A Short Sequence for the Iterative Synthesis of Fused Polyethers

Article abstract of DOI:10.1002/hlca.201900161

A simple and efficient four-step sequence for the synthesis of fused polyether arrays has been developed. Cyclic ethers are installed by sequential alkynyl ether formation, carbocupration, ring-closing metathesis and hydroboration with acidic workup. Cruc

Full text of DOI:10.1002/hlca.201900161

DOI: 10.1002/hlca.201900161
FULL PAPER
A Short Sequence for the Iterative Synthesis of Fused
Polyethers
a
b
b
Frédéric Elustondo, Venkaiah Chintalapudi, and J. Stephen Clark*
a
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom
b
School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow, G12 8QQ,
United Kingdom, e-mail: stephen.clark@glasgow.ac.uk
th
Dedicated to Professor Philippe Renaud to mark the occasion of his 60 birthday
©
2019 The Authors. Published by Wiley-VHCA AG. This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
A simple and efficient four-step sequence for the synthesis of fused polyether arrays has been developed.
Cyclic ethers are installed by sequential alkynyl ether formation, carbocupration, ring-closing metathesis and
hydroboration with acidic workup. Crucially, the alkene required for the subsequent ring formation by ring-
closing metathesis is present in the substrate but is masked in the form of a vinylic silane, which prevents
competitive metathesis of the side chain. Generation of the reactive alkene from the unreactive vinylic silane is
accomplished by hydroboration and subsequent acid-mediated Peterson elimination of the intermediate
hydroxysilane.
Keywords: fused polyether, ring-closing metathesis, hydroboration, latent alkene, Peterson elimination.
along the backbone. Several of the natural products
Introduction
(e.g., the ciguatoxins and brevetoxins) possess eight-
Fused polyether natural products are produced by and nine-membered rings embedded within their
various marine dinoflagellates and are found in structures. However, the most common sub-units
[1,2]
organisms that feed on these algae.
Members of found in the fused polyethers are six- and seven-
this family3,4]of natural products include the membered cyclic ethers, and in many of the natural
[
[5–8]
[9,10]
[14]
[11,16]
brevetoxins,
ciguatoxins,
gambieric acids,
products (e.g., gymnocin-A and gambierol,
Fig-
[
11,12]
[13]
gymnocins,
tamulamides,
yessotoxin,
ure 1) the polycyclic array is composed entirely or
almost entirely of fused rings of these sizes.
[
15]
[16]
[17]
[18]
adriatoxin, gambierol, gambierone, brevenal
and maitotoxin,[ the largest non-polymeric natural
19]
Marine polyethers are popular targets for total syn-
product known. Many marine polyethers (e.g., the thesis because of their size, structural complexity and the
ciguatoxins) are potent neurotoxins that affect verte- synthetic challenges they present. They are also of
brates at very low concentrations, but some possess interest because of their potent biological activities. Total
[
22–26]
[27–33]
[38–42]
little or no neurotoxic activity and are potential lead syntheses of the brevetoxins,
ciguatoxins,
gambierol
[34,35]
[36,37]
compounds for the development of therapeutic gambieric acids,
gymnocins,
have been accomplished, but synthe-
[43–45]
agents. For example, the gambieric acids exhibit and brevenal
potent anti-fungal activity and brevenal has been ses of the larger natural products (i.e., those that possess
identified as a lead for the development of treatments more than eight rings) are generally extremely lengthy
for cystic fibrosis.[
20,21]
and cannot provide sufficient quantities of the natural
Marine polyethers are some of the most structurally products for full biological evaluation or extensive
complex and challenging targets confronting contem- analogue synthesis. Consequently, new strategies for the
porary organic synthesis. They contain arrays of trans- rapid construction of fused polyethers are required to
fused cyclic ethers, ranging in ring size from six to reduce the step count significantly and improve both
nine, in which the position of the ether alternates synthetic convergence and efficiency.
Helv. Chim. Acta 2019, 102, e1900161
© 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
Figure 1. Structures of gymnocin A and gambierol.
In previous work, we have devised several poten-
tially efficient approaches to the synthesis of fused
polyether systems.[
46–48]
Our work has focused on the
use of ring-closing metathesis (RCM) reactions of enol
[49,50]
[51,52]
[53–55]
ethers,
allylic ethers
and alkynyl ethers
to prepare six- to nine-membered cyclic ether units of
the type found in marine fused polyether natural
products. We have used these reactions iteratively and
in a bidirectional manner to prepare significant
portions of the large polyether natural products
[56]
[57,58]
CTX3C and gambieric acid A.
During our work, we have found that RCM
reactions of acyclic enol ethers and functionalization
of the resulting cyclic enol ethers is a particularly
effective sequence for the synthesis of polyether sub-
units that contain six- and seven-membered rings. In
contemporaneous studies, Rainier and co-workers
Scheme 1. Synthesis of fused cyclic ethers by sequential RCM
have demonstrated the power of RCM reactions of and hydroboration.
enol ethers[
59–62]
and have used this method to
[42,45]
synthesise and gambierol and brevenal,
and to
construct significant fragments of the larger natural
products yessotoxin and adriatoxin.[
63]
constructing polyethers that contain 10 or more fused
In the approach developed by us previously, an rings.
acyclic enol ether 3 is prepared by methylenation of
To accomplish ring construction as efficiently as
an ester 1 or by carbocupration of an alkynyl ether 2 possible, we sought to develop a synthetic sequence
Scheme 1).[ The acyclic enol ether 3 is subjected to in which the alkene required for the subsequent RCM
57]
(
RCM to provide the cyclic ether 4 that is then reaction would be present in a masked form and
hydroborated to give the alcohol 5. To repeat the would be revealed after hydroboration but without
sequence and thereby construct a further ring, a series requiring additional steps. In the proposed sequence
of reactions is required to introduce an alkene into the of reactions, an acyclic enol ether 6, which contains a
3
R substituent because the presence of an unprotected group (X) in the side chain that could be converted
terminal alkene is incompatible with the preceding into an alkene, would be subjected to RCM to produce
RCM and hydroboration reactions. Because of the the cyclic enol ether 7 (Scheme 2). Instead of the cyclic
additional functionalisation reactions required to gen- enol ether 7 being subjected to hydroboration to give
3
erate an alkene at the R position, a relatively efficient the alcohol 8 followed by a multistep sequence to
four-step sequence is rendered much less efficient. produce the terminal alkene 9, the group X would be
The additional steps in each iteration would have a chosen so that hydroboration and alkene formation
deleterious impact on the overall step count when would be accomplished concurrently to give the
hydroxyalkene 9 directly from the enol ether 7. The
www.helv.wiley.com (2 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
Scheme 2. General scheme for iterative fused cyclic ether
construction.
alcohol 9 would be converted into the enol ether 11
either by esterification to give 10 and subsequent
methylenation, or by sequential alkynyl ether forma-
tion and carbocupration. Thus, ring construction
would be complete in just four steps and the
sequence (6!7!9!11) could be repeated.
The power of the proposed iterative ring construc-
tion procedure could be further amplified by its
application in a bidirectional manner. We have dem-
onstrated that bidirectional synthesis can be used to
Scheme 3. Bidirectional synthesis of the G–I fragment of the
gambieric acids.
prepare the G–I fragment of the gambieric acids
Scheme 3).[ In course of this work, carbocupration of
57]
(
Results and Discussion
the bis-alkynyl ether 12 was performed to give the bis-
enol ether 13 and a subsequent double RCM reaction As outlined in Scheme 2, the development of a four-
mediated by the Grubbs second generation pre- step sequence for the construction of six- and seven-
catalyst (14) delivered the tricyclic bis-enol ether 15. membered cyclic ethers requires a group (X) that can
Final double hydroboration and acetal formation function as a latent alkene in the side chain during
afforded the tetracyclic alcohol 16. Application of the RCM and then be converted into a terminal alkene
new synthetic procedure in an analogous bidirectional upon hydroboration so that additional steps are
manner would allow construction of fused polycyclic avoided. These requirements led us to select a vinylic
ethers to be accomplished at the rate of just two steps silane as a latent terminal alkene because bulky,
per ring.
electron-rich 2-trialkylsilyl-1-alkenes would be rela-
tively unreactive in metathesis reactions but could
www.helv.wiley.com (3 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
undergo subsequent hydroboration.[64] The resulting
hydroxysilane would then undergo Peterson elimina-
tion to reveal the unfunctionalised terminal alkene
required for the next iteration of the reaction
sequence.
The proposed new annulation sequence was ex-
plored using tetrahydropyranols derived from com-
mercially available 3,4,6-tri-O-benzyl-D-glucal (17;
Scheme 4). Epoxidation of the enol ether 17 with
Scheme 4. Synthesis of the alcohols 19–21 from 3,4,6-tri-O-
benzyl-D-glucal (17).
dimethyldioxirane (DMDO)[65,66] afforded the epoxide
1
8 with high diastereofacial selectivity and subsequent
reaction with allylmagnesium bromide afforded the Scheme 5. Four-step sequence for the synthesis of the bicyclic
alcohol 19 in excellent yield. Reaction of the epoxide ether 29a from the cyclic ether 19.
1
8
with either 2-methyl-2-propen-1-ylmagnesium
bromide or 3-buten-1-ylmagnesium bromide afforded
the alcohols 20 and 21 in modest yield.[
67,68]
the RCM products 27 and 28 and then immediate
The alcohol 19 was the first substrate to be acid-mediated Peterson elimination. Hydroboration
subjected to the four-step annulation sequence was accomplished by treatment of each RCM product
(Scheme 5). Greene’s one-pot method was used to (27 and 28) with excess thexylborane followed by
convert the alcohol 19 into the alkynyl ether 22 in oxidation under mild conditions. Peterson elimination
[69]
excellent yield.
Carbometallation of the alkynyl was performed simply by dissolving the crude hydro-
ether using organocopper reagents prepared from the boration products in trifluoroacetic acid as part of the
[
71]
Grignard reagents 23 and 24 afforded the enol ethers workup procedure. In the case of the enol ether 27,
1
2
5 and 26 in high yield. The key RCM reactions were the hydroboration and Peterson elimination sequence
then effected by treatment of the enol ethers 25 and delivered the alcohol 29a in 45% yield. The enol ether
6 with the ruthenium complex 14 in benzene at 28 was found to be an even better substrate; in this
2
reflux. In both cases, very high yields of the cyclic enol case, the alcohol 29a was obtained in 62% yield along
ethers 27 and 28 were obtained. The vinylic silane was with the diastereomeric alcohol 29b in 11% yield after
unreactive under the RCM conditions and so the silyl sequential hydroboration and Peterson elimination.
substituent did provide a high level of protection to The alcohol 29b was converted into the required
the side-chain alkene, as anticipated.
diastereomeric alcohol 29a by sequential oxidation,
The final step in the sequence involved hydro- base-mediated epimerization and ketone reduction.
boration of both the enol ether and vinylic silane in
Most polyether natural products possess at least
one methyl substituent at a ring junction position, and
so we wanted to discover whether the annulation
1
The Grignard reagent 24 was prepared from the sequence could accommodate this structural feature
(Scheme 6). The alcohol 20 was converted into the
corresponding bromide, see ref. [70].
www.helv.wiley.com (4 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
Scheme 6. Four-step sequence for synthesis of the bicyclic ether 32 from the cyclic ether 20.
alkynyl ether 30 using the one-pot procedure that had
been employed to prepare alkynyl ether 22 from the
alcohol 19 (Scheme 5).[
69]
Carbometallation of the
alkynyl ether 30 using an organocopper reagent
prepared from the Grignard reagent 24 was performed
to give the enol ether 31.[ The RCM reaction of the
acyclic enol ether 31 to give the tetrasubstituted cyclic
enol ether was challenging and a complex mixture of
products was obtained from the reaction mediated by
the complex 14. The mixture was then subjected to
immediate hydroboration using thexylborane and the
resulting crude hydroxysilane was dissolved in tri-
fluoroacetic acid to facilitate Peterson elimination. The
required alcohol 32 was obtained in modest yield after Scheme 7. Synthesis of a fused bicyclic ether with a propenyl
70]
side chain.
sequential RCM, hydroboration and Peterson elimina-
tion.
