Chemical synthesis of the GHIJK ring system and further experimental support for the originally assigned structure of maitotoxin

Article abstract of DOI:10.1002/anie.200703742

(Chemical Equation Presented) Accepting the proposal: The originally proposed structure of maitotoxin has recently come under scrutiny based on biosynthetic and computational considerations. A newly synthesized ring framework corresponding to the GHIJK ri

Full text of DOI:10.1002/anie.200703742

Angewandte
Chemie
DOI: 10.1002/anie.200703742
Natural Product Synthesis
Chemical Synthesis of the GHIJK Ring System and Further
Experimental Support for the Originally Assigned Structure of
Maitotoxin**
K. C. Nicolaou,* Kevin P. Cole, Michael O. Frederick, Robert J. Aversa, and Ross M. Denton
Maitotoxin is a notorious
marine neurotoxin that
possesses
unsurpassed
molecular size and toxicity
compared to any other
known secondary metabo-
lite.[1–4] In a recent essay[5]
we provided computa-
tional support for the orig-
inally proposed struc-
ture[2–4] of maitotoxin (1,
Scheme 1), whose stereo-
chemistry at the JK ring
junction was questioned
on the basis of rational
biosynthetic
considera-
tions.[6] Herein we provide
further experimental sup-
port of the originally
assigned structure of mai-
Scheme 1. Originally proposed structure of maitotoxin (1)and the targeted GHIJK ring system 2.
totoxin through chemical synthesis and NMR spectroscopic
analysis of GHIJK ring system 2 (Scheme 1), a fragment that
corresponds to the GHIJK domain of the naturally occurring
molecule.
Representing the relevant region of maitotoxin, 2 was
targeted for synthesis with the intention of comparing its
13C NMR spectral data to those of the naturally occurring
substance, an exercise of well-recognized diagnostic value in
stereochemical assignments of complex molecules.[4,7] Con-
current with this objective, we had in mind the development
of synthetic strategies suitable for an eventual total synthesis
of larger fragments of maitotoxin for biological investigations.
The devised synthetic plan for the construction of the GHIJK
ring system 2 required the coupling and elaboration of
fragments 13 (Scheme 2) and 33 (Scheme 5) to the targeted
structure.
Scheme 2 depicts the enantioselective construction of the
G-ring intermediate 13 from prochiral furan derivative 3 and
features a Noyori reduction with catalyst 6[8] as a means to
introduce chirality into the emerging molecule. Thus, lithia-
tion (nBuLi) of furan 3[9] in THF at 08C followed by the
addition of Weinreb amide 4[10] at À788C afforded ketone 5
(91% yield), which was then reduced asymmetrically with the
(S,S)-Noyori catalyst 6 (5 mol%) in a 5:2 mixture of formic
acid/triethylamine at 258C (94% yield, > 95% ee) to afford,
after selective pivaloate protection of the primary hydroxy
group (PivCl, 2,6-lut., 92% yield), chiral furan 7. An
Achmatowicz rearrangement[11] was then initiated by the
action of NBS in the presence of NaOAc and NaHCO3 in
aqueous THF to afford the corresponding hemiacetal, which
proved quite unstable and was, therefore, reduced immedi-
ately with Et3SiH in the presence of BF3·Et2O in MeCN to
pyran 8, obtained in 60% overall yield as a single stereoiso-
mer. The enone moiety within pyran 8 was then reduced
selectively (b isomer) under Luche conditions[12] (NaBH4,
CeCl3·7H2O, 94% yield) to the corresponding allylic alcohol,
[*] Prof. Dr. K. C. Nicolaou, Dr. K. P. Cole, M. O. Frederick, R. J. Aversa,
Dr. R. M. Denton
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92037 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by the National
Institutes of Health (USA)and the Skaggs Institute of Chemical
Biology, as well as fellowships from the National Science Founda-
tion (predoctoral to M.O.F.)and the National Institutes of Health
(USA)(postdoctoral to K.P.C.)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8875 –8879
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8875
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Communications
NaBH4] that afforded, after deacetylation with K2CO3 in
MeOH, the desired diol 11 in 95% overall yield. With all four
asymmetric centers set in the desired configuration for ring G,
diol 11 was then selectively converted into the primary iodide
in 89% yield through the action of iodine in the presence of
Ph3P and imidazole. The remaining secondary hydroxy group
was then protected as a TES ether (TESOTf, 2,6-lut., 93%
yield). At this point we were forced to call upon selenide 12 to
serve as a precursor to the targeted ring G fragment 13
because of the failure of the corresponding iodide to furnish
the desired elimination product in more than 40% yield
under a variety of basic conditions. Thus, displacement of the
iodide from the last intermediate of the sequence (PhSeSePh,
NaBH4) led to selenide 12 which was converted into 13 in
86% overall yield by exposure to O3 at À788C followed by
heating (808C) in benzene containing excess iPr2NH.
