Synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone e from a common synthetic intermediate

Article abstract of DOI:10.1039/c9ob00623k

The stereoselective synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone E, from a common synthetic intermediate, is disclosed. The propargylic sulfide stereocenter is created stereoselectively via carbon-carbon bond formation in the reaction of α-chloro sulfides with alkynylzinc reagents via 1,2-asymmetric induction by a β-siloxy group. The characteristic 1,4-diol motif of the natural products is introduced by a [2,3] sigmatropic rearrangement of an allylic sulfoxide or by the Mislow-Evans-Braverman rearrangement of a propargylic sulfoxide followed by stereoselective reduction of the ensuing α,β-unsaturated ketone. Unlike earlier reports, the C11/C9 carbinol center is created with excellent stereocontrol and derivatives of natural products differing at C14/C12 can be readily obtained. Catalytic asymmetric protocols and substrate-controlled asymmetric induction are utilized for the efficient introduction of the stereogenic centers.

Full text of DOI:10.1039/c9ob00623k

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Raghavan and
R. Yalla, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00623K.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
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 58
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00623K
Synthesis of Solandelactone F, Constanolactone A, Advanced
Intermediate Towards Solandelactone E from a Common
Synthetic Intermediate
Raju Yalla and Sadagopan Raghavan*
Organic Synthesis and Process Chemistry Division, Indian Institute of Chemical Technology,
Hyderabad, India
sraghavan@iict.res.in
Abstract: The stereoselective synthesis of solandelactone F, constanolactone A and an
advanced intermediate towards solandelactone E, from a common synthetic intermediate, is
disclosed. The propargylic sulfide stereocenter is created stereoselectively via carbon-carbon
bond formation in the reaction of α-chloro sulfides with alkynylzinc reagents via 1,2-
asymmetric induction by a β-siloxy group. The characteristic 1,4-diol motif of the natural
products is introduced by a [2,3] sigmatropic rearrangement of an allylic sulfoxide or by
Mislow-Evans-Braverman rearrangement of a propargylic sulfoxide followed by
stereoselective reduction of the ensuing α, β-unsaturated ketone. Unlike earlier reports, the
C11/C9 carbinol center is created with excellent stereocontrol and derivatives of natural
products differing at C14/C12 can be readily obtained. Catalytic asymmetric protocols and
substrate-controlled asymmetric induction is utilized for the efficient introduction of the
stereogenic centers.
Introduction
The marine environment is a source of a multitude of new compounds belonging to
unique structural classes. In 1996, Shin and co-workers isolated solandelactones E (1) and F
(2) from the hydroid Solanderia secunda, near the Jaeju island in Korea.1 Solandelactones
constitute the family of oxygenated fatty acids, oxylipins that include constanolactones A (3)
and B (4),2 halicholactone (5) and neohalicholactone (6)3, (Figure 1).
1

Organic & Biomolecular Chemistry
Page 2 of 58
O
R R'
H
R R'
H
View Article Online
DOI:O10.1039/C9OB00623K
O
22
20
O
14
12
1
18
16
9
11
7
5
1
H
H
OH
OH
3
4
, R = H, R' = OH, Constanolactone A
, R = OH,R' = H, Constanolactone B
1
2
, R = H, R' = OH, Solandelactone E
, R = OH,R' = H, Solandelactone F
O
OH
H
O
15
1
12
X
8
H
OH
2
5
6
, X = CH2-CH2, Halicholactone
, X = cis CH=CH, Neohalicholactone
Figure 1. Oxylipins isolated from marine organisms.
The structural features common to oxylipins include a long alkyl chain incorporating a 2-ene-
1,4-diol moiety and a lactone ring attached to a trans-cyclopropane ring. While
solandelactones, halicholactone and neohalicholactone possess a (R,R)-disubstituted
cyclopropane motif, constanolactones are endowed with the reversed (S,S)-configuration.
Another difference is that while the lactone oxygen and the remote carbinol in the alkyl chain
have the same configuration in solandelactones and constanolactones, it is reversed in
halicholactones and neohalicholactones. The oxylipins display inhibitory activity against 5-
lipoxygenase3 and farnesyl transferase,4 found in cancer cells. Their unique structural features
and limited availability from natural sources have attracted the attention of synthetic
chemists. Martin and co-workers reported the first, linear stereoselective synthesis of
solandelactone E and F thereby correcting the original incorrect absolute configuration
assignment at C11.5 Subsequently, White6 and Pietruszka7 disclosed the synthesis of
solandelactones A-H exploiting the Nozaki-Hiyama-Kishi reaction. The same strategy was
adopted in many syntheses of halicholactones8 and constanolactones9 to create the C-11
carbinol stereocenter which unfortunately, proceeded with poor stereocontrol (dr 2:1).
Recently, Aggarwal and co-workers reported a stereoselective synthesis of solandelactones E
and F through a lithiation-borylation-allylation sequence.10
2

Page 3 of 58
Organic & Biomolecular Chemistry
View Article Online
The main challenges to be overcome in any new synthetic proposal towarDdOsI:o10x.1y0l3i9p/Cin9OsB00623K
includes the creation of the C11 carbinol with perfect stereocontrol and the cyclopropane ring
with the correct absolute stereochemistry. Our unique strategy for the synthesis of
solandelactones E, F and constanolactone A with stereocontrol at C11/C9 (natural product
numbering respectively) relied on taking advantage of a new methodology11 developed for
the stereocontrolled synthesis of 1,4-diols from β-siloxy propargylic sulfides. The method
comprised of the stereoselective preparation of propargylic sulfide 7, its semihydrogenation
to sulfide 8, oxidation to sulfoxide and Mislow-Evans rearrangement to afford tetrol
derivative 9. Cyclopropanation following Furukawa's protocol,12 directed by the newly
created C9-carbinol (constanolactone numbering), would serve to secure the (S,S)-
configuration of the cyclopropane ring as present in constanolactone A. Alternately,
homoallylic C12-hydroxy (solandelactone numbering) directed cyclopropanation following
Charette's report13 would deliver the (R,R)-cyclopropane configuration present in
solandelactone E. Oxidation of sulfide 7 followed by [2,3] sigmatropic shift would furnish
unsaturated ketone 10 that on asymmetric reduction would afford alcohol 11, the epimer of
compound 9. Cyclopropanation following Furukawa's protocol directed by the secondary
hydroxyl would serve to introduce the (R,R)-cyclopropane configuration of solandelactone F.
Thus, a common synthon was envisioned to access solandelactones E, F and constanolactone
A, Scheme 1.
3

Organic & Biomolecular Chemistry
Page 4 of 58
View Article Online
DOI: 10.1039/C9OB00623K
SPh
SPh
OP3
O
OP1
OP1
P3O 12
mCPBA
Reduction
P3O
7
(5)
7
OP1
(10)
2
2
(5)
P O
P O
[2,3] sigma-
tropic rearr.
12
(10)
S
8
7
OP2
Ph
OH
H
H
C(9)-OH
directed
P3O
OP1
5
10
OP2
OH
P3O
OP1
Intermediate toward
constanolactone A
OP3
12
7
(5)
2
(10)
P O
H
9
C12-OH
directed
HO
OP1
7
12
OP2
H
Intermediate toward
solandelactone E
SPh
O
Noyori transfer
OP1
hydrogenation
OP1
P3O
mCPBA
[2,3] sigma-
tropic rearr.
P3O
7
12
7
OP2
OP2
12
7
10
OH
OH
H
C11-OH
directed
H
P3O
OP1
P3O
OP1
7
12
12
7
OP2
OP2
Intermediate toward
solandelactone F
11
Scheme 1. Strategy for the synthesis of solandelactones E, F and constanolactones A from a
common intermediate 7.
Results and discussion
Synthesis of Solandelactone F
The synthesis of solandelactone F began from the known epoxide 1214 which on
reaction with thiophenol in the presence of catalytic amount of DBU afforded the hydroxy
sulfide 13. Protection under standard conditions furnished silyl ether 14. Propargylic sulfide
17 was prepared stereoselectively by reaction of the α-chloro sulfide 15, obtained by
treatment of sulfide 14 with N-chlorosuccinimide (NCS), with the alkynylzinc bromide
prepared from propargyl ether 16.11 The configuration of the newly created stereocenter in
1
compound 17 was unambiguously established by comparison of the H NMR spectra of the
diastereomeric mandelate esters derived from allylic alcohol 36 (vide infra). Selective
4

