Synthesis of the C10-C22 bis-spiroacetal domain of spirolides B and D via iterative oxidative radical cyclization.

Article abstract of DOI:10.1021/ol026605c

[reaction: see text] A synthetic approach to the novel bis-spiroacetal moiety of spirolides B and D is reported. The strategy hinges upon successive formation of the spirocenters at C15 and C18 by radical oxidative cyclization, followed by base-induced re

Full text of DOI:10.1021/ol026605c

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3655-3658
Synthesis of the C10−C22
Bis-spiroacetal Domain of Spirolides B
and D via Iterative Oxidative Radical
Cyclization
Daniel P. Furkert and Margaret A. Brimble*
Department of Chemistry, UniVersity of Auckland, 23 Symonds St.,
Auckland, New Zealand
m.brimble@auckland.ac.nz
Received July 24, 2002
ABSTRACT
A synthetic approach to the novel bis-spiroacetal moiety of spirolides B and D is reported. The strategy hinges upon successive formation
of the spirocenters at C15 and C18 by radical oxidative cyclization, followed by base-induced rearrangement of a C19−20 r-epoxide to introduce
the C19 hydroxyl group.
Spirolides B and D (1 and 2, Figure 1) are members of a
novel family of marine macrolides isolated from mussels
(Mytilus edulis) and scallops (Placopecten magellanicus)
during routine monitoring for diarrhetic shellfish toxins in
Nova Scotia, Canada, in 1995.1 They induce characteristic
symptoms in the mouse bioassay (LD100 250µg/kg ip)
possibly through muscarinic acetylcholine receptor antago-
nism and are weak activators of L-type transmembrane Ca2+
channels. The relative and absolute stereochemistry has not
been established to date, but a tentative assignment based
on NMR studies has been reported.2 The spirolides are
metabolites of the marine dinoflagellate Alexandrium osten-
feldii3 and exhibit much structural homology with macrolides
of similar origin, including gymnodimine,4 the pteriotoxins,5
and most notably the pinnatoxins.6 In common with the
pinnatoxins, the spirolides possess a seven-membered spiro-
linked cyclic imine together with a novel bis-spiroacetal ring
system. The 1,7,9-trioxadispiro[4.1.5.2]tetradecane moiety
present in the spirolides has yet to be synthesized and forms
the focus of the current studies.7
Synthetic Strategy. The bis-spiroacetal moiety is present
in several classes of natural products and represents a unique
synthetic challenge. Most reported syntheses have proceeded
(1) Hu, T.; Curtis, J. M.; Oshima, Y.; Walter, J. A.; Watson-Wright, W,
M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995, 2159.
(2) Falk, M.; Burton, I. W.; Hu, T.; Walter, J. A.; Wright, J. L. C.
Tetrahedron 2001, 57, 8659.
(3) Cembella, A. D.; Bauder, A. G.; Lewis, N. I.; Quilliam, M. A. J.
Plankton Res. 2001, 12, 1413.
(4) Seki, T.; Masayuki, S.; MacKenzie, L.; Kaspar, H. F.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093.
(5) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495.
(6) Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155.
(7) Caprio, V.; Furkert, D. P.; Brimble, M. A. Tetrahedron 2001, 57,
4023.
Figure 1. Spirolides B (1, R ) H) and D (2, R ) Me).
Stereochemistry as assigned by Falk et al.2
10.1021/ol026605c CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/14/2002

