Synthesis of the gymnodimine tetrahydrofuran core through a Ueno-Stork radical cyclization

Article abstract of DOI:10.1039/c1ob05240c

A straightforward access to the C10-C20 skeleton of gymnodimine, incorporating a tetrahydrofuran fragment, is described. The elaboration of the THF moiety is based on a stereocontrolled Ueno-Stork cyclization. A Lewis-acid mediated allylation of the resulting acetal at C13 and a Horner-Wadsworth-Emmons olefination on the ketone at C17 complete the synthesis.

Full text of DOI:10.1039/c1ob05240c

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PAPER
Synthesis of the gymnodimine tetrahydrofuran core through a Ueno–Stork
radical cyclization†‡
Sylvestre Toumieux,a Redouane Beniazza,a Vale´rie Desvergnes,a Ro´mulo Ara´oz,b Jordi Molgo´b and
Yannick Landais*a
Received 15th February 2011, Accepted 11th March 2011
DOI: 10.1039/c1ob05240c
A straightforward access to the C10–C20 skeleton of gymnodimine, incorporating a tetrahydrofuran
fragment, is described. The elaboration of the THF moiety is based on a stereocontrolled Ueno–Stork
cyclization. A Lewis-acid mediated allylation of the resulting acetal at C13 and a
Horner–Wadsworth–Emmons olefination on the ketone at C17 complete the synthesis.
from the chiral pool, which exploits the Ueno–Stork reaction as
Introduction
a key-step.9 It was envisioned that the elaboration of the five-
Gymnodimine 1 belongs to a family of macrocyclic imine phy-
cotoxins produced from dinoflagellate Karenia selliformis and
Gymnodinium cf. mikimotoi and isolated by Yasumoto et al.
from oysters collected off the Foveaux Strait, South Island
coast in New-Zealand.1 Its relative and absolute configuration
membered ring heterocycle could be carried out through the
cyclization of an halogenated intermediate such as IV (Scheme 1).
This would be followed by introduction of the C10–C12 carbon
chain at C13 through allylation of the resulting acetal and the
side chain would be oxidized to provide the ketone III. The
were elucidated later by Munro, Blunt and co-workers through
trisubstituted olefinic appendage at C16 would be generated
X-ray crystallographic studies.2 Closely related analogues such
as gymnodimine B and C were recently isolated, possessing the
through a Horner–Wadsworth–Emmons reaction on the C17-
ketone affording II. Inexpensive (S)-lactate V and (S)-Roche ester
same macrocyclic structure, but differing from 1 in the substitution
VI were designed as potent chiral starting materials.
pattern at C17–C18.3 These marine algal toxins are concentrated
into shellfish, moving up the food chain to reach crabs, fish,
then human beings. While their mode of action has not yet
been fully established,4 recent studies indicate that they likely act
as specific inhibitors of nicotinic acetylcholine receptors of the
peripheral and central nervous system.5 The proliferation of these
neurotoxic shellfish poisoning (NSP) compounds associated with
their lipophilicity and their ability to cross the blood-brain barrier
thus constitutes a potent threat for public health.
The low availability of these phycotoxins along with their
relevant biological activities has led several teams to investigate
their synthesis. Total synthesis of 1 has recently been reported
by Romo et al.,6 while various approaches to the main subunits
have been described since its isolation in 1995.7,8 We report herein a
straightforward approach to the tetrahydrofuran core of 1 starting
aUniversite´ de Bordeaux, Institut des Sciences Mole´culaires, UMR-CNRS
5255, 351, Cours de la Libe´ration, F-33405 Talence cedex, France. E-mail:
y.landais@ism.u-bordeaux1.fr; Fax: +33 05 4000 6286; Tel: +33 05 4000
2289
Scheme 1 Retrosynthetic analysis of 1.
bCNRS, Institut Fe´de´ratif de Neurobiologie Alfred Fessard FRC2118,
Laboratoire de Neurobiologie et De´veloppement, UPR 3294, 1 Avenue de la
Terrasse, baˆtiments 32-33, 91198-Gif sur Yvette cedex, France
Results and discussion
† Dedicated to the memory of Prof. A. L. J. Beckwith in recognition of his
major achievements in the field of radical chemistry.
‡ Electronic supplementary information (ESI) available: Compound char-
acterization, spectra and supplementary information are available. See
DOI: 10.1039/c1ob05240c
Preparation of haloacetals 3a–b was first carried out through
halo-etherification of the corresponding known alcohols 2a10
and 2b11 with vinylethyl ether. Our preliminary attempts
were made following standard procedures using NIS,9d,12 NBS,
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I2–AgOTf or Hg(OAc)2.13 Unfortunately, all our efforts resulted
either in recovered starting material or low conversion into the
desired halo-ethers. More satisfying results were obtained by using
instead an excess of 1,2-dibromo-1-ethoxyethane freshly prepared
through bromination of vinylethyl ether.14 When an excess of this
reagent was added in fractions to allylic alcohols 2a–b, the desired
bromides 3a–b were obtained, after purification, in 87% and 77%
yields respectively as an inseparable mixture of two diastereomers
(3a d.r.~6/4, 3b d.r.~55/45) (Scheme 2).
Table 1 Lewis-acid mediated allylation of acetals 4a–b and 6
cis/trans
Entry Acetal Product Conditions
Ratioa
Yield
73%
75%
83%
70%
67%
71%
61%
77%
1
2
3
4
5
6
7
8
4a
4a
4a
4b
6
5a
5a
5a
5b
7
BF3–OEt2 (1.5 equiv.),
-80 ◦C, 30 h
1 : 1
1 : 1
TMSOTf (1 equiv.),
-80 ◦C, 2.5 h
SnBr4 (1.6 equiv.),
-80 ◦C, 24 h
1.25 : 1
2.7 : 1
TMSOTf (1 equiv.),
-80 ◦C, 2 h
SnCl4 (1.5 equiv.), 0 ◦C, 2.5 : 1
4 hb
6
7
TMSOTf (1.2 equiv.),
4 : 1
-80 ◦C, 2 h
4a
4a
7
TMSOTf (5 equiv.),
-80 ◦C, 24 h
2 : 1
7
TMSOTf (5 equiv.),
BF3–OEt2 (2.5 equiv.),
-80 ◦C, 2 h
2.3 : 1
9
4a
7
TMSOTf (5 equiv.), CsF 1.5 : 1
63%
(5 equiv.), -80 ◦C, 20 h
a Estimated from the 1H NMR of the crude reaction mixture. b The
allylation reaction was carried out with allyldimethylchlorosilane.
