Synthesis of the C1-C26 northern portion of azaspiracid-1: Kinetic versus thermodynamic control of the formation of the bis-spiroketal

Article abstract of DOI:10.1002/anie.200503733

North-South divide: An efficient synthesis of the entire C1-C26 (northern) portion of azaspiracid-1 is disclosed (see picture). Key transformations include the formation of a bis-spiroketal, the oxidation of a sulfone at C10 to form a β,γ-unsaturated keto

Full text of DOI:10.1002/anie.200503733

Angewandte
Chemie
Natural Product Synthesis
DOI: 10.1002/anie.200503733
Synthesis of the C1–C26 Northern Portion of
Azaspiracid-1: Kinetic versus Thermodynamic
Controlof the Formation of the Bis-spiroketa*l *
Xiao-Ti Zhou and Rich G. Carter*
Dedicated to Professor James D. White
on the occasion of his 70th birthday
Azaspiracid-1, a toxin found in European shellfish, was first
observed in the mid-1990s when several individuals became ill
from eating mussels harvested off the coast of Western
Ireland.Considerable synthetic attention has been directed
toward this compound by our group[1] and others.[2] Addi-
tional excitement was generated by the revelation that the
initial structure of azaspiracid-1 (1) had been misassigned
(Figure 1).[3] The genesis of the error was believed to be in the
ABCDE northern portion of the molecule.Recently, the
revised structure 2 was determined in an impressive series of
publications by Nicolaou et al.[4] Independently and concur-
rently, we also converged on the same stereochemical
conclusion.[5] Herein, we disclose our successful synthesis of
the C1–C26 northern portion of the revised structure of
azaspiracid-1 (2).
Figure 1. Original (1) and revised (2) structures of azaspiracid-1.
Our retrosynthetic analysis, as shown in Scheme 1,
involved disconnection of 3 at the C19–20 linkage to provide
the tetracycle 5 and the previously reported keto-phospho-
nate 6.[5] The bis-spiroketal could be accessed from the ketone
7, which would, in turn, be available from the sulfone 8 and
the known aldehyde 9.[5] It is important to note that the
revised structure of azaspiracid 2 contains a new challenge in
its synthetic architecture: the bisallylic carbon–oxygen bond
at C6.We hypothesized that attempted formation of the bis-
spiroketal in the presence of this labile functionality might
prove problematic, particularly under acidic conditions.On
the basis of this assumption, care was taken not to incorporate
[*] Dr. X.-T. Zhou, Prof. Dr. R. G. Carter
Department of Chemistry
Oregon State University
Corvallis, OR 97331 (USA)
Fax: (+1)541-737-9486
E-mail: rich.carter@oregonstate.edu
Scheme 1. Retrosynthetic analysis of azaspiracid-1 (2). PNB=para-
nitrobenzoate; TBS=tert-butyldimethylsilyl; Boc=tert-butyloxycar-
bonyl; TBDPS=tert-butyldiphenylsilyl; TES=triethylsilyl; Bn=benzyl.
[**] Financial support was provided by the National Institutes of Health
(GM63723). This publication was made possible in part by grant
number P30 ES00210 from the National Institute of Environmental
Health Sciences, NIH. The authors would also like to thank
Professor Max Deinzer (OSU) and Dr. Jeff MorrØ (OSU) for mass
spectral data, Rodger Kohnert (OSU) and Dr. Clemens Anklin
(Brüker Biospin) for NMR assistance, Damien Kuiper (OSU) for
synthetic assistance with sulfone 14 and aldehyde 9, and Dr. Roger
Hanselmann (Rib-X Pharmaceuticals) for helpful discussions.
both alkenes in this region until the bis-spiroketal had been
formed.
