Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin 2

Article abstract of DOI:10.1021/ol302751b

Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin-2 (PTX-2) is described that features a stereoselective annulation to generate the C-ring by triple asymmetric Nozaki-Hiyama-Kishi coupling followed by oxidative cyclization. Preparation of the C1-C14 AB spriroketal-containing subunit employs a recently developed metallacycle-mediated reductive cross-coupling between a TMS-alkyne and a terminal alkene.

Full text of DOI:10.1021/ol302751b

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5748–5751
Synthesis of the C1ꢀC26 Hexacyclic
Subunit of Pectenotoxin 2
Ozora Kubo, Daniel P. Canterbury, and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458,
United States
micalizio@scripps.edu
Received October 5, 2012
ABSTRACT
Synthesis of the C1ꢀC26 hexacyclic subunit of pectenotoxin-2 (PTX-2) is described that features a stereoselective annulation to generate the
C-ring by triple asymmetric NozakiꢀHiyamaꢀKishi coupling followed by oxidative cyclization. Preparation of the C1ꢀC14 AB spriroketal-
containing subunit employs a recently developed metallacycle-mediated reductive cross-coupling between a TMS-alkyne and a terminal alkene.
Pectenotoxin-2 (PTX2) is araremarine-derivedpolyether
natural product that displays rather profound anticancer
properties (Figure 1A).1ꢀ3 Discovered in the digestive glands
of the scallop Patinopecten yessoensis4 and traced back to the
dinoflagellates Dinophysis fortii and D. acuminata,5 recent
studies have described the isolation of PTX2 from a two-
sponge association (Poecillastra sp. and Jaspis sp.).2 Initial
biological evaluation of PTX2 established its substantial
cytotoxic profile, with later studies concluding that this
natural product is a unique actin depolymerizing agent.
Binding to a site on G-actin that is distinct from other known
marine toxins,6 recent studies have determined that PTX2 is
selectively cytotoxic to p53 mutant and p53(ꢀ) cancers
(representing approximately 50% of all human cancers).1,7
While no laboratory synthesis of PTX2 has been
reported,8 a number of studies directed toward this goal
have appeared.9 Here, we describe an efficient assembly of
the C1ꢀC26 ABCDEF hexacyclic subunit of PTX2 (2) by
convergent union of the functionalized vinyliodide 3 with
the tricyclic acetal-containing aldehyde 4 (Figure 1B).
While these pursuits have led to the generation of a
substantial subunit of pectenotoxin-2 (2), they have also
defined an approach to stereodefined 2,2,5-trisubstituted
THFs based on double or triple asymmetric Nozakiꢀ
HiyamaꢀKishi (NHK) coupling (8 þ 9 f 7) and site
(8) For total syntheses of pectenotoxin-4 and -8, see: (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.
(9) For partial synthesis and studies toward the syntheses of the
pectenotoxins, see: (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3,
1949–1952. (b) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4,
937–940. (c) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849–3852. (d)
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H.; Igarashi, T.; Fujita, N. Bull. Jpn. Soc. Sci. Fish. 1980, 46, 1405–1411.
(b) Lee, J.; Igarashi, T.; Fraga, S.; Dahl, E.; Hovgaard, P.; Yasumoto, T.
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r
10.1021/ol302751b
Published on Web 10/26/2012
2012 American Chemical Society

