Synthesis of the ABCD trioxadispiroketal subunit of azaspiracid-1: An iodoetherification-dehydroiodination strategy for complex spiroketals

Article abstract of DOI:10.1021/ol701866v

An unusual spiroketalization strategy in which a hydroxyalkene serves as a precursor to a cyclic enol ether was applied to the synthesis of the ABCD trioxadispiroketal subunit of azaspiracid-1. The trioxadispiroketal product, which represents a double ano

Full text of DOI:10.1021/ol701866v

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4303-4306
Synthesis of the ABCD
Trioxadispiroketal Subunit of
Azaspiracid-1: An
Iodoetherification−Dehydroiodination
Strategy for Complex Spiroketals
Xiaohua Li, Jialiang Li, and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park AVenue,
New York, New York 10065, and The Graduate Center, CUNY, 365 5th AVenue,
New York, New York 10016
dmootoo@hunter.cuny.edu
Received August 1, 2007
ABSTRACT
An unusual spiroketalization strategy in which a hydroxyalkene serves as a precursor to a cyclic enol ether was applied to the synthesis of
the ABCD trioxadispiroketal subunit of azaspiracid-1. The trioxadispiroketal product, which represents a double anomeric effect, was obtained
as a single trioxadispiroketal diastereomer. A key ploy in the synthesis of the CD segment was the use of a cyclopropane as a synthon for
the C-14 methyl group.
The unique bioactivity and structural complexity of the
marine shellfish toxin azaspiracid-1 11,2 (Figure 1) has led
to considerable interest in its synthesis. Total syntheses of 1
by the Nicolaou group led to correction of the originally
reported structure.3 The synthesis of ent-1 was subsequently
reported by the Evans group.4 In the correct structure, the
alkene in ring A is located at C7-C8 and the configuration
of the trioxadispiroketal corresponds to a double anomeric
effect, which appears to be thermodynamically favored.3f,5g
The laboratories of Carter and Forsyth have also completed
(1) McMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2.
(2) Ito, E.; Satake, M.; Ofuji, K.; Kurita, N.; McMahon, T.; James, K.;
Yasumoto, T. Toxicon 2000, 38, 917-930.
(3) (a) Nicolaou, K. C.; Vyskocil, S.; Koftis, V. T.; Yamada, Y. M. A.;
Ling, T.; Chen, D. Y.-K.; Tang, W.; Petrovic, G.; Frederick, M. O.; Satake,
Y. M. Angew. Chem., Int. Ed. 2004, 43, 4312-4318. (b) Nicolaou, K. C.;
Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.; Yamada, Y. M. A.; Tang,
W.; Frederick, M. O. Angew. Chem., Int. Ed. 2004, 43, 4318-4324. (c)
Nicolaou, K. C.; Pihko, P. M.; Bernal, F.; Frederick, M. O.; Qian, W.;
Uesaka, N.; Diedrichs, N.; Hinrichs, J.; Koftis, T. V.; Loizidou, E.; Petrovic,
G.; Rodriquez, M.; Sarlah, D.; Zou, N. J. Am. Chem. Soc. 2006, 128, 2244-
2257. (d) Nicolaou, K. C.; Chen, D. Y.-K.; Li, Y.; Uesaka, N.; Petrovic,
G.; Koftis, T. V.; Bernal, F.; Frederick, M. O.; Govindasamy, M.; Ling,
T.; Pihko, P. M.; Tang, W.; Vyskocil, S. J. Am. Chem. Soc. 2006, 128,
2258-2267. (e) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.;
Tang, W.; Frederick, M. O.; Chen, D. Y.-k.; Li, Y.; Ling, T.; Yamada, Y.
M. A. J. Am. Chem. Soc. 2006, 128, 2859-2872. (f) Nicolaou, K. C.;
Frederick, M. O.; Petrovic, G.; Cole, K. P.; Loizidou, E. Z. Angew. Chem.,
Int. Ed. 2006, 45, 2609-2615.
