Total synthesis of marine natural products separacenes A and B

Article abstract of DOI:10.1039/c7ob00345e

A short and convergent route for the stereoselective total synthesis of separacenes A and B has been developed using (+)-methyl d-lactate and d-(-)-tartaric acid as the chiral pools. The characteristic features of this synthesis include the Trost-Rychnovsky alkyne rearrangement to construct the C₇-C₉ conjugated diene, the Horner-Wadsworth-Emmons olefination to form the C₅-C₆ and C₁₁-C₁₂ olefins and the Corey-Bakshi-Shibata reaction to install the C-13 hydroxy functionality.

Full text of DOI:10.1039/c7ob00345e

View Article Online
View Journal
Organic &
Biomol ec ular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Das and R. K.
Goswami, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB00345E.
Volume 14 Number
1
7
January 2016 Pages 1–372
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
Total Synthesis of Marine Natural Products Separacenes A and B
Subhendu Das and Rajib Kumar Goswami*
Department of Organic Chemistry,
Indian Association for the Cultivation of Science, Jadavpur,
Kolkataꢀ700032, India.
Email: ocrkg@iacs.res.in
HWE Olefination
OH
OH
OH
OH
R
S
OH
OH
OH
OH
CBS Reduction
Trost-Rychnovsky
alkyne rearrangement Separacene A
Separacene B
Abstract:
A short and convergent route for the stereoselective total synthesis of separacenes A and
B has been developed using (+)ꢀmethyl Dꢀlactate and Dꢀ(ꢀ)ꢀtartaric acid as the chiral pools. The
characteristic features of this synthesis include TrostꢀRychnovsky alkyne rearrangement to
construct the C ꢀC conjugated diene, HornerꢀWadsworthꢀEmmons olefination to form the C ꢀC
6
7
9
5
and C ꢀC olefins and CoreyꢀBakshiꢀShibata reaction to install the Cꢀ13 hydroxy functionality.
11
12

Organic & Biomolecular Chemistry
Page 2 of 24
View Article Online
DOI: 10.1039/C7OB00345E
Secondary metabolites of actinomycetes are known as rich sources of bioactive natural
1
products which possess significant structural diversities. During the search of bioactive
compounds from marine actinomycetes collected in the southern area of Jeju Island, Oh and
coworkers were the first to have isolated, in 2013, the secondary metabolites separacenes AꢀD
2
(
Figure 1) from Streptomyces strains, SNJ210. The structures of separacenes AꢀD were
evaluated using advanced NMR, mass, UV and IR spectroscopic techniques and by chemical
derivatizations with Mosher’s acids. Architecturally both separacenes AꢀB (1ꢀ2) have an
identical planar tetraene moiety flanked by two diol subunits, but the relative configuration in
one of the hydroxy centers is different. On the other hand separacenes CꢀD (3ꢀ4) are structural
isomers of separacenes AꢀB which possess a triene moiety between a pair of diol subunits. Each
member of the separacenes family bears a common terminal methylene olefin moiety.
Separacenes AꢀD are structurally novel as no comparable natural or synthetic compounds are
known in literature to the best of our knowledge. Separacene A (1) exhibited inhibitory activity
Figure 1: Chemical structure of separacenes AꢀD (1ꢀ4).
OH
OH
1
OH
OH
OH
OH
2
OH
OH
OH
OH
3
OH
OH
OH
OH
4
OH
OH
against Candida albicans isocitrate lyase and weak cytotoxicity against the human colon (HCTꢀ
2
1
16) and lungs (A549) cancer cell lines. Interesting linear structural features together with the
limited natural abundance necessities the development of efficient synthetic routes to render
these materials readily available for further biological evaluation. As a part of our ongoing

Page 3 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
3
program towards the synthesis of marine natural products, we initially envisaged the total
synthesis of separacenes AꢀB (1ꢀ2). Herein we report a convergent and flexible stereoselective
synthetic route of separacenes AꢀB (1ꢀ2) for the first time.
The retrosynthetic analysis of separacenes AꢀB (1ꢀ2) is delineated in Scheme 1.
Separacenes AꢀB (1ꢀ2) could be accessed from the suitably protected compound 5 by selective
4
reduction of the carbonyl functionality using a CoreyꢀBakshiꢀShibata (CBS) reaction followed
by global deprotection of all the protecting groups. The common intermediate 5 could be
constructed further from compound 6 and keto phosphonate 7 using the HornerꢀWadsworthꢀ
5
(aꢀc)
Emmons (HWE) olefination
prepared from phosphonate 8 and alcohol 9 using HWE olefination
Phosphonate 8 could further be constructed from alkyne 10 using the TrostꢀRychnovsky alkyne
as one of the key coupling steps. Compound 6 could be
5
(dꢀe)
as one of the key steps.
6
7
rearrangement and the Arbuzov reaction as the pivotal steps.
Scheme 1: Retrosynthetic analysis of separacenes AꢀB (1-2).
OH
OH
OTBS
O
O
1
0
6
1
3
3
CBS
Reduction
5
OH
OH
O
O
HWE Olefination
1
(C-13 = R)
2
(C-13 = S)
OTBS
O
OMe
P
EtO C
2
+
6
OMe
O
O
7
HWE Olefination
O
O
OEt
O
O
Trost-Rychnovsky
P
+
HO
MeO
OEt
alkyne rearrangement
MeO
10
8
9
O
TBSO
Our synthetic endeavor began with the preparation of phosphonate 8 (Scheme 2).
Commercially available 4ꢀpentyneꢀ1ꢀol was first treated with TBSCl in presence of Et N/DMAP
3
to achieve the corresponding TBS ether which further was reacted with ethyl chloroformate

Organic & Biomolecular Chemistry
Page 4 of 24
View Article Online
DOI: 10.1039/C7OB00345E
n
(
ClCO Et) in presence of BuLi to get the alkyne carbonyl compound 10 in good overall yield
2
(
70%). Next, alkyne 10 was treated with Ph P in presence of phenol following the Trostꢀ
3
6
Rychnovsky reaction to rearrange it into the conjugatedꢀdiene carbonyl compound 11 in 74%
yield with complete regioselectivity. The TBS ether of compound 11 was then deprotected using
TBAF to obtain the corresponding alcohol. This was subsequently treated with CBr /Ph P
4
3
8
following the Appel reaction to yield the corresponding bromo compound which finally was
7
transmuted to phosphonate 8 using P(OMe) following the Arbuzov reaction conditions.
3
Scheme 2: Synthesis of phosphonate 8.
O
a
OEt
O
HO
pent-4-yn-1-ol
TBSO
10
b
O
P
O
c
TBSO
MeO
OEt
OEt
MeO
8
1
1
n
Reagents and conditions: (a) (i) TBSCl, Et N, DMAP, CH Cl , 0 ᵒC to RT, 2.5 h; (ii) BuLi,
3
2
2
ClCO Et, THF, ꢀ78 ᵒC to RT, 3.5 h, 70% after 2 steps. (b) C H OH, PPh , benzene, RT, 12 h,
2
6
5
3
7
4% (c) (i) TBAF, THF, 0 ᵒC to RT, 1 h, 83%; (ii) CBr , PPh , CH Cl , 0 ᵒC to RT, 1 h, 82%;
4 3 2 2
(
iii) P(OMe) , reflux, 12 h, 87%.
3
Our initial attempts towards the total synthesis of separacene A (1) are summarized in
9
Scheme 3. The known alcohol 9, prepared from Dꢀ(ꢀ)ꢀtartaric acid, was oxidized to its
1
0
corresponding aldehyde using Swern conditions and subsequently reacted with phosphonate 8
5
(aꢀc)
following HWE reaction protocols
to result in compound 12 as the major isomer (dr ~ 5:1).
The minor geometrical counterpart was separated during the column purification. The ester
functionality of compound 12 was reduced using DIBALꢀH to get alcohol 13 which was

