Asymmetric total synthesis of cryptoconcatone I

Article abstract of DOI:10.1039/C9OB00399A

Asymmetric total synthesis of the naturally occurring cryptoconcatone I, which possesses a γ-Z-butenolide framework, is described here for the first time. Asymmetric propargylation, E-selective cross metathesis, and regioselective reductive epoxide ring o

Full text of DOI:10.1039/C9OB00399A

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DOI: 10.1039/C9OB00399A
Asymmetric Total Synthesis of Cryptoconcatone I
Ranjan Kumar Acharyya, Pratik Pal, Shrestha Chatterjee and Samik Nanda*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302,
India
Tel: +91-3222-283328; E-mail: snanda@chem.iitkgp.ac.in
ABSTRACT: Asymmetric total synthesis of naturally occurring cryptoconcatone I having,
the γ-Z-butenolide framework was described here for the first time. Asymmetric
propargylation, E-selective cross metathesis, and regioselective reductive ring opening of
epoxide were employed to access enantiopure terminal alkyne. Late stage bimetallic cascade
cyclization of the alkyne with (Z)-3-bromoacrylic acid afforded the natural product in an
efficient way.
OH R1
R2
OP1 OP2 OH
OP1
O
Ph
Ph
Ph
OH
O
P = PMB; P = TBS
1
2
O
R = OH; R = OAc; Cryptoconcatone I
1
2
INTRODUCTION
Cryptocarya is a well-known genus of evergreen trees belonging to the laurel family
1
(
Lauraceae), and there are almost 350 species, known until today. They are mainly
distributed through the tropical and subtropical zones of India, China, South America, Java,
and Mauritius. These trees can grow up to 60 m tall and having a canopy like structure and
can withstand lower temperature. Earlier investigations on the phytochemical aspects of such
species have led to isolation of several secondary metabolites such as α-pyranones,
2
flavonoids, alkaloids. Cryptocarya concinna Hance is such an evergreen species, widely
3
distributed in lower subtropical part of mainland China. The crude extract from the leaves
1

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and branches of C. concinna was shown to exhibit potent anti-inflammatory activities. A
DOI: 10.1039/C9OB00399A
recent investigation led to the isolation of 10 new secondary metabolites (Cryptoconcatones
A-J) from the leaves and twigs of C. concinna.4 Close structural inspection of all the natural
products reveals cryptoconcatone A-H, all having an α-pyranone framework and an E-
cinnamyl side chain. Cryptoconcatone H contains a tetrahydropyran ring, whereas
cryptoconcatones I and J (1-2) both having a γ-Z-butenolide moiety in its structure.
O
OH
O
OH
O
R1 R2 R3
O
H
O
O
Ph
O
Ph
O
R4
Cryptoconcatone H
proposed)
Cryptoconcatone H
(revised)
(
R = OH; R = OH; R = OAc; R = H; Cryptoconcatone A
1
2
3
4
R 1 = OH; R = OAc; R = OH; R = H; Cryptoconcatone B
2
3
4
OH R2 R1
R = OH; R = R = OAc; R = H; Cryptoconcatone C
1
2
3
4
R = OH; R = R = OH; R = H; Cryptoconcatone D
1
2
3
4
R = OH = R = R = R ; Cryptoconcatone E
1
2
3
4
O
R = OH = R = R ; R = OAc; Cryptoconcatone F
1
2
4
3
O
R = OH = R = R ; R = OAc; Cryptoconcatone G
1
3
4
2
R = OAc; R = OH; Crypconcatone I, 1
1
2
R = OH; R = OAc; Cryptoconcatone J, 2
1
2
Figure 1: Structural features of cryptoconcatones A-J.
Compounds 1 and 2 both have been found to exhibit strong inhibitory activity toward NO
(nitric oxide) production in lipopolysaccharide induced RAW 264.7 macrophages with IC50
4
values 3.4±0.5 μM and 3.2±0.2 μm respectively. Recently first asymmetric total synthesis of
cryptoconcatone H and structural reassignment was reported by Pilli and co-workers.5
6
Asymmetric allylation by Kirsche’s protocol, Pd-catalyzed THP ether formation through
7
Tsuji-Trost method and RCM (ring closing metathesis) reaction were employed in the total
synthesis of cryptoconcatone H. The total synthesis of α-pyranone containing natural
products cryptomoscatones D2, E3 and F1 (structurally related to cryptoconcatones A-G)
have also been reported in the recent past.8
2

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DOI: 10.1039/C9OB00399A
RESULTS AND DISCUSSION
The total synthesis of the naturally occurring crypconcatone I, is hitherto not reported and
hence poses a significant challenge in designing an efficient scalable synthetic route for that
purpose. Our proposed Retrosynthetic disconnection for cryptoconcatone I was presented in
Scheme 1. We thought to explore a late stage bimetallic (Pd-Cu) cascade lactonization
reaction on a properly functionalized terminal alkyne with Z-bromo-acrylic acid. This
cascade cyclization sequence seemed to be very effective for the construction of γ-Z-
butenolide core due to its atom economical nature.9a-c In addition, an exclusive formation of
Z-olefinic unsaturation (in the butenolide core) and preservation of stereochemical
information in the final product (the stereocenters in the starting alkyne remains unaltered) is
the major highlight of this reaction. Recently asymmetric total synthesis of naturally
occurring γ-Z-butenolides have been accomplished in our group by successful exploration of
such bimetallic cascade cyclization reaction.9d-e The alkyne with the stereochemically pure
triol functionality was thought to be accessed from reductive ring opening of epoxide in
1
0
regioselective fashion. The enantiopure epoxide, in turn, can be accessed through Sharpless
asymmetric epoxidation 11 of E-allylic alcohol. An E-selective Julia-Kocienski olefination
1
2
reaction
of sulfone and alkyne-aldehyde was proposed in the initial stage. E-
cinnamaldehyde was viewed as a starting precursor to access both the fragments required for
Julia-Kocienski olefination.
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DOI: 10.1039/C9OB00399A
OH OH OAc
"
Pd-Cu" cascade
OPg OH OAc
lactonization
Ph
Ph
Crypyoconcatone I (1)
O
O
Directed
epoxide
openning
OPg
OH
OPg
OH
SAE
O
Ph
Ph
JK-olefination
Ph
OPg
OAc
CHO
Ph
E-cinnamaldehyde
+
SO PT
OHC
EKR
2
Asymmetric allylation
SAE: Sharpless Asymmetric Epoxidation; JK: Julia-Kocienski; Pg = PMB
EKR: Enzymatic Kinetic Resolution
Scheme 1. Retrosynthetic disconnection of cryptoconcatone I through reductive ring
opening of epoxide and bimetallic cascade cyclization
The synthesis was initiated with the Barbier propargylation reaction 13 of E-cinnamaldehyde
with Zn-metal and propargyl bromide to furnish the racemic homopropargylic alcohol 3 in
8
6% yield. Enzymatic kinetic resolution (EKR) was next attempted on racemic 3 by using
vinyl acetate as an active acyl donor and Lipase-PS (Burkholderia cepacia) as a biocatalyst to
afford acetate 4 in 46% (ee = 98%) and alcohol 5 in 48% yield (ee = 98%). Enantiopure
alcohol 5 was converted to corresponding acetate 6 as shown in Scheme 2. The unwanted
acetate 4 was converted to compound 6 through a two-step protocol (acetate removal by
1
4
K CO and Mitsunobu inversion with AcOH). With acetate 6 in hand, oxidative cleavage of
2
3
the cinnamyl part was achieved under Johnson-Lemieux condition 15 to afford the aldehyde 7
in 65% yield (in two steps). The sulfone partner for Julia-Kocienski olefination was
synthesized from E-cinnamaldehyde. Asymmetric allylation under modified Keck condition
1
6
developed by Maruoka and co-workers16d afforded the homoallylic alcohol 8 in 85% yield
(ee = 98%). The free hydroxyl group was protected as its PMB ether by treating compound 8
with NaH and PMB-Br to furnish compound 9 in 89% yield. Regioselective oxidative
cleavage of less hindered olefinic unsaturation under stoichiometric control afforded
4

