Synthesis of the ABCD and ABCDE ring systems of azaspiracid-1

Article abstract of DOI:10.1039/b410092a

The efficient syntheses of the ABCD ring system of the originally proposed structure of azaspiracid-1 and the ABCDE ring system of the revised structure of azaspiracid-1 containing the correct stereochemistry at C₆, C ₁₀, Q₃, C₁₄, C₁₆, C₁₇, C₁₉, C₂₁, C₂₂, C₂₄ and C ₂₅ have been achieved.

Full text of DOI:10.1039/b410092a

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Synthesis of the ABCD and ABCDE ring systems of azaspiracid-1{{
Xiao-Ti Zhou and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis OR 97331, USA.
E-mail: rich.carter@oregonstate.edu
Received (in Cambridge, UK) 5th July 2004, Accepted 2nd August 2004
First published as an Advance Article on the web 20th September 2004
The efficient syntheses of the ABCD ring system of the
versus the one isomer observed by Yasumoto. While the data put
forth by Nicolaou to justify his proposed structure 6 was clearly
enticing, we were troubled by the complications created by the
relocation of the C8,9 olefin.2 It was not apparent to us what
stereochemical difference would be relayed to the bisspiroketal by
movement of the C8,9 alkene.
originally proposed structure of azaspiracid-1 and the
ABCDE ring system of the revised structure of azaspiracid-1
containing the correct stereochemistry at C6, C10, C13, C14,
C16, C17, C19, C21, C22, C24 and C25 have been achieved.
Azaspiracid-1 (1) was discovered in 1995 when several individuals
became ill after consuming mussels harvested from Killary Harbor
in Ireland.1 Yasumoto and co-workers soon concluded a new
toxin, azaspiracid-1 (1), was the cause of the outbreak in Ireland
(Fig. 1).2 Subsequent to Yasumoto’s original report, several
derivatives 2–5 have been isolated from Ireland3 and there is
growing evidence of the spread of azaspiracid throughout other
regions of Europe.4 A recent report appears to link the presence of
azaspiracid to an ubiquitous alga.5 The toxic effects of azaspiracid
have been shown to include serious injury to the digestive tracts,
liver, pancreas, thymus and spleen in mice.6 The significant effect of
this toxin on the European shellfish industry4 and its daunting
structure garnered our attention7 as well as the interest of several
other laboratories.8
One particularly challenging portion of the azaspiracid archi-
tecture is the C10,C13 transoidal bisspiroketal moiety. This
transoidal stereochemistry in 1 is proposed to exist with the C13
furan oxygen in an equatorial or ‘‘non-anomeric’’ orientation
(Fig. 2). Given the fact that no external stabilizing force appears to
be present, the non-anomeric orientation at this position has
proven to be a demanding structural motif to construct. Our
laboratory7d–f as well as the Nicolaou8h and Nishiyama8m
laboratories have developed solutions to address this hurdle.
Recently, Nicolaou and co-workers revealed, in a series of
impressive publications,9 that azaspiracid-1 was actually mis-
assigned. They initially proposed an alternate structure 6 involving
the relocation of the C8,9 alkene to the C7,8 position and the
enantiomer of C28–C47 FGHI ring system (FGHI-ent).9a,b
Nicolaou and co-workers asserted that movement of the alkene
to the C7,8 position might address their observation of two
inseparable compounds (presumably due to the bisspiroketal)
It was our belief that the major error(s) in structural assignment
of azaspiracid lay in the CD ring system. We were intrigued by the
possibility that the actual structure of azaspiracid might instead
possess the epimeric C14 stereocenter (e.g. compound 8). This
modification would potentially allow the C13 spiroketal to return to
its preferred anomeric conformation (Fig. 2). The differences in
chemical shifts reported by Nicolaou9a,b at H4–H6 and H8–H9
might be explained by the significant difference in local environ-
ment caused by returning the C13 furan oxygen on the C ring to the
anomeric conformation. Independent and concurrent to our
efforts, the Nicolaou laboratory has revised their original proposal
to include the epimeric C14 stereochemistry while establishing the
correct structure of azaspiracid-1 (7).9c,d Herein, we describe our
synthesis of the ABCD and ABCDE ring systems of azaspiracid.
Our overall retrosynthetic strategy for compounds 1 and 8 is shown
in Scheme 1.
Synthesis of the keto phosphonate 11 began from the com-
mercially available Masamune auxiliary (Scheme 2).10 Boron-
mediated anti-aldol reaction11 of 2-bromoacrolein with the
norephedrine auxiliary produced the anti adduct in good
diastereoselectivity. Subsequent protection of the C25 hydroxyl as
Fig. 1 Originally proposed structure assignments for azaspiracid-1 to
azaspiracid-5.
