Total Synthesis of the Anticancer Marine Natural Product Mycalol

Article abstract of DOI:10.1002/ejoc.201701562

This communication describes a synthetic study of the originally proposed structure of mycalol (1) and the total synthesis of the actual structure of the anticancer marine natural product mycalol (2). The total synthesis of the originally proposed structu

Full text of DOI:10.1002/ejoc.201701562

A Journal of
Accepted Article
Title: Total Synthesis of Anticancer Marine Natural Product Mycalol
Authors: Kalikinidi Nageswara Rao, Katragunta Kumar, and Subhash
Ghosh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701562
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10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
Total Synthesis of Anticancer Marine Natural Product Mycalol
K. Nageswara Rao,a Katragunta Kumar,b and Subhash Ghosh*a
OAc
Abstract: This communication describes the synthetic study of the
19
proposed structure of mycalol (1) and the total synthesis of the
OAc
OH
OH
actual structure of anticancer marine natural product mycalol (2).
The total synthesis of the proposed structure of mycalol (1) was
targeted via late stage asymmetric dihydroxylation, which ended up
with inseparable mixture of diastereomers. Thus a new strategy has
been developed for the total synthesis of the revised structure of
mycalol (2), where all the stereocenters, except the C2′ꢀOH have
been created via asymmetric fashion by utilizing Maruoka allylation,
Noyori asymmetric reduction and asymmetric alkynylation.
OH
OH
HO
O
2'
8
4
HO
O
7
3
OH
OH
OH
OH
OH
OH
Proposed structure of Mycalol (1)
Revised structure of Mycalol (2)
Figure 1: Proposed and revised structures of mycalol
Results and discussion
Introduction
Because of the interesting structure and biological activity
of mycalol, we also became interested to develop a synthetic
strategy for the proposed structure of mycalol (1) after its
immediate isolation, via a late stage asymmetric dihydroxylation
as a key step (Scheme 1). The precursor 3 for asymmetric
dihydroxylation was planned to obtain from compound 5 by
alkylation with 4 followed by protecting group manipulation. We
thought the diene compound 5 might be obtained by means of
alkylation of alkyne 7 with the iodide 6 followed by cis selective
reduction of alkyne functionality and oxidative removal of PMB
group.
Marine organisms have produced a large number of potent
anticancer compounds and many of them are either in clinical
development or in the market used for the treatment of cancer.1
Mycalol, a polyhydroxylated lipid molecule is an example of a
cytotoxic marine natural product that was isolated from the
marine sponge by Fontana and coꢀworkers in 2013.2 Initial
biological studies revealed that mycalol selectively kills human
anaplastic thyroid carcinoma (ATC). Initially, the structure of
mycalol was proposed to be 1 based on detailed NMR study. In
2015, Reddy et al. developed an elegant strategy for the
synthesis of the proposed structure of mycalol (1) by utilizing
Sharpless asymmetric kinetic resolution, Jacobsen kinetic
resolution and crossꢀmetathesis reaction as key steps and found
the structure proposed by Fontana et al. is incorrect.
Subsequently, they hypothesized the correct structure could be
2 (Figure 1) based on detailed NMR data comparison and
confirmed the same via its total synthesis.3 Subsequently,
Goswami et al. reported the synthesis of the proposed structure
of mycalol and several of its analogs by using Lꢀarabinose as a
chiral pool material and confirmed the structural revision
reported by Reddy et al.4 Very recently Reddy et al. also
synthesized several analogs of mycalol (2) and tested their
anticancer activity against human derived ATC cell lines.5
[a]
[b]
K. Nageswara Rao, Subhash Ghosh*
Organic and Biomolecular Chemistry Division
CSIRꢀIndian Institute of Chemical Technology
Hyderabad 500007, India
Eꢀmail: subhash@iict.res.in
Katragunta Kumar
Division of Natural Products Chemistry
CSIRꢀIndian Institute of Chemical Technology
Hyderabad 500007, India
Scheme 1. Retrosynthetic analysis of the proposed structure of mycalol (1)
1
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10.1002/ejoc.201701562
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Scheme 2. Synthesis of iodide 6
Thus as per the plan, the synthesis of iodide 6 commenced
from known alcohol 86, which on oxidation under Swern
conditions followed by CoreyꢀChaykovsky reaction7 furnished
racemic epoxide 9 in good overall yield 75% (Scheme 2).
Hydrolytic kinetic resolution of the terminal epoxide 9 under
Jacobsen conditions8 provided enantiomerically pure epoxide 10
(95% ee) in 45% yield. The epoxide 10 was opened with
propylmagnesium chloride in presence of catalytic amount of
CuI to afford an alcohol 11a in 82% yield.9 Protection of the
hydroxyl group of 11a as its TBS ether followed by
debenzylation via hydrogenolysis (H2, 10% Pd/C) furnished
alcohol 12 in 89% over two steps. Finally, alcohol 12 on
treatment with TPP and iodine gave the iodo compound 6 in
87% yield.10
The synthesis of alkyne 7 is depicted in Scheme 3.
Oxidation of the known alcohol 1311 under Swern conditions
gave an aldehyde, which on reaction with ylide generated from
known phosphoniumbromide 1412a,b with KHMDS afforded
desired Zꢀolefin 15 in 70% yield over two steps (Z/E = 20:1).13
Deprotection of TMS group from compound 15 was carried with
K2CO3 in MeOH to afford alkyne 7 in 97% yield.
The final strategy for the completion of the synthesis of the
proposed structure of mycalol (1) is depicted in scheme 4.
Alkylation of the alkyne 7 with the iodide 6 in presence of nꢀBuLi
and HMPA went smoothly to furnish compound 16 in good yield
(70%).14 Partial reduction of the alkyne functionality of 16 under
Lindlar hydrogenation conditions15 (Pd/BaSO4, quinoline),
subsequently oxidative removal of PMB group with DDQ
furnished alcohol 5 in 72% yield over two steps. Williamson type
etherification16 between alcohol 5 and tosyl derivative of (R)ꢀ
Solketal 417 was performed in presence of 50% aqueous NaOH
and TBAB to give compound 17 in 80% yield. Deprotection of
TBS group from 17 was carried out with TBAF to obtain an
alcohol 3a, which on acetylation with Ac2O in presence of Et3N,
DMAP afforded compound 3 in 92% yield over two steps. Now
the stage was set for crucial dihydroxylation with ADꢀmix β to
complete the synthesis. However, dihydroxylation of the
compound 3 with ADꢀmix β gave an inseparable mixture of
diastereomers of compound 18.18 At this stage we wanted to
develop a new strategy for for the synthesis of the proposed
structure of mycalol (1). However by this time the structure of
mycalol was revised by Reddy et al. Therefore we planned to
device a new strategy for the revised structure of mycalol (2).
In the new strategy, we planned to generate all the stereo
centers except the C2' center via catalytic way so that structural
and stereochemical analogs of mycalol (2) can be generated
easily. Thus retrosynthetically mycalol (2) could be synthesized
from ynone 19 via asymmetric reduction followed by functional
group manipulations (Scheme 5). The ynone 19 could be
obtained by the addition of alkyne 21 to the aldehyde 20
followed by oxidation. Alkyne 21 would be obtained from alcohol
22 via oxidation followed by asymmetric alkynylation and then
protecting group manipulations. Compound 22 might be
obtained through the Noyori asymmetric reduction of ynone 23
followed by functional group manipulation. Ynone 23 could be
Scheme 3. Synthesis of alkyne 7
2
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10.1002/ejoc.201701562
European Journal of Organic Chemistry
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Scheme 4. Final strategy for the synthesis of proposed structure of mycalol (1)
Scheme 5. Retrosynthetic analysis of revised structure of mycalol (2)
3
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10.1002/ejoc.201701562
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bisꢀ(R)ꢀTi(IV)oxide catalyst
(i) O3, PPh3, CH2Cl2
78 Cꢀrt, 6 h
(28a), allyltributyltin, CH2Cl2
BnBr, NaH, TBAI
O
OH
OBn
OPMB
OPMB
OPMB
H
15 Cꢀ0 C, 16 h, 80%
THF, 0 Cꢀrt, 16 h
85%
(ii) NaBH4, MeOH
0 Cꢀrt, 30 min
96% ee
28
29
30
80% (over two steps)
OTs
O
OBn
OBn
O
DDQ, CH2Cl2, pH 7.4
OBn
OPMB
OH
32
O
O
O
O
OPMB
HO
O
O
50% aq NaOH, TBAB
phospate buffer (2:1)
0 C, 4 h, 72%
31
33
34
rtꢀ90 C, 48 h, 92%
OBn
O
DMP, NaHCO3, CH2Cl2
O
O
O
O
PriO
O
O
Ti
O
0 Cꢀrt, 30 min, quantitative
Ti
20
OiPr
O
bisꢀ(R)ꢀTi(IV)oxide catalyst
(28a)
Scheme 6. Synthesis of aldehyde 20
accessed via the addition of the alkyne 24 to the aldehyde 25
followed by oxidation of the resulting propargylic alcohol. The
terminal alkyne 24 would be obtained from the propargylic
alcohol 26 through alkyne Zipper reaction. Finally, the
propargylic alcohol 26 could be obtained from ynone 27 by
asymmetric reduction.
Thus the synthesis of the actual structure of mycalol (2)
commenced with the asymmetric allylation of the known
aldehyde 2819 under Maruoka allylation conditions20 to give
enantiomerically pure alcohol 29 in 80% yield with 96% ee
(Scheme 6). Protection of the alcohol 29 as its benzyl ether
followed by ozonolysis21 of the olefin furnished an aldehyde, that
on reduction with NaBH4 produced the alcohol 31 in 68% yield
over three steps. Etherification of the alcohol 31 with the tosyl
derivative of (S)ꢀSolketal 3222 in presence of 50% aqueous
NaOH and TBAB afforded compound 33 in 92% yield. Oxidative
removal of PMB group from 33 was carried out with DDQ23 to
afford alcohol 34 in 72% yield. Finally, oxidation of the alcohol
34 with DMP24 afforded aldehyde 20 in quantitative yield.
Synthesis of alkyne 21 was eventually begun from known
ynone 2725 (Scheme 7). The keto moiety of 27 was reduced with
(R,R)ꢀRu catalyst 23a26 in presence of HCOOH/Et3N to obtain
enantiomerically pure alcohol 26 (94% ee by Mosher ester
analysis) in 88% yield and the configuration of 26 was confirmed
by Mosher ester analysis. Internal triple bond of 26 was
transferred to the terminal position through Zipper reaction with
1,3ꢀdiaminopropane and NaH to get compound 35 in 82%
yield.27 The hydroxyl group of 35 was protected as PMB ether
with PMBCl/NaI/DIPEA to afford compound 24 in 95% yield.28
The addition of the anion generated from compound 24 with nꢀ
BuLi on known aldehyde 2529 afforded an inseparable mixture of
diastereomeric alcohols, (dr = 2.8:1) that on oxidation with DMP
provided ynone 23 in 75% yield over two steps. The ynone 23
was subjected to Noyori reduction with (R,R)ꢀRu catalyst (23a)
in presence of HCOOH/Et3N to give alcohol 36 in 87% yield
(94% de ). The free hydroxyl group of 36 was protected as TBS
ether with TBSOTf/2,6ꢀlutidine to afford compound 37 in 97%
yield. Selective removal of benzyl group and reduction of triple
bond of compound 37 was carried out with Raney Ni/H2 to obtain
alcohol 22 in 94% yield.30 Alcohol 22 was oxidized under Swern
conditions to give an aldehyde that on treatment with TMSꢀ
acetylene in presence of (R)ꢀBINOL/Ti(OiPr)4, provided required
compound in poor yield (10%).31a However reaction of the
aldehyde with TIPSꢀacetylene in presence of (R)ꢀ
BINOL/Ti(OiPr)4 afforded highly diastereomerically pure
compound 38 in 53% yield over two steps (98% de).31b
Deprotection of both TIPS and TBS groups from compound 38
was carried out with TBAF to obtain a diol compound 21a which
on acetonide protection with 2,2ꢀDMP in presence of PPTS
afforded alkyne 21 in 87% yield over two steps.