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aldehyde 10 as shown in Scheme 2. The aldehyde 10 was then immediately reduced with
DOI: 10.1039/C9OB00399A
NaBH to afford alcohol 11 in 90% yield. Mitsunobu reaction of alcohol 11 with PT-SH
4
(afforded the sulfide 12) and subsequent oxidation with (NH ) Mo O afforded sulfone 13
4 6 7 24
(72% yield in two steps). Attempted Julia-Kocienski olefination reaction of sulfone 13 with
aldehyde 7 furnished the corresponding E-olefin in the presence of KHMDS as a base only in
5% yield. All our attempts to enhance the yield of compound 14 (by changing bases and
1
additives) met with limited success.
OAc
OR
OH
a
CHO
b
Ph
+
Ph
Ph
Ph
4
3
4
6%, ee = 98%
R=H; 5; 48%, ee = 98%
R = OAc; 6; 92%
c
OAc
OAc
e
OAc
d
O
Ph
Ph
4
Ph
6
7
OPMB
OPMB
j
OPMB
OR
f
h
i
CHO
Ph
Ph
Ph
Ph
11
10
CHO
OH
SPT
R = H; 8
R = PMB; 9
g
N N
OPMB
N
OPMB
OAc
k
N
l
PT =
Ph
Ph
Ph
14
1-phenyl-1H-tetrazol-5-yl
SO PT
2
Scheme 2. Preparation of compound 14, Reagents and conditions: (a) Zn, THF-NH Cl,
4
propargyl bromide, rt, 8 h, 86%; (b) Lipase-PS, iPr O, vinyl acetate, rt, 10 h; (c) Ac O, Et N,
2
2
3
DCM, rt, 2 h, 92%; (d) (i) K CO , MeOH, rt, 2 h, 92%; (ii) DIAD, Ph P, THF, AcOH, -20
2
3
3
°
C, rt, 12 h, 78%; (e) (i) OsO , NMO, THF-H O (3:1), rt, 12 h, (ii) NaIO , rt, 1 h, 65% (2
4 2 4
steps); (f) TiCl , Ti(OiPr) , (S)-BINOL, Ag O, allyltributyltin, DCM, -15 °C, 48 h, 85%; (g)
4
4
2
NaH, PMB-Br, THF, 0 °C – rt, 5 h, 89%; (h) same as e, (i) NaBH , MeOH, rt, 2 h, 90%; (j)
4
Ph P, DIAD, PTSH, THF, -20 °C, 2 h, 80%; (k) (NH ) Mo O .4H O, H O , EtOH, rt, 16 h,
3
4 6
7
24
2
2
2
9
0%; (l) 7, KHMDS, 18-c-6, THF, -78 ºC, 2 h, 15%.
As the Julia-Kocienski olefination reaction did not afford the required compound in high
yield, we have opted for switching the protecting group. The free alcohol in compound 8 was
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now protected as its TBDPS ether by treatment with TBDPS-Cl and imidazole to furnish
DOI: 10.1039/C9OB00399A
compound 15 in 90% yield. Compound 15 was then converted to sulfone 19 by a similar
sequence of functional group interconversion as depicted earlier in Scheme 2. The sulfone 19
was next reacted with aldehyde 7 in the presence of KHMDS as a base and 18-crown-6 as an
additive to afford the E-olefin 20 exclusively in 86% yield. The acetate group in compound
2
0 was next removed by treatment with methanolic K CO to afford allylic alcohol 21. With
2 3
alcohol 21 in our hand, SAE reaction with cumene hydroperoxide furnished the desired
1
7
epoxide 22 in 78% yield. Hydroxy group directed reductive ring opening of epoxide under
Gansauer condition was next attempted.10c The epoxide was subjected to PhSiH /TBAF (10
3
mol%) treatment, but the desired ring opening product was not isolated. We argued that after
the initial “Si-O” bond formation transfer of the hydride is favored in 5-exo-tet fashion to
yield the 1,3-diol. Whereas competing 6-endo-tet pathway was not favored (according to
1
8
Baldwin rule ) and formation of 1,2-diol was not observed as pointed out by Gansauer and
co-workers. But the formation of 1,3-diol (through 5-exo-tet fashion) was also hindered due
to the presence of bulky TBDPS group hence we did not observe the desired 1,3-diol
(Scheme 3). Starting material was mostly remain unaltered with desilylation of TBDPS group
was also observed (by catalytic TBAF). We reasoned that hydride transfer from a
pentacoordinated Si-species to the epoxide might be hindered by the presence of the bulky R1
group (-OTBDPS and cinnamyl group). Hydroxy group directed reductive ring opening of
epoxide in the presence of hydride donor reagents (LAH, Red-Al)19, 10b were also tried, but
unfortunately, the reaction was met with limited success.
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DOI: 10.1039/C9OB00399A
OR
OTBDPS
OTBDPS
OTBDPS
b
c
d
Ph
Ph
Ph
O
Ph
OH
16
17
R
R = H; 8
R = TBDPS, 15
a
R = SPT; 18
e
R = SO PT; 19
2
f
OPg
OH
OPg OH OH
i or j or k
OTBDPS OR
O
h
X
Ph
Ph
Ph
22
Pg = TBDPS
R = Ac; 20
R = H; 21
g
PhSiH , F-
O
3
OH
R2
H
R2
R1
6
-endo-tet
Si
O
R1
1
H
(
disfavored)
OH
Ph
F
,2-diol (not observed)
OH
O
R1
R2
O
R2
OH OH
R2
PhSiH , F-
3
O
R1
X
H
()
R1
Si
5-exo-tet
H
(favored)
F
1
,3-diol (expected product)
Ph
Steric shielding by
bulky TBDPS and
cinnamyl group.
Scheme 3. Preparation of compound 22 and unsuccessful attempt of reductive ring
opening of the epoxide, Reagents and conditions: (a) Imidazole, TBDPS-Cl, rt, 2 h, 90%;
(
b) OsO , NMO, THF-H O (3:1), rt, NaIO , 80% (two steps); (c) NaBH , MeOH, rt, 2 h,
4 2 4 4
9
0%; (d) Ph P, DIAD, PTSH, THF, -20 °C, 2 h, 82%; (e) (NH ) Mo O .4H O, H O , EtOH,
3 4 6 7 24 2 2 2
rt, 16 h, 73%; (f) KHMDS, 18-c-6, aldehyde 7, THF, -78 °C, 2 h, 86%; (g) K CO , MeOH, rt,
2
3
2
h, 95%; (h) (+)-DET, Ti(OiPr) , cumene hydroperhoxide, -35 °C, 36 h, 78%; (i) PhSiH ,
4 3
TBAF, 2 M, NaOH, rt; (j) LiAlH , ether, 0 °C, 6 h; (k) Red-Al, THF, -25 °C, 2 h.
4
At this stage, we decided to opt for sterically less demanding PMB protecting group for the
reductive ring opening of epoxide to access the 1,3-anti-diol. But as Julia-Kocienski
olefination to access the E-olefinic unsaturation remains futile we tend to apply a more direct
2
0
approach through CM (cross-metathesis) reaction. Then asymmetric propargylation reaction
was also envisioned to access the homopropargyl alcohol moiety required for the late stage
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cascade cyclization sequence. The modified retrosynthetic disconnection was outlined in
DOI: 10.1039/C9OB00399A
Scheme 4.
OH OH OAc
Bimetallic cascade
lactonization
OP1 OP2 OH
Br
+
Ph
Ph
CO H
2
Cryptoconcatone I
O
O
Asymmetric
propargylation
OP1
OP1 OP2
directed epoxide opening
O
CHO
Ph
OH
Ph
OP1
Ph
OP1
SAE
OP1
CM
CHO
+
Ph
OH
Ph
CHO
P = PMB; P = TBS; CM = Cross Metathesis
Crotonaldehyde
1
2
SAE: Sharpless Asymmetric Epoxidation
Scheme 4. Revised retrosynthetic scheme of cryptoconcatone I
Initially, compound 9 was subjected to CM reaction with crotonaldehyde in the presence of
HG-II catalyst (3 mol %) to furnish the compound 23 in 78% yield (exclusively E isomer was
obtained). Reduction of the aldehyde functionality with DIBAL-H afforded the E-allylic
alcohol 24 in 85% yield. Sharpless asymmetric epoxidation of 24 by following a similar
condition as depicted earlier (Scheme 3) the enantiopure epoxide 25 was obtained in 82%
yield. Reductive ring opening of the epoxide now went smoothly and furnished the desired
1
,3-diol 26 as expected in 92% yield. With the diol in our hand, silylation with TBS-Cl and
imidazole afforded compound 27 in 88% yield. Selective desilylation of primary –TBS ether
o
21
with CSA/MeOH at -20 C afforded alcohol 28 in 76% yield. Oxidation of 28 under Swern
condition 22 afforded corresponding aldehyde 29. Asymmetric propargylation was next
attempted on aldehyde 29 by taking chiral amino alcohol (30) as a source of a
stereocontrolling factor.23 Metallic Indium mediated Barbier propargylation proceeded
smoothly and furnished the desired compound in 31 and undesired compound 32 in 72%
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yield with good diastereoselection (4:1). The stereochemical relationship between the diol
DOI: 10.1039/C9OB00399A
2
4
functionality was confirmed by Rychnovsky method. Desilylation of compound 31 and 32
with TBAF afforded corresponding diols, which was next reacted with 2,2-DMP to afford the
acetonides 33 and 34. 13C-NMR analysis of the corresponding acetonides 33 and 34
confirmed the 1,3-anti and 1,3-syn relationship between the two hydroxyl groups (Scheme 5).
OPMB
OP1
OPMB
OPMB
b
c
O
a
CHO
Ph
OH
OH
Ph
Ph
Ph
OH
25
12
23
24
d
f
e
g
OP1 OTBS
OP1 OTBS
OP1 OH
Ph
OH
Ph
OTBS
Ph
28
27
26
OP1 OTBS
CHO
OP1 OP2 OH
h
OP1 OP2 OH
+
Ph
Ph
Ph
32
29
31
i
i

