Geometry-selective synthesis of the unsaturated side chains of the isodomoic acids

Article abstract of DOI:10.1016/j.tet.2015.02.055

Abstract Three unsaturated vinylic or allylic halides were made in enantiomerically pure form, ready for coupling with a vinyl metal as part of a divergent strategy for the synthesis of members of the domoic/isodomoic acid family and their analogues. The

Full text of DOI:10.1016/j.tet.2015.02.055

Tetrahedron 71 (2015) 7204e7208
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Geometry-selective synthesis of the unsaturated side chains of the
isodomoic acids
*
ꢀ
Nadia Fleary-Roberts, Gilles Lemiere, Jonathan Clayden
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 October 2014
Received in revised form 5 February 2015
Accepted 16 February 2015
Available online 20 February 2015
Three unsaturated vinylic or allylic halides were made in enantiomerically pure form, ready for coupling
with a vinyl metal as part of a divergent strategy for the synthesis of members of the domoic/isodomoic
acid family and their analogues. The trisubstituted alkene 3 was made by an E-selective Wittig reaction,
while 4 and 5 were made by stereoselective hydrometallation or hydroboration of an alkyne.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Alkene
Coupling
Metalcatalysed
Natural product synthesis
1. Introduction
domoic acid; E selective for isodomoic acids B, E and F). We have
realised this aim in palladium-catalysed couplings of the E-stan-
Domoic acid and the isodomoic acids (Scheme 1) are a series of
metabolites produced by marine algae Chondria armata and Pseu-
donitzschia spp.1 They have neurological activity as glutamate an-
alogues, and domoic acid has been implicated as the causative
agent of amnesic shellfish poisoning.2 As a result, its toxicology has
been widely studied in humans and marine animals. More detailed
binding studies have revealed differences between the binding
affinity of some of the isodomoic acids for their targets, the kainate
subfamily of ionotropic glutamate receptors. However, the limited
supply of the natural products has hampered detailed exploration
in this area.
An alternative source of domoic acid and the isodomoic acids is
provided by total synthesis. (ꢀ)-Domoic acid was synthesised in
1982 by Ohfune;3 our group has reported syntheses of (ꢀ)-iso-
domoic acids B,4 C,5 E,4 and F;4 the groups of Mongomery6 and
Denmark7 have reported synthesis of (ꢀ)-isodomoic acids G and H.
The isodomoic acids are all double bond regio- and stereoiso-
mers with the same constitutional formula, and five of them, along
with domoic acid, share the same three unsaturated side chains, as
shown in Scheme 1. Our strategy for the synthesis of isodomoic
acids B, E and F, which could in principle be extended to isodomoic
acids A and D and domoic acid itself, was to synthesise a core al-
kyne 1 and to functionalise this to give either Z- or E-2 by stereo-
selective carbometallation (Z selective for isodomoic acids A, D and
nane E-2 (Met¼SnBu3) resulting from cis-stannylcupration and
methylation of 1, which allowed the synthesis of (ꢀ)-isodomoic
acids B, E and F.4 Similar routes isodomoic acids A, D and domoic
acid are awaiting the development of a suitable method for trans-
carbometallation of 1 to give Z-2. This divergent strategy could also
provide, in a simple manner, analogues of the domoic acid family
for further biological evaluation.
Central to the effectiveness of the strategy are practical routes to
the coupling partners 3, 4 and 5 in geometrically and (for 4 and 5)
enantiomerically pure form. Brief details of our syntheses of these
compounds were provided previously,4 but in this paper we de-
scribe the optimisation of routes to these side chains, and their
syntheses in quantities sufficient for ligation to a vinylmetal cou-
pling partner. For reasons of practicality in the final deprotection
step, tert-butyl ester protecting groups were used for all the car-
boxylic acid functions, since the route to the alkyne 14 necessitates
the use of tert-butyl ester protection.
2. Results and discussion
2.1. Synthesis of 3
A synthesis of the methyl ester analogous to 3 has been re-
ported, and 3 was conveniently made by a modification of this
route.8a tert-Butyl 2-bromoproprionate 6 was converted to a phos-
phonium salt and treated with glyoxylic acid under basic condi-
tions to provide the half-ester 7 as its E isomer with complete
* Corresponding author. E-mail address: clayden@man.ac.uk (J. Clayden).
http://dx.doi.org/10.1016/j.tet.2015.02.055
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

N. Fleary-Roberts et al. / Tetrahedron 71 (2015) 7204e7208
7205
Scheme 1. Divergent strategy for the synthesis of the domoic/isodomoic acid family.
geometrical selectivity, though in lower yield and more slowly than
the corresponding methyl ester (Scheme 2). Reduction with borane
dimethyl sulfide complex gave alcohol 8, which was brominated
with phosphorus tribromide to afford protected side chain 3.