The remaining part of the synthesis is depicted in Scheme
8. The addition of the anion generated from alkyne 21 on
aldehyde 20 afforded an inseparable mixture of diastereomers
(dr = 1.3:1) which was oxidized under Swern conditions to give
ynone 19 in 75% yield over two steps. The keto functionality of
19 was reduced with (R,R)ꢀRu catalyst (23a) in presence of
HCOOH/Et3N to afford diastereomerically pure alcohol 39 in
85% yield (99% de). Alcohol 39 was subjected to hydrogenation
with H2 filled balloon in presence of 10% Pd/C to afford triol 40 in
91% yield. Acetonide protection of triol 40 with 2,2ꢀDMP in
presence of PPTS followed by acetylation of the C19ꢀOH with
Ac2O in presence of DMAP/Et3N afforded triacetonide 41 in 89%
yield over two steps. Finally, global deprotection of triacetonide
41 was carried out with
1
N
HCl to complete the
4
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10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
synthesis of mycalol (2) in 82% yield. Whose spectral and
(2)} were in good agreement with the data reported in the
literature
25
analytical data {[α]D = +3.45 (c 0.10, MeOH) for Natural
mycalol, and [α]D25 = +4.28 (c 0.20, MeOH) for synthetic Mycalol
(R, R)ꢀRu catalyst (23a)
O
OH
1,3ꢀdiamino propane
(0.5 mol %), HCOOH
NaH, 0 Cꢀ80 oC, 2 h
Et3N, CH2Cl2, 0 Cꢀrt
82%
24 h, 88%, 94% ee
27
26
OH
OPMB
(i) 24, nꢀBuLi, THF, 78 C
PMBCl, NaI, DIPEA
150 C, 2 h, 95%
then 25, 3 h, 88%, dr 2.8:1
(ii) DMP, CH2Cl2, 0 Cꢀrt, 1 h
85%
35
24
OPMB
OPMB
(R, R)ꢀRu catalyst (23a)
TBSOTf, 2,6ꢀlutidine
CH2Cl2, 0 Cꢀrt, 30 min
(0.5 mol %), HCOOH
Et3N, CH2Cl2, 0 Cꢀrt
97%
BnO
BnO
24 h, 87%, 94% de
O
OH
23
36
OPMB
OPMB
(i) (COCl)2, DMSO, Et3N, CH2Cl2
Raney Ni, H2
rt, 24 h, 94%
78 Cꢀ0 C, 90 min
(i) TIPSꢀacetylene, Et2Zn, Ti(OiPr)4
HO
(R)ꢀBINOL, toluene, ether, rt, 16 h
BnO
OTBS
53% (over two steps), 98% de
OTBS
37
22
OPMB
OPMB
2,2ꢀDMP, PPTS
TBAF, THF, 0 Cꢀrt
30 min, 95%
OH
OH
acetone, 0 Cꢀrt
16 h, 92%
21a
TIPS
OTBS
OH
38
CH3
CH3
H3C
OPMB
O
O
S
Cl
Ru
NH
N
H3C
O
Ph
Ph
(R,R)ꢀRu catalyst (23a)
O
21
Scheme 7. Synthesis of the alkyne 21
5
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10.1002/ejoc.201701562
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Scheme 8. Completion of the synthesis of mycalol (2)
General information: Under inert atmosphere (nitrogen or argon) all
the air and moisture sensitive reactions were carried out in an ovenꢀdried
Conclusions
glass
apparatus.
Yields
refer
to
chromatographically
and
In conclusion, the total synthesis of the proposed structure of
mycalol (1) was targeted via late stage asymmetric
spectroscopically unless otherwise stated. Anhydrous tetrahydrofuran
(THF) and diethyl ether (Et2O) were prepared via distillation over
sodium/benzophenone. Toluene was distilled over sodium wire prior to
use. Triethylamine (Et3N), dimethyl sulfoxide (DMSO), N,Nꢀ
a
dihydroxylation, which ended up with an inseparable mixture of
diastereomers. That forced us to modify the strategy for the
synthesis of the actual structure of the natural product by
utilizing Noyori asymmetric reduction, Zipper reaction,
asymmetric alkynylation, Maruoka allylation and Williamson type
etherification. With the modified strategy the total synthesis of
natural mycalol (2) was achieved in 26 steps (19 longest linear
sequences) from the known compound 27, with an overall yield
of 8.04%). The strategy developed here is quite different from
the strategy developed by Reddy et al (12 longest linear
sequences, overall yield 2.3%) and Goswami et al (16 longest
linear sequences, overall yield 11.1%). Both the cases chiral
pool materials were used extensively for getting the stereo
centers present in the molecule. Whereas, in the present case
most of the stereo centers has been generated via asymmetric
reactions. The strategy is highly convergent, and can be used
for the synthesis of structural and stereochemical analogs of the
molecule.
dimethylformamide
(DMF),
dichloromethane
(CH2Cl2)
and
hexamethylphosphoramide (HMPA) were distilled from CaH2 prior to use.
Acetic anhydride (Ac2O) was distilled from P2O5 to make free from acetic
acid and acetone was distilled from KMnO4. Triphenylphosphine (PPh3)
was recrystallized from hexane. Commercially available reagents were
used without further purification unless otherwise stated. Purification of
compounds was carried out via column chromatography by using silica
gel (100ꢀ200 mesh) packed in glass columns. 1H NMR and 13C NMR
were recorded in CDCl3, and C5D5N solvents on 300 MHz, 400 MHz, 500
MHz, 700 MHz and 75 MHz, 100 MHz, 125 MHz, 175 MHz spectrometer
respectively, using TMS as an internal standard. Chemical shifts are
measured as ppm values relative to internal CHCl3 δ 7.26 or TMS δ 0.0
or C5D5N δ 7.19, for 1H NMR and CDCl3 δ 77.0, C5D5N δ 123.50 for 13
C
NMR. In 1H NMR multiplicity defined as: s = singlet; d = doublet; t =
triplet; q = quartet; quin = quintet, dd = doublet of doublet; ddd = doublet
of doublet of doublet; dddd = doublet of doublet of doublet of doublet; dt
= doublet of triplet; td = triplet of doublet; qd = quartet of doublet; ddt =
doublet of doublet of triplet; dtd = doublet of triplet of doublet; tdd = triplet
of doublet of doublet; dtd = doublet of triplet of doublet; m = multiplet; brs
= broad singlet; bd = board doublet. Optical rotation values were
recorded on Horiba sepa 300 polarimeter using a 2 mL cell with a 10 mm
path length. FTIR spectra were recorded on Alpha (Bruker) infrared
spectrophotometer. High resolution mass spectra (HRMS) [ESI+] were
Experimental section
6
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10.1002/ejoc.201701562
European Journal of Organic Chemistry
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obtained using either
a
TOF or
a
double focusing spectrometer.
MHz, CDCl3): δ 7.37ꢀ7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.8 Hz, 2H),
2.94ꢀ2.87 (m, 1H), 2.77ꢀ2.72 (m, 1H), 2.46 (dd, J = 5.3, 3.0 Hz, 1H), 1.67ꢀ
1.21 (m, 20H); 13C NMR (75 MHz, CDCl3): δ 138.62, 128.27, 127.54,
127.39, 72.79, 70.46, 52.37, 47.10, 32.44, 29.70, 29.46, 29.41, 26.12,
25.92; HRMS (ESI): [M + Na]+ calcd. for C20H32O2Na 327.2300, found
327.2295.
Abbreviations: KHMDS = Potassium bis(trimethylsilyl)amide; DDQ =
2,3ꢀDichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzo quinone; DMP DessꢀMartin
periodinane; DMAP 4ꢀ(Dimethylamino) pyridine; TBAI Tetra
=
=
=
butylammonium iodide; TBAB = Tetrabutylammonium bromide; TBAF =
Tetrabutylammonium fluoride; DIPEA = N,Nꢀdiisopropylethylamine; PPTS
= Pyridinium pꢀtoluenesulfonate; PMBCl = 4ꢀMethoxybenzyl chloride; 2,2ꢀ
DMP = 2,2ꢀdimethoxypropane.
(R)-16-(Benzyloxy)hexadecan-5-ol (11a): To
a stirred solution of
epoxide 10 (1.73, 5.68 mmol) in anhydrous THF (17 mL) was added CuI
(108 mg, 0.568 mmol) followed by nꢀpropylmagnesium chloride (2 M
ether solution, 7.1 mL, 14.2 mmol) at –40 °C and stirred for 1 h. After
which time, the solution was warmed to 0 °C and quenched with
saturated aqueous NH4Cl (30 mL) and stirred for 30 min and diluted with
water (30 mL) and ethyl acetate (50 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (3 × 30 mL) three
times. The combined organic extracts were washed with water (30 mL)
and brine (30 mL). The organic layer was dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material which was purified by silica gel column
chromatography (SiO2, 100ꢀ200 mesh, 10% EtOAc/hexane) to afford
alcohol 11a (1.63 g, 4.68 mmol, 82%) as a pale yellow oil. Rf = 0.5 (SiO2,
20% EtOAc/hexane); [α]D25 = −2.60 (c 1.50, CHCl3); IR (Neat): νmax 3388,
2925, 2854, 1459, 1364, 1206, 1104, 1026, 735, 698, 611 cm—1; 1H NMR
(300 MHz, CDCl3): δ 7.38ꢀ7.25 (m, 5H), 4.50 (s, 2H), 3.63ꢀ3.53 (m, 1H),
3.46 (t, J = 6.7 Hz, 2H), 1.67ꢀ1.55 (m, 3H), 1.51ꢀ1.20 (m, 23H), 0.91 (t, J
= 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 138.62, 128.30, 127.60,
127.42, 72.78, 71.97, 70.49, 37.44, 37.12, 29.73, 29.67, 29.54, 29.44,
27.81, 26.15, 25.63, 22.75, 14.08; HRMS (ESI): [M + Na]+ calcd. for
C23H40O2Na 371.2926, found 371.2934.
2-(11-(Benzyloxy)undecyl)oxirane (9): To a stirred solution of oxalyl
chloride (3.14 mL, 35.90 mmol) in anhydrous CH2Cl2 (70 mL) was added
anhydrous DMSO (5.45 mL, 76.58 mmol) drop wise over a period of 5
min at –78 °C and stirred for 15 min. To the reaction mixture alcohol 8
(7.0 g, 23.93 mmol) in anhydrous CH2Cl2 (70 mL) was added at –78 °C
and stirred for 45 min. To the reaction mixture was added Et3N (16.65 mL,
119.65 mmol) at –78 °C and the solution was warmed to 0 °C and stirred
for 30 min. At which time, the reaction was quenched with saturated
aqueous NH4Cl (50 mL) and diluted with water (50 mL) and CH2Cl2 (50
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic extracts were washed
with water (50 mL) and brine (50 mL). The organic layer was dried over
anhydrous sodium sulphate and filtered. The filtrate was concentrated
under reduced pressure to give a crude material which was purified by
silica gel column chromatography (SiO2, 100ꢀ200 mesh, 20%
EtOAc/hexane) to afford aldehyde (6.65 g, 22.90 mmol) as a colourless
oil. Rf = 0.7 (SiO2, 30% EtOAc/hexane). The obtained aldehyde was used
immediately in the next step without further characterization. A stirred
solution of trimethylsulfonium iodide (7.0 g, 34.35 mmol) in anhydrous
DMSO (35 mL) was treated with NaH (1.37 g. 34.35 mmol) at 0 °C and
the solution was slowly warmed to room temperature and stirred for 15
min. To this solution aldehyde (6.65 g, 22.90 mmol) in anhydrous THF
(49 mL) was cannulated at room temperature and stirred for 2 h. After
which time, TLC (10% EtOAc/hexane) indicated the complete
consumption of aldehyde. The reaction was quenched with saturated
aqueous NH4Cl (40 mL) at 0 °C and diluted with water (40 mL) and ethyl
acetate (50 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (3 × 50 mL) three times. The combined
organic extracts were washed with water (50 mL) and brine (50 mL). The
organic layer was dried over anhydrous sodium sulphate and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material which was purified by silica gel column chromatography (SiO2,
100ꢀ200 mesh, 3% EtOAc/hexane) to afford racemic epoxide 9 (5.55 g,
18.06 mmol, 75% over two steps) as a colourless oil. Rf = 0.7 (SiO2, 30%
EtOAc/hexane); IR (Neat): νmax 3035, 2925, 2853, 1457, 1362, 1266,
(R)-((16-(Benzyloxy)hexadecan-5-yl)oxy)(tert-butyl) dimethylsilane
(11): A stirred solution of alcohol 11a (1.6 g, 4.59 mmol) in anhydrous
DMF (9 mL) was treated with imidazole (624 mg, 9.18 mmol) followed by
TBSCl (1.04 g, 6.89 mmol) at 0 °C and stirred at room temperature for 16
h. The reaction was quenched with saturated aqueous NaHCO3 (20 mL)
at 0 °C and diluted with ether (40 mL). The layers were separated and
the aqueous layer was extracted with diethyl ether (2 × 30 mL) two times.
The combined organic extracts were washed with water (30 mL) and
brine (30 mL). The organic layer was dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material which was purified by silica gel column
chromatography (SiO2, 100ꢀ200 mesh, 3% EtOAc/hexane) to provide
TBSꢀprotected compound 11 (2.0 g, 4.32 mmol, 94%) as a colourless oil.
25
Rf = 0.7 (SiO2, 10% EtOAc/hexane); [α]D = −1.10 (c 2.0, CHCl3); IR
1206, 1105, 1028, 912, 837, 737, 698, 610 cm—1 1H NMR (300 MHz,
;
(Neat): νmax 2927, 2855, 1462, 1365, 1252, 1099, 1252, 1099, 1007, 939,
835, 773, 734, 699 cm—1; 1H NMR (300 MHz, CDCl3): δ 7.36ꢀ7.24 (m, 5H),
4.50 (s, 2H), 3.61 (quin, J = 5.5 Hz, 1H), 3.46 (t, J = 6.4 Hz, 3H), 1.68ꢀ
1.55 (m, 3H), 1.47ꢀ1.18 (m, 22H), 0.94ꢀ0.84 (m, 12H), 0.04 (s, 6H); 13C
NMR (75 MHz, CDCl3): δ 138.69, 128.31, 127.58, 127.43, 72.84, 72.36,
70.52, 37.14, 36.83, 29.87, 29.76, 29.65, 29.60, 29.48, 27.55, 26.19,
25.95, 25.33, 22.91, 18.16, 14.13, –4.42; HRMS (ESI): [M + Na]+ calcd.
for C29H54O2SiNa 485.3791, found 485.3777.
CDCl3): δ 7.37ꢀ7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.8 Hz, 2H), 2.94ꢀ
2.87 (m, 1H), 2.77ꢀ2.72 (m, 1H), 2.46 (dd, J = 5.3, 3.0 Hz, 1H), 1.67ꢀ1.21
(m, 20H); 13C NMR (75 MHz, CDCl3): δ 138.62, 128.26, 127.54, 127.39,
72.75, 70.43, 52.37, 47.09, 32.44, 29.70, 29.46, 29.41, 26.12, 25.92;
HRMS (ESI): [M + Na]+ calcd. for C20H32O2Na 327.2300, found 327.2292.