Figure 1. Revised structure of azaspiracid-1.
10.1021/ol701866v CCC: $37.00
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syntheses of the ABCD subunit,5g,6f and several other
synthetic studies have been reported.5-7
Scheme 1. Retrosynthetic Analysis
At the onset of our studies, we were interested in a plan
that would be compatible with the different functional groups
contained in the ABCD subunit, not the least of which was
the potentially sensitive homoallylic acetal that comprises
the trioxadispiroketal residue. In this vein, we envisaged a
strategy in which a hydroxy-iodo-THP such as 3 could serve
as a precursor to spiroketal 4 through the intermediacy of
an exocyclic enol ether. Since highly functionalized variants
of iodo cyclic ether 3 could be obtained from the iodoetheri-
fication of dihydroxyalkenes such as 2,8 which may be
assembled in a convergent fashion, such an approach would
be especially appropriate for complex spiroketal frame-
works.9,10 In essence the alkene moiety in 2 is regioselectively
elaborated to an acetal, a transformation that is synthetically
similar to the metal-mediated elaboration of an alkyne.11
A
possible application of this plan to the ABCD azaspiracid-1
subunit 5 calls for a hydroxy-hemiacetal-alkene precursor
6 and provided an opportunity for examination of this spiro-
ketalization strategy in a complex setting.12 The C10-C11
(azaspiracid numbering) alkene in 6 provides a practical point
for retrosynthetic dissection into olefination partners 7 and
8 (Scheme 1). The likelihood that alkene geometry is incon-
sequential to the synthetic outcome means that a stereose-
lective alkene synthesis would not be necessary.
Sulfone 7 was obtained from the known aldehyde 9
(Scheme 2)13 via a reaction sequence involving standard
(4) Evans, D. A.; Kvœrnø, L.; Mulder, J. A.; Raymer, B.; Dunn, T. B.;
Beauchemin, A.; Olhava, E. J.; Juhl, M.; Kagechika, K. Angew. Chem.,
Int. Ed. 2007, 46, 4693-4697. Evans, D. A.; Dunn, T. B.; Kvœrnø, L.;
Beauchemin, A.; Raymer, B.; Olhava, E. J.; Mulder, J. A.; Juhl, M.;
Kagechika, K.; Favor, D. A. Angew. Chem. 2007, 119, 4782-4787; Angew.
Chem., Int. Ed. 2007, 46, 4698-4703.
Scheme 2. Synthesis of Sulfone 7
(5) (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913-3916. (b)
Carter, R. G.; Graves, D. E. Tetrahedron Lett. 2001, 42, 6035-6039. (c)
Carter, R. G.; Bourland, T. C.; Graves, D. E. Org. Lett. 2002, 4, 2177-
2179. (d) Carter, R. G.; Graves, D. E.; Gronemeyer, M. A.; Bourland, T.
C.; Zhou, X.-T.; Gronemeyer, M. A. Tetrahedron 2003, 59, 8963-8974.
(e) Carter, R. G. Chem. Commun. 2004, 2138, 2140. (f) Zhou, X.-T.; Carter,
R. G. Angew. Chem., Int. Ed. 2006, 45, 1787-1790.
(6) (a) Dounay, A. B.; Forsyth, C. J. Org. Lett. 2001, 3, 975-978. (b)
Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979-982. (c) Aiguade,
J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 817-820. (d) Hao,
J.; Aiguade, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 821-824. (e)
Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001, 40, 3663-
3667. (f) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46,
279-282.
(7) (a) Sasaki, M.; Iwamuro, Y.; Nemoto, J.; Oikawa, M. Tetrahedron
Lett. 2003, 44, 6199-6201. (b) Ishikawa, Y.; Nishiyama, S. Tetrahedron
Lett. 2004, 45, 351-354. (c) Ishikawa, Y.; Nishiyama, S. Heterocycles 2004,
63, 539-565. (d) Ishikawa, Y.; Nishiyama, S. Heterocycles 2004, 63, 885-
893. (e) Oikawa, M.; Uehara, T.; Iwayama, T.; Sasaki, M. Org. Lett. 2006,
8, 3943-394.