via acid-catalyzed cyclization of a suitably functionalized
dihydroxy diketone precursor to furnish the corresponding
tricyclic bis-spiroacetal.8 The present study demonstrates the
viability of the construction of bis-spiroacetals using an
iterative oxidative radical cyclization strategy (Scheme 1).
Scheme 2. Synthesis of C16-C22 Dihydropyran. (8a, X )
Br; 8b, X ) I)
Scheme 1. Synthetic Strategy for the C10-C22 Domain of
the Spirolides
acetylide of 9 to aldehyde 10, available in two steps from
propane-1,3-diol. The TMS ether in 11 was selectively
cleaved by catalytic K2CO3 in methanol followed by Lindlar
reduction of the acetylene to give (Z)-alkene 12 in high yield.
Tosylation of the primary alcohol followed by treatment with
1 equiv of sodium hydride in THF afforded dihydropyran
13, which after cleavage of the silyl ether using TBAF was
converted to halide 8 via displacement of the corresponding
tosylate. Preparation of aldehyde 7 (Scheme 3) began with
Homoallylic alcohol 3 is a key intermediate for the
synthesis of spirolides B and D because it contains the 1,7,9-
trioxadispiro[4.1.5.2]tetradecane ring system and a glycal-
like functionality that may be readily hydrated to provide a
suitable electrophile for coupling with allylstannane deriva-
tives.9 Homoallylic alcohol 3 would be derived from epoxi-
dation and base-induced rearrangement of bis-spiroacetal 4,
for which precedent has been established on a simpler bis-
spiroacetal system.10 The two spiroacetal centers in 4 would
be formed by successive oxidative radical cyclization of
precursors 5 and 6 mediated by hypervalent iodine.8,11
Dihydropyran 6 in turn would be assembled from aldehyde
7 and an organometallic derivative of 8, enabling flexible
introduction of stereochemistry at C12 and C13 in order to
aid the assignment of the natural product. The thermo-
dynamically preferred configurations of bis-spiroacetals 3
and 4 are difficult to predict, due to the subtle interplay of
steric and electronic effects. Recent work on the synthesis
of azaspiracid and the pinnatoxins has demonstrated that the
stereochemistry of bis-spiroacetals obtained upon equilibra-
tion is dependent on the nature of the substituents present
on the ring system.12a-d
Scheme 3. Synthesis of C10-C15 Aldehyde
stereocontrolled crotylmetallation of aldehyde 14 to give
(12R,13R)-15 in 82% yield and >32:1 dr.13 The 12R,13R
configuration was selected both by analogy with pinnatoxin
A14 and the relative stereochemistry of the spirolides
proposed by Falk et al.2 Homoallylic alcohol 15 was then
The most practical preparative route to the C16-C22
dihydropyran 8 (Scheme 2) involved addition of the lithium
(12) (a) Nicolaou, K. C.; Qian, W.; Bernal, F.; Uesaka, N.; Pihko, P.
M.; Hinrichs, J. Angew. Chem., Int. Ed. 2001, 21, 4068. (b) Sugimoto, T.;
Ishihara, J.; Murai, A. Synlett 1999, 5, 541. (c) Carter, R. G.; Bourland, T.
C.; Graves, D. E. Org. Lett. 2002, 13, 2177. (d) Carter, R. G.; Graves, D.
E.; Gronemeyer, M. A.; Tschumper, G. S. Org. Lett. 2002, 13, 2181.
(13) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(b) Brimble, M. A.; Fares, F. A.; Turner, P. Aust. J. Chem. 2000, 10, 845.
(14) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zeng,
S. Z.; Chen, H. S. J. Am. Chem. Soc. 1995, 117, 1155.
(8) Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55, 7661.
(9) Brimble, M. A.; Fares, F. A.; Turner, P. J. Chem. Soc., Perkin Trans.
1 1998, 4, 677.
(10) Brimble, M. A.; Johnston, A. D. J. Org. Chem. 1998, 63, 471.
(11) (a) Dorta, R. L.; Mart´ın, A.; Salazar, J. A.; Suarez, E. J. Org. Chem.
1998, 63, 2251. (b) Allen, P. R.; Brimble, M. A.; Fares, F. A. J. Chem.
Soc., Perkin Trans. 1 1998, 2403.
3656
Org. Lett., Vol. 4, No. 21, 2002