In the annulation sequences shown in Schemes 5
and 6, a butenyl side chain had been installed, which precursor – enol ether 37 – was prepared from the
would be used to construct a seven-membered cyclic alcohol 21 by conversion into the alkynyl ether 36 and
ether in a further iteration of the four-step reaction subsequent carbocupration of the alkyne with an
sequence. However, in many cases a propenyl side organocopper reagent generated from the Grignard
chain would be required to construct a six-membered reagent 24 (Scheme 8).
ring in the subsequent RCM reaction. The enol ether
33, prepared from the alkynyl ether 22 by the route
shown in Scheme 7, was used to test the reaction
sequence. The organocopper reagent used in the
carbocupration reaction was prepared by the addition
of a higher-order cuprate, generated by the reaction
of phenyldimethylsilyl lithium with copper(I) cyanide,
[72]
to allene. Reaction of the alkynyl ether 22 with an
excess of the organocopper reagent delivered the enol
ether 33 in 73% yield. Subsequent ring formation by
RCM was successful and the bicyclic enol ether 34 was
produced in good yield. However, this compound
proved to be unstable and so the hydroboration, and
Peterson elimination sequence was not explored.
We had shown that the four-step sequence could
be used to construct fully-functionalised six-mem-
bered cyclic ethers and we wanted to establish
whether the sequence could be used to construct a
seven-membered cyclic ether. The requisite RCM
Scheme 8. Synthesis of cyclisation precursor 37.
www.helv.wiley.com (5 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
The RCM reaction of the enol ether 37 proved to 40 nor homologous compound 29a could be isolated
be more challenging than the RCM reactions of from the complex mixture of products and attempts
substrates 25, 26, 31 or 33. The RCM reaction was very to suppress isomerization of the terminal alkene 37 to
slow and isomerisation of the substrate 37 to give the give 1,2-disubstituted alkene 38 by the inclusion of
alkene 38 occurred in competition with the cyclisation various additives were unsuccessful.3[73]
reaction to give the required seven-membered cyclic
Although it was not possible to suppress isomer-
2
enol ether 39. The RCM reaction of the isomerised ization of 37, the fact that this reaction occurs might
alkene produced the previously characterized cyclic offer some advantages, provided the process can be
enol ether 28, the lower homologue of the required controlled fully. In principle, the ability to perform
product 39. Thus, a mixture of the cyclic enol ethers isomerization or suppress it completely would allow
2
8 and 39 was obtained, but separation was not either 29a or 40 to be prepared from the same
possible because the compounds were prone to substrate (37) and would obviate the need to perform
hydrolysis on extended contact with silica gel. The the sequence shown in Scheme 7, which involves a
mixture of enol ethers was subjected to immediate sensitive intermediate and proved difficult to com-
hydroboration and acidic workup to produce the plete. Work is continuing to discover whether it is
required alcohol 40 and the previously prepared possible to accomplish complete in situ isomerization
alcohol 29a (Scheme 9). However, neither the alcohol of 37 to give 38 prior to RCM when a six-membered
cyclic ether is required and suppress the reaction
when the construction of a seven-membered ring is
required.
Conclusions
A four-step sequence of alkynyl ether formation,
carbocupration, ring-closing metathesis and hydro-
boration with acidic workup, has been used to
synthesise fused polyether systems. The alkene re-
quired for the further ring construction by a subse-
quent RCM reaction is present in the substrate but is
protected in the form of a vinylic silane, which
prevents competitive side-chain metathesis. The four-
step sequence can be used to add tetrahydropyranol
rings to existing polyether arrays and ring junction
methyl groups are tolerated. The use of the reaction
for the synthesis of seven-membered cyclic ethers is
hampered by competitive isomerization of the termi-
nal alkene in the substrate prior to RCM, which leads
to a mixture of the required seven-membered cyclic
enol ether and the corresponding six-membered cyclic
enol ether.
Scheme 9. Synthesis of a bicyclic ether containing an oxepane.
3
The following reagents were added to the ring-closing
2
Competitive isomerization of terminal alkenes during metathesis reaction in unsuccessful attempts to suppress
RCM reactions of dienes to form medium-sized rings is isomerization: triethylamine, water, styrene, tricyclohex-
well precedented. For examples, see ref. [73].
ylphosphine and tricyclohexylphosphine oxide.
www.helv.wiley.com (6 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
Experimental Section
1.3); 2.81 (1 H, t, J=2.4). 13C-NMR (125 MHz, CDCl3):
1
1
39.1; 138.7; 138.2; 128.4; 128.3; 128.2; 128.1; 128.0;
Materials and Instrumentation
1H-NMR spectra were recorded on Bruker DRX 500, AM
27.8; 127.6; 127.4; 127.4; 79.4; 77.5; 74.6; 74.3; 73.3;
+
71.7; 69.9; 68.5; 52.2. HR-CI–MS (NH ): 432.1911 (M ,
3
+
4
00 and AV 400 instruments at ambient temperature. C H O ; calc. 432.1937). EI-MS: 359 (10), 181 (17), 91
27
28
5
All spectra were obtained from samples dissolved in (100).
deuterochloroform unless otherwise stated. Chloro-
form or tetramethylsilane was used as the internal
(2S,3S,4R,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyl-
reference (δ 7.27 and 0.0 ppm, resp.). J values are oxy)methyl]-2-(prop-2-en-1-yl)oxan-3-ol (19). The
given in Hertz. Signals in NMR spectra are described as crude epoxide 18 (5.2 g, 12 mmol) was dissolved in
singlets (s), doublets (d), triplets (t), quartets (q), dry THF (120 mL) and the solution was cooled to
multiplets (m), broad (b) or a combination of these, À 20°C. Allylmagnesium chloride (12 mL of a 2.0 M
which refers to the spin–spin coupling pattern solution in THF, 24 mmol) was added dropwise and
1
3
observed. C-NMR spectra were recorded on either the mixture was stirred for 2 h. The reaction was
Bruker DRX 500 (125 MHz) or AV 400 (100 MHz) instru- quenched by the addition of a saturated solution of
ments at ambient temperature. All spectra were NH Cl (50 mL) and the resulting mixture was extracted
4
obtained from samples dissolved in deuterochloroform with dichloromethane (3×100 mL). The combined
unless otherwise stated, using chloroform as the organic extracts were dried (MgSO ) and the solvent
4
internal reference (δ 77.1 ppm). IR spectra were was removed in vacuo. The residue was purified by
À 1
recorded in the range 4000–600 cm on a Perkin- flash column chromatography over silica gel (Et O/
2
Elmer 1600 series FT-IR spectrometer. Melting points hexane 1:1) to give the alcohol 19 (4.95 g, 92%) as a
were determined using a Mel-Temp II melting point white solid. R =0.52 (Et O/hexane 1:1). M.p.=66–
f
2
[
75]
20
apparatus. Elemental analyses were carried out on an 67°C (Lit.
63–65°C). [α] = +40.8 (c=1.28 in
D
[
75]
Exeter analytical Inc. CE-440 Elemental analyser. Mass CHCl ) (Lit.
[α] = +37.5 (c=0.9 in CHCl )). IR
3
D
3
1
spectra and accurate mass measurements were re- (CHCl ): 3610, 2956, 1460, 1047. H-NMR (500 MHz,
3
corded under EI, FAB, CI and ES conditions on a CDCl ): 7.49–7.31 (15 H, m); 6.06 (1 H, dddd, J=17.1,
3
FISSONS VG Autospec instrument. Optical rotations 10.1, 7.0, 7.0); 5.26 (1 H, dd, J=17.1, 1.9); 5.20 (1 H, d,
were determined using a Jasco DIP-370 digital polar- J=10.1); 5.08 (1 H, d, J=11.5); 4.93 (1 H, d, J=10.9);
imeter.
4.87 (1 H, d, J=11.5); 4.76 (1 H, d, J=12.3); 4.73 (1 H, d,
J=10.9); 4.70 (1 H, d, J=12.3); 3.88–3.80 (2 H, m); 3.72
(
3
1 H, t, J=9.3); 3.60 (1 H, t, J=8.9); 3.57–3.53 (1 H, m);
.49 (1 H, t, J=8.9); 3.39 (1 H, ddd, J=8.9, 7.5, 3.3);
2.73–2.67 (1 H, m); 2.44 (1 H, dt, J=14.6, 7.2); 2.27 (1
Synthetic Procedures and Compound Characterisation
(
1S,3R,4R,5S,6R)-4,5-Bis(benzyloxy)-3-[(benzyloxy)-
1
3
methyl]-2,7-dioxabicyclo[4.1.0]heptane (18). To a H, br. s). C-NMR (125 MHz, CDCl ): 138.6; 138.3; 138.1;
3
solution of 3,4,6-tri-O-benzyl-D-glucal (=(2R,3S,4R)-3,4- 134.7; 128.7; 128.5; 128.4; 128.0; 127.9; 127.8; 127.6;
bis(benzyloxy)-2-[(benzyloxy)methyl]-3,4-dihydro-2H-
pyran; 17; 5.0 g, 12 mmol) in dichloromethane (20 mL) HR-EI-MS: 474.2416 (M , C H O ; calc. 474.2406). EI-
117.1; 86.8; 79.2; 78.8; 78.5; 75.2; 74.8; 73.5; 68.9; 36.2.
+
+
30 34 5
+
at 0°C was added dropwise a solution of freshly MS: 474 (1, M ), 383 (45), 293 (1), 259 (2), 181 (11), 133
prepared dimethyldioxirane (300 mL of a 0.08
M
(9), 91 (100). Anal. calc. for C H O : C 75.92, H 7.22;
30 34 5
[65,66]
solution in acetone, 24 mmol).
After the addition, found: C 76.15, H 7.28.
the solvent was removed in vacuo (<5°C). The
resulting solid was dissolved in dichloromethane and
(2S,3S,4R,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyl-
dried (Na SO ). The solvent was removed in vacuo oxy)methyl]-2-(2-methylprop-2-en-1-yl)oxan-3-ol
2
4
(
<5°C) to give the epoxide 18 as a white solid (5.2 g, (20). Crude epoxide 18 (5.0 g, 12 mmol) was dissolved
[
74]
17
quant.). M.p.=62–64°C (Lit.