Scheme 2 Ueno–Stork cyclization of bromoethers 3a–b.
et al.20 for related Lewis acid-mediated allylation, the approach of
the allylmetal reagent onto the oxonium intermediate should occur
“inside” an envelope conformation, with a C3 methyl substituent
in a pseudo-equatorial position (Model B, Fig. 1), to give the 1,3-
trans product with high diastereocontrol. Decreasing the steric
hindrance at C4 should in turn favor the desired stereochemistry.
This is effectively the case, as shown by the slightly improved
diastereocontrol observed with 4b.
These acetals were then submitted to the Ueno–Stork reaction
conditions using Bu3SnH and AIBN in benzene, either under re-
flux or under UV irradiation at room temperature (see experimen-
tal part). Initiation using Et3B and oxygen at room temperature led
in contrast to poor conversion.9d The corresponding cyclic acetals
4a–b were isolated as a 1 : 1 mixture of two diastereomers at the
C13 position, indicating that the cyclization had occurred with
complete diastereocontrol, likely through transition state models
A and A¢ proposed originally by Beckwith15 and later refined by
Renaud and Schiesser.16 The C10–C12 chain was then installed
through a Lewis acid-mediated allylation at C13 on acetals
4a–b.7a–b,17
Our preliminary attempts using acetal 4a, treated with al-
lyltrimethylsilane and BF3–OEt2, led to the desired tetrahydro-
furan 5a in 73% yield but with no stereocontrol (Table 1, entry 1).
The use of other Lewis acids such as TMSOTf or SnBr4 provided
no beneficial effects (entries 2–3). In contrast, when 4b was treated
under the same conditions (entry 4), tetrahydrofuran 5b was
obtained in good yield and with slightly better diastereocontrol. In
order to improve the required C13–C16 stereoselectivity, we also
tried to deliver intramolecularly (in a syn fashion) the allyl moiety
by treating 618 with allyldimethylchlorosilane and TMSOTf (entry
5).19 The reaction proceeded cleanly to afford 7 in reasonable yield
but again with poor diastereocontrol. As rationalized by Woerpel
Fig. 1 Transition-state models for the allylation of acetals 4a–b, and 6.
In such a model, a bulky substituent at C4 (such as OTBDMS in
4a), should however induce strong interactions with the incoming
allylsilane. In this case, the diequatorial oxocarbenium conformer
B would be disfavored and the attack of the nucleophile might
instead occur “inside” another envelope conformation B¢, in
which the methyl substituent at C3 would occupy a pseudo-axial
position, leading to the 1,3-cis product.
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In transition state B¢, one may however predict strong destabiliz-
ing 1,3-diaxial interactions between the incoming nucleophile and
the methyl substituent at C3. Therefore, with bulky substituents
at C4, low stereocontrol should be predicted, as verified by
experiments in entries 1–2 (Table 1). Based on these premises,
we repeated the reaction with precursor 6 having a smaller free
hydroxyl group. Using TMSOTf as a Lewis acid, 6, (which may
however react as its OTMS form) effectively led to tetrahydrofuran
7 in good yield and a 4 : 1 ratio (entry 6). This is in good agreement
with the selectivity observed by Romo et al.7a during their synthesis
of the THF core of 1, through allylation of a related intermediate.
Other Lewis acids, including Bi(OTf)3, APTS or SnCl4 led to
recovered starting material along with the hemiacetal derived
from 6, which could not be isolated pure. We finally tried to
carry out both the deprotection of 4a into 6 and the subsequent
allylation in one pot (entries 7–9). An excess of TMSOTf was
first added fractionally to provide 7 in good yield, albeit with low
diastereocontrol (entry 7). Deprotection of the TBDMS protective
group using TMSOTf probably generates, under our conditions,
the corresponding trimethylsilyl ether, leading as in 4a to low
diastereocontrol. Additives such as CsF and BF3–OEt2 were thus
introduced in order to remove the putative TMS protective group.
Unfortunately, none of them were able to afford 7 with much
higher selectivity (entries 8–9). The remaining part of the synthesis
was thus performed with THF 7, having the desired C13–C16-cis-
configuration, which was obtained pure, on a gram scale, after
simple chromatography. Tetrahydrofuran 7 was then subjected to
the Dess–Martin periodinane oxidation,21 affording the volatile
ketone 8 in 87% yield (Scheme 3). Horner–Wadsworth–Emmons
olefination on 8 was carried out using NaH in THF, eventually
affording the desired unsaturated ester 9 in 78% yield as 9 : 1
mixture of E- andZ-stereoisomers that could be separated through
column chromatography.22 Subsequent hydroboration–oxidation
sequence of the allylic chain at C13 using BH3–Me2S then H2O2–
NaOH led to the desired alcohol 10, but in a non reproducible
manner. In contrast, when the reaction was carried out adding
BH3–Me2S at room temperature, then gently heating the mixture
at 35 ◦C, followed by the oxidation of the borane using NaBO3 and
H2O,23 the alcohol 10 was obtained in reasonable yield. Protection
of the primary alcohol with TBDMSCl (71% yield) followed by
the ester reduction with DIBAL-H gave the corresponding allylic
alcohol 12 (68% yield). In Parallel, 10 could be directly reduced
into diol 11 using again DIBAL-H in a moderate 50% yield.
Scheme 3 Synthesis of the tetrahydrofuran core of gymnodimine 1.
with an IC50 of 7.65 ¥ 10-8 M (6.94 ¥ 10-8 to 8.42 ¥ 10-8 M, 95%
confidence limits).
