Synthesis of the C1-C21 domain of azaspiracids-1 and -3

Article abstract of DOI:10.1021/ol400487e

An efficient synthesis of the C1-C21 fragment of azaspiracids-1 and -3 is described. This features a Nozaki-Hiyama-Kishi reaction to couple the AB and CD ring precursors and formation of the THF-fused ABCD trioxadispiroketal system under thermodynamic conditions.

Full text of DOI:10.1021/ol400487e

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of the C1ÀC21 Domain
of Azaspiracids‑1 and À3
Zhigao Zhang, Yue Ding, Jianyan Xu, Yong Chen, and Craig J. Forsyth*
Department of Chemistry & Biochemistry, The Ohio State University, Columbus,
Ohio 43210, United States
forsyth@chemistry.ohio-state.edu
Received February 21, 2013
ABSTRACT
An efficient synthesis of the C1ÀC21 fragment of azaspiracids-1 and À3 is described. This features a NozakiÀHiyamaÀKishi reaction to couple
the AB and CD ring precursors and formation of the THF-fused ABCD trioxadispiroketal system under thermodynamic conditions.
The azaspiracids (Aza, Figure 1) are structurally com-
plex marine toxins that display a range of human health
related activities.1,2 Among the latter is inhibition of the
hERG ion channel.3 Accordingly, the discovery of the
azaspiracids has stimulated intense synthetic activity.4 The
total synthesis of azaspiracids and non-natural analogs
may uniquely contribute to immunodetection of the
(1) (a) MacMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2. (b)
Satake, M.; Ofuji, K.; Naoki, H.; James, K.; Furey, A.; McMahom, T.;
Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967. (c) Tillmann,
€
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James, K. J. Toxicon 2010, 56, 173. (b) Twiner, M. J.; Rehmann, N.;
Hess, P.; Doucette, G. J. Marine Drugs 2008, 6, 39.
Figure 1. Azaspiracids.
(3) Twiner, M. J.; Douchette, G. J.; Huang, X.-P.; Rasky, A.; Roth,
B. L.; Sanguinetti, M. C. Chem. Res. Toxicol. 2012, 25, 1975.
(4) (a) Dounay, A. B.; Forsyth, C. J. Org. Lett. 2001, 3, 975. (b)
Forsyth, C. J.; Hao, J. L.; Aiguade, J. Angew. Chem., Int. Ed. 2001, 40,
3663. (c) Nicoloau, K. C.; Qian, W. Y.; Bernal, F.; Uesaka, N.; Pihko,
P. M.; Hinrichs, J. Angew. Chem., Int. Ed. 2001, 40, 4068. (d) Geisler,
L. K.; Nguyen, S.; Forsyth, C. J. Org. Lett. 2004, 6, 4159. (e) Zhou, X. T.;
Carter, R. G. Angew. Chem., Int. Ed. 2006, 45, 1787. (f) Forsyth, C. J.;
Xu, J. Y.; Nguyen, S.; Samdal, I. A.; Briggs, L. R.; Rundberget, T.;
Sandvik, M.; Miles, C. O. J. Am. Chem. Soc. 2006, 128, 15114. (g) Li,
X. H.; Li, J. L.; Mootoo, D. R. Org. Lett. 2007, 9, 4303. (h) Li, Y. F.;
Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279.
(5) (a) Vilarino, N.; Nicoloau, K. C.; Federick, M. O.; Cagide, E.;
Ares, I. R.; Louzao, M. C.; Vieytes, M. R.; Botana, L. M. Chem. Res.
Toxicol. 2006, 19, 1459. (b) Ito, E.; Frederick, M. O.; Koftis, T. V.; Tang,
W.; Petrovic, G.; Ling, T.; Nicolaou, K. C. Harmful Algae 2006, 5, 586.
(6) (a) Nicoloau, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada,
Y. M. A.; Ling, T. T.; Chen, D. Y. K.; Tang, W. J.; Petrovic, G.;
Frederick, M. O.; Li, Y. W.; Satake, M. Angew. Chem., Int. Ed. 2004, 43,
4312. (b) Nicoloau, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling,
T. T.; Yamada, Y. M. A.; Tang, W. J.; Federick, M. O. Angew. Chem.,
Int. Ed. 2004, 43, 4318. (c) Nicoloau, K. C.; Federick, M. O.; Petrovic,
G.; Cole, K. P.; Loizidou, E. Z. Angew. Chem., Int. Ed. 2006, 45, 2609.
azaspiracids4f and definition of their molecular pharmacol-
ogy.5 Notable total syntheses of Aza1 and cogeners by the
Nicoloau group6 and a total synthesis of ent-Aza1 by the
Evans group7 have been reported. Both successful ap-
proaches involved the joining of advanced C1ÀC19 and
C20ÀC40 intermediates via the addition of C20 acyl anion
equivalents to C19 carbonyls. To enahance the overall
efficiency, an alternative fragment coupling approach in-
volving a C22ÀC40 nucleophilic partner with a C1ÀC21
aldehyde was designed to deliver Aza1 and Aza3. Herein,
(7) (a) Evans, D. A.; Kværnø, 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. (b) Evans, D. A.; Dunn, T. B.; Kværnø,
L.; Beauchemin, A.; Raymer, B.; Olhava, E. J.; Mulder, J. A.; Juhl, M.;
Kagechika, K.; Favor, D. A. Angew. Chem., Int. Ed. 2007, 46, 4698.
r
10.1021/ol400487e
XXXX American Chemical Society