: 19.9 ppm

: 24.8 ppm
: 30.1 ppm
P = PMB; P = TBS
: 24.9 ppm
1
2

: 98.9

: 100.6 ppm
ppm
OP1
O
O
OP1
O
O
Ph
Ph
34
33
CH3
H C
3
N
N
NH2
H C
3
CH3
Ph
H C
3
CH3
Ph
Cl
OH
30
Ru
Cl
H C
O
3
CH3
HG (II)
Scheme 5. Preparation of enantiopure alkyne 31, Reagents and conditions: (a)
Crotonaldehyde, HG (II), DCM, reflux, 3 h, 78%; (b) DIBAL-H, DCM, -40 °C, 2 h, 85%; (c)
(
+)-DET, Ti(OiPr) , cumene hydroperoxide, -35 °C, 36 h, 82%; (d) PhSiH , TBAF, THF,
4
3
2
(M) NaOH, rt, 2 h, 92%; (e) imidazole, TBS-Cl, DCM, rt, 8 h, 88%; (f) CSA, MeOH-DCM,
-
20 °C, 2 h, 76%; (g) (COCl) , DMSO, Et N, -78 °C, (h) propargyl bromide, In, pyridine, 30,
2 3
THF, -20 °C, 8 h, 72%; (i) (i) TBAF, THF, rt, (ii) 2,2-DMP, PPTS, DCM, rt.
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To complete the total synthesis of the target molecule, next acetylation of compound 31 with
DOI: 10.1039/C9OB00399A
Ac O and Et N in the presence of catalytic DMAP furnished acetate 35 in 90% yield. Next
2
3
compound 35 was subjected to the “Pd-Cu” cascade cyclization to construct the γ-Z-
butenolide core. Treatment of compound 35 with Z-3-Bromo-acrylic acid (36) in the presence
of Pd(Ph P) Cl and CuI afforded the desired γ-Z-butenolide core in 78% yield. Removal of
3
2
2
TBS group was achieved by treating compound 37 with HF-pyridine to afford compound 38
in 92% yield. Attempted removal of PMB ether functionality under an oxidative condition
8
b
with DDQ is problematic in our hand as well as reported by others. Always deprotection
followed by allylic oxidation afforded the unsaturated ketone 39 in good yield. Substrate
2
5
directed reduction under Evans-Saksena condition with Me N(OAc) BH
afforded the
4
3
naturally occurring cryptoconcatone I (1) in 90% yield (Scheme 6). The Z-geometry in the γ-
butenolide core in compound 1 was confirmed by 2D-NOESY NMR analysis. The analytical
data of synthesized cryptoconcatone I (1) and naturally occurring compound are in good
agreement (see the SI).
OP1 OP2 OAc
OP1 OP2 OH
36, Pd(PPh ) Cl ,
Ac O, Et N
3 2
2
2
3
CuI, Et N, ACN
3
Ph
Ph
DCM, rt, 3 h, 90%
35
31
rt, 5 h, 78%
OP1 OP2 OAc
OP1 OH OAc
HF-Py, Py, THF
rt, 8 h, 92%
Ph
Ph
38
37
O
O
O
2D-NOESY
O
DDQ, DCM: phosphate
buffer (19:1)
O
OH OAc
OH OH OAc H
H
Me N(OAc) BH
4
3
Ph
Ph
rt, 0.5 h, 86%
39
AcOH, ACN, 40 °C
h, 90%
O
1
8
O
O
O
Br
CO H P = PMB
25
2
1
Natural product: []D = -5.2 (c = 0.1, MeOH)
P = TBS
2
25
Reported value: []D = -5.0 (c = 0.1, MeOH)
36
Scheme 6. Completion of the synthesis of cryptoconcatone I
CONCLUSION
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In conclusion, asymmetric total synthesis of naturally occurring γ-Z-butenolide
DOI: 10.1039/C9OB00399A
cryptoconcatone I was synthesized for the first time with 9.1% overall yield in 15 steps (from
E-cinnamaldehyde). Hydroxy group directed reductive ring opening of unsymmetrical
epoxide was one of the key reactions employed to access 1,3-anti-diol functionality.
Asymmetric Keck allylation and Barbier type propargylation were also explored to create two
hydroxyl stereocenters in the target molecule. Finally, a late-stage bimetallic cascade
lactonization was applied to create the core γ-Z-butenolide framework in an efficient and
atom economical way. Further exploration of such synthetic strategies en route to structurally
related natural products are currently under investigation.
EXPERIMENTAL SECTION
General procedures: All oxygen and/or moisture-sensitive reactions were carried out under
N atmosphere in glassware that had been flame-dried under vacuum (ca. 0.5 Torr) and
2
purged with N prior to use. Unless otherwise stated, materials were obtained from
2
commercial suppliers and used without further purification. THF, diethyl ether were distilled
from sodium benzophenone ketyl. Dichloromethane (DCM), hexane were distilled from
calcium hydride. Reactions were stirred magnetically using Teflon-coated magnetic stirring
bars. Teflon-coated magnetic stirring bars and syringe needles were dried in an oven at 120
°
C for at least 12 h prior to use then cooled in a desiccator cabinet over Drierite. Reactions
were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates
with UV light, ethanolic anisaldehyde, and phosphomolybdic acid/heat as developing agents.
Silica gel 100-200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materials unless otherwise stated.
°
NMR spectra were recorded on 600, 400 & 200 MHz spectrometers at 25 C in CDCl using
3
TMS as the internal standard. Chemical shifts are shown in δ. 13C NMR spectra were
recorded with a complete proton decoupling environment. Coupling constants (J) are reported
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in hertz (Hz) and the resonance multiplicity abbreviations used are s, singlet; d, doublet; dd,
DOI: 10.1039/C9OB00399A
doublet of doublet; t, triplet; q, quartet; m, multiplet; comp, overlapping multiplets of
magnetically non-equivalent protons. Mass spectrometric analysis was performed in the CRF,
IIT-Kharagpur (TOF analyzer). Chiral HPLC analysis was performed with Daicel Chiral Pak
OD-H (25cm × 0.46 cm ϕ) as a stationary phase.
(E)-1-phenylhex-1-en-5-yn-3-ol (3):
To a suspension of activated Zn-dust (6.5 g, 100 mmol) in THF (100 mL) (E)-
cinnamaldehyde (6.6 g, 50 mmol) and propargyl bromide (14.87 g, 125 mmol) was added
sequentially in THF at 0 °C and stirred for 10 minutes. A saturated solution of ammonium
chloride (15 mL) was then added drop wise to the reaction mixture at the same temperature
and stirred at room temperature for 8 h. After the completion of the reaction, the solid part
was filtered through a celite pad and washed with ethyl acetate. The combined organic layer
was dried over anhydrous Na SO and evaporated under reduced pressure. The residue was
2
4
then purified through flash column chromatography (EtOAc:Hexane = 1:10) to afford
compound 3 (7.4 g, 43 mmol) in 86% yield as a yellow oil. R = 0.2 (EtOAc/hexane = 1:10).
f
(
R,E)-1-phenylhex-1-en-5-yn-3-yl acetate (4) and (S,E)-1-phenylhex-1-en-5-yn-3-ol (5):
To a suspension of finely crushed flame dried molecular sieves (4 Å, 4 g) and compound 3
7.4 g, 43 mmol) in dry diisopropyl ether (160 mL), vinyl acetate (3.2 mL, 34.7 mmol) was
(
added at room temperature. To the reaction mixture, Amano lipase-PS (3.7 g, Burkholderia
cepacia) was added, and the reaction was stirred at room temperature for 10 h. After 50% of
conversion (as indicated by TLC analysis) the reaction mixture was quickly filtered through a
celite pad and washed with diethyl ether. The combined organic part was evaporated under
reduced pressure. The two products were purified by flash column chromatography (EtOAc:
12

