Total synthesis of the furanocembrane bis-deoxylophotoxin

Article abstract of DOI:10.1055/s-2001-18741

A total synthesis of the bis-deoxylophotoxin 25a, the probable biological precursor to the neurotoxin lophotoxin 1 is described. The synthesis uses a strategy based on sequential carbanion alkylation and Stille coupling between the chiral building blocks

Full text of DOI:10.1055/s-2001-18741

LETTER
1869
Total Synthesis of the Furanocembrane bis-Deoxylophotoxin
Total
Synthesis of the
aFuranocem
n
brane, Bis-D
u
e
oxylophoto
e
xin l Cases, Felix González-López de Turiso, Gerald Pattenden*
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: gp@nottingham.ac.uk
Received 8 October 2001
R
CHO
Abstract: A total synthesis of the bis-deoxylophotoxin 25a, the
probable biological precursor to the neurotoxin lophotoxin 1 is de-
scribed. The synthesis uses a strategy based on sequential carbanion
alkylation and Stille coupling between the chiral building blocks 5
O
O
O
O
O
and 6, leading to the furanocembranolide 23, following by function-
R'
al group manipulation.
OAc
O
O
Key words: furanocembranes, lophotoxin, Stille macrocyclisation
O
O
1
2
a, R=CHO, R'=OAc;
b, R=CO2Me, R'=H
Lophotoxin 1 is a unique furanocembrane isolated from
species of the Pacific sea whip Lophogorgia.1 The com-
R
5
pound is a potent neurotoxin that binds selectively and ir-
7
O
reversibly to acetylcholine recognition sites in nicotinic
acetylcholine receptors, leading to paralysis and asphyxi-
ation.2 Lophotoxin co-occurs with the deoxylophotoxin
15
1
O
14
R'
10
2a in L. chilensis, and both metabolites share a structural
O
resemblance to the natural products pukalide 2b and to
O
deoxypukalide 3a found in L. alba.2,3 Circumstantial evi-
3
4
a, R=CO2Me, R'=H
dence would suggest that the metabolites 1–3 share a
common biosynthetic origin involving elaboration of the
furanocembrane carbon framework 4 followed by sequen-
tial oxidation, to 3a/3b and then epoxidation to 2a/2b en
route to 1. With its unusual juxtapositioned and diverse
oxygen functionality, embedded in a reactive macrocyclic
furan-based framework, lophotoxin 1 is a deceptively
challenging synthetic target.4 In earlier synthetic work we
outlined an approach to the core hydrocarbon furanocem-
brane macrocyclic system 4 in lophotoxin based on a nov-
el acyl radical macrocyclisation strategy.5 However,
attempts to extend this strategy to the macrocyclisation of
oxygen-functionalised acyl radical precursors met with
failure, and competing cyclisation processes became
dominant.6 Building on our investigations of the scope for
intramolecular sp2-sp2 coupling reactions in macrocyclic
constructions,7 we now describe a total synthesis of the
bis-deoxylophotoxin 3b using a stratagem based on se-
quential carbanion alkylation and Stille coupling between
the chiral building blocks 5 and 6 (Figure).8
b, R=CHO, R'= α-OAc
OTBS
I
Me3Sn
O
3b
O
O
SePh
O
5
6
Figure
lation-iodination of 8b,10 next gave the E-vinyl iodide 9,
which was converted into the epoxide 10 in the presence
of NaOH. When the chiral epoxide 10 was treated with the
lithium salt derived from 1-ethoxyacetylene, and then
with p-toluenesulphonic acid, work up and chromatogra-
phy gave the (+)-lactone 11, in 60% overall yield.11
Deprotonation of 11, using LiHMDS, followed by
quenching the resulting anion with phenylselenenyl bro-
mide at –78 °C finally gave a 2:1 mixture of diastereomers
of the -phenylselenolactone intermediate 5, as a viscous
oil.12
The substituted phenylseleno lactone 5 was synthesised
from commercially available (R)-(–)-epichlorohydrin as
shown in Scheme 1. Thus, treatment of the epoxide 7 with
the lithium salt derived from trimethylsilylacetylene at –
78 °C, under Yamaguchi conditions,9 first gave the corre-
sponding chlorohydrin 8a which was then deprotected
leading to the monosubstituted acetylene 8b. Carbometa-
The furylstannane building block 6 was prepared starting
with the oxazolidinone 13 derived from 3-methylbuten-2-
oyl chloride and the lithium salt of the Evans’ auxiliary
1213. Thus, deprotonation of the oxazolidine 13 with NaH-
MDS in THF at –78 °C, followed by addition of ethyl 2-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1869,1872,ftx,en;D21201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1870