Scheme 3. Synthesis of the aldehydes 12a and 12b. Reagents and conditions: For 10a
t
a tBuMe2SiCl, DMAP, Et3N, CH2Cl2, 12 h, rt, 94%; for 10b a BuPh2SiCl, imid., DMF, 0 ꢁC,
Scheme 2. Synthesis of 3 by E-selective Wittig reaction. Reagents and conditions: a (i)
PPh3, MeCN, 65 ꢁC, 24 h; (ii) glyoxylic acid monohydrate, EtNiPr2, MeCN, 0 ꢁC to rt, 72 h
(33%); b Me2S$BH3, THF, rt, 16 h (68%); c PBr3, CCl4, 0 ꢁC, 2 h, (21%).
2 h, 98%; b 11a DIBAL (2 equiv), tol, ꢀ40 ꢁC, 3 h, 82%; 11b: DIBAL (2.5 equiv), CH2Cl2,
ꢀ40 ꢁC, 2 h, 98%); c (COCl)2, Me2SO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h 30 min (12a: 61%; 12b:
88%).
2.2. Synthesis of 4 and 5
The geometrical isomers of the enantiomerically pure vinyl io-
dides 4 and 5 were envisaged as divergent derivatives of a single
common starting material, the aldehyde 12, which would be ole-
finated with either E or Z selectivity. The aldehyde 12 was itself
made from (S)-Roche ester 9 as shown in Scheme 3.8b Protection of
the hydroxyl group as either its TBDMS or TBDPS ether gave the
esters 10a and 10b. Attempts to effect a reported partial reduction
of esters 10 directly to the aldehydes8c 12 with DIBAL were un-
successful, so instead a two-step procedure was used: the reaction
of 2.5 equiv of DIBAL gave the alcohols 11a and 11b, and Swern
oxidation returned the aldehydes 12a and 12b. We found that the
TBDPS protecting group gave much better yields than the TBDMS
group, possibly because of the volatility of the TBDMS-protected
compounds.

7206
N. Fleary-Roberts et al. / Tetrahedron 71 (2015) 7204e7208
Our initial attempts to form the Z-alkenes 13a and 13b made use
of a Wittig olefination (Scheme 4)8 of aldehydes 12a or 12b with
iodomethyltriphenylphosphonium iodide.9 However, under these
reaction conditions alkenes 13 could be obtained only in moderate
yields as a mixture of geometrical isomers (Z/E¼ca. 9:1: see Table 1,
entries 1e5) even after repeated column chromatography.
Scheme 6. Synthesis of iodoalkene 4 by iodination of an E-vinylzirconium species.
Reagents and conditions: a Cp2ZrHCl, CH2Cl2, 25 min, rt; b I2, CH2Cl2, 30 min, rt, TBAF,
THF, 1 h, rt (82% over two steps); c CrO3, H2SO4, H2O, acetone (36%), ꢀ10 ꢁC; d tBuOH,
TFAA (49%), 1 h rt.
Scheme 4. Vinyl iodides by Wittig or Takai olefination. Reagents and conditions:
a (Ph3PþCHI)Iꢀ, NaHMDS, DMPU, THF, ꢀ78 ꢁC; b CHI3, CrCl2, dioxaneeTHF, 0 ꢁC to rt.
Esterification with tert-butanol provided the E iodoalkene 4 in six
steps from the starting methyl ester 9.
Methods for converting alkyne 14 into the Z vinyl iodide Z-13b
were investigated. One such method has been reported by Takami
et al. who demonstrated a one-step indium-mediated reduction of
alkynes to Z-iodoalkenes.15 However, in our hands this method
returned only the starting material.
Alternative approaches were therefore explored using the
iodoalkyne 18 as an intermediate, which we planned to reduce
selectively by cis addition of hydrogen. Iodoalkyne 18 was formed
by treatment of alkyne 14 with N-iodosuccinimide (Scheme 7).
