Studies toward the total synthesis of gambieric acids A and C: Convergent assembly of the nonacyclic polyether skeleton

Article abstract of DOI:10.1002/anie.200604625

(Chemical Equation Presented) A solid approach to ethereal rings: Key features of a convergent synthesis of the nonacyclic polyether skeleton of gambieric acids A and C include the connection of the BCD and GHIJ ring systems by esterification, the construction of the E ring in the form of a lactone, a stereoselective allylation to establish the C26 stereocenter, and the formation of the F ring by ring-closing metathesis (see scheme; Bn = benzyl, NAP = 2-naphthylmethyl).

Full text of DOI:10.1002/anie.200604625

Communications
DOI: 10.1002/anie.200604625
Natural Products Synthesis
Studies toward the Total Synthesis of Gambieric Acids A and C:
Convergent Assembly of the Nonacyclic Polyether Skeleton**
Kazushi Sato and Makoto Sasaki*
A number of polycyclic-ether natural products with potent
and diverse biological activities have been isolated from
marine sources.[1] Gambieric acids A–D (1–4,Scheme 1) were
We reported previously a convergent synthesis of the
central CDEFG ring system of the gambieric acids.[4] The
synthetic approach involved the convergent union of the CD-
and G-ring fragments through esterification,followed by
construction of the E and F rings. We envisaged the applica-
tion of this strategy to the construction of the nonacyclic
BCDEFGHIJ polyether skeleton 5 of gambieric acids A and
C from the two complex fragments 6 and 7,as illustrated in
Scheme 2. The nine-membered F ring of 5 would be accessible
by ring-closing metathesis (RCM) from the precursor diene 8,
which we planned to obtain from lactone 9 through reductive
acylation[7] followed by stereoselective allylation. Lactone 9,
in turn,could be derived from the a-cyano ether 10,which
could be obtained from two complex fragments,the BCD-ring
carboxylic acid 6 and the GHIJ-ring alcohol 7,according to
previously described chemistry.[4]
Scheme 1. Structures of gambieric acids A–D.
The synthesis of the BCD-ring fragment 6 (Scheme 3)
started with the known alcohol 11,which is available in four
steps from tri-O-acetyl-d-glucal.[8] Parikh–Doering oxida-
tion[9] and Wittig olefination,followed by hydroboration
isolated by Nagai,Yasumoto,and co-workers from the culture
media of the marine dinoflagellate Gambierdiscus toxicus,
which is the causative organism of ciguatera seafood poison-
ing.[2] These polycyclic ethers exhibited extremely potent
antifungal activity against Aspergillus niger (their potency is
2000 times greater than that of amphotericin B),whereas they
show only moderate toxicity toward mice or cultured
mammalian cells. These useful biological aspects make
polycyclic ethers potential lead compounds for the discovery
of antifungal agents. Moreover,Inoue et al. reported recently
that gambieric acid A (1) inhibits the binding of
[3H]dihydrobrevetoxin B ([3H]PbTx-3) to voltage-sensitive
sodium channels,although its binding affinity is significantly
lower than those of the brevetoxins and ciguatoxins.[3] These
intriguing biological properties and the molecular complexity
of the gambieric acids have generated considerable interest
within the synthetic community,and several synthetic
approaches toward the total synthesis of these potentially
useful polycyclic ethers have been reported to date.[4–6]
Herein,we describe a convergent synthesis of the nonacyclic
polyether skeleton 5 of gambieric acids A and C.
[*] K. Sato, Prof. Dr. M. Sasaki
Laboratoryof Biostructural Chemstry
Graduate School of Life Sciences, Tohoku University
Aoba-ku, Sendai 981-8555 (Japan)
Fax: (+81)22-717-8897
E-mail: masasaki@bios.tohoku.ac.jp
[**] This research was supported financiallyin part bythe Sumitomo
Foundation and Grants-in-Aid for Scientific Research from the Japan
Societyfor Promotion of Science (JSPS) and the Ministryof
Education, Culture, Sports, Science and Technology, Japan (Scien-
tific Research (B) 16310145 and PriorityArea 16073202). A research
fellowship to K.S. from the JSPS is acknowledged.
Scheme 2. Retrosynthesis of the nonacyclic BCDEFGHIJ ring system 5
of gambieric acid A and C. Bn=benzyl, NAP=2-naphthylmethyl.