Page 5 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
1
1
oxidized further by IBX to yield the conjugated aldehyde 14 in good overall yield (81%). Next,
the known ketoꢀphosphonate 7 prepared from (+)ꢀmethyl Dꢀlactate following a literature
1
2
5(dꢀe)
protocol was reacted with the conjugated aldehyde 14 following the HWE reaction.
A
number of reagents (Tableꢀ1) had been screened at this stage to optimize the conditions for
efficient synthesis of compound 3. It was observed that organic bases DIPEA (entryꢀ1) and DBU
(
entryꢀ2) in presence of LiCl were not effective in the required transformation. Cs CO (entryꢀ3)
2 3
functioned with good yields (60%) and regioselectivity (dr ~ 5.5:1) but Ba(OH) (entryꢀ4) was
2
the best and produced the coupling product in excellent yield (80%) and good
diastereoselectivity (dr ~ 5.5:1). The keto functionality of compound 3 was then reduced using
4
RꢀCBS in presence of BH ꢀDMS to get compound 15 as the major isomer (dr ~ 3:1) which was
3
separated easily from its minor counterpart by silica gel column chromatography. We went two
more steps forward to determine the relative configuration of the newly generated hydroxy
center. Therefore, the TBS ether of compound 15 was deprotected using TBAF to get the
corresponding diol and subsequently treated with 2,2ꢀDMP in presence of CSA to get the
1
3
acetonide compound 16. The C NMR analysis of acetonide 16 exhibited well separated signals
27.5 and 27.1 ppm) characteristic for the methyl acetals of dioxolane ring (Cꢀ13 and Cꢀ14
(
13
centers) of cisꢀconformation which confirmed the Rꢀconfiguration of the Cꢀ13 hydroxy center.
Having a stereochemically defined the structure of compound 15, we then planned for an acidꢀ
catalyzed global deprotection of all the protecting groups to get separacene A (1). A number of
reagents like AcOHꢀH O, CSA, PTSA and HFꢀPy have been tested separately in different
2
conditions but in every case the starting material decomposed completely. These results revealed
that compound 15 is acid sensitive which compelled us to modify our synthetic strategy, so that
the use of acidic reagents in the prefinal stage of the synthesis could be avoided.

Organic & Biomolecular Chemistry
Page 6 of 24
View Article Online
DOI: 10.1039/C7OB00345E
Scheme 3: Attempts towards the synthesis of separacene A (1)
OH
O
O
ref-9
CO Et
a
b
2
HO
EtO C
2
EtO C
2
OH
D-(-)-Tartaric acid
O
12
O
9
O
OTBS
O
OH
O
O
P
ref-12
c
OMe
OMe
OMe
HO
OHC
1
3
O
O
14
O
7
(
+)-Methyl D-
d
lactate
OTBS
O
O
3
O
e
O
O
Acid-catalyzed global
deprotection
OTBS
OH
O
f
1
1
6
15
O
O
O
Reagents and conditions: (a) (i) (COCl) , DMSO, Et N, CH Cl , ꢀ78 to 0 ᵒC, 2 h; (ii) 8, LDA,
2
3
2
2
THF, ꢀ78 ᵒC then aldehyde, 2h, 54% after 2 steps; (b) DIBALꢀH, CH Cl , −78 ᵒC, 30 min, 90%;
2
2
(
c) IBX, EtOAc, reflux, 3 h, 90%; (d) 7, Ba(OH) , THF, RT then aldehyde, 12 h, 61% after 2
2
steps. (e) RꢀCBS, BH ꢀMe S, THF, ꢀ20 ᵒC, 3 h, 80%; (f) (i) TBAF, THF, 0 ᵒC, 30 min; (ii) 2,2
3
2
DMP, CSA, CH Cl , 0 ᵒC; 68% after 2 steps.
2
2
Table 1: Optimization of HWE reaction between phosphonate 7 and aldehyde 14.
Entry
i
ii
iii
iv
Conditions
Time
24 h
24 h
12 h
12 h
Yield(%)
dr ratio (E/Z)
DIPEA, LiCl, THF, 0 ᵒC to RT
DBU, LiCl, THF, 0 ᵒC to RT
Cs CO , CH CN, RT
ꢀ
ꢀ
60
80
ꢀ
ꢀ
5.5:1
5.5:1
2
3
3
Ba(OH) , THF:H O (40:1), RT
2
2
It was observed that TBAF mediated conversion of compound 15 to its corresponding
desilylated product was efficient which prompted us to revisit our protecting group strategy as
described in Scheme 4. Compound 11 first was subjected to acetonide deprotection using
CSA/EtOH to access the corresponding diol and subsequently converted to silylated compound

Page 7 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
17 using TBSOTf/2,6ꢀlutidine in good overall yield (83%). Ester 17 was then converted to
aldehyde 18 in two consecutive steps as mentioned earlier and concomitantly was reacted with
the ketoꢀphosphonate 7 in the presence of Ba(OH) , the optimized condition for our system
2
(Tableꢀ1), to afford compound 19 with similar yield and selectivity compared to compound 3.
4
Next, the keto functionality of compound 19 was reduced separately using RꢀCBS and SꢀCBS to
yield compounds 20 (dr ~ 3:1) and 21 (dr ~ 3.1:1), respectively, as the major isomers. The minor
isomers obtained in the above reduction process were separated from their major counterparts
using silica gel column chromatography. The low diastereoselectivity in CBS reduction was
most likely due to the presence of the αꢀhydroxy center bearing bulky TBS ether. Both the
compounds 20 and 21 were then treated with TBAF separately to obtain compounds 1 and 2 in
1
4
good overall yield. The spectral data (see the comparison TableꢀS1 and S2 in SI) and specific
2
5
rotations of the synthesized compounds 1{observed [α]D = ꢀ12.8 (c 0.01, MeOH); reported [α]D
25
=
ꢀ15.0 (c 0.075, MeOH)} and 2{observed [α]D = ꢀ10.1 (c 0.01, MeOH); reported [α] = ꢀ12.0
D
2
(
c 0.05, MeOH)} were in good agreement with those reported for the isolated natural products
which confirmed the total synthesis of separacenes A and B.
Scheme 4: Completion of total synthesis of separacenes AꢀB (1ꢀ2).
O
OTBS
OTBS
b
a
EtO C
EtO C
2
2
OHC
1
1
18
O
17
OTBS
OTBS
OTBS
O
OTBS
OTBS
OH
OTBS
c
d
e
1
1
9
OTBS
20
OTBS
f
OTBS
OTBS
e
2
21
OH
OTBS
Reagents and conditions: (a) (i) CSA, EtOH, 0 ᵒC to RT, 48 h, 87%; (ii) TBSOTf, 2,6ꢀlutidine,
CH Cl , 0 ᵒC, 15 min, 95%; (b) (i) DIBALꢀH, CH Cl , −78 ᵒC, 30 min, 95%; (ii) IBX, EtOAc,
2
2
2
2

Organic & Biomolecular Chemistry
Page 8 of 24
View Article Online
DOI: 10.1039/C7OB00345E
reflux, 3 h; 90%; (c) 7, Ba(OH) ꢀH O, THF, RT then aldehyde, 12 h, 67%; (d) RꢀCBS, BH ꢀ
2
2
3
Me S, THF, ꢀ20 ᵒC, 3 h, 60%; (e) SꢀCBS, BH ꢀMe S, THF, ꢀ20 ᵒC, 3 h, 60%; (f) TBAF, THF,
2
3
2
0
ᵒC, 8 h, 80%.
Conclusion:
In summary, we have developed a convergent and concise synthetic strategy to
accomplish the first stereoselective total synthesis of the novel secondary metabolites
separacenes A and B from the known precursors 7 and 9 in 9 linear steps with an overall yield of
12.3%. Out of four chiral hydroxy groups in separacenes AꢀB, three have been installed from the
chiral pool, (+)ꢀmethyl Dꢀlactate and Dꢀ(ꢀ)ꢀtartaric acid. The TrostꢀRychnovsky alkyne
rearrangement and the HWE reaction have been adopted to construct the conjugated tetraene
moiety in good stereoselectivity.
Experimental section:
General Experimental Procedure: All moisture sensitive reactions were performed in oven or
flameꢀdried glassware with teflon coated magnetic stirring bar under argon atmosphere using
dry, freshly distilled solvents, unless otherwise noted. Airꢀ and moistureꢀsensitive liquids were
transferred via a gastight syringe and a stainlessꢀsteel needle. Reactions were monitored by thin
layer chromatography (TLC, Silica gel 60 F254) plates with UV light, ethanolic anisaldehyde
(
with 1% AcOH and 3.3% conc. H SO )ꢀheat and aqueous KMnO4 (with K CO and 10%
2 4 2 3
aqueous NaOH solution) as developing agents. All workup and purification procedures were
carried out with reagentꢀgrade solvents under ambient atmosphere unless otherwise stated.
Column chromatography was performed using silica gel 60ꢀ120 mesh and 230ꢀ400 mesh. Yields
mentioned as chromatographically and spectroscopically homogeneous materials unless