77–78°C). [α] = + in dry THF (100 mL) and the solution was cooled to
D
[
74]
25
1
3.7 (c=0.42 in CHCl ) (Lit. [α] = +31.1 (c=0.5 in À 20°C. 2-Methylallylmagnesium chloride (46 mL of
3
D
1
CHCl )). H-NMR (500 MHz, CDCl ): 7.42–7.20 (15 H, m); 0.50 M solution in THF, 23 mmol) was added dropwise
3
3
4
1
.98 (1 H, d, J=11.4); 4.85 (1 H, br. s); 4.79 (1 H, d, J= and the mixture was stirred for 2 h. The reaction was
1.4); 4.54 (1 H, d, J=11.9); 7.53 (1 H, d, J=11.8); 4.44 quenched by the addition of a saturated solution of
(
1 H, d, J=11.9); 4.43 (1 H, d, J=11.8); 4.09 (1 H, d, J= NH Cl (100 mL) and the resulting mixture was ex-
4
7
.8); 4.00 (1 H, bd, J=10.1); 3.92 (1 H, ddd, J=10.1, 7.7, tracted with dichloromethane (3×80 mL). The com-
1
.7); 3.85 (1 H, dd, J=10.8, 3.1); 3.68 (1 H, dd, J=10.8, bined organic extracts were dried (MgSO ) and the
4
www.helv.wiley.com (7 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
+
+
solvent removed in vacuo. The resulting residue was HR-FAB-MS: 489.2667 ([M+H] , C H O
1 37 5
; calc.
3
+
purified by flash column chromatography over silica 489.2641). FAB-MS: 489 (9, [M+H] ), 307 (21), 289
gel (Et O/hexane 1:2) to give alcohol 20 (2.9 g, 52%) (11), 154 (93), 136 (68), 91 (100). Anal. calc. for
2
as a white solid. R =0.67 (Et O/hexane 1:1). M.p.= C H O : C 76.20, H 7.43; found: C 75.98, H 7.28.
f
2
31 36 5
2
0
6
3
(
9–70°C. [α] = +30.4 (c=1.15 in CHCl ). IR (CHCl ):
D
3
3
1
600, 2869, 1602, 1454, 1360, 1075, 992, 895. H-NMR
(2R,3R,4S,5S,6S)-3,4-Bis(benzyloxy)-2-[(benzyl-
400 MHz, CDCl ): 7.41–7.23 (15 H, m); 4.99 (1 H, d, J= oxy)methyl]-5-(ethynyloxy)-6-(prop-2-en-1-yl)ox-
3
1
1.5), 4.87(2 H, br. s), 4.85 (1 H, d, J=10.8), 4.80 (1 H, d, ane (22). A solution of alcohol 19 (1.0 g, 2.1 mmol) in
J=11.5), 4.67 (1 H, d, J=12.3), 4.65 (1 H, d, J=10.8), Et O (10 mL) was added slowly by cannula to a
2
4
.61 (1 H, d, J=12.3), 3.78 (1 H, dd, J=11.0, 2.0), 3.72 suspension of KH (200 mg, 4.99 mmol) in Et O (20 mL)
2
(
3
1 H, dd, J=11.0, 4.3), 3.65 (1 H, dd, J=9.6, 9.0), 3.57– at room temperature. The mixture was stirred for
.51 (1 H, m); 3.46 (1 H, ddd, J=9.6, 4.3, 2.0), 3.41–3.28 10 min and then cooled to 0°C. Freshly distilled
(2 H, m); 2.58 (1 H, dd, J=15.0, 2.3), 2.20 (1 H, dd, J= trichloroethene (320 mg, 2.44 mmol) in Et O (2 mL)
2
1
3
1
5.0, 7.6), 2.19 (1 H, d, J=0.9), 1.84 (3 H, s). C-NMR was added dropwise to the solution. The mixture was
(
100 MHz, CDCl ): 143.2; 138.7; 138.4; 138.2; 128.7; allowed to warm to room temperature and stirred for
3
1
1
4
4
28.5; 128.4 (CH); 128.0 (CH); 127.9; 127.9; 127.8; 127.6; 1 h. The solution was cooled to À 78°C, and BuLi
12.6; 86.9; 79.2; 78.5; 78.2; 75.3; 74.8; 74.3; 73.5; 69.1; (2.5 mL of a 2.5 M solution in hexanes, 6.3 mmol) was
+
+
0.3; 23.3. HR-EI-MS: 488.2538 (M , C H O ; calc. added dropwise. The mixture was stirred at À 78°C for
31 36 5
+
88.2563). EI-MS: 488 (1, M ), 397 (60), 235 (14), 181 30 min, then allowed to warm to À 40°C and stirred at
(35), 91 (100), 51 (16).
that temperature for 45 min. The reaction was
quenched by the addition of methanol (5 mL) and the
(2S,3S,4R,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyl-
mixture was poured into a saturated solution of NH Cl
4
oxy)methyl]-2-(but-3-en-1-yl)oxan-3-ol (21). Crude (50 mL). The mixture was extracted with Et O (50 mL)
2
epoxide 18 (6.4 g, 15 mmol) was dissolved in dry THF and the organic extract was washed with brine
(
150 mL) and the solution was cooled to À 20°C. 3- (50 mL) and then dried (MgSO ). The solvent removed
4
Butenylmagnesium bromide (30 mL of a 0.50 M solu- in vacuo and the residue was purified by flash column
tion in THF, 60 mmol) was added dropwise and the chromatography over silica gel (Et O/hexane 1:9 with
2
mixture was stirred for 3 h. The reaction was quenched 1% Et N) to give alkyne 22 (960 mg, 91%) as a
3
2
0
by the addition of a saturated solution of NH Cl colourless oil. R 0.45 (Et O/hexane 1:9). [α] = +24.9
4
f
2
D
(
100 mL), and the resulting mixture was extracted with (c=0.950 in CHCl ). IR (CHCl ) 3322, 2869, 2154, 1642,
3 3
1
dichloromethane (3×150 mL). The organic extracts 1454, 1095, 996, 913. H-NMR (500 MHz, CDCl ): 7.40 (2
3
were combined and dried (MgSO ) and the solvent H, dd, J=7.3, 1.2); 7.35–7.23 (6 H, m); 7.18–7.15 (2 H,
4
was removed in vacuo. The resulting residue was m); 5.91 (1 H, dddd, J=17.4, 10.5, 7.1, 7.1); 5.21 (1 H,
purified by flash column chromatography over silica dd, J=17.4, 1.3); 5.13 (1 H, d, J=10.5); 4.96 (1 H, d, J=
gel (1:1 Et O/hexane) to give the alcohol 21 (2.1 g, 10.6); 4.81 (1 H, d, J=10.8); 4.79 (1 H, d, J=10.8); 4.59
2
3
3%) as a white solid. R =0.62 (Et O/hexane 1:1). (1 H, d, J=12.2); 4.55 (1 H, d, J=10.6); 4.53 (1 H, d, J=
f 2
2
3
M.p.=60–62°C. [α] = +24.8 (c=1.01 in CHCl ). IR 12.2); 3.90 (1 H, dd, J=9.0, 8.8); 3.85 (1 H, dd, J=9.6,
D
3
(
CHCl ): 3516, 2868, 1640, 1603, 1454, 1076, 996, 912. 9.0); 3.71 (1 H, dd, J=11.2, 2.0); 3.65 (1 H, dd, J=11.2,
H-NMR (400 MHz, CDCl ): 7.29–7.14 (15 H, m); 5.75 (1 4.4); 3.61 (1 H, dd, J=9.8, 8.8); 3.53 (1 H, ddd, J=9.6,
3
1
3
H, dddd, J=17.0, 10.2, 6.7, 6.7); 4.96 (1 H, dddd, J= 7.1, 3.2); 3.41 (1 H, ddd, J=9.8, 4.4, 2.0); 2.68–2.63 (1 H,
1
4
7.0, 1.7, 1.7, 1.7); 4.88 (1 H, dddd, J=10.2, 1.7, 1.3, 1.3); m); 2.40 (1 H, dt, J=14.5, 7.1); 1.63 (1 H, s). 13C-NMR
.60 (1 H, d, J=11.7); 4.55 (1 H, d, J=11.4); 4.51 (1 H, d, (125 MHz, CDCl ): 138.2; 138.0; 133.3; 128.5; 128.4;
3
J=11.7); 4.50 (1 H, d, J=12.1); 4.49 (1 H, d, J=11.4); 128.3; 128.0; 127.9; 127.8; 127.7; 118.3; 89.0; 88.0; 83.2;
4
3
3
3
2
5
.44 (1 H, d, J=12.1); 3.92 (1 H, ddd, J=5.5, 5.1, 4.4); 79.0; 78.1; 76.4; 75.4; 75.2; 73.5; 68.7; 35.6; 28.3. HR-CI–
+
+
.81 (1 H, dt, J=9.6, 3.9); 3.72 (1 H, dd, J=10.2, 5.7); MS (isobutane): 499.2473 ([M+H] , C H O ; calc.
32 35 5
.66 (1 H, t, J=5.7); 3.63 (1 H, dd, J=10.2, 5.1); 3.60– 499.2484).
.53 (2 H, m); 2.74 (1 H, d, J=7.9); 2.19–2.08 (1 H, m);
.07–1.96 (1 H, m); 1.71 (1 H, dddd, J=14.2, 9.3, 9.3,
(4-{(4aS,6R,7R,8S,8aS)-7,8-Bis(benzyloxy)-6-
.5); 1.58 (1 H, dddd, J=14.2, 9.6, 6.8, 4.4). 13C-NMR [(benzyloxy)methyl]-4,4a,6,7,8,8a-hexahydropyra-
(
125 MHz, CDCl ): 142.1; 141.9; 141.8; 141.3; 132.3; no[3,2-b]pyran-2-yl}but-1-en-2-yl)(trimethyl)silane
3
1
32.3; 132.2; 131.7; 131.5; 132.4; 131.4; 118.6; 82.1; (27).
A
mixture of copper bromide (213 mg,
8
1.2; 80.9; 80.7; 79.1; 76.8; 75.1; 73.6; 72.1; 33.4; 31.0. 1.50 mmol) and lithium bromide (140 mg, 1.50 mmol)
www.helv.wiley.com (8 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
was dried at 60°C for 4 h under high vacuum suspension was cooled to À 90°C and the Grignard
(
<1 mbar) and then suspended in THF (10 mL). The reagent 24 (7.2 mL of a 0.5 M solution in THF,
suspension was cooled to À 90°C and the Grignard 3.6 mmol) was added dropwise over a period of 5 min.
reagent 23 (3.0 mL of a 0.50 M solution in THF, The resulting mixture was stirred at À 90°C for 5 min.
1
.5 mmol) was added dropwise over a period of 5 min. A solution of the alkynyl ether 22 (1.5 g, 3.0 mmol) in
The resulting solution was stirred at À 90°C for 5 min. THF (20 mL) was added dropwise over 5 min at
A solution of the alkynyl ether 22 (500 mg, 1.00 mmol) À 90°C, and the mixture was allowed to warm to
in THF (10 mL) was added dropwise over 5 min at À 78°C then stirred for a further 30 min. The reaction
À 90°C and the mixture was warmed to À 78°C then was quenched by the addition of a 10% aqueous
stirred for a further 30 min. The reaction was solution of NH OH (50 mL) and the mixture was
4
quenched by the addition of a 10% aqueous solution extracted with Et O (2×120 mL). The combined organ-
2
of NH OH (50 mL) and the mixture was extracted with ic extracts were dried (MgSO ) and the solvent
4
4
Et O (2×50 mL). The combined organic extracts were removed in vacuo. The residue was purified by flash
2
dried (MgSO ) and the solvent was removed in vacuo. column chromatography over silica gel (hexane!