(8) Cardilo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408.
(9) For general reviews on spiroketal syntheses: (a) Perron, F.; Albizati,
K. F. Chem. ReV. 1989, 89, 1617-1661. (b) Pietruszka, J. Angew. Chem.,
Int. Ed. 1998, 37, 2629-2636. (c) Francke, W.; Kitching, W. Curr. Org.
Chem. 2001, 5, 233-251. (d) Brimble, M. A.; Furkert, D. P. Curr. Org.
Chem. 2003, 7, 1461-1484. (e) Mead, K. T.; Brewer, B. N. Curr. Org.
Chem. 2003, 7, 227-225. Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem.
ReV. 2005, 105, 4406-4440.
Wittig olefination, Mitsunobu, and thioether oxidation pro-
tocols.14 We envisaged a synthesis of the CD fragment 8, in
which the C14 methyl group would be installed through the
opening of a cyclopropanated glycal.15 Thus, the D-ring was
identified in the known C-allylated ribofuranoside 12,16
which was transformed to the 3-deoxy derivative 14 through
straightforward alcohol protection and deoxygenation steps
(Scheme 3).17,18
(10) Selected recent synthesis of complex spiroketals: (a) Hao, J.;
Forsyth, C. J. Tetrahedron Lett. 2002, 43, 1-2. (b) Crimmins, M. T.; Katz,
J. D.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc.
2002, 124, 5661-5663. (c) Holson, E. B.; Roush, W. R. Org. Lett. 2002,
4, 3719-3723. (d) Tsang, K. I.; Brimble, M. A.; Bremner, J. B. Org. Lett.
2003, 5, 4425-4427. (e) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6,
569-572. (f) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273-2276. (g)
Statsuk, A. V.; Liu, D.; Kozmin, S. J. Am. Chem. Soc. 2004, 126, 9546-
9547. (h) Takaoka, L. R.; Buskmelter, A. J.; LaCruz, T. E.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2005, 127, 528-529. (i) Potuzaz, J. S.; Moilanen,
S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796-13797.
(11) For a recent example of Au(I) alkyne spiroketalization: Liu, B.;
De Brabander, J. K. Org. Lett. 2006, 8, 4907-4910.
Hydroxyalkene 14 was next transformed to bicyclic glycal
16 following the protocol developed by Postema (Scheme
(13) Earle, M. J.; Abdur-Rashid, A.; Priestley, N. D. J. Org. Chem. 1996,
61, 5697-5700.
(14) Zhu, L.; Mootoo, D. R. Org. Biomol. Chem. 2005, 3, 2750-2754.
(15) (a) Bertinato, P.; Sorensen, E. J.; Meng, D.; Danishefsky, S. J. J.
Org. Chem. 1996, 61, 8000-8001. (b) Ramana, C. V.; Murali, R.;
Nagarajan, M. J. Org. Chem. 1997, 62, 7694-7703.
(16) 12 is obtained in two steps from commercially available 1-O-acetyl-
2,3,5-tri-O-benzoyl-â-D-ribofuranose: Kozikowski, A. P.; Sorgi, K. L.;
Wang, B. C.; Xu, Z. B. Tetrahedron Lett. 1983, 24, 1563-1566.
(17) Bertus, P.; Zhang, J. H.; Sir, G.; Weibel, J. M.; Pale, P. Tetrahedron
Lett. 2003, 44, 3391-3395.
(12) For a strategically similar approach to the ABCD subunit, based
on alkyne functionalization, see ref 6f.
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Org. Lett., Vol. 9, No. 21, 2007

reprotection of the resulting primary alcohol as the benzyl
ether. The stereochemistry of 18 was deduced from the
structure of the final product (vide infra). An attempt to
access 18 directly from 16 using Simmons-Smith conditions
favored the undesired cyclopropane diastereomer, presumably
due to chelation control involving the homoallylic oxygen
substituent. Exposure of 18 to IDCP in methanol followed
by Bu3SnH reduction of the resulting C14-iodomethyl methyl
acetal product provided a single C14 methyl isomer 19, for
which the configuration of the acetal was not determined.