The G-ring coupling partner 13 was also synthesized
through an alternative route starting from known tetraol 14
(available in seven steps from methyl-d-glucopyranoside)[13]
as shown in Scheme 3. Protection of the 1,3-diol system
Scheme 2. Construction of G ring system 13. Reagents and conditions:
a) 3 (2.5 equiv), nBuLi (2.5m in hexanes, 2.5 equiv), THF, 08C, 30 min;
then À788C, 4 (1.0 equiv), 2 h, 91%; b) 6 (0.05 equiv), HCO2H/Et3N
(5:2), 258C, 72 h, 94% (>95% ee); c) PivCl (1.4 equiv), 2,6-lut.
(3.0 equiv), CH2Cl2, À788C, 1 h, 92%; d)NBS (1.0 equiv), NaOAc
(1.0 equiv), NaHCO3 (2.0 equiv), THF/H2O (3:1), 08C, 1 h; e)Et 3SiH
(5.0 equiv), BF3·Et2O (2.0 equiv), MeCN, 08C, 30 min, 60% over two
steps; f)CeCl 3·7H2O (0.5 equiv), NaBH4 (1.0 equiv), MeOH/CH2Cl2
(1:1), À108C, 10 min, 94%; g)PMBOC(NH)CCl (1.5 equiv), La(OTf)3
3
(0.05 equiv), PhMe, 258C, 30 min, 92%; h) mCPBA (5.0 equiv), CH2Cl2,
258C, 48 h, 75%; i)Ti(OBn) 4 (3.0 equiv), PhMe, 1008C, 28 h, 77%;
j) AcCl (1.1 equiv), 2,6-lut. (3.0 equiv), CH2Cl2, À788C, 1 h, 95%;
k)(COCl) 2 (3.0 equiv), DMSO (5.0 equiv), CH2Cl2, À788C, 2 h; then
Et3N (7.0 equiv), 08C, 1 h; l)NaBH 4 (4.0 equiv), MeOH, 08C, 15 min;
then K2CO3 (5.0 equiv), 258C, 16 h, 95% over two steps; m)I 2
(2.0 equiv), Ph3P (2.0 equiv), imid. (2.0 equiv), THF, 258C, 2 h, 89%;
n) TESOTf (2.0 equiv), 2,6-lut. (3.0 equiv), CH2Cl2, 08C, 30 min, 93%;
o)(PhSe) 2 (1.1 equiv), NaBH4 (2.0 equiv), EtOH/THF (5:3), 0 to 258C,
3 h; p) O3, CH2Cl2/MeOH (5:1), À788C, 10 min; q) iPr2NH:C6H6
(1:10), 808C, 3 h, 86% over three steps. Bn=benzyl, TBS=tert-
butyldimethylsilyl, THF=tetrahydrofuran, Piv=trimethylacetyl, lut.=
lutidine, NBS=N-bromosuccinimide, PMB=para-methoxybenzyl,
mCPBA=meta-chloroperbenzoic acid, DMSO=dimethyl sulfoxide,
imid.=imidazole, TES=triethylsilyl, Tf=trifluoromethanesulfonyl.