4
The residue was purified by flash column chromatog- Et O/hexane 1:20 with 1% Et N) to afford enol ether
2
3
raphy over silica gel (hexane!Et O/hexane 20:1 with 26 (1.81 g, 86%) as a colourless oil. R 0.49 (Et O/
2
f
2
1
% Et N) to afford enol ether 25 (530 mg, 84%) as a hexane 1:9). The unstable enol ether was used
3
colourless oil. R 0.45 (Et O/hexane 1:9). The unstable immediately in the subsequent RCM reaction.
f
2
enol ether was used immediately in the subsequent
RCM reaction.
A solution of alkene 26 (1.8 g, 2.6 mmol) in toluene
(130 mL) was added to a solution of ruthenium
A solution of alkene 25 (530 mg, 0.84 mmol) in catalyst 14 (110 mg, 130 μmol) in toluene (130 mL) at
toluene (50 mL) was added to a solution of ruthenium room temperature under an atmosphere of argon. The
complex 14 (40 mg, 46 μmol) in toluene (50 mL) at solution was heated to 80°C and stirred at this
room temperature under an atmosphere of argon. The temperature for 4 h. The solvent was removed in vacuo
solution was heated to 80°C and stirred at this and the crude product was purified by flash column
temperature for 4 h. The solvent was removed in vacuo chromatography over silica gel (Et O/hexane 1:7 with
2
and the crude product was purified by flash column 1% Et N) to give cyclic enol ether 28 (1.6 g, 91%) as
3
20
chromatography over silica gel (Et O/hexane 1:20! colourless oil. R =0.45 (Et O/hexane 1:1). [α]
=
2
f
2
D
1
(
1
2
:10 with 1% Et N) to give cyclic enol ether 27 þ44:7 (c=1.01 in CHCl ). IR (CHCl ): 2912, 2863, 1678,
3
3
3
1
432 mg, 86%) as colourless oil. R =0.42 (Et O/hexane 1454, 1028, 998, 910, 834. H-NMR (500 MHz, CDCl ):
f
2
3
2
0
:9). [α]D = +39.0 (c=1.05 in CHCl ). IR (CHCl ): 7.79–7.74 (2 H, m); 7.66–7.62 (2 H, m); 7.61–7.48 (14
3 3
913, 2862, 1678, 994, 862, 839. H-NMR (500 MHz, H, m); 7.44–7.40 (2 H, m); 6.00 (1 H, d, J=1.0); 5.73 (1
1
CDCl ): 7.61–7.58 (2 H, m); 7.54–7.40 (11 H, m); 7.37– H, s); 5.26 (1 H, d, J=11.3); 5.15 (1 H, d, J=10.8); 5.04
3
7
5
.33 (2 H, m); 5.79–5.76 (1 H, m); 5.54 (1 H, d, J=2.7); (1 H, d, J=11.3); 4.86 (1 H, d, J=12.3); 4.79 (1 H, d, J=
.24 (1 H, d, J=11.2); 5.07 (1 H, d, J=10.8); 5.00 (1 H, d, 12.3); 4.79 (1 H, d, J=10.8); 4.62 (1 H, d, J=4.5); 4.03–
J=11.2); 4.79 (1 H, d, J=12.3); 4.72 (1 H, d, J=12.3); 3.93 (2 H, m); 3.95 (1 H, dd, 10.8, 4.5); 3.90 (1 H, t, J=
4
.71 (1 H, d, J=10.8); 4.66 (1 H, dd, J=3.5, 1.9); 3.98– 9.3); 3.86 (1 H, t, J=9.3); 3.82–3.76 (1 H, m); 3.68 (1 H,
.78 (5 H, m); 3.74 (1 H, ddd, J=9.7, 4.5, 1.9); 3.68–3.62 ddd, J=9.5, 9.5, 6.3); 2.65–2.60 (2 H, m); 2.57 (1 H, dt,
3
(
1 H, m); 2.60–2.48 (3 H, m); 2.43–2.31 (3 H, m); 0.28 (9 J=16.0, 5.9) 2.43–2.32 (3 H, m); 0.65 (6 H, s). 13C-NMR
1
3
H, s). C-NMR (125 MHz, CDCl ): 153.6; 151.4; 138.9; (125 MHz, CDCl ): 153.1; 149.2; 138.7; 138.2; 138.0;
3
3
1
1
6
38.4; 138.2; 128.5; 128.2; 128.1; 128.1; 127.8; 127.8; 133.8; 128.9; 128.2; 127.9; 127.8; 127.8; 127.7; 127.5;
24.4; 93.5; 84.5; 79.6; 79.1; 77.6; 75.3; 75.2; 73.6; 72.5; 127.5; 126.3; 93.3; 84.1; 79.2; 78.8; 77.4; 75.0; 74.9; 73.4;
9.3; 33.5; 27.5; À 1.2.
72.1; 69.0; 33.2; 33.0; 27.2; À 3.0.
(
4-{(4aS,6R,7R,8S,8aS)-7,8-Bis(benzyloxy)-6-
(2S,4aS,6R,7R,8S,8aS)-7,8-Bis(benzyloxy)-6-
[(benzyloxy)methyl]-2-(but-3-en-1-yl)octahydropy-
[
(benzyloxy)methyl]-4,4a,6,7,8,8a-hexahydropyra-
no[3,2-b]pyran-2-yl}but-1-en-2-yl)(dimethyl)phenyl- rano[3,2-b]pyran-2-ol (29a) and (2R,4aS,6R,7R,8S,
silane (28). A mixture of copper bromide (520 mg, 8aS)-7,8-Bis(benzyloxy)-6-[(benzyloxy)methyl]-2-
3
.60 mmol) and lithium bromide (320 mg, 3.60 mmol) (but-3-en-1-yl)octahydropyrano[3,2-b]pyran-2-ol
was dried at 60°C for 4 h under high vacuum (29b). A solution of thexylborane (30 mL of a 0.50 M
(
<1 mbar) and then suspended in THF (20 mL). The solution in THF, 15 mmol) was added dropwise to the
www.helv.wiley.com (9 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
enol ether 28 (1.6 g, 2.4 mmol) in THF (50 mL) at NMR (500 MHz, CDCl ): 7.40–7.20 (13 H, m); 7.13–7.08
3
À 20°C. The mixture was stirred at À 20°C for 30 min (2 H, m); 5.85 (1 H, dddd, J=16.9, 10.2, 6.6, 6.6); 5.06 (1
and then warmed to 0°C. After a further 30 min, the H, dq, J=16.9, 1.6); 5.05 (1 H, d, J=11.0); 5.01 (1 H, ddt,
ice bath was removed, and the mixture stirred for 1 h. J=10.2, 1.6, 1.1); 4.85 (1 H, d, J=10.8); 4.77 (1 H, d, J=
The reaction was quenched by the slow addition of 11.0); 4.61 (1 H, d, J=12.3); 4.53 (1 H, d, J=12.3); 4.47
methanol (5 mL). After 5 min, pH 7 buffer (20 mL) and (1 H, d, J=10.8); 3.91–3.85 (2 H, m); 3.72 (1 H, dd, J=
NaBO (1.64 g, 20 mmol) were added, and the mixture 10.7, 2.0); 3.68 (1 H, t, J=9.5); 3.67 (1 H, dd, J=10.9,
3
was agitated vigorously for 3 h. AcOEt (100 mL) was 4.0); 3.61 (1 H, t, J=9.7); 3.58–3.49 (2 H, m); 3.40 (1 H,
added, and the solution was washed with brine (2× t, J=9.3); 2.35–2.27 (1 H, m); 2.23–2.14 (2 H, m); 1.99
5
0 mL). The aqueous washings were extracted with (1 H, dddd, J=14.0, 10.8, 8.9, 5.3); 1.88 (1 H, br. s); 1.85
AcOEt (2×100 mL), and the combined organic extracts (1 H, ddd, J=13.5, 12.0, 2.8); 1.58–1.50 (1 H, m). 13C-
were dried (MgSO ) and the solvent was removed in NMR (100 MHz, CDCl ): 138.9; 138.2; 138.0; 137.6;
4
3
vacuo. The residue was dissolved in AcOEt (200 mL) 128.5; 128.4; 128.4; 128.1; 128.1; 128.1; 127.8; 127.8;
and filtered through a plug of silica. The solvent was 127.7; 116.7; 84.3; 79.4; 77.8; 77.7; 77.4; 75.4; 75.3; 74.7;
removed in vacuo and the residue was dissolved in 73.5; 71.3; 69.7; 69.0; 32.7; 29.5; 27.8. HR-EI-MS:
+
+
neat trifluoroacetic acid (5 mL) and stirred for 2 min. 544.2845 (M , C H O ; calc. 544.2825). EI-MS: 544
34 40 6
+
The acid was neutralised by slow addition of a (11, M ), 543 (37), 181 (8), 91 (100). Anal. calc. for
saturated aqueous solution of K CO and the aqueous C H O : C 74.97, H 7.40; found: C 75.19, H 7.32.
2
3
34 40 6
mixture was extracted with Et O (3 × 100 mL). The
2
combined organic extracts were dried (MgSO ), and
Synthesis of Compound 29a from 29b. Solid Dess–
4
the solvent was removed in vacuo. The residue was Martin periodinane (18 mg, 0.43 mmol) was added in
purified by flash column chromatography over silica three portions over 1 h to a solution of alcohol 29b
gel (Et O/hexane 1:4!4:6) to give the alcohol 29a (20 mg, 0.036 mmol) in dichloromethane (2 mL). The
2
(805 mg, 62%) as a white solid. Further elution gave mixture was poured into NaOH (3 M, 5 mL) and stirred
the alcohol 29b (145 mg, 11%) as a white solid.