Experimental part
(3R,4S)-5-(Benzyloxy)-4-methylpent-1-en-3-ol 2b: 3 step-sequence
synthesis
Roche ester (447 mg, 3.793 mmol) was dissolved in dry
dichloroethane, then MgO (303 mg, 7.586 mmol, 2 equiv.) and
Dudley reagent25 (2.647 g, 7.586 mmol, 2 equiv.) were added. The
reaction was refluxed during 15 h. The reaction media was filtered
on a celite pad then washed with 15 mL of a mixture petroleum
ether (PE)/EtOAc (80/20). Purification on silica gel (PE 100%
then PE/EtOAc: 96/4) provided the benzylated intermediate ester
as a clear oil (665 mg, 84% yield). The protected ester (665 mg,
3.193 mmol) was dissolved in dry Et2O (32 mL) under an inert
atmosphere at -110 ◦C and then DIBAL-H (1.2 M in toluene)
was added (5.31 mL, 6.38 mmol, 2 equiv.). After 18 min, TLC
indicated that reaction went to completion. 10 mL of a Rochelle’s
salt solution were added at -110 ◦C and the reaction medium
was allowed to warm to room temperature. 100 mL water were
added and then extraction was performed with Et2O (3 ¥ 20 mL).
The organic layers were dried over MgSO4 and solvents were
removed under vacuum. The intermediate aldehyde (550 mg,
3.0859 mmol, 97%) was obtained clean enough to be used in the
next step without any further purification. The crude aldehyde
was dissolved in dry Et2O (10 mL) under an inert atmosphere
and the solution was cooled at -80 ◦C, then vinylmagnesium
bromide (1 M in THF) (6.17 mL, 6.17 mmol, 2 equiv.) was added
Conclusions
In summary, we reported along these lines a straightforward access
to the tetrahydrofuran core of gymnodimine 1 in only 9 steps
starting from alcohol 2a. Both 11 and 12 possess the functionalities
for further coupling to the spiroimine skeleton of 1. Efforts at
synthesizing the spiroimine skeleton and connecting the fragments
together are underway and will be reported in due course.
The ability of 11 and allylic alcohol 12 to inhibit the binding of
biotinylated a-bungarotoxin to nicotinic acetylcholine receptors
(nAChRs) was finally assessed by a non-radioactive ligand binding
assay (see the ESI‡).24 Neither 11 nor 12 could inhibit biotinylated
a-bungarotoxin binding to Torpedo-nAChR even at millimolar
concentrations, while gymnodimine-A inhibited a-bungarotoxin
binding to the nAChRs in a concentration dependent manner
◦
slowly. The mixture was stirred at -80 C overnight. At reaction
completion, the reaction was quenched with a saturated aqueous
solution of NH4Cl (10 mL). The mixture was warmed to room
temperature and water was added. Extraction was performed with
Et2O (3 ¥ 15 mL), organic layers were dried over Na2SO4 and
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solvents were removed under vacuum. Purification of the crude by
automatically performed flash chromatography (gradient from PE
100% to PE/EtOAc 92/8) provided the anti desired isomer 2b as
a colourless oil (240 mg, 67%). FTIR (film, NaCl): n = 3422, 2967,
(S)-1-((2R,3R)-5-Ethoxy-3-methyl-tetrahydrofuran-2-yl)ethanol
4a. To a solution of ((2S,3R)-3-(2-bromo-1-ethoxyethoxy)pent-
4-en-2-yloxy)(tert-butyl)dimethylsilane (7.852 g, 21.39 mmol) in
degassed benzene (200 mL), was added fresh Bu3SnH (6.90 mL,
26.674 mmol, 1.2 eq) and AIBN (350 mg, 2.14 mmol, 0.1 eq.).
The solution was then refluxed until reaction completion (~3 h
TLC control). Benzene was removed under vacuum and the crude
was purified on silica gel (PE/EA – 98/2). Filtration with SiO2
and KF (PE/EA – 8/2) was performed to remove tin derivatives
providing pure product 4a as a clear oil (5.145 g, 83%, d.r.~6/4).
Diastereoisomers could be separated and fully characterized
but they were used as a mixture in further steps. FTIR (film,
NaCl): n/cm-1 = 2970, 2930, 2853, 1257, 1092. 1H NMR (CDCl3,
300 MHz). Fraction 1: d (ppm) 5.09–5.02 (m, 1 H), 3.86–3.64
(m, 2 H), 3.51–3.33 (m, 2 H), 2.26–2.07 (m, 2 H), 1.58–1.44 (m,
1H), 1.22–1.08 (m, 10 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3
H). Fraction 2: d (ppm) 5.0 (d, J~ 4.8 Hz, 1 H), 3.77–3.58 (m,
2 H), 3.45–3.29 (m, 2 H), 2.36–2.21 (m, 1 H), 2.04 (dd, J~ 12.6,
7.3 Hz, 1 H), 1.65–1.52 (m, 1 H), 1.22 (d, J~ 6.0 Hz, 3 H), 1.16
(t, J~ 7.2 Hz, 3 H), 1.10 (d, J~ 6.6 Hz, 3 H), 0.89 (s, 9 H), 0.07
(s, 6 H). 13C NMR (CDCl3, 75.5 MHz): Fraction 1: d (ppm)
104.1, 89.4, 70.4, 62.7, 41.2, 32.9, 26.0, 20.8, 20.6, 18.2, 15.5,
-4.4, -4.5. Fraction 2: d (ppm) 103.5, 90.9, 72.8, 62.4, 42.1, 35.4,
26.0, 21.4, 19.5, 18.2, 15.3, -4.1, -4.5. HRMS (ESI): [M+Na]+
C15H32O3SiNa: calcd. 311.20184, found 311.2018
1
2901, 1454, 1364, 1075, 924, 737, 698 cm-1. H NMR (CDCl3,
200 MHz): d (ppm) = 7.49–7.19 (m, 5H), 5.85 (ddd, J ~ 6.6, 10.4,
17 Hz, 1H), 5.24 (d, J ~ 24.6 Hz, 1 H), 5.18 (d, J ~ 17.6 Hz, 1 H),
4.52 (s, 2H), 4.03 (t, J ~ 6.8 Hz, 1 H), 3.61 (dd, J ~ 3.2, 4.4 Hz,
1 H), 3.48 (dd, J ~ 7, 9 Hz, 1 H), 3.38 (br s, 1H), 2.05–1.80 (m,
1H), 0.92 (d, J ~ 7 Hz, 3 H). 13C NMR (CDCl3, 52.5 MHz): d
(ppm) = 139.6, 137.9, 128.5, 127.8, 127.7, 115.9, 77.5, 74.6, 73.5,
38.6, 13.8. HRMS (ESI): [M+Na]+ C13H18O2Na: calcd 229.12045;
found 229.1205.