M. Cases et al.
LETTER
R
which, on further reduction with NaBH4, gave the alcohol
19. Deprotonation of the 2,3-disubstituted furan 19, using
n-BuLi, next gave the corresponding 5-lithiofuran which
was quenched with Me3SnCl at 0 °C to produce the 5-tri-
methylstannylfuran 20. Finally, oxidation of the substitut-
ed alcohol 20 using TPAP gave the key furylstannane
aldehyde intermediate 6 (Scheme 2).17
I
i
iii
Cl
O
Cl
Cl
OH
OH
7
8
9
a, R=TMS
b, R=H
ii
Deprotonation of the phenylselenolactone 5 using LiH-
MDS in THF at –78 °C, followed by addition of the alde-
hyde 6 gave a satisfying 75% yield of the secondary
alcohol 21 which was isolated as a mixture of diastere-
omers.18 Oxidation of the selenide 21 using hydrogen
peroxide19 was accompanied by in situ dehydroseleneny-
lation producing the unsaturated lactone 22.20 An intramo-
lecular Stille reaction with 22 under the conditions
described by Farina et al21 (Pd2dba3, AsPh3, NMP) at
40 °C, then led to the macrocycle 23 which was obtained
as an oily mixture of two diastereomers in 20% yield over
three steps from 21. Acetylation of the macrocyclic alco-
hol 23, followed by deprotection of the t-butyldimethyls-
ilyl ether group next produced the primary alcohol 24 as a
mixture of epimeric acetates which could be separated by
chromatography. Finally, oxidation of each of the epimer-
ic acetates led to the -25a and to the -25b epimers of the
bis-deoxylophotoxin 3b (Scheme 3).22
I
I
v, vi
vii
iv
5
O
O
O
11
10
Scheme 1 Reagents: (i) TMSCCH, n-BuLi, BF3, –78 °C; (ii) TB-
AF, HCl, THF, r.t., 42% over 2 steps; (iii) Me3Al, Cp2ZrCl2, CH2Cl2,
r.t., 3 days, then I2/THF, –30 °C to r.t., 2 h, 62%; (iv) NaOH, Et2O,
r.t., 14 h; (v) 1-ethoxyacetylene, n-BuLi, BF3, 2 h; (vi) p-TsOH,
EtOH, 2 h, then CHCl3, reflux, 14 h, 60% overall from 9; (vii)
LiHMDS, THF, 5 min, then PhSeBr, 40 min., –78 °C, 75%
bromomethyl-3-furoate14 first led to the product 14, re-
sulting from deconjugative alkylation.15 The absolute ste-
reochemistry of 14, melting point 59–61 °C, was
established from X-ray crystal measurements.16 Reduc-
tion of 14 with Super Hydride next produced the alcohol
15 which was then converted into the nitrile 17 by sequen-
tial tosylation, reduction, cyanide displacement (to 16)
and, finally, alcohol group protection. The nitrile group in
17 was reduced with Dibal-H leading to the aldehyde 18
Preliminary investigations of the regio- and stereo-selec-
tive epoxidations of the bis-deoxylophotoxin diastere-
omers 25 have been carried out, but the dearth of material
has not allowed us to assign unambiguous structures and
stereochemistries to the epoxide products resulting from
these studies. Further studies are now in progress and will
be reported in future publications.
O
O
O
O
O
OEt
OEt
i
ii
iii
NH
O
N
O
O
O
O
χA
OH
12
13
14
15
χA= Evans' auxiliary.