Page 5 of 58
Organic & Biomolecular Chemistry
View Article Online
oxidation of the sulfide with mCPBA at low temperature afforded an epimeric mixture of
DOI: 10.1039/C9OB00623K
sulfoxides which without isolation was subjected to Mislow-Evans-Braverman
rearrangement15 in the presence of N-methyl thioimidazole16 to furnish α,β-unsaturated
ketone 18. Stereoselective transfer hydrogenation using (R,R)-TsDPEN-[RuCl(cymene)] in
aqueous media17 afforded allyl alcohol 19 (dr 96:4, 89%). Hydroxy directed cyclopropanation
following Furukawa's protocol cleanly furnished the cyclopropane derivative 20. Protection
of the carbinol as its silyl ether 21 followed by deprotection of the PMB ether18 afforded
alcohol 22. Following Hata's protocol,19 alcohol 22 was converted to sulfide 23 (Scheme 2)
setting the stage for further C-C bond (C12-C13) formation.
Cl
PhSH, DBU, Toluene
0 oC - rt, 6 h, 92%
NCS, PhH,
15 min
OTBDPS
OTBDPS
OTBDPS
PhS
PhS
O
OR
OTBS
TBS-Cl, Imid.
DCM, 0 oC - rt
30 min, 96%
12
13
15
, R = H
14, R = TBS
OPMB
H
SPh
TBSO
SPh
OPMB
16
iPrMgCl, ZnBr2,
OTBS
SPh
OTBDPS
ZnBr
PMBO
OTBS
OTBDPS
THF, 0 oC-rt,
6 h, 72%
2
2
H H
17
H
OTBDPS
17
OPMB
O
OH
mCPBA, CHCl3,
-40 oC, 30 min
PMBO
OTBDPS
PMBO
OTBDPS
(R,R) Noyori cat., 3.5 mol %
TBABr, HCOONa
DCM, H2O (1:1) ratio
17 h, rt, 89%
Toluene, 60 oC,
OTBS
OTBS
NMe
HN
18
3 h, 83%
19
S
OR
H
H
DDQ, DCM,
pH 7 Buffer,
2 h, 0 oC, 81%
OTBS
H
H
PMBO
OTBDPS
DME, Et2Zn, CH2I2
HO
OTBDPS
DCM, -20 oC-rt,
6 h, 86%
OTBS
20, R = H
OTBS
22
TBS-OTf, 2,6-Lutidine,
DCM, -40oC, 30 min, 94%
21
, R = TBS
Cl
O
S N
Ru
NH2
OTBS
H
O
H
(PhS)2, Toluene,
Bu3P, rt, 12 h, 87%
PhS
OTBDPS
Noyori Catalyst
OTBS
23
Scheme 2. Synthesis of sulfide 23.
5

Organic & Biomolecular Chemistry
Page 6 of 58
Treatment of sulfide 23 with NCS followed by reaction of the ensuing chloro suVlifeiwdAerticle Online
DOI: 10.1039/C9OB00623K
with alkynylzinc bromide prepared from enyne 2420 afforded propargylic sulfide 25
stereoselectively.11 The two choices available for further progress towards the target were a)
creation of the C14 carbinol stereocenter and b) construction of the lactone ring by Wittig
olefination of an aldehyde, derived eventually from the primary silyl ether 25. To avoid the
extra obligatory step of protecting the C14 hydroxyl during the oxidation of the primary
hydroxyl to an aldehyde, the first option was not exercised. Proceeding, the primary silyl
ether in compound 25 was selectively deprotected using ammonium fluoride21 in methanol to
yield alcohol 26. Oxidation with IBX22 afforded the aldehyde 27 which was subjected to
homologation with the ylide generated from phosphonium salt 2823 to afford unsaturated acid
29. Deprotection of the TBS ethers using HF-pyridine24 afforded the seco acid 30 which on
lactonization using Shiina's protocol25 afforded the sulfide 31. The C11-hydroxy group was
protected as its TES ether 32 and the sulfide transformed into unsaturated ketone 33
following the two step one-pot protocol discussed above.26 Reduction of the unsaturated
ketone using (R)-CBS reagent27 yielded alcohol 34 (dr >95:<5, 85%). Deprotection of the
TES ether using TBAF buffered with acetic acid furnished solandelactone F (2), Scheme 3
with physical constants in good agreement with reported data.10b The overall yield is 4.05%.
6

Page 7 of 58
Organic & Biomolecular Chemistry
IBX, DMSO, DCM
3 h, rt, 90%
View Article Online
DOI: 10.1039/C9OB00623K
OTBS
OTBS
NCS,PhH, 15 min
H
H
23
OR
24
CHO
iPrMgCl, ZnBr2,
THF, 0 oC - rt,
7 h, 73%
H
SPh
OTBS
H
SPh
27
OTBS
25, R = TBDPS
NH4F, MeOH,
3 h, 60 oC, 78%
26
, R = H
MNBA, DMAP,
DCM, rt, 18 h, 82%
Br Ph3P
COOH
28
O
O
OR
H
NaHMDS, THF
OR
0 to -78 oC, 2 h,
H
81%
CO2H
SPh
H
H
SPh
OR
31, R = H
32
TES-OTf, 2,6-Lutidine,
29
HF.Py, CH3CN
0 oC - rt, 12 h, 79%
, R = TBS
, R = H
DCM, -40 oC, 30 min,
94%
, R = TES
30
(R)-CBS Cat.,
O
BH3.Me2S, THF,
-5 to -78 oC, 3h,
85%
O
OTES
OTES
H
H
mCPBA, CHCl3,
-40 oC, 15min
Toluene, 60 oC,
H
O
O
H
NMe
HN
O
OH
34
2 h, 80%
33
S
Ph
H
Ph
TBAF, AcOH,
THF, 0 oC - rt,
5 h, 88%
O
O
OH
H
N
O
B
Me
(R)-CBS Catalyst
H
OH
2
Scheme 3. Synthesis of solandelactone F.
Synthesis of constanolactone A
The synthesis of constanolactone A began from propargylic sulfide 17 which on
semihydrogenation using dicyclohexylborane afforded allylic sulfide 35. Oxidation of the
sulfide followed by rearrangement furnished the allyl alcohol 36.28 Cyclopropanation
proceeded stereoselectively to furnish alcohol 37 which was protected as its silyl ether 38.
Deprotection of the PMB ether afforded primary alcohol 39 which was readily converted to
sulfide 40. Propargyl sulfide 41 was obtained stereoselectively11 by reaction of the derived
chloro sulfide and alkynylzinc bromide. Selective deprotection of the silyl ether followed by
oxidation of the resulting alcohol 42 afforded aldehyde 43. Wittig olefination afforded the
trans-ester 44 selectively. Unsaturated ketone 45 was obtained cleanly by the one-pot
oxidation-rearrangement sequence. Reduction using (R)-CBS reagent furnished alcohol 46.
7

Organic & Biomolecular Chemistry
Page 8 of 58
29
View Article Online
DOI: 10.1039/C9OB00623K
Conjugate reduction of the unsaturated ester using Mg/MeOH yielded compound 47. TBAF
promoted desilylation resulted in concomitant cyclization to furnish constanolactone A (3),
(Scheme 4) with physical characteristics in good agreement with literature data.2b The overall
yield is 5.47%.
SPh
SPh
mCPBA, CHCl3,
OTBDPS
-40 oC, 15 min
OTBDPS
PMBO
Toluene, 60 oC,
PMBO
PMBO
OTBS
Cy2BH, THF, 0 - 20 oC,
6 h, then AcOH, 0 oC - rt,
OTBS
HN
NMe
35
3 h, 84%
17
S
2 h, 80%
DDQ, DCM,
pH 7 Buffer,
2 h, 0 oC, 82%
DME, Et2Zn, CH2I2
OH
OR
H
H
DCM, -20 oC - rt,
6 h, 87%
OTBDPS
PMBO
OTBDPS
OTBS
OTBS
36
37, R = H
TBS-OTf, 2,6-Lutidine,
DCM, -40 oC, 30 min, 94%
38, R = TBS
OTBS
OTBS
H
NCS,PhH, 15 min
H
H
(PhS)2, Toluene,
Bu3P, rt, 12 h, 88%
HO
OTBDPS
PhS
OTBDPS
24
H
OTBS
OTBS
iPrMgCl, ZnBr2,
THF, 0 oC - rt,
7 h, 71%
39
40
Ph3PCHCO2Et,
PhH, 5 h, rt, 92%
IBX, DMSO, DCM
3 h, rt, 89%
OTBS
OTBS
H
OTBS
H
H
H
OR
O
OEt
H
SPh
OTBS
H
O
SPh
OTBS
SPh
OTBS
41, R = TBDPS
43
44
NH4F, MeOH,
3 h, 60 oC, 80%
42
, R = H
OTBS
H
H
Mg, MeOH,
0 oC - rt, 6 h, 85%
mCPBA, CHCl3,
-40 oC, 15 min
OEt
Toluene, 60 oC,
R R'
(R)-CBS Cat.,
BH3.Me2S, THF,
-5 to -78 oC, 3 h,
87%
NMe
HN
OTBS
O
2 h, 83%
S
45
, R, R' = O
46, R = OH, R' = H
TBAF, THF,
0 oC - rt, 72 h, 76%
OH
OTBS
H
H
H
O
O
OMe
H
OTBS
O
OH
OH
47
3
Scheme 4. Synthesis of constanolactone A.
8

Page 9 of 58
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00623K
Synthesis of an intermediate towards Solandelactone E
The creation of (R,R)-cyclopropane ring of solandelactone E was envisioned using
homoallylic hydroxyl directed cyclopropanation of compound 49, anti to the C11-silyl ether,
based on the precedent of Charette.13 Alcohol 36 was protected as its silyl ether 48 and the
PMB ether was deprotected to furnish the requisite alcohol 49. Cyclopropanation using Shi's
protocol30 as disclosed by Charette and co-workers returned unreacted starting material along
with minor quantities of desilylated alcohol. Extended periods of time, excess reagents or
elevated temperatures were of no avail.31 Having been unsuccessful in using the homoallylic
alcohol to direct cyclopropanation, we turned to the C-7 hydroxy group directed
cyclopropanation to create the desired configuration. Towards this objective, alcohol 13 was
protected as its TES ether 50. Further reaction with NCS and alkynylzinc bromide afforded
propargylic sulfide 51 stereoselectively.11
OR
OTBS
DDQ, DCM,
pH 7 Buffer,
2 h, 0 oC, 82%
Et2Zn, CH2I2,
PMBO
OTBDPS
HO
OTBDPS
TFA, -20 oC - 0 oC, 12 h
Rec. s m
OTBS
36
OTBS
49
, R = H
TBS-OTf, 2,6-Lutidine,
DCM, -40 oC, 30 min, 95% 48
, R = OTBS
Cy2BH, THF, 0 - 20 oC,
5 h, then AcOH, 0 oC - rt,
2 h, 81%
NCS, PhH, 15 min
SPh
OPMB
OTBDPS
OTBDPS
16
PhS
iPrMgCl, ZnBr2,
PMBO
OR
OTES
THF, 0 oC - rt,
6 h, 72%
TES-Cl, Imid.
DCM,0 o
13
50
, R = H
51
C
, R = TES
30 min, 97%
mCPBA, CHCl3,
OR
SPh
PPTS, MeOH,
0 oC, 30 min, 87%
-40 oC, 15 min
PMBO
OTBDPS
OTBDPS
PMBO
Toluene, 60 oC,
NMe
HN
OTES
OTES
53
6 h, 84%
52
S
, R = H
TBS-OTf, 2,6-Lutidine,
DCM, -40 oC, 30 min, 95%
54
, R = TBS
OTBS
OTBS
H
Steps
DME, Et2Zn, CH2I2
PMBO
OTBDPS
PMBO
OTBDPS
DCM, -20 oC - rt,
6 h, 84%
H
O
OH
OH
56
55
OH
H
O
H
OH
1
9