(5S,6R)-8-(Bromomethyl)-2,2,3,3,5-pentamethyl-6-vinyl-4,7,9-
trioxa-3-silaundecane 3a. Preparation of 1,2-dibromo-1-
ethoxyethane solution (sol. A): To a solution of vinyl ethyl ether
(16.7 mL, 186.2 mmol, 7 eq.) in CH2Cl2 (53 mL, ~2 mL mmol-1 of
alcohol) at -78 ◦C, was added dropwise Br2 (8.2 mL, 159.6 mmol,
6 eq.). The mixture turned slightly yellow and was stirred 1 h at
-78 ◦C prior its use.
4 equiv. of sol. A (4 ¥ 12 mL) were added at RT by portion
every hour to a solution of 2a (5.767 g, 26.6 mmol) in Et3N (53 mL,
~ 2 mL mmol-1 of alcohol). At reaction completion (TLC), the
mixture was quenched with water and extracted with DCM (3 ¥
20 mL). The organic layer was dried over MgSO4, filtrated and
solvents were removed under vacuum. Purification on silica gel
(PE/EtOAc: 99/1 to 96/4) provided 3a as a clear oil (8.50 g, 87%
yield). FTIR (film, NaCl): n/cm-1 = 3084, 2931, 2866, 1256, 1111.
1H NMR (CDCl3, 400 MHz): d (ppm) = 5.85–5.67 (m, 1 H), 5.35–
5.19 (m, 2 H), 4.75 (dd, J~ 6.5, 4.0 Hz, 0.4 H), 4.71 (appearing t,
J~ 5.2 Hz, J~ 5.6 Hz, 0.6 H), 3.89–3.77 (m, 2 H), 3.74–3.56 (m, 1.8
H), 3.52–3.41 (m, 1 H), 3.40–3.28 (m, 1.6 H), 1.22 (t, J~ 6.1 Hz,
1.8 H), 1.19 (t, J~ 7.0 Hz, 1.2 H), 1.13 (d, J~ 6.4 Hz, 1.8 H), 1.12
(d, J~ 6.4 Hz, 1.2 H), 0.88 (s, 3.6 H), 0.87 (s, 5.4 H), 0.05 (s, 2.4
H), 0.04 (s, 3.6 H).13C NMR (CDCl3, 100 MHz): d (ppm) = 136.3,
135.3, 119.9, 117.9, 102.0, 99.0, 84.6, 82.7, 71.3, 70.7, 62.6, 61.7,
32.6, 32.3, 26.0, 20.2, 19.0, 18.3, 18.2, 15.4, 15.1, -4.4, -4.5, -4.6.
HRMS (ESI): [M+Na]+ C15H31BrO3SiNa: calcd. 389.11235 found
389.1123.
(2R,3R)-2-((S)-1-(Benzyloxy)propan-2-yl)-5-ethoxy-3-methyl-
tetrahydrofuran 4b. To a solution of (((2S,3R)-3-(2-bromo-1-
ethoxyethoxy)-2-methylpent-4-enyloxy)methyl)benzene (450 mg,
1.264 mmol) in degassed benzene (12 mL), was added Bu3SnH
(distillated or freshly opened) (400 mL, 1.516 mmol, 1.2 eq) and
AIBN (20.67 mg, 0.1264 mmol, 0.1 eq.). The solution was then
refluxed until reaction completion (~3 h TLC control). Benzene
was removed under vacuum and the crude was purified on silica
gel (PE/EA – 97/3). To remove tin derivative, purification was
performed using SiO2 (20 g) and KF (1% weight), providing the
expected product as a colorless oil (220 mg, 63%, d.r.~55/45).
Diastereoisomers were used as a mixture in further steps. FTIR
(film, NaCl): n = 2972, 2902, 1454, 1372, 1201, 1084, 1042, 995,
1
934, 734, 696 cm-1. H NMR (CDCl3, 200 MHz): d (ppm) 7.47–
7.18 (m, 5H, d1+d2), 5.06 (dd, J ~ 1.8 Hz, 5 Hz, 0.45H), 4.99 (d,
J ~ 4.8 Hz, 0.55H), 4.60–4.46 (m, 2 H, d1+d2), 3.83–3.24 (m, 5H,
d1+d2), 2.45–1.85 (m, 3H, d1+d2), 1.72–1.44 (m, 1H, d1+d2), 1.41–
0.82 (m, 9 H, d1+d2). 13C NMR (CDCl3, 52.5 MHz): d (ppm) 138.9,
138.8, 128.3, 127.5, 127.41, 127.37, 103.3, 103.0, 88.3, 86.0, 73.1,
73.0, 73.0, 72.8, 62.5, 62.2, 42.3, 41.4, 39.5, 37.5, 34.8, 34.7, 19.7,
18.9, 15.4, 15.2, 14.6, 14.1. HRMS (ESI): [M+Na]+ C17H26O3Na:
calcd 301.17796; found 301.1779.