Synthesis of the sulfone fragment commenced with the
commercially available maleic acid 10 (Scheme 2).Following
a known four-step protocol,[6] the cis-unsaturated ester 11 was
constructed.Subsequent reduction of the carbonyl moiety
Supporting information for this article is available on the WWW
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Scheme 2. Synthesis of the sulfone. Reagents and conditions:
a) DIBAL-H, CH2Cl2, ꢀ788C, 98%; b) Ph3P, CBr4, MeCN, 92%;
c) NaH, PhSH, DMF, 08C, 73%; d) NaSO2Ph, DMF, 86%; e) nBuLi, 14
(2.6 equiv), THF, ꢀ788C; f) 2n HCl, MeCN, 58% (over two steps);
g) TBDPSCl, imid., CH2Cl2, 92%; h) TESOTf, 2,6-lutidine, CH2Cl2, 95%;
i) NaHMDS, THF then (TMSO)2, 72% (BORSM); j) NH4F, MeOH/
CH2Cl2 (4:1); k) PPTS, MeOH, 68% (over two steps, BORSM);
l) TPAP, NMO, MeCN, 408C, 88%. DIBAL-H=diisobutylaluminum
hydride; DMF=N,N-dimethylformamide; imid=imidazole; TESOTf=
triethylsilyl triflate; HMDS=hexamethyldisilazide; TMS=trimethylsilyl;
PPTS=pyridinium p-toluenesulfonate; TPAP=tetra-n-propylammo-
nium perruthenate; NMO=N-methylmorpholine-N-oxide. BORSM=
based on recovered starting material.
Scheme 3. Synthesis and equilibration of bis-spiroketals. Reagents and
conditions: a) 2,2,6,6-tetramethylpiperidine, nBuLi, THF then 9;
b) TPAP, NMO, CH2Cl2, M.S., 92% over two steps; c) Na/Hg,
Na2HPO4, THF, H2O, 86%; d) PPTS, THF/H2O (4:1), 18 h; e) CSA,
tBuOH/PhMe (1:1), 18 h. M.S.=molecular sieves; CSA=camphorsul-
fonic acid.
as the minor product (2.5:1 19/20).This result is in stark
contrast to the C8–9 series in which ketone 23 gave solely the
transoidal bis-spiroketal 24.[5] Interestingly, resubmission of
the cisoidal bis-spiroketal 20 to the same reaction conditions
did not lead to formation of any transoidal bis-spiroketal 19.
On the basis of these results, the location of the alkene in the
A ring at the C8–9 position (allylic to C10) appears to be a
catalyst for the unraveling and subsequent equilibration at
C10.Even more intriguing, treatment of the TBDPS-pro-
tected cisoidal bis-spiroketal 20 under our first-generation
conditions (CSA, tBuOH/PhMe)[1d–f] led to complete equili-
bration to the transoidal bis-spiroketal 19.It would appear
from these experiments that the use of PPTS in THF/H2O
leads to formation of the bis-spiroketal under kinetic control,
whereas with CSA in tBuOH/PhMe the reaction proceeds
under thermodynamic control.Additional support for this
conclusion can be found in the exclusive formation of
transoidal bis-spiroketal 19 from 7 upon treatment with
CSA in tBuOH/PhMe.Note that decomposition appears to be
a significant contributor to the low yield (20–30%) in the
formation of the spiroketal from 7 using the first-generation
conditions.The second-generation conditions were optimal
for the initial formation of the bis-spiroketal of 7, whereas the
first-generation conditions were preferred for the equilibra-
tion of 20.
followed by conversion into the allylic bromide provided 12.
Coupling of this electrophile with the readily available
sulfone 14 (synthesized from the commercially available
sodium salt of benzenesulfinic acid, thiophenol, and 1,3-
dibromopropane (13)) and deprotection of the acetal gave the
diol 15 as a mixture of stereoisomers at C10.Sequential
protection at C4 and C6 provided the bis-silyl species 16.
After careful optimization, we found that the sulfone 16 could
be cleanly converted into the b,g-unsaturated ketone 17 using
sodium hexamethyldisilizane and bis(trimethylsilyl) perox-
ide.[7] Despite our fears of the possible instability of 17, this
compound proved to be remarkably robust (stable to
chromatography and prolonged storage in the freezer).
Subsequent conversion into the methoxy ketal followed by
oxidation of the sulfone[8] using Leyꢀs TPAP reagent[9] yielded
the coupling partner 8.