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Hexane = 1:10) to furnish compound 4 (4.23 g, 19.78 mmol) in 46% yield and compound 5
DOI: 10.1039/C9OB00399A
(3.55 g, 20.64 mmol) in 48% yield.
2
5
1
Compound 4: R = 0.4 (EtOAc/hexane = 1:10); [α] = +30.2 (c 1.0, CHCl ). H NMR (400
f
D
3
MHz, CDCl ) δ 7.43 – 7.39 (m, 2H), 7.36 – 7.31 (m, 2H), 7.30 – 7.25 (m, 1H), 6.70 (d, J =
3
1
2
1
6.0 Hz, 1H), 6.25 (dd, J = 16.0, 7.2 Hz, 1H), 5.59 – 5.49 (m, 1H), 2.65 (dd, J = 6.1, 2.7 Hz,
1
3
H), 2.12 (s, 3H), 2.05 (t, J = 2.7 Hz, 1H). C NMR (125 MHz, CDCl ) δ 170.1, 136.0,
3
33.5, 128.6, 128.2, 126.7, 125.7, 79.3, 72.2, 70.8, 24.9, 21.2.
2
5
1
Compound 5: R = 0.2 (EtOAc/hexane = 1:10); [α] = ‒18.6 (c 1.0, CHCl ); H NMR (400
f
D
3
MHz, CDCl ) δ 7.42 – 7.38 (m, 2H), 7.35 – 7.30 (m, 2H), 7.28 – 7.25 (m, 1H), 6.67 (dd, J =
3
1
2
1
1
6.0, 1.2 Hz, 1H), 6.29 (dd, J = 16.0, 6.3 Hz, 1H), 4.55 – 4.40 (m, 1H), 2.59 – 2.52 (m, 2H),
1
3
.10 (t, J = 2.6 Hz, 1H). ). C NMR (100 MHz, CDCl ) δ 136.3, 131.3, 129.9, 128.6, 127.9,
3
+
26.6, 80.2, 71.1, 70.7, 27.7. HRMS (ESI) m/z: for C H ONa[M + Na] , calculated:
1
2
12
95.0786; found: 195.0781.
S,E)-1-phenylhex-1-en-5-yn-3-yl acetate (6): To a solution of compound 5 (3.44 g, 20
(
mmol) in dry DCM (70 mL), triethyl amine (4.2 mL, 30.2 mmol) was added at 0 °C and the
reaction mixture was stirred at the same temperature for 10 min. After that time acetic
anhydride was added to the reaction solution at 0 °C and then it was allowed to warm at room
temperature. After that the reaction solution was stirred for 2 h, and then it was quenched
with water and extracted with DCM (100 mL). The organic layer was washed with brine and
dried over anhydrous Na SO . The solvent was evaporated under reduced pressure and the
2
4
product was purified by flash column chromatography (EtOAc/hexane = 1:10) to furnish the
2
5
compound 6 (3.94 g, 18.4 mmol) in 92% yield. R = 0.4 (EtOAc/hexane = 1:10); [α]
=
f
D
1
‒
2
5
30.4 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ 7.43 – 7.39 (m, 2H), 7.36 – 7.31 (m,
3
3
H), 7.30 – 7.25 (m, 1H), 6.70 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 7.2 Hz, 1H), 5.59 –
1
3
.49 (m, 1H), 2.65 (dd, J = 6.1, 2.7 Hz, 2H), 2.12 (s, 3H), 2.05 (t, J = 2.7 Hz, 1H). C NMR
13

Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00399A
(
125 MHz, CDCl ) δ 170.1, 136.0, 133.6, 128.6, 128.2, 126.7, 125.7, 79.3, 72.2, 70.8, 24.9,
3
+
2
1.2. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated: 237.0892; found: 237.0897.
14 14 2
(R,E)-1-phenylhex-1-en-5-yn-3-ol (ent-5): To a stirred solution of the compound 4 (4 g,
1
8.68 mmol) in methanol (64 mL) at 0 ºC, K CO (3.0 g, 22.42 mmol) was added, and the
2
3
reaction mixture was allowed to warm at room temperature. After that, the reaction solution
was stirred for 2 h, and it was then concentrated under vacuo. The mixture was then extracted
with diethyl ether (80 mL). The organic layer was washed with brine, dried over anhydrous
Na SO and evaporated under reduced pressure. The product was purified by flash column
2
4
chromatography (EtOAc:Hexane = 1:7) to furnish the compound ent-5 (2.45 g, 14.4 mmol)
in 92% yield as a colorless liquid. R = 0.2 (EtOAc/hexane = 1:10).
f
(
S,E)-1-phenylhex-1-en-5-yn-3-yl acetate (6): Ph P (5.55 g, 21.17 mmol) and DIAD (3.3
3
mL, 16.93 mmol) were added to a stirred solution of compound ent-5 (2.4 g, 14.11 mmol) in
dry THF (56 mL) at -20 °C. The reaction solution was then stirred for 10 min and AcOH was
added to the reaction mixture. The reaction solution was stirred for another 12 h at the same
temperature. After completion of the reaction, the mixture was then extracted with diethyl
ether (50 mL). The organic part was washed with brine, dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The crude product was then purified by flash column
chromatography to provide compound 6 (2.3 g, 11 mmol) in 78% yield as a colorless liquid.
The optical rotation and the NMR spectra of the resulting product matched with the
previously synthesized product.
(S)-1-oxopent-4-yn-2-yl acetate (7): To a solution of compound 6 (1 g, 4.67 mmol) in THF
(
15 mL) and H O (5 mL), NMO (821 mg, 7 mmol) and OsO (0.05 M in toluene, 9.3 mL,
2
4
0
.46 mmol) were added sequentially at room temperature and stirred at the same temperature
14