Page 9 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
otherwise stated. Optical rotations were measured using sodium (589, D line) lamp and are
2
5
reported as follows: [α]D (c = mg/100 ml, solvent). IR spectra were recorded as thin films (for
liquids). HRMS were taken using QuadrupleꢀTOF (QꢀTOF) micro MS system using electrospray
1
ionisation (ESI) technique. H NMR spectra were recorded on 300 MHz spectrometers in
appropriate solvents and calibrated using residual undeuterated solvent as an internal reference,
and the chemical shifts are shown in δ ppm scales. Multiplicities of NMR signals are designated
as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), td (triplet of doublet), m
1
3
(
multiplet, for unresolved lines) etc. C spectra were recorded on 75 MHz spectrometers.
Ethyl 6-((tert-butyldimethylsilyl)oxy)hex-2-ynoate (10): To an ice cold solution of 4ꢀpentyneꢀ
ꢀol (1.15 g, 13.67 mmol) in anhydrous CH Cl (45 mL) under argon, Et N (2.86 mL, 20.5
1
2
2
3
mmol), TBSCl (2.47 g, 16.4 mmol) and DMAP (167 mg, 1.37 mmol) were added sequentially.
The reaction mixture was warmed to the ambient temperature and stirred for another 2.5 h prior
to quench with saturated aqueous NH Cl solution (20 mL). The resultant mixture was extracted
4
with CH Cl (3 x 50 mL), washed with water, brine, dried over Na SO and concentrated under
2
2
2
4
reduced pressure. Flash column chromatographic purification (SiO , 230ꢀ400 mesh, 1% EtOAc
2
in hexane as eluent) of the resultant residue furnished the corresponding TBS ether (2.52 g, 93%)
1
as a colorless liquid. R = 0.8 (10% EtOAc/hexane); H NMR (CDCl , 300 MHz) δ 3.69 (t, J =
f
3
6.0 Hz, 2H), 2.27 (dt, J = 6.9, 2.4 Hz, 2H), 1.92 (t, J = 2.7 Hz, 1H), 1.76ꢀ1.68 (m, 2H), 0.89 (s,
1
3
9
H), 0.05 (s, 6H); C NMR (CDCl , 75 MHz) δ 84.4, 68.4, 61.6, 31.7, 26.1, 18.5, 15.0, ꢀ5.2
3
ꢀ1
+
ppm; IR(neat) vmax 2934, 2863, 2201 cm ; HRMS (ESI) m/z calcd for C H OSiNa [M+Na]
11
22
221.1338, found 221.1334.

Organic & Biomolecular Chemistry
Page 10 of 24
View Article Online
DOI: 10.1039/C7OB00345E
To a solution of the above compound (2.45 g, 12.35 mmol) in anhydrous THF (35 mL) at
n
ꢀ
78 ᵒC under argon, BuLi (6.42 mL, 16.05 mmol, 2.5 M solution in toluene) was added and the
reaction mixture was stirred for 30 min prior to slow addition of ethyl chloroformate (1.77 mL,
8.52 mmol). The reaction mixture was warmed gradually to the room temperature and the
1
reaction was continued for 15h. The reaction was then quenched by saturated aqueous NH Cl
4
solution (5 mL), extracted with Et O (3 x 50 mL), washed with water, brine, dried over Na SO ,
2
2
4
filtered and concentrated under vacuo. Purification of the crude residue by flash column
chromatography (SiO , 230ꢀ400 mesh, 1% EtOAc in hexane as eluent) afforded ester 10 (2.54 g,
2
1
7
6%) as a colorless liquid. R = 0.5 (5% EtOAc/hexane); H NMR (CDCl , 300 MHz) δ 4.20 (q,
f
3
J = 6.9 Hz, 2H), 3.67 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.80ꢀ1.74 (m, 2H), 1.29 (t, J =
1
3
7
.2 Hz, 3H), 0.88 (s, 9H), 0.04(s, 6H); C NMR (CDCl , 75 MHz) δ 153.9, 89.2, 73.4, 61.9,
3
ꢀ1
6
1.3, 30.7, 26.0, 18.4, 15.3, 14.2, ꢀ5.3 ppm; IR(neat) vmax 2931, 2858, 2215, 1712, 1456 cm ;
+
HRMS (ESI) m/z calcd for C H O SiNa [M+Na] 293.1549, found 293.1550.
1
4
26
3
Ethyl (2E,4E)-6-((tert-butyldimethylsilyl)oxy)hexa-2,4-dienoate (11): To a stirred solution of
ester 10 (2.36 g, 8.72 mmol) in anhydrous benzene (25 mL) under argon at the room
temperature, Ph P (2.29 g, 8.72 mmol) and phenol (0.77 mg, 8.72 mmol) were added
3
sequentially. The reaction was continued for 12 h at the same temperature. The reaction mixture
was diluted with Et O (10 mL) and then 1 (N) NaOH solution (10 mL) was added into it. The
2
resultant mixture was extracted with Et O (3 x 40 mL), washed with water, brine, dried over
2
Na SO and concentrated under vacuo. Flash column chromatographic purification (SiO , 230ꢀ
2
4
2
400 mesh, 3% EtOAc in hexane as eluent) of the resultant residue (1.74 g, 74%) gave the
1
corresponding olefin as a colorless liquid. R = 0.7 (5% EtOAc/hexane); H NMR (CDCl , 300
f
3
MHz) δ 7.34ꢀ7.25 (m, 1H), 6.45ꢀ6.35 (m, 1H), 6.17 (td, J = 15.3, 4.2 Hz, 1H), 5.87 (d, J = 15.6

Page 11 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
Hz, 1H), 4.31ꢀ4.27 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H), 0.92 (s, 9H), 0.08
1
3
(
s, 6H); C NMR (CDCl , 75 MHz) δ 167.3, 144.1, 141.9, 127.0, 120.9, 63.0, 60.4, 26.0, 18.5,
3
ꢀ1
1
4.4, ꢀ5.2 ppm; IR(neat) vmax 2923, 2874, 1725, 1630 cm ; HRMS (ESI) m/z calcd for
+
C H O SiNa [M+Na] 293.1549, found 293.1547.
14
26
3
(2E,4E)-Ethyl 6-(dimethoxyphosphoryl)hexa-2,4-dienoate (8): To a stirred solution of
compound 11 (1.68 g, 6.21 mmol) in anhydrous THF (20 mL) at 0 ᵒC under argon, TBAF (8.08
mL, 8.08 mmol, 1 M solution in THF) was added. The reaction mixture was then warmed to the
room temperature and stirred for 30 min prior to quench with saturated aqueous NH Cl solution
4
(10 mL). The resultant mixture was extracted with EtOAc (3 × 30 mL), washed with water,
brine, dried over Na SO and concentrated under vacuum. Flash column chromatographic
2
4
purification (SiO , 60−120 mesh, 10% EtOAc in hexane as eluent) of the crude residue yielded
2
1
alcohol (800 mg, 83%) as a light yellow liquid. R = 0.5 (20% EtOAc/hexane); H NMR (CDCl ,
f
3
3
4
1
1
00 MHz) δ 7.32ꢀ7.22 (m, 1H), 6.44ꢀ6.35 (m, 1H), 6.20 (td, J = 15.6, 4.8 Hz, 1H), 4.27 (bd, J =
13
.5 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 75 MHz) δ
3
67.2, 143.9, 141.2, 127.8, 121.0, 62.7, 60.5, 51.7, 14.4 ppm; IR(neat) vmax 3456, 2945, 2838,
ꢀ1
+
731 cm ; HRMS (ESI) m/z calcd for C H O Na [M+Na] 179.0684, found 179.0685.
8
12
3
To an ice cold solution of above alcohol (790 mg, 5.06 mmol) in anhydrous CH Cl (15
2
2
mL) under argon, Ph P (1.59 g, 6.07 mmol) and CBr (2.52 g, 7.6 mmol) were added
3
4
sequentially. The reaction mixture was warmed to the ambient temperature and stirred for
another 1 h prior to quench with saturated aqueous NaHCO solution (10 mL). The resultant
3
mixture was extracted with Et O (3 x 30 mL), washed with water, brine, dried over Na SO and
2
2
4
concentrated under vacuo. Flash column chromatographic purification (SiO , 100ꢀ200 mesh, 2%
2
EtOAc in hexane as eluent) of the resultant residue furnished the corresponding bromide (910