(((2S,3R)-3-(2-Bromo-1-ethoxyethoxy)-2-methylpent-4-enyl-
oxy)methyl)benzene 3b. Following the same procedure as for
3a, 3b was obtained from (3R,4S)-5-(benzyloxy)-4-methylpent-
1-en-3-ol (350 mg, 1.699 mmol) in dry DCM in Et3N (3.4 mL,
~2 mL mmol-1 of alcohol) and 12 eq. sol. A (2.2 mL) at 25 ◦C. After
30 min, sol. A was added by portion of 2 eq. successively (6 ¥ 2eq,
6 ¥ 2.2 mL). Purification on silica gel (PE/EA: 98/2 then 97/3)
provided 3b as a clear oil (458 mg, 77% yield). FTIR (film, NaCl):
n = 3030, 2976, 2877, 1642, 1454, 1422, 1374, 1202, 1105, 1023,
929, 735, 697 cm-1. 1H NMR (CDCl3, 200 MHz): d = 7.47–7.14 (m,
5H, d1+d2), 5.89–5.54 (m, 1H, d1+d2), 5.36–5.09 (m, 2 H, d1+d2),
4.77–4.56 (m, 1H, d1+d2), 4.50 (s, 2H, d1+d2), 4.09 (t, J ~ 7.8 Hz,
0.5 H, d1 or d2), 3.93 (t, J ~ 7.8 Hz, 0.5 H, d1 or d2), 3.82–3.22 (m,
7 H, d1+d2), 2.16–1.89 (m, 1H, d1+d2), 1.33–1.06 (m, 4H, d1+d2),
0.99–0.77 (m, 4H, d1+d2). 13C NMR (CDCl3, 52.5 MHz): d =
138.8, 138.6, 136.8, 136.1, 128.4, 127.8, 127.6, 119.4, 118.3, 100.7,
99.1, 80.7, 79.8, 73.2, 73.1, 71.7, 63.0, 61.7, 38.2, 38.0, 32.6, 32.4,
15.4, 15.1, 13.1. HRMS (ESI): [M+Na]+ C17H25BrO3Na: calcd
379.08848; found 379.0888.
tert-Butyl((S)-1-((2R,3R)-5-ethoxy-3-methyl-tetrahydrofuran-
2-yl)ethoxy)dimethylsilane 5a. To a solution of (S)-1-((2R,3R)-
5-ethoxy-3-methyl-tetrahydrofuran-2-yl)ethanol
(60
mg,
0.208 mmol) in DCM (4 mL) at -78 ◦C was added BF3·Et2O
(26 mL, 0.208 mmol, 1 eq.) and then allyltrimethylsilane (100 mL,
0.624 mmol, 3 eq.). The reaction was stirred overnight at
-40 ◦C, then quenched with a saturated aqueous solution of
NaHCO3 at -78 ◦C and warmed quickly to RT. The crude was
extracted with DCM (3 ¥ 20 mL), organic layers were dried over
MgSO4 and concentrated under reduced pressure. Purification
on silica gel (PE/EA – 99/1) afforded a clean mixture of the
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two diastereoisomers as a clear oil (43 mg, yield 73%). Clear
NOESY connectivities established unambiguously the 2,5-cis
configuration of THF core of the major compound. FTIR (film,
(m, 9 H). 13C NMR (CDCl3, 75.5 MHz): d (ppm) = 104.1 (M),
104.0 (m), 91.6 (M), 88.3 (m), 68.4 (M), 68.0 (m), 63.4 (M), 62.9
(m), 42.5 (M), 41.6 (m), 31.3 (m), 29.8 (M), 20.3 (m), 20.2 (M),
18.0 (M), 18.0 (m), 15.4 (m), 15.2 (M). HRMS (ESI): [M+Na]+
C9H18O3Na: calcd. 197.11536, found 197.1155
1
NaCl): n/cm-1 = 3079, 2964, 2861, 1644, 1254, 1102. H NMR
(CDCl3, 300 MHz): d (ppm) = 5.88–5.71 (m, 1 H), 5.11–4.98 (m,
2 H), 4.00–3.87 (m, 1 H), 3.82 (m, 0.5 H), 3.72 (m, 0.5 H), 3.35
(dd, J~ 7.2, 4.8 Hz, 0.5 H), 3.24 (t, J~ 5.4 Hz, 0.5 H), 2.42–2.05
(m, 4 H), 1.74–1.48 (m, 1 H), 1.17–1.02 (m, 6 H), 0.88 (s, 9 H),
0.06 (s, 6 H). 13C NMR (CDCl3, 75 MHz): d (ppm) = 135.4, 135.3,
116.7, 116.6, 90.9, 89.6, 78.6, 77.7, 71.2, 70.7, 42.0, 40.4, 40.3,
39.8, 35.5, 34.2, 26.0, 20.9, 20.8, 20.4, 19.9, 18.2, -4.2, -4.3, -4.4,
-4.5. HRMS (ESI): [M+Na]+ C16H32O2SiNa: calcd. 307.20693,
found 307.2070
1-((2S,3R,5R)-5-Allyl-3-methyltetrahydrofuran-2-yl)ethanol 7.
To a solution of 6 (1.365 g, 7.84 mmol) in DCM (20 mL) at
-78 ◦C was added TMSOTf (1.70 mL, 9.41 mmol, 1.2 equiv.)
and then allyltrimethylsilane (4.96 mL, 31.36 mmol, 4 eq.). After
2 h the mixture was quenched with saturated aqueous NaHCO3
solution at -78 ◦C and warmed quickly to RT. The crude was
extracted with DCM (3 ¥ 20 mL), organic layers were dried over
MgSO4 and concentrated under reduced pressure. Purification by
automatic flash chromatography on silica gel (15–40 m) (petroleum
ether/ethyl acetate: 9/1 to 8/2 (1% Et3N)) afforded a 4 : 1 mixture
of the two diastereomers (951 mg, overall yield 71%). 7 eluted
first and was obtained as a clear oil (760 mg). [a]D = -1.1 (c =
0.3, CHCl3). FTIR (film, NaCl): n/cm-1 = 3438, 3078, 2964–2873,
(2R,3R,5R)-5-Allyl-2-((S)-1-(benzyloxy)propan-2-yl)-3-methyl-
tetrahydrofuran 5b. To a solution of (2R,3R)-2-((S)-1-(benzyl-
oxy)propan-2-yl)-5-ethoxy-3-methyltetrahydrofuran (210 mg,
0.754 mmol) in DCM (3 mL) at -84 ◦C was added TMSOTf
(163 mL, 0.905 mmol, 1.2 eq.) and then allyltrimethylsilane
(481 mL, 3.016 mmol, 4 eq.). After 2 h the mixture was quenched
with a saturated aqueous solution of NaHCO3 (4 mL) at -84 ◦C
and warmed quickly to RT. 30 mL H2O were added and then
the crude was extracted with DCM (3 ¥ 20 mL), organic layers
were dried over MgSO4 and concentrated under reduced pressure.