Scheme 3. Alternate construction of G ring system 13. Reagents and
conditions: a)PhCH(OMe) 2 (1.5 equiv), CSA (0.02 equiv), 4-Š MS,
CH2Cl2, 258C, 2 h, 74%; b) TBSCl (2.0 equiv), imid. (3.0 equiv), DMF,
258C, 18 h, 88%; c) PMBCl (10 equiv), TBAI (0.5 equiv), NaH
(6.0 equiv), DMF, 258C, 18 h, 80%; d)TBAF (5.0 equiv), THF, 25 8C,
18 h, 83%; e)(COCl) 2 (5.0 equiv), DMSO (10 equiv), CH2Cl2, À788C,
1 h; Et3N (20 equiv), 08C, 30 min; f)NaBH 4 (2.2 equiv), MeOH, 08C,
86% over two steps; g) BnBr (7.0 equiv), TBAI (0.2 equiv), NaH
(5.0 equiv), DMF, 258C, 18 h, 88%; h)TsOH (0.2 equiv), MeOH,
258C, 18 h, 85%. TBDPS=tert-butyldiphenylsilyl, CSA=(Æ)-camphor-
10-sulfonic acid, MS=molecular sieves, DMF=N,N-dimethylform-
amide, TBAI=tetra-n-butylammonium iodide, TBAF=tetra-n-butylam-
monium fluoride.
involving the primary alcohol within 14 (C-1, C-3) was
accomplished with PhCH(OMe)2 and CSA (cat.) in 74%
yield. The less hindered secondary hydroxy group of the
molecule (C-4) was then protected as the TBS ether (TBSCl,
imid.), and the remaining free hydroxy group was converted
into its PMB ether (PMBCl, TBAI, NaH) to give to the fully
protected pyran system 15 (70% yield for the two steps).
Treatment of the latter intermediate with TBAF then effected
removal of both its silyl groups, thereby furnishing the
corresponding diol in 83% yield. The secondary hydroxy
moiety was then inverted through an oxidation/reduction
sequence [(COCl)2, DMSO, Et3N; NaBH4, 86% yield over
which was protected as the PMB ether (PMBOC(NH)CCl3,
La(OTf)3, 92% yield) and epoxidized with mCPBA to afford
epoxide 9 as a single isomer in 75% yield. Treatment of the
latter compound with Ti(OBn)4 in toluene at 1008C led to
regioselective opening of its epoxide moiety and cleavage of
its pivaloate ester to afford, after selective acetylation (AcCl,
2,6-lut.), hydroxy acetate 10 in 73% overall yield. The
obligatory inversion of stereochemistry of the secondary
hydroxy group was then carried out within compound 10 by
an oxidation/reduction sequence [(COCl)2, DMSO, Et3N;
8876 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8875 –8879
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Angewandte
Chemie
two steps] to provide the desired diol 16. Benzylation of 16
(BnBr, TBAI, NaH, 88% yield) followed by removal of the
benzylidene group (TsOH, MeOH) then provided 1,3-diol 11
(85% yield), which was converted into coupling partner 13 as
described in Scheme 2.
