a homoallylic alcohol to install
the bicyclic D ring acetal onto the E ring fragment. A simple
tetrahydrofuran C ring was used as a model for our ABC
tricyclic fragment. The highly functionalized tetracycle 5 is
constructed by epoxidation of homoallylic alcohol 6, which
in turn is assembled via the union of E ring aldehyde 4 with
sulfone 7 (Figure 2).
TPAP and NMO provided methyl ketone 11. Elongation of
the carbon skeleton via addition of a homoallyl Grignard
reagent prior to installation of the tertiary methyl group
proceeded with low stereoselectivity. Gratifyingly, changing
the order of introduction of the two alkyl groups afforded
some improvement in that addition of the Grignard reagent
derived from 4-bromo-1-butene to methyl ketone 11 favored
the desired tertiary alcohol 12 over the undesired alcohol
13 (12:13; 2.1:1).8
Subjecting the major alcohol 12 to iodoetherification9
readily provided the requisite trans-tetrahydrofuran 14 in
excellent yield with 6.1:1 trans/cis selectivity. Interestingly,
iodoetherification of the undesired alcohol 13 proceeded
indiscriminately, affording both cis and trans ethers 15 in
nearly equal amounts. Confirmation of the relative stereo-
chemistry in trans-tetrahydrofuran 14 was achieved using
(7) (a) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849. (b) Bondar,
D.; Liu, J.; Muller, T.; Paquette, L. A. Org. Lett. 2005, 7, 1813. (c) Halim,
R.; Brimble, M. A.; Merten, J. Org. Lett. 2005, 7, 2659. (d) Halim, R.;
Brimble, M. A.; Merten, J. Org. Biomol. Chem. 2006, 4, 1387. (e) Vellucci,
D.; Rychnovsky, S. D. Org. Lett. 2007, 9, 711. (f) Lotesta, S. D.; Hou, Y.;
Williams, L. J. Org. Lett. 2007, 9, 869. (g) Amano, S.; Fujiwara, K.; Murai,
A. Synlett 1997, 1300. (h) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett.
2002, 4, 937. (i) Peng, X.; Bondar, D.; Paquette, L. A. Tetrahedron 2004,
60, 9589. (j) Fujiwara, K.; Kobayashi, M.; Yamamoto, F.; Aki, Y.;
Kawamura, M.; Awakura, D.; Amano, S.; Okano, A.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 5067. (k) O’Connor, P. D.;
Knight, C. K.; Friedrich, D.; Peng, X.; Paquette, L. A. J. Org. Chem. 2007,
72, 1747. (l) Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733. (m)
Aho, J. E.; Saloma¨ki, E.; Rissansen, K.; Pihko, P. M. Org. Lett. 2008, 10,
4179. (n) Fujiwara, K.; Aki, Y.; Yamamoto, F.; Kawamura, M.; Kobayashi,
M.; Okano, A.; Awakura, D.; Shiga, S.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2007, 48, 4523. (o) Kolakowski, R. V.; Williams, L. J.
Tetrahedron Lett. 2007, 48, 4761. (p) Micalizio, G. C.; Roush, W. R. Org.
Lett. 2001, 3, 1949. (q) Helmboldt, H.; Aho, J. E.; Pihko, P. M. Org. Lett.
2008, 10, 4183. (r) Heapy, A.; Wagner, T. M.; Brimble, M. A. Synlett 2007,
2359.
Figure 2. Synthetic strategy for the construction of tetracycle 5.
Our plans initially focused on the synthesis of the E ring
fragment (Scheme 1) using an iodoetherification to construct
the trans-trisubstituted tetrahydrofuran ring. Thus, our syn-
thesis of E ring aldehyde 4 started from Roche ester 8, which
was then protected, reduced, and substituted via a mesylate
to give iodide 9. Extension of the carbon chain via cyanide
displacement and subsequent DIBALH reduction afforded
aldehyde 10. Methylation of 10 followed by oxidation with
(8) Alcohols 12 and 13 were converted to tetrahydrofuran derivatives,
which were then subjected to NOE experiments.
(9) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963.
564
Org. Lett., Vol. 11, No. 3, 2009

NOE analysis (Scheme 1). Finally, employment of potassium
superoxide was required to convert the unreactive iodide 14 to
an alcohol which then underwent oxidation using Dess-Martin
periodinane to afford the unstable aldehyde 4.
With E ring aldehyde 4 in hand, efforts next turned to the
union of 4 with sulfone 7 in which the tetrahydrofuran ring
served as a model for the ABC spiroacetal-containing
fragment of PTX-4 that we have previously prepared.7d
Accordingly, addition of allyl metal reagents derived from
allylic alcohol 1610 (via allyl bromide 17) to (S)-tetrahydro-
furan aldehyde 18 was investigated (Scheme 2). (S)-Aldehyde
4 afforded an equal mixture of the four diastereomeric
hydroxy sulfones in 91% yield that were immediately
oxidized with Dess-Martin periodinane to afford a 1:1
mixture of the two diastereomeric keto sulfones 21. Gratify-
ingly, careful removal of the phenylsulfonyl group using 5%
sodium amalgam at -35 °C and deprotection of the EM
group using catalytic NaHSO4·SiO2 in CH2Cl2 proceeded
cleanly affording secondary alcohol 6 in 75% yield (Sch-
eme 3).
Scheme 3
.