With the sulfone subunit 8 in hand, we embarked on the
combination of the subunits 8 and 9 (Scheme 3).Julia
coupling of 8 and 9 with LDA proved problematic; however,
use of the more hindered lithium base derived from 2,2,6,6-
tetramethylpiperidine nicely addressed this issue.Subsequent
oxidation with TPAP provided the ketosulfone species 18 in
excellent yield (92%) over the two steps.Desulfonylation of
18 using Na/Hg amalgam followed by the formation of the
bisspiroketal of 7 under our second-generation conditions
(PPTS, THF/H2O)[5] led cleanly to the desired transoidal bis-
spiroketal 19 with the corresponding cisoidal bis-spiroketal 20
Removal of the C4-silyl protecting group on 20 revealed
additional information (Scheme 4).Treatment of 21 under the
first-generation conditions once again leads to complete
conversion into the transoidal bis-spiroketal 22.Interestingly,
use of our second-generation conditions also led to slow
formation of the transoidal bis-spiroketal 22 (1:1 ratio of bis-
spiroketals 21/22 after 72 h).Decomposition became a com-
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Completion of the northern portion of azaspiracid-1 (2) is
shown in Scheme 5.Wadsworth–Emmons coupling of 5 and 6
using KHMDS with in situ, intramolecular hetero-Michael
addition yielded 27 with single stereochemistry at C19 of the
furan D ring.Deprotonation using NaHMDS followed by a
large excess of the Davis oxaziridine provided the hydroxy-
[10]
ketone 29 as a single stereoisomer.Mosher ester analysis
confirmed that 30 displayed the undesired a stereochemistry.
The stereochemical outcome in the hydroxylation can be
explained through chelation of the sodium Z-enolate 28 to the
oxygen atom of the furan D ring.Initial attempts to invert the
stereochemistry at C20 using Mitsunobu-type conditions
proved unsuccessful.Fortunately, triflation followed by dis-
placement using the potassium salt of p-nitrobenzoic acid in
DMF cleanly provided the desired b stereochemistry.The
stereochemistry of 31 was once again confirmed by means of
Mosher ester analysis.Desilylation using CSA followed
selenation, and oxidation/elimination using TPAP yielded
the reactive bisallylic pyran 34.To the best of our knowledge,
the TPAP-mediated oxidation of selenium has not been
previously reported.[11] Attempted oxidation of the selenide
using traditional conditions (e.g. H2O2, THF)[12] led to multi-
ple products.Finally, selective olefin metathesis with 35 using
the second-generation Grubbs catalyst[13] gave the target 3.
In summary, an efficient approach to the entire C1–C26
northern portion of azaspiracid-1 has been described (27 steps
from known ester 12).We have unearthed novel controlling
factors for formation of the bis-spiroketal under kinetic versus
Scheme 4. Equilibration of C4-hydroxy bis-spiroketals. Reagents and
conditions: a) TBAF, THF; b) CSA, tBuOH/PhMe (1:1), 18 h;
c) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 99%; d) LiDBB, THF, ꢀ788C,
95%; e) TPAP, NMO, CH2Cl2, M.S.; 67%; f) DIBAL-H, CH2Cl2, 90%.
TBAF=tetra-n-butylammonium fluoride; DBB=lithium 4,4–di-tert-
butylbiphenylide.
petitive pathway upon extended reaction times, making
complete conversion of 21 into 22 under the second-gener-
ation conditions not feasible.The hydroxy group at C4 would
appear to assist in the ionization of the bis-spiroketals,
presumably through increasing the acidity of the local
environment and/or a hydrogen-bonding interaction.Finally,
debenzylation and oxidation/reduction at C19 provided the
tetracycle 5 (Scheme 4).
Scheme 5. Completion of the northern portion of azaspiracid-1 (2). Reagents and conditions: a) 6, KHMDS, THF, ꢀ788C!RT, 84%;
b) NaHMDS, THF, then Davis oxaziridine, 70%, >20:1 d.r.; c) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ788C, 88%; d) KO2C-p-NO2-C6H4 (20 equiv), DMF,
90%; e) CSA, MeOH/CH2Cl2, 93%; f) o-NO2C6H4SeCN, Bu3P, THF 93%; g) TPAP, NMO, Et3N, CH2Cl2, 66%; h) second-generation Grubbs
catalyst, 35, CH2Cl2, 95% (BORSM), >10:1 E/Z; i) (R)/(S)-Mosher acid chloride, DMAP, CH2Cl2. MTPA=a-methoxy-a-trifluoromethylphenylacetic
acid (Mosher); DMAP=4-(dimethylamino)pyridine. The stereochemistry at C20 was confirmed by Mosher ester analysis. Representative data
points for the difference in the chemical shift values [(S)-Mosher esterꢀ(R)-Mosher ester (in ppm); CDCl3, 300 or 400 MHz] are shown for
structures 30 and 33.
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Communications
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this synthetic sequence include the oxidation of a sulfone at
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Received: October 21, 2005
Revised: November 17, 2005
Published online: February 10, 2006
Keywords: azaspiracid-1 · fused-ring systems · natural products ·
.
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