The synthesis of the J-ring fragment 26 also started from a
prochiral furan and proceeded through a route that intro-
duced chirality in high enantioselectivity through a Noyori
reduction as shown in Scheme 4. Lithiation of furan (17) with
nBuLi in THFat 08C, followed by addition of g-butyrolactone
(18) at À788C afforded the corresponding keto alcohol (58%
yield), which was then converted into its pivaloate ester 19
(PivCl, py, 86% yield). Asymmetric reduction of the carbonyl
group in the latter compound with 2.5 mol% (S,S)-Noyori
catalyst 6 in formic acid and triethylamine (5:2) provided
chiral alcohol 20 in 89% yield and greater than 95% ee. An
Achmatowicz rearrangement was then induced on 20 by
treatment with NBS, NaOAc, and NaHCO3 in aqueous THF
(96% yield), and the resulting hemiacetal was protected as
the pivaloate 21 (PivCl, DMAP, Et3N) in 64% yield. The
undesired anomer of 21 was also produced in this reaction
(20% yield). Enone 21 was then reduced selectively under
Luche conditions (NaBH4, CeCl3·7H2O, À788C, 100% yield)
to give the corresponding allylic alcohol, which was converted
into its pivaloate ester 22 (PivCl, DMAP, Et3N, 89% yield).
The ensuing dihydroxylation of the olefinic bond within 22
(NMO, cat. OsO4) proceeded selectively from the face
opposite the pivaloate groups, thus furnishing the expected
1,2-diol, whose selective monobenzylation (nBu2SnO, BnBr,
TBAI, benzene, D, 98% yield) proceeded smoothly at the
equatorial hydroxy group (C-3). This was followed by
acetylation at the remaining axial hydroxy moiety (C-2) to
afford the fully protected intermediate 23 (97% yield).
Addition of allylTMS to 23 in the presence of BF3·Et2O
(MeCN, 608C) then afforded stereoselectively the allyl
derivative 24 (87% yield). The acetate in 24 was then
exchanged for a TBS group (K2CO3, MeOH; TBSCl, imid.,
72% overall yield) and the terminal double bond was
migrated inside the carbon chain by using RhCl3·H2O[14]
(EtOH, 808C) to afford E-olefin 25. Ozonolysis of the latter
compound (O3, CH2Cl2/MeOH, À788C; Ph3P) then led to the
targeted aldehyde 26 in 96% yield for the last two steps.
Scheme 5 summarizes the construction of the IJK building
block 33 from the J-ring aldehyde 26. Thus, aldehyde 26 was
added to the lithium anion derived from cyclohexylacetylene
(27) and nBuLi in THF at À788C to afford, after oxidation of
the resulting propargylic alcohol with DMP,[15] ynone 28 in
89% overall yield. Exposure of the latter compound to
aqueous HF in MeCN resulted in the cleavage of the TBS
group to afford the corresponding hydroxy ynone intermedi-
ate, whose ring closure required considerable experimenta-
tion. It was finally discovered that treatment of this substrate
with AgOTf in CH2Cl2 at 408C cleanly promoted the desired
cyclization to afford pyranone 29 in 84% overall yield from
28. Subsequent reduction of 29 under Luche conditions
(NaBH4, CeCl3·7H2O) led stereoselectively to the corre-
sponding hydroxy compound (a isomer) whose hydrobora-
tion/oxidation (BH3·THF; NaOH, H2O2) proceeded regio-
and stereoselectively to afford, after protection of the
resulting diol with TESOTf in the presence of 2,6-lutidine,
the bis-TES silyl ether 30 in 65% overall yield for the three
steps. Lactone 31 was then derived from bis-pivaloate 30 by
reduction with DIBAL-H, followed by oxidation of the
resulting diol mediated by a PhI(OAc)2/TEMPO catalyst[16]
(82% overall yield). Lactone 31 was finally converted into the
requisite coupling partner, vinyl triflate 33, in 93% yield by
treatment with KHMDS and Cominꢀs reagent (32) in THF at
À788C, thus setting the stage for the casting of the final two
rings.