(S)-2-(11-(Benzyloxy)undecyl)oxirane (10): To stirred solution of
Co(II)(S,S)ꢀN,Nꢀbis(3,5ꢀdiꢀtertꢀbutylsalicylidene)ꢀ1,2ꢀcyclohexanediamino
precatalyst (38.7 mg, 0.064 mmol, 0.5 mol %) in dry toluene (1.0 mL)
was added acetic acid (7.3 ꢁL, 0.128 mmol) at room temperature and
stirred under open atmosphere for 1 h. During this time the solution
colour changed to dark red. After which time, the solvent was evaporated
under reduced pressure and the formed catalyst (S,S)ꢀSalenꢀCo(III)ꢀ
(OAc) was dried in high vacuum for 1 h to make catalyst free from acetic
acid. The catalyst was treated with racemic epoxide 9 (3.9 g, 12.81
mmol) in isopropanol (0.5 mL) at 0 °C. To the solution water (231 ꢁL,
12.81 mmol) was added portion wise over a period of 1 h and stirred at
room temperature for 72 h. The reaction mixture was purified by silica gel
column chromatography (SiO2, 100ꢀ200 mesh, 3% EtOAc/hexane) to
(R)-12-((tert-Butyldimethylsilyl)oxy)hexadecan-1-ol (12):
A stirred
solution of above TBSꢀprotected compound 11 (1.95 g, 4.21 mmol) in
anhydrous ethyl acetate (20 mL) was treated with 10% Pd/C (390 mg,
20% w/w) and hydrogenated by using hydrogen filled balloon at room
temperature for 16 h. The reaction mixture was filtered through celite
plug and washed with ethyl acetate (50 mL). The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 14%
EtOAc/hexane) to afford alcohol 12 (1.49 g, 4.0 mmol, 95%) as a
colourless oil. Rf = 0.5 (SiO2, 20% EtOAc/hexane); [α]D25 = −1.42 (c 1.55,
CHCl3); IR (Neat): νmax 3359, 2927, 2856, 1464, 1370, 1252, 1127, 1055,
938, 835, 773, 717, 665 cm—1; 1H NMR (300 MHz, CDCl3): δ 3.67ꢀ3.57 (m,
3H), 1.57 (quin, 6.7 Hz, 2H), 1.49ꢀ1.20 (m, 24H), 0.94ꢀ0.85 (m, 12H),
0.04 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 72.32, 63.01, 37.09, 36.77,
32.76, 29.82, 29.55, 29.38, 27.48, 25.89, 25.69, 25.28, 22.86, 14.08, –
afford enantiomerically pure epoxide 10 (1.76 g, 5.78 mmol, 45%, 95%
25
ee) as a colourless oil. Rf = 0.7 (SiO2, 30% EtOAc/hexane); [α]D
=
+1.67 (c 0.60, CHCl3); IR (Neat): νmax 3035, 2925, 2853, 1457, 1362,
1266, 1206, 1105, 1028, 912, 837, 737, 698, 610 cm—1 1H NMR (300
;
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
4.48; HRMS (ESI): [M + Na]+ calcd. for C22H48O2SiNa 395.3321, found
395.3304.
Hz, 1H), 4.45 (s, 2H), 3.80 (s, 3H), 3.46 (t, J = 7.0 Hz, 2H), 2.38 (m, 2H),
2.32ꢀ2.26 (m, 2H), 2.25ꢀ2.20 (m, 2H), 1.94 (t, J = 2.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): δ 159.08, 130.49, 129.44, 129.21, 127.32, 113.71,
84.05, 72.52, 69.49, 68.38, 55.22, 28.00, 26.39, 18.68; HRMS (ESI): [M +
Na]+ calcd. for C16H20O2Na 267.1361, found 267.1363.
(R)-tert-Butyl((16-iodohexadecan-5-yl)oxy)dimethyl silane (6):
A
stirred solution of TPP (1.41 g, 5.37 mmol) and imidazole (365 mg, 5.37
mmol) in anhydrous CH2Cl2 (11 mL) was treated with Iodine (1.36 g, 5.37
mmol) at 0 °C and the solution was warmed to room temperature and
stirred for 10 min. To the solution, alcohol 12 (1.0 g, 2.68 mmol) in
anhydrous CH2Cl2 (6 mL) was cannulated at room temperature and
stirred for 30 min. The reaction was quenched with saturated aqueous
hypo (20 mL) at 0 °C and diluted with water (20 mL), CH2Cl2 (30 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL) three times. The combined organic extracts were
washed with water (30 mL) and brine (30 mL). The organic layer was
dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 2%
EtOAc/hexane) to obtain iodide 6 (1.13 g, 2.34 mmol, 87%) as a
colourless oil (Rf = 0.7 (SiO2, 5% EtOAc/hexane), which was taken for
the next reaction without further characterization.
(R,Z)-tert-Butyl((24-((4-methoxybenzyl)oxy)tetracos-21-en-17-yn-5-
yl)oxy)dimethylsilane (16): A stirred solution of alkyne 7 (762 mg, 3.12
mmol) in anhydrous THF (6 mL) was treated with nꢀBuli (1.6 M hexane
solution, 1.89 mL, 3.02 mmol) at –78 °C and stirred at the same
temperature for 20 min. To the reaction mixture was added anhydrous
HMPA (1.05 mL, 8.58 mmol) followed by iodide 6 (500 mg, 1.04 mmol) in
anhydrous THF (3 mL) at –78 °C and stirred at the same temperature for
2 h. The reaction mixture was slowly warmed to 0 °C over a period of 1 h
and quenched with saturated aqueous NH4Cl (20 mL) at 0 °C. It was
diluted with water (20 mL) and ethyl acetate (30 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate (3 × 30
mL) three times. The combined organic extracts were washed with water
(30 mL) and brine (30 mL). The organic layer was dried over anhydrous
sodium sulphate and filtered. The filtrate was concentrated under
reduced pressure to give a crude material which was purified by silica gel
column chromatography (SiO2, 100ꢀ200 mesh, 2% EtOAc/hexane) to
afford compound 16 (434 mg, 0.725 mmol, 70%) as a colourless oil. Rf =
0.5 (SiO2, 10% EtOAc/hexane); [α]D25 = −2.51 (c 1.55, CHCl3); IR (Neat):
νmax 2927, 2855, 1613, 1513, 1462, 1362, 1301, 1248, 1174, 1091, 1042,
938, 833, 773, 719, 665 cm—1; 1H NMR (300 MHz, CDCl3): δ 7.26ꢀ7.19 (m,
2H), 6.87ꢀ6.82 (m, 2H), 5.54ꢀ5.37 (m, J = 11.3, 6.8 Hz, 2H), 4.41 (s, 2H),
3.77 (s, 3H), 3.61 (quin, J = 5.6 Hz, 1H), 3.45 (t, J = 7.1 Hz, 2H), 2.37 (m,
2H), 2.29ꢀ2.08 (m, 6H), 1.53ꢀ1.20 (m, 26H), 0.95ꢀ0.83 (m, 12H), 0.04 (s,
6H); 13C NMR (75 MHz, CDCl3): δ 159.07, 130.52, 130.12, 129.19,
126.72, 113.70, 80.57, 79.50, 72.51, 72.34, 69.61, 55.22, 37.12, 36.81,
29.86, 29.66, 29.61, 29.55, 29.17, 29.11, 28.89, 28.02, 27.54, 27.14,
25.93, 25.33, 22.89, 19.09, 18.74, 18.15, 14.13, –4.44; HRMS (ESI): [M +
Na]+ calcd. for C38H66O3SiNa 621.4679, found 621.4703.
(Z)-(8-((4-Methoxybenzyl)oxy)oct-5-en-1-yn-1-yl) trimethylsilane (15):
Alcohol 13 (2.0 g, 12.80 mmol) was oxidized under Swern conditions to
give aldehyde (1.85 g) as a colourless oil. Rf = 0.7 (SiO2, 30%
EtOAc/hexane). A stirred solution of phosphoniumbromide 14 (12.5 g,
23.98 mmol) in anhydrous THF (20 mL) was treated with KHMDS (0.5 M
toluene solution, 45.56 mL, 22.78 mmol) at –78 °C and stirred at this
temperature for 20 min. To the solution, the above aldehyde (1.85 g,
11.99 mmol) in anhydrous THF (12 mL) was cannulated at –78 °C and
stirred for 30 min. The reaction was quenched with saturated aqueous
NH4Cl (40 mL) at 0 °C and diluted with water (20 mL) and diethyl ether
(50 mL). The layers were separated and the aqueous layer was extracted
with diethyl ether (3 × 30 mL) three times. The combined organic extracts
were washed with water (40 mL) and brine (40 ml). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 3%
EtOAc/hexane) to provide compound 15 (2.84 g, 9.00 mmol, 70% over
two steps, Z/E = 20:1) as a pale yellow oil. Rf = 0.5 (SiO2, 10%
EtOAc/hexane); IR (Neat): νmax 2956, 2925, 2855, 2174, 1713, 1609,
tert-Butyl(((R,17Z,21Z)-24-((4-methoxybenzyl)oxy)tetra cosa-17,21-
dien-5-yl)oxy) dimethyl silane (5a): A stirred solution of compound 16
(200 mg, 0.33 mmol) in ethyl acetate (3 mL) was treated with quinoline
(20 mg, 10% w/w) followed by Pd/BaSO4 (30 mg. 15% w/w) and
hydrogenated by using H2 filled balloon at room temperature for 24 h.
Then the reaction mixture was filtered through celite plug and washed
with ethyl acetate (30 mL). The filtrate and the washings were
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 2%
EtOAc/hexane) to obtain diene compound 5a (180 mg, 0.30 mmol, 90%)
1513, 1248, 1171, 1095, 1037, 841, 761, 700, 640 cm—1 1H NMR (300
;
MHz, CDCl3): δ 7.28ꢀ7.24 (m, 2H), 6.90ꢀ6.86 (m, 2H), 5.50 (dt, J = 11.0,
6.4 Hz, 1H), 5.47 (dt, J = 11.0, 6.7 Hz, 1H), 4.45 (s, 2H), 3.81 (s, 3H),
3.45 (t, J = 7.0 Hz, 2H), 2.38 (dd, J = 12.8, 6.9 Hz, 2H), 2.30ꢀ2.24 (m, 4H),
0.15 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 159.10, 130.53, 129.64,
129.20, 127.05, 113.74, 106.89, 84.58, 72.53, 69.58, 55.25, 28.02, 26.68,
20.13, 0.13; HRMS (ESI): [M + Na]+ calcd. for C19H28O2SiNa 339.1756,
found 339.1739.
25
as a colourless oil. Rf = 0.6 (SiO2, 3% EtOAc/hexane); [α]D = −1.93 (c
1.35, CHCl3); IR (Neat): νmax 2926, 2854, 1613, 1513, 1463, 1249, 1092,
1042, 833, 733 cm—1 1H NMR (300 MHz, CDCl3): δ 7.29ꢀ7.23 (m, 2H),
;
6.91ꢀ6.84 (m, 2H), 5.51ꢀ5.32 (m, 4H), 4.45 (s, 2H), 3.80 (s, 3H), 3.61 (m,
1H), 3.45 (t, J = 7.0 Hz, 2H), 2.36 (m, 2H), 2.14ꢀ1.96 (m, 6H), 1.46ꢀ1.20
(m, 26H), 0.94ꢀ0.85 (m, 12H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ 159.08, 131.26, 130.57, 130.47, 129.19, 128.91, 125.88, 113.71, 72.50,
72.36, 69.67, 55.23, 37.13, 36.82, 29.87, 29.73, 29.66, 29.57, 29.32,
27.98, 27.54, 27.49, 27.26, 27.23, 25.93, 25.33, 22.90, 18.15, 14.12, –
4.43; HRMS (ESI): [M + Na]+ calcd. for C38H68O3SiNa 623.4835, found
623.4849.
(Z)-1-Methoxy-4-((oct-3-en-7-yn-1-yloxy)methyl)benzene (7): A stirred
solution of compound 15 (2.8 g, 8.85 mmol) in MeOH (16 mL) was
treated with K2CO3 (2.45 g, 17.70 mmol) at 0 °C and the solution was
warmed to room temperature and stirred for 30 min. The reaction mixture
was filtered through celite plug and the cake was washed with ethyl
acetate (30 mL). The filtrate and the washings were concentrated under
reduced pressure to give crude compound, which was diluted with ethyl
acetate (30 mL) and saturated aqueous ammonium chloride (30 mL).