the TBDPS ether with TBAF followed by esterification under
standard conditions led to bromobenzoate 18, which upon
equilibration with p-toluenesulfonic acid in dichloromethane
formed a mixture of the same three isomers in approximately
the same ratio (18a:18b:18c, Figure 2). Disappointingly,
none of the bromobenzoate derivatives yielded crystals
suitable for X-ray analysis.
Scheme 4. Bis-spiroacetal Formation via Radical Cyclization
Epoxidation of the major isomer of 4 (Scheme 5) was then
effected using dimethyldioxirane in acetone to give 19 as a
single diastereomer in 83% yield. Disappointingly, however,
base-induced rearrangement with excess LDA in THF did
not proceed at any temperature from -78 °C to reflux. This
difficulty was circumvented by the use of pentane or hexane
as the solvent, which allowed more effective coordination
of LDA to the epoxide oxygen, affording allylic alcohol 20
by syn â-deprotonation. Rearrangement to the thermody-
namically more stable homoallylic alcohol 3 was then
effected by further treatment with excess LDA in THF.
Interestingly, when rearrangement of epoxide 19 was per-
formed in hexane with lithium pyrrolidinyl amide, a 2:1 ratio
of 20:3 resulted, indicating that the nature of the base also
influences the extent of homoallylic alcohol formation.15
converted into aldehyde 7 in good yield using standard
transformations.
Coupling of 7 and 8 (Scheme 4) proved to be somewhat
problematic. Standard Grignard reaction conditions failed to
yield the desired product, and only mediocre yields were
obtained using an organolithium species derived from iodide
8b. Alcohol 6 was finally prepared reproducibly in 64% yield
using Barbier conditions in diethyl ether, together with the
undesired Wurtz coupling product of 8a.
Scheme 5. Epoxidation and Rearrangement of the C19-C20
Olefin
Cyclization of 6 in the presence of PhI(OAc)2 and iodine
under irradiation cleanly gave spiroacetal 17 in 90% yield.
The TES ether of 17 was then selectively cleaved in THF
by portionwise addition of HF‚pyridine over several hours.
Finally, the resultant hydroxy spiroacetal 5 underwent smooth
cyclization to 4 upon treatment with PhI(OAc)2 and iodine.
Prolonged stirring of the initial 1:1:1:1 product mixture with
a catalytic quantity of p-toluenesulfonic acid in dichloro-
methane gave a 3:1:0.9 mixture (4a:4b:4c, Figure 2) of three
of the four possible C15,C18 configurational isomers that
were separable by careful chromatography. Deprotection of
In an effort to clarify the stereochemistry of the thermo-
dynamically preferred isomers of the 1,7,9-trioxadispiro-
[4.1.5.2]tetradecane ring system (Figure 2), computer mod-
eling was carried out for 4 (TBDPS replaced by TMS for
calculations), bromobenzoate 18, and the parent alcohol (R
) H). Relative energies were calculated at the ab initio level
(Hartree-Fock, 3-21G* basis set), using semiempirical
optimized geometries (AM1) for all molecular mechanics
conformers (MMFF94) within 3 kcal/mol of the global
minimum. In all cases, the calculated energies follow the
trend cis/syn < trans/syn < trans/anti , cis/anti, where cis/
trans refers to the arrangement of oxygens across the central
ring and syn/anti to the central oxygen and the alkyl
substituent at C12. Extensive two-dimensional NMR studies
support tentative assignments of 4a-c and 18a-c (Figure
2) in agreement with calculation.
In summary, a synthetic route to the novel 1,7,9-
trioxadispiro[4.1.5.2]tetradecane ring system of spirolides B
and D has been developed using an iterative oxidative radical
Figure 2. Putative assignments for 4a-c and 18a-c showing
selected NOESY correlations.
(15) Rickborn, B.; Kissel, C. L. J. Org. Chem. 1972, 13, 2060.
Org. Lett., Vol. 4, No. 21, 2002
3657

cyclization strategy to form the C15 and C18 spirocenters.
Bis-spiroacetal 4 was prepared as a separable 3:1:1 thermo-
dynamic mixture of diastereomers for which the stereochem-
istry has been assigned on the basis of two-dimensional NMR
and ab initio molecular modeling.
Acknowledgment. The authors thank the University of
Auckland and the Royal Society of New Zealand Marsden
Fund for financial support.
OL026605C
3658
Org. Lett., Vol. 4, No. 21, 2002