Scheme 4. Construction of J ring aldehyde 26. Reagents and condi-
tions: a) nBuLi (1.05 equiv), THF, 08C, 1 h; then 18 (2.0 equiv),
À788C, 1 h, 58%; b) PivCl (1.25 equiv), py (3.0 equiv), CH2Cl2, 08C,
4 h, 86%, c) 6 (2.5 mol%), HCO2H/Et3N (5:2), 308C, 48 h, 89%
(>95% ee); d) NBS (1.0 equiv), NaOAc (1.0 equiv), NaHCO3
(2.0 equiv), THF/H2O (3:1), 08C, 1 h, 96%; e)PivCl (1.5 equiv), Et 3N
(2.5 equiv), DMAP (0.05 equiv), CH2Cl2, À788C, 2 h, 64% (+20%
other anomer); f) CeCl 3·7H2O (0.5 equiv), NaBH4 (1.0 equiv), MeOH/
CH2Cl2 (1:1), À788C, 30 min, 100%; g)PivCl (1.5 equiv), Et 3N
(3.0 equiv), DMAP (0.05 equiv), CH2Cl2, 08C, 6 h, 89%; h)OsO 4
(0.02 equiv), NMO (2.0 equiv), acetone/H2O (10:1), 258C, 48 h, 93%;
i) nBu2SnO (1.0 equiv), C6H6, reflux, 18 h; then BnBr (1.4 equiv), TBAI
(1.0 equiv), 3 h, 98%; j) Ac2O (4.0 equiv), DMAP (0.05 equiv), py
(8.0 equiv), CH2Cl2, 258C, 12 h, 97%; k)allylTMS (5.0 equiv), BF 3·Et2O
(2.5 equiv), MeCN, 608C, 4 h, 87%; l)K 2CO3 (0.1 equiv), MeOH, 258C,
6 h, 84%; m) TBSCl (2.0 equiv), imid. (4.0 equiv), DMF, 408C, 24 h,
85%; n)RhCl 3·H2O (0.05 equiv), EtOH, 808C, 3 h; o)O 3, CH2Cl2/
MeOH (5:1), À788C, 5 min; then Ph3P (1.5 equiv), 96% over two
steps. py=pyridine, DMAP=4-dimethylaminopyridine, NMO=4-
methylmorpholine N-oxide, TMS=trimethylsilyl.
Scheme 6 depicts the completion of the synthesis of the
GHIJK ring system 2. Hydroboration of the G-ring alkene 13
with 9-BBN in THF at 508C furnished the expected alkylbor-
ane which underwent smooth B-alkyl Suzuki coupling[17] with
vinyl triflate 33 in the presence of a Pd(OAc)2 catalyst, SPhos
Angew. Chem. Int. Ed. 2007, 46, 8875 –8879
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8877
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Communications
tively to afford the expected hydroxy compound (a isomer,
71% yield) which was oxidized to the corresponding ketone
in 95% yield through the action of DMP. Heating this
compound with TsOH in MeOH at 508C for 48 h resulted in
the formation of pentacyclic trihydroxy methyl acetal 35,
through removal of the PMB and TES groups and ring
closure, in 85% yield. The methoxy group was then reduc-
tively removed from 35 by the action of Et3SiH in the
presence of TMSOTf in MeCN at 08C to afford, after
hydrogenolysis of the three benzyl groups (H2, 20% Pd(OH)2/
C (cat.), EtOH, 69% overall yield), the targeted GHIJK ring
system 2 (see the Experimental Section).[19]
The much-anticipated comparison of the 13C chemical
shifts of the GHIJK ring system 2 with those of the
corresponding region of maitotoxin (1)[2d] was then made
(Figure 1). As shown, the 13C NMR chemical shifts (ppm) for
the two compounds are in excellent agreement, with an
average difference (Dd/ppm) of less than 0.1 ppm and a
maximum deviation of 0.6 ppm for carbon atoms C-42 to C-
53. The larger differences between the values of the two
compounds for carbon atoms C-39 to C-41 and C-54 to C-55
are apparently due to the special functional groups present on
rings G (a sulfate moiety) and K (a dihydroxypyran) of