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for 12 h. After complete disappearance of the starting material, the reaction mixture was
DOI: 10.1039/C9OB00399A
extracted with ethyl acetate. The combined organic layer was washed with brine and dried
over Na SO . The solvent was completely evaporated under reduced pressure, and the residue
2
4
was dissolved in THF. Water was added to the reaction mixture and stirred at room
temperature for 2 min. Then to the reaction mixture NaIO (1.56 g, 7 mmol) was added and
4
the reaction solution was stirred for 1 h at the same temperature. After completion of the
reaction, the reaction mixture was extracted with diethyl ether. The combined organic layer
was washed with brine and dried over anhydrous Na SO and evaporated under reduced
2
4
pressure. The residue was then purified through flash column chromatography
(EtOAc/hexane = 1:7) to afford compound 7 (425 mg, 3.03 mmol) in 65% (two steps) as a
1
colorless oil. R = 0.4 (EtOAc/hexane = 1:5). H NMR (600 MHz, CDCl ) δ 9.61 (s, 1H),
f
3
1
3
5
.14 (t, J = 6.2 Hz, 1H), 2.79 – 2.69 (m, 2H), 2.22 (s, 3H), 2.08 (t, J = 2.7 Hz, 1H). C NMR
(
150 MHz, CDCl ) δ 196.8, 170.2, 77.5, 75.4, 71.5, 20.5, 19.4. HRMS (ESI) m/z: for
3
+
C H O [M + H] , calculated: 141.0546; found: 141.0547.
7
9
3
(
S,E)-1-phenylhexa-1,5-dien-3-ol (8): Ti(OiPr) (1.36 mL, 4.5 mmol) was added to a stirred
4
solution of TiCl (0.16 mL, 1.5 mmol) in CH Cl (50 mL) at 0 °C under a nitrogen
4
2
2
atmosphere. After 1 h, Ag O (0.69 g, 3 mmol) was added to the solution at room temperature,
2
and the reaction mixture was stirred in the dark for 5 h. (S)-BINOL (1.7 g, 6 mmol) was then
added at room temperature, and the reaction mixture was stirred for a further 2 h. The in-situ
generated solution of catalyst was cooled to −15 °C and treated sequentially with E-
cinnamaldehyde (3.9 g, 30 mmol) and allyltributyltin (10.2 mL, 33 mmol), and the reaction
mixture was stirred for 48 h at the same temperature. The reaction mixture was then
quenched with saturated NaHCO (30 mL) solution and extracted with Et O (3 × 40 mL).
3
2
The combined organic layers were dried over anhydrous Na SO , concentrated under reduced
2
4
pressure, and purified by flash column chromatography (EtOAc/hexane = 1:15) to furnish
15

Organic & Biomolecular Chemistry
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homoallyl alcohol 8 (4.38 g, 25.5 mmol) in 85% yield (>98% ee) as a colorless liquid: R =
DOI: 10.1039/Cf9OB00399A
.4 (EtOAc/hexane = 1:10); [α]D25 = ‒25.3 (c 1.0, CHCl ). H NMR (500 MHz, CDCl ) δ
1
0
7
1
3
3
.42 – 7.40 (m, 2H), 7.39 – 7.33 (m, 2H), 7.30 – 7.25 (m, 1H), 6.64 (dd, J = 15.9, 1.3 Hz,
H), 6.27 (dd, J = 15.9, 6.3 Hz, 1H), 5.35 – 5.85 (m, 1H), 5.24 – 5.18 (m, 2H), 4.41 – 4.37
1
3
(
m, 1H), 2.51 – 2.38 (m, 2H). C NMR (125 MHz, CDCl ) δ 136.7, 134.0, 131.6, 130.4,
3
1
28.6, 127.7, 126.5, 118.5, 71.7, 42.0.
(S,E)-1-methoxy-4-((1-phenylhexa-1,5-dien-3-yloxy)methyl)benzene (9): To a suspension
of NaH (60%, 800 mg, 20 mmol) in dry THF (70 mL) compound 8 (3.4 g, 20 mmol) in dry
THF (10 mL) was added drop wise at 0 °C. After that the reaction mixture was stirred for 1 h
at room temperature, it was then cooled to 0 °C and freshly prepared PMB-Br in dry THF (10
mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature
for 5 h and the reaction solution was quenched with saturated NH Cl solution (10 mL). The
4
organic layer was separated and the aqueous part was washed with ethyl acetate (30 × 2 mL).
Combined organic layer was washed with brine (20 mL) and dried over anhydrous Na SO .
2
4
The solvent was then evaporated under reduced pressure and the crude residue was purified
by flash column chromatography (EtOAc/hexane = 1:30) to furnish compound 9 (5.2 g, 17.8
2
5
mmol) in 89% yield as colorless oil. R = 0.4 (EtOAc/hexane = 1:20); [α] = ‒34.6 (c 1.0,
f
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ 7.43 (d, J = 8.0 Hz, 2H), 7.38 – 7.33 (m, 2H), 7.32 –
3
3
7
.26 (m, 3H), 6.92 – 6.88 (m, 2H), 6.57 (d, J = 15.8 Hz, 1H), 6.19 – 6.13 (m, 1H), 5.93 – 5.82
(m, 1H), 5.15 – 5.07 (m, 2H), 4.60 (dd, J = 11.5, 1.4 Hz, 1H), 4.39 (dd, J = 11.5, 1.4 Hz, 1H),
1
3
3
.99 (q, J = 7.0 Hz, 1H), 3.82 (d, J = 1.5 Hz, 3H), 2.56 – 2.37 (m, 2H). C NMR (100 MHz,
CDCl ) δ 159.1, 136.6, 134.6, 132.5, 130.7, 130.1, 129.3, 128.6, 127.7, 126.5, 117.0, 113.8,
3
+
7
9.3, 69.8, 55.3, 40.4. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated: 317.1518;
2
0
22
2
found: 317.1517.
16

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DOI: 10.1039/C9OB00399A
(
S,E)-3-(4-methoxybenzyloxy)-5-phenylpent-4-enal (10): To a solution of compound 9 (4.4
g, 15 mmol) in THF (45 mL) and H O (15 mL), NMO (2.63 g, 22.5 mmol) and OsO (0.05 M
2
4
in toluene, 9 mL, 0.45 mmol) were added sequentially at 0 °C and stirred at the same
temperature for 24 h. After complete disappearance of the staring material, the reaction
mixture was extracted with ethyl acetate. The solvent was completely evaporated under
reduced pressure and the residue was dissolved in THF (40 mL) and H O (13 mL). Then to
2
the reaction mixture NaIO (5 g, 22.5 mmol) was added and it was stirred for 1 h at room
4
temperature. After completion of the reaction, the reaction solution was extracted with diethyl
ether. The combined organic layer was washed with brine, dried over anhydrous Na SO and
2
4
evaporated under reduced pressure. The residue was purified through flash column
chromatography (EtOAc/hexane = 1:10) to afford compound 10 (2.9 g, 9.75 mmol) in 65%
2
5
1
yield (two steps). R = 0.5 (EtOAc/hexane = 1:7); [α]
= ‒21.8 (c 0.5, CHCl ). H NMR
3
f
D
(
600 MHz, CDCl ) δ 9.80 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.5 Hz,
3
2
H), 7.31 (t, J = 7.4 Hz, 1H), 7.29 – 7.26 (m, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 15.9
Hz, 1H), 6.18 (dd, J = 15.9, 7.9 Hz, 1H), 4.62 (d, J = 11.4 Hz, 1H), 4.52 (td, J = 8.1, 4.6 Hz,
H), 4.41 (d, J = 11.4 Hz, 1H), 3.83 (s, 3H), 2.85 (ddd, J = 16.3, 8.3, 2.5 Hz, 1H), 2.65 (ddd,
1
1
3
J = 16.3, 4.8, 1.7 Hz, 1H). C NMR (150 MHz, CDCl ) δ 200.7, 159.3, 136.0, 133.3, 130.0,
3
1
29.5, 128.7, 128.2, 128.1, 126.6, 113.9, 74.7, 70.1, 55.3, 49.5. HRMS (ESI) m/z: for
+
C H O Na[M + Na] , calculated: 319.1305; found: 319.1312.
1
9
20
3
(S,E)-3-(4-methoxybenzyloxy)-5-phenylpent-4-en-1-ol (11): To a solution of compound 10
(
2.5 g, 8.4 mmol) in MeOH (33.6 mL), NaBH (319 mg, 8.4 mmol) was added portion wise
4
over 5 min at 0 °C, after complete addition of the reagent the reaction mixture was allowed to
warm at room temperature and stirred for 2 h. After completion of the reaction, the reaction
solution was quenched with addition of saturated solution of ammonium chloride. Methanol
was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The
17