Organic & Biomolecular Chemistry
Page 12 of 24
View Article Online
DOI: 10.1039/C7OB00345E
1
mg, 82%) as pale yellow oil. R = 0.5 (2% EtOAc/hexane); H NMR (CDCl , 300 MHz) δ 7.23
f
3
(dd, J = 15.3, 7.8 Hz, 1H), 6.37 (dd, J = 15.0, 10.5 Hz, 1H), 6.27ꢀ6.17 (m, 1H), 5.91 (d, J = 15.3
13
Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.01 (d, J = 7.5 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H); C NMR
(
CDCl , 75 MHz) δ 166.6, 142.6, 136.6, 132.0, 123.4, 60.6, 31.3, 14.3 ppm; IR(neat) vmax 2918,
3
ꢀ1
+
2
856, 1725 cm ; HRMS (ESI) m/z calcd for C H BrO Na [M+Na] 240.9840, found 240.9842.
8 11 2
A solution of the above bromide (890 mg, 4.06 mmol) and P(OMe) (1.44 mL, 12.19
3
mmol) in anhydrous toluene (12 mL) was refluxed for 12 h under argon atmosphere. The solvent
was evaporated and the crude mixture was purified by flash column chromatography (silica gel,
60ꢀ120 mesh, 70% EtOAc in hexane as eluent) to achieve phosphonate 8 (880 mg, 87%) as a
1
colorless oil. R = 0.3 (70% EtOAc/hexane); H NMR (CDCl , 300 MHz) δ7.22ꢀ7.17 (m, 1H),
f
3
6.34ꢀ6.24 (m, 1H), 6.07ꢀ5.97 (m, 1H), 5.82 (d, J = 15.3 Hz, 1H), 4.20ꢀ4.13 (m, 2H), 3.77ꢀ3.68
1
3
(
m, 6H), 2.75 (d, J = 7.5 Hz, 1H), 2.67 (d, J = 7.5 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H); C NMR
(
CDCl , 75 MHz) δ166.9, 143.4, 133.1, 131.0, 121.6, 60.5, 53.0, 52.9, 31.2, 29.4, 14.3 ppm;
3
ꢀ1
+
IR(neat) vmax 2909, 2867, 1727 cm ; HRMS (ESI) m/z calcd for C H O PNa [M+Na]
10
17
5
271.0711, found 271.0710.
Ethyl
(2E,4E,6E)-7-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)hepta-2,4,6-trienoate
(
12): To a solution of oxalyl chloride (0.4 mL, 4.69 mmol) in anhydrous CH Cl (10 mL) at ꢀ78
2 2
ᵒC, anhydrous DMSO (0.75 mL, 10 mmol) was added slowly with constant stirring under argon
atmosphere. After 15 min, compound 9 (500 mg, 3.12 mmol) dissolved in anhydrous CH Cl (10
2
2
mL) was added to the reaction mixture at the same temperature. After 30 min of stirring at ꢀ78
ᵒC, Et N (2.25 mL, 15.62 mmol) was added and stirred for another 30 min at the same
3
temperature. The reaction mixture was then allowed to warm to room temperature and quenched
with slow addition of saturated aqueous solution of NH Cl. The reaction mixture was then
4

Page 13 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
extracted with CH Cl (3 x 10 mL). The combined organic layer was washed with NaHCO
3
2
2
solution, brine, dried over Na SO , filtered and concentrated in vacuo to get the corresponding
2
4
aldehyde as a light yellow liquid. The aldehyde was taken directly to the next reaction without
further purification and characterizations.
To a stirred solution of diisopropylamine (0.62 mL, 4.38 mmol) in anhydrous THF (12
n
mL) at ꢀ78 ᵒC under argon, BuLi (2.6 mL, 4.22 mmol, 1.6 M solution in hexane) was added and
the reaction mixture was stirred for 15 min prior to addition of phosphonate 8 (1 g, 4.1 mmol,
dissolved in 8 mL anhydrous THF) at the same temperature. After 30 min, the above aldehyde
dissolved in anhydrous THF (5 mL) was added into the reaction mixture. The resultant reddish
brown solution was stirred for another 30 min at same temperature and warmed slowly to 0 ᵒC
over 1 h. The reaction was then quenched with saturated aqueous NH Cl solution (2.5 mL). The
4
resultant mixture was extracted with EtOAc (3 x 10 mL), washed with water, brine, dried over
Na SO and concentrated under vacuum. Flash column chromatographic purification (SiO , 230ꢀ
2
4
2
400 mesh, 5ꢀ7% EtOAc in hexane as eluent) of the resultant residue furnished compound 12 (524
2
4
mg, 60% in two steps, dr ~ 5:1) as a colorless liquid. R = 0.5 (10% EtOAc/hexane); [α]D = ꢀ
f
1
5
.49 (c 1.02, CHCl ); H NMR (CDCl , 300 MHz) δ 7.29 (dd, J = 11.1, 15.3 Hz, 1H), 6.59ꢀ6.50
3
3
(
m, 1H), 6.44ꢀ6.28 (m, 1H), 5.90 (d, J = 11.1 Hz, 1H), 5.87ꢀ5.75 (m, 2H), 5.36 (d, J = 17.1 Hz,
H), 5.27 (d, J = 10.2 Hz, 1H), 4.20 (q, J = 6.9 Hz, 2H), 4.15ꢀ4.07 (m, 2H), 1.45 (s, 6H), 1.29 (t,
1
1
3
J = 7.2 Hz, 3H); C NMR (CDCl , 75 MHz) δ 167.1, 144.0, 139.1, 134.1, 133.0, 132.7, 131.2,
3
ꢀ1
1
22.0, 119.4, 109.6, 82.6, 81.5, 60.5, 27.1, 27.1, 14.4 ppm; IR(neat) vmax 2949, 2837, 1730 cm ;
+
HRMS (ESI) m/z calcd for C H O Na [M+Na] 301.1416, found 301.1414.
1
6
22
4
(2E,4E,6E)-7-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)hepta-2,4,6-trien-1-ol (13): To
a cold solution (−78 ᵒC) of compound 12 ( 250 mg, 0.89 mmol) in anhydrous CH Cl (3 mL)
2
2

Organic & Biomolecular Chemistry
Page 14 of 24
View Article Online
DOI: 10.1039/C7OB00345E
under argon, DIBALꢀH (2.7 mL, 2.7 mmol, 1.0 M in toluene) was added slowly, and the reaction
mixture was stirred for 30 min at the same temperature before quenching with MeOH (0.5 mL).
A saturated solution of sodium potassium tartrate (5 mL) was then added into it. After 3 h of
vigorous stirring at the room temperature, the resultant mixture was extracted with CH Cl (2 ×
2
2
1
0 mL). The organic layers were washed with water and brine, dried (Na SO ), and concentrated
2 4
in vacuo. Purification by column chromatography (SiO , 60−120 mesh, 20% EtOAc in hexane as
2
eluent) afforded pure alcohol 13 (191 mg, 90%) as a colorless liquid. R = 0.5 (30% EtOAc in
f
2
4
1
hexane); [α]D = ꢀ5.49 (c 1.02, CHCl ); H NMR (CDCl , 300 MHz) δ 6.37ꢀ6.21 (m, 4H), 5.93ꢀ
3
3
5.80 (m, 1H), 5.79ꢀ5.75 (m, 1H), 5.65 (dd, J = 6.9, 14.4 Hz, 1H), 5.35 (d, J = 16.8 Hz, 1H), 5.24
1
3
(
dd, J = 4.8, 10.3 Hz, 1H), 4.25ꢀ4.17 (m, 2H), 4.14ꢀ4.07 (m, 2H), 1.45 (m, 6H); C NMR
(
CDCl , 75 MHz) δ 134.2, 134.0, 133.3, 133.2, 131.9, 131.1, 128.9, 119.1, 109.3, 82.5, 81.9,
3
ꢀ1
6
3.4, 27.1 ppm; IR(neat) vmax 3452, 2987, 1722 cm ; HRMS (ESI) m/z calcd for C H O Na
13 18 3
+
[
M+Na] 245.1154, found 245.1153.
(2E,4E,6E)-7-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl) hepta-2,4,6-trienal (14): To a
stirred solution of alcohol 13 (110 mg, 0.46 mmol) in EtOAc (3 mL) under argon IBX (260 mg,
.92 mmol) was added and refluxed for 1.5 h. The reaction mixture was then cooled to room
0
temperature, filtered through a short pad of Celite, washed with EtOAc (10 mL), and
concentrated in vacuo, to afford pure aldehyde 14 (98 mg, 90%) as a yellow liquid. R = 0.5 (5%
f
1
EtOAc in hexane); H NMR (CDCl , 300 MHz) δ 9.5 (d, J = 8.1 Hz, 1H), 7.16ꢀ7.07 (m, 1H),
3
6
5
1
.69ꢀ6.62 (m, 1H), 6.50ꢀ6.39 (m, 2H), 6.21ꢀ6.13 (m, 1H), 5.93 (dd, J = 6.6, 15.3 Hz, 1H), 5.85ꢀ
1
3
.25 (m, 1H), 4.22ꢀ4.15 (m, 1H),4.13ꢀ4.08 (m, 1H), 1.46 (s, 6H); C NMR (CDCl , 75 MHz) δ
3
93.6, 151.4, 141.1, 134.8, 133.9, 132.2, 132.1, 131.0, 119.5, 109.8, 82.6, 81.3, 27.1, 17.1 ppm.