Attempted cis selective partial hydrogenation of 18 with 2-
nitrobenzenesulfonylhydrazide (NBSH)16 afforded a mixture of
the Z-iodo alkene Z-13b and the alkane 19 arising from over-
reduction of the product. With less NBSH and shorter reaction
time, a 2:1 mixture of the desired alkene Z-13b and the starting
iodoalkyne 18 was produced.
Table 1
Olefinations of 12
Entry
SM
Method
13, yield (%)
Z/E
1
2
3
4
5
6
7
12a
12a
12a
12b
12b
12a
12b
a
a
a
a
a
b
b
13a, 15
13a, 59
13a, 25
13b, 34
13b, 19
13b, 62
13b, 25
91:9
89:11
91:9
87:13
88:12
9:91
6:94
In contrast to Wittig olefination with unstabilised ylids, E geo-
metrical selectivity is characteristic of Takai olefination, and treat-
ment of aldehydes 12a and 12b with iodoform and chromium(II)
salts10 gave predominantly the E iodoalkenes E-13 (Scheme 4).11
However, as with the Wittig olefination, only moderate yields and
incomplete selectivities were obtained (Table 1, entries 6 and 7).
The difficulty of separating the pairs of E and Z-alkenes from one
another led us to seek a more stereoselective way of making the
two geometrical isomers from a common precursor. The stereo-
divergent preparation of geometrically pure alkenes from an alkyne
was already part of our strategy for the synthesis of vinylmetals 2
from 1, so we proposed a similar strategy for the synthesis of the
coupling partners 4 and 5. Alkyne 14 would be accessible from
aldehyde 12b in a single step by homologation (Scheme 5), and
stereoselective hydroiodination of the alkyne would give the re-
quired E or Z precursors of 4 and 5.
Scheme 7. Synthesis of 5 by reduction of an iodoalkyne. Reagents and conditions:
a NIS, AgNO3, acetone, 2.5 h, rt (92%); b 2-nitrobenzenesulfonyl chloride, N2H4.H2O,
THF, ꢀ30 ꢁC, then 18, Et3N, MeCN, iPrOH/THF, 32 h; c (i) BH3eMe2S, cyclohexene, 0 ꢁ
C
to rt, 1 h, Et2O; (ii) AcOH, 0 ꢁC, 30 min (78%); d Bu4NF, THF, 0 ꢁC, 2 h (67%); e CrO3,
t
H2SO4, acetone, 0 ꢁC, 1 h (49%); f BuOH, (CF3CO)2O, 0 ꢁC, 1.5 h (38%).
Hydroboration of alkynes followed by protonolysis has also
been reported to furnish Z-alkenes.17 Hydroboration of iodoalkyne
18 (Scheme 7) with dicyclohexylborane followed by protonolysis of
the resulting vinylborane with acetic acid gave Z-iodo alkene Z-13b
in 78% yield. The remaining steps of the synthesis were analogous
to those used during the synthesis of the E iodo alkene: removal of
the silyl protecting group to give Z-20, oxidation to the acid Z-17
and final esterification afforded the side chain 5 over six steps from
the starting ester 9.
Scheme 5. Homologation of aldehyde 12b. Reagents and conditions: a CBr4, PPh3, Zn,
n
CH2Cl2, 0 ꢁC to rt, 4 h; b BuLi, ꢀ78 ꢁC, THF, 1 h (64%).
Homologation of aldehyde 12b was first tried with the Ohira-
Bestmann reagent.12 This reagent had been previously used to
form the enantiopure alkyne for the pyrrolidine core of the target
molecules, but with this substrate this reagent gave poor results and
the alkyne 14 was not formed. The CoreyeFuchs reaction is another
well established way of preparing alkynes from aldehydes and can
do so without compromising the integrity of adjacent stereogenic
centres.13 Aldehyde 12b was treated under the conditions shown in
Scheme 5 and the alkyne 14 was formed in 64% yield.
The treatment of the alkyne 14 with Schwartz’s reagent
(Cp2ZrHCl)14 formed the E-vinylzirconium species 15, which was
quenched with iodine, forming the E iodo alkene E-16 as a single
isomer after deprotection with TBAF (Scheme 6). Oxidation with
3. Conclusion
In conclusion, we here report three methods for the synthesis of
the side chains of isodomoic acids. Allyl bromide 3 was made by E-
selective Wittig olefination, while 4 and 5 were made from alkyne
14 by cis selective hydrozirconation and iodination or by conver-
sion to iodoalkyne 18 and cis selective hydroboration/proto-
deboronation. The three unsaturated halides have already been
Jones’ reagent gave the acid E-17 in
a modest 36% yield.