Removal of the PMB ether and oxidation of the primary
alcohol provided 8, which contains the CD segment of
precursor 6.
Scheme 3. Synthesis of the D-Ring Synthona
Julia-Kocienski olefination on 7 and 8 followed by
desilylation of the product provided 6 as a 5:1 mixture in
which the major component was presumed to be the E alkene
(Scheme 5). Treatment of 6 with iodonium dicollidine
a The product resulting from the cleavage of the silyl ether in
13 was obtained in 33% yield. This material was re-silylated to 13
in close to quantitative yield.
4).19 An esterification-ester olefination sequence on 14 and
3-p-methoxybenzyloxypropanoic acid provided 15, which
was subjected to RCM using Grubbs second-generation
catalyst. The resulting bicyclic glycal 16 was transformed
to the key cyclopropane 18. The required cyclopropane
Scheme 5. Trioxadispiroketal Synthesis
Scheme 4. Synthesis of CD Adehyde 8
perchlorate (IDCP), in anhydrous CH2Cl2, afforded 20 as
an unstable mixture of products. NMR analysis of the
partially purified material indicated two major iodo-THP
products in an approximately 1:1 ratio. Dissolution of the
mixture in methanol and treatment with silver trifluo-
romethanesulfonate followed by addition of water and PPTS
to the reaction mixture afforded 5 as a single trioxa-
dispiroketal product in 62% isolated yield from hydroxy
diene 6. We presume that the spiroketalization step proceeds
via the six-membered ring oxocarbenium ion 21, which could
arise from an initially formed exocyclic enol ether or via
iodide activation and cation formation, followed by hydride
transfer. The structure of 5 was assigned by 2D COSY,
NOESY, HSQC, NMR, and HRMS. In particular, the
stereochemistry of the C14-methyl group was confirmed by
an NOE between CH3-14 and H-6, which is diagnostic of
the stereochemical motif represented in 5.3d The NMR data
for 5 were also in close agreement with the previously
reported, 20-O-TBDPS, 22-O-PMB, derivative.6f
stereoselectivity was achieved by dichlorocyclopropanation
of 16, followed by LAH reduction.15 The reducing conditions
effected clevage of the silylether, and this necessitated
(18) Pettus, T. R. R.; Chen, X. T.; Danishefsky, S. J. J. Am. Chem. Soc.
1998, 120, 12684-12685.
(19) Postema, M. H. D.; Piper, J. L.; Liu, L.; Shen, J.; Faust, M.;
Andreana, P. J. Org. Chem. 2003, 68, 4748-4754.
In conclusion, this synthesis of the ABCD trioxadispiro-
ketal subunit of azaspiracid-1 5 illustrates an unusual
intramolecular iodoetherification-spiroketalization strategy
Org. Lett., Vol. 9, No. 21, 2007
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and also entails a novel approach to the CD segment. The
complexity represented in 5 and the convergent nature of
this synthesis suggest that the spiroketalization methodology
may be suitable for other classes of highly functionalized
spiroketals. In principle, spiroketals with different ring sizes
could originate from appropriate dihydroxyalkene precursors.
More detailed mechanistic and synthetic studies are underway
and will be reported in due course.
National Institutes of Health (NIH). “Research Centers in
Minority Institutions” award RR-03037 from the National
Center for Research Resources of the NIH, which supports
the infrastructure and instrumentation of the Chemistry
Department at Hunter College, is also acknowledged.
Supporting Information Available: Procedures and
characterization of all new compounds and NMR charts for
selected intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This investigation was supported by
grants R01 GM57865 and SCORE S06 GM60654 from the
National Institute of General Medical Sciences of the
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Org. Lett., Vol. 9, No. 21, 2007