Organic & Biomolecular Chemistry
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organic layer was washed with brine and dried over anhydrous Na SO and evaporated under
DOI: 10.1039/C9OB00399A
2
4
reduced pressure. The crude product was then purified by flash column chromatography
(EtOAc/hexane=1:5) to provide compound 11 (2.25 g, 7.56 mmol) in 90% yield as colorless
2
5
1
oil. R = 0.3 (EtOAc/hexane = 1:5); [α]
= ‒28.2 (c 0.6, CHCl ). H NMR (400 MHz,
3
f
D
CDCl ) δ 7.43 (d, J = 7.4 Hz, 2H), 7.40 – 7.31 (m, 2H), 7.32 – 7.24 (m, 3H), 6.92 – 6.88 (m,
3
2
1
H), 6.59 (d, J = 15.8 Hz, 1H), 6.22 – 6.14 (m, 1H), 4.66 – 4.57 (m, 1H), 4.36 (dd, J = 11.2,
.8 Hz, 1H), 4.19 (dt, J = 13.1, 6.1 Hz, 1H), 3.87 – 3.74 (m, 5H), 2.30 (s, 1H), 2.03 – 1.83
1
3
(
m, 2H). C NMR (100 MHz, CDCl ) δ 159.2, 136.3, 132.6, 130.2, 129.5, 129.4, 128.7,
3
1
27.9, 126.5, 113.9, 79.2, 70.0, 60.7, 55.3, 38.1. HRMS (ESI) m/z: for C H O Na[M +
19 22 3
+
Na] , calculated: 321.1467; found: 321.1461.
(S,E)-5-(3-(4-methoxybenzyloxy)-5-phenylpent-4-enylthio)-1-phenyl-1H-tetrazole (12):
To a solution of compound 11 (2 g, 6.7 mmol) in dry THF (20 mL), TPP (3.5 g, 13.4 mmol),
DIAD (1.97 mL, 10 mmol), PTSH (2.38 g, 13.4 mmol) were added sequentially at -20 °C and
the reaction solution was stirred at the same temperature for 2 h. After complete consumption
of the starting material water was added to the reaction mixture and stirred at room
temperature for 10 min. The mixture was then extracted with diethyl ether. Combined organic
layer was washed with brine and dried over anhydrous Na SO and evaporated under reduced
2
4
pressure. The product was then purified by flash column chromatography (EtOAc/hexane =
1
:15) to furnish compound 12 (2.45 g, 5.36 mmol) in 80% yield as colorless oil. R = 0.4
f
EtOAc/hexane = 1:7); [α]D25 = ‒18.7 (c 0.2, CHCl ). H NMR (400 MHz, CDCl ) δ 7.55 (s,
1
(
3
3
5
2
1
–
H), 7.40 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.30 – 7.24 (m, 3H), 6.87 – 6.84 (m,
H), 6.60 (d, J = 15.9 Hz, 1H), 6.19 – 6.06 (m, 1H), 4.58 (d, J = 11.2 Hz, 1H), 4.33 (d, J =
1.3 Hz, 1H), 4.09 (q, J = 7.4 Hz, 1H), 3.79 (d, J = 2.0 Hz, 3H), 3.50 (t, J = 7.3 Hz, 2H), 2.20
1
3
2.14 (m, 2H). C NMR (100 MHz, CDCl ) δ 159.2, 151.1, 143.2, 136.2, 133.1, 130.3,
3
18

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1
30.0, 129.7, 129.5, 129.1, 128.6, 128.0, 126.5, 123.8, 113.8, 77.7, 70.0, 55.3, 35.2, 29.6.
DOI: 10.1039/C9OB00399A
+
HRMS (ESI) m/z: for C H N O SNa[M + Na] , calculated: 481.1674; found: 481.1670.
2
6
26
4
2
(
S,E)-5-(3-(4-methoxybenzyloxy)-5-phenylpent-4-enylsulfonyl)-1-phenyl-1H-tetrazole
13): To a solution of compound 12 (2.0 g, 4.36 mmol) in ethanol, H O (50%, 3.2 mL) was
(
2
2
added at room temperature. Ammonium molybdate (807 mg, 0.65 mmol) was then added to
the reaction mixture. The reaction solution was then stirred at the same temperature for 16 h.
After completion of the reaction, solvent was evaporated under reduced pressure and the
residue was extracted with ethyl acetate. The organic layer was washed with brine and dried
over anhydrous Na SO and evaporated under reduced pressure. The product was then
2
4
purified by flash column chromatography (EtOAc/hexane = 1:10) to provide compound 13
2
5
(
1.92 g, 3.92 mmol) in 90% yield as colorless oil. R = 0.4 (EtOAc/hexane = 1:7); [α]
=
f
D
1
‒
7
7
7
25.2 (c 0.8, CHCl ). H NMR (400 MHz, CDCl ) δ 7.66 (d, J = 7.6 Hz, 2H), 7.60 (td, J =
3
3
.3, 3.3 Hz, 3H), 7.41 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H),
.24 (d, J = 1.8 Hz, 1H), 6.94 – 6.85 (m, 2H), 6.63 (d, J = 16.2 Hz, 1H), 6.09 (dd, J = 16.1,
.5 Hz, 1H), 4.58 (dd, J = 11.5, 1.9 Hz, 1H), 4.34 (d, J = 11.5 Hz, 1H), 4.13 (q, J = 6.7, 5.9
Hz, 1H), 3.90 (td, J = 17.7, 16.6, 8.8 Hz, 1H), 3.81 (d, J = 2.0 Hz, 3H), 2.28 (q, J = 7.3 Hz,
1
3
2
1
H). C NMR (100 MHz, CDCl ) δ 159.3, 153.4, 135.9, 133.8, 133.0, 131.5, 129.9, 129.7,
3
29.5, 128.1, 128.2, 128.0, 126.6, 125.1, 113.9, 70.1, 60.4, 55.3, 52.7, 28.4. HRMS (ESI)
+
m/z: for C H N O SNa[M + Na] , calculated: 513.1573; found: 513.1570.
2
6
26
4
4
(4S,5E,8S,9E)-8-(4-methoxybenzyloxy)-10-phenyldeca-5,9-dien-1-yn-4-yl acetate (14):
Compound 13 (490 mg, 1 mmol) and 18-crown-6 (317 mg, 1.2 mmol) were dissolved in dry
THF (3.5 mL) and the mixture was cooled to -78 ºC. KHMDS (0.5 M, 2.4 mL, 1.2 mmol)
and the aldehyde 7 (117 mg, 0.9 mmol) were then added sequentially to the reaction solution
and the pale yellow colored reaction mixture was then allowed to warm at room temperature
19