Organic & Biomolecular Chemistry
Page 10 of 58
View Article Online
DOI: 10.1039/C9OB00623K
Scheme 5. Synthesis of an advanced intermediate towards solandelactone E.
Semihydrogenation using dicyclohexylborane afforded sulfide 52 which was transformed
into alcohol 53. Protection of the hydroxyl as its TBS ether afforded compound 54 which on
selective deprotection of the TES ether using PPTS yielded alcohol 55. Cyclopropanation
using Furukawa's protocol proceeded cleanly to furnish alcohol 56, which is a key
intermediate that can be elaborated to solandelactone E following an identical sequence of
reactions delineated for the synthesis of the epimer solandelactone F, from compound 20,
Scheme 5. The alcohol 56 possesses the correct absolute configuration of the C11 carbinol
and the cyclopropane ring for elaboration to solandelactone E.
Conclusions
A highly stereoselective route to solandelactone E, F and constanolactone A is
disclosed. The stereogenic centers are created by catalytic asymmetric reactions and
substrate-controlled asymmetric induction. The potential of α-chloro sulfides for
stereoselective carbon-carbon bond formation is elegantly demonstrated. The propargyl/allyl
sulfides have been utilized for 1,4-diol synthesis in an iterative fashion to create the carbinol
stereocenters of oxylipins. The disclosed route permits to vary the configuration of C11 and
C14 carbinols at will by appropriate choice of Noyori/CBS catalysts. Attempted use of a
homoallylic alcohol to direct cyclopropanation anti to the existing allyl silyl ether based on
Charette's precedent did not bear fruit.
Experimental
General Information
Dry reactions were performed under an inert atmosphere using nitrogen. All glassware
apparatus used for reactions were thoroughly oven-dried. Anhydrous solvents were distilled
prior to use: THF from Na and benzophenone; CH2Cl2 and toluene from CaH2; MeOH from
Mg cake; CHCl3 from P2O5; acetone from KMnO4 and K2CO3. Commercial reagents were
10

Page 11 of 58
Organic & Biomolecular Chemistry
View Article Online
used without purification. Column chromatography was carried out by using silica gel
DOI: 10.1039/C9OB00623K
(100−200 mesh). Analytical thin-layer chromatography (TLC) was run on silica gel 60 F254
precoated plates (250 μm thickness). Optical rotations [α]D were measured on a polarimeter
and are given in units of 10−1 deg cm2 g−1. Infrared spectra were recorded neat or in KBr (as
mentioned) and reported in wavenumbers (cm−1). Mass spectral data were obtained using MS
(EI) ESI and HRMS mass spectrometers. High-resolution mass spectra (HRMS; ESI+) were
1
obtained using either a TOF or a double-focusing spectrometer. H NMR spectra were
13
recorded at 300, 400, or 500 MHz and C NMR spectra at 75, 100, or 125 MHz in CDCl3
with the residual solvent signal as an internal standard unless mentioned otherwise; chemical
shifts are in ppm downfield from tetramethylsilane, and coupling constants (J) are reported in
hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
(R)-4-((tert-Butyldiphenylsilyl)oxy)-1-(phenylthio)butan-2-ol (13): To a stirred mixture of
DBU (0.75 mL, 5 mmol) and thiophenol (5.6 mL, 54.5 mmol) in toluene (20 mL) cooled at 0
°C was added a solution of epoxide 12 (16.14 g, 49.5 mmol) in toluene (50 mL). The
resulting reaction mixture was stirred at rt for 6 h and quenched by the addition of 0.5 N HCl
(20 mL). The layers were separated and the aq layer extracted with EtOAc (2x30 mL). The
combined organic layers were washed with 1 N NaOH (30 mL), brine (30 mL), dried over
Na2SO4 and concentrated under reduced pressure. The resulting compound was purified by
silica gel column chromatography using 10% EtOAc/hexanes as the eluent to afford
compound 13 (19.86 g, 45.6 mmol) in 92% yield as an oil. TLC: Rf 0.3 (10%
EtOAc/hexanes); [α]20 = -3.4 (c 1.05, CHCl3); IR (neat): 3478, 3069, 2931, 2857, 1585,
D
1427, 1109, 703, 505 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.68–7.61 (m, 4H), 7.44–7.34 (m,
8H), 7.31–7.23 (m, 2H), 7.22–7.14 (m, 1H), 4.07–3.97 (m, 1H), 3.92–3.77 (m, 2H), 3.40 (s,
1H), 3.12–2.97 (m, 2H), 1.90–1.71 (m, 2H), 1.03 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
11

Organic & Biomolecular Chemistry
Page 12 of 58
View Article Online
135.7, 135.3, 132.9, 132.8, 129.6, 129.3, 128.8, 127.6, 126.0, 68.7, 62.0, 41.0, 37.4, 26.7,
DOI: 10.1039/C9OB00623K
18.9; MS (ESI-TOF) m/z: 459 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C26H32NaO2SSi 459.1784; found 459.1782.
(R)-(R)-4-((tert-Butyldiphenylsilyl)oxy)-1-(phenylthio)butan-2-yl2-methoxy-2-phenyl
acetate:
To a solution of alcohol 13 (15 mg, 0.034 mmol) in dichloromethane (0.5 mL) cooled at 0 oC
was added (R)-methoxyphenylacetic acid (6.8 mg, 0.041 mmol), DMAP (1 mg, 20 mol%)
and EDC.HCl (9.8 mg, 0.051 mmol). The reaction mixture was stirred at rt for 2 h. After
complete consumption of starting material, the reaction mixture was diluted with
dichloromethane (2 mL) and H2O (2 mL). The layers were separated and the aq layer was
extracted with dichloromethane (2x5 mL). The combined organic layers were sequentially
washed with satd aq NaHCO3 (5 mL), 1 N HCl (5 mL), H2O (2x5 mL), brine (10 mL), dried
over Na2SO4 and concentrated under reduced pressure to afford the corresponding ester in
89% yield as a liquid. The crude product was characterised by 1H NMR spectroscopy. TLC:
1
Rf 0.4 (10% EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.63–7.53 (m, 4H), 7.48–7.11
(m, 16H), 5.31–5.20 (m, 1H), 4.68 (s, 1H), 3.67–3.55 (m, 2H), 3.38 (s, 3H), 3.08 (dd, J =
13.7, 6.1 Hz, 1H), 2.89 (dd, J = 13.7, 6.6 Hz, 1H), 2.11–1.96 (m, 1H), 1.89–1.74 (m, 1H),
0.97 (s, 9H).
(R)-(S)-4-((tert-Butyldiphenylsilyl)oxy)-1-(phenylthio)butan-2-yl 2-methoxy-2-phenyl
acetate:
12

Page 13 of 58
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00623K
Alcohol 13 (15 mg, 0.034 mmol) was reacted with (S)-methoxyphenylacetic acid (6.8 mg,
0.041 mmol) as described above to furnish the corresponding ester in 92% yield as a liquid.
1
The crude product was characterised by H NMR spectroscopy. TLC: Rf 0.35 (10%
1
EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.55–7.48 (m, 4H), 7.44–7.37 (m, 4H),
7.37–7.29 (m, 6H), 7.29–7.16 (m, 6H), 5.31–5.23 (m, 1H), 4.53 (s, 1H), 3.44–3.36 (m, 1H),
3.34 (s, 3H), 3.32–3.24 (m, 1H), 3.20 (dd, J = 14.0, 6.2 Hz, 1H), 3.10 (dd, J = 14.0, 6.0 Hz,
1H), 1.94–1.83 (m, 1H), 1.76–1.66 (m, 1H), 0.93 (s, 9H).
Note: The configuration of alcohol 13 was unambiguously assigned by comparison of the 1H
NMR spectra of the mandelate esters. In agreement with the assignment of ‘R’ configuration
for the carbinol 13, the CH2OTBDPS appeared downfield in the 'R' ester while the CH2SPh
appeared downfield in the 'S' ester.
(R)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-5-((phenylthio)methyl)-4,8-dioxa-3,9-disila
undecane (14): To a solution of alcohol 13 (19 g, 43.75 mmol) in anhydrous
dichloromethane (40 mL) cooled at 0 °C was added imidazole (6.25 g, 91.9 mmol) followed
by TBS-Cl (6.92 g, 45.9 mmol). The reaction mixture was allowed to warm to rt and stirred
for 30 min. The reaction mixture was quenched by the addition of water (30 mL) and diluted
with dichloromethane (30 mL). The layers were separated, the organic layer was washed with
water (30 mL), brine (20 mL) and dried over Na2SO4. The solvent was evaporated under
reduced pressure to afford the crude product which was purified by column chromatography
using 2% EtOAc/hexane (v/v) to give the pure silyl ether 14 (23.1 g, 42 mmol) in 96% yield
as a gummy oil. TLC: Rf 0.5 (2% EtOAc/hexane); [α]20 = +21.6 (c 1.0, CHCl3); IR (neat):
D
1
3068, 2954, 2857, 1585, 1470, 1253, 1108, 701, 503 cm−1. H NMR (400 MHz, CDCl3) δ
13