Page 15 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
(2R,4E,6E,8E,10E)-2-((tert-butyldimethylsilyl)oxy)-11-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-
dioxolan-4-yl)undeca-4,6,8,10-tetraen-3-one (3): To a solution of phosphonate 7 (45 mg, 0.14
mmol) in anhydrous THF (2 mL) under argon at the room temperature, Ba(OH) (25 mg, 0.14
2
mmol, dried at 110 ᵒC °C for 4 h) was added and the reaction mixture was stirred for 30 min.
Aldehyde 14 (30 mg, 0.13 mmol) dissolved in a THF (anhydrous)/H O mixture (2 mL, 40:1) was
2
then cannulated into the reaction mixture and the resultant mixture was stirred further for 12 h
prior to quench with the saturated aqueous NH Cl solution (0.5 mL). The resultant mixture was
4
then extracted with EtOAc (2 x 10 mL). The organic layers were washed with water and brine,
dried (Na SO ), and concentrated in vacuo. Purification of the crude mixture by column
2
4
chromatography (SiO , 230−400 mesh, 3% EtOAc in hexane as eluent) afforded pure compound
2
2
4
3
(37 mg, 68%, dr ~ 5.5:1) as a yellow liquid. R = 0.5 (10% EtOAc/hexane); [α]D = +7.12 (c
f
1
0
.3, CHCl ); H NMR (CDCl , 300 MHz) δ 7.36 (dd, J = 11.4, 15.3 Hz, 1H), 6.66 (d, J = 15.0
3
3
Hz, 1H), 6.65 (t, J = 15.0 Hz, 1H), 6.44ꢀ6.34 (m, 4H), 5.87ꢀ5.74 (m, 2H), 5.36 (d, J = 17.1 Hz,
H), 5.26 (d, J = 10.2 Hz, 1H), 4.27 (q, J = 3.6 Hz, 1H), 4.24ꢀ4.07 (m, 2H), 1.46 (s, 6H), 1.31 (d,
1
1
3
J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); C NMR (CDCl , 75 MHz) δ 202.3,
3
143.5, 141.7, 136.0, 134.2, 133.3, 133.1, 131.8, 131.5, 123.9, 119.2, 109.5, 82.6, 81.7, 74.7, 27.1,
ꢀ1
2
5.9, 18.3, ꢀ4.6, ꢀ4.8; IR(neat) vmax 2954, 1725 cm ; HRMS (ESI) m/z calcd for C H NaO Si
24
38
4
+
[
M+Na] 441.2437, found 441.2435.
(2R,3R,4E,6E,8E,10E)-2-((tert-butyldimethylsilyl)oxy)-11-((4R,5R)-2,2-dimethyl-5-vinyl-
1,3-dioxolan-4-yl)undeca-4,6,8,10-tetraen-3-ol (15): To a stirred solution of RꢀCBS (1.5 mg,
0
.005 mmol) in anhydrous THF (1.5 mL) at ꢀ20 ᵒC under argon, BH .S(CH ) (0.05 mL, 0.1
3
3 2
mmol, 2 M solution in THF) was added and a solution of the compound 3 (20 mg, 0.05 mmol)
dissolved in anhydrous THF (1.5 mL) was added drop wise. The reaction was continued further

Organic & Biomolecular Chemistry
Page 16 of 24
View Article Online
DOI: 10.1039/C7OB00345E
for 3 h at ꢀ20 ᵒC before cautious quenching with MeOH (0.2 mL). The reaction mixture was then
diluted with saturated aqueous NH Cl (0.5 mL) and extracted with EtOAc (3 x 5 mL). The
4
combined organic extracts were washed with brine, dried over anhydrous Na SO and
2
4
concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2,
230−400 mesh, 5% EtOAc in hexane as eluent) to produce the pure alcohol 15 (13 mg, 60%, dr
27
1
~
3:1) as a colorless liquid. R = 0.5 (10% EtOAc in hexane); [α]D = +18.71 (c 0.32, CHCl ); H
f
3
NMR (CDCl , 300 MHz) δ 6.39ꢀ6.25 (m, 6H), 5.86ꢀ5.75 (m, 1H), 5.70ꢀ5.61 (m, 2H), 5.35 (d, J =
3
1
1
0
1
3
4
7.1 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 4.17ꢀ4.06 (m, 2H), 3.86ꢀ3.83 (m, 1H), 3.70ꢀ3.62 (m,
H), 2.61 (d, J = 4.5 Hz, 1H), 1.45 (s, 6H), 1.15 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H),
1
3
.07 (s, 3H); C NMR (CDCl , 75 MHz) δ 134.3, 134.2, 134.1, 133.5, 133.2, 132.8, 132.1,
3
31.9, 128.6, 119.1, 109.3, 82.6, 81.9, 76.9, 72.2, 27.2, 25.9, 20.2, 18.2, ꢀ4.1, ꢀ4.7; IR(neat) vmax
ꢀ1
+
482, 2956, 1718 cm ; HRMS (ESI) m/z calcd for C H NaO Si [M+Na] 443.2594, found
2
4
40
4
45.2592.
4R,5R)-4-((1E,3E,5E,7E)-8-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)octa-1,3,5,7-
(
tetraen-1-yl)-2,2,5-trimethyl-1,3-dioxolane (16): To an ice cold solution of compound 15 (25
mg, 0.06 mmol) in anhydrous THF (2 mL), TBAF (0.1 g, 0.1mmol) was added and the reaction
mixture was stirred for 1h at room temperature. The reaction mixture was then quenched by
saturated aqueous NH Cl (2 mL) solution and was extracted with EtOAc (3 x 5 mL). The organic
4
layers were washed with brine, dried over Na SO and concentrated in vacuo. The crude residue
2
4
was purified by flash column chromatography (SiO , 60ꢀ120 mesh, 30ꢀ40% EtOAc in hexanes as
2
eluent) to yield the corresponding diol (16 mg, 91%) as a colorless liquid. R = 0.4 (20%
f
2
6
1
EtOAc/hexane); [α]D = +13.04 (c 1.4, CHCl ). H NMR (CDCl , 300 MHz) δ 6.37ꢀ6.23 (m,
3
3
6H), 5.84ꢀ5.70 (m, 1H), 5.72ꢀ5.62 (m, 2H), 5.35 (d, J = 17.1 Hz, 1H), 5.32ꢀ5.22 (m, 1H), 4.17ꢀ