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and stirred for another 2 h at room temperature. After complete disappearance of the
DOI: 10.1039/C9OB00399A
aldehyde, the reaction was quenched with saturated ammonium chloride solution. The
mixture was extracted with diethyl ether (20 × 2 mL). Combined organic layer was washed
with brine, dried over anhydrous Na SO and evaporated under reduced pressure. The residue
2
4
was then purified through flash column chromatography (EtOAc/hexane = 1:15) to furnish
the compound 14 (53 mg, 0.13 mmol) in 15% (with respect to the aldehyde) yield as colorless
2
5
1
oil. R = 0.5 (EtOAc/hexane = 1:10); [α] = ‒ 34.98 (c 1.0, CHCl ). H NMR (400 MHz,
f
D
3
CDCl ) δ 7.41 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.7 Hz, 3H), 6.88
3
(
dd, J = 8.3, 2.0 Hz, 2H), 6.61 – 6.47 (m, 1H), 6.16 – 6.08 (m, 1H), 5.84 (dt, J = 14.7, 7.1 Hz,
H), 5.59 (dd, J = 15.5, 7.0 Hz, 1H), 5.34 (t, J = 6.9 Hz, 1H), 4.57 (d, J = 11.4 Hz, 1H), 4.35
dd, J = 11.5, 2.0 Hz, 1H), 3.97 (p, J = 7.6, 7.0 Hz, 1H), 3.81 (d, J = 2.1 Hz, 2H), 2.54 – 2.46
1
(
(
1
3
m, 3H), 2.38 (dt, J = 13.9, 6.7 Hz, 1H), 2.07 – 1.94 (m, 4H). C NMR (100 MHz, CDCl ) δ
3
1
70.0, 159.1, 136.5, 132.6, 131.1, 130.6, 129.8, 129.3, 129.1, 128.6, 127.8, 126.5, 113.8,
+
7
9.5, 72.1, 70.5, 69.9, 55.3, 38.8, 24.7, 21.1. HRMS (ESI) m/z: for C H O Na[M + Na] ,
2
6
28
4
calculated: 427.1886; found: 427.1882.
(S,E)-tert-butyldiphenyl(1-phenylhexa-1,5-dien-3-yloxy)silane (15): To a solution of
compound 8 (7.83g, 45 mmol) in dry DCM (135 mL) at 0 °C, imidazole (3.98 g, 58.5 mmol)
was added and the mixture was stirred for 10 min at the same temperature. After that time
TBDPS-Cl (14.14 mL, 54 mmol) was added to the reaction mixture and the solution was
allowed to warm at room temperature and stirred for further 2 h. After completion of the
reaction it was quenched with H O (10 mL) and extracted with DCM. The organic part was
2
washed with brine and dried over anhydrous Na SO . The solvent was evaporated under
2
4
reduced pressure and the residue was purified through flash column chromatography
(
EtOAc/hexane = 1:50) to afford compound 15 (16.68 g, 40.5 mmol) in 90% yield. R = 0.6
f
EtOAc/hexane = 1:20); [α]D25 = ‒38.6 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ 7.73 –
1
(
3
3
20

Page 21 of 41
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7
1
2
1
.66 (m, 4H), 7.46 – 7.18 (m, 11H), 6.24 (d, J = 15.9 Hz, 1H), 6.14 (dd, J = 15.9, 6.5 Hz,
DOI: 10.1039/C9OB00399A
H), 5.82 – 5.71 (m, 1H), 5.01 – 4.93 (m, 2H), 4.36 (q, J = 6. Hz, 1H), 2.33 (t, J = 6.3 Hz,
1
3
H), 1.09 (s, 9H). C NMR (100 MHz, CDCl ) δ 137.1, 136.0, 135.9, 134.3, 134.3, 134.1,
3
32.0, 130.0, 129.6, 129.5, 128.4, 127.5, 127.4, 127.3, 126.4, 117.2, 74.1, 42.7, 27.1, 19.4.
+
HRMS (ESI) m/z: for C H OSiNa[M + Na] , calculated: 435.2120; found: 435.2122.
2
8
32
(S,E)-3-(tert-butyldiphenylsilyloxy)-5-phenylpent-4-enal (16): To a stirred solution of
compound 15 (12.36 g, 30 mmol) in THF (90 mL) and H O (30 mL), NMO (5.26 g, 45
2
mmol) and OsO (0.05 M in toluene, 12 mL, 0.6 mmol) were added sequentially at 0 °C and
4
stirred at the same temperature for 24 h. After complete disappearance of the staring material,
the reaction solution was extracted with ethyl acetate. The combined organic layer was
concentrated under reduced pressure and the residue was dissolved in THF. Water was added
to the reaction mixture and stirred at room temperature for 2 min. Then to the reaction
mixture NaIO (8.02 g, 36 mmol) was added and the reaction solution was stirred for 1 h at
4
the same temperature. After completion of the reaction, the reaction solution was extracted
with diethyl ether. The combined organic layer was washed with brine and dried over
anhydrous Na SO and evaporated under reduced pressure. The crude residue was purified
2
4
through flash column chromatography (EtOAc/hexane = 1:10) to furnish compound 16 (9.94
2
5
g, 24 mmol) in 80% yield (two steps). R = 0.3 (EtOAc/hexane = 1:10); [α] = ‒28.8 (c 1.0,
f
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ 9.77 (t, J = 2.5 Hz, 1H), 7.73 – 7.66 (m, 4H), 7.58 –
3
3
7
1
1
2
4
.11 (m, 11H), 6.32 (d, J = 15.9 Hz, 1H), 6.18 (dd, J = 15.9, 6.5 Hz, 1H), 4.83 (q, J = 5.6 Hz,
1
3
H), 2.72 – 2.56 (m, 2H), 1.09 (s, 9H). C NMR (100 MHz, CDCl ) δ 201.3, 136.3, 135.9,
3
35.9, 133.5, 133.4, 130.8, 130.5, 129.9, 129.8, 128.5, 127.7, 127.6, 127.6, 126.5, 70.3, 51.3,
+
7.0, 19.3. HRMS (ESI) m/z: for C H O SiNa[M + Na] , calculated: 437.1907; found:
2
7
30
2
37.1911.
21

Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00399A
(
S,E)-3-(tert-butyldiphenylsilyloxy)-5-phenylpent-4-en-1-ol (17): To a solution of
compound 16 (9.9 g, 23.91 mmol) in MeOH (95 mL), NaBH (1.0 g, 26.3 mmol) was added
4
portion wise over 5 min at 0 °C, After complete addition of the reagent the reaction was
allowed to warm at room temperature and stirred for 2 h. After completion of the reaction, it
was quenched with a saturated solution of ammonium chloride. Methanol was evaporated
under reduced pressure and the residue was extracted with ethyl acetate. The organic layer
was washed with brine and dried over anhydrous Na SO and evaporated under reduced
2
4
pressure. The product was purified by flash column chromatography (EtOAc/hexane = 1:5) to
provide compound 17 (8.95 g, 21.52 mmol) in 90% yield as colorless oil. R = 0.3
f
EtOAc/hexane = 1:5); [α]D25 = ‒31.5 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ 7.74 –
1
(
3
3
7
.64 (m, 4H), 7.47 – 7.35 (m, 5H), 7.35 – 7.15 (m, 9H), 6.21 (d, J = 15.9 Hz, 1H), 6.18 – 6.10
1
3
(
m, 1H), 4.57 (q, J = 5.7 Hz, 1H), 3.89 – 3.61 (m, 2H), 1.96 – 1.76 (m, 3H), 1.09 (s, 9H). C
NMR (101 MHz, CDCl ) δ 136.7, 136.0, 135.9, 134.8, 133.8, 133.6, 131.5, 130.3, 129.8,
3
1
29.7, 128.4, 127.7, 127.5, 126.4, 73.4, 59.7, 39.9, 27.1, 19.3. HRMS (ESI) m/z: for
+
C H O SiNa[M + Na] , calculated: 439.2070; found: 439.2075.
2
7
32
2
(
S,E)-5-(3-(tert-butyldiphenylsilyloxy)-5-phenylpent-4-enylthio)-1-phenyl-1H-tetrazole
18): To a solution of compound 17 (8.9 g, 21.39 mmol) in dry THF (80 mL), TPP (8.4 g,
(
3
2.09 mmol), DIAD (5 mL, 25.67 mmol), PTSH (5.72 g, 32.09 mmol) were added
sequentially at -20 °C and it was stirred at the same temperature for 2 h. After complete
consumption of the starting material water was added to the reaction solution and stirred at
room temperature for 10 min. The reaction mixture was then extracted with diethyl ether.
Combined organic layer was washed with brine and dried over anhydrous Na SO and
2
4
evaporated under reduced pressure. The crude product was then purified by flash column
chromatography (EtOAc/hexane = 1:20) to furnish compound 18 (10.1 g, 17.54 mmol) in
2
5
1
8
2% yield as colorless oil. R = 0.6 (EtOAc/hexane = 1:5); [α] = ‒40.2 (c 1.0, CHCl ). H
f D 3
22