N. Fleary-Roberts et al. / Tetrahedron 71 (2015) 7204e7208
7207
used in the synthesis of isodomoic acids B, E and F, and current
work is seeking to develop an efficient route to the Z vinylmetal Z-2
required to make the remaining members of the isodomoic acid
family, isodomoic acids A and D and domoic acid itself.4
was quenched with water (25 mL) and extracted with CH2Cl2
(2ꢂ100 mL). The combined organic phases were washed with
brine, dried (Na2SO4), filtered and concentrated. The crude product
was purified by column chromatography (petrol/EtOAc 9:1) to af-
ford the title compound 12a (1.10 g, 61%) as a colourless oil.
4. Experimental
Rf 0.83 (petrol/EtOAc 1:1); 1H NMR (300 MHz; CDCl3)
d 9.69 (1H,
s, CHO), 3.90e3.78 (2H, m, CH2) 2.60e2.48 (1H, m, CH(CH3)), 1.10
Compounds 3, 4, 5, 7, 8, 10b, 11a, 11b, 12a, 12b, Z-13b, 14, E-16, E-
17, Z-17, 18 and Z-20 were described as part of our total synthesis of
isodomoic acids B, E and F.4
(3H, d, J¼7.1, CH3), 0.88 (9H, s, (CH3)3), 0.06 (9H, s, Si(CH3)2); 13C
NMR (75 MHz; CDCl3)
d 204.6 (CHO), 63.4 (CH2), 48.8 (CH(CH3)),
25.8 (CH3)3, 18.2 (C(CH3)3), 10.3 (CH3), ꢀ5.6 (Si(CH3)2); MS m/z (CI)
t
201 (MꢀH), 145 (Mꢀ Bu). Spectroscopic data matched that re-
4.1. (S)-3-(tert-Butyldimethylsilanyloxy)-2-methylpropionic
ported in the literature.8b,20
acid methyl ester 10a18
4.4. (R,Z)-tert-Butyl((4-iodo-2-methylbut-3-en-1-yl)oxy)di-
To a solution of methyl (S)-(þ)-3-hydroxy-2-methyl propionate
9 (0.93 mL, 8.46 mmol, 1 equiv) in CH2Cl2 (16 mL) at 0 ꢁC was added
triethylamine (1.41 mL, 10.2 mmol, 1.2 equiv) followed by tert-
butyldimethylsilyl chloride (1.53 g, 10.2 mol, 1.2 equiv) and DMAP
(51.3 mg, 0.42 mmol, 0.05 equiv) in CH2Cl2 (4 mL). The reaction
mixture was stirred at room temperature for 12 h before being
quenched with water (10 mL) and CH2Cl2 (20 mL). The title com-
pound 10a (1.86 g, 94%) was obtained as a pale yellow oil.
methylsilane 13a
NaHMDS 1 M in THF (3.11 mL, 3.11 mmol, 2.1 equiv) was added
dropwise to a suspension of iodomethyltriphenylphosphonium
iodide (1.18 g, 2.22 mmol,1.5 equiv) in THF (20 mL). The red solution
was stirred for 5 min at rt before being cooled to ꢀ78 ꢁC and DMPU
(1.36 mL, 11.3 mmol, 7.6 equiv) was added. The mixture was stirred
for 15 min and (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-
propionaldehyde 12a (300 mg, 1.48 mmol, 1 equiv) in THF (6 mL)
was added dropwise to the solution. The reaction mixture was
stirred for 3 h at ꢀ78 ꢁC then allowed to warm to rt. The reaction
mixture was quenched with NaHCO3, diluted with Et2O and filtered
through Celite, which was washed with Et2O. The filtrate was
washed with brine, dried (MgSO4) and the solvent removed in
vacuo. The crude residue was purified by column chromatography
(petrol then petrol/EtOAc 9:1) to afford the title compound Z-13a
91:9 Z/E (119 mg, 25%) as a colourless oil.