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steps). The terminal olefinic unit of 14 was converted into a
methyl ketone by a standard four-step sequence,and the TBS
ether was replaced with a b-alkoxy E acrylate group to give
15. The treatment of 15 with SmI2 in the presence of MeOH
induced reductive cyclization[11] to afford the CD ring system
16 as a single diastereomer. After TMS protection of the
hydroxy group,the ethyl ester was reduced with DIBAL-H,
and the resulting aldehyde underwent a Wittig reaction to
give a terminal alkene in 86% overall yield. Subsequent
treatment with 1,3-propanedithiol in the presence of
TMSOTf provided the dithiane diol 17 in 93% yield. A
selective hetero-Michael reaction of the secondary hydroxy
group in 17 with ethyl propiolate,followed by TBS protection
of the remaining tertiary hydroxy group and hydrolysis of the
thioacetal,delivered aldehyde 18 in 89% yield. The reductive
cyclization of 18 with SmI2 again proceeded smoothly to form
the seven-membered B ring. The sole product formed was g-
lactone 19,the stereostructure of which was confirmed by the
observed NOEs indicated. After reduction with LiAlH4,the
resulting diol was protected as the corresponding NAP ethers
(85% from 18).[12,13] Hydroboration of the terminal olefinic
unit with 9-BBN provided a primary alcohol (99%),which
was subjected to a two-step oxidation to furnish the desired
BCD-ring carboxylic acid 6 in 87% yield for the two steps.
The GHIJ-ring fragment 7 was synthesized by connecting
the G and J rings (20 and 21) followed by formation of the H
and I rings according to the strategy developed by the Nakata
research group (Scheme 6).[14] The synthesis of the G-ring
aldehyde 20 began with the known alcohol 22,[15] which was
protected as the benzyl ether 23 (Scheme 4). Oxidative
cleavage of the double bond followed by a Wittig reaction
gave the a,b-unsaturated ester 24 in 80% yield. Subsequent
treatment with MeMgBr and TMSCl in the presence of the
CuII salt 25[16] gave the desired 1,4-adduct 26 in 96% yield.[4,8]
DIBAL-H reduction,benzyl protection,and hydrolysis of the
benzylidene acetal provided diol 27 in 90% yield for the three
steps. The secondary hydroxy group of 27 was protected
selectively as the TBS ether by double TBS protection
Scheme 3. Reagents and conditions: a) SO3·pyridine, Et3N, DMSO/
CH2Cl2, 08C!RT; b) Ph3PCH3Br, NaN(TMS)2, THF, 08C!RT, 95%
(2 steps); c) 9-BBN, THF; aq NaOH, H2O2, 08C!RT, 79%;
=
d) SO3·pyridine, Et3N, DMSO/CH2Cl2, 08C!RT; e) Ph3P C(Me)CO2Et,
toluene, 1008C, 90% (2 steps); f) DIBAL-H, CH2Cl2, ꢀ788C, 99%;
g) tBuOOH, (+)-DET, Ti(OiPr)4, 4-Š MS, CH2Cl2, ꢀ208C;
h) SO3·pyridine, Et3N, DMSO/CH2Cl2, 08C!RT; i) Ph3PCH3Br, NaN-
(TMS)2, THF, 08C!RT, 89% (3 steps); j) TBAF, THF, 08C!RT, 93%;
k) PPTS, CH2Cl2, 08C!RT, 96%; l) TBSOTf, 2,6-lutidine, CH2Cl2,
08C!RT, 97%; m) BH3·SMe2, 2-methyl-2-butene, THF; aq NaOH,
H2O2, 08C!RT, 98%; n) SO3·pyridine, Et3N, DMSO/CH2Cl2, 08C;
o) MeMgBr, THF, 08C!RT, 89% (2 steps); p) TPAP, NMO, 4-Š MS,
CH2Cl2, 08C!RT, 92%; q) TBAF, THF, 08C!RT, 99%; r) ethyl propio-
late, NMM, CH2Cl2, 08C!RT; s) SmI2, MeOH, THF, 08C!RT, 81%
(2 steps); t) TMSOTf, 2,6-lutidine, CH2Cl2, 08C, 92%; u) DIBAL-H,
toluene, ꢀ788C; v) Ph3PCH3Br, NaN(TMS)2, THF, 08C!RT, 93%
(2 steps); w) 1,3-propanedithiol, TMSOTf, MeCN, 08C, 93%; x) ethyl
propiolate, NMM, CH2Cl2, 08C!RT, 94%; y) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C!RT, 97%; z) MeI, NaHCO3, MeCN/H2O, RT, 96%;
aa) SmI2, MeOH, THF, RT; bb) LiAlH4, THF, 08C, 89% (2 steps);
cc) NaH, NAPBr, TBAI, DMF, 08C!RT, 96%; dd) 9-BBN, THF; aq
NaOH, H2O2, 08C!RT, 99%; ee) SO3·pyridine, Et3N, DMSO/CH2Cl2,
08C!RT; ff) NaClO2, 2-methyl-2-butene, KH2PO4, tBuOH/H2O, 08C!