{ Electronic Supplementary Information (ESI) available: Complete
experimental procedures and 1H and 13C spectra are provided for all
new compounds. See http://www.rsc.org/suppdata/cc/b4/b410092a/
{ Dedicated to Professor Li-Xin Dai on the occasion of his 80th birthday.
Fig. 2 Alternate proposed structures for azaspiracid-1.
2 1 3 8
C h e m . C o m m u n . , 2 0 0 4 , 2 1 3 8 – 2 1 4 0
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 4 (i) NaHMDS, ICH2CH~CHCH2CH2OBn, THF, 92%; (ii) AD
mix b*, NaHCO3, t-BuOH, H2O, r.t., 4 : 1 d.r., 55%; (iii) TIPSOTf, imid.
DMF, 88%; (iv) LiBH4, MeOH, THF, 99%; (v) PivCl, DMAP, Et3N,
CH2Cl2, 82%; (vi) BnBr, NaH, DMF; (vii) TBAF, THF, 24% over 2 steps;
(viii) TESCl, DMAP, Et3N, CH2Cl2, 99%; (ix) LiBH4, MeOH, THF, 89%;
(x) TPAP, NMO, CH2Cl2, mol. sieves, 95%.
Scheme 1 Retrosynthetic plan for targets 1 and 8.
bisspiroketals. Working in parallel, removal of the C16 O-benzyl
ether from 17 and 18 using LiDBB14 followed by conversion to the
diazoester yielded 19 and C14-epi product 20. Rhodium-catalyzed
C–H insertion using traditional catalysts such as Rh2(OAc)4
performed poorly in our hands, yielding none of the desired
lactone. Based on recent work by Doyle’s15 and Wee’s16 labora-
tories using the chiral catalyst Rh2[(4S)-(MPPIM)]4,17 treatment of
the diazo ester with 1 mol% of the rhodium catalyst in refluxing
dichloromethane yielded the desired lactone in an unoptimized
12% yield for 21. This compound proved to be unstable upon
prolonged storage. The transoidal nature of the spiroketal 21 was
confirmed by extensive 2D NMR. Unfortunately, the analogous
C–H insertion with C14-epi compound 20 appeared to provide only
a trace of the presumed product 22. Based on this result, synthesis
of a C14 epi-variant of bisspirocyclization precursor 15, which
possessed C18 and C19 needed to be constructed.
Scheme 2 (i) Cyx2BOTf, Et3N, 2-bromoacrolein, Et2O, 92%, 93 : 7 d.r.;
(ii) TBSOTf, Et3N, DMAP, CH2Cl2, 62%; (iii) DIBAL-H, CH2Cl2,
278 uC, 86%; (iv) Ph3P, imid., I2, CH2Cl2, 88%; (v) LDA, LiCl, 14, THF,
92%; (vi) LDA, BH3.NH3, THF, 84%; (vii) TPAP, NMO, CH2Cl2, mol.
sieves; (viii) Me(O)P(OEt)2, n-BuLi, THF; (ix) PDC, DMF, mol. sieves,
53% over 3 steps.
its TBS ether followed by reduction yielded the alcohol 13.
Alteration to the corresponding iodide, Myers alkylation12 and
conversion to the keto phosphonate provided 11.
The synthesis of the northern portion of azaspiracid commenced
with previously reported ketone 157e (Scheme 3). Acid-catalyzed
bisspirocyclization using PPTS in THF/H2O yielded the two
bisspiroketals 16 and 17 in near equal amounts (10 : 9). As observed
previously, the unwanted cisoidal bisspiroketal 16 could be recycled
to provide the transoidal bisspiroketal 17. These conditions are an
improvement on our original CSA, PhMe/t-BuOH conditions7d–f
which provided a 5 : 3 ratio (16 : 17). Interestingly, treatment of the
ketone 15 with CSA in hexanes led to formation of the C14-epi
transoidal compound 1813 as the major product (4.5 : 1 : 6 ratio for
16 : 17 : 18). Unlike the bisspiroketals 16 and 17, the C14-epi
compound 18 could not be re-equilibrated to the alternate
spiroketals. It appears from this experiment that C14-epi transoidal
adduct 18 is the thermodynamic ‘‘sink’’ for the C16-benzyloxy
Synthesis of the required aldehyde began with the readily
available Evans alkylated product 24 (Scheme 4). We initially
hypothesized that Sharpless dihydroxylation with AD mix b should
provide the desired stereochemical combination at C16,17. This
stereochemical result would have been opposite of what would be
predicted by the accepted Sharpless model;18 however, we expected
preferential p-stacking of the 1u O-benzyl ether7a with the AD mix
ligands would reverse the selectivity. Subsequent functional group
manipulation, in accord with our prior work,7e,f gave aldehyde 26.