maitotoxin (1) as compared to the simpler model system 2
which contains only free hydroxy groups on ring G and a
cyclohexyl moiety on ring K (Figure 1). These observations
lend strong support for our computationally derived conclu-
sion[5] that the originally proposed structure[2–4] for maitotoxin
(1) is, indeed, most likely correct, at least in this region of the
molecule, despite the noted biosynthetic anomaly.[6]
Scheme 5. Construction of IJK ring system 33. Reagents and condi-
tions: a) nBuLi (2.0 equiv), 27 (2.0 equiv), THF, À788C, 1 h; then 26
(1.0 equiv), 15 min, 93%; b) DMP (1.5 equiv), CH2Cl2, 258C, 1 h, 96%;
c)48% aq HF/MeCN (1:3), 25 8C, 18 h, 94%; d)AgOTf (0.1 equiv),
CH2Cl2, 408C, 18 h, 89%; e)CeCl 3·7H2O (0.2 equiv), NaBH4
(1.1 equiv), MeOH/CH2Cl2 (1:1), 08C, 15 min; f)BH 3·THF (1.0m in
THF, 10 equiv), THF, 08C, 3 h; then NaOH (1.0m aq), H2O2 (35% aq),
1 h, 71% over two steps; g)TESOTf (15 equiv), 2,6-lut. (20 equiv),
CH2Cl2, 08C, 2 h, 92%; h)DIBAL-H (1.0 m in CH2Cl2, 10 equiv),
CH2Cl2, À788C, 10 min; i)TEMPO (0.1 equiv), PhI(OAc) (3.0 equiv),
2
CH2Cl2, 258C, 18 h, 82% over two steps; j) 32 (2.0 equiv), KHMDS
(0.5m in THF, 2.0 equiv), THF, À788C, 10 min, 93%. DMP=Dess–
Martin periodinane, DIBAL-H=diisobutylaluminum hydride,
TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy, KHMDS=potassium
bis(trimethylsilyl)amide.
The described chemistry provides further experimental
support for the originally proposed stereochemical assign-
ment for the JK junction of maitotoxin, and should facilitate
the construction of larger fragments
of this notable marine neurotoxin.
Experimental Section
2: Rf = 0.27 (silica gel, EtOAc/MeOH
4:1); [a]2D5 = À5.7 degcm3 gÀ1 dmÀ1 (c =
0.11 gcmÀ3, MeOH); IR (film): n˜max
=
3453, 3414, 2925, 2850, 1648, 1446,
1350, 1069 cmÀ1 1H NMR (600 MHz,
;
[D4]MeOD/[D5]pyridine): d = 4.30 (t,
J = 2.4 Hz, 1H), 4.22 (t, J = 4.8 Hz,
1H), 3.92 (dt, J = 9.0, 3.0 Hz, 1H), 3.88
(dd, J = 10.8, 8.4 Hz, 1H), 3.88–3.82 (m,
2H), 3.81–3.77 (m, 2H), 3.74 (t, J =
8.4 Hz, 1H), 3.74–3.70 (m, 1H), 3.61
(dd, J = 10.8, 4.8 Hz, 1H), 3.55 (t, J =
9.6 Hz, 1H), 3.43 (dd, J = 9.6, 3.0 Hz,
1H), 3.25 (dd, J = 9.6, 1.8 Hz, 1H), 3.16–
3.08 (m, 3H), 2.40 (dt, J = 10.8, 3.6 Hz,
1H), 2.35 (dt, J = 10.8, 4.2 Hz, 1H),
2.33–2.27 (m, 1H), 1.93–1.87 (m, 1H),
1.75 (ddt, J = 14.4, 8.4, 6.0 Hz, 1H),
1.68–1.63 (m, 1H), 1.63–1.53 (m, 3H),
Scheme 6. Completion of the synthesis of GHIJK ring system 2. Reagents and conditions: a) 13
(2.0 equiv), 9-BBN (4.0 equiv), THF, 508C, 3 h; then KHCO3 (1.0m aq, 20 equiv), 33 (1.0 equiv),
SPhos (0.2 equiv), Pd(OAc)2 (0.1 equiv), 258C, 48 h, 78%; b)BH 3·THF (1.0m in THF, 10 equiv),
THF, 08C, 18 h; then NaOH (1.0m aq), H2O2 (35% aq), 1 h, 71%; c) DMP (1.5 equiv), CH2Cl2, 258C,
2 h, 95%; d)TsOH (1.0 equiv), MeOH, 50 8C, 48 h, 85%; e)Et 3SiH (5.0 equiv), TMSOTf (2.0 equiv),
MeCN, 08C, 15 min, 98%; f)H 2, 20% Pd(OH)2/C (25% w/w), EtOH, 258C, 18 h, 70%. 9-BBN=9-
borabicyclo[3.3.1]nonane, SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, Ts=p-toluenesul-
fonyl.
