A convergent total synthesis of hemibrevetoxin B

Article abstract of DOI:10.1021/ja029225v

A convergent biomimetic synthesis of hemibrevetoxin B from d-glucal and d-arabinose utilizes an electrophile-promoted cascade anti-Baldwin cyclization of an epoxy alcohol. The epoxy alcohol arises from a palladium-catalyzed coupling of a highly functionalized organozinc compound and an alkenyl iodide, which serve as two chiral building blocks of similar size and complexity. This first successful implementation of a cascade epoxy alcohol cyclization for the synthesis of marine polycyclic ether toxins proceeds in 39 steps and 4% overall yield. Copyright

Full text of DOI:10.1021/ja029225v

Published on Web 06/06/2003
A Convergent Total Synthesis of Hemibrevetoxin B
Armen Zakarian, Alexandre Batch, and Robert A. Holton*
Department Of Chemistry, Florida State UniVersity, Tallahassee, Florida 32306
Received November 5, 2002; E-mail: holton@chem.fsu.edu
Hemibrevetoxin B (Scheme 1) belongs to a structurally unique
tion of Ireland’s protocol (Scheme 3).5 Allylation of lactone 6,
prepared from 5 in three steps and 89% yield, afforded 7 (83%)
and its diastereomer (5%). Oxidative cleavage of the double bond,
reduction, and conversion of the resultant primary alcohol to iodide
3 proceeded in 83% yield. By this route, fragment 3 was obtained
in 12 steps and 56% overall yield from benzyl â-D-arabinopyrano-
side.
family of marine neurotoxins isolated from the dinoflagellate
Gymnodinium breVe.1 Other members of the group, such as the
ciguatoxins and brevetoxins A and B, are potent ichthyotoxins that
bind to receptor site 5 of voltage-dependent sodium channels and
cause membrane depolarization in neurons at nanomolar concentra-
tions.2 These compounds possess an impressive molecular archi-
tecture incorporating a trans-fused cyclic polyether framework with
ring sizes ranging from five to nine and a plethora of chiral centers.
Three total and three formal total syntheses of hemibrevitoxin B,
all utilizing a linear strategy, have been reported.3
Scheme 3 a
Scheme 1
a Conditions: (a) n-Bu2SnO; TrBr, TBAI, PhMe, 8 h; (b) NaH,
BrCH2CO2Bu-t, DME, 80 °C, 5 h; (c) 0.1 equiv of CSA, PhH, 80 °C, 20
h; (d) 0.07 equiv of OsO4, 5 equiv of NaIO4, NaHCO3, t-BuOH-H2O-
Et2O, rt, 3 h; (e) NaBH3CN, THF-AcOH (9:1), rt, 20 min; (f) Ph3P, I2,
2,6-lutidine, CH2Cl2, rt, 2 h.
A cascade epoxy alcohol cyclization has been proposed for the
biosynthesis of the polyether toxins (Scheme 1).1 In this Com-
munication we report the first conVergent total synthesis of
hemibrevetoxin B utilizing a biomimetic epoxy alcohol cyclization
as the key step.
On the basis of extensive model studies,4 we envisioned that
the B and C rings of hemibrevetoxin B could be formed by a
biomimetic cyclization of 2, initiated by electrophilic attack on the
double bond and proceeding via a bicyclic epoxonium ion (Scheme
2). A precursor of 2 could be formed by the union of two fragments
of roughly equal size and complexity, iodide 3 representing the
C12-C21 fragment and vinyl iodide 4 representing the C1-C11
fragment.
The synthesis of fragment 4 commenced with BF3-promoted
C-allylation of tri-O-acetyl-D-glucal6 with ethyl 2-trimethylstannyl-
acrylate,7 which afforded 8 (93%) and the C4 epimer of 8 (7%)
(Scheme 4). Acetate hydrolysis, epoxidation and protection of the
diol produced benzylidene acetal 9 in 83% overall yield. One-pot
reduction of the epoxide and conjugated ester groups in 9 gave
diol 10 in 93% yield. Hydroboration-oxidation and selective
protection of the triol afforded acetonide 11 (92%), which was
converted to 13 in 79% yield via triflate 12.8 Hydrozirconation-
iodination9 of 13 gave a mixture of regioisomers in low yield.