for 1 h. Dichloromethane (20 mL) was added and the
organic phase was separated and washed with brine
Data for 29a. R =0.28 (Et O/hexane 1:1). M.p.= (10 mL). The organic phase was dried (MgSO ) and the
f
2
4
1
7
8
3
(
0–81°C. [α] =À 7.3 (c=1.01 in CHCl ). IR (CHCl ): solvent removed in vacuo. The residue was purified by
D
3
3
1
617, 3869,1640, 1604, 1454, 996, 913. H-NMR flash column chromatography over silica gel (Et O/
2
500 MHz, CDCl ): 7.51–7.47 (2 H, m); 7.46–7.46 (11 H, hexane 1:1) to afford ketone (16.4 mg, 82%). R =0.72
3
f
2
1
m); 7.26–7.23 (2 H, m); 5.97 (1 H, ddd, J=16.9, 10.2, (Et O/hexane 1:1). M.p.=61–62°C. [α]
+1.93 (c=
2
D
6
.6); 5.18–5.13 (1 H, m); 5.13 (1 H, d, J=10.9); 5.09 (1 1.05 in CHCl ). IR (CHCl ): 2869, 1726, 1641, 1454, 1363,
3 3
1
H, d, J=10.2); 4.97 (1 H, d, J=10.7); 4.88 (1 H, d, J= 1097, 996, 909. H-NMR (500 MHz, CDCl ): 7.44–7.27
3
1
0.9); 4.71 (1 H, d, J=12.2); 4.64 (1 H, d, J=12.2); 4.60 (13 H, m); 7.20–7.16 (2 H, m); 5.84 (1 H, dddd, J=17.0,
(1 H, d, J=10.7); 3.82 (1 H, dd, J=10.7, 1.7); 3.76 (1 H, 10.3, 6.7, 6.7); 5.10–5.02 (3 H, m); 4.92 (1 H, d, J 10.7);
dd, J=10.7, 4.9); 3.74 (1 H, dd, J=8.8, 8.4); 3.67 (1 H, 4.85 (1 H, d, J=11.0); 4.63 (1 H, d, J=12.2); 4.56 (1 H, d,
dd, J=9.2, 8.8); 3.60 (1 H, ddd, J=9.4, 4.9, 1.7); 3.48 (1 J=12.2); 4.55 (1 H, d, J=11.0); 3.85 (1 H, dd, J=8.6,
H, ddd, J=10.7, 9.5, 4.7); 3.28 (1 H, dd, J=9.4, 9.2); 3.6); 3.79–3.68 (4 H, m); 3.60–3.51 (3 H, m); 3.02 (1 H,
3
2
.26–3.21 (2 H, m); 2.56 (1 H, ddd, J=11.8, 4.3, 4.3); dd, J=16.1, 5.3); 2.59 (1 H, dd, J=16.1, 10.7); 2.34–2.17
.51–2.42 (1 H, m); 2.35–2.25 (1 H, m); 2.08 (1 H, dddd, (2 H, m); 2.09–2.01 (1 H, m); 1.73 (1 H, dddd, J=14.1,
1
3
J=16.3, 7.4, 7.0, 2.2); 1.85 (1 H, br. s); 1.70–1.58 (2 H, 8.9, 8.5, 5.3). C-NMR (100 MHz, CDCl ): 204.9; 138.6;
m). C-NMR (125 MHz, CDCl ): 138.8; 138.3; 138.2; 138.1; 137.9; 137.6; 128.4; 128.0; 128.0; 127.9; 127.8;
3
1
3
3
1
1
6
38.0; 128.4; 128.1; 128.0; 127.9; 127.8; 127.7; 127.7; 127.8; 115.6; 84.0; 82.0; 81.4; 79.2; 77.4; 75.3; 75.3; 74.3;
+
15.0; 84.1; 82.2; 81.2; 79.2; 77.6; 75.3; 75.1; 73.9; 73.5; 73.6; 68.9; 45.0; 29.4; 28.4. HR-EI-MS: 542.2680 (M ,
+
+
+
9.7; 69.2; 38.8; 31.1; 29.8. HR-EI-MS: 544.2833 (M , C H O ; calc. 542.2668). EI-MS: 542 (8), 181 (8, M ),
34 38 6
+
+
C H O ; calc. 544.2825). EI-MS: 544 (1, M ), 454 (42), 91 (100).
3
4 40 6
3
63 (6), 209 (19), 181 (26), 91 (100) 65 (18). Anal. calc.
for C H O : C 74.97, H 7.40; found C 75.16, H 7.35.
(2R,3R,4S,5S,6S)-3,4-Bis(benzyloxy)-2-[(benzyl-
3
4 40 6
oxy)methyl]-5-(ethynyloxy)-6-(2-methylprop-2-en-
Data for 29b. R =0.18 (Et O/hexane 1:1). M.p.= 1-yl)oxane (30). A solution of alcohol 20 (1.0 g,
f
2
2
3
9
3
2–93°C. [α]D = +15.3 (c=0.63 in CHCl ). IR (CHCl ): 2.1 mmol) in Et O (10 mL) was added by cannula to a
3
3
2
1
612, 2926, 2869, 1640, 1454, 1364, 1088, 996, 913. H- suspension of KH (180 mg, 4.5 mmol) in Et O (20 mL)
2
www.helv.wiley.com (10 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
at room temperature. The mixture was stirred for was extracted with Et O (2×50 mL). The combined
2
1
0 min and then cooled to 0°C. Freshly distilled organic extracts were dried (MgSO ) and the solvent
4
trichloroethene (320 mg, 2.40 mmol) in Et O (2 mL) was removed in vacuo. The residue was purified by
was added dropwise to the solution. The mixture was flash column chromatography over silica gel
2
allowed to warm to room temperature and stirred for (hexane!Et O/hexane 1:20 with 1% Et N) to afford
2
3
1
h. The solution was then cooled to À 78°C and BuLi the enol ether 31 (530 mg, 84%) as a colourless oil.
(2.5 mL of a 2.5 M solution in hexanes, 6.3 mmol) was R =0.53 (Et O/hexane 1:9). The unstable enol ether
f 2
added dropwise. The mixture was stirred at this was used immediately in the subsequent RCM reac-
temperature for 30 min and then allowed to warm to tion.
À 40°C and stirred for 45 min. The reaction was
quenched by the addition of methanol (5 mL), and the
resulting mixture was poured into a saturated solution toluene (30 mL) was added a solution of ruthenium
A solution of alkene 31 (0.45 g, 0.67 mmol) in
of NH Cl (50 mL). The mixture was extracted with Et O complex 14 (29 mg, 34 μmol) in benzene (40 mL) at
4
2
(50 mL), and the organic phase was washed with brine room temperature under an atmosphere of argon, and
(
50 mL) and then dried (MgSO ). The solvent was the mixture was heated at reflux for 4 h. The solvent
4
removed in vacuo, and the residue was purified by was removed in vacuo and the residue was purified by
flash column chromatography over silica gel (Et O/ flash column chromatography over silica gel (Et O/
2
2
hexane 1:9 with 1% Et N) to give the alkynyl ether 30 hexane 1:7 with 1% Et N) to give a complex mixture
3
3
(
960 mg, 91%) as a colourless oil. R =0.50 (Et O/ of products (323 mg) as colourless oil.
f 2
2
0
hexane 1:9). [α]D = +30.6 (c=0.960 in CHCl ). IR
3
(
1
CHCl ): 3322, 2959, 2917, 2871, 2154, 1454, 1650,
A solution of thexylborane (5.0 mL of a 0.50 M
3
1
361, 1094, 999, 897. H-NMR (500 MHz, CDCl ): 7.51 (2 solution in THF, 2.5 mmol) was added dropwise to the
3
H, d, J=7.1); 7.45–7.34 (11 H, m); 7.31–7.27 (2 H, m); mixture of enol ethers (0.32 g, 0.47 mmol) in THF
5
1
.08 (1 H, d, J=10.6); 4.97 (2 H, br. s); 4.92 (1 H, d, J= (5 mL) at À 20°C. The mixture was stirred at À 20°C for
0.8); 4.91 (1 H, d, J=10.6); 4.68 (1 H, d, J=12.2); 4.67 30 min, then warmed to 0°C. After a further 30 min,
(1 H, d, J=10.8); 4.64 (1 H, d, J=12.2); 4.04 (1 H, t, J= the ice bath was removed, and the mixture was stirred
9
3
.0); 3.92 (1 H, t, J=9.4); 3.81 (1 H, dd, J=11.0, 1.7); for 1 h. The reaction was quenched by the slow
.77–3.70 (3 H, m); 3.50 (1 H, ddd, J=9.8, 4.4, 1.7); 2.71 addition of methanol (1 mL). After 5 min, pH 7 buffer
(
(
1 H, dd, J=14.6, 0.9); 2.41 (1 H, dd, J=14.6, 7.7); 1.91 (5 mL) and NaBO (430 mg, 5 mmol) were added, and
3
1
3
3 H, s); 1.74 (1 H, s). C-NMR (125 MHz, CDCl ): 141.8; the mixture was agitated vigorously for 3 h. AcOEt
3
1
1
7
5
38.3; 138.2; 138.1; 128.5; 128.4; 128.3; 128.0; 127.9; (50 mL) was added and the solution was washed with
27.7; 127.6; 113.3; 88.9; 88.4; 83.2; 79.1; 78.2; 76.1; brine (2×25 mL). The aqueous washings were ex-
5.5; 75.2; 73.5; 68.8; 39.4; 28.5; 23.4. HR-EI-MS: tracted with AcOEt (2×50 mL). The combined organic
+
+
12.2583 (M , C H O ; calc. 512.2563). EI-MS: 512 extracts were dried (MgSO ) and the solvent was
33
36
5
4
+
(1, M ), 415 (2), 181 (6), 131 (8), 91 (100).
removed in vacuo. The residue was dissolved in AcOEt
(100 mL) and filtered through a plug of silica. The
(
2S,3R,4aS,6R,7R,8S,8aS)-7,8-Bis(benzyloxy)-6-
solvent was removed in vacuo and the residue was
dissolved in neat trifluoroacetic acid (2 mL) and stirred
[
(benzyloxy)methyl]-2-(but-3-en-1-yl)-3-methyl-
octahydropyrano[3,2-b]pyran-3-ol (32). A mixture of for 2 min. The acid was neutralised by slow addition of
copper bromide (213 mg, 1.50 mmol) and lithium a saturated solution of K CO and the aqueous mixture
2
3
bromide (140 mg, 1.50 mmol) was dried at 60°C for was extracted with Et O (3×50 mL). The combined
2
4
h under high vacuum (<1 mbar) and then sus- organic extracts were dried (MgSO ) and the solvent
4
pended in THF (10 mL). The suspension was cooled to was removed in vacuo. The residue was purified by
À 90°C and the Grignard reagent 24 (3.0 mL of a flash column chromatography over silica gel (Et O/
2
0
.50 M solution in THF, 1.5 mmol) was added dropwise hexane 1:4!3:6) to give the alcohol 32 (81 mg, 22%
over a period of 5 min. The resulting mixture was over two steps) as a clear oil. R =0.32 (Et O/hexane
f
2
2
4
stirred at À 90°C for 5 min. A solution of the alkynyl 1:1). [α]D = +9.3 (c=0.85 in CHCl ). IR (CHCl ): 3610,
3
3
1
ether 30 (500 mg, 1.00 mmol) in THF (10 mL) was 2926, 2856, 1640, 1073, 997, 943, 912. H-NMR
added dropwise at À 90°C and the mixture was (500 MHz, CDCl ): 7.33–7.22 (13 H, m); 7.12–7.09 (2 H,
3
warmed to À 78°C then stirred for a further 30 min. m); 5.81 (1 H, dddd, J=16.9, 10.2, 6.6, 6.6); 5.01 (1 H, d,
The reaction was quenched by the addition of a 10% J=11.2); 5.02–4.97 (1 H, m); 4.95 (1 H, d, J=10.2); 4.83
aqueous solution of NH OH (50 mL) and the mixture (1 H, d, J=10.8); 4.74 (1 H, d, J=11.2); 4.55 (1 H, d, J=
4
www.helv.wiley.com (11 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
1
2.2); 4.50 (1 H, d, J=12.2); 4.44 (1 H, d, J=10.8); 3.67 129.1; 128.4; 128.3; 128.2; 128.0; 127.8; 127.7; 127.6;
(1 H, dd, J=10.7, 1.4); 3.61 (1 H, t, J=8.4); 3.60 (1 H, dd, 117.2; 111.5; 87.7; 86.2; 79.7; 79.1; 79.0; 78.0; 75.2; 73.5;
J=10.7, 5.2); 3.52 (1 H, dd, J=9.8, 8.4); 3.46 (1 H, ddd, 69.1; 35.8; 22.6; À 2.1; À 2.6.