The layers were separated and the aqueous layer was extracted with
ethyl acetate (3 × 30 mL) three times. The combined organic extracts
were washed with water (30 mL) and brine (30 mL). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 4%
EtOAc/hexane) to afford alkyne 7 (2.10 g, 8.60 mmol, 97%) as a pale
yellow oil. Rf = 0.45 (SiO2, 10% EtOAc/hexane); IR (Neat): νmax 3295,
3009, 2856, 1692, 1609, 1512, 1458, 1360, 1302, 1245, 1173, 1091,
(R,3Z,7Z)-20-((tert-Butyldimethylsilyl)oxy)tetracosa-3,7-dien-1-ol (5):
A solution of diene compound 5a (215 mg, 0.36 mmol) in a mixture of
solvents CH2Cl2 and pH = 7 phosphate buffer (3 mL, 10:1) was treated
with DDQ (204 mg, 0.90 mmol) at 0 °C and the solution was warmed to
room temperature and stirred for 4 h. After which time, the reaction was
quenched with saturated aqueous NaHCO3 (20 mL) at 0 °C and diluted
with water (20 mL) and ethyl acetate (20 mL). The layers were separated
and the aqueous layer was extracted with ethyl acetate (3 × 20 mL) three
times. The combined organic extracts were washed with saturated
aqueous NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The organic
layer was dried over anhydrous sodium sulphate and filtered. The filtrate
1033, 820, 638 cm—1 1H NMR (300 MHz, CDCl3): δ 7.28ꢀ7.24 (m, 2H),
;
6.90ꢀ6.86 (m, 2H), 5.52 (dt, J = 11.0, 5.9 Hz, 1H), 5.49 (dt, J = 11.0, 6.1
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
was concentrated under reduced pressure to give a crude material which
was purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh,
5% EtOAc/hexane) to afford alcohol 5 (137 mg, 0.29 mmol, 80%) as a
colourless oil. Rf = 0.25 (SiO2, 10% EtOAc/hexane); [α]D25 = +5.62 (c
1.05, CHCl3); IR (Neat): νmax 3335, 2926, 2855, 1462, 1370, 1252, 1126,
1051, 939, 835, 773, 720, 666 cm—1; 1H NMR (300 MHz, CDCl3): δ 5.60ꢀ
5.53 (m, 1H), 5.43ꢀ5.32 (m, 3H), 3.64 (t, J = 6.4 Hz, 2H), 3.60 (dd, J =
11.4, 5.8 Hz, 1H), 2.36ꢀ2.30 (m, 2H), 2.16ꢀ2.06 (m, 4H), 2.01 (m, 2H),
1.46ꢀ1.20 (m, 26H), 0.91ꢀ0.86 (m, 12H), 0.03 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 132.78, 130.68, 128.73, 125.44, 72.34, 62.23, 37.09, 36.80,
30.78, 29.81, 29.67, 29.61, 29.53, 29.29, 27.52, 27.43, 27.23, 27.17,
25.89, 25.31, 22.87, 18.12, 14.11, –4.48; HRMS (ESI): [M + Na]+ calcd.
for C30H60O2SiNa 503.4260, found 503.4275.
27.83, 27.47, 27.25, 27.21, 26.75, 25.64, 25.40, 22.75, 14.06; HRMS
(ESI): [M + Na]+ calcd. for C30H56O4Na 503.4076, found 503.4077.
(R,17Z,21Z)-24-(((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)
tetracosa-17,21-dien-5-yl acetate (3): To a stirred solution of alcohol 3a
(60 mg, 0.125 mmol) in anhydrous CH2Cl2 (1.0 mL) were added Et3N (52
ꢁL, 0.375 mmol) followed by catalytic amount of DMAP (1.5 mg, 0.0125
mmol) at 0 °C and stirred for 10 min. To the reaction mixture Ac2O (24 ꢁL,
0.25 mmol) was added at 0 °C and the solution was warmed to room
temperature and stirred for 2 h. After which time, the reaction was
quenched with saturated aqueous NaHCO3 (5 mL) at 0 °C and diluted
with water (10 mL), CH2Cl2 (10 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL) three times. The
combined organic extracts were washed with water (10 mL) and brine
(10 mL). The organic layer was dried over anhydrous sodium sulphate
and filtered. The filtrate was concentrated under reduced pressure to give
a crude material which was purified by silica gel column chromatography
(SiO2, 100ꢀ200 mesh, 4% EtOAc/hexane) to afford compound 3 (63 mg,
tert-Butyl((R,17Z,21Z)-24-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)
methoxy)tetracosa-17,21-dien-5-yl)oxy)dimethyl silane (17):
A
solution of alcohol 5 (110 mg, 0.23 mmol) in 50% aqueous NaOH (1.1
mL, 13.8 mmol) was stirred at 80 °C for 30 min then to this solution TBAB
(14.8 mg, 0.046 mmol) was added at same temperature and stirred for
30 min. The reaction mixture was cooled to room temperature and tosyl
compound 4 (263 mg, 0.92 mmol) in minimum amount of diethyl ether
(0.5 mL) was added and solution was again warmed to 80 °C and stirred
for 24 h. The reaction mixture was cooled to room temperature and
diluted with water (15 mL) and the aqueous layer was extracted with
CH2Cl2 (3 × 15 mL) three times. The combined organic extracts were
washed with water (15 mL) and brine (15 mL). The organic layer was
dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 2%
EtOAc/hexane) to afford compound 17 (110 mg, 0.184 mmol, 80%) as a
colourless oil. Rf = 0.4 (SiO2, 5% EtOAc/hexane); [α]D25 = +8.86 (c 0.35,
CHCl3); IR (Neat): νmax 2927, 2856, 1695, 1649, 1463, 1374, 1251, 1215,
1118, 1056, 939, 837, 774, 727, 665 cm—1; 1H NMR (300 MHz, CDCl3): δ
5.53ꢀ5.31 (m, 4H), 4.27 (quin, J = 6.0 Hz 1H), 4.06 (dd, J = 8.3, 6.8 Hz,
1H), 3.73 (dd, J = 8.3, 6.8 Hz, 1H), 3.61 (m, 1H), 3.54 (dd, J = 9.8, 6.0 Hz,
2H), 3.48 (dd, J = 6.8, 2.3 Hz, 1H), 3.44 (m, 1H), 2.34 (q, J = 6.8 Hz, 2H),
2.15ꢀ1.96 (m, 6H), 1.43 (s, 3H), 1.37 (s, 3H), 1.35ꢀ1.22 (m, 26H), 0.93ꢀ
0.86 (m, 12H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 131.42, 130.54,
128.88, 125.60, 74.73, 72.38, 71.84, 71.33, 66.90, 37.15, 36.84, 29.88,
29.66, 29.58, 29.35, 27.86, 27.55, 27.49, 27.29, 27.23, 26.77, 25.95,
25.43, 25.34, 22.91, 18.17, 14.13, –4.41; HRMS (ESI): [M + Na]+ calcd.
for C36H70O4SiNa 617.4941, found 617.4952.
0.120 mmol, 96%) as
a colourless oil. Rf = 0.6 (SiO2, 10%
EtOAc/hexane); [α]D25 = −9.58 (c 0.95, CHCl3); IR (Neat): νmax 2925, 2856,
1736, 1460, 1373, 1242, 1116, 1053, 847, 729 cm—1; 1H NMR (500 MHz,
CDCl3): δ 5.51ꢀ5.30 (m, 4H), 4.86 (quin, J = 6.2 Hz, 1H), 4.26 (quin, J =
6.0 Hz, 1H), 4.05 (dd, J = 8.2, 6.2 Hz, 1H), 3.73 (dd, J = 8.2, 6.4 Hz, 1H),
3.53 (dd, J = 9.8, 5.7 Hz, 1H), 3.51ꢀ3.46 (m, 2H), 3.44 (dd, J = 9.8, 5.5
Hz, 1H), 2.34 (qd, J = 7.1, 1.0 Hz, 2H), 2.12ꢀ2.07 (m, 3H), 2.04 (s, 3H),
2.03ꢀ1.99 (m, 3H), 1.54ꢀ1.47 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H), 1.35ꢀ
1.22 (m, 22H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
170.93, 131.41, 130.51, 128.86, 125.58, 109.36, 74.71, 74.42, 71.82,
71.31, 66.87, 34.12, 33.80, 29.72, 29.62, 29.54, 29.32, 27.83, 27.47,
27.27, 27.21, 26.75, 25.41, 25.30, 22.59, 21.28, 13.98; HRMS (ESI): [M +
Na]+ calcd. for C32H58O5Na 545.4182, found 545.4187
(5R)-24-(((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-17,18,21,22-
tetrahydroxytetracosan-5-yl acetate (18): A stirred solution of ADꢀmix
β (214 mg, 2.8 g/mmol) in tꢀBuOH:H2O (1:1, 4 mL) was treated with
MeSO2NH2 (22 mg, 0.23 mmol) at room temperature and stirred until the
solution becomes clear (5 min). Now the solution was cooled to 0 °C and
treated with compound 3 (40 mg, 0.077 mmol) in minimum amount of tꢀ
BuOH (0.5 mL) and stirring continued at 0 °C for 48 h. After which time,
the reaction was quenched with Na2S2O5 (220 mg, 1.16 mmol) at 0 °C
and the solution was warmed to room temperature and stirred for 30 min.
The reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (3 × 15 mL) three times. The combined organic extracts
were washed with water (10 mL) and brine (10 mL). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 3%
MeOH/CHCl3) to afford an inseparable mixture of diastereomers of
compound 18 (39 mg, 0.066 mmol, 85%) as a pale brown semi solid. Rf
= 0.3 (SiO2, 10% MeOH/CHCl3); IR (Neat): νmax 3620, 3300, 2923, 2854,
(R,17Z,21Z)-24-(((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)
tetracosa-17,21-dien-5-ol (3a): To a stirred solution of compound 17 (85
mg, 0.14 mmol)) in anhydrous THF (1.0 mL) was added TBAF (1 M THF
solution, 0.42 mL, 0.42 mmol) at 0 °C and solution was warmed to room
temperature and stirred for 3 h. After which time, the solution was
quenched with saturated aqueous NH4Cl (5 mL) at 0 °C and diluted with
water (5 mL) and ethyl acetate (15 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (3 × 15 mL) three
times. The combined organic extracts were washed with water (15 mL)
and brine (15 mL). The organic layer was dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material which was purified by silica gel column
chromatography (SiO2, 100ꢀ200 mesh, 10% EtOAc/hexane) to afford
alcohol 3a (65 mg, 0.135 mmol, 96%) as a colourless oil. Rf = 0.4 (SiO2,
20% EtOAc/hexane); [α]D25 = −5.84 (c 1.25, CHCl3); IR (Neat): νmax 3434,
1734, 1700, 1522, 1462, 1373, 1242, 1120, 1060, 1026, 848 cm—1 1H
;
NMR (500 MHz, CDCl3): δ 4.86 (quin, J = 6.2 Hz, 1H), 4.27 (quin, J = 5.7
Hz, 1H), 4.05 (m, 1H), 3.80ꢀ3.59 (m, 7H), 3.57ꢀ3.50 (m, 2H), 2.04 (s, 3H),
1.90ꢀ1.80 (m, 1H), 1.79ꢀ1.73 (m, 2H), 1.61ꢀ1.48 (m, 4H), 1.44 (s, 3H),
1.36 (s, 3H), 1.34ꢀ1.22 (m, 27H), 0.91ꢀ0.86 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 171.01, 109.60, 109.56, 74.73, 74.55, 74.44, 74.35, 74.32,
74.19, 74.13, 73.99, 72.06, 71.95, 70.25, 70.10, 66.34, 66.24, 34.09,
33.79, 31.61, 30.50, 29.67, 29.56, 29.50, 28.35, 27.52, 27.46, 26.68,
26.65, 26.03, 25.28, 25.24, 25.22, 22.58, 21.29, 13.98; HRMS (ESI): [M +
Na]+ calcd. for C32H62O9Na 613.4292, found 613.4299.
2924, 2855, 1721, 1460, 1374, 1252, 1214, 1114, 1053, 845, 725 cm—1
;
1H NMR (500 MHz, CDCl3): δ 5.50ꢀ5.32 (m, 4H), 4.26 (quin, J = 6.0 Hz,
1H), 4.05 (dd, J = 8.2, 6.4 Hz, 1H), 3.73 (dd, J = 8.2, 6.4 Hz, 1H), 3.61ꢀ
3.55 (m, 1H), 3.53 (dd, J = 9.8, 5.6 Hz, 1H), 3.51ꢀ3.46 (m, 2H), 3.44 (dd,
J = 9.9, 5.6 Hz, 1H), 2.34 (qd, J = 7.0, 1.0 Hz, 2H), 2.12ꢀ2.04 (m, 4H),
2.01 (q, J = 6.7 Hz, 2H), 1.48ꢀ1.43 (m, 2H), 1.42 (s, 3H), 1.41ꢀ1.37 (m,
2H), 1.36 (s, 3H), 1.35ꢀ1.24 (m, 22H), 0.91 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 131.40, 130.50, 128.86, 125.59, 109.35, 74.70,
71.97, 71.81, 71.30, 66.88, 37.48, 37.16, 29.70, 29.62, 29.53, 29.30,
(R)-1-((4-Methoxybenzyl)oxy)pent-4-en-2-ol (29): A stirred solution of
TiCl4 (1 M toluene solution, 0.42 mL, 0.42 mmol) in anhydrous CH2Cl2
(16 mL) was treated with Ti(OiPr)4 (0.37 mL, 1.25 mmol) at 0 °C and the
solution was warmed to room temperature and stirred for 1 h in the
absence of light. To the solution, freshly prepared Ag2O (192 mg, 0.83
mmol) was added at room temperature and stirred for additional 5 h. The
solution was diluted with anhydrous CH2Cl2 (4 mL) and treated with (R)ꢀ
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
BINOL (478 mg, 1.67 mmol) at room temperature and stirring was
continued for 2 h. At this point the solution was turned to brick red colour.