Organic & Biomolecular Chemistry
Page 14 of 58
View Article Online
7.67–7.63 (m, 4H), 7.42–7.32 (m, 8H), 7.27–7.22 (m, 2H), 7.18–7.13 (m, 1H), 4.D1O2I:–140..100349/(Cm9O,B00623K
1H), 3.74 (t, J = 6.2 Hz, 2H), 3.05–3.00 (m, 2H), 2.0-1.91 (m, 1H), 1.79–1.69 (m, 1H), 1.03
(s, 9H), 0.84 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 136.9,
135.54, 135.52, 133.78, 133.73, 129.5, 129.3, 128.7, 127.6, 125.8, 68.6, 60.3, 41.2, 39.1,
26.8, 25.8, 19.1, 18.0, -4.4, -4.7; MS (ESI-TOF) m/z: 573 [M + Na]+. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C32H46NaO2SSi2 573.2649; found 573.2656.
(R)-5-((R)-4-((4-Methoxybenzyl)oxy)-1-(phenylthio)but-2-yn-1-yl)-2,2,3,3,10,10-hexa
methyl -9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (17): To a solution of alkyne 16 (3.52
i
g, 20 mmol) in anhydrous THF (10 mL) cooled at 0 °C was added PrMgCl·LiCl (1.5 M in
THF, 14.6 mL, 22 mmol) and the mixture stirred for 30 min at the same temperature. To the
so generated Grignard reagent was added a solution of ZnBr2 (1.5 M in THF, 20 mL, 30
mmol) at 0 °C and the mixture stirred for 30 min. Separately, in another round-bottom flask,
the chloro sulfide 15 was prepared by adding a solution of sulfide 14 (5.50 g, 10 mmol) in
anhydrous benzene (50 mL) to NCS (1.33 g, 10 mmol) in anhydrous benzene (50 mL) and
stirring for 15 min. To the organozinc reagent maintained at 0 °C was added a solution of
chloro sulfide in benzene. The reaction mixture was stirred gradually allowing it to attain rt,
and stirred further for a period of 6 h when TLC examination indicated complete
consumption of the chloro sulfide. The reaction mixture was cooled to 0 °C and quenched by
the addition of satd aq NH4Cl solution (20 mL). It was allowed to warm to rt and diluted with
Et2O (20 mL). The layers were separated and the aq layer was extracted with Et2O (3×20
mL). The combined organic layers were washed with H2O (30 mL), brine (20 mL) and dried
over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford a crude
compound that was purified by column chromatography using 5% EtOAc/hexane (v/v) as the
eluent to give the pure product 17 (5.22 g, 7.2 mmol) in 72% yield as a colorless liquid. TLC:
Rf 0.3 (5% EtOAc/hexane); [α]20 = -20.1 (c 0.85, CHCl3); IR (neat): 3066, 2932, 2857,
D
14

Page 15 of 58
Organic & Biomolecular Chemistry
1
1612, 1512, 1249, 1084, 701, 504 cm−1. H NMR (500 MHz, CDCl3) δ 7.69–7.65 (m, V4ieHw A)r,ticle Online
DOI: 10.1039/C9OB00623K
7.51–7.48 (m, 2H), 7.44–7.34 (m, 6H), 7.30–7.20 (m, 5H), 6.84 (d, J = 8.6 Hz, 2H), 4.45 (s,
2H), 4.19–4.11 (m, 3H), 4.07 (dt, J = 3.7, 1.7 Hz, 1H), 3.81–3.77 (m, 5H), 2.19–2.11 (m,
1H), 1.96–1.88 (m, 1H), 1.05 (s, 9H), 0.86 (s, 9H), 0.01 (s, 3H), -0.03 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 159.2, 135.54, 135.51, 134.6, 133.8, 133.7, 132.4, 129.7, 129.55, 129.52,
128.9, 127.6, 127.5, 127.4, 113.7, 84.0, 81.5, 70.5, 70.4, 60.3, 56.9, 55.1, 46.2, 36.1, 26.8,
25.7, 19.1, 18.0, -4.68, -4.70; MS (ESI-TOF) m/z: 747 [M + Na]+. HRMS (ESI-TOF) m/z: [M
+ Na]+ calcd for C43H56NaO4SSi2 747.3330; found 747.3342.
(R,E)-5-((tert-Butyldimethylsilyl)oxy)-7-((tert-butyldiphenylsilyl)oxy)-1-((4-methoxy
benzyl) oxy)hept-3-en-2-one (18): To a solution of sulfide 17 (20.95 g, 29 mmol) in
dichloromethane (20 mL) cooled at -40 °C was added mCPBA (7.15 g, 29 mmol) and the
reaction mixture stirred at the same temperature for 30 min. Toluene (50 mL) and 2-
mercapto-1-methyl-imidazole (3.97 g, 34.8 mmol) were added. The reaction mixture was
stirred at 60 °C for 3 h and then quenched by the addition of satd aq NaHCO3 (30 mL). The
mixture was diluted with dichloromethane (30 mL) and the layers were separated. The
combined organic layers were washed successively with water (50 mL), brine (30 mL) and
dried over Na2SO4. The solvent was evaporated under reduced pressure to furnish the crude
compound which was purified by column chromatography using 5% EtOAc/hexanes (v/v) as
the eluent to afford the product 18 (15.16 g, 24 mmol) in 83% yield as a liquid. TLC: Rf 0.1
(5% EtOAc/hexanes); [α]20 = +13.2 (c 0.6, CHCl3); IR (neat): 3070, 2954, 2857, 1695,
D
1
1629, 1513, 1251, 1108, 704, 505 cm−1. H NMR (500 MHz, CDCl3) δ 7.66–7.62 (m, 4H),
7.44–7.34 (m, 6H), 7.29–7.25 (m, 2H), 6.92 (dd, J = 15.8, 4.7 Hz, 1H), 6.89–6.86 (m, 2H),
6.44 (dd, J = 15.8, 1.6 Hz, 1H), 4.59–4.55 (m, 1H), 4.52 (s, 2H), 4.17 (d, J = 16.8 Hz, 1H),
4.14 (d, J = 16.8 Hz, 1H) 3.80 (s, 3H), 3.78–3.74 (m, 1H), 3.71–3.65 (m, 1H), 1.77–1.71 (m,
13
2H), 1.04 (s, 9H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); C NMR (101 MHz, CDCl3) δ
15

Organic & Biomolecular Chemistry
Page 16 of 58
View Article Online
197.1, 159.3, 150.0, 135.4, 133.5, 129.6, 129.55, 129.5, 129.2, 127.6, 127.57, 123.6, 113.8,
DOI: 10.1039/C9OB00623K
73.8, 72.8, 68.8, 59.8, 55.1, 40.2, 26.8, 25.7, 19.0, 18.1, -4.6, -5.1; MS (ESI-TOF) m/z: 655
[M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C37H52NaO5Si2 655.3245; found
655.3239.
(2S,5R,E)-5-((tert-Butyldimethylsilyl)oxy)-7-((tert-butyldiphenylsilyl)oxy)-1-((4-methoxy
benzyl)oxy)hept-3-en-2-ol (19): To a solution of ketone 18 (13.90 g, 22 mmol) in a 1:1
mixture of dichloromethane (110 mL) and water (110 mL) were added HCO2Na (14.96 g,
220 mmol), n-Bu4NBr (1.41 g, 4.4 mmol) and (R,R)-TsDPEN catalyst (350 mg, 2.5 mol%).
The biphasic reaction mixture was vigorously stirred for 12 h, an additional 1 mol% of
catalyst was added and the reaction mixture was stirred for an additional 5 h. The layers were
separated and the aq layer was extracted with dichloromethane (2x30 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to afford the crude compound which was purified by column chromatography using
10% EtOAc/hexanes (v/v) as the eluent to furnish the alcohol 19 (dr 9.6:0.4) in 89% yield as
a clear liquid. TLC: Rf 0.2 (10% EtOAc/hexanes); [α]20 = +9.6 (c 1.0, CHCl3); IR (neat):
D
1
3451, 3069, 2931, 2857, 1612, 1513, 1250, 1106, 704, 505 cm−1. H NMR (300 MHz,
CDCl3) δ 7.68–7.62 (m, 4H), 7.43–7.32 (m, 6H), 7.28–7.22 (m, 2H), 6.92–6.86 (m, 2H), 5.74
(ddd, J = 15.6, 6.0, 0.9 Hz, 1H), 5.54 (ddd, J = 15.6, 5.7, 0.8 Hz, 1H), 4.48 (s, 2H), 4.38 (q, J
= 6.2 Hz, 1H), 4.33–4.24 (m, 1H), 3.82–3.69 (m, 4H), 3.70–3.60 (m, 1H), 3.44 (dd, J = 9.4,
3.3 Hz, 1H), 3.29 (dd, J = 9.4, 8.3 Hz, 1H), 2.36 (d, J = 2.9 Hz, 1H), 1.82–1.62 (m, 2H), 1.04
13
(s, 9H), 0.86 (s, 9H), 0.02 (d, J = 3.0 Hz, 6H); C NMR (101 MHz, CDCl3) δ 159.1, 135.3,
135.1, 133.7, 129.7, 129.4, 129.2, 127.9, 127.4, 113.6, 73.9, 72.7, 70.4, 69.6, 60.2, 54.9, 40.9,
26.7, 25.8, 19.0, 18.0, -4.3, -5.0; MS (ESI-TOF) m/z: 657 [M + Na]+. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C37H54NaO5Si2 657.3402; found 657.3416.
16