J=9.8, 4.7, 1.5); 3.18–3.12 (2 H, m); 3.10 (1 H, dd, J=
9
2
1
.6, 4.2); 2.38–2.29 (1 H, m); 2.20 (1 H, dd, J=11.3, 4.2);
.17–2.08 (1 H, m); 1.79–1.71 (1 H, m); 1.62 (1 H, t, J= [(benzyloxy)methyl]-4,4a,6,7,8,8a-hexahydropyra-
(3-{(4aS,6R,7R,8S,8aS)-7,8-Bis(benzyloxy)-6-
1.3); 1.66–1.53 (1 H, m); 1.49–1.40 (1 H, m); 1.19 (3 H, no[3,2-b]pyran-2-yl}prop-1-en-2-yl)(dimethyl)phe-
13
s). C-NMR (125 MHz, CDCl ): 138.8; 138.3; 138.2; nylsilane (34). A solution of the alkene 33 (202 mg,
3
1
1
7
38.1; 128.4; 128.0; 128.0; 128.0; 127.8; 127.7; 127.7; 0.299 mmol) in toluene (15 mL) was added to a
15.1; 84.2; 83.8; 83.3; 79.4; 77.7; 75.3; 75.1; 73.9; 73.5; solution of ruthenium catalyst 14 (37 mg, 23 μmol) in
0.9; 69.2; 45.6; 30.9; 27.8; 21.7. HR-EI-MS: 558.2989 benzene (15 mL) at room temperature under an
+
+
+
(
M , C H O ; calc. 558.2981). EI-MS: 558 (3, M ), atmosphere argon. The solution was heated at 80°C
34 42 6
3
63 (12), 209 (25), 181 (23), 91 (100) 65 (15).
for 4 h. The solvent was removed in vacuo and the
crude product was purified by flash column chroma-
(
4-{[(2S,3S,4S,5R,6R)-4,5-Bis(benzyloxy)-6-[(ben-
tography over silica gel (Et O/hexane 1:9 with 1%
2
zyloxy)methyl]-2-(prop-2-en-1-yl)oxan-3-yl]oxy}-
penta-1,4-dien-2-yl)(dimethyl)phenylsilane
Et N) to give cyclic enol ether 34 (146 mg, 76%) as
3
23
(33). colourless oil. R =0.70 (Et O/hexane, 2:8). [α] =
f
2
D
Copper cyanide (34 mg, 0.38 mmol) was dried at 60°C +14.2 (c=0.950 in CHCl ). IR (CHCl ): 2950, 2869,
3
3
1
for 4 h under high vacuum (<1 mbar) and then 1460, 1090. H-NMR (500 MHz, CDCl ): 7.48–7.45 (2 H,
3
suspended in THF (5 mL). The suspension was cooled m); 7.37–7.34 (2 H, m); 7.31–7.22 (14 H, m); 7.13–7.09
to À 78°C and lithium dimethylphenylsilane (0.75 mL (2 H, m); 5.27 (1 H, d, J=0.9); 5.06 (1 H, d, J=11.1); 4.84
of a 1.0 M solution in THF, 0.75 mmol) was added (1 H, d, J=10.7); 4.81 (1 H, d, J=11.1); 4.77 (1 H, dd, J=
dropwise and the resulting solution stirred at À 78°C 5.3, 2.4); 4.69 (1 H, br. s); 4.57 (1 H, d, J=12.2); 4.52 (1
for 30 min. Allene (1.5 mL of a 2.0 M solution in THF, H, d, J =12.2); 4.48 (1 H, d, J=10.7); 3.75 (1 H, dd, J=
3
.0 mmol) was added and the mixture was warmed to 8.8, 8.8); 3.69 (1 H, dd, J=10.7, 1.5); 3.64 (1 H, dd, J=
À 30°C for 30 min. The mixture was cooled to À 78°C 10.7, 4.7); 3.59 (1 H, dd, J=9.5, 9.0); 3.50 (1 H, dd, J=
and the alkyne 22 (250 mg, 0.501 mmol) in THF 9.4, 9.1); 3.48–3.51 (1 H, m); 3.37 (1 H, ddd, J=9.6, 9.5,
(
10 mL) was added dropwise over 5 min at À 78°C. The 6.4); 2.30 (1 H, ddd, J=17.2, 6.4, 5.3); 2.11 (1 H, ddd, J=
mixture was stirred for a further 10 min, and the 17.2, 9.6, 2.4); 1.91 (1 H, d, J=14.0); 1.86 (1 H, d, J=
reaction was quenched by the addition of a 10% 14.0); 0.27 (6 H, s). C-NMR (125 MHz, CDCl ): 151.9;
1
3
3
aqueous solution of NH OH (20 mL). The mixture was 138.9; 138.9; 138.8; 138.3; 138.0; 134.9; 133.7; 129.3;
4
extracted with Et O (2×50 mL), and the combined 129.1; 128.4; 128.1; 128.1; 128.0; 127.7; 110.1; 97.5;
2
organic extracts were dried (MgSO ). The solvent was 84.4; 79.4; 78.9; 77.5; 75.3; 75.2; 73.6; 69.1; 27.9; 22.5;
4
removed in vacuo, and the residue was purified by À 2.9; À 3.0.
flash column chromatography over silica gel
(
hexane!Et O/hexane 1:10 with 1% Et N) to afford
(2R,3R,4S,5S,6S)-3,4-Bis(benzyloxy)-2-[(benzyl-
2
3
enol ether 33 (242 mg, 73%) as a colourless oil. R 0.65 oxy)methyl]-6-(but-3-en-1-yl)-5-(ethynyloxy)oxane
f
2
3
(
(
Et O/hexane 1:9). [α] = +2.5 (c=0.56 in CHCl ). IR (36). A solution of alcohol 21 (1.5 g, 3.0 mmol) in Et O
2 D 3 2
CHCl ): 2232, 2922, 2155, 1095. H-NMR (500 MHz, (10 mL) was added by cannula to a suspension of KH
1
3
CDCl ): 7.50–7.48 (2 H, m); 7.35–7.22 (15 H, m); 7.17– (0.28 g, 7.0 mmol) in Et O (15 mL) at room temper-
3
2
7
5
.14 (2 H, m); 5.90 (1 H, dddd, J=17.1, 10.3, 6.9, 6.9); ature. The mixture was stirred for 10 min and then
.46 (1 H, d, J=1.8); 5.10–5.03 (2 H, m); 4.81 (1 H, d, cooled to 0°C. A solution of freshly distilled trichloro-
J=10.9); 4.78 (1 H, d, J=10.7); 4.77 (1 H, br. s); 4.64 (1 ethene (0.48 g, 3.7 mmol) in Et O (5 mL) was added
H, d, J=10.7); 4.62 (1 H, d, J=11.2); 4.58 (1 H, br. s); dropwise and the mixture was allowed to warm to
2
4
.56 (1 H, d, J=11.2); 4.54 (1 H, d, J=10.9); 4.46 (1 H, d, room temperature then stirred for 1 h. The mixture
J=2.8); 4.02 (1 H, dd, J=9.1, 9.1); 3.73 (1 H, dd, J= was cooled to À 78°C and BuLi (4 mL of a 2.5 M
1
1
9
0.8, 1.2); 3.70 (1 H, t, J=9.1, 9.1); 3.67 (1 H, dd, J= solution in hexanes, 10.0 mmol) was added dropwise.
0.8, 4.2); 3.61 (1 H, dd, J=9.7, 9.1); 3.44 (1 H, ddd, J= The mixture was stirred at this temperature for 30 min
.7, 4.2, 1.2); 3.38 (1 H, ddd, J=9.1, 8.6, 2.8); 2.46–2.39 and then allowed to warm to À 40°C and stirred for
(1 H, m); 2.19 (1 H, ddd, J=14.7, 8.6, 6.9); 1.97 (2 H, s); 45 min. The reaction was quenched by the addition of
1
3
0
.28 (6 H, s). C-NMR (125 MHz, CDCl ): 159.7; 140.1; methanol (5 mL), and the resulting mixture was
3
1
39.1; 138.6; 138.4; 134.8; 134.1; 133.8; 133.7; 131.9; poured into a saturated solution of NH Cl (80 mL). The
4
www.helv.wiley.com (12 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
biphasic mixture was extracted with Et O (2×100 mL) J=12.7); 4.34 (1 H, d, J=12.2); 4.29 (1 H, d, J=10.8);
2
and the organic phases were combined and washed 4.18–4.05 (2 H, m); 3.89 (1 H, d, J=2.4); 3.75 (1 H, d,
with brine (100 mL) then dried (MgSO ). The solvent J=2.4); 3.66 (1 H, t, J=8.5); 3.55 (1 H, dd, J=10.5, 4.0);
4
was removed in vacuo, and the residue was purified by 3.53–3.41 (3 H, m); 2.20–2.11 (2 H, m); 2.10–1.93 (3 H,
flash column chromatography over silica gel (Et O/ m); 1.92–1.79 (1 H, m); 1.61 (1 H, dddd, J=14.4, 11.1,
2
hexane 1:9 with 1% Et N) with to give alkyne 36 9.3, 5.1); 1.44–1.31 (1 H, m); 0.19 (6 H, s); 13C-NMR
3
(
1
3
1.35 g, 86%) as a colourless oil. R =0.49 (Et O/hexane (101 MHz, CDCl ): 161.1; 149.6; 138.8; 138.3; 138.1;
f 2 3
2
1
:9). [α]D = +32.3 (c=1.85 in CHCl ). IR (CHCl ): 138.1; 138.0; 138.0; 134.0; 129.1; 128.5; 128.4; 128.4;
3 3
1
322, 2913, 2868, 2151, 1641, 1093, 996, 944, 912. H- 128.2; 128.0; 128.0; 128.0; 127.9; 127.8; 127.8; 127.7;
NMR (400 MHz, CDCl ): 7.31–7.13 (13 H, m); 7.08–7.04 125.9; 115.1; 82.6; 81.6; 77.9; 75.3; 75.1; 73.6; 71.6; 71.1;
3
(
2 H, m); 5.76 (1 H, dddd, J=17.0, 10.2, 6.6, 6.6); 4.98 (1 69.1; 34.9; 33.6; 29.4; 24.3; À 3.00. HR-ESI-MS: 725.3609
+ +
H, dddd, J=17.0, 1.7, 1.7, 1.7); 4.91 (1 H, dddd, J=10.2, ([M+Na] , C H NaO Si ; calc. 725.3633).