Page 17 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
4
6
1
1
.06 (m, 2H), 3.91 (t, J = 6.9 Hz, 1H), 3.67ꢀ3.63 (m, 1H), 2.29 (s, 2H), 1.45 (s, 6H), 1.17 (d, J =
13
.3 Hz, 3H); C NMR (CDCl , 75 MHz) δ 134.2, 134.1, 133.8, 133.6, 133.0, 132.9, 132.7,
3
32.4, 129.0, 119.1, 109.3, 82.6, 81.9, 77.4, 71.0, 27.2, 19.1 ppm; IR(neat) vmax, 3479, 2960,
ꢀ1
+
719 cm ; HRMS (ESI) m/z calcd for C H NaO [M+Na] 329.1729, found 329.1728.
1
8
26
4
To a stirred solution of the above diol (15 mg, 0.05 mmol) in anhydrous CH Cl (1.5 mL)
2
2
at 0 ᵒC, 2,2 DMP (0.02 mL, 0.15 mmol) and CSA (1 mg, 0.005 mmol) was added sequentially
and the reaction was continued for 4 h at the room temperature. The reaction was then quenched
with Et N and evaporated in vacuo. The crude residue was purified by column chromatography
3
(
SiO , 60−120 mesh, 5% EtOAc/ hexane) to get compound 16 (12 mg, 75%) as a colorless
2
2
5
1
liquid. R = 0.5 (5% EtOAc in hexane); [α]D = +5.2 (c 0.35, CHCl ); H NMR (CDCl , 300
f
3
3
MHz) δ 6.39ꢀ6.26 (m, 6H), 5.86ꢀ5.75 (m, 1H), 5.69ꢀ5.60 (m, 2H), 5.35 (d, J = 17.1 Hz, 1H), 5.25
(d, J = 10.0 Hz, 1H), 4.17ꢀ4.03 (m, 2H), 3.96 (t, J = 8.1 Hz, 1H), 3.82ꢀ3.73 (m, 1H), 1.42 (d, J =
1
3
3
.3 Hz, 3H), 1.25 (s, 12H); C NMR (CDCl , 75 MHz) δ 134.3, 134.1, 133.8, 133.7, 132.6,
3
132.5, 129.9, 129.1, 119.1, 109.4, 108.6, 83.7, 82.6, 81.9, 77.4, 27.5, 27.2, 27.2, 27.1 22.8 ppm;
ꢀ1
+
IR(neat) vmax, 2965, 1709 cm ; HRMS (ESI) m/z calcd for C H NaO [M+Na] 369.2042,
21
30
4
found 369.2040.
Ethyl (2E,4E,6E,8R,9R)-8,9-bis((tert-butyldimethylsilyl)oxy)undeca-2,4,6,10-tetraenoate
17): To a stirred solution of compound 11 (250 mg, 0.89 mmol) in anhydrous EtOH (5 mL) at 0
(
ᵒC, CSA (21 mg, 0.089 mmol) was added and stirred for 48 h at room temperature. The reaction
was then quenched with Et N and evaporated in vacuo. The crude residue was purified by
3
column chromatography (SiO , 60−120 mesh, 20% EtOAc/ hexane) to get the corresponding
2
acetonide deprotected compound (184 mg, 87%) as a colorless liquid. R = 0.5 (40% EtOAc in
f
2
5
1
hexane); [α]D = +16.14 (c 1.97, CHCl ); H NMR (CDCl , 300 MHz) δ 7.32ꢀ7.23 (m, 2H),
3
3

Organic & Biomolecular Chemistry
Page 18 of 24
View Article Online
DOI: 10.1039/C7OB00345E
6.58ꢀ6.27 (m, 3H), 5.93ꢀ5.80 (m, 2H), 5.36 (d, J = 10.5 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.12
1
3
(
q, J = 7.2 Hz, 2H), 2.69 (s, 2H), 1.31ꢀ1.22 (m, 3H); C NMR (CDCl , 75 MHz) δ 167.2, 144.2,
3
1
2
2
39.5, 136.6, 136.0, 131.6, 130.8, 121.7, 117.8, 75.9, 75.1, 60.5, 14.3 ppm; IR(neat) vmax 3460,
ꢀ1
+
945, 2839, 1727 cm ; HRMS (ESI) m/z calcd for C H O Na [M+Na] 261.1103, found
13
18
4
61.1102.
To an ice cold solution of acetonide deprotected compound (200 mg, 0.84 mmol) in
anhydrous CH Cl (5 mL) under argon, 2,6ꢀlutidine (0.2 mL, 1.72 mmol) and TBSOTf (0.3 mL,
2
2
1.6 mmol) were added sequentially. The reaction mixture was then warmed to the ambient
temperature and stirred further for 30 min prior to quench with saturated NaHCO solution (1.5
3
mL). The resultant mixture was extracted with CH Cl (2 × 10 mL), washed with aqueous
2
2
CuSO solution, water, and brine, dried (Na SO ), and concentrated in vacuo. Purification by
4
2
4
column chromatography (SiO ,60−120 mesh, 1% EtOAc in hexane as eluent) furnished the
2
corresponding TBS protected compound (372 mg, 95%) as a colorless liquid: R = 0.6 (2%
f
2
5
1
EtOAc in hexane); [α]D = +48.13 (c 1.97, CHCl ); H NMR (CDCl , 300 MHz) δ 7.23 (dd, J =
3
3
11.1, 15.1 Hz, 1H), 6.56 (dd, J = 10.8, 15.0 Hz, 1H), 6.33ꢀ6.21 (m, 2H), 5.97 (dd, J = 4.8, 15.3
Hz, 1H), 5.88ꢀ5.77 (m, 2H), 5.22ꢀ5.09 (m, 2H), 4.23ꢀ4.11 (m, 4H), 1.29 (t, J = 6.9 Hz, 3H), 0.92
13
(
s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 6H); C NMR (CDCl , 75 MHz) δ
3
167.3, 144.8, 140.6, 138.3, 136.9, 129.9, 129.2, 120.6, 115.8, 76.3, 75.5, 60.4, 25.9, 18.3, 14.4, ꢀ
ꢀ1
4
.5, ꢀ4.5, ꢀ4.6, ꢀ4.7 ppm; IR(neat) vmax 2929, 2880, 1724, 1627 cm ; HRMS (ESI) m/z calcd for
+
C H O NaSi [M+Na] 489.2832, found 489.2831.
25
46
4
2
(2E,4E,6E,8R,9R)-8,9-bis((tert-butyldimethylsilyl)oxy)undeca-2,4,6,10-tetraenal
(18):
Following the same synthetic procedure used for compound 13, compound 17 ( 200 mg, 0.43
mmol) dissolved in anhydrous CH Cl (3 mL) under argon was converted to its corresponding
2
2

Page 19 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
alcohol (173 mg, 95%, colorless liquid, purified by SiO , 60−120 mesh, 20% EtOAc in hexane
2
as eluent) using DIBALꢀH (1.3 mL, 1.3 mmol, 1.0 M in toluene). R = 0.6 (30% EtOAc in
f
2
4
1
hexane); [α]D = +51.20 (c 1.31, CHCl ); H NMR (CDCl , 300 MHz) δ 6.28ꢀ6.16 (m, 4H),
3
3
5.90ꢀ5.72 (m, 3H), 5.21ꢀ5.01 (m, 2H), 4.20ꢀ4.16 (m, 1H), 4.12ꢀ4.09 (m, 1H), 0.91 (s, 18H), 0.07
1
3
(
s, 6H), 0.04 (s, 6H); C NMR (CDCl , 75 MHz) δ 137.2, 133.9, 133.3, 131.9, 131.7, 131.0,
3
130.6, 115.6, 76.5, 75.7, 63.6, 25.9. 18.3, ꢀ4.5, ꢀ4.5, ꢀ4.6, ꢀ4.7 ppm; IR(neat) vmax 3455, 2990,
ꢀ1
+
1
720 cm ; HRMS (ESI) m/z calcd for C H O NaSi [M+Na] 447.2727, found 447.2723.
2
3
44
3
2
Following the same synthetic procedure used for compound 14, the above alcohol (100
mg, 0.23 mmol) dissolved in EtOAc (3 mL) under argon was transformed to aldehyde 18 (88
1
mg, 90%, yellow liquid) using IBX (130 mg, 0.46 mmol). R = 0.5 (5% EtOAc in hexane); H
f
NMR (CDCl , 300 MHz) δ 9.55 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 11.1, 15.3 Hz, 1H), 6.69 (dd, J
3
=
10.8, 15.0 Hz, 1H), 6.43ꢀ6.29 (m, 2H), 6.18ꢀ6.05 (m, 2H), 5.88ꢀ5.77 (m, 1H), 5.23ꢀ5.09 (m,
1
3
2
H), 4.27ꢀ4.24 (m, 1H), 4.17ꢀ4.13 (m, 1H), 0.92 (s, 9H), 0.92 (s, 9H), 0.09ꢀ0.06 (m, 12H); C
NMR (CDCl , 75 MHz) δ 193.8, 152.4, 142.7, 140.3, 136.8, 131.1, 129.7, 129.2, 115.9, 76.2,
3
75.4, 25.9, 18.3, ꢀ4.5, ꢀ4.6, ꢀ4.6, ꢀ4.7 ppm.
(5R,7E,9E,11E,13E,15R,16R)-15-((tert-butyldimethylsilyl)oxy)-2,2,3,3,5,18,18,19,19-
nonamethyl-16-vinyl-4,17-dioxa-3,18-disilaicosa-7,9,11,13-tetraen-6-one (19): Following the
same synthetic procedure used for compound 3, aldehyde 18 (55 mg, 0.13 mmol) dissolved in a
THF/H O mixture (40:1, 3 mL) was converted to pure compound 19 (53 mg, 67%, dr ~ 5.5:1,
2
yellow liquid, purified by SiO , 230−400 mesh, 3% EtOAc in hexane as eluent) using
2
phosphonate 7 ( 45 mg, 0.14 mmol) and Ba(OH) (dried at 110 ᵒC for 4 h, 25 mg, 0.14 mmol). R
2
f
1
=
0.5 (5% EtOAc in hexane); H NMR (CDCl , 300 MHz) δ 7.37 (dd, J = 11.4, 15.3 Hz, 1H),
3
6.64 (d, J = 15.0 Hz, 1H), 6.49ꢀ6.23 (m, 4H), 5.91 (dd, J = 4.8, 14.8 Hz, 1H), 5.86ꢀ5.78 (m, 1H),