Rf 0.90 (petrol/EtOAc 1:1); 1H NMR (300 MHz; CDCl3)
d
3.79e3.74 (1H, m, CHH), 3.67 (3H, s, OCH3), 3.65e3.62 (1H, m,
CHH), 2.70e2.59 (1H, m, CH), 1.13 (3H, d, J¼7.2, CH3), 0.87 (9H, s,
(CH3)3), 0.03 (6H, s, Si(CH2)2); 13C NMR (75 MHz; CDCl3)
175.5
d
(CO2CH3), 65.2 (SiOCH2), 51.5 (OCH3), 42.5 (CH2CHCH3), 25.8
(C(CH3)3), 18.2 (C(CH3)3), 13.4 (CH3), ꢀ5.1(Si(CH3)2); MS m/z (ESþ)
255.0 (100%, MNaþ). Spectroscopic data matched that reported in
the literature.18
4.2. (R)-3-(tert-Butyldimethylsilanyloxy)-2-methylpropan-1-
Rf 0.78 (petrol/EtOAc 9:1); [
a
]
22 ꢀ33.6 (c 1, CHCl3); IR ymax (film/
D
ol 11a19
cmꢀ1) 2955 (CeH), 1606 (C]C); 1H NMR (400 MHz; CDCl3)
d
6.20
(1H, d, J¼7.3, CHI), 6.05 (1H, dd, J¼7.3, 8.6, CH]CHI), 3.58e3.54 (1H,
m, CHH), 3.52e3.58 (1H, m, CHH), 2.73e2.63 (1H, m, CH(CH3)), 1.03
(3H, d, J¼6.8, CH3), 0.90 (9H, s, (CH3)3), 0.06 (6H, s, Si(CH3)2); 13C
To
a
solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-
methyl-propionic acid methyl ester 10a (1.00 g, 4.30 mmol,
1 equiv) in toluene (30 mL) at ꢀ40 ꢁC was added DIBAL 1 M in
toluene (8.60 mL, 8.60 mmol, 2 equiv). The reaction mixture was
stirred at this temperature for 3 h before quenching with methanol
(1 mL) and Rochelle’s salt (35 mL). The mixture was stirred vigor-
ously for 30 min before adding water (11 mL) and Et2O (4 mL). The
resultant cloudy mixture was stirred for approx. 30 min until clear.
The aqueous layer was extracted with Et2O (3ꢂ15 mL) and the
combined organic phases dried (Na2SO4), filtered and the solvent
removed in vacuo. The title compound 11a (720 mg, 82%) was ob-
tained without further purification as a colourless oil.
NMR (100 MHz; CDCl3)
d 143.9 (C]CHI), 81.6 (C]CHI), 66.2 (CH2),
42.1 (CH(CH3)), 29.7 (C(CH3)3), 25.9 (C(CH3)3), 15.6 (CH3), ꢀ5.3
t
(Si(CH3)2); MS m/z (GCeMS) 269 (Mꢀ Bu); HRMS found Mþ
327.0633, C11H23IOSiH requires Mþ 327.0636.
4.5. (R,Z)-4-Iodo-2-methylbut-3-enyloxy(tert-butyl)diphe-
nylsilane 13b
4.5.1. Method 1. To a suspension of iodomethyltriphenylphos-
phonium iodide (1.18 g, 2.23 mmol, 1.5 equiv) in THF (10 mL) was
added NaHMDS 0.6 M in toluene (5.22 mL, 3.13 mmol, 2.1 equiv) at
rt. After stirring for 5 min, the solution was cooled down to ꢀ78 ꢁC
and DMPU (1.36 mL, 11.3 mmol, 7.6 equiv) was added. The mixture
was stirred for approx. 15 min and a solution of (2S)-3-(tert-
butyldiphenylsilylsilyloxy)-2-methylpropanal 12b (486 mg,
1.40 mmol, 1 equiv) in THF (6 mL) was added dropwise. The re-
action was stirred for 3 h at this temperature before being diluted
with Et2O and filtered through Celite. The filter cake was rinsed
with more Et2O. The organic layer was washed with aqueous NH4Cl
and brine, dried (MgSO4), filtered and the solvent removed. The
residue was purified by column chromatography (petrol/Et2O 95:5)
to afford the title compound Z-13b (226 mg, 34%) as a colourless oil.
Rf 0.50 (petrol/EtOAc 4:1); 1H NMR (300 MHz; CDCl3)
d
3.67e3.44 (4H, m, (CH2)2), 1.95e1.79 (1H, m, CH), 0.83 (9H, s,
(CH3)3), 0.76 (3H, d, J¼6.9, CH3), 0.00 (6H, s, Si(CH3)2); 13C NMR
(75 MHz; CDCl3) d 68.7 (CH2OH), 68.3 (CH2OH), 37.0 (CH(CH3)), 25.8
(C(CH3)3), 18.2 (C(CH3)), 13.1 (CH3), ꢀ5.6 (Si(CH3)2); MS m/z (ESþ)
205 (100%, MHþ). Spectroscopic data matched that reported in the
literature.19
4.3. (S)-3-(tert-Butyldimethylsilanyloxy)-2-
methylpropionaldehyde 12a8b,20
DMSO (1.77 mL, 24.9 mmol, 2.8 equiv) was added dropwise to
a solution of oxalyl chloride (1.71 mL, 19.6 mmol, 2.2 equiv) in
CH2Cl2 (18 mL) at ꢀ78 ꢁC and the mixture was stirred for 15 min. A
4.5.2. Method 2.21 ((R)-4-Iodo-2-methylbut-3-ynyloxy)(tert-butyl)
diphenylsilane 14 (1.00 g, 2.23 mmol, 1 equiv) was dissolved in
iPrOH (5 mL) and THF (5 mL) and treated with triethylamine
(0.42 mL, 2.99 mmol, 1.34 equiv) and nitrobenzenesulfonylhydra-
zine (544 mg, 2.54 mmol, 1.14 equiv). The mixture was stirred for
15 h at rt before being quenched with water (10 mL) and extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were washed
solution
of
(R)-3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-
propan-1-ol 11a (1.80 g, 8.90 mmol, 1 equiv) in CH2Cl2 (6 mL) was
added dropwise to the reaction flask. The reaction mixture was
stirred for 1 h, then triethylamine (6.21 mL, 44.5 mmol, 5 equiv)
was added and the resultant mixture gradually warmed to room
temperature, then stirred for 30 min. The white reaction mixture

7208
N. Fleary-Roberts et al. / Tetrahedron 71 (2015) 7204e7208
with brine, dried (MgSO4) and the solvent removed in vacuo. Crude
1H NMR showed a 2:1 mixture of starting material 14 and desired
product Z-13b.
chromatography (petrol 100%, then petrol/EtOAc 2:1) to afford the
title compound E-13b (573 mg, 62%) as an orange oil containing 9%
Z-13b.
22
Rf 0.60 (petrol/EtOAc 9:1); [
a
]
þ11.4 (c 0.7, CHCl3); IR ymax
D
4.5.3. Method 3.4 Me2S$BH3 2 M in toluene (1.97 mL, 3.93 mmol,
3 equiv) was added to a stirred solution of cyclohexene (0.80 mL,
7.87 mmol, 6 equiv) in diethyl ether (4 mL) at 0 ꢁC. The reaction
mixture was stirred at rt for 1 h before adding alkyne 14 (588 mg,
1.31 mmol, 1 equiv) in Et2O (2.5 mL) at 0 ꢁC. After 1 h glacial acetic
acid (1.30 mL, 22.7 mmol, 17 equiv) was added and the reaction
mixture stirred for 30 min at 0 ꢁC. Diethyl ether (9 mL) was added
followed by a saturated aqueous solution of NaHCO3 (4 mL) at 0 ꢁC.
The aqueous layer was washed with brine, dried (MgSO4), filtered
and the solvent removed in vacuo. The crude residue was purified
by column chromatography (petrol 100% then petrol/EtOAc 98:2) to
(film/cmꢀ1) 2928 (CeH), 2855 (CeH), 1426 (C]C); 1H NMR
(300 MHz; CDCl3)
d
7.68ꢀ7.64 (4H, m, ArH), 7.45e7.37 (6H, m, ArH),
6.50 (1H, dd, J¼14.5, 7.7, CHCHI), 6.05 (1H, dd, J¼14.5, C]CHI), 3.52
(2H, d, J¼6.2, CH2), 2.47e2.36 (1H, m, CH), 1.05 (9H, s, (CH3)3), 1.01
(3H, d, J¼6.8, CH3); 13C NMR (100 MHz; CDCl3)
d 149.1 (CH]CHI),
135.6 (ArC), 133.6 (ArC), 129.6 (ArC), 127.7 (ArC), 75.2 (C]CHI), 67.5
(CH2OSi), 43.0 (CHCH3), 26.8 (C(CH3)3), 19.2 (C(CH3)3), 15.6 (CH3);
MS m/z (ESþ) 473 (100%, MNaþ); HRMS found Mþ, 451.0958
C
21H27OISi Mþ requires 451.0949.
Acknowledgements
afford the title compound Z-13b (460 mg, 78%) as a yellow oil.
23
Rf 0.70 (petrol/EtOAc 9:1); [
a]
ꢀ57.4 (c 1.0, CHCl3); IR ymax
D
We acknowledge the EPSRC and the Centre franc¸ ais pour l’accueil
(film)/cmꢀ1 2981 (C]C), 1706 (Ar); 1H NMR (300 MHz; CDCl3)
ꢁ
et les echanges internationaux (Lavoisier fellowship to GL) for sup-
d
7.69e7.66 (4H, m, ArH), 7.43e7.36 (6H, m, ArH), 6.21 (1H, d, J¼7.3,
port of this work.
CH), 6.10e6.05 (1H, m, CH), 3.60e3.58 (2H, m, CH2), 2.84e2.70 (1H,
m, CH), 1.07e1.05 (12H, m, (CH3)3)þCH3); 13C NMR (75 MHz; CDCl3)
References and notes
d
143.9 (CH]CHI), 135.6 (ArC), 133.7 (ArC), 129.6 (ArC), 127.6 (ArC),
81.7 (C]CHI), 67.0 (CH2OSi), 42.2 (CH(CH3)), 26.8 (C(CH3), 19.3
t
1. Takemoto, T.; Daigo, K. Chem. Pharm. Bull. 1958, 6, 578; Maeda, M.; Kodama, T.;
Tanaka, T.; Yoshizumi, H.; Takemoto, T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull.
1986, 34, 4892; Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.;
Nomoto, K.; Fujita, T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1985, 27,
616; Wright, J. L. C.; Falk, M.; McInnes, A. G.; Walter, J. A. Can. J. Chem. 1990, 68,
22; Zaman, L.; Arakawa, O.; Shimosu, A.; Onoue, Y.; Nishio, S.; Shida, Y.; No-
guchi, T. Toxicon 1997, 35, 205; Nomoto, K.; Takemoto, T.; Maeda, M.; In, Y.; Doi,
M.; Inoue, M.; Ishida, T. Biochem. Biophys. Res. Commun. 1992, 187, 325; Bouillon,
R.-C.; Kieber, R. J.; Skrabal, S. A.; Wright, J. L. C. Mar. Chem. 2008, 110, 18; Walter,
J. A.; Falk, M.; Wright, J. L. C. Can. J. Chem. 1994, 72, 430.
2. Tasker, R. A. R. In Molecules of Death; Waring, R. H., Steventon, G. B., Mitchell, S.
C., Eds.; Imperial College Press: London, 2002; Jeffery, B.; Barlow, T.; Moizer, K.;
Paul, S.; Boyle, C. Food Chem. Toxicol. 2004, 42, 545; Quilliam, M. A.; Wright, J. L.
C. Anal. Chem. 1989, 61, 1053A; Todd, E. C. D. J. Food Prot. 1993, 56, 69.
3. Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511.
4. Lemiere, G.; Sedehizadeh, S.; Toueg, J.; Fleary-Roberts, N.; Clayden, J. Chem.
Commun. 2011, 3745.
5. Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412.
6. Ni, Y.; Kassab, R. M.; Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 2009,
131, 17714; Ni, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J. Org. Lett.
2003, 5, 3771e3773.
7. Denmark, S. E.; Liu, J. H.-C.; Muhuhi, J. M. J. Am. Chem. Soc. 2009, 131, 14188.
8. (a) Zumbrunn, A.; Uebelhart, P.; Eugster, C. H. Helv. Chim. Acta 1985, 68, 1519;
(b) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron 2002, 58, 5909; (c) Shiina, I.;
Takasuna, Y. J.; Suzuki, R. S.; Oshiumi, H.; Komiyama, Y.; Hitomi, S.; Fukui, H.
Org. Lett. 2006, 8, 5279.
9. Nakamura, Y.; Kiyota, H.; Ueda, R.; Kuwahara, S. Tetrahedron Lett. 2005, 46,
7107; Congreve, M. S.; Holmes, A. B.; Hughes, A. B.; Looney, M. G. J. Am. Chem.
Soc. 1993, 115, 5815; Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
10. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
11. Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.; Crawford, J. J. Org. Chem.
2003, 68, 6096.
(C(CH3)3), 15.7 (CH3); MS m/z (GCeMSþ) 393 (Mꢀ Bu); HRMS found
t
t
(Mꢀ Buþ) 393.0168, C17H18OISi Mꢀ Buþ requires 393.0166.
4.6. tert-Butyl-((E)-(R)-4-iodo-2-methylbut-3-enyloxy)dime-
thylsilane E-13a22
To a suspension of CrCl2 (2.09 g, 17.0 mmol, 5.3 equiv) at 0 ꢁC in
THF (13 mL) and dioxane (5.2 mL) was added dropwise a solution of
(S)-3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-propionaldehyde
12a (574 mg, 2.84 mmol, 1 equiv) and iodoform (1.97 g, 5.00 mmol,
1.76 equiv) in THF (10 mL). The reaction mixture was stirred at 0 ꢁC
for 1 h and at room temperature for 4 h then quenched with NH4Cl
solution (3 mL) and extracted with EtOAc (3ꢂ10 mL). The combined
organic phases were washed with brine then dried (Na2SO4) and
concentrated. The residue was purified by column chromatography
(petrol then petrol/EtOAc 9:1) to afford the title compound E-13a
(573 mg, 62%) as a pale yellow oil.
Rf 0.66 (petrol/EtOAc 9:1); 1H NMR (300 MHz; CDCl3)
d 6.49 (1H,
dd, J¼7.5, 14.5, HC]CHI), 6.06 (1H, d, J¼14.5, HC]CHI), 3.48e3.45
(2H, m, CH2), 2.44e2.31 (1H, m, CH(CH3)), 1.00 (3H, d, J¼6.8, CH3),
0.90 (9H, s, (CH3)3), 0.05 (6H, s, Si(CH3)2); 13C NMR (75 MHz; CDCl3)
d
149.1 (HC]CHI), 75.0 (HC]CHI), 66.9 (CH2), 43.1 (CH(CH3)), 25.9
((CH3)3), 18.3 (C(CH3)3), 15.5 (CH3), ꢀ5.3 (Si(CH3)2); MS m/z
t
(GCeMS) 268 (Mꢀ Bu). Spectroscopic data matched that reported
in the literature.22
12. Patil, U. D. Synlett 2009, 2880.
13. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769 The enantiomeric purity of
the final product was confirmed by its coupling to the enantiopure pyrrolidine
core of the natural product, which gave a single diastereoisomer (see Ref. 4).
14. Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115; Schwartz, J.; Labinger,
J. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 333.
4.7. (R,E)-4-Iodo-2-methylbut-3-enyloxy(tert-butyl)diphe-
nylsilane E-13b
15. Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org. Chem.
A solution of (2S)-3-(tert-butyldiphenylsilylsilyloxy)-2-methyl-
propanal 12b (574 mg, 2.84 mmol, 1 equiv) and iodoform (1.97 g,
5.00 mmol, 1.76 equiv) in THF (3 mL) was slowly added to a sus-
pension of CrCl2 (2.09 g, 17.0 mmol, 6 equiv) in THF (20 mL) and
dioxane (5.24 mL) at 0 ꢁC. The mixture was stirred at this tem-
perature for 1 h and at rt for 16 h before being quenched with
aqueous NH4Cl (5 mL) and extracted with EtOAc (3ꢂ10 mL). The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
2003, 68, 6627.
16. Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
17. Brown, H. C.; Blue, C. D.; Nelson, D. J.; Bhat, N. G. J. Org. Chem. 1989, 54, 6064.
18. Elmarrouni, A.; Fukuda, A.; Heras, M.; Arseniyadis, S.; Cossy, J. J. Org. Chem.
2010, 75, 8478.
19. Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem.
2004, 69, 6294.
20. Scheck, M.; Waldmann, H. Can. J. Chem. 2002, 80, 571.
21. Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667.
22. Meiries, S.; Bartoli, A.; Decostanzi, M.; Parrain, J. L.; Commeiras, L. Org. Biomol.
Chem. 2013, 11, 4882.