Synthesis of the bis-spiroacetal moiety of spirolides B and D

Article abstract of DOI:10.1021/ol051260u

(Chemical Equation Presented) An enantioselective synthesis of the bis-spiroacetal fragment of spirolides B and D is reported. The carbon framework was constructed via Barbier reaction of dihydropyran 3 with aldehyde 4, followed by a double oxidative radi

Full text of DOI:10.1021/ol051260u

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3497-3500
Synthesis of the Bis-spiroacetal Moiety
of Spirolides B and D
Kai Meilert and Margaret A. Brimble*
Department of Chemistry, UniVersity of Auckland, 23 Symonds Street,
Auckland, New Zealand
m.brimble@auckland.ac.nz
Received May 29, 2005
ABSTRACT
An enantioselective synthesis of the bis-spiroacetal fragment of spirolides B and D is reported. The carbon framework was constructed via
Barbier reaction of dihydropyran 3 with aldehyde 4, followed by a double oxidative radical cyclization to construct the bis-spiroacetal. A
silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor. The initial
unsaturated bis-spiroacetals 2a−d underwent equilibration during epoxidation to trans-epoxide 14 that was converted to a tertiary alcohol.
The spirolides,1 (Scheme 1) structurally related to the
pinnatoxins,2 gymnodimines,3 and pteriatoxins,4 are a family
of marine toxins isolated from mussels (Mytilus edulis) and
scallops (Placopecten magellanicus) from the eastern coast
of Nova Scotia, Canada. The spirolides have been determined
to be metabolites of the marine dinoflagellate Alexandrium
ostenfeldii5 that induce characteristic symptoms in the mouse
bioassay (LD100 250 µg/kg ip) and are weak activators of
L-type transmembrane Ca2+ channels. The complete relative
and absolute stereochemistry of the spirolides has not been
established to date, but a tentative assignment based on NMR
studies and molecular modeling has been reported.6 The
absolute stereochemistry at C2 and C4 remains uncertain,
except for their syn relationship, but is predicted to be similar
to that of pinnatoxin.7 In common with the pinnatoxins, the
Scheme 1. Synthetic Strategy for the C10EnDash-C23
Fragment of Spirolides B and D
(1) (a) 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. (b)
Aasen, J.; MacKinnon, S. L.; LeBlanc, P.; Walter, J. A.; Hovgaard, P.;
Aune, T.; Quilliam, M. A. Chem. Res. Toxicol. 2005, 18, 509.
(2) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155. (b) Chou, T.;
Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023. (c) Chou, T.;
Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996, 37, 4027.
(d) Takada, N.; Uemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.; Haino,
T.; Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3491.
(3) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto,
T. Tetrahedron Lett. 1995, 36, 7093. (b) Stewart, M.; Blunt, J. W.; Munro,
M. H. G.; Robinson, W. T.; Hannah, D. J. Tetrahedron Lett. 1997, 38,
4889. (c) Miles, C. O.; Wilkins, A. L.; Stirling, D. J.; MacKenzie, A. L. J.
Agric. Food Chem. 2000, 48, 1373.
(4) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495.
(5) Cembella, A. D.; Bauder, A. G.; Lewis, N. I.; Quilliam, M. A. J.
Plankton Res. 2001, 12, 1413.
10.1021/ol051260u CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/01/2005