Silylcupration10 proceeded smoothly, but iododesilylation gave
stereoisomeric mixtures in several different solvents, presumably
due to solvent participation.11 However, in 1,1,1,3,3,3-hexafluoro-
2-propanol (HFIP),12 a polar solvent with low nucleophilicity,
iododesilylation of the vinylsilane with NIS proceeded with
complete retention, giving 4 in 89% yield from 13. Thus, the
synthesis of 4 from tri-O-acetyl-D-glucal required 13 steps and
proceeded in 46% overall yield.
Scheme 2
The coupling of the two fragments was accomplished by Pd-
(dppf)Cl2-catalyzed reaction of organozinc iodide 14 with vinyl
iodide 4 (Scheme 5).13 When the preparation of 14 was carried out
via metal-iodine exchange between primary iodide 3 and diethyl-
zinc employing palladium or Mn/Cu mixed metal catalysis,14 the
yield of 15 was low and variable (∼30-50%), and significant
quantities of the ethyl-coupled byproduct were obtained. However,
when alkylzinc iodide 14 was prepared using Rieke active zinc,15
alkene 15 was reproducibly obtained in 76% yield at 86%
conversion.
The synthesis of 3 began with diol 5, which was prepared from
benzyl â-D-arabinopyranoside in 90% overall yield by a modifica-
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C O M M U N I C A T I O N S
Scheme 4 a
A major challenge in the application of tandem epoxy alcohol
cyclizations to the synthesis of trans-fused polycyclic ethers is the
known preference of epoxides to undergo intramolecular openings
in a 5-exo, rather than a 6-endo, fashion.17 This issue was recently
addressed by Houk et al. through ab initio calculations for proton-
catalyzed 5-exo and 6-endo epoxy alcohol cyclizations.18 They
inferred that 6-endo cyclizations have a looser, SN1-type transition
state. Therefore, we proposed that the regioselectivity of the
intramolecular epoxide opening could be shifted in the 6-endo
direction by the proper choice of highly polar solvent, and HFIP
proved to be an excellent selection.
In the event, using HFIP as solvent, 2 underwent a smooth
cyclization in the 6-endo mode upon treatment with a variety of
electrophiles. The optimum conditions involved treatment of 2 in
HFIP solution with N-(phenylseleno)phthalimide at 0 °C to give
18 as a single diastereomer in 83% yield. Thus, two ether rings of
hemibrevetoxin B were assembled in a single synthetic operation.
In a control experiment, no reaction was observed when a solution
of 2 in HFIP was stirred at 0 °C for 1.5 h.
The completion of the synthesis is depicted in Scheme 6.
Oxidation-elimination of the selenide gave olefin 19 in 91% yield,
but removal of the benzyl protecting groups on the pyranose ring
in 19 proved troublesome due to the sensitivity of the allylic ether.
Ultimately, the deprotection was achieved (78%) by inverse addition
of lithium in ammonia to a THF solution of 19. Lactol 20 underwent
olefination and deprotection to give triol 21 (88%), and its efficient
(85%) ring closure to triol 22 was achieved using the second-
generation ruthenium-based olefin metathesis catalyst.19 The C20-
C25 side chain was constructed by cleavage of the diol, olefination
of the resulting aldehyde, reduction of the double bonds, protection
of the tertiary hydroxyl as the TMS ether, and reduction of the
amide to give aldehyde 23 in 79% overall yield. Peterson olefination
of 23 using the (E)-γ-silylallylboronate reagent20 gave 24 (78%)
along with 5% of the E isomer. Finally, removal of the acetonide
and TMS groups of 24, mono-tosylation of the triol, oxidation, and
final MOM ether cleavage with LiBF4 in aqueous acetonitrile21
delivered 1 in 69% overall yield.