Crude 1H-NMR in C6D6 (600 MHz) allowed to measure a 2.7 : 1
d.r. in favour of cis isomer. Purification on silica gel afforded the
mixture of both diastereoisomers as clear oil (145 mg, yield 70%).
FTIR (film, NaCl): n = 3030, 2958, 1642, 1248, 1089, 1028, 995,
913, 838, 733, 696 cm-1. 1H NMR (C6D6, 600 MHz): d = 7.27 (d, J ~
7.8 Hz, 2H), 7.18–7.10 (m, 2H), 7.06 (t, J ~ 7.2 Hz, 1H), 5.86–5.77
(m, 1H), 5.06–4.97 (m, 2H), 4.37–4.30 (m, 2H), 3.82–3.75 (m, 1H),
3.64 (dd, J ~ 4.8 Hz, 6.6 Hz, 0.25H), 3.62 (dd, J ~ 4.8 Hz, 9 Hz,
0.70H), 3.40 (t, J ~ 6.6 Hz, 0.25H), 3.39–3.34 (m, 1H), 3.29 (t, J
~ 6.6 Hz, 0.7H), 2.38–2.26 (m, 1H), 2.18–2.08 (m, 1H), 1.99–1.84
(m, 2H), 1.80–1.75 (m, 0.25H), 1.51–1.44 (m, 0.75H), 1.25 (ddd,
J ~ 4.8 Hz, 6 Hz, 12 Hz, 1H), 1.03 (d, J ~ 6.6 Hz, 3H), 0.85 (d,
J ~ 6.6 Hz, 0.86H), 0.81 (d, J ~ 6.6 Hz, 2.14 H). 13C NMR (C6D6,
151 MHz): d = 140.2, 136.31, 136.30, 129.1, 128.3, 128.1, 117.1,
88.9, 87.7, 78.3, 77.6, 73.8, 73.8, 73.7, 42.5, 41.4, 41.3, 40.7, 39.3,
39.2, 38.2, 36.3, 20.2, 19.4, 15.3, 15.3. HRMS (ESI): [M+Na]+
C18H26O2Na: calcd 297.18305; found 297.1831.
1
1092, 1027. H NMR (CDCl3, 300 MHz): d (ppm) = 5.91–5.72
(m, 1 H), 5.15–5.01 (m, 2 H), 4.06–86 (m, 2 H), 3.37 (dd, J ~ 6.3,
3.3 Hz, 1 H), 2.41–2.17 (m, 3 H), 2.11 (broad s, 1H), 1.83–1.67
(m, 1 H), 1.65–1.53 (m, 1 H), 1.16 (d, J ~ 6.6 Hz, 3 H), 1.05
(d, J ~ 6.9 Hz, 3 H).13C NMR (CDCl3, 75.5 MHz):.d (ppm) =
134.8, 117.1, 90.1, 77.4, 68.2, 40.0, 32.3, 19.8, 18.0. HRMS (ESI):
[M+Na]+ C10H18O2Na: calcd. 193.12045, found 193.1206.
1-((2R,3R,5R)-5-Allyl-3-methyl-tetrahydrofuran-2-yl)ethanone
8. To a solution of (S)-1-((2R,3R)-5-allyl-3-methyl-tetrahy-
drofuran-2-yl)ethanol (450 mg, 2.65 mmol) in DCM (13 mL), was
added Dess–Martin periodinane at RT (1.68 g, 3.975 mmol, 1.5
eq.). The mixture was then stirred at RT for 5 h. Saturated aqueous
NaHCO3 was added to quench the reaction. After extraction with
DCM (3 ¥ 20 mL), the organic layers were dried over MgSO4,
filtered and concentrated under vacuum. The crude was purified
on silica gel (pent/Et2O: 9/1) to give 8 as a clear white oil (582 mg,
87%). FTIR (film, NaCl): n/cm-1 = 3078, 2964, 2931, 2873, 1715,
1
1107. H NMR (CDCl3, 200 MHz): d (ppm) = 5.95–5.71 (m, 1
H), 5.17–5.01 (m, 2 H), 4.14 (quint, J ~ 6.5 Hz, 1 H), 3.75 (d, J ~
7.4 Hz, 1 H), 2.50–2.11 (m, 3 H), 2.19 (s, 3H), 1.90–1.57 (m, 2 H),
1.12 (d, J ~ 6.8 Hz, 3 H). 13C NMR (CDCl3, 50.3 MHz): d (ppm) =
210.0, 134.4, 117.1, 90.4, 78.8, 40.3, 38.7, 36.8, 25.6, 17.9. HRMS
(ESI): [M+Na]+ C10H16O2Na: calcd. 191.10480, found 191.1049
(S)-1-((2R,3R)-5-Ethoxy-3-methyl-tetrahydrofuran-2-yl)ethanol
6. To
a
solution of tert-butyl((S)-1-((2R,3R)-5-ethoxy-3-
methyl-tetrahydrofuran-2-yl)ethoxy)dimethylsilane 4a (3.025 g,
10.50 mmol) in dry acetonitrile, was added CsF (7.98 g, 52.5 mmol,
5 eq.) and a 1 M solution of TBAF in THF (210 mL, 2.1 mmol,
0.2 eq.). The insoluble mixture was stirred at 80 ◦C for 22 h. After
cooling to RT, water was added and the mixture was extracted
with DCM (3 ¥ 20 mL). Organic layers were dried over MgSO4,
filtered and solvents were removed under vacuum. Purification
on silica gel (PE/EA – 9/1 to 8/2 +1% Et3N) afforded the
expected product as a clear oil (1.539 g, 84%, d.r. ~6/4). Major
diastereoisomer was noted M and the minor one m. FTIR (film,
NaCl): n/cm-1 = 3848, 2975, 2880, 1083, 1001. 1H NMR (CDCl3,
300 MHz): d (ppm) = 5.13–5.07 (m, 0.4 H, m), 5.02 (d, J ~ 5.1 Hz,
0.6 H, M), 4.02–3.87 (m, 1 H, M+m), 3.81–3.67 (m, 1 H, M+m),
3.64 (dd, J ~ 6.9, 2.7 Hz, 0.6 H), 3.58 (dd, J ~ 6.6, 3.3 Hz, 0.4 H,
m), 3.51–3.37 (m, 1 H, M+m), 3.15 (broad s, 0.6 H, M), 2.61–2.44