and stereoselective oxidative cyclization via 5-exo ring
closure (Figure 1C).
Scheme 1. C-Ring Annulation Strategy and Synthesis of 8
(1) silylation with TBDPSCl, (2) regioselective hydrostan-
nylation,14 and (3) iodination.
Next, to explore the basic steps of the annulation process
on a model aldehyde, asymmetric NHK coupling11 with
cyclohexane carboxaldehyde delivered allylic alcohol 17 in
54% yield with 87% ee (Scheme 2). Subsequent desilyla-
tion with TBAF provided diol 18 in 99% isolated yield,
an intermediate that proved to be an ideal substrate for
site-selective and stereoselective Sharpless asymmetric
epoxidation15/ring closure. Exposure of 18 to reaction
conditions for asymmetric epoxidation with (þ)-diethyl-
tartrate delivered the 2,2,5-cis trisubstituted THF 19 in
86% yield (dr = 10:1) by tandem asymmetric epoxidation/
5-exo ring closure. While unrelated to the synthetic chal-
lenge associated with the C-ring of PTX2, use of (ꢀ)-
diethyltartrate in this reaction process resulted in forma-
tion of the 2,2,5-trans trisubstituted product 20 in 86%
yield (dr = 6:1).16
Withconfidencegainedfrom thesuccessful couplingof8
with a simple aldehyde, we next studied the utility of this
sequence for synthesis of the C10ꢀC26 tetracyclic frag-
ment of PTX2 12. As illustrated in Scheme 3, aldehyde 4
was prepared as previously described from linalool by an
11-step sequence.9o While single asymmetric NHK cou-
pling between aldehyde 4 and vinyl iodide 8 proceeded
without appreciable stereoselection (ds = 1.5:1), a double
asymmetric variant of this process delivered the allylic
alcohol 10 with exquisite levels of selectivity (dr g 20:1)
Figure 1. Introduction.
With the initial focus on a more modest target than
2, and deriving inspiration from Professor Kishi’s ap-
proach to the synthesis of heterocyclic motifs present
in the halichondrins,10 we targeted construction of the
PTX2 CDEF heterocyclic system by double asymmetric
NHK coupling11 between aldehyde 49o and vinyliodide 8
(Scheme 1A). Site-selective and stereoselective epoxidation
ofthe diol product (10f 11) followedby5-exo ring closure
(11 f 12) was then envisioned as a means to establish the
complex C10ꢀC26 tetracycle of PTX2.
As illustrated in Scheme 1B, vinyl iodide 8 was pre-
pared by a simple six-step sequence from isoprene. First,
conversion to the stereodefined vinylchloride 14 was
accomplished by exposure to t-BuOCl in AcOH,12 and
subsequent tranformation to enyne 15 was realized by
sequential homologation with TMS-acetylene and desilyla-
tion.13 Conversion to the fully functionalized coupling part-
ner 8 was then achieved by a simple three-step sequence:
(10) Choi, H.; Demeke, D.; Kang, F.; Kishi, Y.; Nakajima, K.;
Nowak, P.; Wan, Z.; Xie, C. Pure Appl. Chem. 2003, 75, 1–17.
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Liu, X.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387–15393.
(12) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.; Hardcastle,
K. I. Org. Lett. 2003, 5, 2123–2126.
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M. Org. Lett. 2011, 13, 1106–1109.
(15) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
(16) Unfortunately, all attempts to employ an epoxide-containing
vinyl iodide in the NHK coupling delivered a complex mixture of
products.
(13) Davies, K. A.; Abel, R. C.; Wulff, J. E. J. Org. Chem. 2009, 74,
3997–4000.
Org. Lett., Vol. 14, No. 22, 2012
5749

and Carreira’s asymmetric acetylide addition18 [propyne,
Zn(OTf)2, (ꢀ)-N-methylephedrine, Et3N, PhMe] to
deliver the propargylic alcohol product 24 in 78% yield
(dr g 20:1). Protodesilylation of the vinylsilane (1 M HCl,
THF, EtOH), oxidative cleavage of the alkene (O3,
MeOH, then Me2S), and acid-promoted dehydration then
delivered the AB spiroketal-containing subunit 25 as a
mixture of C7-spiroketal isomers (dr = 14:1) in 84% yield.
As expected, this spirocyclization provided the product
containing the incorrect C7 stereochemistry for PTX2,
a structural feature that we plan to address in late stage
acid-mediated equilibration once the fully functionalized
macrocycle is in place. Finally, conversion to vinyliodide 3
was accomplished by regioselective hydrozirconationꢀ
iodination (Cp2ZrCl2, DIBAL, THF, then I2) and cou-
pling with 2-iodo-allylbromide (n-BuLi, i-PrMgBr,
CuCN•2LiCl).19
Scheme 2. NHK-Based Annulation for 2,2,5-Trisubstituted
THFs
Scheme 4. Synthesis of the AB Spiroketal-Containing Subunit 3
in 76% yield (after desilylation: TBAF, THF). Also, site-
selective Sharplessasymmetricepoxidationand cyclization
proved effective for advancing triene 10 to the tetracyclic
target 12 in 83% yield.
Scheme 3. Synthesis of a CDEF-Containing Subunit of PTX2
As illustratred in Scheme 5, triple asymmetric20 NHK
coupling between vinyl iodide 3 and aldehyde 4 delivered
the allylic alcohol product 26 in 79% yield (ds g20:1;
Scheme 5). While we were delighted that this coupling
proceeded with outstanding levels of stereochemical con-
trol and good yield, we were unable to identify reaction
With a sound foundation of preliminary data that
supported the utility of NHK coupling for establishment
of the functionalized C-ring of the pectenotoxins, we then
targeted synthesis of the fully functionalized C1ꢀC26
subunit of PTX2. As illustrated in Scheme 4, synthesis of
the AB spriroketal-containing subunit began with reduc-
tive cross-coupling between the stereodefined homoallylic
alcohol 21 and TMS-alkyne 22.17 This Ti-mediated, hy-
droxyl-directed coupling process proceeded in 77% yield
and delivered 23 as a single regio- and stereoisomer.
Next, TBS deprotection (TBAF, THF) was followed by
selective oxidation of the primary alcohol to the alde-
hyde (TEMPO, NCS, Bu4NCl, CH2Cl2, pH 8.6 buffer)
€
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cene complexes, see: (a) Wipf, P.; Jahn, H. Tetrahderon 1996, 52, 12853–
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Lin, M.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249. For a
similar process for allylation of a vinyliodide, see: (c) Kitagawa, K.;
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5750
Org. Lett., Vol. 14, No. 22, 2012

