Pectenotoxin-2 synthetic studies. 2. Construction and conjoining of ABC and DE eastern hemisphere subtargets

Article abstract of DOI:10.1021/ol0504291

(Chemical Equation Presented) Practical asymmetric synthesis of aldehyde 2 and tetrazolyl sulfone 3 has allowed for their coupling via Julia olefination to generate 32 as a single product. This substance possesses the entire carbon backbone of the A-E substructure of pectenotoxin-2.

Full text of DOI:10.1021/ol0504291

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1813-1816
Pectenotoxin-2 Synthetic Studies. 2.
Construction and Conjoining of ABC
and DE Eastern Hemisphere Subtargets
Dmitriy Bondar, Jian Liu, Thomas Mu1ller, and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received February 26, 2005
ABSTRACT
Practical asymmetric synthesis of aldehyde 2 and tetrazolyl sulfone 3 has allowed for their coupling via Julia olefination to generate 32 as a
single product. This substance possesses the entire carbon backbone of the A E substructure of pectenotoxin-2.
−
The pectenotoxins comprise a small unique family of
complex marine natural products.1 As a result of their
nanomolar cytotoxic properties2 and fascinating structural
features, a unified, highly convergent route to the most potent
member, pectenotoxin-2 (1), has been undertaken at Ohio
State3 and leading laboratories elsewhere.4,5 The considerable
progress made in devising a route to the western FG sector
has been detailed in our earlier report.3 In continuation of
this theme, we detail herein the assembly of subunits ABC
(2) and DE (3) (Scheme 1). Taken together, these building
blocks constitute the entire C1-C26 eastern two-thirds of
the target compound.
From among several possible options for constructing 2,
we came to favor a strategy wherein convergency would be
realized via coupling to a Weinreb amide, with spiroacetal
generation following soon thereafter. The pathway originated
by aldol condensation involving chiral auxiliary 46 and the
known aldehyde 57 in the presence of dibutylboron triflate,
which resulted in the stereocontrolled generation of 68
(Scheme 2). Here we were able to protect the hydroxyl group
as the PMB ether via trichloroacetimidate technology9 in
advance of reductive cleavage of the oxazolidinone ring with
LiAlH410 and formation of the tert-butyldiphenylsilyl ether11
as in 8. The latter was subjected to hydrogenolysis over W-2
(1) (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M,; Matsumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019. (b) Sasaki, K.; Wright, J. L.
C.; Yasumoto, T. J. Org. Chem. 1998, 63, 2475. (c) Daiguji, M.; Satake,
M.; James, K. J.; Bishop, A.; Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem.
Lett. 1998, 653.
(2) (a) Ishige, M.; Satoh, N.; Yasumoto, T. Rep. Hokkaido Inst. Health
1988, 38, 15. (b) Jung, J. H.; Sim, S.; Lee, C. O. J. Nat. Prod. 1995, 58,
1722. (c) Zhou, Z. H.; Komiyama, M. K.; Terao, K.; Shimada, Y. Nat.
Toxins 1994, 58, 1722.
(3) (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.
(4) For relevant preliminary reports dealing with other approaches to 1,
consult: (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300. (b)
Awahura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733. (c) Micalizio,
G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. (d) Pihko, P. M.; Aho, J. E.
Org. Lett. 2004, 6, 3849.
(5) For successful completion of an asymmetric synthesis of pecteno-
toxins-4 and -8, see: (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.
(6) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
(7) Kiddle, J. J.; Green, D. L. C.; Thompson, C. M. Tetrahedron 1995,
51, 2851.
(8) Okuno, T.; Ohmori, K.; Nishiyama, S.; Yamamura, S.; Nakamura,
K.; Houk, K. N.; Okamoto, K. Tetrahedron 1996, 52, 14723.
(9) Humada, Y.; Yokokawa, F.; Kabeya, M.; Hatano, K.; Kurono, Y.,
Shioiri, T. Tetrahedron 1996, 52, 8297.
(10) Mori, Y.; Asai, M.; Kawade, J.; Furukawa, H. Tetrahedron 1995,
51, 5315.
10.1021/ol0504291 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/06/2005

Scheme 1
Raney nickel,12 which catalyst was instrumental in removing
the benzyl group selectively in the presence of the OPMB
prepared from L-glutamic acid as outlined in Scheme 3.15-17
Since the chromatographic purification of the precursor to
11 on silica gel often resulted in reversion to the lactone,18
immediate conversion to the PMB derivative was always
undertaken.
Ketone 12 was integrated within the synthetic path-
way by reaction with DDQ in the presence of moist
CH2Cl2.12 This 2-fold deprotection step resulted in cycli-
zation to give predominantly that spiroacetal assumed to
be the diastereomer stabilized by the anomeric effect
(Figure 1). The first of two chain extensions was suitably
addressed by reductive cleavage of the benzyl ether with
lithium di-tert-butylbiphenyl,19 oxidation with the Dess-
Martin periodinane,20 and a Wittig reaction. This se-
quence of steps delivered 14 efficiently, and made pos-
sible the acquisition of 15 by subsequent Dibal-H reduc-
tion and asymmetric epoxidation with L-(+)-diethyl tar-
trate.21 Incorporation of the requisite two additional car-
bons was accomplished in a comparable way with the
Figure 1. MM3 calculations of the two possible stereoisomers of
13 as the dimethoxy derivative.
ether. Following the conversion of 9 into iodide 10 in a
conventional manner,13 we proceeded to effect its lithiation
with tert-butyllithium14 in advance of the addition of 11,
Scheme 2. Synthesis of 2
1814
Org. Lett., Vol. 7, No. 9, 2005

as a 15:1 E/Z mixture. The subsequent three-step con-
version of 23 to ester 25 was notably efficient, thereby set-
ting the stage for establishing the feasibility of selective
acetonide hydrolysis in the presence of a tertiary MOM
ether. In practice, we turned to 60% acetic acid at 0 °C.
Acceptable yields of the targeted diol were realized, how-
ever, only if reaction was allowed to proceed for ap-
proximately 5 h. In view of the limited solubility of 25 in
the reaction medium, its selective extraction into hexane
allowed for the convenient isolation of the diol and its
stereocontrolled conversion to epoxide 26. The reaction of
this intermediate with AD-mix-â was next studied and
several products were observed under standard conditions.
Ultimately, treatment with H2S in place of a standard workup
procedure promoted acid-catalyzed cyclization and afforded
uniquely tetrahydrofuran 27, whose structural formulation
rests convincingly on the results of detailed COSY and
NOESY experiments.
Scheme 3. Preparation of 11
lower ylide. The final steps in the pursuit of 2 involved the
formation of 16 by oxidation catalyzed with bis(dipivaloyl-
methanato)manganese(III) complex,22 protection as the PMB
derivative, and controlled reduction of the ester group.
To position ourselves to produce 3, benzyl ether 1723
was subjected to asymmetric dihydroxylation24 with
AD-mix-R25 and selective silylation of the primary car-
binol as in 18 (Scheme 4). After proper modification of
the hydroxyl protecting groups, the 1-phenyl-1H-tetrazol-
5-yl sulfone 21 was synthesized according to the Kocienski
protocol.26 Concurrently, access to 22 was likewise gained
from 17 by sequential Sharpless dihydroxylation, conver-
sion to the acetonide, hydrogenolytic cleavage of the
benzyl ether, and periodinane oxidation. The Julia-Lythgoe
coupling of 21 to 22 proceeded as planned to provide 23
The sequel to this concise routing consisted of selec-
tive primary hydroxyl protection as the TBS ether in
advance of reduction to the lactol and ring-opening
Wittig olefination. Subsequent formation of the PMB
ether made possible terminal functionalization of the chain
via hydroboration and formation of the tetrazolyl sul-
fone 3.
Once 2 and 3 became available, they were conjoined
by means of the Julia protocol to afford 32 as a single
product in 89% yield (Scheme 5). The E nature of the
Scheme 4. Synthetic Route to 3
Org. Lett., Vol. 7, No. 9, 2005
1815

Note Added after ASAP Publication. Reference 4d was
missing from the version published on April 6, 2005; the
corrected version was published on April 11, 2005.
Scheme 5. Conjoining of 2 and 3
Supporting Information Available: Experimental details
1
and H NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0504291
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interconnective double bond so generated was apparent
from the coupling constant of 15.7 Hz for the olefinic
protons.
(20) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(21) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
In summary, the entire carbon backbone of the A-E
subsector of pectenotoxin-2 has been assembled through total
synthesis. Ongoing work is targeting the more advanced
oxygenation of 32 and its proper attachment to the western
FG building block whose construction we have previously
reported.3
(22) (a) Inoki, S.; Kato, K.; Isayama, S.; Mukaiyama, T. Chem. Lett.
1990, 1869. (b) Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Rainey,
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(23) Prepared by heating methallyl alcohol with triethyl orthoacetate in
the presence of pivalic acid followed by LiAlH4 reduction and O-benzylation
of the Claisen rearrangement product.
(24) The enantiomeric purity of the resulting diol of [R]23D -2.5 (c 0.67,
CHCl3) was shown to be > 95% ee by hplc analysis on a chiral OD column
and by hydrogenolysis to give the triol whose [R]21D -1.1 (c 2.5, CH3OH)
(11) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc. 1981,
103, 1224.
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2010.
compared closely to the value, [R]23 -1.2 (c 1.7, CH3OH), reported by
D
Mori [Mori, K. Tetrahedron 1975, 31, 1381] for 100% pure material.
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1816
Org. Lett., Vol. 7, No. 9, 2005