(m, 0.6 H, M), 2.27–2.06 (m, 1.8 H), 1.69–1.50 (m, 1 H), 1.22–1.05
(E)-Methyl 3-((2R,3R,5R)-5-allyl-3-methyl-tetrahydrofuran-2-
yl)but-2-enoate 9. To a solution of fresh dry NaH (85 mg,
3.56 mmol, 2 eq.) in THF (3.7 mL) was added methyl diethylphos-
phonoacetate (691 mL, 3.74 mmol, 2.1 eq.) dropwise at 0 ◦C. After
stirring 10 min at 0 ◦C, this solution was added dropwise to
a solution of 1-((2R,3R,5R)-5-allyl-3-methyl-tetrahydrofuran-2-
yl)ethanone 8 (300 mg, 1.78 mmol, 1 eq.) in THF (3.7 mL) at
0
◦C. The temperature was allowed to slowly reach RT. After
completion (5 h) the reaction was quenched with saturated
aqueous NH4Cl and extracted with DCM (3 ¥ 10 mL). The organic
layers were dried over MgSO4, filtered and concentrated under
vacuum. Purification on silica gel (PE/EA: 98/2 to 95/5) afforded
9 as a colorless oil (312 mg, 78%). [a]D = -19.4 (c = 0.24, CHCl3).
FTIR (film, NaCl): n/cm-1 = 2961, 2873, 1721, 1654, 1232, 1139.
1H NMR (CDCl3, 300 MHz): d (ppm) = 5.91–5.72 (m, 2 H), 5.14–
4.99 (m, 2 H), 4.07 (quint, J ~ 6.5 Hz, 1 H), 3.77 (d, J ~ 7.0 Hz,
3730 | Org. Biomol. Chem., 2011, 9, 3726–3732
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1 H), 3.67 (s, 3 H), 2.45–2.18 (m, 2 H), 2.10 (s, 3 H), 2.15–1.95 (m,
1 H), 1.90–1.71 (m, 1 H), 1.69–1.55 (m, 1 H), 1.04 (d, J ~ 6.8 Hz,
3 H). 13C NMR (CDCl3, 75.5 MHz): d (ppm) = 167.2, 158.4,
134.8, 117.2, 115.0, 90.5, 78.1, 51.0, 40.5, 39.0, 38.1, 18.2, 14.7.
HRMS (ESI): [M+Na]+ C13H20O3Na: calcd. 247.13101, found
247.1310.
and a 0.5 M solution of Rochelle salt at -50 ◦C. When the mixture
was at RT, it was extracted with DCM (3 ¥ 15 mL). The organic
layers were dried over MgSO4, filtrated and concentrated under
vacuum. Purification on silica gel (DCM/acetone: 95/5) afforded
12 as a clear oil (53 mg, 68%). [a]D = -14.2 (c = 0.196, CHCl3).
1
FTIR (film, NaCl): n/cm-1 = 2388, 2956, 2858, 1097. H NMR
(CDCl3, 300 MHz): d (ppm) = 5.64 (t, J ~ 6.3 Hz, 1 H), 4.28–4.10
(m, 2 H), 4.05–3.91 (m, 1 H), 3.73–3.54 (m, 3 H), 2.0 (q, J ~ 7 Hz,
1 H), 1.85–1.39 (m, 10 H), 0.97 (d, J ~ 6.6 Hz, 3 H), 0.88 (s, 9
H), 0.03 (s, 6 H). 13C NMR (CDCl3, 75.5 MHz): d (ppm) = 137.7,
126.5, 91.6, 78.0, 63.2, 59.3, 39.9, 36.5, 32.8, 29.5, 26.1, 18.5,
17.5, 11.7, -5.2. HRMS (ESI): [M+Na]+ C18H36O3Si Na: calcd.
351.23314, found 351.2330
(E)-Methyl 3-((2R,3R,5R)-5-(3-hydroxypropyl)-3-methyl-tetra-
hydrofuran-2-yl)but-2-enoate 10. To
a
solution of (E)-
methyl 3-((2R,3R,5R)-5-allyl-3-methyl-tetrahydrofuran-2-yl)but-
◦
2-enoate 9 (102 mg, 0.455 mmol) in THF (4.5 mL) at 0 C, was
added a 2 M solution of BH3–Me2S in THF (228 mL, 0.91 mmol,
1 eq.). The mixture was allowed to reach◦RT and stirred for
1.5 h Then The mixture was cooled to -40 C and NaBO3·H2O
(136 mg, 1.365 mmol, 3 eq.) then water (4.5 mL) were added.
The mixture was stirred 5 h. Water was then added and the
mixture was extracted with DCM (3 ¥ 15 mL). The organic layers
were dried over MgSO4, filtrated and concentrated under vacuum.
Purification on silica gel (DCM/acetone: 98/2 to 95/5) provided
10 as a colorless oil (73 mg, 66%). [a]D = -10.5 (c = 0.36, CHCl3).
FTIR (film, NaCl): n/cm-1 = 3362, 2958, 2875, 1720, 1652, 1159.
1H NMR (CDCl3, 300 MHz): d (ppm) = 5.89 (br s, 1 H), 4.11–3.98
(m, 1 H), 3.81 (d, J ~ 6.9 Hz, 1 H), 3.73–3.61 (m, 2 H), 3.69 (s, 3H),
2.19 (t, J ~ 5.7 Hz, 1 H), 2.15–2.00 (m, 1 H), 2.11 (s, 3 H), 1.82–1.59
(m, 6 H), 1.06 (d, J ~ 6.9 Hz, 3 H). 13C NMR (CDCl3, 75.5 MHz):
d (ppm) = 167.2, 158.3, 115.0, 90.6, 78.9, 62.9, 51.1, 39.8, 38.2,
32.9, 29.9, 18.5, 14.8. HRMS (ESI): [M+Na]+ C13H22O4Na: calcd.