spirolides possess a seven-membered spirolinked cyclic imine
together with a novel bis-spiroacetal ring system. Initial
reports into the structure-activity relationship of these
macrolides indicated that the spirocyclic imine is the key
pharmacophore.8 The total synthesis of the spirolides has not
been reported to date; however, a synthesis of the bis-
spiroacetal moiety via an acid-catalyzed cyclization has
recently been reported.9
Scheme 2. Synthesis of the C16-C23 Dihydropyran
Fragment
In addition to our work on the synthesis of model
spiroimines10 related to the spirolides, we have previously
also reported the synthesis of a C10-C22 bis-spiroacetal
fragment that lacked the C19 tertiary alcohol group using a
double oxidative radical cyclization.11 However, problems
were encountered during the introduction of functionality at
C19 and extension of the carbon framework at C22, thus
prompting adoption of a modified synthetic plan in which
disconnection of the C23-C24 bond rather than the C22-
C23 bond was a pivotal step. The results of this revised
strategy are presented herein, providing rapid access to the
fully functionalized C10-C23 bis-spiroacetal fragment of
spirolides B and D that is homologous to our previous
fragment. This new approach relies on a silyl-modified Prins
cyclization12 to access dihydropyran 3 with the required (S)-
configuration at C22 (Scheme 1). The two spiroacetal centers
are then formed by oxidative radical cyclization of the
alcohol resulting from the Barbier coupling of this dihydro-
pyran with aldehyde 4. The syn stereochemistry in aldehyde
4 is available from an enantioselective crotylation. The alkene
in bis-spiroacetal 2 provides functionality for subsequent
installation of the tertiary alcohol. It is also envisaged that
the cis stereochemistry between the terminal rings of the bis-
spiroacetal will be established by equilibration after incor-
poration into the macrocyclic ring. Thus, initial synthesis of
trans-bis-spirocetals 1 and 2 was required.
prepared by semihydrogenation of the corresponding acety-
lene 6 in the presence of a poisoned catalyst. Use of the
Rosenmund catalyst (Pd/BaSO4)16 gave moderate E/Z selec-
tivities and poor yields, while Lindlar’s catalyst (Pd/CaCO3/
Pb)17 gave variable selectivities.18 Similar selectivity prob-
lems have been observed by others for alkynes bearing a
trimethylsilyl substituent.19
Eventually, hydroalumination of 6 in ether12a using
DIBAL-H (1 M in hexane) gave the desired olefin 7 with
high (Z)-selectivity (92:8). The desired 1,3-cis (cis/trans >
4:1) dihydropyran 3 was then prepared using a silyl-modified
Prins cyclization of vinylsilane 7 with acetal 8 catalyzed by
either indium trichloride (72%)12c,d or iron trichloride (52%).12e
Aldehyde 4 was synthesized in five steps (44% overall
yield) from monoprotected 1,3-propanediol 920 (Scheme 3).
Swern oxidation21 followed by reagent-controlled enantiose-
lective crotylation22 gave the desired (3R,4R)-allylic alcohol23
10 in 97% optical purity and dr > 95:5.24 After protection
as a tert-butyldiphenylsilyl ether, hydroboration with borane
dimethyl sulfide afforded an alcohol that was oxidized with
Dess-Martin periodinane25 to give the required aldehyde 4.
Use of Barbier conditions26a to couple aldehyde 4 with
bromide 3 proved to be more efficient than use of standard
The synthesis of the dihydropyran fragment 3 was carried
out in three steps (51% overall yield), starting from enan-
tiomerically pure O-benzyl-protected13 (R)-(+)-glycidol
(Scheme 2). Ring opening of epoxide 5 with lithium
trimethylsilylacetylide in the presence of a catalytic amount
of trimethylaluminum14 afforded homopropargyl alcohol 6
in higher yield than when using a stoichiometric amount of
boron trifluoride diethyl etherate.15 Vinylsilane 7 was initially
(15) For method, see: Ichikawa, Y.; Isobe, M.; Bai, D.-L.; Goto, T.
Tetrahedron 1987, 43, 4737.
(16) Rosenmund, K. W. Chem. Ber. 1918, 51, 686.
(17) (a) Lindlar, H. HelV. Chim. Acta 1952, 35, 446. (b) Kurihara, M.;
Ishii, K.; Kasahara, Y.; Miyata, N. Tetrahedron Lett. 1999, 40, 3183.
(18) Optimum solvent was THF, affording 85:15 selectivity in favor of
the desired (Z)-7 (69%). The (Z)-configuration of 7 is crucial for the
formation of dihydropyran 3, as elimination of the trimethylsilyl group from
the resultant six-membered ring formed from the (E)-isomer is very slow
(<10% conversion after 12 h).
(19) (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1990, 31, 5113.
(b) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823. (c)
Trost, B. M.; Braslau, R. Tetrahedron Lett. 1989, 30, 4657. (d) Kini, A.
D.; Nadkarni, D. V.; Fry, J. L. Tetrahedron Lett. 1994, 35, 1507.
(20) Coelho, F.; Diaz, G. Tetrahedron 2002, 58, 1647. For a two-step
procedure, see: Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 889.
(6) Falk, M.; Burton, I. W.; Hu, T.; Walter, J. A.; Wright, J. L. C.
Tetrahedron 2001, 57, 8659.
(7) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(8) Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron
Lett. 1996, 37, 7671.
(9) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron
Lett. 2004, 45, 7855.
(10) Brimble, M. A.; Trzoss, M. Tetrahedron 2004, 60, 5613.
(11) Brimble, M. A.; Furkert, D. P. Org. Biomol. Chem. 2004, 2, 3573.
(12) Silyl-modified Prins cyclization and the silyl-modified Sakurai
cyclization are in fact the same reaction, and the name silyl Prins is adopted
herein. See: (a) Marko, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141.
(b) Marko, I. E.; Mekhalfia, A.; Bayston, D. J.; Adams, H. J. Org. Chem.
1992, 57, 2211. (c) Dobbs, A. P.; Martinovic, S. Tetrahedron Lett. 2002,
43, 7055. (d) Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S. J.;
Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880. (e) Miranda, P. O.; Diaz,
D. D.; Padron, J. I.; Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979.
(13) Lai, M. T.; Oh, E.; Shih, Y.; Liu, H.-W. J. Org. Chem. 1992, 57,
2471.
(21) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(22) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(23) Absolute configuration of ent-10 has been assigned by X-ray
diffraction of the derived camphanic ester; see: Meilert, K. T.; Clark, G.
R.; Groutso, T.; Brimble, M. A. Acta Crystallogr. Sect. E 2005, E61, O6.
(24) Enantiomeric excess was measured by 19F NMR after formation of
the Mosher ester.
(14) For method, see: Ooi, T.; Kagoshima, N.; Ichikawa, H.; Maruoka,
K. J. Am. Chem. Soc. 1999, 121, 3328.
(25) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
3498
Org. Lett., Vol. 7, No. 16, 2005