Page 17 of 58
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00623K
(R)-((2S,5R,E)-5-(tert-Butyldimethylsilyloxy)-7-(tert-butyldiphenylsilyloxy)-1-(4-
methoxybenzyloxy)hept-3-en-2-yl) 2-methoxy-2-phenylacetate:
To a solution of alcohol 19 (15 mg, 0.023 mmol) in dichloromethane (0.5 mL) cooled at 0 oC
was added (R)-methoxyphenylacetic acid (4.8 mg, 0.028 mmol), DMAP (1 mg, 20 mol%),
and EDC.HCl (8.8 mg, 0.046 mmol). The reaction mixture was stirred at rt for 2 h. After
complete consumption of starting material, the reaction mixture was diluted with
dichloromethane (2 mL) and H2O (2 mL). The layers were separated and the aq layer was
extracted with dichloromethane (2×5 mL). The combined organic layers were sequentially
washed with satd aq NaHCO3 (10 mL), 1 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried
over Na2SO4 and concentrated under reduced pressure to afford the corresponding ester in
91% yield as a liquid. The crude product was characterised by 1H NMR spectroscopy. TLC:
1
Rf 0.3 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.66–7.60 (m, 4H), 7.44–7.33
(m, 8H), 7.31–7.24 (m, 3H), 7.22–7.18 (m, 2H), 6.89–6.84 (m, 2H), 5.50 (ddd, J= 7.2, 5.7,
4.1,1H), 5.41 (dd, J = 15.6, 5.8 Hz, 1H), 5.33 (dd, J = 15.5, 5.7 Hz, 1H), 4.77 (s, 1H), 4.46 (d,
J = 11.6 Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 4.18 (q, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.65 (dt, J
= 10.3, 6.2 Hz, 1H), 3.53 (dt, J = 10.3, 6.2 Hz, 1H), 3.49 (dd, J = 10.8, 7.1 Hz, 1H), 3.44 (dd,
J = 10.8, 4.1 Hz, 1H), 3.39 (s, 3H), 1.68–1.40 (m, 2H), 1.03 (s, 9H), 0.80 (s, 9H), -0.07 (s,
3H), -0.11 (s, 3H).
(S)-((2S,5R,E)-5-(tert-Butyldimethylsilyloxy)-7-(tert-butyldiphenylsilyloxy)-1-(4-methoxy
benzyloxy)hept-3-en-2-yl) 2-methoxy-2-phenylacetate:
17

Organic & Biomolecular Chemistry
Page 18 of 58
View Article Online
DOI: 10.1039/C9OB00623K
Alcohol 19 (15 mg, 0.023 mmol) was reacted with (S)-methoxyphenylacetic acid (4.8 mg,
0.028 mmol) as described above to furnish the corresponding ester in 88% yield as a liquid.
1
The crude product was characterised by H NMR spectroscopy. TLC: Rf 0.35 (10%
1
EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.64–7.59 (m, 4H), 7.44–7.40 (m, 2H),
7.40–7.31 (m, 6H), 7.29–7.26 (m, 3H), 7.07–7.02 (m, 2H), 6.81–6.76 (m, 2H), 5.66 (dd, J =
15.0, 6.2 Hz, 1H), 5.53 (dd, J = 15.0, 6.2 Hz, 1H), 5.51–5.44 (m, 1H), 4.74 (s, 1H), 4.31 (q, J
= 6.2 Hz, 1H), 4.26 (d, J = 11.6 Hz, 1H), 4.21 (d, J = 11.6 Hz, 1H), 3.78 (s, 3H), 3.70 (dt, J =
10.3, 6.0 Hz, 1H), 3.60 (dt, J = 10.4, 6.1 Hz, 1H), 3.40 (s, 3H), 3.38 (dd, J = 10.7, 4.0 Hz,
1H), 3.34 (dd, J = 10.7, 4.0 Hz, 1H), 1.71–1.52 (m, 2H), 1.04 (s, 9H), 0.83 (s, 9H), -0.02 (s,
3H), -0.05 (s, 3H).
Note: The configuration of alcohol 19 was unambiguously assigned by comparison of the 1H
NMR spectra of mandelate esters. Thus, supporting the ‘S’ configuration of the carbinol 19,
the CH2OPMB appeared downfield in the 'R' ester while CHOTBS appeared downfield in the
'S' ester.
(S)-1-((1R,2R)-2-((R)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-4,8-dioxa-3,9-disilaundecan
-5-yl)cyclopropyl)-2-((4-methoxybenzyl)oxy)ethanol (20): To a stirred solution of Et2Zn
(1.0 M in hexanes, 10 mL, 10 mmol) in a mixture of dichloromethane (15 mL) and 1,2-
dimethoxyethane (1 mL, 10 mmol) cooled at -20 °C, was added CH2I2 (1.61 mL, 20 mmol)
over a 15-20 min period while maintaining the internal temperature between -8 °C and -15
°C. After the addition was completed, the resulting white suspension was stirred for 40 min at
-20°C. A solution of alcohol 19 (3.17 g, 5 mmol) in dichloromethane (10 mL) was added via
cannula under argon over a 5-6 min period. The cooling bath was removed and the clear
18

Page 19 of 58
Organic & Biomolecular Chemistry
reaction mixture was allowed to warm to rt and stirred for 6 h at the same tempDeOraI:t1u0.r1e03.V9iT/eCwh9AOertBic0le0O6n2li3nKe
reaction was quenched with satd aq NH4Cl (15 mL) and extracted with dichloromethane
(2x10 mL). The organic layer was sequentially washed with aq 10% HCl (10 mL), satd aq
NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. The solvent was concentrated under
reduced pressure to afford the crude product which was purified by flash chromatography
using 12% EtOAc/petroleum ether (v/v) to give pure cyclopropyl alcohol 20 (2.79 g, 4.3
mmol) in 86% yield as a colouress oil. TLC: Rf 0.1 (10% EtOAc/hexane); [α]20 = -2.2 (c
D
0.55, CHCl3); IR (neat): 3450, 3066, 2935, 2858, 1613, 1513, 1466, 1249, 1103, 832, 703,
502 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.67–7.63 (m, 4H), 7.45–7.34 (m, 6H), 7.24 (d, J =
8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.46 (s, 2H), 3.79 (s, 3H), 3.78–3.70 (m, 2H), 3.53 (dd,
J = 9.4, 3.0 Hz, 1H), 3.42–3.33 (m, 2H), 3.21–3.14 (m, 1H), 2.32 (s, 1H), 1.74–1.67 (m, 2H),
1.04 (s, 9H), 0.83 (s, 9H), 0.81–0.69 (m, 2H), 0.58–0.53 (m, 2H), 0.03 (s, 3H), -0.02 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 159.2, 135.5, 133.9, 133.8, 129.9, 129.56, 129.52, 129.3,
127.5, 113.8, 73.9, 73.7, 73.0, 71.4, 60.6, 55.2, 40.7, 26.8, 25.8, 22.3, 19.1, 18.4, 18.0, 8.7, -
3.9, -4.7; MS (ESI-TOF) m/z: 671 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C38H56NaO5Si2 671.3564; found 671.3563.
(R)-5-((1R,2R)-2-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)oxy)ethyl)
cyclopropyl)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (21):
To a solution of alcohol 20 (4.9 g, 7.6 mmol) in anhydrous dichloromethane (15 mL) cooled
at -40 °C was added 2,6-lutidine (1.84 mL, 16 mmol) followed by TBSOTf (1.9 mL, 8.32
mmol). The reaction mixture was stirred at the same temperature for 30 min, quenched by the
addition of water (10 mL) and diluted with dichloromethane (15 mL). The layers were
separated, the organic layer was washed with water (20 mL), brine (20 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product
which was purified by column chromatography using 2% EtOAc/hexane (v/v) to give pure
19