The in situ generated bisꢀ(R)ꢀTi(IV)oxide catalyst (28a) was cooled to –
15 °C and treated with aldehyde 28 (1.5 g, 8.33 mmol) in anhydrous
CH2Cl2 (4 mL) followed by allyltributyltin (2.81 mL, 9.16 mmol) and the
solution was warmed to 0 °C and stirred for 16 h. The reaction was
quenched with saturated aqueous NaHCO3 (20 mL) at 0 °C and stirred
for 30 min and filtered through celite plug and washed with CH2Cl2 (3 ×
30 mL) three times. The filtrate was diluted with water (30 mL) the layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 × 40
mL) three times. The combined organic extracts were washed with water
(40 mL) and brine (40 mL) and dried over anhydrous sodium sulphate
and filtered. The filtrate was concentrated under reduced pressure to give
a crude material which was purified by silica gel column chromatography
(SiO2, 100ꢀ200 mesh, 15% EtOAc/hexane) to afford alcohol 29 (1.48 g,
6.66 mmol, 80%, 96% ee) as a pale yellow oil. Rf = 0.25 (SiO2, 20%
methanol (4 mL) was added NaBH4 (66 mg, 1.75 mmol) at 0 °C and the
solution was warmed to room temperature and stirred for 30 min. The
reaction mixture was quenched with saturated aqueous ammonium
chloride (10 mL) at 0 °C and diluted with water (20 mL) and CH2Cl2 (20
mL). The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) three
times. The combined organic extracts were washed with water (20 mL)
and brine (20 mL). The organic layer was dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material, which was purified by silica gel column
chromatography (SiO2, 100-200 mesh, 40% EtOAc/hexane) to afford
alcohol 31 (450 mg, 1.42 mmol, 80% over two steps) as a colourless oil.
Rf = 0.3 (SiO2, 50% EtOAc/hexane); [α]D25 = +30.91 (c 1.1, CHCl3); IR
(Neat): νmax 3395, 2927, 2857, 1715, 1611, 1513, 1455, 1248, 1174, 1090,
1033, 820, 740, 699 cm—1 1H NMR (400 MHz, CDCl3) : δ 7.35ꢀ7.23 (m,
;
7H), 6.90ꢀ6.85 (m, 2H), 4.71 (d, J = 11.7 Hz, 1H), 4.56 (d, J = 11.7 Hz,
1H), 4.48 (s, 2H), 3.83ꢀ3.77 (m, 4H), 3.72 (t, J = 5.7 Hz, 2H), 3.59 (dd, J
= 9.7, 4.8 Hz, 1H), 3.53 (dd, J = 10.1, 5.0 Hz, 1H), 2.42 (brs, 1H), 1.82
(dd, J = 11.4, 5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 159.21, 138.29,
130.02, 129.27, 128.40, 127.83, 127.70, 113.78, 76.95, 73.06, 72.08,
72.01, 60.19, 55.23, 34.64; HRMS (ESI): [M + Na]+calcd. for C19H24O4Na
339.1567, found 339.1579.
25
EtOAc/hexane); [α]D = −4.0 (c 1.7, CHCl3); IR (Neat): νmax 3458, 2915,
2860, 1713, 1609, 1513, 1461, 1300, 1248, 1174, 1095, 1033, 917, 822
cm—1; 1H NMR (500 MHz, CDCl3): δ 7.26 (m, 2H), 6.89 (m, 2H), 5.82 (ddt,
J = 17.2, 10.2, 7.0 Hz, 1H), 5.14ꢀ5.07 (m, 2H), 4.49 (s, 2H), 3.87 (m, 1H),
3.81 (s, 3H), 3.49 (dd, J = 9.4, 3.4 Hz, 1H), 3.35 (dd, J = 9.4, 7.5 Hz, 1H),
2.27ꢀ2.23 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.22, 134.19, 129.97,
129.30, 117.52, 113.77, 73.53, 72.95, 69.64, 55.19, 37.84; HRMS (ESI):
[M + Na]+ calcd. for C13H18O3Na 245.1154, found 245.1154.
(S)-4-(((R)-3-(Benzyloxy)-4-((4-methoxybenzyl)oxy) butoxy)methyl)-
2,2-dimethyl-1,3-dioxolane (33): A stirred solution of alcohol 31 (420
mg, 1.33 mmol) in 50% aqueous NaOH (6.4 mL, 79.8 mmol) was treated
with TBAB (87 mg, 0.27 mmol) at room temperature and the solution was
warmed to 90 °C and stirred for 30 min. The reaction mixture was cooled
to room temperature and treated with tosyl compound 32 (762 mg, 2.66
mmol) in a minimum amount of diethyl ether (1 mL) and the solution was
again warmed to 90 °C and stirred for 48 h. The reaction mixture was
cooled to room temperature and diluted with water (20 mL) and CH2Cl2
(30 mL) two phases were separated. The aqueous phase was extracted
with CH2Cl2 (3 × 30 mL) three times. The combined organic phases were
washed with water (40 mL) and brine (30 mL). The organic layer was
dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 18%
EtOAc/hexane) to obtain compound 33 (528 mg, 1.23 mmol, 92%) as a
(R)-1-(((2-(Benzyloxy)pent-4-en-1-yl)oxy)methyl)-4-methoxybenzene
(30): To a suspension of NaH (135 mg, 3.38 mmol) in anhydrous THF
(3.5 mL) was cannulated alcohol 29 (500 mg, 2.25 mmol) in anhydrous
THF (3.5 mL) at 0 °C and the resulting solution was warmed to room
temperature and stirred for 30 min. To this solution, benzyl bromide (0.4
mL, 3.38 mmol) followed by TBAI (83 mg, 0.225 mmol) were added at
0 °C and the solution was warmed to room temperature and stirred for 16
h. After which time, TLC (20% EtOAc/hexane) indicated the complete
consumption of alcohol 29. The reaction was slowly quenched with
saturated aqueous ammonium chloride (20 mL) at 0 °C and diluted with
water (20 mL). The aqueous layer was extracted with ethyl acetate (3 ×
30 mL) three times. The combined organic phases were washed with
water (40 mL) and brine (40 mL) and dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material which was purified by silica gel column
chromatography (SiO2, 100ꢀ200 mesh, 4% EtOAc/hexane) to afford
compound 30 (600 mg, 1.92 mmol, 85%) as a colourless oil. Rf = 0.4
(SiO2, 10% EtOAc/hexane); [α]D25 = +4.42 (c 0.95, CHCl3); IR (Neat): νmax
2904, 2858, 1610, 1511, 1453, 1351, 1300, 1245, 1175, 1091, 1033, 995,
914, 818, 737, 696, 580 cm—1; 1H NMR (300 MHz, CDCl3): δ 7.40ꢀ7.22 (m,
7H), 6.90ꢀ6.84 (m, 2H), 5.83 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.13ꢀ5.01
(m, 2H), 4.65 (d, J = 11.8 Hz, 1H), 4.60 (d, J = 11.8 Hz, 1H), 4.48 (s, 2H),
3.81 (s, 3H), 3.65 (quin, J = 5.6 Hz,1H), 3.53 (dd, J = 5.2, 0.6 Hz, 2H),
2.39ꢀ2.32 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 159.12, 138.76, 134.60,
130.41, 129.20, 128.23, 127.66, 127.42, 117.08, 113.71, 77.68, 72.97,
71.87, 71.77, 55.24, 36.29; HRMS (ESI): [M + Na]+calcd. for C20H24O3Na
335.1623, found 335.1627.
25
colourless oil. Rf = 0.3 (SiO2, 20% EtOAc/hexane); [α]D = +22.61 (c
1.15, CHCl3); IR (Neat): νmax 2922, 2854, 1715, 1612, 1513, 1456, 1371,
1248, 1093, 844, 823, 740, 699 cm—1 1H NMR (500 MHz, CDCl3) : δ
;
7.36ꢀ7.23 (m, 7H), 6.90ꢀ6.85 (m, 2H), 4.69 (d, J = 11.6 Hz, 1H), 4.54 (d, J
= 11.6 Hz, 1H), 4.48 (s, 2H), 4.20 (quin, J = 6.0 Hz, 1H), 4.0 (dd, J = 8.1,
6.4 Hz, 1H), 3.80 (s, 3H), 3.77ꢀ3.71 (m, 1H), 3.67 (dd, J = 8.1, 6.6 Hz,
1H), 3.60ꢀ3.50 (m, 4H). 3.44 (dd, J = 9.9, 5.6 Hz, 1H), 3.38 (dd, J = 9.9,
5.6 Hz, 1H), 1.88ꢀ1.76 (m, 2H), 1.40 (s, 3H), 1.35 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 159.11, 138.79, 130.39, 129.19, 128.25, 127.77, 127.45,
113.71, 109.30, 75.19, 74.62, 72.94, 72.46, 72.09, 71.81, 67.97, 66.83,
55.23, 32.16, 26.73, 25.39; HRMS (ESI): [M + Na]+ calcd. for C25H34O6Na
453.2248, found 453.2247.
(R)-2-(Benzyloxy)-4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)
methoxy)
butan-1-ol (34): A stirred solution of compound 33 (500 mg, 1.16 mmol)
in CH2Cl2 and pH = 7.4 phosphate buffer (6 mL, 2:1) was treated with
DDQ (395 mg, 1.74 mmol) at 0 °C and stirring was continued at the same
temperature for 2 h. After which time, the reaction mixture was again
treated with DDQ (132 mg, 0.58 mmol) at 0 °C and stirring was continued
at the same temperature for 2 h. The reaction was quenched with
saturated aqueous NaHCO3 (20 mL) at 0 °C and diluted with water (20
mL), ethyl acetate (40 mL) the layers were separated and the aqueous
layer was extracted with ethyl acetate (3 × 30 mL) three times. The
combined organic extracts were washed with saturated aqueous
NaHCO3 (30 mL), water (30 mL) and brine (30 mL). The combined
organic extracts were dried over anhydrous sodium sulphate and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material which was purified by silica gel column chromatography (SiO2,
100ꢀ200 mesh, 40% EtOAc/hexane) to provide alcohol 34 (260 mg, 0.84
mmol, 72%) as a pale yellow oil. Rf = 0.4 (SiO2, 40% EtOAc/hexane);
(R)-3-(Benzyloxy)-4-((4-methoxybenzyl)oxy)butan-1-ol (31): Ozone
was purged to a solution of compound 30 (550 mg, 1.76 mmol) in CH2Cl2
(10 mL) at –78 °C until the solution colour becomes sky blue (10 min).
After which time, TLC (10% EtOAc/hexane) indicated the complete
consumption of compound 30 and formation of ozonide. The solution was
warmed to
0 °C and oxygen was bubbled to the solution until
disappearance of sky blue colour (5 min). To the reaction mixture,
triphenylphosphine (508 mg, 1.94 mmol) was added at 0 °C and the
solution was warmed to room temperature and stirred for 6 h. The
reaction mixture was concentrated under reduced pressure to obtain
crude material which was purified by silica gel column chromatography
(SiO2, 100-200 mesh, 20% EtOAc/hexane) to afford aldehyde (500 mg)
as a colourless oil, which was immediately taken for the next reaction
without further characterization. Rf = 0.7 (SiO2, 50% EtOAc/hexane); To
a stirred solution of above obtained aldehyde (500 mg, 1.59 mmol) in
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
25
[α]D = +11.54 (c 0.65, CHCl3); IR (Neat): νmax 3501, 2985, 2928, 2871,
1712, 1468, 1454, 1372, 1255, 1213, 1054, 842, 740, 699 cm—1; 1H NMR
(500 MHz, CDCl3): δ 7.37ꢀ7.28 (m, 5H), 4.60 (d, J = 11.7 Hz, 1H), 4.58 (d,
J = 11.7 Hz, 1H) 4.24 (quin, J = 6.0 Hz, 1H), 4.04 (dd, J = 8.2, 6.6 Hz,
1H), 3.73 (dd, J = 11.7, 3.8 Hz, 1H), 3.70 (dd, J = 8.2, 6.4 Hz, 1H), 3.66
(m, 1H), 3.61ꢀ3.54 (m, 3H), 3.47 (dd, J = 9.9, 5.8 Hz, 1H), 3.46 (dd, J =
9.9, 5.2 Hz, 1H), 2.26 (brs, 1H), 1.95ꢀ1.88 (m, 1H), 1.87ꢀ1.80 (m, 1H),
1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.35, 128.44,
127.75, 109.42, 74.59, 71.93, 71.62, 67.77, 66.66, 64.07, 31.20, 26.71,
25.35; HRMS (ESI): [M + Na]+ calcd. for C17H26O5Na 333.1672, found
333.1676.
100ꢀ200 mesh, 3% EtOAc/hexane) to afford compound 35 (1.6 g, 6.71
mmol, 82%) as a pale yellow oil. Rf = 0.45 (SiO2, 10% EtOAc/hexane);
25
[α]D = +1.0 (c 1.05, CHCl3); IR (Neat): νmax 3312, 2926, 2855, 2118,
1
1463, 1375, 1301, 1248, 1125, 1040, 833, 723, 628 cm—1; H NMR (400
MHz, CDCl3): δ 3.58 (m, 1H). 2.18 (td, J = 7.2, 2.6 Hz, 2H), 1.94 (t, J =
2.6 Hz, 1H), 1.52 (quin, J = 7.3 Hz, 2H), 1.48ꢀ1.36 (m, 7H), 1.36ꢀ1.25 (m,
13H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 84.72,
71.96, 68.03, 37.44, 31.90, 29.61, 29.43, 29.01, 28.70, 28.44, 25.60,
25.30, 22.62, 18.36, 14.01; HRMS (ESI): [M + H]+ calcd. for C16H31O
239.2375, found 239.2375.