Organic & Biomolecular Chemistry
Page 20 of 24
View Article Online
DOI: 10.1039/C7OB00345E
5.18 (td, J = 1.8, 17.4 Hz, 1H), 5.11 (td, J = 1.8, 10.5 Hz, 1H), 4.29ꢀ4.20 (m, 2H), 4.14ꢀ4.11 (m,
1
3
1
H), 1.31 (d, J = 6.9 Hz, 3H), 0.92ꢀ0.91 (m, 27H), 0.07ꢀ0.05 (m, 18H); C NMR (CDCl , 75
3
MHz) δ 202.4, 144.0, 142.6, 137.5, 137.1, 136.8, 131.2, 130.6, 130.4, 123.1, 115.7, 76.4, 75.6,
ꢀ1
7
4.7, 25.9, 25.9, 21.5, 18.4, 18.3, ꢀ4.5, ꢀ4.6, ꢀ4.7, ꢀ4.8 ppm; IR(neat) vmax 2990, 2927, 1719 cm ;
+
HRMS (ESI) m/z calcd for C H O NaSi [M+Na] 629.3854, found 629.3845.
3
3
62
4
3
(5R,6R,7E,9E,11E,13E,15R,16R)-15-((tert-butyldimethylsilyl)oxy)-2,2,3,3,5,18,18,19,19-
nonamethyl-16-vinyl-4,17-dioxa-3,18-disilaicosa-7,9,11,13-tetraen-6-ol (20): Following the
same synthetic procedure used for compound 15, compound 19 (30 mg, 0.05 mmol) dissolved in
anhydrous THF (2 mL) was transmuted to pure alcohol 20 (18 mg, 60%, dr ~ 3:1, colorless
liquid, purified by SiO , 230−400 mesh, 5% EtOAc in hexane as eluent) using RꢀCBS (1.5 mg,
2
0
.005 mmol dissolved in 1 mL anhydrous THF ) and BH .S(CH ) (0.05 mL, 0.1 mmol, 2 M
3 3 2
25
1
solution in THF). R = 0.5 (10% EtOAc in hexane); [α]D = +13.56 (c 0.55, CHCl ); H NMR
f
3
(
CDCl , 300 MHz) δ 6.37ꢀ6.17 (m, 6H), 5.90ꢀ5.71 (m, 2H), 5.62 (dd, J = 6.6, 14.8 Hz, 1H), 5.16
3
(td, J = 1.8, 25.5 Hz, 1H), 5.11 (td, J = 1.5, 20.4 Hz, 1H), 4.18 (t, J = 5.1 Hz, 1H), 4.13ꢀ4.09 (m,
1
0
1
1
H), 3.87ꢀ3.84 (m, 1H), 3.69ꢀ3.65 (m, 1H), 2.59 (d, J = 4.2 Hz, 1H), 1.14 (d, J = 6.3 Hz, 3H),
1
3
.91ꢀ0.89 (m, 27H), 0.08ꢀ0.04 (m, 18H); C NMR (CDCl , 75 MHz) δ 137.3, 133.7, 133.5,
3
33.3, 132.6, 132.5, 131.9, 131.9, 130.9, 115.6, 77.0, 76.5, 75.8, 72.2, 26.0, 25.9, 20.2, 18.4,
ꢀ1
8.2, ꢀ4.0, ꢀ4.4, ꢀ4.5, ꢀ4.6, ꢀ4.6 ppm; IR(neat) vmax 3445, 2998, 1713 cm ; HRMS (ESI) m/z calcd
+
for C H O NaSi [M+Na] 631.4010, found 631.4006.
3
5
64
4
3
(5R,6S,7E,9E,11E,13E,15R,16R)-15-((tert-butyldimethylsilyl)oxy)-2,2,3,3,5,18,18,19,19-
nonamethyl-16-vinyl-4,17-dioxa-3,18-disilaicosa-7,9,11,13-tetraen-6-ol (21): Following the
same synthetic procedure used for compound 15, compound 19 (30 mg, 0.05 mmol) dissolved in
anhydrous THF (2 mL) was transmuted to pure alcohol 21 (18 mg, 60%, dr ~ 3.1:1, colorless

Page 21 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
liquid, purified by SiO , 230−400 mesh, 5% EtOAc in hexane as eluent) using SꢀCBS (1.5 mg,
2
0
.005 mmol dissolved in 1 mL anhydrous THF ) and BH .S(CH ) (0.05 mL, 0.1 mmol, 2 M
3
3 2
27
1
solution in THF). R = 0.5 (10% EtOAc in hexane); [α]D = +3.85 (c 0.74, CHCl ); H NMR
f
3
(
CDCl , 300 MHz) δ 6.37ꢀ6.22 (m, 6H), 5.90ꢀ5.76 (m, 2H), 5.62 (dd, J = 14.8, 6.6 Hz, 1H), 5.16
3
(td, J = 27.0, 1.8 Hz, 1H), 5.11 (d, J = 20.4 Hz, 1H), 4.18 (t, J = 5.1 Hz, 1H), 4.13ꢀ4.09 (m, 1H),
3
0
1
.86 (s, 1H), 3.69ꢀ3.65 (m, 1H), 2.58 (s, 1H), 1.14 (d, J = 6.3 Hz, 3H), 0.91ꢀ0.90 (m, 27H), 0.09ꢀ
13
.04 (m, 18H); C NMR (CDCl , 75 MHz) δ 137.3, 133.7, 133.5, 133.3, 132.6, 132.5, 131.9,
3
31.9, 130.9, 115.6, 77.0, 76.5, 75.8, 72.2, 26.0, 25.9, 20.2, 18.4, 18.2, ꢀ4.1, ꢀ4.4, ꢀ4.5, ꢀ4.6, ꢀ4.6
ꢀ1
+
ppm; IR(neat) vmax 3445, 2996, 1715 cm ; HRMS (ESI) m/z calcd for C H O NaSi [M+Na]
35
64
4
3
631.4010, found 631.4009.
(2R,3R,4E,6E,8E,10E,12R,13R)-pentadeca-4,6,8,10,14-pentaene-2,3,12,13-tetraol (1): To an
ice cold solution of compound 20 (10 mg, 0.016 mmol) in anhydrous THF (2 mL), TBAF (0.08
mL, 0.08 mmol) was added. The reaction mixture was stirred at the room temperature for 6h and
then quenched by saturated aqueous NH Cl solution (1.5 mL). The reaction mixture was
4
extracted with EtOAc (3 x 5 mL), washed with brine, dried over Na SO and concentrated in
2
4
vacuo. The crude residue was purified by flash column chromatography (SiO , 60ꢀ120 mesh, 30ꢀ
2
40% AcOEt in hexanes as eluent) to yield pure compound 1 (3.4 mg, 80%) as a colorless liquid.
25
D
1
R = 0.4 (70% EtOAc/hexane); [α] = ꢀ12.8 (c 0.01, MeOH); H NMR (C D N, 300 MHz) δ
f
5
5
6
5
4
1
.83ꢀ6.72 (m, 2H), 6.42ꢀ6.28 (m, 5H), 6.22 (dd, J = 15.0, 6.0 Hz, 2H), 5.69 (d, J = 17.4 Hz, 1H),
.31 (d, J = 10.8 Hz, 1H), 4.65ꢀ4.57 (m, 1H), 4.59ꢀ4.55 (m, 2H), 4.46 (t, J = 6.0 Hz, 1H), 4.18ꢀ
1
3
.09 (m, 1H), 1.45 (d, J = 6.3 Hz, 3H); C NMR (C D N, 75 MHz) δ 139.8, 133.4, 133.3, 132.9,
5
5
ꢀ1
32.8, 131.7, 131.6, 115.5, 77.4, 76.7, 76.1, 71.3, 19.6 ppm; IR(neat) vmax 3368, 2965, 1615 cm ;
+
HRMS (ESI) m/z calcd for C H O Na [M+Na] 289.1416, found 289.1414.
1
5
22
4