Organic & Biomolecular Chemistry
Page 20 of 58
View Article Online
silyl ether 21 (5.4 g, 7.1 mmol) in 94% yield as a gummy oil. TLC: Rf 0.2 (2%
DOI: 10.1039/C9OB00623K
EtOAc/hexane); [α]20 = -8.8 (c 0.25, CHCl3); IR (neat): 3068, 2953, 2891, 1613, 1513,
D
1
1467, 1250, 1102, 833, 774 cm−1. H NMR (400 MHz, CDCl3) δ 7.67–7.63 (m, 4H), 7.42–
7.33 (m, 6H), 7.24 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.45 (d, J = 11.6 Hz, 1H),
4.41 (d, J = 11.6 Hz, 1H), 3.79 (s, 3H), 3.77–3.69 (m, 2H), 3.42–3.36 (m, 3H), 3.36–3.29 (m,
1H), 1.79–1.66 (m, 2H), 1.03 (s, 9H), 0.87 (s, 9H), 0.83 (s, 9H), 0.81–0.76 (m, 2H), 0.52–
13
0.46 (m, 1H), 0.46–0.40 (m, 1H), 0.07 (s, 3H), 0.03 (s, 6H), -0.02 (s, 3H); C NMR (101
MHz, CDCl3) δ 158.9, 135.5, 134.0, 133.9, 130.5, 129.5, 129.4, 129.1, 127.6, 113.6, 75.1,
73.2, 72.9, 72.3, 60.8, 55.1, 40.8, 26.8, 25.9, 25.8, 22.1, 19.9, 19.1, 18.2, 18.10, 8.5, -3.8, -
4.3, -4.4, -4.6; MS (ESI-TOF) m/z: 785 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C44H70O5NaSi3 785.4429; found 785.4429.
(S)-2-((tert-Butyldimethylsilyl)oxy)-2-((1R,2R)-2-((R)-2,2,3,3,10,10-hexamethyl-9,9-di
phenyl -4,8-dioxa-3,9-disilaundecan-5-yl)cyclopropyl)ethanol (22): To a solution of the
compound 21 (4.96 g, 6.5 mmol) in a mixture of dichloromethane (20 mL) and pH 7
o
phosphate buffer (2 mL) cooled at 0 C was added DDQ (1.77 g, 7.8 mmol). The reaction
mixture was stirred for 2 h at the same temperature and then quenched by the addition of satd
aq NaHCO3 (10 mL), diluted with dichloromethane (10 mL) and stirred for 30 min. The
layers were separated, the organic layer was washed with water (10 mL), brine (15 mL) and
dried over Na2SO4. The solvent was concentrated under reduced pressure and crude residue
was purified by flash column chromatography using 5% EtOAc/hexane (v/v) as the eluent to
afford alcohol 22 (3.4 g, 5.2 mmol) in 81% yield as a clear, colorless liquid. TLC: Rf 0.3 (5%
EtOAc/hexane); [α]20 = -0.5 (c 0.65, CHCl3); IR (neat): 3483, 3068, 2929, 2857, 1730,
D
1
1466, 1254, 1103, 834, 772, 702 cm−1. H NMR (500 MHz, CDCl3) δ 7.68–7.63 (m, 4H),
7.44–7.35 (m, 6H), 3.78–3.70 (m, 2H), 3.54 (dd, J = 10.9, 3.3 Hz, 1H), 3.45 (dd, J = 10.9, 6.7
Hz, 1H), 3.42–3.36 (m, 1H), 3.16–3.10 (m, 1H), 1.94 (s, 1H), 1.76–1.69 (m, 2H), 1.04 (s,
20

Page 21 of 58
Organic & Biomolecular Chemistry
9H), 0.90 (s, 9H), 0.83 (s, 9H), 0.80–0.67 (m, 2H), 0.58–0.52 (m, 1H), 0.51–0.45 (m, V1ieHw A)r,ticle Online
DOI: 10.1039/C9OB00623K
13
0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), -0.01 (s, 3H); C NMR (101 MHz, CDCl3) δ 135.5,
133.9, 129.6, 129.5, 127.6, 127.5, 76.2, 71.6, 66.9, 60.6, 40.6, 26.8, 25.8, 22.4, 19.1, 18.1,
9.9, -3.9, -4.0, -4.6, -4.7; MS (ESI-TOF) m/z: 665 [M + Na]+. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C36H62O4NaSi3 665.3854; found 665.3856.
(R)-5-((1R,2R)-2-((S)-1-((tert-Butyldimethylsilyl)oxy)-2-(phenylthio)ethyl)cyclopropyl)-
2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (23): To a solution of
alcohol 22 (2.90 g, 4.5 mmol) in toluene (9 mL) at rt was added diphenyldisulfide (1 g, 5
mmol) followed by tri-n-butylphosphine (1.35 mL, 5.4 mmol). The reaction mixture was
stirred at ambient temperature for 12 h. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography on silica gel using 2%
EtOAc/hexane (v/v) as the eluent to afford sulfide 23 as colorless oil (2.88 g, 3.9 mmol) in
87% yield. TLC: Rf 0.3 (2% EtOAc/hexane); [α]20D = -12.4 (c 0.25, CHCl3); IR (neat): 3070,
1
2930, 2857, 1585, 1468, 1253, 1106, 835, 774 cm−1. H NMR (400 MHz, CDCl3) δ 7.68–
7.63 (m, 4H), 7.44–7.33 (m, 6H), 7.32–7.28 (m, 2H), 7.27–7.22 (m, 2H), 7.15 (tt, J = 8.6, 1.3
Hz, 1H), 3.79–3.72 (m, 2H), 3.43 (q, J = 6.7 Hz, 1H), 3.36 (q, J = 6.1 Hz, 1H), 3.05–3.02 (m,
2H), 1.81–1.71 (m, 2H), 1.05 (s, 9H), 1.00–0.90 (m, 1H), 0.88 (s, 9H), 0.86–0.77 (m, 10H),
0.52–0.44 (m, 2H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), -0.01 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 137.3, 135.5, 134.0, 133.9, 129.6, 129.5, 128.83, 128.81, 127.6, 127.5, 125.6,
73.3, 71.5, 60.8, 41.6, 40.9, 26.9, 25.9, 25.8, 22.8, 21.9, 19.1, 18.13, 18.10, 8.9, -3.9, -4.2, -
4.4, -4.6; MS (ESI-TOF) m/z: 757 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C42H66O3NaSSi3 757.3938; found 757.3948.
21

Organic & Biomolecular Chemistry
Page 22 of 58
View Article Online
DOI: 10.1039/C9OB00623K
(Z)-Dec-4-en-1-yne (24):
Oct-2-yn-1-ol (I): To a stirred solution of 1-heptyne (1.44 g, 15 mmol) in anhydrous THF
(30 mL) cooled at –78 °C was added nBuLi (2.5 M/hexanes, 6 mL, 15 mmol) dropwise. After
stirring for 1 h, paraformaldehyde (496 mg, 16.5 mmol) was added to the reaction mixture,
stirring continued for an additional 2 h at the same temperature and then gradually warmed to
rt over 3 h. The reaction mixture was quenched with satd aq NH4Cl solution (50 mL) and
extracted with diethyl ether (3x20 mL). The combined organic extracts were washed with
brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to afford the crude product. Purification by the flash column chromatography using
20% EtOAc/Hexane (v/v) as the eluent affored oct-2-yn-1-ol I (1.78 g, 14.1 mmol) in 94%
yield as a yellow oil. TLC: Rf 0.1 (20% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 4.20
(t, J = 2.1 Hz, 2H), 2.50 (bs, 1H), 2.16 (tt, J = 7.1, 2.1 Hz, 2H), 1.52–1.41 (m, 2H), 1.37–1.20
(m, 4H), 0.85 (t, J = 7.0 Hz, 3H).
Oct-2-en-1-ol (II): To a solution of the above alkynol I (1.76 g, 14 mmol) in hexane (14 mL)
was added Lindlar’s catalyst (88 mg, 5 wt%), quinoline (18 μL) and the mixture stirred under
H2 atmosphere for 3 h. The catalyst was filtered using a Celite pad. The filtrate was
evaporated under reduced pressure and the residue was purified by the flash column
chromatography using 20% EtOAc/Hexane (v/v) as the eluent to give oct-2-en-1-ol II (1.56
1
g, 12.2 mmol) in 87% yield as a colorless oil. TLC: Rf 0.2 (20% EtOAc/Hexanes); H NMR
22

Page 23 of 58
Organic & Biomolecular Chemistry
(400 MHz, CDCl3) δ 5.64–5.50 (m, 2H), 4.20 (d, J = 6.3 Hz, 2H), 2.07 (q, J = 6.6 Hz, V2ieHw A)r,ticle Online
DOI: 10.1039/C9OB00623K
1.62 (bs, 1H) 1.42–1.23 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H).
1-Trimethylsilyl-deca-4(Z)-en-1-yne (IV): To a solution of oct-2-en-1-ol II (1.53 g, 12
o
mmol) in anhydrous dichloromethane (25 mL) cooled at 0 C was added Et3N (3.7 mL, 26.4
mmol) followed by MsCl (1 mL, 13.2 mmol) and the mixture stirred at the same temperature
for 1 h. After completion the reaction mixture was quenched with water (20 mL) and
extracted with dichloromethane (3x20 mL). The combined organic extracts were washed with
1N HCl (30 mL), water (30 mL), brine (30 mL) and dried over anhydrous Na2SO4. Solvent
was removed under reduced pressure to afford the crude mesylate III which was used in the
next step without further purification.
To a solution of trimethylsilylacetylene (1.8 mL, 13.2 mmol) in anhydrous DMF (6 mL),
successively K2CO3 (3.32 g, 24 mmol), NaI (3.6 g, 24 mmol), CuI (2.3 g, 12 mmol) and the
solution of the crude mesylate III in DMF (6 mL) were added. The yellow-green suspension
was vigorously stirred at room temperature for 6 h, then quenched with satd aq NH4Cl (15
mL) and diluted with diethylether (20 mL). The layers were separated and the organic layer
was washed with H2O (3x10 mL), brine (20 mL) and dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure at low temperature to afford a crude
compound that was purified by column chromatography using pentane as the eluent to give 1-
trimethylsilyl-deca-4(Z)-en-1-yne IV (1.87 g, 9 mmol) in addition to the product of SN2ʹ
1
displacement in a 5:1 ratio in 75% combined yield. TLC: Rf 0.8 (hexane); H NMR (500
MHz, CDCl3, the signals for the minor isomer is denoted with an asterisk) δ 5.78–5.71 (m,
1H)*, 5.70–5.64 (m, 1H), 5.42–5.35 (m, 1H), 5.28 (dt, J = 17, 1.5 Hz, 1H)*, 5.07 (dt, J = 10,
1.4 Hz, 1H)*, 3.09–3.04 (m, 1H)*, 2.97–2.93 (m, 2H), 2.04–1.98 (m, 2H), 1.40–1.34 (m,
6H)*, 1.33–1.23 (m, 6H), 0.88 (t, J = 7.1, 6H), 0.16 (s, 18H).
23