45
54
5
1
1
.7, 1.4, 1.4); 4.81 (1 H, d, J=10.8); 4.71 (1 H, d, J=
0.8); 4.64 (1 H, d, J=10.8); 4.52 (1 H, d, J=12.1); 4.40
(
1 H, d, J=12.1); 4.38 (1 H, d, J=10.8); 4.26–4.20 (2 H,
Acknowledgements
m); 3.76 (1 H, dd, J=8.3, 8.3); 3.60 (1 H, dd, J=10.5,
3
.8); 3.59–3.48 (3 H, m); 2.21–2.10 (1 H, m); 2.08–1.97 This work was supported by studentship funding from
(
(
1 H, m); 1.77–1.58 (2 H, m); 1.51 (1 H, s). 13C-NMR the University of Nottingham (F. E.) and funding from
125 MHz, CDCl ): 138.0; 137.9; 137.4; 128.4; 128.4; EPSRC (EP/R035423/1) to support a postdoctoral
3
1
7
28.1; 127.9; 127.8; 127.7; 115.4; 89.7; 87.5; 80.4; 77.5; researcher (V. C.).
5.2; 75.0; 73.5; 72.0; 71.4; 68.7; 29.0; 27.1; 24.1. HR-ESI-
+
+
MS: 535.2445 ([M+Na] , C H NaO ; calc. 535.2455).
33
36
5
Author Contribution Statement
(5-{[(2S,3S,4S,5R,6R)-4,5-Bis(benzyloxy)-6-[(ben-
zyloxy)methyl]-2-(but-3-en-1-yl)oxan-3-yl]oxy}-
hexa-1,5-dien-2-yl)(dimethyl)phenylsilane
J. S. C. conceived the synthetic routes, supervised the
(37). project and wrote the paper; J. S. C., F. E. and V. C.
Copper bromide (225 mg, 1.59 mmol) and lithium designed the experiments; all synthetic laboratory
bromide (138 mg, 1.59 mmol) were dried at 60°C for work was performed by F. E. (Schemes 4–9) and V. C.
4
h under high vacuum (<1 mbar) and then sus- (Schemes 8 and 9).
pended in THF (15 mL). The suspension was cooled to
–
100°C and the Grignard reagent 24 (3.2 mL of 0.5 M
solution in THF, 1.6 mmol) was added dropwise over a
period of 5 min. The resulting mixture was stirred at
À 90°C for 5 min and the alkyne 36 (270 mg,
References
0
5
.53 mmol) in THF (15 mL) was added dropwise over
[1] T. Yasumoto, M. Murata, ‘Marine toxins’, Chem. Rev. 1993,
min at À 90°C. The mixture was allowed to warm to
93, 1897–1909.
[
[
2] T. Yasumoto, ‘The chemistry and biological function of
natural marine toxins’, Chem. Rec. 2001, 1, 228–242.
3] Y.-Y. Lin, M. Risk, S. M. Ray, D. Van Engen, J. Clardy, J. Golik,
J. C. James, K. Nakanishi, ‘Isolation and structure of
brevetoxin B from the “red tide” dinoflagellate Ptychodis-
cus brevis (Gymnodinium breve)’, J. Am. Chem. Soc. 1981,
À 78°C, and the solution was stirred at this temper-
ature for a further 1 h. The reaction was quenched by
the addition of a 10% aqueous solution of NH OH
4
(50 mL), and the resulting mixture was extracted with
Et O (2×80 mL). The combined organic extracts were
2
1
03, 6773–6775.
4] Y. Shimizu, H. N. Chou, H. Bando, G. Van Duyne, J. Clardy,
Structure of brevetoxin A (GB-1 toxin), the most potent
dried (MgSO ), filtered and the solvent was removed in
4
[
vacuo. The residue was purified by flash column
‘
chromatography over silica gel (hexane!Et O/hexane
2
toxin in the Florida red tide organism Gymnodinium breve
(Ptychodiscus brevis)’, J. Am. Chem. Soc. 1986, 108, 514–
515.
1
6
:20 with 1% Et N) to afford enol ether 37 (252 mg,
3
8%) as a colourless oil. R 0.5 (Et O/hexane 1:4). IR
f
2
1
(liquid film): 2950, 2865, 1615, 1090. H-NMR (400 MHz,
[5] P. J. Scheuer, W. Takahashi, J. Tsutsumi, T. Yoshida,
Ciguatoxin: Isolation and Chemical Nature’, Science 1967,
15, 1267–1268.
‘
1
CDCl ): 7.41–7.25 (2 H, m); 7.20–7.08 (15 H, m); 6.99–
3
6
5
1
4
.94 (3 H, m); 5.64 (1 H, ddt, J=16.9, 10.2, 6.6); 5.54–
.51 (1 H, m); 5.27–5.25 (1 H, m); 4.86 (1 H, dd, J=16.9,
.8); 4.81 (1 H, dd, J=10.2, 1.8); 4.64 (1 H, d, J=10.8);
.64 (1 H, d, J=10.8); 4.51 (1 H, d, J=11.2); 4.48 (1 H, d,
[
6] M. Satake, M. Murata, T. Yasumoto, ‘The structure of
CTX3C, a ciguatoxin congener isolated from cultured
Gambierdiscus toxicus’, Tetrahedron Lett. 1993, 34, 1975–
1978.
www.helv.wiley.com (13 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
[
[
7] J.-P. Vernoux, R. J. Lewis, ‘Isolation and characterisation of
[21] C. Potera, ‘Florida Red Tide Brews up Drug for Cystic
Fibrosis’, Science 2007, 316, 1561–1562.
Caribbean ciguatoxins from the horse-eye jack (Caranx
latus)’, Toxicon 1997, 35, 889–900.
8] M. Satake, M. Fukui, A.-M. Legrand, P. Cruchet, T.
Yasumoto, ‘Isolation and structures of new ciguatoxin
analogues, 2,3-dihydroxyCTX3C and 51-hydroxyCTX3C, ac-
cumulated in tropical reef fish’, Tetrahedron Lett. 1998, 39,
[22] K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes,
M. Sato, E. Untersteller, ‘Total Synthesis of Brevetoxin B. 2.
Completion’, J. Am. Chem. Soc. 1995, 117, 1173–1174.
[23] K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes,
M. Sato, E. Untersteller, ‘Total Synthesis of Brevetoxin B. 3.
Final Strategy and Completion’, J. Am. Chem. Soc. 1995,
117, 10252–10263.
1197–1198.
[
9] H. Nagai, K. Torigoe, M. Satake, M. Murata, T. Yasumoto, H.
Hirota, ‘Gambieric acids: unprecedented potent antifungal
substances isolated from cultures of a marine dinoflagel-
late Gambierdiscus toxicus’, J. Am. Chem. Soc. 1992, 114,
[
[
[
[
[
[
[
[
[
24] K. C. Nicolaou, ‘The Total Synthesis of Brevetoxin B: A
Twelve-Year Odyssey in Organic Synthesis’, Angew. Chem.
Int. Ed. 1996, 35, 589–607.
25] K. C. Nicolaou, Z. Yang, G.-Q. Shi, J. L. Gunzner, K. A. Agrios,
P. Gärtner, ‘Total Synthesis of Brevetoxin A’, Nature 1998,
1
102–1103.
10] H. Nagai, M. Murata, K. Torigoe, M. Satake, T. Yasumoto,
Gambieric acids, new potent antifungal substances with
[
3
92, 264–269.
‘
26] M. T. Crimmins, J. L. Zuccarello, J. M. Ellis, P. J. McDougall,
P. A. Haile, J. D. Parrish, K. A. Emmitte, ‘Total Synthesis of
Brevetoxin A’, Org. Lett. 2009, 11, 489–492.
27] M. Hirama, T. Oishi, H. Uehara, M. Inoue, M. Maruyama, H.
Oguri, M. Satake, ‘Total Synthesis of Ciguatoxin CTX3C’,
Science 2001, 294, 1904–1907.
28] M. Inoue, H. Uehara, M. Maruyama, M. Hirama, ‘Practical
Total Synthesis of Ciguatoxin CTX3C by Improved Protec-
tive Group Strategy’, Org. Lett. 2002, 4, 4551–4554.
29] M. Inoue, M. Hirama, ‘Evolution of a Practical Total
Synthesis of Ciguatoxin CTX3C’, Acc. Chem. Res. 2004, 37,
unprecedented polyether structures from a marine dino-
flagellate Gambierdiscus toxicus’, J. Org. Chem. 1992, 57,
5448–5453.
[
[
11] M. Satake, M. Shoji, Y. Oshima, H. Naoki, T. Fujita, T.
Yasumoto, ‘Gymnocin-A, a cytotoxic polyether from the
notorious red tide dinoflagellate, Gymnodinium mikimotoi’,
Tetrahedron Lett. 2002, 43, 5829–5832.
12] M. Satake, Y. Tanaka, Y. Ishikura, Y. Oshima, H. Naoki, T.
Yasumoto, ‘Gymnocin-B with the largest contiguous poly-
ether rings from the red tide dinoflagellate, Karenia
(Formerly Gymnodinium) mikimotoi’, Tetrahedron Lett.
9
61–968.
30] M. Inoue, K. Miyazaki, H. Uehara, M. Maruyama, M. Hirama,
First- and second-generation total synthesis of ciguatoxin
2
005, 46, 3537–3540.
[
[
[
[
[
13] L. T. Truxal, A. J. Bourdelais, H. Jacocks, W. M. Abraham,
D. G. Baden, ‘Characterization of Tamulamides A and B,
Polyethers Isolated from the Marine Dinoflagellate Karenia
brevis’, J. Nat. Prod. 2010, 73, 536–540.
14] M. Murata, M. Kumagai, J. S. Lee, T. Yasumoto, ‘Isolation
and structure of yessotoxin, a novel polyether compound
implicated in diarrhetic shellfish poisoning’, Tetrahedron
Lett. 1987, 28, 5869–5872.
15] P. Ciminiello, E. Fattorusso, M. Forino, S. Magno, R. Poletti,
R. Viviani, ‘Isolation of adriatoxin, a new analogue of
yessotoxin from mussels of the adriatic sea’, Tetrahedron
Lett. 1998, 39, 8897–8900.
16] M. Satake, M. Murata, T. Yasumoto, ‘Gambierol: a new toxic
polyether compound isolated from the marine dinoflagel-
late Gambierdiscus toxicus’, J. Am. Chem. Soc. 1993, 115,
‘
CTX3C’, Proc. Natl. Acad. Sci. USA 2004, 101, 12013–12018.
31] M. Hirama, ‘Total synthesis of ciguatoxin CTX3C: a venture
into the problems of ciguatera seafood poisoning’, Chem.
Rec. 2005, 5, 240–250.
32] M. Inoue, K. Miyazaki, Y. Ishihara, A. Tatami, Y. Ohnuma, Y.
Kawada, K. Komano, S. Yamashita, N. Lee, M. Hirama, ‘Total
Synthesis of Ciguatoxin and 51-HydroxyCTX3C’, J. Am.
Chem. Soc. 2006, 128, 9352–9354.
[
[
33] A. Hamajima, M. Isobe, ‘Total Synthesis of Ciguatoxin’,
Angew. Chem. Int. Ed. 2009, 48, 2941–2945.
34] H. Fuwa, K. Ishigai, K. Hashizume, M. Sasaki, ‘Total Synthesis
and Complete Stereostructure of Gambieric Acid A’, J. Am.
Chem. Soc. 2012, 134, 11984–11987.
[
35] M. Sasaki, H. Fuwa, ‘Total Synthesis and Complete Struc-
tural Assignment of Gambieric Acid A, a Large Polycyclic
Ether Marine Natural Product’, Chem. Rec. 2014, 14, 678–
361–362.
17] I. Rodríguez, G. Genta-Jouve, C. Alfonso, K. Calabro, E.
