Synthesis of the ABC ring system of azaspiracid. 1. Effect of D ring truncation on bis-spirocyclization

Article abstract of DOI:10.1021/ol026033w

(matrix presented) Synthesis of a spirocyclization precursor with a truncated D ring has been accomplished. Subsequent bis-spirocyclization induced the formation of equal amounts of the natural transoidal 10R,13S bis-spirocycle and its cisoidal 10R,13S ep

Full text of DOI:10.1021/ol026033w

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2177-2179
Synthesis of the ABC Ring System of
Azaspiracid. 1. Effect of D Ring
Truncation on Bis-spirocyclization†
,‡
Rich G. Carter,* T. Campbell Bourland,§ and David E. Graves§
Department of Chemistry, Oregon State UniWersity, CorVallis, Oregon 97331, and
Department of Chemistry and Biochemistry, UniVersity of Mississippi,
UniVersity, Mississippi 38677
rich.carter@oregonstate.edu
Received April 17, 2002
ABSTRACT
Synthesis of a spirocyclization precursor with a truncated D ring has been accomplished. Subsequent bis-spirocyclization induced the formation
of equal amounts of the natural transoidal 10R,13R bis-spirocycle and its cisoidal 10R,13S epimer under an apparent thermodynamically
controlled process.
A new class of toxins in shellfish, the azaspiracids, has been
recently observed in mussels harvested in the surrounding
waters of Europe (Scheme 1).1 Azaspiracid (1)2 and its related
structures, azaspiracids 2-5 (2-5),3,4 have been shown to
induce serious injury to the digestive tracts, liver, pancreas,
thymus, and spleen in mice. In addition to their significant
biological properties, the azaspiracids represent a daunting
synthetic challenge as the parent structure 1 possesses 20
stereocenters and three separate spirocyclic linkages. For
these reasons, the azaspiracids have garnered significant
recent attention in both the biological1-5 and synthetic
communities.6-8 This paper discloses the successful con-
struction of the C1-C17 portion of azaspiracid including the
crucial C10, C13 transoidal bis-spirocyclic array.
Strategy. The major stumbling block in the synthesis of
the northern portion of azaspiracid has been the effective
(5) Ito, E.; Satake, M.; Ofuji, K.; Kurita, N.; McMahon, T.; James, K.;
Yasumoto, T. Toxicon. 2000, 38, 917.
(6) (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913. (b) Carter,
R. G.; Weldon, D. J. Bourland, T. C. 221st National Meeting of the
American Chemical Society, San Diego, April 2001; American Chemical
Society: Washington, DC, 2001; ORGN-479. (c) Carter, R. G.; Graves,
D. E. Tetrahedron Lett. 2001, 42, 6035.
(7) (a) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001,
40, 3662. (b) Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou, N., Bernal,
F. Angew. Chem., Int. Ed. 2001, 40, 1262. (c) Dounay, A. B.; Forsyth, C.
J. Org. Lett. 2001, 3, 975. (d) Aiguade, J.; Hao, J.; Forsyth C. J. Org. Lett.
2001, 3, 979. (e) Aiguade, J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001,
42, 817. (f) Hao, J.; Aiguade, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42,
821. (g) Buszek, K. R. 221st National Meeting of the American Chemical
Society, San Diego, April 2001; American Chemical Society: Washington,
DC, 2001; ORGN-5701.
(8) Nicolaou and co-workers recently reported an alternate solution to
the C10, C13 bis-spiroketal involving substitution of the C8,9 alkene with a
C9 hydroxyl function. Nicolaou, K. C.; Qian, W.; Bernal, F.; Uesaka, N.;
Pihko, P. M.; Hinrichs, J. Angew. Chem., Int. Ed. 2001, 40, 4068.
† This work was performed at the University of Mississippi. The
corresponding author’s present address is Department of Chemistry, Oregon
State University, Corvallis, OR 97331.
‡ Oregon State University.
§ University of Mississippi.
(1) MacMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2.
(2) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon,
T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967.
(3) Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K. J.; Naoki,
H.; Oshima, Y.; Yasumoto, T. Nat. Toxins 1999, 7, 99.
(4) Ofuji, K.; Satake, M.; McMahon, T.; James, K. J.; Naoki, H.; Oshima,
Y.; Yasumoto, T. Biosci. Biotechnol. Biochem. 2001, 65, 740.
10.1021/ol026033w CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/05/2002