RT, 87% (2 steps). 9-BBN=9-borabicyclo[3.3.1]nonane, DET=diethyl
tartrate, DIBAL-H=diisobutylaluminum hydride, DMF=N,N-dimethyl-
formamide, DMSO=dimethyl sulfoxide, MS=molecular sieves,
NMM=4-methylmorpholine, NMO=4-methylmorpholine N-oxide,
PPTS=pyridinium p-toluenesulfonate, TBAF=tetrabutylammonium
fluoride, TBAI=tetrabutylammonium iodide, TBS=tert-butyldimethyl-
silyl, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl, TPAP=tetra-n-
propylammonium perruthenate.
with 9-BBN,produced an alcohol in 75% overall yield. This
primary alcohol was subjected to a second oxidation/Wittig
reaction sequence to afford the a,b-unsaturated ester 12 in
90% yield. Ester 12 was reduced with DIBAL-H,and the
resulting allylic alcohol was subjected to Sharpless asymmet-
ric epoxidation. The oxidation of the epoxy alcohol thus
formed and a Wittig reaction,followed by desilylation,gave
the hydroxy epoxide 13 in 82% overall yield. The treatment
of 13 with PPTS effected 6-endo cyclization[10] to afford the C-
ring tetrahydropyran 14 after TBS protection (93%,two
Scheme 4. Reagents and conditions: a) NaH, BnBr, TBAI, DMF, 08C!
=
RT, 99%; b) OsO4, NMO, THF/H2O2, RT; NaIO4; c) Ph3P CHCO2Me,
THF, RT, 80% (2 steps); d) MeMgBr, TMSCl, 25, THF, ꢀ458C, 96%;
e) DIBAL-H, CH2Cl2, ꢀ788C, 99%; f) NaH, BnBr, TBAI, DMF, 08C!
RT; g) TsOH, MeOH, 40!708C, 91% (2 steps); h) TBSOTf, 2,6-
lutidine, CH2Cl2, 08C!RT; i) CSA, MeOH/CH2Cl2, 08C, 95% (2 steps);
j) SO3·pyridine, Et3N, DMSO/CH2Cl2, 08C!RT, 96%. CSA=camphor-
sulfonic acid, TsOH=p-toluenesulfonic acid.
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followed by selective deprotection of the primary hydroxy
oxidation of 32 afforded the corresponding ketone 33,which
was then treated with sodium methoxide to give the b-
methoxyenone 34 in 91% overall yield. After removal of the
TBS group,the resulting alcohol 35 was treated with PPTS to
induce an intramolecular hetero-Michael reaction,which led
to dihydropyranone 36 in 87% yield. DIBAL-H reduction of
36 proceeded stereoselectively to afford alcohol 37,with the
hydroxy group in the b orientation,as the sole product in
93% yield. Hydroboration of the enol ether led exclusively to
diol 38 (91%),which was then protected as the bis(TES)
ether 39 in 99% yield. Removal of the PMB group in 39,
followed by oxidation of the resulting alcohol with TPAP/
NMO[18] and removal of the TES groups,afforded dihydroxy-
ketone 40 in 81% yield (three steps). The treatment of 40 with
Et3SiH and TMSOTf delivered the tetracyclic ether 41 in
83% yield. The stereostructure of 41 was established on the
basis of 1H NMR spectroscopic analysis of the corresponding
acetate 42. A further four-step sequence of protecting-group
manipulations yielded 43 from 41 in 65% overall yield. Diol
43 was converted in a further three steps into the primary
alcohol 44,which was in turn converted into the terminal
alkene 45 by the method developed by Grieco,Gilman,and
Nishizawa.[20] The TIPS and acetonide groups in 45 were
exchanged for benzyl protecting groups,and the PMB group
was removed selectively[21] to complete the synthesis of the
desired GHIJ-ring fragment 7.
group (95%,two steps). The resulting primary alcohol was
oxidized under Parikh–Doering conditions[9] to furnish the G-
ring aldehyde 20 in 96% yield.