a Conditions: (a) 0.05 equiv of MeONa, MeOH, 0 °C to rt, 2 h; (b)
MCPBA, NaHCO3, CH2Cl2, rt, 80 h; (c) PhCH(OMe)2, cat. CSA, MeCN,
reflux, 2 h; (d) BH3‚DMS, THF, rt, 3 h; 30% H2O2, pH 7 phosphate buffer,
25 °C, 12 h; (e) 0.05 equiv of CSA, Me2C(OMe)2-Me2CO, 25 °C, 1 h; (f)
MOMCl, i-Pr2NEt-CH2Cl2 (1:1), 25 °C, 12 h; (g) Li, NH3, THF, -78 °C,
1 h; (h) Tf2O, 2,6-lutidine, -78 °C, 0.5 h; TESOTf, CH2Cl2, 0 °C, 0.5 h;
(i) (MePh2Si)2Cu(CN)Li2, THF-Et2O (1:1), -78 to -40 °C, 4 h; (j) NIS,
(CF3)2CHOH, 0 °C, 90 s.
Hydrolysis of lactone 15 gave a hydroxy acid which underwent
diastereoselective iodolactonization, providing 16 (75%) along with
its diastereomer (11%). Protection of the hydroxyl group and
methanolysis provided the C10-C11 epoxide 17, having the desired
stereochemistry, in 95% yield. Conversion of 17 to the cascade
cyclization substrate 2 was then carried out by reduction of the
ester, oxidation to the aldehyde, Wittig olefination and, finally,
selective removal of the triethylsilyl protecting group, in 83%
overall yield.
This cyclization substrate was designed so that the cyclization
could be initiated by electrophilic attack on the olefin, and its Z
configuration was chosen with the hope that facial selectivity in
the electrophilic addition would be controlled by allylic 1,3-strain.16
This approach seemed particularly attractive because the double
bond can react with a number of electrophiles without interference
from the epoxide and hydroxyl groups.
The synthetic material had physical data (1H, 13C, IR, [R]D,
elemental analysis) identical with those reported for the natural
product.1b Thus, the convergent synthesis of hemibrevetoxin B was
accomplished in 39 steps and ca. 4% overall yield in the longest
linear sequence from tri-O-acetyl-D-glucal.
Scheme 5 a
a Conditions: (a) LiOH, THF-H2O (2:1), 0 °C, 20 min; (b) NIS, 2,6-lutidine, CH2Cl2, -10 °C, 3 h; (c) TIPSOTf, 2,6-lutidine, t-BuOAc, -10 °C, 15
min; (d) 1.1 equiv of MeONa/MeOH, CH2Cl2, -35 °C, 1 h; (e) LiAlH4, THF, -78 °C, 1 h; (f) (COCl)2-DMSO, i-Pr2NEt, -78 to 0 °C, 30 min; (g)
Ph3PEt+Br-, NaHMDS, THF-DMPU (3:2), rt, 2 h; (h) 6 M aqueous HF-Py-MeCN, rt, 8 h.
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C O M M U N I C A T I O N S
Scheme 6 a
a Conditions: (a) 30% aqueous H2O2, THF, reflux, 1 h; (b) Li, NH3, 3 equiv of ethyl allyl ether, THF, -78 °C; (c) Me3SiCH2MgCl, THF, reflux, 1 h;
(d) t-BuOK, THF, 25 °C, 30 min; TBAF, 25 °C, 30 min; (e) NaIO4, Et2O-t-BuOH-H2O, (5:1:1), rt, 10 min; (f) (EtO)2P(O)CH2C(O)N(Me)OMe, NaH,
THF, 30 min; (g) H2, 20% Pd(OH)2/C, EtOAc, rt, 15 h; (h) TMSCl, Et3N, CH2Cl2, rt, 12 h; (i) DIBAL, THF, -78 °C, 1 h; (j) n-Bu2SnO; TsCl, TBAI,
CH2Cl2, 0 °C, 2 h; (k) (COCl)2, DMSO, -78 °C; Et3N, rt, 0.5 h; (l) LiBF4, 4% aqueous MeCN, reflux, 2 h.
(8) Mori, Y.; Yaegassi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158.
In conclusion, a biomimetic cascade epoxy alcohol cyclization
has been successfully implemented in the total synthesis of a trans-
fused polycyclic ether toxin, allowing for development of the first
convergent approach to hemibrevetoxin B.
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Acknowledgment. We thank the FSU Research Foundation and
donors to the FSU Foundation for financial support of this work.
Supporting Information Available: Selected experimental pro-
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