(R)-1-((Hexadec-15-yn-6-yloxy)methyl)-4-methoxy benzene (24):
A
(R)-2-(Benzyloxy)-4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)
methoxy]
mixture of compound 35 (1.45 g, 6.08 mmol) and DIPEA (2.1 mL, 12.16
mmol) was treated with PMBCl (1.23 mL, 9.12 mmol) followed by sodium
iodide (183 mg, 1.22 mmol) at room temperature and the reaction
mixture was warmed to 150 °C and stirred for 2 h. After which time, TLC
(10% EtOAc/hexane) indicated the complete consumption of compound
35. The reaction was quenched with saturated aqueous ammonium
chloride (20 mL) at 0 °C and diluted with water (20 mL) and ethyl acetate
(30 mL) two phases were separated and the aqueous phase was
extracted with ethyl acetate (3 × 30 mL) three times. The combined
organic phases were washed with water (30 mL) and brine (30 mL). The
organic layer was dried over anhydrous sodium sulphate and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material which was purified by silica gel column chromatography (SiO2,
100ꢀ200 mesh, 2% EtOAc/hexane) to afford compound 24 (2.08 g, 5.80
mmol, 95%) as a pale yellow oil. Rf = 0.7 (SiO2, 10% EtOAc/hexane);
butanal (20): To a stirred solution of alcohol 34 (220 mg, 0.71 mmol) in
anhydrous CH2Cl2 (3 mL) at 0 °C was added NaHCO3 (179 mg, 2.13
mmol) followed by DMP (454 mg, 1.07 mmol) and the reaction mixture
was warmed to room temperature and stirred for 30 min. After which time,
TLC (40% EtOAc/hexane) indicated the complete consumption of alcohol
34. The reaction was quenched with (1:1) mixture of saturated aqueous
hypo and saturated aqueous NaHCO3 (30 mL) at 0 °C and diluted with
CH2Cl2 (30 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 30 mL) three times. The combined organic
extracts were washed with water (30 mL) and brine (30 mL). The organic
layer was dried over anhydrous sodium sulphate and filtered. The filtrate
was concentrated under reduced pressure to give a crude material which
was purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh,
30% EtOAc/hexane) to afford aldehyde 20 (219 mg, 0.71 mmol,
quantitative) as a colourless oil, which was taken for the next reaction
without further characterization. Rf = 0.7 (SiO2, 40% EtOAc/hexane).
25
[α]D = −1.82 (c 0.83, CHCl3); IR (Neat): νmax 2927, 2856, 1704, 1610,
1513, 1461, 1248, 1171, 1075, 1037, 822, 630 cm—1; 1H NMR (500 MHz,
CDCl3): δ 7.28ꢀ7.24 (m, 2H), 6.89ꢀ6.85 (m, 2H), 4.43 (s, 2H), 3.80 (s, 3H),
3.33 (quin, J = 5.9 Hz, 1H), 2.18 (td, J = 7.0, 2.6 Hz, 2H), 1.94 (t, J = 2.6
Hz, 1H), 1.55ꢀ1.42 (m, 4H), 1.41ꢀ1.22 (m, 18H), 0.89 (t, J = 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ 158.99, 131.31, 129.26, 113.67, 84.77,
78.66, 70.35, 68.02, 55.26, 33.87, 33.83, 32.05, 29.76, 29.47, 29.05,
28.72, 28.47, 25.34, 25.03, 22.66, 18.38, 14.06; HRMS (ESI): [M + Na]+
calcd. for C24H38O2Na 381.2770, found 381.2764.
(R)-Hexadec-7-yn-6-ol (26): A stirred solution of ynone 27 (2.5 g, 10.58
mmol) in anhydrous CH2Cl2 (50 mL) was treated with a preꢀmixed
solution of HCOOH (2.99 mL, 79.35 mmol) and Et3N (11.04 mL, 79.35
mmol) in CH2Cl2 (10 mL) at 0 °C under argon atmosphere and stirred for
5 min. The reaction mixture was treated with freshly prepared (R,R)ꢀRu
catalyst 23a (35 mg, 0.053 mmol, 0.5 mol %) at 0 °C and the solution
was warmed to room temperature and stirred for 24 h. The reaction was
quenched with saturated aqueous NH4Cl (30 mL) and diluted with water
(20 mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL) three times. The combined organic extracts
were washed with water (30 mL) and brine (30 mL). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 3%
EtOAc/hexane) to afford alcohol 26 (2.23 g, 9.35 mmol, 88%, 94% ee) as
(R)-1-(Benzyloxy)-13-((4-methoxybenzyl)oxy)octadec-3-yn-2-one
(23): To a stirred solution of compound 24 (1.70 g, 4.74 mmol) in
anhydrous THF (10 mL) was added nꢀBuli (1.6 M hexane solution, 2.96
mL, 4.74 mmol) at –78 °C and the solution was slowly warmed to 0 °C
over a period of 45 min and again cooled to –78 °C. To this solution
aldehyde 25 (855 mg, 5.69 mmol) in anhydrous THF (6 mL) was
cannulated and stirring was continued at same temperature for 2 h. The
solution was slowly warmed to room temperature over a period of 1 h.
The reaction was quenched with saturated aqueous ammonium chloride
(20 mL) at 0 °C and diluted with water (20 mL) and ethyl acetate (30 mL)
two phases were separated and the aqueous phase was extracted with
ethyl acetate (3 × 30 mL) three times. The combined organic phases
were washed with water (30 mL) and brine (30 mL). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give crude compound which
was purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh,
15% EtOAc/hexane) to afford diastereomeric mixture of alcohols (2.13 g,
4.19 mmol, 88%, dr = 2.8:1) as a colourless oil that was dissolved in
anhydrous CH2Cl2 (20 mL) and treated with DMP (3.55 g, 8.38 mmol) at
0 °C. After stirring at room temperature for 1 h, the reaction mixture was
quenched with (1:1) mixture of saturated aqueous hypo and saturated
aqueous NaHCO3 (30 mL) at 0 °C and stirred at room temperature until
the solution becomes clear (2 h). The aqueous layer was extracted with
CH2Cl2 (3 × 40 mL) three times. The organic extracts were washed with
water (30 mL) and brine (30 mL). The combined organic layer was dried
over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 6%
EtOAc/hexane) to afford ynone 23 (1.815 g, 3.58 mmol, 85%) as a
colourless oil. Rf = 0.7 (SiO2, 20% EtOAc/hexane); [α]D25 = +2.0 (c 0.75,
CHCl3); IR (Neat): νmax 2920, 2851, 1711, 1551, 1514, 1460, 1254, 1168,
25
a pale yellow oil. Rf = 0.25 (SiO2, 5% EtOAc/hexane); [α]D = +3.16 (c
0.95, CHCl3); IR (Neat): νmax 3394, 2955, 2926, 2856, 1712, 1465, 1022,
772 cm—1 1H NMR (500 MHz, CDCl3) : δ 4.35 (tt, J = 6.5, 1.8 Hz, 1H),
;
2.20 (td, J = 7.0, 1.8 Hz, 2H), 1.77ꢀ1.60 (m, 2H), 1.53ꢀ1.42 (m, 3H), 1.40ꢀ
1.22 (m, 15H), 0.92ꢀ0.86 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 85.53,
81.32, 62.77, 38.17, 31.82, 31.47, 29.17, 29.07, 28.83, 28.66, 24.87,
22.64, 22.56, 18.66, 14.07, 13.98; HRMS (ESI): [M + Na]+ calcd. for
C16H30ONa 261.2194, found 261.2188.
(R)-Hexadec-15-yn-6-ol (35): NaH (3.93 g, 98.16 mmol) was slowly
treated with anhydrous 1,3ꢀdiamino propane (49 mL) at 0 °C under argon
atmosphere and the solution was warmed to 80 °C and stirred for 1 h.
The solution was cooled to room temperature and alcohol 26 (1.95 g,
8.18 mmol) in 1,3ꢀdiamino propane (10 mL) was cannulated and the
solution was again warmed to 80 °C and stirred for 2 h. After which time,
TLC (10% EtOAc/hexane) indicated the complete consumption of alcohol
26. The reaction was slowly quenched with water (30 mL) at 0 °C and
diluted with CH2Cl2 (40 mL) two phases were separated and the aqueous
phase was extracted with CH2Cl2 (3 × 40 mL) three times. The combined
organic phases were washed with water (30 mL) and brine (30 mL). The
organic layer was dried over anhydrous sodium sulphate and filtered.
The filtrate was concentrated under reduced pressure to give a crude
material which was purified by silica gel column chromatography (SiO2,
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
772 cm—1; 1H NMR (300 MHz, CDCl3): δ 7.41ꢀ7.23 (m, 7H), 6.90ꢀ6.84 (m,
2H), 4.64 (s, 2H), 4.43 (s, 2H), 4.20 (s, 2H), 3.80 (s, 3H), 3.33 (quin, J =
5.5 Hz, 1H), 2.37 (t, J = 6.9 Hz, 2H), 1.63ꢀ1.44 (m, 4H), 1.43ꢀ1.18 (m,
18H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 185.06,
158.98, 137.09, 131.28, 129.25, 128.46, 127.99, 127.93, 113.67, 97.61,
78.70, 78.64, 75.78, 73.30, 70.35, 55.25, 33.85, 33.81, 32.04, 29.75,
29.39, 28.97, 28.83, 27.56, 25.32, 25.03, 22.65, 19.07, 14.07; HRMS
(ESI): [M + Na]+ calcd. for C33H46O4Na 529.3294, found 529.3287.
colourless oil. Rf = 0.3 (SiO2, 10% EtOAc/hexane); [α]D25 = +8.13 (c 0.75,
CHCl3); IR (Neat): νmax 3409, 2927, 2855, 1613, 1514, 1301, 1249, 1173,
1081, 1040, 1007, 835, 776 cm—1 1H NMR (500 MHz, CDCl3): δ 7.28ꢀ
;
7.25 (m, 2H), 6.88ꢀ6.85 (m, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.72 (ddd, J =
11.8, 6.1, 3.6 Hz, 1H), 3.56 (dd, J = 10.9, 3.7 Hz, 1H), 3.44 (dd, J = 10.9,
5.3 Hz, 1H), 3.33 (quin, J = 5.9 Hz, 1H), 1.89 (brs, 1H), 1.57ꢀ1.42 (m, 6H),
1.41ꢀ1.21 (m, 22H), 0.90 (s, 9H), 0.88 (t, J = 7.2 Hz, 3H), 0.09 (s, 6H) );
13C NMR (125 MHz, CDCl3): δ 158.96, 131.29, 129.26, 113.65, 78.67,
72.91, 70.33, 66.26, 55.25, 33.95, 33.87, 33.82, 32.05, 29.84, 29.76,
29.64, 29.6, 29.56, 25.84, 25.37, 25.33, 25.03, 22.67, 18.08, 14.07, –
4.44, –4.58. HRMS (ESI): [M + Na]+ calcd. for C32H60O4SiNa 559.4159,
found 559.4153.
(2S,13R)-1-(Benzyloxy)-13-((4-methoxybenzyl)oxy) octadec-3-yn-2-ol
(36): Following the same Noyori reduction conditions as described in the
synthesis of compound 26, the above ynone 23 (1.7 g, 3.36 mmol) was
converted to the corresponding alcohol 36 (1.5 g, 2.95 mmol, 87%, 94%
de; purification by silica gel column chromatography, SiO2, 100ꢀ200 mesh,
(3R,4S,15R)-4-(tert-Butyldimethylsilyl)oxy)-15-((4-methoxybenzyl)
oxy)-1-(triisopropylsilyl) icos-1-yn-3-ol (38): Alcohol 22 (1.25 g, 2.33
mmol) was oxidized under Swern conditions to afford aldehyde (1.2 g,
2.24 mmol, purification by silica gel column chromatography, SiO2, 100ꢀ
200 mesh, 10% EtOAc/hexane) as a colourless oil, which was taken for
the next reaction without further characterization. Rf = 0.8 (SiO2, 10%
EtOAc/hexane). A stirred solution of TIPSꢀacetylene (2 mL, 8.96 mmol) in
dry toluene (10 mL) was treated with Et2Zn (1 M hexane solution, 8.96
mL, 8.96 mmol) carefully at room temperature. The solution was warmed
to 120 °C and stirred for 1 h. Then the reaction was cooled to room
temperature and (R)ꢀBINOL (257 mg, 0.90 mmol) followed by anhydrous
diethyl ether (20 mL) and Ti(OiPr)4 (0.67 mL, 2.24 mmol) were added at
room temperature and stirred for 1 h. To this solution above obtained
aldehyde (1.2 g, 2.24 mmol) in anhydrous diethyl ether (20 mL) was
cannulated at room temperature and stirred for 16 h. The reaction
mixture was quenched with 1 M aqueous tartaric acid (20 mL) at 0 °C
and stirred at room temperature for 30 min and diluted with water (30 mL)
and diethyl ether (50 mL). Two phases were separated and the aqueous
phase was extracted with diethyl ether (3 × 40 mL) three times. The
combined organic phases were washed with water (30 mL) and brine (30
mL). The organic layer was dried over anhydrous sodium sulphate and
filtered. The filtrate was concentrated under reduced pressure to give a
crude material which was purified by silica gel column chromatography
(SiO2, 100ꢀ200 mesh, 3% EtOAc/hexane) to afford compound 38 (900
mg, 1.25 mmol, 53% over two steps, 98% de) as a pale yellow oil. Rf =
16% EtOAc/hexane) as
EtOAc/hexane); [α]D = +4.74 (c 0.68, CHCl3); IR (Neat): νmax 3425,
a colourless oil. Rf = 0.45 (SiO2, 20%
25
2927, 2856, 1612, 1512, 1459, 1355, 1303, 1246, 1174, 1111, 1074,
1035, 898, 820, 738, 699 cm—1; H NMR (400 MHz, CDCl3): δ 7.37ꢀ7.24
1
(m, 7H), 6.89ꢀ6.84(m, 2H), 4.61 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0,
1H), 4.43 (s, 2H), 3.79 (s, 3H), 3.62 (dd, J = 9.8, 3.4 Hz, 1H), 3.52 (dd, J
= 9.8, 7.7 Hz, 1H), 3.33 (quin, J = 5.6 Hz, 1H), 2.49 (brs, 1H), 2.19 (td, J
= 7.2, 2.0 Hz, 2H), 1.57ꢀ1.43 (m, 4H), 1.42ꢀ1.20 (m, 18H), 0.88 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.96, 137.69, 131.28, 129.25,
128.43, 127.80, 127.73, 113.65, 86.58, 78.65, 77.60, 74.03, 73.32, 70.33,
61.83, 55.24, 33.86, 33.82, 32.03, 29.76, 29.45, 29.05, 28.81, 28.49,
25.33, 25.03, 22.64, 18.68, 14.05; HRMS (ESI): [M + Na]+ calcd. for
C33H48O4Na 531.3445, found 531.3450.