The synthesis of the J-ring alkyne 21 commenced with the
known alcohol 28 (Scheme 5).[17] Its protection as the PMB
Scheme 5. Reagents and conditions: a) NaH, PMBCl, TBAI, DMF,
08C!RT; b) CSA, MeOH, 08C!RT, 86% (2 steps); c) NaH, BnBr,
TBAI, DMF, 08C!RT, 94%; d) 9-BBN, THF, 08C!RT; aq NaOH,
H2O2, 08C!RT, 71%; e) TPAP, NMO, 4-Š MS, CH2Cl2, 08C!RT, 77%;
f) Cs2CO3, iPrOH, 08C!RT, 93%. PMB=p-methoxybenzyl.
ether,followed by removal of the benzylidene acetal and
benzylation of the resulting diol,provided 29 in 81% yield.
Hydroboration of the terminal alkene unit with 9-BBN and
oxidation of the resulting alcohol with TPAP/NMO[18]
afforded aldehyde 30 (55%). The treatment of aldehyde 30
with the Ohira–Bestmann reagent 31[19] completed the syn-
thesis of the J-ring alkyne 21 in 93% yield.
The lithium acetylide derived from alkyne 21 was treated
with aldehyde 20 to provide the propargylic alcohol 32 in
95% yield as a mixture of diastereomers (Scheme 6). Swern
With the requisite key fragments 6 and 7 in hand,the stage
was now set for the union of these fragments and subsequent
formation of the E and F rings. Acid 6 and alcohol 7 were
joined by esterification under Yamaguchi conditions[22] to
afford ester 46 in 92% yield (Scheme 7). Ester 46 was then
subjected to reductive acetylation according to the protocol of
Rychnovsky and co-workers[7] to give the a-acetoxy ether 47
Scheme 6. Reagents and conditions: a) tBuLi, THF/HMPA, ꢀ788C; then 20, ꢀ788C, 95%; b) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ788C!RT, 93%;
c) NaOMe, MeOH/THF, RT, 98%; d) HF·pyridine/pyridine/THF (2:1:4), 08C!RT, 91%; e) PPTS, toluene, 1008C, 87%; f) DIBAL-H, toluene,
ꢀ788C, 93%; g) BH3·THF, THF; aq NaOH, H2O2, THF, 08C!RT, 91%; h) TESOTf, 2,6-lutidine, CH2Cl2, 08C!RT, 99%; i) DDQ, CH2Cl2/pH 7
buffer, 08C; j) TPAP, NMO, 4-Š MS, CH2Cl2, 08C!RT; k) TBAF, AcOH, THF, RT, 81% (3 steps); l) TMSOTf, Et3SiH/MeCN (1:4), ꢀ108C, 83%;
m) TIPSOTf, 2,6-lutidine, CH2Cl2, 08C!RT; n) H2, Pd/C, MeOH, RT; o) 2,2-dimethoxypropane, CSA, DMF, 308C; p) PPTS, MeOH, CH2Cl2, 08C,
65% (4 steps); q) PivCl, pyridine, 08C, 82%; r) NaH, PMBCl, TBAI, DMF, 08C!RT, 78%; s) DIBAL-H, CH2Cl2, ꢀ788C, 72%; t) o-nitrophenyl-
selenocyanate, nBu3P, THF, RT; u) MCPBA, Et3N, CH2Cl2, 0!358C, 94% (2 steps); v) TBAF, THF, 08C!RT, 92%; w) TsOH, MeOH, 08C;
x) NaH, BnBr, TBAI, DMF, 08C!RT, 89% (2 steps); y) BF3·OEt2, Et3SiH, MeCN, 08C, 99%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
HMPA=hexamethylphosphoramide, MCPBA=m-chloroperbenzoic acid, Piv=pivaloyl, TES=triethylsilyl, TIPS=triisopropylsilyl.
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8 in 58% yield. Finally,a RCM reaction of 8 with the second-
generation Grubbs catalyst 51[24,25] resulted in the formation
of the nine-membered F ring to furnish the targeted non-
acyclic BCDEFGHIJ ring system 5 in 67% yield (Table 1).
The stereostructure of 5 was established unequivocally by
extensive NMR experiments to be that shown in Scheme 7.
Table 1: Selected physical properties of compound 5.