Alonso, J. A. Sánchez, A. Alfonso, O. P. Thomas, L. M.
Botana, ‘Gambierone, a Ladder-Shaped Polyether from the
Dinoflagellate Gambierdiscus belizeanus’, Org. Lett. 2015,
7
03.
[
[
36] C. Tsukano, M. Sasaki, ‘Total Synthesis of Gymnocin-A’, J.
Am. Chem. Soc. 2003, 125, 14294–14295.
1
7, 2392–2395.
37] T. Sakai, S. Matsushita, S. Arakawa, K. Mori, M. Tanimoto, A.
Tokumasu, T. Yoshida, Y. Mori, ‘Total Synthesis of Gymno-
cin-A’, J. Am. Chem. Soc. 2015, 137, 14513–14516.
[
[
[
18] A. J. Bourdelais, H. M. Jacocks, J. L. C. Wright, P. M. Bigwarfe
Jr., D. G. Baden, ‘A New Polyether Ladder Compound
Produced by the Dinoflagellate Karenia brevis’, J. Nat. Prod.
[
38] H. Fuwa, M. Sasaki, M. Satake, K. Tachibana, ‘Total Synthesis
2
005, 68, 2–6.
of Gambierol’, Org. Lett. 2002, 4, 2981–2984.
19] M. Murata, T. Iwashita, A. Yokoyama, M. Sasaki, T.
Yasumoto, ‘Partial structures of maitotoxin, the most
potent marine toxin from the dinoflagellate Gambierdiscus
toxicus’, J. Am. Chem. Soc. 1992, 114, 6594–6596.
[39] H. Fuwa, N. Kainuma, K. Tachibana, M. Sasaki, ‘Total
Synthesis of (–)-Gambierol’, J. Am. Chem. Soc. 2002, 124,
14983–14992.
[40] I. Kadota, H. Takamura, K. Sato, A. Ohno, K. Matsuda, Y.
Yamamoto, ‘Total Synthesis of Gambierol’, J. Am. Chem.
Soc. 2003, 125, 46–47.
20] H. Nagai, Y. Mikami, K. Yazawa, T. Gonoi, T. Yasumoto,
‘Biological Activities of Novel Polyether Antifungals, Gam-
bieric Acids A and B from a Marine Dinoflagellate
Gambierdiscus toxicus’, J. Antibiot. 1993, 46, 520–522.
[41] I. Kadota, H. Takamura, K. Sato, A. Ohno, K. Matsuda, M.
Satake, Y. Yamamoto, ‘Convergent Total Syntheses of
www.helv.wiley.com (14 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG

Helv. Chim. Acta 2019, 102, e1900161
Gambierol and 16-epi-Gambierol and Their Biological System of the Gambieric Acids’, Org. Lett. 2015, 17, 4694–
Activities’, J. Am. Chem. Soc. 2003, 125, 11893–11899.
42] H. W. B. Johnson, U. Majumder, J. D. Rainier, ‘Total Syn-
thesis of Gambierol’, J. Am. Chem. Soc. 2005, 127, 848–849.
43] H. Fuwa, M. Ebine, A. J. Bourdelais, D. G. Baden, M. Sasaki,
4697.
[
[
[59] J. D. Rainier, S. P. Allwein, ‘A highly efficient iterative
approach to fused ether ring systems’, Tetrahedron Lett.
1998, 39, 9601–9604.
[60] J. D. Rainier, J. M. Cox, S. P. Allwein, ‘Enol ether–olefin ring
closing metathesis using the Grubbs ruthenium imidazole
catalyst’, Tetrahedron Lett. 2001, 42, 179–181.
[61] U. Majumder, J. D. Rainier, ‘Olefinic-ester cyclizations using
Takai–Utimoto reduced titanium alkylidenes’, Tetrahedron
Lett. 2005, 46, 7209–7211.
[62] K. Iyer, J. D. Rainier, ‘Olefinic Ester and Diene Ring-Closing
Metathesis Using a Reduced Titanium Alkylidene’, J. Am.
Chem. Soc. 2007, 129, 12604–12605.
[63] Y. Zhang, J. D. Rainier, ‘Synthesis of the ABCDEF and FGHI
ring system of yessotoxin and adriatoxin’, J. Antibiot. 2016,
69, 259–272.
[64] C. Pietraszuk, H. Fischer, S. Rogalski, B. Marciniec, ‘The
effect of substituents at silicon on the cross-metathesis of
trisubstituted vinylsilanes with olefins’, J. Organomet.
Chem. 2005, 690, 5912–5921.
[65] R. W. Murray, M. Singh, ‘Synthesis of Epoxides Using
Dimethyldioxirane: trans-Stilbene Oxide’, Org. Synth. 1997,
74, 91–96.
[66] H. Mikula, D. Svatunek, D. Lumpi, F. Glöcklhofer, C.
Hametner, J. Fröhlich, ‘Practical and Efficient Large-Scale
Preparation of Dimethyldioxirane’, Org. Process Res. Dev.
2013, 17, 313–316.
[67] D. A. Evans, B. W. Trotter, B. Côté, ‘Addition of allylstan-
nanes to glycal epoxides. A diastereoselective approach to
β-C-glycosidation’, Tetrahedron Lett. 1998, 39, 1709–1712.
[68] S. P. Allwein, J. M. Cox, B. E. Howard, H. W. B. Johnson, J. D.
Rainier, ‘C-Glycosides to fused polycyclic ethers’, Tetrahe-
dron 2002, 58, 1977–2009.
‘
Total Synthesis, Structure Revision, and Absolute Config-
uration of (À )-Brevenal’, J. Am. Chem. Soc. 2006, 128,
6989–16999.
1
[
[
[
[
[
44] H. Takamura, S. Kikuchi, Y. Nakamura, Y. Yamagami, T.
Kishi, I. Kadota, Y. Yamamoto, ‘Total Synthesis of Brevenal’,
Org. Lett. 2009, 11, 2531–2534.
45] Y. Zhang, J. Rohanna, J. Zhou, K. Iyer, J. D. Rainier, ‘Total
Synthesis of Brevenal’, J. Am. Chem. Soc. 2011, 133, 3208–
3216.
46] J. S. Clark, O. Hamelin, ‘Synthesis of Polycyclic Ethers by
Two-Directional Double Ring-Closing Metathesis’, Angew.
Chem. Int. Ed. 2000, 39, 372–374.
47] J. S. Clark, ‘Construction of fused polycyclic ethers by
strategies involving ring-closing metathesis’, Chem. Com-
mun. 2006, 3571–3581.
48] J. Skardon-Duncan, M. Sparenberg, A. Bayle, S. Alexander,
J. S. Clark, ‘Stereoselective Synthesis of Medium-Sized
Cyclic Ethers by Sequential Ring-Closing Metathesis and
Tsuji–Trost Allylation’, Org. Lett. 2018, 20, 2782–2786.
49] J. S. Clark, J. G. Kettle, ‘Synthesis of brevetoxin sub-units by
sequential ring-closing metathesis and hydroboration’,
Tetrahedron Lett. 1997, 38, 123–126.
50] J. S. Clark, J. G. Kettle, ‘Synthesis of sub-units of marine
polycyclic ethers by ring-closing metathesis and hydro-
boration of enol ethers’ Tetrahedron 1999, 55, 8231–8248.
51] J. S. Clark, J. G. Kettle, ‘Enantioselective synthesis of
medium-ring sub-units of brevetoxin A by ring-closing
metathesis’, Tetrahedron Lett. 1997, 38, 127–130.
[
[
[
[
52] J. S. Clark, O. Hamelin, R. Hufton, ‘Synthesis of medium-
sized cyclic allylic ethers by ring-closing metathesis and
subsequent elaboration to sub-units found in the breve-
toxins and ciguatoxins’, Tetrahedron Lett. 1998, 39, 8321–
[69] A. Moyano, F. Charbonnier, A. E. Greene, ‘A simple
preparation of chiral acetylenic ethers’, J. Org. Chem. 1987,
52, 2919–2922.
8324.
[70] M. A. Rivero-Crespo, A. Leyva-Pérez, A. Corma, ‘A Ligand-
[
[
53] J. S. Clark, G. P. Trevitt, D. Boyall, B. Stammen, ‘Synthesis of
alkenyl-substituted cyclic enol ethers by catalytic ring-
closing metathesis of alkynyl ethers’, Chem. Commun.
Free Pt Cluster Catalyzes the Markovnikov Hydrosilylation
of Alkynes with up to 10 Turnover Frequencies’, Chem.
Eur. J. 2017, 23, 1702–1708.
3
6
1
998, 2629–2630.
[71] M. Asaoka, N. Fujii, K. Shima, H. Takei, ‘3-Substituted-γ-
butyrolactones from 5-Trimethylsilyl-2-cyclohexanone. Syn-
thesis of (À )-Enterolactone’, Chem. Lett. 1988, 805–808.
[72] I. Fleming, M. Rowley, P. Cuadrado, A. M. González-Nogal,
F. J. Pulido, ‘The silyl-cupration and stannyl-cupration of
allenes’, Tetrahedron 1989, 45, 413–424.
54] J. S. Clark, F. Elustondo, G. P. Trevitt, D. Boyall, J. Robertson,
A. J. Blake, C. Wilson, B. Stammen, ‘Preparation of cyclic
ethers for polyether synthesis by catalytic ring-closing
enyne metathesis of alkynyl ethers’, Tetrahedron 2002, 58,
1973–1982.
[
55] J. S. Clark, F. Elustondo, M. C. Kimber, ‘Construction of
building-blocks for polyether synthesis using sequential
catalytic ring-closing enyne and cross metathesis’, Chem.
Commun. 2004, 2470–2471.
[73] D. Bourgeois, A. Pancrazi, S. P. Nolan, J. Prunet, ‘The
Cl (PCy )(IMes)Ru(=CHPh) catalyst: olefin metathesis versus
2
3
olefin isomerization’, J. Organomet. Chem. 2002, 643–644,
247–252.
[
[
56] J. S. Clark, J. Conroy, A. J. Blake, ‘Rapid Synthesis of the A–E
Fragment of Ciguatoxin CTX3C’, Org. Lett. 2007, 9, 2091–
[74] H. Yamaguchi, C. Schuerch, ‘Synthesis of 1,2-anhydro-3,4,6-
tri-O-benzyl-α-D-glucopyranose’, Carbohydr. Res. 1980, 81,
192–195.
[75] L. Cipolla, L. Lay, F. Nicotra, ‘New and Easy Access to C-
Glycosides of Glucosamine and Mannosamine’, J. Org.
Chem. 1997, 62, 6678–6681.
2094.
57] J. S. Clark, M. C. Kimber, J. Robertson, C. S. P. McErlean, C.
Wilson, ‘Rapid Two-Directional Synthesis of the F–J Frag-
ment of the Gambieric Acids by Iterative Double Ring-
Closing Metathesis’, Angew. Chem. Int. Ed. 2005, 44, 6157–
6
162.
[
58] J. S. Clark, F. Romiti, B. Sieng, L. C. Paterson, A. Stewart, S.
Received June 28, 2019
Accepted August 2, 2019
Chaudhury, L. H. Thomas, ‘Synthesis of the A–D Ring
www.helv.wiley.com (15 of 15) e1900161 © 2019 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG