Studies on the Synthesis of Gymnodimine. Stereocontrolled Construction of the Tetrahydrofuran Subunit

Article abstract of DOI:10.1021/ol030101c

(Equation presented) A bis-(2,6-dichlorobenzyl) ether is shown to undergo efficient and highly stereoselective intramolecular iodoetherification to yield a cis-2,5-disubstituted tetrahydrofuran, thus providing a powerful illustration of a stereodirecting

Full text of DOI:10.1021/ol030101c

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4109-4112
Studies on the Synthesis of
Gymnodimine. Stereocontrolled
Construction of the Tetrahydrofuran
Subunit
James D. White,* Guoqiang Wang, and Laura Quaranta
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received August 13, 2003
ABSTRACT
A bis-(2,6-dichlorobenzyl) ether is shown to undergo efficient and highly stereoselective intramolecular iodoetherification to yield a cis-2,5-
disubstituted tetrahydrofuran, thus providing a powerful illustration of a stereodirecting effect first noted by Rychnovsky and Bartlett. The
tetrahydrofuran was transformed into a subunit suitable for incorporation into the shellfish toxin gymnodimine.
Gymnodimine (1) first came to the public’s attention in 1994
when commercial oysters grown in Southland, New Zealand,
were found to contain high levels of a biotoxin that exhibited
neurotoxic shellfish poisoning in a mouse bioassay.1 The
same compound, isolated from oysters (Tiostrea chilensis)
collected at Foveaux Strait, New Zealand, was found to have
a minimum lethal dose (intraperitoneal) of 700 µg/mL in
the mouse bioassay.2 The structure of gymnodimine was
initially elucidated by NMR spectroscopy1 and confirmed
by X-ray crystallographic analysis, which also established
its absolute configuration.2
The azaspiro[5.5]undecadiene core of gymnodimine places
this substance in a close structural relationship with the
pinnatoxins3 and spirolides,4 neurotoxins in which the
spiroimine portion of the molecule appears to be the
pharmacophore.5 In concordance with this hypothesis, reduc-
tion of the imine moiety of 1 to give gymnodamine resulted
in a significant decrease in toxicity (MLD of gymnodamine
is >4040 mg/kg). Although gymnodimine is available in
quantity from its natural source (5 kg of oysters yielded 8.4
mg of 1), it is chemically unstable. The dihydro derivative
gymnodamine is more tractable and is being used to form
haptens in order to develop an immunoassay for a direct,
quantitative detection of 1 in shellfish.2
The novel features associated with the structure of gym-
nodimine have excited the interest of several groups, notably
those of Murai6 and Romo,7 who have disclosed their
syntheses of portions of the molecule. Our own efforts toward
the synthesis of 1 have focused on independent constructions
of the tetrahydrofuran and spiroimine subunits with the
eventual goal of connecting these segments to form the
complete macrocyclic core of 1. In this report, we describe
an approach to the tetrahydrofuran moiety that employs a
remarkably stereoselective cyclization of an acyclic bis-(2,6-
(1) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093.
(2) Stewart, M.; Blunt, J. W.; Munro, M. H.G.; Robinson, W. T.; Hannah,
D. J. Tetrahedron Lett. 1997, 38, 4889.
(3) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155.
(5) Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron
Lett. 1996, 37, 7671.
(6) (a) Ishihara, J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997,
1417. (b) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett 2002,
399.
(4) Hu, J.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Waston-Wright, W. M.; Wright, J. L. C. Chem. Commun. 1995, 2159.
(7) (a) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763. (b)
Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett. 2001, 3, 751.
10.1021/ol030101c CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