(((2S,13R)-1-(Benzyloxy)-13-((4-methoxybenzyl)oxy) octadec-3-yn-2-
yl)oxy)(tert-butyl) dimethylsilane (37): To a stirred solution of alcohol
36 (1.45 g, 2.85 mmol) in anhydrous CH2Cl2 (15 mL) was added 2,6ꢀ
lutidine (1.0 mL, 8.55 mmol) followed by TBSOTf (0.73 mL, 3.14 mmol) at
0 °C and the solution was warmed to room temperature and stirred for 30
min. After which time, TLC (5% EtOAc/hexane) indicated the complete
consumption of alcohol 36. The reaction was quenched with saturated
aqueous NaHCO3 (20 mL) at 0 °C and diluted with water (20 mL) and
CH2Cl2 (30 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL) three times. The combined organic
extracts were washed with water (20 mL) and brine (20 mL). The organic
layer was dried over anhydrous sodium sulphate and filtered. The filtrate
was concentrated under reduced pressure to give a crude material which
was purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh,
3% EtOAc/hexane) to afford compound 37 (1.72 g, 2.76 mmol, 97%) as a
colourless oil. Rf = 0.5 (SiO2, 5% EtOAc/hexane); [α]D25 = +10.47 (c 0.85,
CHCl3); IR (Neat): νmax 2928, 2855, 2376, 2311, 1713, 1512, 1256, 1170,
25
0.4 (SiO2, 10% EtOAc/hexane); [α]D = −1.0 (c 1.10, CHCl3); IR (Neat):
νmax 3500, 2927, 2857, 1612, 1513, 1463, 1364, 1301, 1249, 1172, 1076,
1
1039, 883, 836, 777, 677 cm—1; H NMR (500 MHz, CDCl3): δ 7.28ꢀ7.25
(m, 2H), 6.88ꢀ6.85 (m, 2H), 4.43 (s, 2H), 4.35ꢀ4.32 (m, 1H), 3.80 (s, 3H),
3.77ꢀ3.73 (m, 1H), 3.34 (quin, J = 5.6 Hz, 1H), 2.39 (d, J = 6.0 Hz, 1H),
1.75ꢀ1.42 (m, 7H), 1.41ꢀ1.20 (m, 21H), 1.12ꢀ1.02 (m, 21H), 0.9 (s, 9H),
0.88 (t, J = 7.2 Hz, 3H), 0.10 (s. 3H), 0.09 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 158.96, 131.28, 129.26, 113.65, 105.19, 86.79, 78.68, 74.99,
70.34, 66.39, 55.24, 33.88, 33.83, 33.04, 32.05, 29.87, 29.76, 29.66,
29.62, 29.60, 29.49, 25.77, 25.40, 25.37, 25.04, 22.67, 18.57, 18.04,
1101, 834, 776, 612, 590 cm—1; H NMR (400 MHz, CDCl3): δ 7.35ꢀ7.24
1
(m, 7H), 6.88ꢀ6.85 (m, 2H), 4.62 (d, J = 12.3 Hz, 1H), 4.60 (d, J = 12.3
Hz, 1H), 4.55 (m, 1H), 4.42 (s, 2H), 3.79 (s, 3H), 3.55 (dd, J = 10.1, 5.0
Hz, 1H), 3.54 (dd, J = 10.1, 6.7 Hz, 1H), 3.33 (quin, J = 5.5 Hz, 1H), 2.18
(td, J = 7.1, 2.0 Hz, 2H), 1.56ꢀ1.43 (m, 4H), 1.42ꢀ1.21 (m, 18H), 0.92 (s,
9H), 0.88 (t, J = 7.0 Hz, 3H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 158.99, 138.40, 131.31, 129.25, 128.25, 127.51, 127.43,
113.67, 85.70, 79.27, 78.67, 74.92, 73.31, 70.35, 63.19, 55.24, 33.88,
33.83, 32.05, 29.82, 29.53, 29.12, 28.84, 28.55, 25.81, 25.37, 25.04,
22.66, 18.71, 18.31, 14.06, –4.64, –4.86; HRMS (ESI): [M + K]+ calcd. for
C39H62O4SiK 661.4049, found 661.4076.
14.07, 11.12, –4.34, –4.56; HRMS (ESI): [M
C43H80O4Si2Na 739.5493, found 739.5494.
+
Na]+ calcd. for
(3R,4S,15R)-15-((4-Methoxybenzyl)oxy)icos-1-yne-3,4-diol (21a):
A
stirred solution of compound 38 (850 mg, 1.18 mmol)) in anhydrous THF
(7 mL) was treated with TBAF (1 M THF solution, 4.72 mL, 4.72 mmol) at
0 °C and the solution was warmed to room temperature and stirred for 30
min. After which time, TLC (10% EtOAc/hexane) indicated the complete
consumption of compound 38. The reaction was quenched with saturated
aqueous NH4Cl (10 mL) and diluted with water (10 mL) and CH2Cl2 (20
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL) three times. The combined organic extracts
were washed with water (20 mL) and brine (20 mL). The organic layer
was dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 21%
(2S,13R)-2-((tert-Butyldimethylsilyl)oxy)-13-((4-methoxy
benzyl)
oxy)octadecan-1-ol (22): A stirred solution of compound 37 (1.6 g, 2.57
mmol) in EtOH (30 mL) was treated with freshly activated Raney nickel
(800 mg, 50% w/w) and hydrogenated by using hydrogen filled balloon at
room temperature for 24 h. After which time, TLC (20% EtOAc/hexane)
indicated the complete consumption of compound 37. Then the reaction
mixture was filtered through celite plug carefully under nitrogen
atmosphere and washed with ethyl acetate (30 mL). The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 6%
EtOAc/hexane) to afford alcohol 22 (1.3 g, 2.42 mmol, 94%) as a
EtOAc/hexane) to provide diol compound 21a (500 mg, 1.12 mmol,
25
95%) as a colorless oil. Rf = 0.3 (SiO2, 30% EtOAc/hexane); [α]D
=
+1.52 (c 1.05, CHCl3); IR (Neat): νmax 3392, 3306, 2925, 2854, 1612,
1
1513, 1461, 1301, 1246, 1175, 1037, 819, 653, 632 cm—1; H NMR (400
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3): δ 7.29ꢀ7.24 (m, 2H), 6.89ꢀ6.85 (m, 2H), 4.43 (s, 2H), 4.32
(dd, J = 3.5, 2.2 Hz, 1H), 3.8 (s, 3H), 3.69 (ddd, J = 7.1, 6.4, 3.5 Hz, 1H),
3.34 (quin. 5.6 Hz, 1H), 2.5 (d, J = 2.0 Hz, 1H), 2.27 (brs, 2H), 1.61ꢀ1.42
(m, 7H), 1.41ꢀ1.22 (m, 21H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 158.96, 131.26, 129.28, 113.66, 81.31, 78.68, 74.86, 73.97,
70.33, 66.17, 55.25, 33.85, 33.81, 32.72, 32.03, 29.79, 29.67, 29.59,
29.54, 29.50, 25.54, 25.34, 25.03, 22.65, 14.05; HRMS (ESI): [M + Na]+
calcd. for C28H46O4Na 469.3294, found 469.3290.
Hz, 1H), 3.79 (s, 3H), 3.67 (dd, J = 7.9, 6.4 Hz, 1H), 3.65ꢀ3.53 (m, 2H),
3.41 (qd, J = 9.8, 5.8 Hz, 2H), 3.36ꢀ3.28 (m, 1H), 2.10 (m, 1H), 1.97 (m,
1H), 1.79 (m, 1H), 1.66 (m, 1H), 1.51 (s, 3H), 1.50ꢀ1.42 (m, 3H), 1.40 (s,
3H), 1.36 (s, 3H), 1.35 (s, 3H), 1.34ꢀ1.22 (m, 23H), 0.89 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 188.36, 158.95, 137.26, 131.28,
129.20, 128.34, 127.98, 127.87, 113.63, 110.25, 109.25, 91.00, 84.01,
81.66, 78.63, 78.13, 74.49, 72.52, 71.86, 70.31, 69.17, 66.83, 55.20,
33.85, 33.80, 32.20, 32.01, 30.47, 29.82, 29.62, 29.58, 29.51, 29.47,
27.79, 26.71, 26.03, 25.97, 25.37, 25.00, 22.62, 14.03; HRMS (ESI): [M +
Na]+ calcd. for C48H72O9Na 815.5074, found 815.5078.
(4R,5S)-4-Ethynyl-5-((R)-11-((4-methoxybenzyl)oxy) hexadecyl)-2,2-
dimethyl-1,3-dioxolane (21): A stirred solution of diol 21a (480 mg, 1.07
mmol) in anhydrous acetone (5 mL) was treated with 2,2ꢀDMP (1.32 ml,
10.7 mmol) followed by catalytic amount of PPTS (27 mg, 0.11 mmol) at
0 °C and stirred at room temperature for 16 h. After which time, TLC
(30% EtOAc/hexane) indicated the complete consumption of diol 21a.
The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and
acetone was evaporated under reduced pressure. The crude residue was
diluted with water (15 mL) and ethyl acetate (30 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate (3 × 20
mL) three times. The combined organic extracts were washed with water
(20 mL) and brine (20 mL). The organic layer was dried over anhydrous
sodium sulphate and filtered. The filtrate was concentrated under
reduced pressure to give a crude material which was purified by silica gel
column chromatography (SiO2, 100ꢀ200 mesh, 2% EtOAc/hexane) to
afford alkyne 21 (481 mg, 0.99 mmol, 92%) as a colourless oil. Rf = 0.3
(SiO2, 5% EtOAc/hexane); [α]D25 = +20.05 (c 1.88, CHCl3); IR (Neat): νmax
2925, 2855, 1612, 1513, 1460, 1373, 1300, 1243, 1170, 1040, 862, 655
cm—1; 1H NMR (500 MHz, CDCl3): δ 7.29ꢀ7.24 (m, 2H), 6.88ꢀ6.85 (m, 2H),
4.71 (dd, J = 5.5, 2.1 Hz, 1H), 4.43 (s, 2H), 4.06 (dt, J = 7.1, 6.1 Hz, 1H),
3.79 (s, 3H), 3.33 (quin, J = 5.6 Hz, 1H), 2.51 (d, J = 2.1 Hz, 1H), 1.85ꢀ
1.64 (m, 3H), 1.54 (s, 3H), 1.53ꢀ1.36 (m, 4H), 1.35 (s, 3H), 1.34ꢀ1.21 (m,
21H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 158.94,
131.25, 129.24, 113.63, 109.60, 80.07, 78.62, 77.92, 75.43, 70.31, 69.05,
55.21, 33.85, 33.79, 32.03, 30.54, 29.82, 29.61, 29.56, 29.50, 29.43,
27.79, 26.08, 25.88, 25.34, 25.01, 22.64, 14.05; HRMS (ESI): [M + Na]+
calcd. for C31H50O4Na 509.3607, found 509.3604.
(3S,4R)-4-(Benzyloxy)-6-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)
methoxy)-1-((4R,5S)-5-((R)-11-((4-methoxybenzyl)oxy)
hexadecyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)hex-1-yn-3-ol (39): A stirred solution of
ynone 19 (50 mg, 0.063 mmol) in anhydrous CH2Cl2 (3 mL) was treated
with a preꢀmixed solution of HCOOH (18 ꢁL, 0.47 mmol) and Et3N (74 ꢁL,
0.54 mmol) in CH2Cl2 (1 mL) at 0 °C under argon atmosphere and stirred
for 5 min. The reaction mixture was treated with (R,R)ꢀRu catalyst 23a
(0.01 M CH2Cl2 solution, 63 ꢁL, 0.63 ꢁmol, 1 mol %) at 0 °C and the
solution was warmed to room temperature and stirred for 24 h. After
which time, TLC (30% EtOAc/hexane) indicated the complete
consumption of ynone 19. The reaction was quenched with saturated
aqueous NH4Cl (5 mL) and diluted with water (5 mL) and CH2Cl2 (10 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 15 mL) three times. The combined organic extracts were
washed with water (15 mL) and brine (15 mL). The organic layer was
dried over anhydrous sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure to give a crude material which was
purified by silica gel column chromatography (SiO2, 100ꢀ200 mesh, 18%
EtOAc/hexane) to afford diastereomerically pure alcohol 39 (43 mg,
0.054 mmol, 85%, 99% de) as a colourless oil. Rf = 0.35 (SiO2, 30%
25
EtOAc/hexane); [α]D = +22.42 (c 1.90, CHCl3); IR (Neat): νmax 3450,
2927, 2857, 1691, 1608, 1513, 1459, 1374, 1246, 1219, 1163, 1039, 847,
;
740, 700 cm—1 1H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.24 (m, 7H), 6.88ꢀ
6.85 (m, 2H), 4.75 (dd, J = 5.5, 1.4 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H),
4.61 (d, J = 11.6 Hz, 1H), 4.56 (m, 1H) 4.43 (s, 2H), 4.22 (quin, J = 5.9
Hz, 1H), 4.07ꢀ4.01 (m, 2H), 3.80 (s, 3H), 3.73 (dd, J = 5.9, 4.2 Hz, 1H),
3.70 (dd, J = 8.2, 6.4 Hz, 1H), 3.65ꢀ3.56 (m, 2H), 3.46 (qd, J = 9.9, 5.6
Hz, 2H), 3.33 (quin, J = 5.8 Hz, 1H), 2.78 (brs, 1H), 1.97 (q, J = 6.0 Hz,
2H), 1.82ꢀ1.58 (m, 4H), 1.51 (s, 3H), 1.50ꢀ1.43 (m, 2H), 1.41 (s, 3H), 1.36
(s, 3H), 1.34 (s, 3H), 1.33ꢀ1.22 (m, 22H), 0.88 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 158.96, 138.09, 131.29, 129.23, 128.39,
127.76, 113.65, 109.40, 85.62, 82.36, 78.66, 78.09, 74.57, 72.46, 71.81,
70.32, 69.29, 67.41, 66.72, 63.97, 55.23, 33.87, 33.81, 32.03, 30.71,
30.02, 29.85, 29.62, 29.56, 27.93, 26.72, 26.10, 25.99, 25.37, 25.02,
22.63, 14.05; HRMS (ESI): [M + Na]+ calcd. for C48H74O9Na 817.5231,
found 817.5229.