Scheme 3. Synthesis of the C10-C15 Aldehyde Fragment
Table 1. Equilibration of Bis-spiroacetals 2a and 2b
and Bis-spiroacetal Formation
entry
conditions
2a/2b (yield)
1
2
3
4
5
HF‚Pyr, MeCN, rt, 12 h
76:24 (81%)
∼81:19 (89%)
76:24 (95%)
∼83:17 (88%)
87:13 (85%)
PPTS (0.2 equiv), MeCN, rt, 18 h
ZnBr2 (0.2 equiv), CH2Cl2, rt, 19 h
ZnCl2 (0.2 equiv), CH2Cl2, rt, 24 h
InCl3 (0.2 equiv), MeCN, rt, 1 h
two-dimensional NMR NOESY experiments,27 which showed
clear correlations between H-9 and H-4 and between 3-CH3
and H-14, respectively (Table 1).
Initially, introduction of the tertiary alcohol onto the
unsaturated bis-spiroacetal 2 was achieved using a hydro-
boration-oxidation sequence. Use of BH3‚SMe2 or BH3‚THF
afforded low yields of the undesired C11 ketone after Dess-
Martin oxidation of the resultant alcohol, together with olefin-
containing side products. Direct introduction of the ketone
by Wacker oxidation28 was also unsuccessful in that oxy-
palladation seemed to be directed toward formation of the
undesired C11 ketone. Finally, treatment of the 1:1:1:1
mixture of bis-spiroacetals 2a-d with m-CPBA afforded the
â-epoxide 14 as a single diastereomer (Scheme 4). Remark-
Grignard26b conditions. The coupled product 11 was isolated
in 88% yield as a ∼1:1 mixture of diastereomers at C3′
(Scheme 3). The two diastereomers were easily separated
by flash chromatography, but the mixture was used through-
out the synthesis, as equilibration of the bis-spiroacetals
2a-d was required at a later stage.
Scheme 4. Equilibration and Introduction of the Tertiary
Alcohol
With alcohol 12 in hand, attention was turned to the
iterative oxidative radical cyclization steps (Scheme 3).11
Irradiation of 11a,b with a 60 W desk lamp in the presence
of iodobenzene diacetate and iodine in cyclohexane gave the
spiroacetal 12 in 86% yield. The tert-butyldiphenylsilyl ether
was then deprotected, and the bis-spiroacetal core structure
was formed upon execution of a second oxidative radical
cyclization providing bis-spiroacetals 2a-d in 81% yield as
a 1:1:1:1 mixture of diastereomers.
Acid-catalyzed equilibration of the 1:1:1:1 mixture of bis-
spiroacetals 2a-d gave a ∼4:1 mixture of two major isomers
(2a and 2b) together with trace quantities (<5%) of two other
minor isomers (Table 1). Interestingly, use of indium
trichloride gave better results than the more commonly used
reagents such as HF‚Pyr, PPTS, ZnBr2 or ZnCl2, affording
an 87:13 mixture of the thermodynamically favored isomers
2a and 2b (Table 1, entry 5). The absolute configuration at
C5 and C7 in isomer 2a was assigned unambiguously using
ably, the presence of meta-chlorobenzoic acid and water in
the m-CPBA29 effected equilibration of the mixture of bis-
spiroacetals 2a-d to the most thermodynamically favored
(27) Use of a 600 MHz spectrometer was necessary in order to see
splitting of the signals.
(28) For examples of heteroatom-directed Wacker oxidations see: (a)
Tsuji, J. Synthesis 1984, 5, 369. (b) Kang, S. K.; Jung, K. Y.; Chung, J. U.;
Namkoong, E. Y.; Kim, T. H. J. Org. Chem. 1995, 60, 4678. (c) Lai, J. Y.;
Shi, X. X.; Dai, L. X. J. Org. Chem. 1992, 57, 3485.
(29) mCPBA purchased from Fluka contains ∼10% m-chlorobenzoic acid
and ∼20% H2O.
(26) (a) Barbier P. Compt. Rend. 1899, 128, 110. (b) Grignard, V. Compt.
Rend. 1890, 130, 1322.
Org. Lett., Vol. 7, No. 16, 2005
3499