OTBS
OTBS
OR
OTBS
iv, v, vi
x
viii
ix
xi
6
Me3Sn
O
O
O
O
CN
16, R=H
17, R=TBS
CHO
18
OH
OH
vii
20
19
Scheme 2 Reagents: (i) n-BuLi, –78 °C, 20 min, then 3-methylbuten-2-oyl chloride, from –78 °C to r.t., 30 min,75%; (ii) NaHMDS, 1 h, –
78 °C, THF; then, 1.2 equiv of ethyl 2-bromomethyl-3-furoate, 65%; (iii) Super Hydride, toluene, –78 °C, 20 min, 80%; (iv) TsCl, Et3N,
DMAP, r.t., 75%; (v) Dibal-H, CH2Cl2, –78 °C, 95%; (vi) n-Bu4NCN, 3equiv, DMSO, 60 °C, 90%; (vii) TBDMSiCl, Et3N, DMAP, r.t., 91%;
(viii) Dibal-H, 1.1 equiv, toluene, –78 °C to r.t., 85%; (ix) NaBH4, MeOH, 0 °C, 70%; (x) n-BuLi, 20 min, then TMEDA for 6 h and n-BuLi
for 20 min, r.t.; then Me3SnCl, 0 °C to r.t. 16 h, 80%; (xi) TPAP, NMO, MS 4, CH2Cl2, 1 h, 75%
Synlett 2001, No. 12, 1869–1872 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Total Synthesis of the Furanocembrane bis-Deoxylophotoxin
1871
OTBS
OTBS
Me3Sn
O
Me3Sn
I
O
ii
i
I
5
PhSe
OH
OH
O
O
O
O
21
22
CHO
OTBS
OH
O
O
O
iii
iv, v
vi
OAc
OH
OAc
O
O
O
O
O
O
24
25
23
a, α-OAc (≡ 3b)
b, β-OAc
Scheme 3 Reagents: (i) LiHMDS, –78 °C, 20 min, then 6, 50 min, 75%; (ii) H2O2, CH2Cl2/pyridine, 1 h, 0 °C; (iii) AsPh3, Pd2dba3, 40 °C,
14 h, 20% from 21; (iv) Ac2O, Et3N, DMAP, r.t., 4 h, 40%; (v) CSA, MeOH:CH2Cl2, 3 h, 0 °C; (vi) Dess–Martin periodinane, pyridine, CH2Cl2,
3 h, 0 °C, 80% over two steps
system: Paterson, I.; Brown, R. E.; Urch, C. J. Tetrahedron
Lett. 1999, 40, 5807.
(9) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(10) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639.
Acknowledgement
We thank the EPSRC for support of this work via a Fellowship (to
MC), and AstraZeneca for financial provision.
(11) For a synthesis of the enantiomer of 11 see: Tius, M. A.;
Trehan, S. J. Org. Chem. 1986, 51, 765.
References
(12) All new compounds showed satisfactory spectroscopic data
together with microanalytical and/or mass spectrometry
data. Compound 11 showed: max/cm–1: 1758; 1H NMR (360
MHz): = 6.11–6.10 (br m, 1 H, =CHI), 4.67–4.59 (m, 1 H,
CH–O), 2.67 (dd, 1 H, J = 7.4, 14.2, CHH–C=C), 2.57–2.48
(m, 3 H, CH2–C=O and CHH–C=C), 2.37–2.28 (m, 1 H,
CHH–CH2–C=O), 1.94–1.83 (m, 4 H, C=C–CH3, CHH–
CH2–C=O); 13C NMR (90 MHz): = 176.5 (C), 142.6 (C),
78.5 (CH), 78.2 (CH), 44.8 (CH2), 28.4 (CH2), 27.5 (CH2),
24.3 (CH3); [ ]20D +41.8 (c = 3.5, CH2Cl2); HRMS:
265.98081 (C8H11O2I requires: 265.98038).
(1) Fenical, W.; Okuda, R. K.; Bandurraga, M. M.; Culver, P.;
Jacobs, R. S. Science 1981, 212, 1512.
(2) Abramson, S. N.; Trischman, J. A.; Tapiolas, D. M.; Harold,
E. E.; Fenical, W.; Taylor, P. J. Med. Chem. 1991, 34, 1798.
(3) Missakian, M. G.; Burreson, B. J.; Scheuer, P. J.
Tetrahedron 1975, 31, 2513.
(4) For some other approaches to the synthesis of
furanocembranoids see: (a) Kondo, A.; Ochi, T.; Iio, H.;
Tokoroyama, T.; Siro, M. Chem. Lett. 1987, 1491.
(b) Gardner, M.; Paterson, I. Tetrahedron 1989, 45, 5283.
(c) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J. Am.
Chem. Soc. 1992, 114, 3910. (d) Rayner, C. M.; Astles, P.
C.; Paquette, L. A. J. Am. Chem. Soc. 1992, 114, 3926.
(e) Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58,
165. (f) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1997,
62, 4313; see also ref.8.
(5) Astley, M. P.; Pattenden, G. Synthesis 1992, 101.
(6) Hadjisoteriou, M. S.; Pattenden, G. unpublished results.
(7) (a) Pattenden, G.; Thom, S. M. Synlett 1993, 215.
(b) Boyce, R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37,
3501. (c) Entwistle, D. A.; Jordan, S. I.; Montgomery, J.;
Pattenden, G. Synthesis 1998, 603. (d) Duncton, M. A. J.;
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235.
(e) Remuiñán, M. J.; Pattenden, G. Tetrahedron Lett. 2000,
41, 7367. (f) Cid, M. B.; Pattenden, G. Tetrahedron Lett.
2000, 41, 7373.