1.52–1.44 (m, 3H), 1.31 (dq, J = 12.6,
3.0 Hz, 1H), 1.21–1.11 (m, 2H), 1.09–
ligand (cat.),[18] and KHCO3 (1.0m aq, 20 equiv) to afford
tetracycle 34 in 78% yield. The hydroboration of 34 with
BH3·THF in THF at 08C proceeded regio- and stereoselec-
1.01 (m, 1H), 0.98–0.90 ppm (m, 1H); 13C NMR (150 MHz, CDCl3):
d = 85.8, 85.0, 81.2, 79.3, 77.8, 77.5, 74.9, 74.5, 73.2, 72.1, 71.3, 70.3,
70.1, 69.8, 67.7, 59.6, 38.7, 37.7, 36.6, 36.3, 31.4, 27.7, 27.31, 27.26,
8878
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8875 –8879
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Angewandte
Chemie
moto, Angew. Chem. 1996, 108, 1782; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1672; e) T.
Nonomura, M. Sasaki, N. Matsumori, M.
Murata, K. Tachibana, T. Yasumoto, Angew.
Chem. 1996, 108, 1786; Angew. Chem. Int.
Ed. Engl. 1996, 35, 1675.
[4] a) W. Zheng, J. A. DeMattei, J.-P. Wu, J. J.-W.
Duan, L. R. Cook, H. Oinuma, Y. Kishi, J.
Am. Chem. Soc. 1996, 118, 7946; b) L. R.
Cook, H. Oinuma, M. A. Semones, Y. Kishi,
J. Am. Chem. Soc. 1997, 119, 7928.
[5] K. C. Nicolaou, M. O. Frederick, Angew.
Chem. 2007, 119, 5372; Angew. Chem. Int.
Ed. 2007, 46, 5278.
[6] A. R. Gallimore, J. B. Spencer, Angew.
Chem. 2006, 118, 4514; Angew. Chem. Int.
Ed. 2006, 45, 4406.
[7] a) S. Higashibayashi, W. Czechtizky, Y.
Kobayashi, Y. Kishi, J. Am. Chem. Soc.
2003, 125, 14379; b) B. A. Blackwell, O. E.
Edwards, J. W. ApSimon, A. Fruchier, Tetra-
hedron Lett. 1995, 36, 1973.
Figure 1. Differences in the 13C chemical shift (Dd/ppm)between GHIJK fragment 2 and
the values reported for maitotoxin (1)in the same solvent system. 13C chemical shifts of 2
[150 MHz, 1:1 [D4]methanol/[D5]pyridine (reported values for maitotoxin in parenthe-
ses)][19]: C-39: 74.5 (72.3), C-40: 73.2 (78.9), C-41: 70.3 (68.5), C-42: 81.2 (80.6), C-43: 69.8
(69.6), C-44: 36.3 (36.3), C-45: 77.8 (77.7), C-46: 77.4 (77.5), C-47: 37.7 (37.4), C-48: 67.7
(67.8), C-49: 85.8 (85.8), C-50: 70.1 (70.1), C-51: 74.9 (74.9), C-52: 72.1 (72.1), C-53: 79.3
(79.4), C-54: 71.3 (69.8), C-55: 85.0 (78.2).