conditions for selective epoxidation of the C11ꢀC12 trisub-
stituted alkene of 26. Standard reaction conditions for Shi
epoxidation21 led to initial partial oxidation of the C14 1,1-
disubstituted alkene, while prolonged exposure to the reac-
tion conditions for this oxidation process was insufficient to
oxidize both the C14 1,1-disubstituted and the C11ꢀC12
trisubstituted alkene. In an attempt to advance substrate 10
to the desired product, mCPBA was also investigated as a
potential oxidant but was similarly ineffective for accom-
plishing the desired epoxidation/cyclization sequence.
Scheme 6. Closure of the C-Ring via Iodoetherification
Scheme 5. NHK Coupling between 3 and 4, and Attempted
Epoxidation/Cyclization Cascade
In conclusion, we report a synthesis of the C1ꢀC26
hexacyclic subunit of PTX2 that proceeds by convergent
establishment of the C-ring through sequential Nozakiꢀ
HiyamaꢀKishi coupling and oxidative cyclization. Our
model studies have confirmed that this general strategy is
quite effective for generating either 2,2,5-cis or 2,2,5-trans
trisubstituted tetrahydrofurans when employing sub-
strates that are amenable to site-selective and stereoselec-
tive Sharpless epoxidation. This annulative process was
initially employed to prepare the C10ꢀC26 subunit of
PTX2 (12) but proved problematic when challenged with
a more complex coupling partner containing the C1ꢀC14
northern hemisphere of PTX2 (3). In efforts to circumvent
the unanticipated low reactivity of the C11ꢀC12 trisub-
stituted alkene of 26 toward standard conditions for
stereoselective epoxidation, we turned to iodoetherifica-
tion as an alternative means of ring closure. The stereo-
chemical control that we achieved in the conversion of 26
to the ABCDEF subunit of PTX2 27 is unique among
iodoetherification reactions and may speak to the role
that hydrogen bonding can play in dictating the stereo-
chemical course of these cyclization reactions. Whether
or not intermediate 27 will serve as a useful intermediate
in efforts to prepare PTX2 is the subject of ongoing
studies.
In an attempt to overcome the unexpected difficulty in
site-selective oxidation of the triene 26, we turned our
attention to a substrate-controlled iodoetherification reac-
tion to establish the 2,2,5-cis trisubstituted THF C-ring of
PTX2. To our delight, treatment with N-iodosuccinimide
in dichloromethane led to efficient cyclization of the C15
hydroxy group onto the trisubstituted alkene to deliver the
polycyclic product containing the desired 2,2,5-cis trisub-
stituted THF 27 in 87% yield (dr = 12:1; Scheme 6).
Stereochemical control in this process is quite interesting,
as early studies of a related cyclization by Rychnovsky and
Bartlett documented the preference of such ring-forming
reactions to deliver 2,2,5-trans trisubstituted THFs with
outstanding stereocontrol (ds = 20:1).23 While further
study is required to understand the sense of stereoselection
observed here, the transition state model A (Scheme 6)
does not adequately support the selectivity observed in the
conversion of 26 to 27. We propose that stereochemical
control in this reaction is a result of an organized transition
state that features minimization of A1,3 strain and stabi-
lization by an intramolecular hydrogen bond (see B in
Scheme 6).24
Acknowledgment. The authors are grateful for financial
support of this work by the National Institutes of Health-
NIGMS (GM080266), Scripps Research Institute, and the
Japan Society for the Promotion of Science (JSPS, post-
doctoral fellowship to O.K.).
Supporting Information Available. Experimental pro-
cedures and tabulated spectroscopic data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
€
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(24) When the iodoetherification is conducted in acetonitrile, a
significant decrease in stereoselection is observed (2,2,5-cis/2,2,5-trans =
3:1).
The authors declare no competing financial interest.
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