Union of Sulfone 7 with Aldehyde 4 and Synthesis
of Alkene 6
Scheme 2. Synthesis of the Sulfone 7
With the entire carbon backbone for the CDE fragment
fully assembled, it was envisaged that epoxidation of alkene
6 would induce facile hemiacetalzation with subsequent
attack of the hemiacetal on the epoxide taking place to
furnish the desired bicyclic acetal core of the CDE fragment
of PTX-4 (5). Our aim was to explore the feasibility of the
proposed tandem cyclization in the first instance addressing
the stereochemical issues associated with the epoxidation step
at a later stage.
Epoxidation of alkene 6 using buffered m-CPBA led to
substantial decomposition whereas use of dimethyldiox-
irane13 furnished a 1:1 inseparable mixture of epoxides 22
in 71% yield (Scheme 4). Epoxides 22 were then treated
1811 is prepared via oxidation of the (S)-alcohol12 that is
derived from the commercial (S)-acid.
Numerous methods to append the allylic fragment to
aldehyde 18 were evaluated in an effort to maximize the
formation of the desired Felkin-Anh product 19. Use of
organozinc reagents and organolithium reagents met with
little success, while Nozaki-Hiyama-Kishi organochro-
mium technology proceeded in moderate yield. After con-
siderable experimentation, the formation of an allylindium
species provided the desired homoallylic alcohol 19 in near-
quantitative yield with modest selectivity. Fortunately,
conversion of alcohol 19 to an ethoxymethyl ether (EM)
faciliated separation of the diastereomeric alcohols 20 after
removal of the TBDPS group. Alcohol 20 underwent
mesylation then treatment with excess triethylamine and
thiophenol to afford a phenyl sulfide that was oxidized to
sulfone 7 using Oxone and wet alumina. In order to achieve
reproducible results, it was imperative that approximately
2 g of wet alumina was used independent of the scale of the
reaction. Notably, scaling down the quantity of alumina
proportionate to the amount of Oxone used, resulted in the
formation of undesired side products (Scheme 2).
Scheme 4. Acid-Catalyzed Cyclization of Epoxide 22
Having assembled sulfone 7 and E ring aldehyde 4, their
union proceeded smoothly. Treatment of sulfone 7 with
nBuLi at -78 °C in THF followed by addition of aldehyde
with catalytic pyridinium p-toluenesulfonate in MeOH for
20 min. Purification by semipreparative HPLC afforded
alcohol 23 as a 1:1 mixture of diastereomers in 40% yield.
(10) Weigand, S.; Bruckner, R. Synthesis 1996, 475.
(11) Belanger, P. C.; Williams, H. W. R. Can. J. Chem. 1983, 61, 1383.
(12) Alajarin, R.; Alvarezbuilla, J.; Vaquero, J. J.; Sunkel, C.; Decasa-
juana, M. F.; Statkow, P. R.; Sanzaparicio, J. Tetrahedron: Asymmetry 1993,
4, 617.
(13) Murray, R. W. Chem. ReV. 1989, 89, 1187.
Org. Lett., Vol. 11, No. 3, 2009
565

The 13C NMR spectrum of the purified product revealed
a mixture of two diastereomers; however, it was apparent
that the cascade type cyclization had not proceeded in the
anticipated fashion. Diastereomeric quaternary carbons at δC
68.6 ppm suggested nucleophilic attack on the terminal
carbon of the epoxide had taken place to furnish quaternary
alcohol 23 (Scheme 4).
Attempts to effect installation of the initial epoxide
functionality in a diastereoselective fashion met with little
success. Epoxidation of alkene 6 using the Shi fructose-
derived dioxirane14 afforded a complex mixture. However,
substrate-directed vanadium-catalyzed epoxidation15 of ho-
moallylic alcohol 6 (Scheme 5) afforded a mixture of two
that eluted was a cleavage product with only resonances
attributed to the elaborated E ring fragment being observed.
It was unclear whether degradation had occurred during the
chromatography step or during the epoxidation.
NMR analysis of the major fraction revealed the formation
of the desired CDE fragment 5 (13% yield after HPLC) as
a single isomer (Scheme 5). Notably, a quaternary carbon
at δC 113.1 ppm and a CH2OH resonance at δC 69.3 ppm
established formation of the desired bicyclic acetal. The 13
C
NMR data were also in agreement with similar data reported
for PTX-4.7
Irrespective of the level of stereoinduction resulting from
the initial substrate-directed epoxidation of alkene 6, the
steric strain experienced in the ensuing cyclization neces-
sitates that only two possible isomers of the CDE fragment
namely, 5 and 24, can be formed proceeding via hemiacetal
intermediates A and B respectively (Scheme 5). Interestingly,
600 MHz NMR analysis of the crude product obtained before
semipreparative HPLC indicated the presence of two dia-
stereomeric CDE fragments. One possible explanation is that
initial formation of the two CDE fragments 5 and 24 takes
place; however, one diastereomer is predisposed to facile
degradation upon purification by HPLC.
Scheme 5. VO(acac)2-Induced Epoxy-Acetalization of Alkene 6
The completion of the structurally complex CDE fragment
5 of the PTX-4 (1) is reported herein. An efficient synthesis
of the 2,5-trans E ring fragment 4 together with a facile
method to append the model C ring aldehyde 18 to an allylic
D ring fragment 17 is also described. Importantly, a tandem
cascade cyclization initiated by vanadyl acetylacetonate
epoxidation of a homoallylic alcohol furnished a novel
method to install the bicyclic acetal motif in the D ring.
compounds with characteristic quaternary carbons in the 13
C
spectrum suggesting the presence of the desired cyclized
product 5. Flash chromatography failed to effect clean
separation of the mixture hence the crude product mixture
was subjected to semipreparative HPLC. The first compound
Supporting Information Available: Experimental pro-
cedures and 13C NMR data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(15) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc.
1981, 103, 7690.
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