calculations showed that truncation of the D ring allows for
a significant narrowing of the energy difference between the
cisoidal and transoidal stereochemical arrays. Based on these
observations, we felt it was prudent to explore a strategy in
which the furan D ring was included after spirocyclization.
Access to the appropriate bis-spirocyclization precursor 11
should be available from our previously established Julia
coupling strategy between sulfone A and aldehyde 7 (Scheme
1).6
Scheme 1. Retrosynthetic Strategy for Truncation of D Ring
in Bis-spirocyclization
Exploration of Simplified Model System. The Julia
coupling of the previously synthesized sulfone A6a with the
readily available aldehyde 79 proceeded smoothly in 81%
yield as a mixture of all four diastereomers (Scheme 3).
Scheme 3. Julia Coupling Strategya
construction of the natural transoidal bis-spirocycle at C10
and C13.8 Our laboratory6b,c as well as others7c,g,8 have
disclosed the apparent preference for the undesired cisoidal
orientation of the spirocycles on systems possessing a fully
functionalized surrounding architecture (Scheme 2). One
possible solution for this problem would be the simplification
of the surrounding functionality in order to facilitate the
desired stereochemical array. Low-level molecular modeling
a Key: (i) TESOTf, 2,6-lutidine, CH2Cl2, -78 °C, 86%; (ii)
LiBH4, MeOH, THF, 81%; (iii) TPAP, NMO, CH2Cl2, molecular
sieves, 96%; (iv) LDA, THF, -78 °C, then add 7, 81%; (v) TPAP,
NMO, CH2Cl2, molecular sieves, 78%; (vi) Na/Hg, Na2HPO4,
MeOH, THF, -10 °C.
Scheme 2. Proposed Truncation of D Ring at C16 and C17
Subsequent TPAP oxidation yielded the desired keto sulfone
15. To construct the viable model system for the spiro-
cyclization, the keto sulfone 15 was converted to the labile
ketone 1110 using Na/Hg amalgam.11
A series of spirocyclization conditions were explored as
shown in Table 1. Our optimum conditions (Table 1, entry
4) employed camphorsulfonic acid (CSA) in an equal mixture
of toluene and tert-butyl alcohol to provide a separable 1:1
ratio of the desired transoidal spirocycle 12 and the undesired
cisoidal spirocycle 13 in a 68% yield from 15. Both
compounds 12 and 13 were assigned via 2D NMR techniques
(CDCl3 for 12, C6D6 for 13). Two key NOEs (H12 to H9 and
H12 to H17) allowed for the establishment of the natural
transoidal 10R,13R spirocycle 12 over the alternate non-
natural transoidal spirocycle that our laboratory has observed
(9) The aldehyde 7 is available in three steps from the known alcohol
14. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(10) It is interesting to note that while the keto sulfones (such as 15)
can be stored indefinitely in the freezer, the desulfonylated carbonyl species
(i.e., ketone 11) are prone to elimination at C10,11 to the corresponding enol
ether. This elimination, however, is not at all detrimental to the subsequent
bis-spirocyclization as the enol ether is the first observed intermediate in
the TES deprotection/spirocyclization sequence.
(11) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477.
2178
Org. Lett., Vol. 4, No. 13, 2002

Scheme 4. Synthesis of C1-C17 Azaspiracid Fragmenta
Table 1. Bis-spirocyclization with a Precursor Lacking
Substitution at C16 and C17
a Key: (i) TBAF, THF, 43% of 16 and 43% of 17; (ii) CSA,
t-BuOH/PhMe (1:1), 44% of 16 and 50% of 17.
PhMe, 14-18 h) led to a similar equilibrium mixture (9:11
for compounds 16/17). Using one equilibration cycle, an
overall 62% yield can be obtained of the desired transoidal
bis-spirocycle 16.
The synthesis of the C1-C17 fragment of azaspiracid has
been accomplished. The natural configurations at the two
key spiroketal linkages have been accessed by truncation of
the D ring at C16 and C17. The bis-spirocyclization appears
to be the result of a thermodynamically controlled process.
The equilibration of cisoidal bis-spirocycles 13 and 17 to
their corresponding transoidal epimers 12 and 16 represent
the first examples of equilibration of a properly functional-
ized ABC ring system possessing the C8,9 alkene. Exploration
into the bis-spirocyclization of precursors containing C16 and
C17 substitution is disclosed in the following paper in this
issue.12
on D-ring-containing systems.6c These NOEs are only
possible in the natural transoidal spirocycle as shown in
structure 12; the alternate non-natural transoidal bis-spiro-
cycle would not provide this NOE pattern. Finally, the
observed data support a “nonanomeric” C ring conformation,
placing both the C13 oxygen and the C14 methyl in the
equatorial positions. This hypothesis is also consistent with
the proposed conformation for the natural product.2 In
addition, resubmission of the undesired cisoidal product 13
to the same reaction conditions (0.04 M CSA, t-BuOH/PhMe,
14-18 h) led to an identical equilibrium mixture. This result
is in contrast to our previous work with substrates containing
the D ring in which resubmission of the cisoidal product
did not lead to formation of any further transoidal material.6c
While the cisoidal and transoidal spirocycles 12 and 13
could be separated by careful chromatography, the similarity
in the two compounds’ Rf’s made this method impractical
for the isolation of significant quantities of material. Removal
of the C1 silyl protecting group, however, facilitated straight-
forward separation of the two spirocycles 16 and 17 in an
86% overall yield (Scheme 4). We were also gratified to
find that resubmission of the cisoidal spirocycle 17 to the
identical spirocyclization conditions (0.04 M CSA, t-BuOH/
Acknowledgment. We thank the National Institutes of
Health (GM63723) and the University of Mississippi for
partial support of this work. In addition, we thank Dr. Jeff
Morre´ and Professor Max Dienzer (Oregon State University)
for mass spectral data. Finally, we thank Dr. Roger Hansel-
mann (Rib-X Pharmaceuticals) for his helpful discussions.
Supporting Information Available: Experimental pro-
cedures and spectral characterization are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026033W
(12) Carter, R. G.; Graves, D. E.; Gronemeyer, M. A.; Tschumper, G.
S. Org. Lett. 2002, 4, 2181 (ol026034o).
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