H11 or H12 as would be expected if epoxidation had taken
place from the R face. For tertiary alcohol 1, clear correla-
tions between H9 and H4 and between H2 and H11 clearly
established the trans arrangement of the oxygen atoms about
the central ring. The absolute configuration of the CH3 at
C12 was assigned by the observed correlation with H13. The
trans stereochemistry adopted by tertiary alcohol 1 represents
the thermodynamically favored isomer,9 and it is envisaged
that reequilibration of the bis-spiroacetal to the desired cis
stereochemistry as found in the spirolides will take place
upon incorporation of this moiety into the macrocyclic
system.
The present work demonstrates the efficient construction
of the bis-spiroacetal ring system present in the spirolides
using an iterative oxidative radical cyclization strategy. Use
of InCl3 and m-CPBA to effect equilibration of the 6,5,5-
bis-spiroacetal ring system provides further examples of
reagents to effect spiroacetalizations in a stereoselective
fashion. Furthermore, the use of a silyl-modified Prins
cyclization provides an efficient entry to the dihydropyran
unit of the cyclization precursor.
Figure 1. Characteristic NOESY correlations for the assignment
of the absolute configuration of 14 and 1.
isomer 2a, which then underwent stereoselective epoxidation
from the â-face, presumably due to hydrogen bonding effects.
Epoxide 14 underwent regioselective reductive opening with
DIBAL-H, and the resultant alcohol was oxidized upon
treatment with Dess-Martin periodinane.25 Analogous to the
observations reported by Ishihara et al.,9 stereoselective axial
addition of methylmagnesium bromide to the ketone afforded
the desired tertiary alcohol 15 with the same stereochemistry
as that present in the spirolides.
Acknowledgment. We would like to thank the Swiss
National Science Foundation and the Royal Society of New
Zealand Marsden Fund for financial support, Michael Walker
for helpful discussions concerning NMR experiments, and
L. Ravi Sumoreeah for preliminary experimentation on the
silyl-modified Prins cyclization.
The stereochemistry of epoxide 14 and tertiary alcohol 1
was assigned unambiguously by two-dimensional NMR
NOESY experiments27 (Figure 1). For epoxide 14, correla-
tions between H9 and H4, between H12 and H13, and
between 3-CH3 and H14 established the stereochemistry as
indicated. No correlations were observed between H9 and
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 2, 14, and 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051260U
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Org. Lett., Vol. 7, No. 16, 2005