Organic & Biomolecular Chemistry
Page 24 of 58
Compound 24: To a stirred solution of 1-trimethylsilyl-deca-4(Z)-en-1-yne IV (1.04 Vgiew, A5rticle Online
DOI: 10.1039/C9OB00623K
mmole) in anhydrous dimethylformamide (5 mL) was added potassium fluoride dihydrate
o
(940 mg, 10 mmole) at 0 C. The reaction mixture was stirred for 2 h at the same
temperature, quenched by the addition water (10 mL) and diluted with diethyl ether (15 mL).
The layers were separated, the organic layer was washed with water (2x10 mL), brine (10
mL) and dried over Na2SO4. The solvent was concentrated under reduced pressure (water
o
bath temperature < 30 C) and the crude residue was distilled. The fraction collected at 105
oC/2 Torr afforded the pure desilylated compound 24 (530 mg, 3.9 mmole) in 78% yield as a
clear, colorless oil. TLC: Rf 0.8 (Hexane); 1H NMR (400 MHz, CDCl3) δ 5.53–5.39 (m, 2H),
2.96–2.92 (m, 2H), 2.04 (q, J = 7.1 Hz, 2H), 1.97 (t, J = 2.7 Hz, 1H), 1.41–1.24 (m, 6H), 0.89
(t, J = 6.8 Hz, 3H).
(R)-5-((1R,2R)-2-((1S,2R,Z)-1-((tert-Butyldimethylsilyl)oxy)-2-(phenylthio)dodec-6-en-3-
yn-1-yl)cyclopropyl)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-3,9-
disilaundecane (25): To a solution of alkyne 24 (408 mg, 3 mmol) in anhydrous THF (1.5
i
mL) cooled at 0 °C was added PrMgCl·LiCl (1.5 M in THF, 2.2 mL, 3.3 mmol) and the
mixture stirred for 30 min at the same temperature. To the so generated Grignard reagent was
added a solution of ZnBr2 (1.5 M in THF, 3 mL, 4.5 mmol) at 0 °C and the mixture stirred for
30 min. Separately, in another round-bottom flask, the chloro sulfide was prepared by adding
a solution of sulfide 23 (735 mg, 1 mmol) in anhydrous benzene (5 mL) to NCS (134 mg, 1
mmol) in anhydrous benzene (5 mL) and stirring for 15 min. To the organozinc reagent
maintained at 0 °C was added a solution of chloro sulfide in benzene. The reaction mixture
was stirred gradually allowing it to attain rt and stirred further for a period of 7 h when TLC
examination indicated complete consumption of the chloro sulfide. The reaction mixture was
cooled to 0 °C and quenched by the addition of satd aq NH4Cl solution (10 mL). It was
allowed to warm to rt and diluted with Et2O (10 mL). The layers were separated and the aq
24

Page 25 of 58
Organic & Biomolecular Chemistry
layer was extracted with Et2O (3×10 mL). The combined organic layers were washed VwiewitAhrticle Online
DOI: 10.1039/C9OB00623K
H2O (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure to afford a crude compound that was purified by column
chromatography using 2% EtOAc/hexane (v/v) as the eluent to give the pure product 25 (630
mg, 0.73 mmol) in 73% yield as a light yellow color gummy liquid. TLC: Rf 0.5 (2%
EtOAc/hexane); [α]20 = +27.6 (c 0.8, CHCl3); IR (neat): 3067, 2930, 2857, 1585, 1467,
D
1252, 1103, 835, 700 cm−1. 1H NMR (500 MHz, CDCl3) δ 7.65–7.60 (m, 4H), 7.46–7.42 (m,
2H), 7.39–7.29 (m, 7H), 7.23–7.15 (m, 2H), 5.40–5.33 (m, 1H), 5.32–5.25 (m, 1H), 3.93–
3.90 (m, 1H), 3.71 (t, J = 6.9 Hz, 2H), 3.47 (td, J = 7.0, 4.7 Hz, 1H), 3.35 (dd, J = 7.1, 3.8 Hz,
1H), 2.86 (d, J = 6.8 Hz, 2H), 1.94 (q, J = 7.1 Hz, 2H), 1.89–1.81 (m, 1H), 1.75–1.67 (m,
1H), 1.33–1.18 (m, 6H), 1.01 (s, 9H), 0.89–0.84 (m, 12H), 0.81–0.78 (m, 11H), 0.57–0.52
13
(m, 1H), 0.52–0.47 (m, 1H), 0.05 (s, 3H), 0.03 (s, 3H), -0.1 (s, 6H); C NMR (101 MHz,
CDCl3) δ 135.5, 134.04, 134.01, 131.8, 131.4, 129.4, 128.6, 127.6, 127.5, 126.8, 124.0, 83.9,
78.2, 77.2, 71.2, 60.8, 47.2, 40.9, 31.4, 29.0, 27.0, 26.9, 25.9, 25.8, 23.0, 22.5, 20.0, 19.1,
18.2, 18.0, 17.4, 14.0, 9.4, -3.9, -4.0, -4.5, -4.6; MS (ESI-TOF) m/z: 891 [M + Na] +. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C52H80NaO3SSi3 891.5034; found 891.5031.
(R)-3-((tert-Butyldimethylsilyl)oxy)-3-((1R,2R)-2-((1S,2R,Z)-1-((tert-butyldimethylsilyl)
oxy)-2-(phenylthio)dodec-6-en-3-yn-1-yl)cyclopropyl)propan-1-ol (26): A solution of
compound 25 (364 mg, 0.42 mmol) and NH4F (78 mg, 2.1 mmol) in MeOH (1.5 mL) was
o
stirred in an oil bath at 60 C for 3 h. The reaction mixture was quenched by the addition of
water (1 mL). MeOH was evaporated under reduced pressure and to the residue was added
Et2O (5 mL). The layers were separated and the organic layer was washed with water (5 mL),
brine (5 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to
afford the crude product which was purified by column chromatography using 5%
EtOAc/hexane (v/v) to give the pure alcohol 26 (208 mg, 0.33 mmol) in 78% yield as a
25

Organic & Biomolecular Chemistry
Page 26 of 58
gummy oil. TLC: Rf 0.2 (5% EtOAc/hexanes); [α]20D = +29.6 (c 0.5, CHCl3); IR (neat): 3444,
View Article Online
DOI: 10.1039/C9OB00623K
1
2929, 2857, 1655, 1466, 1253, 1085, 836, 774 cm−1. H NMR (400 MHz, CDCl3) δ 7.49–
7.44 (m, 2H), 7.32–7.26 (m, 2H), 7.25–7.19 (m, 1H), 5.47–5.39 (m, 1H), 5.38–5.30 (m, 1H),
3.93 (dt, J = 5.7, 2.3 Hz, 1H), 3.86–3.77 (m, 1H), 3.67–3.57 (m, 1H), 3.48–3.41 (m, 1H), 3.38
(dd, J = 7.3, 3.4 Hz, 1H), 2.93 (d, J = 6.8 Hz, 2H), 2.26 (s, 1H), 2.00 (q, J = 6.8 Hz, 2H), 1.86
(ddd, J = 12.7, 8.6, 4.7 Hz, 1H), 1.77–1.67 (m, 1H), 1.39–1.17 (m, 6H), 1.01–0.94 (m, 1H),
0.93–0.81 (m, 22H), 0.65 (t, J = 6.8 Hz, 2H), 0.10 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.03 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 135.7, 131.6, 131.3, 128.7, 126.8, 123.9, 84.0, 78.2,
77.2, 74.7, 60.4, 47.3, 39.2, 31.4, 29.0, 27.0, 25.85, 25.80, 22.5, 22.3, 20.1, 18.1, 17.9, 17.4,
14.0, 10.6, -3.9, -4.1, -4.5, -4.7; MS (ESI-TOF) m/z: 653 [M + Na]+. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C36H62NaO3SSi2 653.3856; found 653.3857.
(R)-3-((tert-Butyldimethylsilyl)oxy)-3-((1R,2R)-2-((1S,2R,Z)-1-((tert-butyldimethylsilyl)
oxy)-2-(phenylthio)dodec-6-en-3-yn-1-yl)cyclopropyl)propanal (27): To a stirred solution
0
of 2-iodoxybenzoic acid (130 mg, 0.46 mmol) in anhydrous DMSO (0.6 mL) cooled at 0 C
was added a solution of alcohol 26 (195 mg, 0.31 mmol) in anhydrous dichloromethane (1.5
mL) and the reaction mixture stirred for a period of 3 h at rt. After completion of the reaction,
the mixture was filtered on a small Celite pad and the filtrate was diluted with
dichloromethane (10 mL), washed with water (5 mL), brine (5 mL) and dried over Na2SO4.
The solvent was evaporated under reduced pressure to afford the residue which was purified
by column chromatography using 3% EtOAc/hexane (v/v) to give the pure aldehyde 27 (177
mg, 0.28 mmol) in 90% yield as a gummy liquid. TLC: Rf 0.7 (5% EtOAc/hexanes); [α]20
=
D
+13.0 (c 0.7, CHCl3); IR (neat): 3014, 2956, 2857, 2714, 1726, 1467, 1254, 1091, 836, 775
cm−1. 1H NMR (400 MHz, CDCl3) δ 9.78 (t, J = 2.4 Hz, 1H), 7.50–7.44 (m, 2H), 7.32–7.20
(m, 3H), 5.46–5.38 (m, 1H), 5.36–5.28 (m, 1H), 3.96–3.92 (m, 1H), 3.76–3.70 (m, 1H), 3.34
(dd, J = 7.4, 3.8 Hz, 1H), 2.92 (d, J = 6.6 Hz, 2H), 2.69-2.63 (m, 1H), 2.63-2.56 (m, 1H),
26