(R)-4-(Benzyloxy)-6-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl) methoxy)-1-
((4R,5S)-5-((R)-11-((4-methoxybenzyl) oxy) hexa decyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)hex-1-yn-3-one (19): A stirred solution of alkyne 21
(477 mg, 0.98 mmol) in anhydrous THF (4 mL) was treated with nꢀBuli
(1.6 M hexane solution, 0.58 mL, 0.93 mmol) drop wise over a period of 3
min at –78 °C and the solution was slowly warmed to 0 °C over a period
of 45 min. The reaction mixture was again cooled to –78 °C and the
aldehyde 20 (150 mg, 0.49 mmol) in anhydrous THF (3 mL) was
cannulated. After stirring at –78 °C for 2 h, the reaction mixture was
slowly warmed to room temperature over a period of 1 h. The reaction
was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and diluted
with water (20 mL) and ethyl acetate (30 mL). The layers were separated
and the aqueous layer was extracted with ethyl acetate (3 × 20 mL) three
times. The combined organic extracts were washed with water (20 mL)
and brine (20 mL). The organic layer was dried over anhydrous sodium
sulphate and filtered. The filtrate was concentrated under reduced
pressure to give a crude material which was purified by silica gel column
chromatography (SiO2, 100ꢀ200 mesh, 19% EtOAc/hexane) to afford an
inseparable diastereomeric mixture of alcohols (316 mg, 0.40 mmol, 81%,
dr = 1.3:1) as a colorless oil. Rf = 0.35 (SiO2, 30% EtOAc/hexane).
Following the same Swern conditions, experimental procedure as
described for the preparation of compound 9, the above obtained
diastereomeric mixture of alcohols (100 mg, 0.126 mmol) was oxidized to
corresponding ynone 19 (93 mg, 0.117 mmol, 93%; purification by silica
gel column chromatography, SiO2, 100ꢀ200 mesh, 14% EtOAc/hexane)
as a colourless oil. Rf = 0.5 (SiO2, 20% EtOAc/hexane); [α]D25 = +41.20 (c
2.50, CHCl3); IR (Neat): νmax 2927, 2857, 1693, 1612, 1513, 1459, 1374,
1245, 1047, 851, 741, 699 cm—1; 1H NMR (500 MHz, CDCl3): δ 7.37ꢀ7.24
(m. 7H), 6.89ꢀ6.84 (m, 2H), 4.85 (d, J = 5.5 Hz, 1H), 4.76 (d, J = 11.6 Hz,
1H), 4.43 (s, 2H), 4.41ꢀ4.38 (m, 1H), 4.17 (quin, J = 6.0 Hz, 1H), 4.12 (dt,
J = 6.5, 5.8 Hz, 1H), 4.08 (dd, J = 8.2, 4.4 Hz, 1H), 4.00 (dd, J = 7.8, 1.2
(3R,4S)-1-(((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy) -6-((4R,5S)-5-
((R)-11-hydroxyhexadecyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hexane-
3,4-diol (40): A stirred solution of alcohol 39 (38 mg, 0.048 mmol) in
anhydrous ethyl acetate (2 mL) was treated with 10% Pd/C (7.6 mg, 20%
w/w) and hydrogenated by using hydrogen filled balloon at room
temperature for 24 h. After which time, TLC (30% EtOAc/hexane)
indicated the complete consumption of alcohol 39. The reaction mixture
was filtered through the celite plug and washed with ethyl acetate (20 mL).
The filtrate was concentrated under reduced pressure to give a crude
material which was purified by silica gel column chromatography (SiO2,
100-200 mesh, 4% MeOH/CHCl3) to afford triol compound 40 (26 mg,
0.044 mmol, 91%) as a colourless oil. Rf = 0.35 (SiO2, 8% MeOH/CHCl3);
[α]D25 = +2.0 (c 0.95, CHCl3); IR (Neat): νmax 3404, 2926, 2856, 1695,
1515, 1460, 1373, 1247, 1215, 1057, 850 cm—1 1H NMR (400 MHz,
;
CDCl3): δ 4.30ꢀ4.23 (m, 1H), 4.08ꢀ4.01 (m, 3H), 3.81ꢀ3.74 (m, 2H), 3.73ꢀ
3.67 (m, 2H), 3.67ꢀ3.61 (m, 1H), 3.60ꢀ3.56 (m, 1H), 3.53 (d, J = 4.9 Hz,
1H), 3.53 (d, J = 5.5 Hz, 1H), 3.30 (brs, 1H), 2.67 (brs, 1H), 1.92ꢀ1.64 (m,
6H), 1.55ꢀ1.39 (m, 14H), 1.36 (s, 3H), 1.33 (s, 3H), 1.32ꢀ1.23 (m, 20H),
0.89 (t, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 109.52, 107.37,
78.37, 78.11, 74.55, 74.09, 74.03, 71.98, 71.98, 70.44, 66.32, 37.44,
13
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10.1002/ejoc.201701562
European Journal of Organic Chemistry
FULL PAPER
37.41, 31.88, 30.33, 29.66, 29.61, 29.56, 29.50, 29.43, 29.05, 28.55,
26.66, 26.42, 26.22, 25.90, 25.62, 25.30, 25.25, 22.62, 14.03; HRMS
(ESI): [M + Na]+ calcd. for C33H64O8Na 611.4499, found 611.4501.
Acknowledgements
K.N.R thanks UGC, New Delhi for the research fellowship. S.G
is thankful to CSIR for funding through ORIGIN and CSIRꢀYoung
Scientist Research Grant.
(R)-16-((4R,5R)-5-(2-((4R,5R)-5-(2-(((S)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)hexadecan-6-ol (41a): Following the same synthetic
procedure as reported in the synthesis of compound 21, the above triol
compound 40 (20 mg, 0.034 mmol) was transformed to the
corresponding compound 41a (20 mg, 0.032 mmol, 94%; silica gel
column chromatography, SiO2, 100ꢀ200 mesh, 18% EtOAc/hexane) as a
colourless oil. Rf = 0.3 (SiO2, 30% EtOAc/hexane); [α]D25 = +14.90 (c 1.0,
CHCl3); IR (Neat): νmax 3506, 2985, 2927, 2857, 1712, 1460, 1374, 1247,
Keywords: Marine natural product• mycalol• cytotoxic• Total
synthesis• Noyori reduction•
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1216, 1164, 1085, 1045, 873, 848 cm—1 1H NMR (400 MHz, CDCl3): δ
;
4.26 (quin, J = 6.0 Hz, 1H), 4.19 (dt, J =10.3, 5.5 Hz, 1H), 4.11ꢀ3.98 (m,
4H), 3.74 (dd, J = 8.2, 6.4 Hz, 1H), 3.67ꢀ3.56 (m, 3H), 3.54 (dd, J = 9.9,
5.5 Hz, 1H), 3.45 (dd, J = 9.9, 5.6 Hz, 1H), 1.79ꢀ1.56 (m, 5H), 1.48 (m,
1H), 1.42 (s, 12H), 1.36 (s, 3H), 1.35ꢀ1.24 (m, 31H), 0.89 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 109.35, 107.60, 107.37, 78.29, 78.18,
78.07, 74.81, 74.60, 72.01, 71.91, 68.67, 66.83, 37.46, 37.42, 36.61,
31.90, 30.15, 29.68, 29.59, 29.55, 29.51, 28.63, 28.57, 27.14, 27.05,
26.74, 26.32, 25.93, 25.90, 25.63, 25.39, 25.31, 24.67, 22.63, 14.03;
HRMS (ESI): [M + Na]+ calcd. for C36H68O8Na 651.4812, found 651.4810.
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(R)-16-((4R,5R)-5-(2-((4R,5R)-5-(2-(((S)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)hexadecan-6-ylacetate (41): Following the same
acetylation experimental procedure as reported in the synthesis of
compound 3, compound 41a (15 mg, 0.024 mmol) was converted to the
corresponding acetylated triacetonide compound 41 (15.2 mg, 0.023
mmol, 95%; purification by silica gel column chromatography, SiO2, 100ꢀ
200 mesh, 16% EtOAc/hexane) as a colourless oil. Rf = 0.35 (SiO2, 30%
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25
EtOAc/hexane); [α]D = +7.21 (c 0.69, CHCl3); IR (Neat): νmax 2928,
2858, 1737, 1460, 1374, 1245, 1086, 1032, 871 cm—1; 1H NMR (500 MHz,
CDCl3): δ 4.86 (quin, J = 6.3 Hz, 1H), 4.26 (quin, J = 6.0 Hz, 1H), 4.19
(ddd, J = 9.7, 5.5, 4.7 Hz, 1H), 4.10ꢀ3.99 (m, 4H), 3.74 (dd, J = 8.2, 6.4
Hz, 1H), 3.67ꢀ3.57 (m, 2H), 3.54 (dd, J = 9.9, 5.6 Hz, 1H), 3.46 (dd, J =
9.9, 5.6 Hz, 1H), 2.04 (s, 3H), 1.79ꢀ1.60 (m, 5H), 1.56ꢀ1.44 (m, 6H), 1.42
(s, 9H), 1.39 (m, 1H), 1.36 (s, 3H), 1.33 (s, 6H), 1.32ꢀ1.21 (m, 22H), 0.88
(t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 170.99, 109.42, 107.67,
107.44, 78.38, 78.27, 78.14, 74.89, 74.69, 74.51, 72.00, 68.76, 66.93,
34.18, 34.13, 31.78, 30.24, 29.80, 29.76, 29.61, 28.71, 28.66, 27.24,
27.14, 26.83, 26.42, 26.00, 25.98, 25.48, 25.38, 25.03, 22.60, 21.36,
14.06; HRMS (ESI): [M + Na]+ calcd. for C38H70O9Na 693.4918, found
693.4913.
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Mycalol (2): A stirred solution of triacetonide compound 41 (6 mg,
0.0089 mmol) in THF (1.8 mL) was treated with 1 N HCl (0.6 mL) at 0 °C
and the solution was warmed to room temperature and stirred for 5 h.
After which time, THF from the reaction mixture was evaporated under
reduced pressure and water was evaporated by lyophilization to afford
crude material which was purified by silica gel column chromatography
(SiO2, 100ꢀ200 mesh, 12% MeOH/CHCl3) to afford mycalol (2) (4.0 mg,
0.0073 mmol, 82%) as a colourless semisolid. Rf = 0.35 (SiO2, 20%
MeOH/CHCl3); [α]D25 = +4.28 (c 0.20, MeOH); IR (Neat): νmax 3392, 3286,
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2921, 2854, 1737, 1516, 1464, 1244, 1056 cm—1 1H NMR (700 MHz,
;
C5D5N): δ 5.07 (m, 1H), 4.36 (m, 1H), 4.19 (m, 1H), 4.14ꢀ4.10 (m, 1H),
4.10ꢀ4.03 (m, 3H), 4.03ꢀ3.95 (m, 3H), 3.91 (dd, J = 9.6, 4.9 Hz, 1H), 3.85
(dd, J = 9.6, 6.1 Hz, 1H), 2.59 (bd, J = 7.5 Hz, 2H), 2.40 (m, 1H), 2.18ꢀ
2.10 (m, 3H), 2.08 (s, 3H), 1.99 (m, 1H), 1.91ꢀ1.82 (m, 2H), 1.63ꢀ1.48 (m,
5H), 1.42ꢀ1.26 (m, 8H), 1.26ꢀ1.16 (m, 12H), 0.82 (t, J = 7.0 Hz, 3H); 13C
NMR (175 MHz, C5D5N): δ 170.70, 75.98, 76.96, 75.26, 74.27, 73.77,
72.97, 72.02, 69.68, 64.76, 34.54, 34.47, 33.67, 33.63, 31.92, 30.72,
30.45, 30.35, 30.11, 29.97, 29.86, 29.84, 26.79, 25.75, 25.35, 22.80,
21.16, 14.16; HRMS (ESI): [M + Na]+ calcd. for C29H58O9Na 573.3979,
found 573.3987.
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European Journal of Organic Chemistry
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15
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FULL PAPER
Natural Product Synthesis
K. N. Rao, K. Kumar, S. Ghosh*
Page No.1 –16
Total Synthesis of Anticancer Marine
Natural Product Mycalol
Total synthesis of anticancer marine natural product mycalol has been achieved by the use of Maruoka asymmetric allylation,
Noyori asymmetric reduction, asymmetric alkynylation and Zipper reaction as key steps.
16
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