265.14158, found 265.1418.
Non-radioactive ligand-binding assay. Biotinylated a-
bungarotoxin and streptavidin coupled to horseradish peroxidase
were purchased from Molecular Probes (Invitrogen). Non-
radioactive ligand-binding assays to assess the biological activity
of the tetrahydrofuran core of gymnodimine A 11 and 12 were
performed at room temperature (25 ◦C) as reported elsewhere with
some modifications.23 Briefly, Torpedo electrocyte membranes
rich in nAChR purified as described previously24,25 were diluted
in TBS (150 mM NaCl, 50 mM Tris-HCl, pH 7.4) containing
0.1% bovine serum albumin (BSA) and 0.1% Tween 20, to a
final protein concentration of 0.14 mg mL-1. Torpedo membranes
(100 mL) were incubated for 4 h with 11, 12 and gymnodimine A in
the concentration range of 10-3 to 10-10 M. Thereafter, a volume of
2 mL of 2 ¥ 10-6 M biotinylated a-bungarotoxin in TBS, 0.1% BSA,
pH 7.4 was added to each reaction mixture. Following 15 min
incubation, Torpedo electrocyte membranes were immobilized
by filtration on a Whatman GF/C glass microfiber membrane
presoaked with TBS, 0.1% BSA using a Hoefer 48-well slot-blot.
The wells were washed with 3 mL ice-cold TBT (TBS, 0.1%
Tween 20, pH 7.4). To detect biotinylated a-bungarotoxin bound
to nAChRs, Torpedo membranes were incubated for 15 min
with streptavidin coupled to horseradish peroxidase (100 mL,
200 ng mL-1 protein). The solution was removed by filtration
and the membrane was washed with 3 mL ice-cold TBT followed
by 250 mL sterile water. The membrane was then incubated for
5 min with ECL-PlusTM detection reagent (50 mL). Peroxidase
activity was recorded directly on the GF/C filter membrane using
a GeneGnome chemiluminescence imager. In the absence of a
competitive nAChR-ligand, peroxidase activity is maximal giving
higher chemiluminescence signals. In contrast, the presence of
a competitive antagonist such as gymnodimine A prevents the
binding of biotinylated a-bungarotoxin to Torpedo nAChR which
results in lower chemiluminescence signals. The percentage of
inhibition was calculated as reported.23 Independent experiments
were performed at least twice in duplicate.
(E)-3-((2R,3R,5R)-5-(3-Hydroxypropyl)-3-methyltetrahydro-
furan-2-yl)but-2-en-1-ol 11. To
a solution of (E)-methyl
3-((2R,3R,5R)-5-(3-hydroxypropyl)-3-methyl-tetrahydrofuran-
2-yl)but-2-enoate (73 mg, 0.301 mmol) in DCM (6 mL) at
-50 ◦C was added DIBAL-H (1 M solution in heptane) (1.2 mL,
1.20 mmol, 4 eq.) dropwise over a period of 20 min. The
mixture was stirred for 1 h at -50 ◦C. The reaction was
quenched by addition of a saturated aqueous NaHCO3 solution
at -50 ◦C, warmed to RT and extracted with DCM (3 ¥ 10
mL). The organic phase was dried over MgSO4, filtered and
solvents were removed under reduced pressure. Purification on
silica gel (DCM/acetone: 7/3) afforded (E)-3-((2R,3R,5R)-5-(3-
hydroxypropyl)-3-methyltetrahydrofuran-2-yl)but-2-en-1-ol 11 as
a colorless oil (32 mg, 50%). [a]D = -15.9 (c = 0.3, CHCl3). FTIR
1
(film, NaCl): n/cm-1 = 3332, 2929, 2869, 1668, 1001. H NMR
(CDCl3, 300 MHz): d (ppm) = 5.63 (t, J~ 6.3 Hz, 1 H), 4.27–4.07
(m, 2 H), 4.06–3.93 (m, 1 H), 3.71 (d, J~ 7.8 Hz, 1 H), 3.66–3.52
(m, 2 H), 2.03 (q, J~ 7.2 Hz, 1 H), 1.89–1.49 (m, 8 H), 0.98 (d, J~
6.6 Hz, 3 H). 13C NMR (CDCl3, 75.5 MHz): d (ppm) = 137.0,
126.6, 91.7, 78.2, 62.8, 59.0, 40.0, 36.6, 33.4, 29.8, 17.6, 11.9.
HRMS (ESI): [M+Na]+ C12H23O3Na: calcd. 237.14666, found
237.1470.
(E)-3-((2R,3R,5R)-5-(3-(tert-Butyldimethylsilyloxy)propyl)-3-
methyl-tetrahydrofuran-2-yl)but-2-en-1-ol 12. To
a solution
Acknowledgements
of (E)-methyl 3-((2R,3R,5R)-5-(3-(tert-butyldimethylsilyloxy)-
propyl)-3-methyl-tetrahydrofuran-2-yl)but-2-enoate (85 mg,
0.238 mmol) in DCM (2.4 mL, C ~ 0.1) stirred at -50 ◦C was
added dropwise DIBAL-H (1 M in heptane) (952 mL, 0.952 mmol,
4 eq.) over 20 min. After, completion (50 min), the reaction was
quenched by addition of a saturated aqueous NaHCO3 solution
We gratefully acknowledge the French “Agence Nationale de
la Recherche” for financial support (ANR-07-PCVI-0008-02).
We also thank the CNRS and Re´gion Aquitaine for their help
and Dr Catherine Guillou and Dr Laurent Chabaud for helpful
discussions and for optical rotation measurements.
This journal is
The Royal Society of Chemistry 2011
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3732 | Org. Biomol. Chem., 2011, 9, 3726–3732
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