Organic & Biomolecular Chemistry
Page 22 of 24
View Article Online
DOI: 10.1039/C7OB00345E
(2R,3S,4E,6E,8E,10E,12R,13R)-pentadeca-4,6,8,10,14-pentaene-2,3,12,13-tetraol
(2):
Following the same synthetic procedure used for compound 1, compound 21 (10 mg, 0.016
mmol) dissolved in anhydrous THF (2 mL) was converted to pure alcohol 2 (3.4 mg, 80%,
colorless liquid, purified by SiO , 60ꢀ120 mesh, 30ꢀ40% EtOAc in hexanes as eluent) using
2
25
1
TBAF (0.08 mL, 0.08 mmol). R = 0.4 (70% EtOAc/hexane); [α]D = ꢀ10.1 (c 0.01, MeOH); H
f
NMR (C D N, 300 MHz) δ 6.82ꢀ6.71 (m, 2H), 6.43ꢀ6.35 (m, 5H), 6.33ꢀ6.31 (m, 1H), 6.26 (dd, J
5
5
=
15.3, 5.7 Hz, 1H), 5.69 (dd, J = 17.1, 0.6 Hz, 1H), 5.31 (dd, J = 10.8, 0.9 Hz, 1H), 4.65ꢀ4.61
1
3
(
m, 1H), 4.59ꢀ4.55 (m, 2H), 4.27ꢀ4.19 (m, 1H), 1.54 (d, J = 6.3 Hz, 3H) ppm; C NMR (C D N,
5 5
7
2
2
5 MHz) δ 140.9, 137.4, 134.5, 134.4, 134.0, 133.9, 132.8, 132.7, 116.6, 78.4, 77.8, 77.2, 72.4,
ꢀ1
+
0.7 ppm; IR(neat) vmax 3370, 2965, 1617 cm ; HRMS (ESI) m/z calcd for C H O Na [M+Na]
15
22
4
89.1416, found 289.1415.
Acknowledgements:
S.D thanks the Council of Scientific and Industrial Research, New Delhi for the research
fellowship. The financial support from Science and Engineering Research Board (Project no.
EMR/2016/000988), India, to carry out this work is gratefully acknowledged.
Supporting Information:
1
13
Copies of NMR ( H & C) and HRMS of representative compounds, 2D NMR data (HSQC) for
compounds 1 and 2, NMR comparison TableꢀS1 and S2.
References and Note:

Page 23 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00345E
(1) (a) J. Bérdy, J. Antibiot., 2005, 58, 1; (b) W. Fenical and P. R. Jensen, Nat. Chem. Biol.,
2006, 2, 666; (c) T. F. Molinski, D. S. Dalisay, S. L. Lievens and J. P. Saludes, Nat. Drug.
Discov., 2009, 8, 69; (d) R. Singh, M. Sharma, P. Joshi and D. S. Rawat, AntiꢀCancer Agents
Med. Chem., 2008, 8, 603.
(
2) M. Bae, H. Kim, Y. Shin, B. Y. Kim, S. K. Lee, K. ꢀB. Oh, J. Shin and D. –C. Oh, Mar.
Drugs, 2013, 11, 2882.
3) (a) S. Das, D. Paul and R. K. Goswami, Org. Lett., 2016, 18, 1908; (b) S. Das, T. K. Kuilya
(
and R. K. Goswami, J. Org. Chem., 2015, 80, 6467; (c) S. Das and R. K. Goswami, J. Org.
Chem., 2014, 79, 9778; (d) S. Chatterjee, S. Guchhait and R. K. Goswami, J. Org. Chem., 2014,
7
9, 7689; (e) T. K. Kuilya, S. Chatterjee and R. K. Goswami, Tetrahedron, 2014, 70, 2905; (f) S.
Das and R. K. Goswami, J. Org. Chem., 2013, 78, 7274.
4) (a) E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987, 109, 5551; (b) E. J.
Corey, R. K. Bakshi and S. Shibata, J. Org, Chem., 1988, 53, 2861.
5) (a) W. S. Jr. Wadsworth and W. D. Emmons, J. Am. Chem. Soc., 1961, 83, 1733; (b) T. R.
(
(
Hoye and M. A. Tennakoon, Org. Lett., 2000, 2, 1481; (c) A. M. Szpilman, D. M. Cereghetti, N.
R. Wurtz, J. M. Manthorpe and E. M. Carreira, Angew. Chem. Int. Ed., 2008, 47, 4335; (d) K. R.
Prasad and P. Gutala, J. Org, Chem., 2013, 78, 3313; (e) J. A. Lafontaine, D. P. Provencal, C.
Gardelli and J. W. Leahy, J. Org. Chem., 2003, 68, 4215.
(6) (a) B. M. Trost and U. Kazmaier, J. Am. Chem. Soc., 1992, 114, 7933; (b) S. D.; Rychnovsky
and K. J. Jinsoo, J. Org. Chem., 1994, 59, 2659; (c) T. J. Hunter and G. A. O’Doherty, Org.
Lett., 2001, 3, 1049.
(7) A. K. Bhattacharya and G. Thyagarajan, Chem. Rev., 1981, 81, 415.

Organic & Biomolecular Chemistry
Page 24 of 24
View Article Online
DOI: 10.1039/C7OB00345E
(8) (a) R. Appel, Angew. Chem. Int. Ed., 1975, 14, 801; (b) J. Igarashi, M. Katsukawa, Y. G.
Wang, H. P. Acharya and Y. Kobayashi, Tetrahedron Lett., 2004, 45, 3783.
(
(
(
9) S. K. Kang and S. B. Lee, Chem. Comm., 1998, 761.
10) K. Omura and D. Swern, Tetrahedron,, 1978, 34, 1651.
11) (a) J. D. More and N. S. Finney, Org. Lett., 2002, 4, 3001; (b) A. Ozanne, L. Pouysegu, D.
Depernet, B. Franc
12) (a) M. Rodriquez, I. Bruno, E. Cini, M. Marchetti, M. L Taddei and L. GomezꢀPaloma, J.
́ ois and S. ̧Q uideau, Org. Lett., 2003, 5, 2903.
(
Org. Chem., 2006, 71, 103; (b) C. R. Reddy, B. Latha, K. Warudikara, K. K. Singarapu, Org.
Biomol. Chem., 2016, 14, 251.
(
13) A. Cutignano, G. Nuzzo, D. D
Angew. Chem., Int. Ed., 2013, 52, 9256.
14) Note that there are some small inconsistencies between the C values reported in Table 1
́
. Angelo, E. Borbone, A. Alfredo Fusco and A. Fontana,
1
3
(
1
3
and the spectral data provided in the SI of reference 2. Accordingly the C data obtained here
are compared with the actual spectra provided in the SI of reference 2. Personal communication
with the isolation group confirmed that those inconsistencies were from typographic mistakes.