Page 27 of 58
Organic & Biomolecular Chemistry
View Article Online
1.99 (q, J = 6.7 Hz, 2H), 1.37–1.21 (m, 6H), 1.10–1.0 (m, 1H), 0.99–0.75 (m, D2O2I:H10).,10039./6C89O–B00623K
13
0.59 (m, 2H), 0.10 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), -0.01 (s, 3H); C NMR (126 MHz,
CDCl3) δ 202.0, 135.3, 131.7, 131.6, 128.8, 127.0, 123.9, 84.4, 77.7, 77.2, 70.8, 51.8, 47.2,
31.4, 29.0, 27.0, 25.78, 25.76, 23.1, 22.5, 20.1, 18.1, 17.9, 17.4, 14.0, 10.0, -4.0, -4.1, -4.6, -
4.7; MS (ESI-TOF) m/z: 651 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C36H60NaO3SSi2 651.3699; found 651.3704.
4-(Bromotriphenylphosphoranyl)butanoic acid (28): A mixture of 4-bromocarboxylic acid
o
(1.84 g, 11 mmol) and triphenylphosphine (2.88 g, 11 mmol) was heated at 80 C for 24 h
under argon. The mixture was allowed to cool at rt. The residue was washed with anhydrous
ether (3x20 mL) and dried under vacuo to afford the pure phosphonium salt 28 as a white
solid (4.2 g) in 90% yield. Mp 242 oC.1H NMR (400 MHz, D2O) δ 7.84–7.78 (m, 3H), 7.77–
7.69 (m, 6H), 7.69–7.61 (m, 6H), 3.35–3.23 (m, 2H), 2.53 (t, J = 6.6 Hz, 2H), 1.98–1.85 (m,
2H); 13C NMR (101 MHz, D2O) δ 179.2, 137.6, 136.1, 132.6, 120.5, 36.2, 23.3, 20.0.
(R,Z)-7-((tert-Butyldimethylsilyl)oxy)-7-((1R,2R)-2-((1S,2R,Z)-1-((tert-butyldimethyl
silyl)oxy)-2-(phenylthio)dodec-6-en-3-yn-1-yl)cyclopropyl)hept-4-enoic acid (29): To a
stirred suspension of phosphonium salt 28 (347 mg, 0.81 mmol) in anhydrous THF (0.8 mL)
o
cooled at 0 C and maintained under an Ar atmosphere was added NaHMDS (1 M in THF,
1.6 mL, 1.62 mmol) and the reaction mixture was stirred for 1 h at the same temperature. The
resulting ylide was cooled to -78 °C and the solution of aldehyde 27 (170 mg, 0.27 mmol) in
anhydrous THF (1 mL) was added slowly and the mixture stirred further for a period of 1 h at
the same temperature. After completion of the reaction as monitored by TLC, the mixture
was quenched with satd aq NH4Cl solution (5 mL), acidified with 1 N HCl solution (2 mL) to
pH=4 and was extracted with EtOAc (2x5 mL). The combined organic layers were dried over
Na2SO4, concentrated and the crude product was purified by silica gel column
chromatography using 20% EtOAc/hexane as the eluent to afford compound 29 (153 mg,
27

Organic & Biomolecular Chemistry
Page 28 of 58
0.22 mmol) in 81% yield as a colorless oil. TLC: Rf 0.1 (20% EtOAc/hexane). The acidViwewaAsrticle Online
DOI: 10.1039/C9OB00623K
characterized as its methyl ester obtained by reaction with ethereal diazomethane. [α]20
=
D
+27.2 (c 0.25, CHCl3); IR (neat): 3010, 2956, 2856, 1741, 1466, 1256, 1088, 835, 774 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m, 2H), 7.23–7.17 (m, 2H), 7.17–7.11 (m, 1H),
5.45–5.21 (m, 4H), 3.89–3.86 (m, 1H), 3.59 (s, 3H), 3.35–3.27 (m, 2H), 2.84 (d, J = 6.8 Hz,
2H), 2.29–2.18 (m, 6H), 1.92 (q, J = 6.7 Hz, 2H), 1.31–1.14 (m, 6H), 0.88–0.77 (m, 23H),
0.58–0.51 (m, 1H), 0.48–0.41 (m, 1H), -0.01 (s, 3H), -0.03 (s, 3H) -0.04 (s, 3H) -0.05 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 173.5, 135.6, 131.6, 131.5, 128.7, 128.6, 127.7, 126.8, 124.0,
83.9, 78.1, 77.1, 73.2, 51.4, 47.1, 36.1, 34.0, 31.4, 29.0, 27.0, 25.87, 25.83, 22.9, 22.6, 22.5,
19.8, 18.2, 18.1, 17.4, 14.0, 8.3, -4.0, -4.1, -4.4, -4.5; MS (ESI-TOF) m/z: 735 [M + Na]+.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C41H68NaO4SSi2 735.4275; found 735.4267.
(R,Z)-7-Hydroxy-7-((1R,2R)-2-((1S,2R,Z)-1-hydroxy-2-(phenylthio)dodec-6-en-3-yn-1-
yl)cyclopropyl)hept-4-enoic acid (30): To a solution of compound 29 (140 mg, 0.2 mmol)
o
in anhydrous CH3CN (1.25 mL) cooled at 0 C was added HF.pyridine (~70% HF, 30 µL)
and the reaction mixture stirred at rt for a period of 12 h. The reaction was cooled at 0 oC and
quenched by the dropwise addition of satd aq NaHCO3 solution (1 mL) and warmed to rt with
stirring. The reaction mixture was extracted with dichloromethane (3x2 mL). The combined
organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure to afford the crude product. Purification by the flash
column chromatography using 60% EtOAc/Hexane (v/v) as the eluent affored compound 30
(78 mg, 0.16 mmol) in 79% yield. TLC: Rf 0.1 (60% EtOAc/Hexanes). The acid was
characterized as its methyl ester, prepared by reaction with ethereal diazomethane. [α]20
=
D
+2.0 (c 0.2, CHCl3); IR (neat): 3448, 2924, 2854, 1735, 1438, 1249, 1164, 1029, 744 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.48–7.43 (m, 2H), 7.26–7.21 (m, 3H), 5.48–5.33 (m, 3H), 5.29–
5.20 (m, 1H), 3.77 (dt, J = 6.9, 2.3 Hz, 1H), 3.58 (s, 3H), 3.17-3.09 (m, 2H), 2.86 (d, J = 6.8
28

Page 29 of 58
Organic & Biomolecular Chemistry
View Article Online
Hz, 2H), 2.63 (s, 1H), 2.39–2.22 (m, 6H), 1.92 (q, J = 7.1 Hz, 2H), 1.31–1.14 (m, 6H), 1.13–
DOI: 10.1039/C9OB00623K
1.06 (m, 1H), 1.05–0.98 (m, 1H), 0.81 (t, J = 7.0 Hz, 3H), 0.62–0.52 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 173.6, 133.6, 132.4, 131.9, 130.4, 128.8, 128.1, 127.1, 123.5, 85.8, 76.5,
73.9, 73.5, 51.6, 47.4, 35.0, 33.6, 31.4, 28.9, 27.1, 22.9, 22.7, 22.5, 19.4, 17.3, 14.0, 6.5; MS
(ESI-TOF) m/z: 507 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C29H40O4SNa
507.2545; found 507.2539.
(R,Z)-8-((1R,2R)-2-((1S,2R,Z)-1-Hydroxy-2-(phenylthio)dodec-6-en-3-yn-1-yl)cyclo
propyl)-3,4,7,8-tetrahydro-2H-oxocin-2-one (31): A solution of hydroxy acid 30 (65 mg,
0.14 mmol) in dichloromethane (40 mL) was added using a mechanically driven syringe to
the solution of 2-methyl-6-nitrobenzoic anhydride (72 mg, 0.21 mmol) and DMAP (34 mg,
0.28 mmol) in dichloromethane (100 mL) over a period of 16 h. After addition was complete,
the reaction mixture was stirred further for a period of 2 h at rt. The reaction mixture was
concentrated to 20 mL by evaporation of the solvent under reduced pressure and then satd aq
NaHCO3 (20 mL) was added at 0 °C. The layers were separated and the aq layer was
extracted with dichloromethane (3x20 mL). The combined organic layers were washed with
water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure to afford a crude compound that was purified by column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to afford the pure product 31
(50 mg, 0.11 mmol) in 82% yield as a gummy liquid. TLC: Rf 0.2 (10% EtOAc/hexane);
[α]20 = +5.20 (c 0.25, CHCl3); IR (neat): 3453, 3015, 2925, 2856, 1741, 1460, 1216, 1056,
D
1
734 cm−1. H NMR (500 MHz, CDCl3) δ 7.55–7.51 (m, 2H), 7.34–7.30 (m, 3H), 5.81–5.70
(m, 2H), 5.49–5.43 (m, 1H), 5.36–5.29 (m, 1H), 4.03 (ddd, J = 9.9, 7.8, 1.7 Hz, 1H), 3.81 (dt,
J = 7.0, 2.3 Hz, 1H), 3.19 (td, J = 6.5, 2.4 Hz, 1H), 2.94 (dt, J = 6.9, 1.7 Hz, 2H), 2.88–2.79
(m, 1H), 2.72 (ddd, J = 13.3, 5.8, 3.0 Hz, 1H), 2.65–2.55 (m, 1H), 2.34–2.25 (m, 2H), 2.14–
2.07 (m, 1H), 2.00 (q, J = 7.0 Hz, 2H), 1.38–1.18 (m, 6H), 0.91–0.82 (m, 5H), 0.75–0.70 (m,
29