After careful inspection of lactone 25 using Mosher ester analysis,19
we discovered that our p-stacking hypothesis had proven to be in
error. As the exact structure of azaspiracid-1 was still unknown at
this point, we chose to pursue the bisspiroketalization with the
aldehyde 26.
Our standard Julia coupling approach7c,f with the previously
prepared sulfone 277a followed by TPAP oxidation gave the keto
sulfone 28 (Scheme 5). Na/Hg amalgam reduction and treatment
with PPTS, THF/H2O yielded the expected transoidal product 29
as the sole bisspiroketal. The formation of a single transoidal
bisspiroketal coupled with the observed H6-H41 NOE (also found
in azaspiracid) led us to suspect that compound 29 possessed the
correct stereochemistry present in the natural product. Finally,
conversion of the lactone 30 was accomplished through LiDBB
debenzylation and TPAP oxidation. Similar NOE correlations
Scheme 5 (i) 27, LDA, THF, then 26, 278 uC; (ii) TPAP, NMO, CH2Cl2,
mol. sieves, 66% yield over 2 steps; (iii) Na/Hg, Na2HPO4, THF, H2O,
82%; (iv) PPTS, THF, H2O, 50%; (v) LiDBB, THF, 278 uC; (vi) TPAP,
NMO, CH2Cl2, mol. sieves, 73% over 2 steps.
Scheme 3 (i) PPTS, THF, H2O, 40% 16, 36% 17; (ii) CSA, hexanes, 42% 18,
32% 16, 7% 17; (iii) LiDBB, THF, 278 uC, 10 min; (iv) ClCOCH~
N-NHTs, N,N-dimethylaniline, Et3N, CH2Cl2, 60% 19 over 2 steps, 65%
20 over 2 steps; (v) Rh2(4S)-(MPPIM)4, CH2Cl2, reflux, 12% 21.
C h e m . C o m m u n . , 2 0 0 4 , 2 1 3 8 – 2 1 4 0
2 1 3 9

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A. Horne (OSU), Dr. Daniel P. Furkert (OSU) and Dr. Roger
Hanselmann (Rib-X Pharmaceuticals) for their helpful discussions.
Notes and references
1 T. MacMahon and J. Silke, Harmful Algae News, 1996, 14, 2.
2 M. Satake, K. Ofuji, H. Naoki, K. J. James, A. Furey, T. McMahon,
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and K. J. James, Environ. Sci. Technol., 2003, 37, 3078–84.
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S. Morris, W. Higman, M. Satake and T. Yasumoto, Toxicon, 2002, 40,
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5 K. J. James, C. Moroney, C. Roden, M. Satake, T. Yasumoto,
M. Lehane and A. Furey, Toxicon, 2003, 41, 145–51.
6 E. Ito, M. Satake, K. Ofuji, N. Kurita, T. McMahon, K. James and
T. Yasumoto, Toxicon, 2000, 38, 917–30.
7 (a) R. G. Carter and D. J. Weldon, Org. Lett., 2000, 2, 3913–16;
(b) R. G. Carter, D. J. Weldon and T. C. Bourland, 221st National ACS
Meeting, San Diego, ORG-479; (c) R. G. Carter and D. E. Graves,
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D. E. Graves, M. A. Gronemeyer and G. S. Tschumper, Org. Lett.,
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M. A. Gronemeyer, Tetrahedron, 2003, 59, 8963–74.
Scheme 6 (i) DIBAL-H, CH2Cl2, 278 uC, 78%; (ii) 11, KHMDS, THF,
278 uC to r.t., 45%; (iii) TBAF, THF, 57%; (iv) TPAP, NMO, CH2Cl2,
mol. sieves, 68%; (v) NaClO2, t-BuOH, H2O, 2-methyl-2-butene, 60%.
8 (a) A. B. Dounay and C. J. Forsyth, Org. Lett., 2001, 3, 975–78;
(b) J. Aiguade, J. Hao and C. J. Forsyth, Org. Lett., 2001, 3, 979–82;
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817–20; (d) J. Hao, J. Aiguade and C. J. Forsyth, Tetrahedron Lett.,
2001, 42, 821–24; (e) K. C. Nicolaou, P. M. Pihko, N. Diedrichs, N. Zou
and F. Bernal, Angew. Chem. Int. Ed., 2001, 40, 1262–65; (f)K. R. Buszek,
221st National ACS Meeting, San Diego, ORGN-570; (g) C. J. Forsyth,
J. Hao and J. Aiguade, Angew. Chem. Int. Ed., 2001, 40, 3663–67;
(h) K. C. Nicolaou, W. Qian, F. Bernal, N. Uesaka, P. M. Pihko and
J. Hinrichs, Angew. Chem. Int. Ed., 2001, 40, 4068–71; (i) M. Sasaki,
Y. Iwamuro, J. Nemoto and M. Oikawa, Tetrahedron Lett., 2003, 44,
6199–201; (j) K. R. Buszek, T. S. Gibson, B. C. Reinhardt and
J. R. Sunde, 226th ACS National Meeting, New York, ORGN-179;
(k) Y. Ishikawa and S. Nishiyama, Tetrahedron Lett., 2004, 45, 351–54;
(l) Y. Ishikawa and S. Nishiyama, Heterocycles, 2004, 63, 539–65;
(m) Y. Ishikawa and S. Nishiyama, Heterocycles, 2004, 63, 885–93.