[a]2D8 =ꢀ2.5 (c=0.28, CHCl3); IR (film): n˜ =2925, 2872, 1632, 1454,
1384, 1069, 739, 698 cmꢀ1; 1H NMR (500 MHz, C6D6): d=7.69–7.56 (m,
14H), 7.45–7.41 (m, 3H), 7.33–7.07 (m, 12H), 6.12 (ddd, J=11.0, 11.0,
5.0 Hz, 1H), 5.63 (dd, J=10.5, 10.5 Hz, 1H), 5.12 (d, J=12.5 Hz, 1H),
4.92 (d, J=12.5 Hz, 1H), 4.53–4.41(m, 6H), 4.29 (d, J=12.0 Hz, 1H),
4.24 (d, J=11.5 Hz, 1H), 4.16–4.10 (m, 1H), 3.82–3.81 (m, 1H), 3.78–
3.70 (m, 2H), 3.67–3.66 (m, 2H), 3.62–3.59 (m, 2H), 3.51–3.46 (m, 4H),
3.32–3.20 (m, 5H), 3.22 (dd, J=12.0, 3.0 Hz, 1H), 3.00–2.98 (m, 1H),
2.92–2.89 (m, 2H), 2.34–2.12 (m, 8H), 1.94–1.53 (m, 15H), 1.32 (s,
3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.09 ppm (s,
3H); 13C NMR (125 MHz, C6D6): d=140.2, 139.4, 139.0, 136.8, 136.5,
134.4, 133.9 (ꢀ2), 133.5 (ꢀ2), 128.54 (ꢀ3), 128.46 (ꢀ2), 128.43 (ꢀ2),
128.3, 128.2 (ꢀ2), 128.1 (ꢀ2), 127.9 (ꢀ2), 127.80 (ꢀ3), 127.75, 127.54
(ꢀ2), 127.48, 126.43 (ꢀ2), 126.31, 126.27, 126.0 (ꢀ3), 125.9 (ꢀ2), 85.1,
85.0, 84.9, 84.7, 83.7, 83.6, 82.0, 81.4, 81.2, 79.9, 79.7, 79.2, 78.6, 77.4,
75.7, 74.6, 74.2, 74.1, 73.53 (ꢀ2), 73.48, 73.36, 73.2, 72.8, 70.9, 70.8, 70.4,
67.3, 54.5, 44.1, 35.9, 33.0, 32.9, 32.6, 32.3, 31.2, 30.7, 27.3, 24.0, 23.4,
18.3, 16.7, 16.3, 16.0, 11.2 ppm; HRMS (ESI): m/z calcd for
C85H100O14Na [M+Na]+: 1367.7113; found: 1367.7224.
In summary,we have synthesized the nonacyclic BCDEF-
GHIJ ring skeleton 5 of gambieric acids A and C in a
convergent fashion. Our synthesis features 1) the convergent
union of the BCD-and GHIJ-ring fragments through esterifi-
cation; 2) the construction of the seven-membered E ring in
the form of a lactone through reductive acetylation; 3) a
stereoselective allylation to establish the C26 stereocenter;
and 4) cyclization to form the nine-membered F ring by ring-
closing metathesis. Further studies along these lines toward
the total synthesis of gambieric acids A and C are in progress,
the results of which will be reported in due course.
Scheme 7. Reagents and conditions: a) 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, 0!408C; DMAP, toluene, 408C, 92%; b) DIBAL-H, CH2Cl2,
ꢀ788C; Ac2O, DMAP, pyridine, CH2Cl2, ꢀ78!08C, 54%; c) TMSCN,
TMSOTf, DTBMP, CH2Cl2, ꢀ78!08C; d) TBAF, MeCN, 708C, 89%
(2 steps); e) KOH, ethylene glycol, 1508C; f) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF/toluene; DMAP, reflux, 37% for 9, 33% for 49
(2 steps); g) DIBAL-H, CH2Cl2, ꢀ788C; Ac2O, DMAP, pyridine, CH2Cl2,
=
ꢀ78!08C, 68%; h) CH2 CHCH2TMS, BF3·OEt2, 4-Š MS, MeCN,
ꢀ40!ꢀ308C, 58%; i) 51, CH2Cl2, 408C, 67%. Cy=cyclohexyl,
DMAP=4-dimethylaminopyridine, DTBMP=2,6-di-tert-butyl-4-methyl-
pyridine.
Received: November 14,2006
Published online: February 27,2007
in 54% yield as an approximately 1:1 mixture of diastereo-
mers. The treatment of 47 with TMSCN afforded the
corresponding a-cyano ether,which was desilylated to give
alcohol 10 in 89% yield (two steps). The cyano group was
hydrolyzed subsequently under alkaline conditions to provide
carboxylic acid 48 as a 1:1 mixture of diastereomers.
Yamaguchi lactonization[22] of 48 provided a mixture of
seven-membered lactones,which was separated by flash
column chromatography to give 9 and 49 in 37 and 33%
yield,respectively (two steps). [23] An NOE observed between
Keywords: cyclization · metathesis · natural products ·
.
polyethers · total synthesis
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