we report an efficient and scalable synthesis of the requisite
C1ÀC21 domain.
yield vinyl iodide 15.17 The E/Z ratio was greater than 15:1
using a 6:1 (v/v) mixture of 1,4-dioxane and THF as the
Takai reaction solvent.18
The present strategy to assemble the trioxadispiroketal
of the C1ÀC21 domain 4 relied upon the acid-catalyzed
bisspiroketalization of 5 (Scheme 1), a transketalization
process related to the original approach toward the ABCD
domain of Aza14a and a synthesis of okadaic acid.8
The C13 (Aza numbering) ketone 5 would be derived
convergently from a NozakiÀHiyamaÀKishi (NHK)
coupling9 of C1ÀC12 iodide 6 and C13ÀC21 aldehyde 7.
The endocyclic alkene of 6 would be installed from the
corresponding vinyl triflate.4c Known glyceral acetonide
derivative 810 provides carbons 5À10of 6. TheTHF ring of
7 would be reductively closed6a,11 from a hemiketal pre-
cursor obtained from a Mukaiyama aldol reaction.12 The
requisite silyl enol ether and aldehyde could be accessed
from known building blocks 8, 9, and 10.13 Asymmetric
dihydroxylation of 9 would install the vicinal C19À20
stereochemistry.
The synthesis of the A-ring containing fragment com-
menced with hydroborationÀoxidation14 of alkene 810
(Scheme 2). The derived primary alcohol 11 was converted
into aldehyde 12 under Swern conditions.15 Addition
of lithium trimethylsilyl acetylide to 12 followed by
oxidation16 gave ynone 13. Upon cleavage of the acetonide
moiety with acidic methanol, cyclization occurred to close
the A-ring as mixed ketal 14. Alcohol 14 was elaborated
into NHK coupling partner 6 (Scheme 3). This began with
ParikhÀDoering oxidation tothecorresponding aldehyde,
followed by a highly stereoselective Takai olefination to
The C1ÀC3 side chain was next installed efficiently
through a Suzuki cross-coupling.19 This was preceded by
hydroboration of allyl TBDPS ether, which then allowed
Pd-mediated sp3Àsp2 coupling with vinyl iodide 15 to give
16. The C7 alkene was installed next. A Stille reduction20 of
a C7ÀC8 vinyl triflate was chosen for this task. Hence, the
C7 O-PMB ether was selectively cleaved and the resultant
alcohol was oxidized to ketone 17. Treatment of 17 with
KHMDS and Comins’ reagent21 gave the anticipated
kinetic enol triflate. This was smoothly reduced in the
presence of the silyl-substituted alkyne under Stille condi-
tions to complete installation of the A-ring alkene. Finally,
a direct alkyne desilylationÀiodination (AgOTf/NIS/
DMF)22 completed the preparation of alkynyl iodide 6.
The synthesis of the C13ÀC21 CD-ring containing
intermediate 7 featured a Mukaiyama aldol coupling of
aldehyde 20 and silyl enol ether 23 (Scheme 4). The
aldehyde was prepared via the known vicinal diol 10
(Scheme 1),13 which was converted into a benzylidene
acetal then regioselectively opened with DIBAL to afford
the primary alcohol. This was then oxidized to aldehyde
20. In parallel, the preparation of 23 commenced with a
Sharpless asymmetric dihydroxylation23 of ethyl crotonate
9 to generate diol 21 in 90% ee. The R-hydroxyl group was
selectively silylated, the ester moiety was reduced, and the
resultant primary alcohol was acylated with pivaloyl
chloride to yield 22. The residual C19 secondary alcohol
was oxidized to the methyl ketone, which was then con-
verted into silyl enol ether 23. The anticipated coupling of
aldehyde 20 with latent nucleophile 23 was thus enabled.
Scheme 1. Retrosynthetic Analysis of the C1ÀC21 Fragment
(9) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179. (b) Jin, H. L.; Uenishi, J.; Christ, W.; Kishi, Y.
J. Am. Chem. Soc. 1986, 108, 5644. (c) Takai, K.; Tagashira, M.;
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1986, 108, 6048.
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€
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Int. Ed. 2007, 46, 9265. Compound 8 was prepared in four steps from
D-mannitol; compound 10 was derived from 2-methyl-1,3-propane diol
in eight steps.
(14) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247.
(15) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
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(16) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(17) Takai, K.; Nitta, K.; Ultimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(18) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993,
115, 11446.
(19) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437. (b) Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 19,
866. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(20) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
(21) Comins, D.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(22) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727.
(8) (a) Pang, Y. C.; Fang, C.; Twiner, M. J.; Miles, C. O.; Forsyth,
C. J. Angew. Chem., Int. Ed. 2011, 50, 7631. (b) Forsyth, C. J.; Sabes,
S. F.; Urbanek, R. A. J. Am. Chem. Soc. 1997, 119, 8381.
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Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Kolb, H. C.;
Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. A-Ring Assembly
Scheme 4. Synthesis of Aldehyde 7
Scheme 3. Synthesis of Alkynyl Iodide 6
the reductive cyclization was confirmed by NOE measure-
ments and is consistent with that of similar systems.24
The major THF product obtained from 25 was the C13
primary alcohol (60%) accompanied with the correspond-
ing C13 O-TBS ether (25%), which was cleanly desilylated
with TsOH in methanol. A final ParikhÀDoering oxida-
tion completed the synthesis of the C12 aldehyde 7.
The A- and D-ring containing fragments 6 and 7, re-
spectively, were finally joined under NHK conditions9
to yield the advanced C1ÀC21 azaspiracid intermediate
26 in 78% yield as an epimeric mixture of propargylic
alcohols(Scheme5). A virtue of thistypeof organometallic
couping is the chemoselectivity for aldehyde addition,
which allows the incorporation of other potential electro-
philic functionalities, exemplified by the D-ring acetate here.
Carbinol oxidation16 followed by conjugated alkyne reduc-
tion25 then transformed 26 into ketone 27 (Scheme 5).
Penultimate intermediate 5 (Scheme 1) was attained
from mildly basic methanolysis of the C17 acetate of 27,
which avoided significant epimerization of the R-keto C14
A chelation controlled Mukaiyama aldol reaction
between 20 and 23 provided C13ÀC21 β-hydroxy ketone
24 (Scheme 4). Various Lewis acids and ligating C16
O-protective groups were screened to optimize this process.
Among the combinations examined, the use of SnCl4 and a
C16 benzyl ether provided the best result with a 76% yield
and 10:1 diastereoselectivity. The C17 hydroxyl group of
24 was then acetylated, and the C16 benzyl ether was
cleaved to afford γ-hydroxy ketone 25 as an equilibrium
mixture of hydroxy ketone and cyclic hemiketal. The
azaspiracid tetrafuranD-ring was permanently closed with
a Kishi reduction.11,6a The standard conditions (BF3 OEt2/
3
Et3SiH at À78 °C) afforded a significant amount of side
products. The use of SnCl4 proved to be the best of the
Lewis acids tested for the reductive cyclization of 25.
The observed exclusive trans-2,5-THF stereochemistry of
(24) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208.
(25) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Synthesis of the C1ÀC21 Domain of Azaspiracid-3
stereogenic center. Finally, the A-ring ketal and C13
ketone were engaged in an acid-triggered transketalization
using PPTs in CH2Cl2 to construct the B- and C-rings of
trioxadispiroketal 4. As had been originally noted in a
similar context,4a the thermodynamically favored configura-
tions at the newly formed C10 and C13 spiroketals were
unaccompanied by appreciable amounts of anomeric
epimers. Thus, stereoselective establishment of the az-
aspiracid AÀC-ring bisspiroketal domain under thermo-
dynamic conditions again provides reliable access to the
natural products’ stereochemistry.
18 steps in 5% overall yield in the longest linear sequence
from the C5ÀC10 building block 8.10 The synthesis of
4 will support ongoing efforts to highlight the utility of
complex molecule synthesis in the context of generating
azaspiracids and informative analogs for targeted phar-
macological studies.
Acknowledgment. This work was sponsored by finan-
cial support from the NIH (R01-ES10615) and The Ohio
State Unversity (OSU). We thank K. Cunningham (OSU)
for keen editorial assistance.
This convergent approach to the fully elaborated
C1ÀC21 domain of Aza1 and Aza3 features both reliable
access to core building blocks and enabling late-stage
transformations. The latter include the NHK coupling of
A- and D-ring bearing fragments,9 regioselective ynone
reduction,25 and thermodynamic transketalizations.4a,8
The generation of the C1ÀC21 intermediate 4 spans
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX