A concise/catalytic approach for the construction of the C14-C28 fragment of eribulin

Article abstract of DOI:10.1039/d1ob00661d

A simple approach for the synthesis of the C14-C28 fragment of eribulin has been developed by employing a one-pot gold-catalyzed alkynol cyclization/Kishi reduction to construct the 1,5-cis-tetrahydropyran unit and a cross-metathesis/Sharpless asymmetric

Full text of DOI:10.1039/d1ob00661d

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A concise/catalytic approach for the construction
of the C14–C28 fragment of eribulin†
Cite this: DOI: 10.1039/d1ob00661d
a,b
Sibadatta Senapatia,b and Chepuri V. Ramana
*
A simple approach for the synthesis of the C14–C28 fragment of eribulin has been developed by employ-
ing a one-pot gold-catalyzed alkynol cyclization/Kishi reduction to construct the 1,5-cis-tetrahydropyran
unit and a cross-metathesis/Sharpless asymmetric dihydroxylation–cycloetherification to install the 1,4-
trans-tetrahydrofuran ring. Use of easily accessible building blocks, ease of operation and catalytic trans-
formations as key reactions for the construction of THF/THP units highlight the current approach.
Received 6th April 2021,
Accepted 26th April 2021
DOI: 10.1039/d1ob00661d
rsc.li/obc
linkage between these two rings are founded upon our recent
Introduction
report on C-glycoside synthesis via a one-pot gold-catalyzed
Halaven® is the trade name of eribulin mesylate, which is one alkynol cyclization and Kishi reduction.7
of the advanced anti-cancer drugs approved for the treatment
of metastatic breast cancer.1 Eribulin is the simplified struc-
tural analogue that was developed as a part of the total syn-
thesis of the natural product halichondrin B.2 Yet, eribulin is a
sufficiently complex macrocyclic polyether skeleton bearing 35
linear carbon atoms embedded with 19 stereocenters. Thus,
the synthesis of eribulin is a challenging task that has been
attempted across several academic and industrial research
labs.3 The commercial synthesis of eribulin by Kishi’s group
took close to 62 steps, comprising the synthesis of three
different fragments, C1–C13, C14–C26 and C27–C35, and the
Nozaki–Hiyama–Kishi (NHK) reaction as the key coupling
tools in the construction of C13–C14 and C26–C27 bonds.4
During the last two decades, several reports have appeared,
mainly on the construction of these fragments, the majority of
which rely on the proven/powerful NHK coupling reaction.3a,5
Yet, in the pursuit of finding alternative/non-infringing
approaches, attempts were made to avoid NHK coupling,
especially in the late stages, to synthesize advanced C1–C26
and C14–C35 building blocks.6 In this manuscript, we describe
a short and stereoselective approach for the synthesis of the
C14–C28 fragment of the eribulin core that comprises tetra-
hydrofuran and tetrahydropyran rings that are separated by
two carbons and bear respectively the 1,4-trans/1,5-cis-configur-
ation and an internal exo-methylene group on each. The key
reactions that we employed to construct the C-glycosidic
Results and discussion
As shown in Fig. 1, in our retrosynthetic strategy for the
orthogonally protected C14–C28 fragment 1, we intended to
use the Wittig olefination to introduce both exo-methylene
aDivision of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha
Road, Pune-411008, India. E-mail: vr.chepuri@ncl.res.in
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
†Electronic supplementary information (ESI) available: NMR and HRMS spectra
of all new compounds. See DOI: 10.1039/d1ob00661d
Fig. 1 Structure of eribulin mesylate and the targeted C14–C28 frag-
ment and the planned retrosynthetic strategy.
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units in one go. For the construction of the 1,5-cis-THP unit 3, even on gram scales.13 Initially, the gold-catalyzed cyclization
a regioselective gold catalysed cyclization of alkynol 5 and sub- of compound 11 was attempted considering the ready de-
sequent stereoselective ketal reduction in the same pot should protection of the acetonide group during the gold-catalyzed
result in the but-3-enyl C-glycoside 3. The terminal olefin in 3 alkynol cycloisomerization.14 As the yields were found to be
was opted as a handle to construct the 1,4-trans-THF ring via moderate, compound 11 was subjected to acetonide hydrolysis
cross-metathesis with the known olefin 48 having a suitably employing 60% acetic acid in water to obtain the key inter-
positioned –OH that will undergo cycloetherification after mediate 5.
Sharpless asymmetric dihydroxylation of the internal olefin
Alkynol 5 was subjected to gold-catalysed cyclization using
resulting from the cross metathesis (Scheme 1).9 The requisite Au(PPh3)Cl and AgSbF6, followed by lactol reduction with
stereocenters on the alkynol fragment 5 could be availed from Et3SiH and BF3·Et2O to afford exclusively the key 1,5-cis-C-gly-
the crotylated D-glyceraldehyde, while the stereocenter of olefin coside 12 in 73% yield over 2 steps (Scheme 2).7 The stereo-
4 could be availed by a Keck allylation8a strategy starting from chemistry of the newly formed anomeric centre in compound
1,4-butane-diol or from L-(+)-glutamic acid8b following a chiral 12 was established with the help of characteristic through-
1
pool approach.
space interactions and H NMR coupling constants.15 The free
The proposed plan to secure the C14–C28 fragment of eri- hydroxyl group in compound 12 was protected as its TBS ether
bulin was started with the synthesis of the key alkynol 5 and to complete the synthesis of the key fragment 3.
its conversion to the C-glycoside 3 (Scheme 1). Following the
Coming to the synthesis of the alkene fragment 4, the Keck
procedure reported by Loh’s group, the crotylation of aceto- allylation resulted only with 83% ee.8a To achieve a quick
nide protected D-glyceraldehyde 6 using crotyl bromide and tin access to enantiopure 4 and validate our approach, it was syn-
in DMF–H2O gave the homoallylic alcohol 7 as a major diaster- thesized from L-glutamic acid following the route developed by
eomer in 61% yield.10 The free –OH in compound 7 was pro- Shibuya’s group.8b After a good amount of experimentation
tected as its benzyl ether 8 and it was converted to alkyne 10 (Scheme 3), the cross-metathesis of fragments 3 and 4 was
by following a three-step protocol – hydroboration, oxidation carried out in excellent yields by following Lipshutz’s pro-
and the Ohira–Bestmann reaction – with an overall yield of cedure using the Grubbs 2nd generation catalyst in the pres-
63%.11 Next, the C-allylation of the terminal alkyne unit in ence of CuI in ether under reflux to afford the inseparable dia-
compound 10 was attempted initially by using n-BuLi and stereomeric mixture 13 (E/Z = 7/1).16 The next task was to con-
allylbromide, which gave the requisite product 11 in 90% struct the 1,4-trans-THF ring with the requisite absolute con-
yield.12 However, when conducted on gram scales, the yield of figuration. As planned, the free hydroxyl group in compound
the product was reduced drastically due to the decomposition 13 was converted to its mesylate and subjected to Sharpless
of the starting alkyne. After a number of trials, the modified asymmetric dihydroxylation using AD-mix-α.9,17 The asym-
alkyne allylation strategy using CuI, K2CO3 and allyl bromide metric dihydroxylation and the cycloetherification proceeded
afforded the allyl homologated product 11 in excellent yields, smoothly to provide the key disaccharide intermediate 2 with
an inseparable diastereomeric ratio 7 : 1.9c Gratifyingly, the
corresponding acetates 2-Ac and 2′-Ac, prepared for the
purpose of characterization, were found to be separable by
simple column chromatography and the relative stereo-
chemistry of the newly constructed THF ring was established
with the help of 13C NMR chemical shift comparison with
similar compounds (Fig. S1, ESI†) and also by 2D NMR
analysis.18
Having the key intermediates 2 and 2′ in our hand, the next
task was the hydrogenolysis of the –OBn group and sub-
Scheme 1 Synthesis of the key alkynol 5.
Scheme 2 Synthesis of the tetrahydropyran fragment 3.
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Conclusions
In conclusion, a simple approach for the synthesis of the C14–
C28 fragment of eribulin has been established starting with
the easily accessible building blocks that comprises a 14-step
linear sequence with an overall yield of 7.2%. The central THF
and THP rings were constructed with complete control over
the stereoselectivity employing catalytic transformations such
as gold-catalyzed alkynol cyclization, cross metathesis and
Sharpless asymmetric dihydroxylation. This synthesis provided
an important stepping stone in terms of finding novel alterna-
tives for the synthesis of the eribulin core. Work in the direc-
tion of extending the key C-gold-catalyzed alkynol cyclization/
Kishi reduction in constructing the cis-THF ring (C29–C32
being the triple bond placed between the C28–C29 carbons)
for the synthesis of larger fragments, in general, and for the
total synthesis of eribulin, in particular, is currently in
progress.
Experimental section
General information
Scheme 3 Synthesis of the key disaccharide 2.
Air and/or moisture sensitive reactions were carried out in
anhydrous solvents under an argon atmosphere in oven-dried
sequent oxidation of both the ring –OH groups to the corres- glassware. All anhydrous solvents were distilled prior to use:
ponding ketones followed by one-carbon Wittig homologation. dichloromethane and DMF from CaH2; methanol from Mg
In this pursuit, the hydrogenolysis of the major diastereomer 2 cake; and benzene and THF on Na/benzophenone.
using 10% Pd/C and H2 was found to be incomplete when con- Commercial reagents were used without purification. Column
ducted under atmospheric pressure and increasing the chromatography was carried out by using silica gel (60–120,
1
pressure resulted in the partial deprotection of the TBS group. 100–200, 230–400 mesh). H and 13C NMR chemical shifts are
At this juncture, the use of DDQ for oxidative debenzylation reported in ppm relative to chloroform-D (δ = 7.27) or TMS and
was found to be promising and provided the corresponding coupling constants (J) are reported in hertz (Hz). The following
diol in a good yield (Scheme 4).19
abbreviations are used to designate signal multiplicity: s =
The resulting diol 14 was subjected to the Swern oxidation singlet, d = doublet, t = triplet, q = quartet, sxt = sextet, hept =
followed by the Wittig olefination (with freshly prepared septet, m = multiplet, b = broad. High Resolution Mass Spectra
Ph3PvCH2 in toluene at 40 °C) to obtain the targeted frag- (HRMS) were recorded on a Q Exactive Hybrid Quadrupole
ment 1 in 75% yield over two steps.20 The resulting compound Orbitrap Mass Spectrometer, where the mass analyser used for
1 was fully characterized with the help of extensive 2D NMR analysis is orbitrap.
analysis and compared with the previous data reported for
(2R,3S,4R)-1,2-O-Isopropylidine-4-methylhex-5-ene-1,2,3-triol
similar derivatives (Table S1, ESI†). To this end, to check the
possibility of selective chain extension, compound 1 was sub-
jected to controlled desilylation with camphorsulfonic acid to
afford the selective TBS deprotected derivative 15 in an excel-
lent yield.
(7)4
At 0 °C, a solution of crotyl bromide (8.54 g, 6.5 mL,
53.8 mmol) in DMF–H2O (DMF = 50 ml & H2O = 1 ml) was
treated with tin (5.02 g, 42.3 mmol), tetrabutylammonium
iodide (710 mg, 1.9 mmol) and sodium iodide (5.76 g,
38.4 mmol) and stirred for five minutes at 0 °C followed by the
addition of a solution of acetonide protected D-glyceraldehyde
(5 g, 38.4 mmol) in DMF (10 mL). The reaction mixture was
stirred at room temperature for 24 h and filtered through a
Celite pad. The filtrate was passed through a short plug of
100–200 mesh silica gel column (petroleum ether : EtOAc,
50 : 50) to afford the crude product, which was further purified
by silica gel column chromatography (petroleum ether : THF,
96 : 4) to afford compound 7 (4.36 g, 61% yield) and compound
iso-7 (1.24 g, 17% yield) as colourless liquids.
Scheme 4 Synthesis of the eribulin C14–C28 fragment.
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Compound 7
(30.4 ml, 15.2 mmol) over a period of 10 min. The reaction
mixture was warmed to rt and stirring was continued for an
additional 4 h. After complete consumption of the starting
compound as indicated by TLC, the reaction mixture was
cooled to 0 °C and treated with ethanol (25 ml) followed by 3
N NaOH (30 mL) and H2O2 (30% w/w, 30 mL). The contents
were refluxed for 1 h and diluted with 10 mL of water. The
organic layer was separated, washed with brine and dried over
Na2SO4. The solvent was evaporated under reduced pressure
and purification of the crude product by silica gel column
chromatography (50% EtOAc in petroleum ether) gave com-
pound 9 (2.27 g, 76% yield) as a colorless oil. Rf = 0.35 (40%
EtOAc in petroleum ether); [α]2D5: +20.1 (c = 0.4, CHCl3); 1H
NMR (400 MHz): δ 0.98 (d, J = 6.9 Hz, 3H), 1.35 (s, 3H), 1.42 (s,
3H), 1.53 (ddd, J = 1.5, 6.1, 13.7 Hz, 1H), 1.76 (dt, J = 6.1, 13.7
Hz, 1H), 1.96–2.10 (m, 2H), 3.53 (dd, J = 3.1, 5.5 Hz, 1H), 3.64
(ddd, J = 6.6, 10.6, 13.6 Hz, 1H), 3.73 (ddd, J = 6.1, 10.9, 12.3
Hz, 1H), 3.92 (t, J = 7.6 Hz, 1H), 4.05 (dd, J = 6.9, 7.6 Hz, 1H),
4.18 (q, J = 6.1 Hz, 1H), 4.63 (d, J = 11.4 Hz, 1H), 4.69 (d, J =
11.4 Hz, 1H), 7.27–7.37 (m, 5H) ppm; 13C NMR (100 MHz): δ
15.0 (q), 25.2 (q), 26.6 (q), 32.4 (d), 36.5 (t), 61.0 (t), 66.6 (t),
74.0 (d), 76.7 (d), 82.9 (d), 108.5 (s), 127.6 (d, 2C), 128.3 (d, 3C),
138.4 (s) ppm; HRMS (ESI) m/z [M + Na]+ calcd for C17H26O4Na
317.1723, found 317.1727.
Rf = 0.4 (10% EtOAc in petroleum ether); [α]2D5: +41.3 (c = 5.0,
1
CHCl3); H NMR (500 MHz): δ 1.10 (d, J = 6.9 Hz, 3H), 1.35 (s,
3H), 1.42 (s, 3H), 2.16 (br. s., 1H), 2.25 (m, 1H), 3.64 (dd, J =
5.0, 6.5 Hz, 1H), 3.90 (dd, J = 8.0, 7.3 Hz, 1H), 3.97 (dd, J = 6.5,
8.0 Hz, 1H), 4.11 (td, J = 4.6, 6.5 Hz, 1H), 5.74 (ddd, J = 8.0,
10.3, 17.2 Hz, 1H), 5.06 (m, 2H) ppm; 13C NMR (125 MHz): δ
15.3 (q), 25.3 (q), 26.5 (q), 40.6 (d), 64.5 (t), 73.6 (d), 7 6.7 (d),
108.7 (s), 115.4 (t), 140.1 (d) ppm; HRMS (ESI) m/z [M + H]+
calcd for C10H19O3 187.1329, found 187.1327.
Compound iso-7
Rf = 0.4 (10% EtOAc in petroleum ether); [α]2D5: +9.2 (c = 1.9,
1
CHCl3); H NMR (400 MHz): δ 1.09 (d, J = 6.9 Hz, 3H), 1.37 (s,
3H), 1.42 (s, 3H), 1.92 (br. s., 1H), 2.36–2.46 (m, 1H), 3.61 (dd,
J = 4.6, 7.6 Hz, 1H), 3.93 (t, J = 7.6 Hz, 1H), 4.0 (t, J = 7.6 Hz,
1H), 4.07 (q, J = 6.1 Hz, 1H), 5.10–5.16 (m, 2H), 5.86 (ddt, J =
7.6, 9.2, 17.6 Hz, 1H) ppm; 13C NMR (100 MHz): δ 16.5 (q),
25.4 (q), 26.6 (q), 40.2 (d), 65.4 (t), 74.7 (d), 77.1 (d), 108.7 (s),
116.3 (t), 139.2 (d) ppm; HRMS (ESI) m/z [M + H]+ calcd for
C10H18O3Na 209.1148, found 209.1150.
(2R,3S,4R)-1,2-O-Isopropylidine-3-O-benzyl-4-methylhex-5-ene-
1,2,3-triol (8)
At 0 °C, a suspension of sodium hydride (560 mg, 14 mmol,
60 wt%) in dry DMF (15 mL) was treated with a solution of com-
pound 7 (2.0 g, 10.7 mmol) in DMF (5 mL) and stirred for
5 min, followed by the addition of benzyl bromide (1.40 mL,
11.8 mmol) dropwise. The cooling bath was removed and the
reaction mixture was stirred at room temperature for 3 h. After
complete consumption of the starting material as indicated by
TLC, the reaction was quenched with cold water, the reaction
mixture was diluted with EtOAc (30 mL) and the organic layer
was separated. The aqueous layer was extracted with EtOAc (3 ×
25 mL) and the combined organic layer was washed with brine,
dried (Na2SO4) and concentrated under reduced pressure. The
resulting crude product was purified by silica gel chromato-
graphy (5% EtOAc in petroleum) to afford the benzyl protected
compound 8 as a colourless liquid (2.91 g, 98% yield). Rf = 0.8
(10% EtOAc in petroleum ether); [α]2D5: +23.6 (c = 5.2, CHCl3); 1H
NMR (400 MHz): δ 1.13 (d, J = 6.9 Hz, 3H), 1.40 (s, 3H), 1.47 (s,
3H), 2.44 (ddd, J = 6.9, 12.9, 13.7 Hz, 1H), 3.58 (t, J = 5.3 Hz,
1H), 3.95–4.05 (m, 2H), 4.22 (ddd, J = 4.6, 6.1, 6.9 Hz, 1H), 4.64
(d, J = 11.4 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 5.07 (dt, J = 1.2,
10.7 Hz, 1H), 5.11 (dt, J = 1.5, 17.5 Hz, 1H), 5.90 (ddt, J = 7.6,
10.7, 17.5 Hz, 1H), 7.31–7.38 (m, 5H) ppm; 13C NMR (100 MHz):
δ 15.3 (q), 25.4 (q), 26.5 (q), 40.3 (d), 65.5 (t), 74.5 (t), 76.8 (d),
82.4 (d), 108.6 (s), 114.6 (t), 127.5 (d), 127.7 (d, 2C), 128.2 (d),
128.3 (d), 138.6 (s), 141.1 (d) ppm; HRMS (ESI) m/z [M + Na]+
calcd for C17H24O3Na 299.1618, found 299.1620.
(2R,3S,4R)-1,2-O-Isopropylidine-3-O-benzyl-4-methylhept-6-yne-
1,2,3-triol (10)
At 0 °C, to a stirred solution of compound 9 (2.30 g, 7.8 mmol)
in dry dichloromethane (25 mL) were added the Dess–Martin
periodinane reagent (4.31 g, 10.2 mmol) and sodium bicar-
bonate (1.97 g, 23.4 mmol) and stirring was continued for 1 h
at room temperature. After completion of the reaction, the
reaction mixture was treated with sat. NaHCO3 (15 mL) and
diluted with dichloromethane (20 mL). The organic layer was
separated and washed with brine, dried (Na2SO4) and concen-
trated under reduced pressure. The resulting crude aldehyde
was forwarded for the next step without any purification.
The above crude aldehyde (2.28 g, 7.8 mmol) was dissolved
in methanol (40 mL) and treated with potassium carbonate
(3.23 g, 23.4 mmol) and the Ohira–Bestmann reagent (2.23 g,
10.14 mmol) and stirred for 24 h at room temperature. The
reaction mass was filtered through a Celite pad and the filtrate
was concentrated under reduced pressure. Purification of the
crude product by silica gel column chromatography (5% EtOAc
in petroleum ether) gave alkyne 10 as a colourless liquid
(1.87 g, 83% yield). Rf = 0.6 (10% EtOAc in petroleum ether);
1
[α]2D5: +10.1 (c = 3.0, CHCl3); H NMR (400 MHz): δ 1.04 (d, J =
7.0 Hz, 3H), 1.38 (s, 3H), 1.46 (s, 3H), 2.04–2.13 (m, 2H), 2.22
(ddd, J = 2.3, 6.1, 16.8 Hz, 1H), 2.34 (ddd, J = 2.3, 7.6, 16.8 Hz,
1H), 3.80 (dd, J = 3.1, 6.1 Hz, 1H), 3.94 (dd, J = 6.1, 7.9 Hz, 1H),
4.07 (dd, J = 6.5, 7.9 Hz, 1H), 4.16 (q, J = 6.1 Hz, 1H), 4.67 (d, J
= 11.4 Hz, 1H), 4.74 (dd, J = 11.4 Hz, 1H), 7.28–7.34 (m, 1H),
7.34–7.38 (m, 4H) ppm; 13C NMR (100 MHz): δ 14.3 (q), 23.2
(2R,3S,4R)-1,2-O-Isopropylidine-3-O-benzyl-4-methylhexane-
1,2,3,6-tetraol (9)
At 0 °C, a stirred solution of compound 8 (2.80 g, 10.1 mmol) (t), 25.2 (d), 26.7 (d), 35.1 (d), 66.3 (t), 69.7 (d), 74.6 (t), 76.8 (d),
in dry THF (20 mL) was treated with a solution of 0.5 M 9-BBN 80.8 (d), 83.1 (s), 108.6 (s), 127.6 (d, 3C), 128.3 (d, 2C), 138.5 (s)
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ppm; HRMS (ESI) m/z [M + Na]+ calcd for C18H24O3Na, ((2R,3S,4R,6S)-3-(Benzyloxy)-6-(but-3-en-1-yl)-4-
311.1618, found 311.1619.
methyltetrahydro-2H-pyran-2-yl)methanol (12)
At room temperature, to a solution of alkynol 5 (900 mg,
3.12 mmol) in dry dichloromethane (10 mL) in a round
bottom flask covered with silver foil was added Au(PPh3)Cl
(15 mg, 31.2 µmol, 1 mol%) followed by AgSbF6 (11 mg,
31.2 µmol, 1 mol%) and stirred for 3 h. After complete con-
sumption of the starting material, triethyl silane (2.50 mL,
15.6 mmol) was added to the reaction mixture and cooled to
0 °C and treated slowly with BF3·Et2O (1.9 mL, 15.6 mmol).
Stirring was continued at 0 °C for 1 h. After complete con-
(2R,3S,4R)-1,2-O-Isopropylidine-3-O-benzyl-4-methyl dec-9-en-
6-yne-1,2,3-triol (11)
At 0 °C, a stirred solution of alkyne 10 (1.0 g, 3.5 mmol) in
dry DMF (10 mL) was treated in sequence with allyl bromide
(0.33 mL, 3.8 mmol), copper iodide (66 mg, 0.35 mmol), pot-
assium carbonate (527 mg, 3.8 mmol), sodium sulphite
(218 mg, 1.7 mmol) and DBU (0.26 mL, 1.7 mmol). The reac-
tion mixture was warmed to rt and stirred for 3 h. The reac-
tion mixture was diluted with EtOAc (50 mL) and water
(50 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (2 × 25 mL). The combined
organic layer was washed with water and brine, dried
(Na2SO4) and concentrated under reduced pressure.
Purification of the resulting crude product by silica gel
column chromatography (5% EtOAc in petroleum ether)
afforded the allylated compound 11 (1.08 g, 95% yield) as a
colourless liquid. Rf = 0.6 (10% EtOAc in petroleum ether);
sumption of the starting material,
5 mL of saturated
ammonium chloride was added and the reaction mixture was
extracted with dichloromethane (2 × 25 mL). The combined
organic layer was washed with brine, dried and concentrated
under reduced pressure. The resulting crude product was puri-
fied by silica gel chromatography (10% EtOAc in petroleum
ether) to afford compound 12 (660 mg, 73% yield) as a colour-
less liquid. Rf = 0.4 (10% EtOAc in petroleum ether); [α]2D5:
+1.02 (c = 5.0, CHCl3); 1H NMR (400 MHz): δ 1.09 (d, J = 6.3 Hz,
3H), 1.10–1.17 (m, 1H), 1.52 (ddd, J = 6.7, 9.8, 14.0 Hz, 1H),
1.62 (td, J = 7.9, 14.0 Hz, 1H), 1.68–1.80 (m, 2H), 2.06–2.26 (m,
3H), 3.02 (t, 1H, J = 9.2 Hz, 1H), 3.29 (ddd, J = 2.5, 4.9, 9.2 Hz,
1H), 3.42 (dt, J = 5.5, 11.0 Hz, 1H), 3.74 (dt, J = 5.5, 11.0 Hz,
1H), 3.89 (ddd, J = 2.4, 5.5, 11.6 Hz, 1H), 4.63 (s, 2H), 4.97 (d, J
= 9.8 Hz, 1H), 5.03 (dd, J = 1.2, 17.1 Hz, 1H), 5.83 (ddt, J = 6.7,
9.8, 17.1 Hz, 1H), 7.27–7.42 (m, 5H) ppm; 13C NMR (100 MHz):
δ 18.6 (q), 29.9 (t), 34.7 (t), 36.9 (d), 39.7 (t), 62.8 (t), 74.7 (t),
76.4 (d), 80.3 (d), 80.7 (d), 114.5 (t), 127.8 (d), 127.9 (d, 2C),
128.4 (d, 2C), 138.1 (s), 138.4 (d) ppm; HRMS (ESI) m/z [M +
H]+ calcd for C18H27O3 291.1955, found 291.1957.
1
[α]2D5: +11.6 (c = 4.8, CHCl3); H NMR (500 MHz): δ 1.02 (d, J =
6.9 Hz, 3H), 1.37 (s, 3H), 1.44 (s, 3H), 2.03 (ddd, J = 3.4, 6.9,
14.9 Hz, 1H), 2.23 (ddt, J = 2.3, 6.5, 14.5 Hz, 1H), 2.35 (ddt, J =
2.3, 8.0, 16.4 Hz, 1H), 2.97 (ddd, J = 2.1, 4.1, 6.7 Hz, 2H), 3.79
(dd, J = 3.4, 5.7 Hz, 1H), 3.92 (dd, J = 6.5, 8.0 Hz, 1H), 4.05
(dd, J = 6.1, 8.0 Hz, 1H), 4.16 (q, J = 6.1 Hz, 1H), 4.66 (d, J =
11.1 Hz, 1H), 4.74 (d, J = 11.1 Hz, 1H), 5.12 (ddt, J = 1.9, 3.4,
9.9 Hz, 1H), 5.33 (ddt, J = 1.5, 3.4, 16.8 Hz, 1H), 5.83 (ddt, J =
5.3, 10.3, 16.8 Hz, 1H), 7.30 (dd, J = 4.6, 8.8 Hz, 1H),
7.34–7.36 (m, 4H) ppm; 13C NMR (125 MHz): δ 14.4 (q), 23.1
(t), 23.7 (t), 25.3 (q), 26.7 (q), 35.6 (d), 66.5 (t), 74.7 (t), 77.0
(d), 78.1 (s), 81.0 (d), 81.2 (s), 108.6 (s), 115.7 (t), 127.6 (d,
3C), 128.3 (d, 2C), 133.2 (d), 138.7 (s) ppm; HRMS (ESI) m/z
[M + Na]+ calcd for C21H28O3Na 351.1931, found 351.1933.
(((2R,3S,4R,6S)-3-(Benzyloxy)-6-(but-3-en-1-yl)-4-
methyltetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)
dimethylsilane (3)
To a stirred solution of compound 12 (620 mg, 2.13 mmol) in
dry DMF (10 mL) was added imidazole (436 mg, 6.40 mmol)
followed by TBSCl (354 mg, 2.35 mmol) at 0 °C. After stirring
(2R,3S,4R)-3-O-Benzyl-4-methyl dec-9-en-6-yne-1,2,3-triol (5)
A solution of compound 11 (1.07 g, 3.26 mmol) in 60% acetic for 6 h at room temperature, the reaction was quenched with
acid in water (20 mL) was stirred at room temperature for 12 h. water (10 mL) and the reaction mixture was diluted with EtOAc
The reaction mixture was concentrated under reduced pressure (25 mL). The organic layer was separated and the aqueous
and the resulting crude product was purified by column layer was extracted with EtOAc (2 × 20 mL). The combined
chromatography (40% EtOAc in petroleum ether) to afford diol organic layer was washed with brine, dried (Na2SO4) and con-
5 (910 mg, 97% yield) as a colourless liquid. Rf = 0.5 (50% centrated under reduced pressure. The residue was purified by
EtOAc in petroleum ether); [α]2D5: +7.1 (c = 3.2, CHCl3); 1H NMR silica gel chromatography (5% EtOAc in petroleum ether) to
(500 MHz): δ 1.07 (d, J = 6.9 Hz, 3H), 2.00–2.08 (m, 1H), afford compound 3 (830 mg, 96% yield) as a colourless liquid.
2.20–2.35 (m, 2H), 2.93–2.97 (m, 2H), 3.67 (dd, J = 3.9, 6.3 Hz, Rf = 0.8 (10% EtOAc in petroleum ether); [α]2D5: +5.8 (c = 2.2,
1H), 3.71–3.77 (m, 2H), 3.80 (ddd, J = 3.1, 5.3, 8.4 Hz, 1H), 4.64 CHCl3); 1H NMR (400 MHz): δ 0.10 (s, 3H), 0.11 (s, 3H), 0.94 (s,
(d, J = 11.4 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 5.10 (ddt, J = 1.5, 9H), 1.05 (d, J = 6.6 Hz, 3H), 1.07–1.13 (m, 1H), 1.49 (ddd, J =
3.8, 9.9 Hz, 1H), 5.31 (ddt, J = 2.3, 3.8, 16.8 Hz, 1H), 5.83 (ddt, J 6.1, 11.0, 14.0 Hz, 1H), 1.55–1.78 (m, 3H), 2.13 (dt, J = 7.9, 14.6
= 4.6, 9.9, 16.8 Hz, 1H), 7.26–7.37 (m, 5H) ppm; 13C NMR Hz, 1H), 2.21 (dt, J = 7.9, 14.6 Hz, 1H), 3.09 (t, J = 9.5 Hz, 1H),
(125 MHz): δ 14.8 (q), 23.1 (t), 23.7 (t), 34.8 (d), 63.8 (t), 71.8 3.17 (dt, J = 2.3, 9.2 Hz, 1H), 3.35 (dt, J = 4.9, 10.4 Hz, 1H), 3.89
(d), 74.7 (t), 78.3 (s), 81.0 (s), 82.0 (d), 115.7 (t), 127.8 (d, 3C), (dd, J = 3.0, 11.6 Hz, 2H), 4.60 (d, J = 11.0 Hz, 1H), 4.72 (d, J =
128.5 (d, 2C), 133.2 (d), 138.2 (s) ppm; HRMS (ESI) m/z [M + 11.0 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1H), 5.03 (d, J = 17.1 Hz, 1H),
H]+ calcd for C18H25O3 289.1798, found 289.1801.
5.84 (ddt, J = 6.7, 10.4, 17.1 Hz, 1H), 7.31 (dd, J = 2.4, 6.1 Hz,
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1H), 7.33–7.40 (m, 4H) ppm; 13C NMR (100 MHz); δ −5.3 (q), trated under reduced pressure. The resulting crude product
−4.8 (q), 18.4 (s), 18.8 (q), 26.0 (q, 3C), 30.0 (t), 35.0 (t), 36.9 was used for the next step without purification.
(d), 39.9 (t), 63.2 (t), 74.5 (t), 76.0 (d), 80.2 (d), 81.2 (d), 114.4
The above crude mesylate (330 mg, 0.4 mmol) was dissolved
t
(t), 127.6 (d), 128.1 (d, 2C), 128.4 (d, 2C), 138.7 (s), 138.8 (d) in BuOH : H2O (10 mL, 1 : 1, v/v) and cooled to 0 °C in a cryo-
ppm; HRMS (ESI) m/z [M + H]+ calcd for C24H41O3Si 405.2819, stat and treated with methane sulphonamide (114 mg,
found 405.2828.
1.2 mmol) and AD-mix-α (800 mg, 2.0 g mmol−1). Stirring was
continued for 96 h at 0 °C. After complete consumption of the
starting compound as indicated by TLC, the reaction was
quenched with saturated sodium sulfite solution (5 mL) and
the reaction mixture was diluted with EtOAc (25 mL). The
organic layer was separated and the aqueous layer was
extracted with EtOAc (2 × 15 mL). The combined organic layer
washed with brine, dried (Na2SO4) and concentrated under
reduced pressure. The resulting crude product was purified by
silica gel column chromatography (15% EtOAc in petroleum
ether) to afford compounds 2 and 2′ in a diastereomeric
mixture (217 mg, 71% yield) as a colourless liquid. Rf = 0.4
(20% EtOAc in petroleum ether).
To the stirred solution of the diastereomeric mixture of
compounds 2 and 2′ (217 mg, 285 µmol) in dry dichloro-
methane (5 mL) were added triethylamine (0.2 mL,
1.43 mmol), acetic anhydride (81 µL, 855 µmol), and DMAP
(7 mg, 57 µmol) at 0 °C and stirred at room temperature for
6 h. The reaction mixture was concentrated and the residue
was dissolved in EtOAc (25 mL), washed with brine, dried
(Na2SO4) and concentrated under reduced pressure.
Purification of the crude product by silica gel chromato-
graphy gave compounds 2-Ac (180 mg, 79% yield) and 2′-Ac
(26 mg, 11% yield) as colourless liquids.
Compound 2-Ac. Rf = 0.3 (10% EtOAc in petroleum ether);
[α]2D5: −0.3 (c = 4.9, CHCl3); 1H NMR (400 MHz): δ 0.08 (s, 3H),
0.09 (s, 3H), 0.92 (s, 9H), 1.03 (d, J = 6.4 Hz, 1H), 1.05 (s, 9H),
1.35–1.43 (m, 1H), 1.51–1.75 (m, 10H), 1.80 (ddd, J = 5.1, 9.1,
14.1 Hz, 1H), 2.05–2.07 (m, 1H), 2.09 (s, 3H), 3.08 (t, J = 9.5
Hz, 1H), 3.15 (ddd, J = 1.6, 3.4, 9.3 Hz, 1H), 3.69 (td, J = 2.3,
5.8 Hz, 2H), 3.29–3.37 (m, 1H), 3.84 (dd, J = 1.6, 11.5 Hz, 1H),
3.70 (td, J = 2.5, 5.9 Hz, 2H), 3.90 (dd, J = 3.5, 11.6 Hz, 1H),
3.95 (ddd, J = 3.6, 5.8, 9.1 Hz, 1H), 4.13 (ddd, J = 5.9, 9.3, 11.8
Hz, 1H), 4.58 (d, J = 10.9 Hz, 1H), 4.71 (d, J = 10.9 Hz, 1H),
5.29 (t, J = 3.9 Hz, 1H), 7.29–7.45 (m, 11H), 7.67 (dd, J = 1.5,
7.8 Hz, 4H) ppm; 13C NMR (100 MHz): δ −5.3 (q), −4.8 (q),
18.4 (s), 18.7 (q), 19.2 (s), 21.1 (q), 25.4 (t), 26.0 (q, 3C), 26.9
(q, 3C), 29.1 (t), 32.1 (t), 32.3 (t), 36.9 (d), 39.3 (t), 39.9 (t), 63.2
(t), 63.8 (t), 74.5 (t), 75.5 (d), 76.4 (d), 76.9 (t), 80.1 (d, 2C),
81.3 (d), 127.6 (q, 4C), 127.6 (d), 128.1 (d, 2C), 128.4 (q, 2C),
129.5 (q, 2C), 134.0 (s, 2C), 135.6 (q, 4C), 138.7 (s), 17.05 (s)
ppm; HRMS (ESI) m/z [M + H]+ calcd for C47H71O7Si2
803.4733, found 803.4734.
Synthesis of 7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ol (4)8b
Compound 4 was prepared following the literature procedure
reported by Shibuya and co-workers.8b
Rf = 0.3 (10% EtOAc in petroleum ether); [α]2D5: +4.1 (c = 2.2,
1
CHCl3); H NMR (400 MHz): δ 1.07 (s, 9H), 1.48–1.57 (m, 1H),
1.63–1.74 (m, 3H), 2.16 (br. s., 1H), 2.20 (ddt, J = 1.0, 6.5, 14.0
Hz, 1H), 2.30 (dddt, J = 1.1, 5.1, 6.5, 11.4 Hz, 1H), 3.65–3.69
(m, 1H), 3.71 (t, J = 6.0 Hz, 2H), 5.11–5.17 (m, 2H), 5.85 (ddt, J
= 7.0, 9.3, 16.8 Hz, 1H), 7.37–7.47 (m, 6H), 7.67–7.70 (m, 4H)
ppm; 13C NMR (100 MHz); δ 19.2 (s), 26.8 (q, 3C), 28.8 (t), 33.5
(t), 41.9 (t), 64.1 (t), 70.5 (d), 117.8 (t), 127.6 (d, 4C), 129.6 (d,
3C), 133.7 (s, 2C), 135.0 (d), 135.6 (d, 3C) ppm; HRMS (ESI) m/z
[M + H]+ calcd for C23H33O2Si 369.2244, found 369.2249.
Synthesis of compound 13 via cross metathesis of 3 with 4
Under argon, to a solution of compounds 3 (340 mg,
840 µmol) and 4 (929 mg, 2.52 mmol) in dry diethyl ether
(20 mL) were added sequentially CuI (16 mg, 84 µmol) and
Grubb’s 2nd generation catalyst (21 mg, 25.2 µmol) at room
temperature. The reaction mixture was kept at 40 °C for 36 h.
The solvent was evaporated under reduced pressure and the
crude product was purified by silica gel column chromato-
graphy (5% EtOAc in petroleum ether) to afford compound 13
(507 mg, 81% yield) as a colourless liquid. Rf = 0.3 (10% EtOAc
in petroleum ether); [α]2D5: +1.04 (c = 1.1, CHCl3); 1H NMR
(400 MHz); δ 0.09 (s, 3H), 0.10 (s, 3H), 0.93 (s, 9H), 1.02–1.05
(m, 3H), 1.06 (s, 9H), 1.44–1.55 (m, 2H), 1.60–1.72 (m, 7H),
2.07–2.25 (m, 5H), 3.08 (t, J = 9.5 Hz, 1H), 3.15 (ddd, J = 1.9,
3.5, 9.3 Hz, 1H), 3.28–3.39 (m, 1H), 3.61 (ddd, J = 4.1, 7.7, 11.9
Hz, 1H), 3.70 (d, J = 5.8 Hz, 2H), 3.83–3.93 (m, 2H), 4.59 (d, J =
10.9 Hz, 1H), 4.71 (d, J = 10.9 Hz, 1H), 5.44 (dt, J = 7.1, 15.1 Hz,
1H), 5.54 (dt, J = 6.6, 15.1 Hz, 1H), 7.29–7.45 (m, 10H),
7.65–7.70 (m, 5H) ppm; 13C NMR (100 MHz): δ −5.2 (q), −4.8
(q), 18.4 (s), 18.7(q), 19.2 (s), 26.0 (q, 3C), 26.8 (q, 3C), 28.8 (t),
28.9 (t), 33.4 (t), 35.5 (t), 36.9 (d), 39.9 (t), 40.7 (t), 63.2 (t), 64.1
(t), 70.8 (d), 74.5 (t), 76.0 (d), 80.2 (d), 81.2 (d), 126.1 (d), 127.6
(d, 5C), 128.1 (d, 2C), 128.4 (d, 2C), 129.6 (d, 2C), 133.8 (s),
134.0 (d), 134.2 (s) 135.6 (d, 4C), 138.7 (s) ppm; HRMS (ESI)
m/z [M + H]+ calcd for C45H69O5Si2 745.4678, found 745.4684.
Synthesis of disaccharide 2
Compound 2′-Ac. Rf = 0.3 (10% EtOAc in petroleum ether);
1
At 0 °C, a solution of compound 13 (300 mg, 0.4 mmol) and [α]2D5: −0.4 (c = 1.7, CHCl3); H NMR (400 MHz): δ 0.08 (s, 3H),
triethyl amine (0.17 mL, 1.21 mmol) in dry dichloromethane 0.09 (s, 3H), 0.92 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H), 1.06 (s, 9H),
(10 mL) was treated with methane sulfonyl chloride (0.047 mL, 1.51–1.74 (m, 12H), 2.05 (s, 3H), 2.43 (dt, J = 7.1, 14.0 Hz, 1H),
0.6 mmol) and stirred at the same temperature for 1 h. The 3.09 (t, J = 9.5 Hz, 1H), 3.16 (ddd, J = 1.6, 3.3, 9.3 Hz, 1H),
reaction was quenched with water and the reaction mixture 3.30–3.40 (m, 1H), 3.70 (t, J = 5.8 Hz, 2H), 3.85 (dd, J = 1.4, 11.4
was diluted with dichloromethane (10 mL). The organic layer Hz, 1H), 3.91 (dd, J = 3.3, 11.5 Hz, 1H), 3.94–4.03 (m, 2H), 4.60
was separated, washed with brine, dried (Na2SO4) and concen- (d, J = 10.9 Hz, 1H), 4.71 (d, J = 10.9 Hz, 1H), 4.93 (dt, J = 3.3,
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6.8 Hz, 1H), 7.28–7.45 (m, 11H), 7.67 (dd, J = 1.5, 7.8 Hz, 4H) NMR (100 MHz): δ −5.3 (q), −4.9 (q), 18.4 (s), 18.7 (q), 19.2 (s),
ppm; 13C NMR (100 MHz): δ −5.3 (q), −4.8 (q), 18.4 (s), 18.7 26.0 (q, 3C), 26.9 (q, 3C), 29.2 (t), 29.3 (t), 31.2 (t), 32.9 (t), 37.0
(q), 19.2 (s), 21.2 (q), 25.9 (q, 3C), 26.9 (q, 3C), 28.6 (t), 29.2 (t), (d), 40.1 (t), 40.6 (t), 63.2 (t), 63.8 (t), 74.6 (t), 76.0 (d), 76.8 (d,
31.6 (t), 32.4 (t), 36.9 (d), 37.5 (t), 39.9 (t), 63.2 (t), 63.7 (t), 74.5 2C), 80.3 (d), 81.4 (d), 84.2 (d), 127.6 (d, 4C), 127.7 (d), 128.0
(t), 76.2 (d), 77.0 (d), 78.7 (d), 80.1 (d), 81.2 (d), 82.6 (d), 127.6 (d, 2C), 128.4 (d, 2C), 129.5 (d, 2C), 134.0 (s, 2C), 135.6 (d, 4C),
(d, 4C), 127.6 (d), 128.1 (d, 2C), 128.4 (d, 2C), 129.5 (d, 2C), 138.5 (s) ppm; HRMS (ESI) m/z [M + H]+ calcd for C45H69O6Si2
134.0 (s, 2C), 135.5 (d, 4C), 138.7 (s), 170.8 (s) ppm; HRMS 761.4627, found 761.4623.
(ESI) m/z [M + Na]+ calcd for C47H70O7NaSi2 825.4552, found
825.4542.
Synthesis of compound 14
To a stirred solution of compound 2 (118 mg, 0.15 mmol) in
dry dichloromethane (5 mL) and water (1 mL) was added DDQ
Compound 2
To a stirred solution of compound 2-Ac (150 mg, 187 µmol) (106 mg, 0.46 mmol) at room temperature. The reaction
in methanol (5 mL) was added potassium carbonate (77 mg, mixture was purged with nitrogen gas and stirred under reflux
560 µmol) at room temperature. The reaction mixture was under an inert atmosphere for 9 h. After completion of the
kept at room temperature for 3 h. After consumption of the reaction, the reaction was quenched with saturated NaHCO3
starting material, methanol was removed under reduced solution (5 mL), the organic layer was separated, and the
pressure. The crude reaction mixture was diluted with ethyl aqueous layer was extracted with dichloromethane (3 × 10 mL).
acetate (5 mL) and partitioned with water (5 mL). The com- The combined organic layer was washed with brine, dried
bined organic layer was washed with brine, dried over Na2SO4 (Na2SO4) and concentrated under reduced pressure.
and concentrated under reduced pressure. Purification of the Purification of the reaction mixture by silica gel column
reaction mixture by silica gel column chromatography gave chromatography gave the diol 14 (80 mg, 77% yield) as a col-
compound 2 (138 mg, 97% yield) as a colourless liquid. Rf = ourless liquid. Rf = 0.5 (30% EtOAc in petroleum ether); [α]2D5:
1
0.4 (20% EtOAc in petroleum ether); [α]2D5: +2.5 (c = 1.5, −0.15 (c = 0.3, CHCl3); H NMR (400 MHz): δ 0.11 (s, 3H), 0.11
1
CHCl3); H NMR (400 MHz): δ 0.09 (s, 3H), 0.10 (s, 3H), 0.92 (s, 3H), 0.91 (s, 9H), 1.05 (s, 9H), 1.06 (d, J = 6.3 Hz, 3H),
(s, 9H), 1.05 (s, 12H), 1.08–1.16 (m, 1H), 1.52–1.72 (m, 10H), 1.47–1.80 (m, 10H), 1.96 (d, J = 4.9 Hz, 1H), 2.07 (dd, J = 6.3,
2.08 (dd, J = 6.3, 13.3 Hz, 1H), 2.35 (d, J = 3.8 Hz, 1H), 3.08 (t, 13.1 Hz, 1H), 3.15 (t, J = 8.6 Hz, 1H), 3.25 (td, J = 4.6, 8.6 Hz,
J = 9.6 Hz, 1H), 3.22 (ddd, J = 2.1, 3.6, 9.3 Hz, 1H), 3.38–3.45 1H), 3.39–3.48 (m, 1H), 3.66–3.72 (m, 3H), 3.74 (d, J = 0.9 Hz,
(m, 1H), 3.69 (td, J = 2.0, 6.1 Hz, 2H), 3.78 (ddd, J = 2.7, 6.0, 1H), 3.76 (ddd, J = 2.8, 6.1, 7.1 Hz, 1H), 3.91 (dd, J = 4.5, 9.9
8.6 Hz, 1H), 3.84–3.91 (m, 2H), 4.15–4.25 (m, 2H), 4.60 (d, J = Hz, 1H), 4.18 (dd, J = 6.1, 9.3 Hz, 1H), 4.22 (d, J = 3.0 Hz, 1H),
11.0 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 7.28–7.45 (m, 11H), 7.36–7.45 (m, 6H), 7.65–7.69 (m, 4H) ppm; 13C NMR
7.67 (dd, J = 1.5, 7.6 Hz, 4H) ppm; 13C NMR (100 MHz); δ −5.3 (100 MHz): δ −5.7 (q), −5.6 (q), 17.9 (q), 18.1 (s), 19.2 (s), 24.3
(q), −4.9 (q), 18.4 (s), 18.7 (q), 19.2 (s), 24.1 (t), 26.0 (q, 3C), (t), 25.8 (q, 3C), 26.9 (q, 3C), 29.1 (t), 31.7 (t), 32.5 (t), 36.9 (d),
26.8 (q, 3C), 29.1 (t), 31.6 (t), 32.5 (t), 36.8 (d), 39.8 (t), 41.4 (t), 38.6 (t), 41.5 (t), 63.8 (t), 66.8 (t), 73.2 (d), 76.4 (d), 76.8 (d),
63.1 (t), 63.8 (t), 73.1 (d), 74.5 (t), 75.9 (d), 76.7 (d), 80.0 (d), 77.2 (d), 78.1 (d), 81.8 (d), 127.6 (d, 4C), 129.5 (d, 2C), 134.0 (s,
81.3 (d), 82.1 (d), 127.6 (d, 4C), 127.7 (s), 128.0 (d, 2C), 128.4 2C), 135.6 (d, 4C) ppm; HRMS (ESI) m/z [M + H]+ calcd for
(d, 2C), 129.5 (d, 3C), 134.0 (s), 135.5 (d, 4C), 138.5 (s) ppm; C38H63O6Si2 671.4158, found 671.4158.
HRMS (ESI) m/z [M + H]+ calcd for C45H69O6Si2 761.4627,
found 761.4617.
Synthesis of the eribulin fragment C14–C28 (1)
At −78 °C, to a solution of trifluoroacetic anhydride (77 µL,
551 µmol) in dry dichloromethane (0.5 mL) was added DMSO
Compound 2′
To a stirred solution of compound 2′-Ac (20 mg, 25 µmol) in (78 µL, 1.10 mmol) in dichloromethane (0.5 mL) and stirred
methanol (2 mL) was added potassium carbonate (10 mg, for 15 minutes. To this mixture, a solution of diol 14 (74 mg,
75 µmol) at room temperature and stirred for 3 h. The reaction 110 µmol) in dichloromethane (0.5 mL) was added dropwise
mixture was concentrated and dissolved in EtOAc (5 mL). The and the mixture was stirred for another 30 min prior to the
organic layer was washed with brine, dried (Na2SO4) and con- addition of diisopropylethylamine (0.3 mL, 1.65 mmol). Then,
centrated under reduced pressure. Purification of the reaction the reaction mixture was warmed to −20 °C and stirred for 1 h.
mixture by silica gel column chromatography gave compound After complete consumption of the starting material, as indi-
2′ (18 mg, 95% yield) as a colourless liquid. Rf = 0.4 (20% cated by TLC, the reaction mixture was warmed to room temp-
EtOAc in petroleum ether). [α]2D5: −0.2 (c = 0.34, CHCl3); 1H erature and treated with cold water (2 mL). The organic layer
NMR (400 MHz): δ 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.05 was separated and the aqueous layer was extracted with di-
(s, 12H), 1.11 (q, J = 12.0 Hz, 1H), 1.48–1.77 (m, 11H), 2.31 (dd, chloromethane (3 × 5 mL). The combined organic layer was
J = 6.9, 13.3 Hz, 1H), 3.03 (t, J = 9.5 Hz, 1H), 3.20 (ddd, J = 2.1, washed with brine, dried (Na2SO4) and concentrated under
4.1, 9.4 Hz, 1H), 3.31–3.43 (m, 1H), 3.68 (t, J = 5.9 Hz, 2H), reduced pressure. The resulting crude product was used for
3.80–3.90 (m, 3H), 3.96 (dt, J = 6.8, 12.8 Hz, 1H), 4.01–4.11 (m, the next step without any purification.
1H), 4.59 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 10.8 Hz, 1H),
To a stirred solution of methyltriphenylphosphonium
7.27–7.25 (m, 11H), 7.67 (dd, J = 1.6, 7.8 Hz, 4H) ppm; 13C bromide (187 mg, 525 µmol) in dry toluene (5 mL) was added
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potassium tert-butoxide (59 mg, 525 µmol) at 0 °C. The solu-
tion was refluxed for 1 h and then cooled to 40 °C. The yellow
Acknowledgements
supernatant solution was transferred to a 40 °C pre-heated The authors acknowledge the CSIR (India) for funding this
solution of crude diketone (70 mg, 105 µmol) in toluene project and for a research fellowship to S. S.
(1 mL) and kept for 30 minutes at the same temperature. The
reaction mixture was cooled to room temperature and diluted
with water (10 mL) and ethyl acetate (20 mL). The organic layer
was separated, washed with brine, dried (Na2SO4) and concen-
Notes and references
trated under reduced pressure. Purification of the crude
product by column chromatography (10% EtOAc in petroleum
ether) gave diene 1 (55 mg, 75% yield) as a colourless liquid. Rf
= 0.5 (10% EtOAc in petroleum ether); [α]2D5: −5.8 (c = 1.1,
CHCl3); 1H NMR (400 MHz): δ 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s,
9H), 1.05 (s, 9H), 1.08 (d, J = 6.1 Hz, 3H), 1.10–1.14 (m, 1H),
1.47–1.57 (m, 3H), 1.61–1.71 (m, 5H), 1.77 (ddd, J = 2.0, 4.4,
12.9 Hz, 1H), 2.19–2.30 (m, 2H), 2.63 (ddd, J = 1.6, 6.4, 15.4
Hz, 1H), 3.55–3.62 (m, 1H), 3.68 (td, J = 1.5, 6.0 Hz, 2H), 3.75
(t, J = 6.0 Hz, 1H), 3.80 (dd, J = 5.9, 10.1 Hz, 1H), 3.95 (dd, J =
5.4, 10.1 Hz, 1H), 3.98 (t, J = 6.5 Hz, 1H), 4.39 (d, J = 6.4 Hz,
1H), 4.83 (d, J = 1.5 Hz, 1H), 4.84 (d, J = 2.0 Hz, 1H), 4.90 (s,
1H), 4.96 (d, J = 1.9 Hz, 1H), 7.36–7.43 (m, 6H), 7.66–7.68 (m,
4H) ppm; 13C NMR (100 MHz): δ −5.3 (q), −5.1 (q), 17.8 (q),
18.3 (s), 19.2 (s), 25.9 (q, 3C), 26.8 (q, 3C), 29.1 (t), 31.2 (t), 31.6
(t, 2C), 35.7 (d), 38.9 (t), 42.9 (t), 63.8 (t), 63.8 (t), 77.0 (d), 77.2
(d), 79.0 (d), 79.4 (d), 104.6 (t), 104.7 (t), 127.6 (d, 4C), 129.5 (d,
2C), 134.0 (s, 2C), 135.6 (d, 4C), 149.4 (s), 151.8 (s) ppm; HRMS
(ESI) m/z [M + H]+ calcd for C40H63O4Si2 663.4259, found
663.4263.
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Compound 15
To a stirred solution of diene 1 (13 mg, 19.6 µmol) in metha-
nol (2 mL) was added camphorsulfonic acid (1 mg, 3.9 µmol)
at 0 °C. After stirring the reaction mixture for 2 h at the same
temperature, triethylamine was added and concentrated under
reduced pressure. Purification of the crude product by column
chromatography gave the TBS deprotected compound 15
(10 mg, 93% yield) as a colourless liquid. Rf = 0.2 (20% EtOAc
in petroleum ether); 1H NMR (400 MHz): δ 1.05 (s, 9H), 1.09
(d, J = 6.5 Hz, 3H), 1.52–1.71 (m, 10H), 1.79 (ddd, J = 2.0, 4.6,
12.9 Hz, 1H), 2.22–2.30 (m, 2H), 2.64 (ddd, J = 1.8, 6.4, 15.4
Hz, 1H), 3.58–3.65 (m, 1H), 3.68 (td, J = 1.3, 5.9 Hz, 1H),
3.80–3.92 (m, 3H), 4.0 (dt, J = 6.4, 12.3 Hz, 1H), 4.40 (d, J = 5.4
Hz, 1H), 4.74 (s,1H), 4.81–4.85 (m, 2H), 4.98 (dd, J = 2.0, 4.1
Hz, 1H), 7.36–7.44 (m, 6H), 7.66 (dd, J = 1.5, 7.8 Hz, 4H) ppm;
13C NMR (100 MHz): δ 17.6 (q), 19.2 (s), 26.8 (q, 3C), 29.1 (t),
31.4 (t), 31.5 (t), 31.7 (t), 35.4 (d), 38.9 (t), 42.5 (t), 63.1 (t), 63.8
(t), 77.1 (d), 77.2 (d), 78.2 (d), 79.4 (d), 104.7 (t, 2C), 127.6 (d,
4C), 129.5 (d, 2C), 134.0 (s, 2C), 135.6 (d, 4C), 148.5 (s), 151.8
(s) ppm; HRMS (ESI) m/z [M + H]+ calcd for C34H49O4Si
549.3395, found 549.3378.
Conflicts of interest
The authors declare no competing financial interest.
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