9 (a) K. C. Nicolaou, Y. Li, N. Uesaka, T. V. Koftis, S. Vyskocil, T. Ling,
M. Govindasamy, W. Qian, F. Bernal and D. Y.-K. Chen, Angew.
Chem. Int. Ed., 2003, 42, 3643–48; (b) K. C. Nicolaou, D. Y.-K. Chen,
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were again observed confirming the transoidal nature of both
compounds.
With the synthesis of the lactone 30 complete, conversion to the
ABCDE ring system was undertaken (Scheme 6). Reduction with
DIBAL-H provided the lactol as a mixture of undetermined
epimers. Subsequent Wadsworth–Emmons olefination with in situ
cyclization20 gave the coupled material 32 in reasonable (45%)
yield. Finally, TBAF removal of the protecting groups and oxida-
tion at C1 gave the ABCDE ring system 34.
Comparison of the NMR spectra of synthetic 33 and 34 and
azaspiracid-1 in identical solvents (CD3OD 1 0.5% CD3CO2D)
revealed some intriguing results. Large sections of the synthetic
materials 33 and 34 were in good agreement with published data
for azaspiracid-1.2 Major points of divergence proved to be the H8,9
alkene position and H6 (1H NMR: 33 H6 ~ 4.36, 34 H6 ~ 4.35,
azaspiracid-1 H6 ~ 4.81; 33 H8 ~ 5.94, 34 H8 ~ 5.95, azaspiracid-
1 H8 ~ 5.76). Given the results presented, we concluded that the
relocation of the alkene to the C7,8 position (e.g. compound 7) was
necessary for the actual structure of azaspiracid-1. Subsequent to
this conclusion, Professor Nicolaou independently reported the
confirmation of this assignment.9d
In summary, efficient approaches to the originally proposed
ABCD ring system (17 steps from oxazolidinone ent-23) and the
revised ABCDE ring system (21 steps from oxazolidinone 23) of
azaspiracid are presented. It is important to note that acid 34
contains the correct stereochemistry at C6, C10, C13, C14, C16, C17,
C19, C21, C22, C24 and C25 necessary for the actual structure of
azaspiracid-1 (7).9d Key transformations include the Wadsworth–
Emmons coupling to form the C19,20 linkage and bisspiroketaliza-
tion of the ketone 28 to provide a single transoidal bisspiroketal 29.
Further progress toward the total synthesis of the actual structure
of azaspiracid-1 (7) will be reported in due course.
Financial support was provided by the National Institutes
of Health (GM63723). We thank Professor Michael Doyle
(University of Maryland) for his generous gift of the rhodium
catalysts. The authors would also like to thank Professor Max
Dienzer (OSU) and Dr. Jeff Morre´ (OSU) for mass spectral data,
Roger Kohnert (OSU) for NMR assistance, Professor David
11 T. Inoue, J.-F. Liu, D. C. Buskke and A. Abiko, J. Org. Chem., 2002, 67,
5250–56.
12 A. G. Myers and L. McKinstry, J. Org. Chem., 1996, 61, 2428–40.
13 Dounay and Forsyth have reported isolation of an additional
bisspiroketal product from selected conditions. Their compound was
assigned to be the C14-epi product bearing a cisoidal bisspiroketal. See
ref. 8a and A. B. Dounay, Ph.D. 2001, University of Minnesota,
pp. 160–166.
14 P. K. Freeman and L. L. Hutchinson, J. Org. Chem., 1980, 45, 1924–30.
15 M. P. Doyle and A. J. Catino, Tetrahedron: Asymm., 2003, 14, 925–28.
16 A. G. H. Wee, J. Org. Chem., 2001, 66, 8513–17.
17 M. P. Doyle, Q.-L. Zhou, C. E. Raab, G. H. P. Roos, S. H. Simonsen
and V. Lynch, Inorg. Chem., 1996, 35, 6064–73.
18 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483–547.
19 See ESI for full account of Mosher model. I. Ohtani, T. Kusumi,
Y. Kashman and H. Kakisawa, J. Am. Chem. Soc., 1991, 113, 4092–96.
20 D. L. Boger, S. Ichikawa and W. Zhong, J. Am. Chem. Soc., 2001, 123,
4161–67.
2 1 4 0
C h e m . C o m m u n . , 2 0 0 4 , 2 1 3 8 – 2 1 4 0