[8] A. Fujii, S. Hashiguchi, N. Uematsu, T.
Ikariya, R. Noyori, J. Am. Chem. Soc. 1996,
118, 2521.
[9] S. Celanire, F. Marlin, J. E. Baldwin, R. M.
Adlington, Tetrahedron Lett. 2005, 61, 3025.
26.2 ppm; HRMS [electrospray ionization (ESI)]: calcd for
C25H40O11Na+ [M+Na+]: 539.2463, found: 539.2451.
[10] Prepared from the corresponding carboxylic acid (L. V. Heu-
mann, G. E. Keck, Org. Lett. 2007, 9, 1951) by reaction with N,O-
dimethylhydroxylamine in the presence of carbonyl diimidazole.
[11] For recent examples of the application of the Achmatowicz
reaction to the conversion of prochiral keto furans into
enantioenriched pyrans, see a) H. Guo, G. A. OꢀDoherty,
Angew. Chem. 2007, 119, 5298; Angew. Chem. Int. Ed. 2007,
46, 5206; b) M. Zhou, G. A. OꢀDoherty, J. Org. Chem. 2007, 72,
2485; c) H. Guo, G. A. OꢀDoherty, Org. Lett. 2006, 8, 1609;
d) J. M. Harris, M. D. Keranen, H. Nguyen, V. G. Young, G. A.
OꢀDoherty, Carbohydr. Res. 2000, 328, 17.
Received: August 14, 2007
Published online: October 17, 2007
Keywords: maitotoxin · natural products · neurotoxins ·
.
NMR spectroscopy · structure elucidation
[1] a) M. Murata, T. Yasumoto, Nat. Prod. Rep. 2000, 17, 293; b) T.
Yasumoto, R. Bagnins, J. E. Randal, A. H. Banner, Bull. Jpn.
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[2] a) M. Murata, T. Iwashita, A. Yokoyama, M. Sasaki, T.
Yasumoto, J. Am. Chem. Soc. 1992, 114, 6594; b) M. Murata,
H. Naoki, T. Iwashita, S. Matsunaga, M. Sasaki, A. Yokoyama, T.
Yasumoto, J. Am. Chem. Soc. 1993, 115, 2060; c) M. Murata, H.
Naoki, S. Matsunaga, M. Satake, T. Yasumoto, J. Am. Chem. Soc.
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[3] a) M. Sasaki, T. Nonomura, M. Murata, K. Tachibana, Tetrahe-
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Murata, K. Tachibana, T. Yasumoto, Tetrahedron Lett. 1995, 36,
9011; c) M. Sasaki, T. Nonomura, M. Murata, K. Tachibana,
Tetrahedron Lett. 1994, 35, 5023; d) M. Sasaki, N. Matsumori, T.
Muruyama, T. Nonomura, M. Murata, K. Tachibana, T. Yasu-
[14] D. L. J. Clive, M. Sannigrahi, S. Hisaindee, J. Org. Chem. 2001,
66, 954.
[15] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[16] T. M. Hansen, G. J. Florence, P. Lugo-Mas, J. Chen, J. N. Abrams,
C. J. Forsyth, Tetrahedron Lett. 2003, 44, 57.
[17] S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem.
2001, 113, 4676; Angew. Chem. Int. Ed. 2001, 40, 4544.
[18] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685.
[19] The 13C NMR signals and NOE interactions ascribed for 2 were
based on COSY, ROESY, and HMQC experiments, and they
closely conform with those reported for maitotoxin.[2c,d]
Angew. Chem. Int. Ed. 2007, 46, 8875 –8879
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8879
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