dichlorobenzyl) ether to produce the requisite cis-2,5-
disubstituted heterocycle. Our plan, outlined in Scheme 1,
bie protocol10 nor reductive displacement of the mesylate
derived from 6 was able to accomplish removal of the
superfluous hydroxyl function. On the supposition that (R)-
alcohol 8 would be less sterically crowded and therefore a
more compliant substrate for deoxygenation than its (S)-
diastereomer 6, the latter was oxidized to ketone 9 and then
reduced with L-Selectride to give 8 with good stereoselec-
tivity. Unfortunately, alcohol 8 proved to be equally resistant
to deoxygenation, the sole product under forcing conditions
being a conjugated diene resulting from elimination.
Scheme 1
In view of these difficulties, it was decided to postpone
removal of the hydroxyl group from 6 and to examine the
cyclization of precursors with this alcohol present in
protected form. Initially, we believed that an epoxide
prepared from 6 would be a suitable candidate for this
purpose, but epoxidation of this homoallylic alcohol pro-
ceeded without stereoselectivity and gave 10 as an insepa-
rable mixture (Scheme 3). Alcohol 6 was therefore converted
Scheme 3
envisioned a pathway from aldehyde 2 to the cyclization
precursor 3, with subsequent elaboration of the cyclization
product to a tetrahydrofuran 4 suitable for linkage to a second
major subunit of 1 such as 5.8
Our initial approach to 3 assumed that alcohol 6, prepared
with excellent stereoselectivity by asymmetric crotylation of
the glyceraldehyde derivative 79 (Scheme 2), could be
Scheme 2
to its p-methoxybenzyl ether, and the acetonide was cleaved
to furnish diol 11, which now became the focal point for
our intramolecular iodoetherification studies.
The diol 11 proved to be a poor substrate for cyclization,
but the monopivalate 12 gave a single tetrahydrofuran in high
yield (Table 1), which was found to be the undesired trans-
2,5-disubstituted iodomethyltetrahydrofuran as determined
by NOE experiments. Some improvement toward the cis-
2,5-disubstituted stereoisomer 18 was noted in the intramo-
lecular iodoetherification of silyl ether 13, the bis-(benzyl)
ether 14, and the pivalate 15, but a dramatic increase in the
proportion of the desired cis-disubstituted product 18 oc-
curred when the bis-(2,5-dichlorobenzyl) ether 16 of diol 11
was treated with iodine in acetonitrile at low temperature
(Table 1, entry 5).
deoxygenated to furnish a precursor suitable for cyclization
to a tetrahydrofuran. However, neither the Barton-McCom-
(9) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(10) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(8) For a different approach to the tetrahydrofuran subunit of gymnodi-
mine, see: Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27.
4110
Org. Lett., Vol. 5, No. 22, 2003

with earlier observations by Rychnovsky and Bartlett,11 who
showed that the 2,6-dichlorobenzyl substituent represents the
optimal combination of steric and electronic properties for
promoting a transition state for cyclization that avoids 1,2-
steric interactions, accommodates 1,3-interactions, and per-
mits facile cleavage of the intermediate oxonium ion 20
(Scheme 4).
With 19 in hand, it was then obligatory to remove the
oxygen function from C4 of the tetrahydrofuran; however,
before this could be done, it was necessary to replace the
iodo substituent with a group that would withstand the
deoxygenation process. This was achieved by displacement
of iodide from 19 with cesium trifluoroacetate followed by
cleavage of the trifluoroacetate ester with diethylamine to
give alcohol 21 (Scheme 5). The latter was then protected
as its silyl ether 22.
Table 1. Effect of Substituents upon Tetrahydrofuran
Formation via Intramolecular Iodoetherification
entry
compd
R1
R2
yield (%)
ratioa 18:17
1
2
3
4
5
12
13
14
15
16
Piv
Piv
Bn
Piv
H
TBS
Bn
Bn
DCBc
80b
85
72
66
87
>1:20
1:3
1:1
3:1
DCBc
>20:1
a Determined by 1H and 13C NMR. b p-Methoxybenzyl group was cleaved
in this case. c DCB ) 2,6-Dichlorobenzyl.
Confirmation of the structure of this tetrahydrofuran as
19 (Scheme 4) was obtained by both NOE experiments and
Scheme 4
Scheme 5
by X-ray crystallographic analysis (Figure 1). The formation
of 19 as the sole detectable isomer from 16 is in concert
After removal of the p-methoxybenzyl protection from 22,
alcohol 23 was subjected to reductive deoxygenation by
reaction with thiocarbonyldimidazole, followed by tributyl-
Figure 1. X-ray crystal structure of 19 (ellipsoids are drawn at
the 50% probability level).
(11) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963.
Org. Lett., Vol. 5, No. 22, 2003
4111

stannane,10 to produce tetrahydrofuran 24 in excellent yield.
Swern oxidation of the primary alcohol from cleavage of
silyl ether 24 afforded aldehyde 25, which reacted with
diethyl diazomethylphosphonate in the presence of base to
give alkyne 26. Stannylcupration-methylation12 of this
alkyne gave (E)-alkenylstannane 27, which underwent metal-
halogen exchange to yield (E)-iodoalkene 28. Finally,
removal of the dichlorobenzyl group from 28 was ac-
complished with trimethylsilyl iodide, generated in situ from
the chloride, and furnished alcohol 29 cleanly. This substance
now stands ready for connection to the second principal
subunit of 1, e.g., 5, whose synthesis will be described in
due course.
Acknowledgment. We thank Professor Alexandre F. T.
Yokochi of this department for the X-ray crystal structure
of 19 and Kurt F. Sundermann for preliminary studies leading
to 11. L.Q. is grateful to the Swiss National Science
Foundation for a Postdoctoral Fellowship. Financial support
for this work was provided by the National Institute of
General Medical Sciences through Grant GM58889.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
crystallographic data for 19. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H. Tetrahedron Lett.
1989, 30, 2065.
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