Compound 6 showed: max/cm–1: 1722; 1H NMR (360 MHz):
= 9.51 (t, 1 H, J = 2.2, CHO), 6.47 (m, 1 H, =CH), 4.79 (br
s, 1 H, C=CHH), 4.76 (s, 1 H, C=CHH), 4.48 (s, 2 H, CH2-
OTBS), 3.11–3.01 (m, 1 H, CH–C=C), 2.84 (dd, 1 H, J =
14.7 and 6.1, CHH-furan), 2.71 (dd, 1 H, J = 14.7 and 8.7,
CHH-furan), 2.45 (dd, 2 H, J = 7.3 and 2.2, CH2–CHO), 1.73
(s, 3 H, =C–CH3), 0.92 (s, 9 H, Si(CH3)3), 0.38–0.13 (m, 9
H, Sn(CH3)3), 0.10 (s, 6 H, (Si(CH3)2); 13C NMR (90 MHz):
= 201.9 (CH), 158.6 (C), 154.2 (C), 146.2 (C), 122.3 (CH),
120.7 (C), 112.0 (CH2), 57.2 (CH2), 46.6 (CH2), 41.0 (CH),
31.1 (CH2), 26.5 (CH3), 20.0 (CH3), 18.5 (C), 1.1 (CH3),
–5.1 (CH3), –9.2 (CH3); [ ]20D +2.7 (c = 1.6, CH2Cl2).
(13) Galatsis, P.; Millan, S. D.; Ferguson, G. J. Org. Chem. 1997,
62, 5048.
(14) For a synthesis of ethyl 2-bromomethyl-3-furoate
see:Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma, D.;
Daliari, S.; Fici, F.; Cirillo, R.; Renzetti, A. R.; Subissi, A.;
(8) In contemporaneous studies I. Paterson and co-workers have
used a similar approach to a simplified lophotoxin model
Synlett 2001, No. 12, 1869–1872 ISSN 0936-5214 © Thieme Stuttgart · New York

1872
M. Cases et al.
LETTER
Belvisi, L.; Bravi, G.; Scolastico, C.; Giachetti, A. J. Med.
Chem. 1995, 38, 4806.
(21) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(22) Main epimer: Cembrane ring numbering: 1H NMR (400
MHz, 318K): = 9.86 (s, 1 H, CHO), 7.31 (br s, 1 H, H-11),
6.44 (s, 1 H, H-5), 5.95 (br s, 1 H, H-7), 5.77 (br m, 1 H,
H-13), 5.27 (br s, 1 H, H-10), 4.91 (s, 1 H, H-15a), 4.88 (s,
1 H, H-15b), 2.92 (dd, 1 H, J = 13.6 and 3.3, H-9a), 2.80–
2.00 (br m, 6 H, H-1, H-2, H-9b, H-14), 1.95 (s, 3 H,
COCH3), 1.85 (s, 3 H, CH3), 1.74 (s, 3 H, CH3); MS (ES):
m/z = 407.1444 (C22H24O6Na requires: 407.1470); Minor
epimer: 1H NMR (400 MHz, 318K): = 9.86 (s, 1 H, CHO),
7.16 (s, 1 H, H-11), 6.44 (s, 1 H, H-5), 6.01 (br s, 1 H, H-7),
5.45 (br d, 1 H, J = 9.7, H-13), 5.27 (br s, 1 H, H-10), 5.21
(s, 1 H, H-15a), 5.02 (s, 1 H, H-15b), 3.03 (dd, 1 H, J = 13.6
and 3.6, H-9a), 2.80–2.00 (br m, 6 H, H-1, H-2, H-9b, H-14),
2.03 (s, 3 H), 1.84 (s, 3 H), 1.71(s, 3 H); MS (ES): m/z =
407.1441 (C22H24O6Na requires: 407.1470).
(15) Fadel, A.; Salaün, J. Tetrahedron Lett. 1988, 29, 6257.
(16) We thank Dr A. J. Blake of this School for this crystal
structure determination, which will be published elsewhere.
(17) Both of the furylstannanes 20 and 6 could be purified by
flash chromatography using Woelm basic alumina without
significant destannylation being observed.
(18) A Stille coupling reaction between 5 and 20 under the
conditions of Farina21 (Pd2dba3, AsPh3, NMP, 40 °C) gave
the corresponding E-furylalkene, but attempts to carry out a
subsequent intramolecular alkylation reaction, via
deprotonation, were unsuccessful.
(19) Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida,
N. Tetrahedron 1999, 55, 3855.
(20) The unsaturated lactone 22 was obtained as a 4:1 mixture of
stannylated and destannylated compounds.
Synlett 2001, No. 12, 1869–1872 ISSN 0936-5214 © Thieme Stuttgart · New York