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NMR (500 MHz, CDCl ) δ 7.72 – 7.67 (m, 4H), 7.63 – 7.47 (m, 6H), 7.47 – 7.19 (m, 12H),
3
DOI: 10.1039/C9OB00399A
6
.29 (d, J = 15.9 Hz, 1H), 6.17 – 6.12 (m, 1H), 4.56 – 4.44 (m, 1H), 3.52 – 3.33 (m, 2H), 2.23
1
3
–
2.02 (m, 2H), 1.11 (s, 9H). C NMR (125 MHz, CDCl ) δ 154.2, 136.6, 136.0, 135.9,
3
1
33.8, 133.7, 133.7, 131.1, 130.9, 130.0, 129.8, 129.7, 129.6, 128.4, 127.7, 127.6, 127.5,
+
1
26.5, 123.8, 73.1, 36.9, 28.9, 27.1, 19.3. HRMS (ESI) m/z: for C H N OSSiNa[M + Na] ,
3
4
36
4
calculated: 599.2277; found: 599.2271.
(S,E)-5-(3-(tert-butyldiphenylsilyloxy)-5-phenylpent-4-enylsulfonyl)-1-phenyl-1H-
tetrazole (19): To a solution of compound 18 (9 g, 15.62 mmol) in ethanol, H O (50%, 11.4
2
2
mL) was added at room temperature. Ammonium molybdate (2.89 g, 2.34 mmol) was then
added to the reaction mixture. The reaction mixture was stirred at the same temperature for
1
6 h. After completion of the reaction, solvent was evaporated under reduced pressure and
the residue was extracted with ethyl acetate. The organic layer was washed with brine and
dried over anhydrous Na SO and evaporated under reduced pressure. The product was then
2
4
purified by flash column chromatography (EtOAc/hexane = 1:7) to furnish the compound 19
2
5
(
7.4 g, 11.4 mmol) in 73% yield as colorless oil. R = 0.6 (EtOAc/hexane = 1:5); [α]
=
f
D
1
‒
1
45.6 (c 1.0, CHCl ). H NMR (500 MHz, CDCl ) δ 7.73 – 7.57 (m, 8H), 7.51 – 7.19 (m,
3
3
2H), 6.41 (d, J = 15.9 Hz, 1H), 6.12 – 6.07 (m, 1H), 4.60 (q, J = 5.8 Hz, 1H), 3.85 – 3.70
1
3
(
m, 2H), 2.24 – 2.11 (m, 2H), 1.14 (s, 9H). C NMR (125 MHz, CDCl ) δ 153.4, 136.2,
3
1
1
35.9, 135.9, 135.8, 133.3, 133.3, 133.0, 131.8, 131.4, 130.0, 129.8, 129.7, 129.6, 128.5,
27.9, 127.6, 126.6, 125.1, 71.7, 52.2, 29.9, 27.1, 19.4. HRMS (ESI) m/z: for
+
C H N O SSiNa[M + Na] , calculated: 631.2175; found: 631.2188.
3
4
36
4
3
(4S,5E,8S,9E)-8-(tert-butyldiphenylsilyloxy)-10-phenyldeca-5,9-dien-1-yn-4-yl
acetate
(20): Compound 19 (6.5 g, 10.68 mmol) and 18-crown-6 (2.82 g, 10.68 mmol) were
dissolved in dry THF (30 mL) and the mixture was cooled to -78 ºC. KHMDS (0.5 M, 23.49
23

Organic & Biomolecular Chemistry
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mL, 11.75 mmol) was then added to the reaction solution and the yellow-red colored reaction
DOI: 10.1039/C9OB00399A
mixture was stirred for another 30 min at the same temperature. After that time, aldehyde 7
1.16 g, 8.92 mmol) was added to the reaction in dry THF (5 mL) and the solution was
(
allowed to warm at room temperature and stirred for another 2 h. After complete
disappearance of the aldehyde, the reaction was quenched with saturated ammonium chloride
solution. The reaction mixture was then poured into a separatory funnel containing 10 mL of
water. The organic part was separated out and the aqueous part was washed with diethyl ether
(30 × 2 mL). Combined organic layer was washed with brine and dried over anhydrous
Na SO and evaporated under reduced pressure. The crude residue was purified through flash
2
4
column chromatography (EtOAc/hexane = 1:20) to afford compound 20 (4.0 g, 7.67 mmol)
in 86% yield (with respect to the aldehyde) as colorless oil. R = 0.6 (EtOAc/hexane = 1:10);
f
α]D25 = ‒38.8 (c 1.5, CHCl ). H NMR (500 MHz, CDCl ) δ 7.74 (dt, J = 8.2, 1.6 Hz, 2H),
1
[
3
3
7
.71 – 7.66 (m, 2H), 7.50 – 7.44 (m, 1H), 7.44 – 7.38 (m, 3H), 7.36 (td, J = 7.0, 6.6, 1.3 Hz,
H), 7.33 – 7.28 (m, 2H), 7.28 – 7.19 (m, 2H), 6.33 – 6.20 (m, 1H), 6.19 – 6.13 (m, 1H), 5.85
5.68 (m, 1H), 5.58 – 5.42 (m, 1H), 5.32 (q, J = 6.4 Hz, 1H), 4.41 (q, J = 6.1 Hz, 1H), 2.51 –
.46 (m, 2H), 2.36 (t, J = 6.6 Hz, 2H), 2.02 (s, 3H), 1.97 (q, J = 2.1, 1.5 Hz, 1H), 1.11 (s,
2
–
2
1
3
9
H). C NMR (125 MHz, CDCl ) δ 170.0, 136.9, 136.0, 135.9, 134.2, 133.9, 131.7, 130.7,
3
1
30.1, 129.7, 129.6, 129.3, 128.4, 127.6, 127.5, 127.4, 126.5, 79.6, 73.9, 72.0, 70.4, 41.1,
+
2
7.1, 24.7, 21.1, 19.4. HRMS (ESI) m/z: for C H O SiNa[M + Na] , calculated: 545.2488;
3
4
8
3
found: 545.2482.
(4S,5E,8S,9E)-8-(tert-butyldiphenylsilyloxy)-10-phenyldeca-5,9-dien-1-yn-4-ol (21): To a
solution of compound 20 (3 g, 5.74 mmol) in methanol (23 mL), K CO (1.19 g, 8.61 mmol)
2
3
was added at 0 ºC and the reaction mixture was stirred at room temperature for 2 h. After
completion of the reaction, solvent was evaporated under reduced pressure and the residue
was extracted with ethyl acetate. The organic layer was washed with brine, dried over
24

Page 25 of 41
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anhydrous Na SO and evaporated under reduced pressure. The product was purified by flash
DOI: 10.1039/C9OB00399A
2
4
column chromatography (EtOAc/hexane = 1:10) to furnish the compound 21 (2.61 g, 5.45
2
5
mmol) in 95% yield as colorless oil. R = 0.3 (EtOAc/hexane = 1:10); [α] = ‒37.45 (c 2.0,
f
D
1
CHCl ). H NMR (500 MHz, CDCl ) δ 7.76 – 7.69 (m, 4H), 7.50 – 7.45 (m, 1H), 7.43 (td, J
3
3
=
7.7, 7.0, 3.1 Hz, 3H), 7.36 (t, J = 7.4 Hz, 2H), 7.34 – 7.30 (m, 2H), 7.30 – 7.23 (m, 4H),
6
1
2
1
1
.31 (d, J = 15.9 Hz, 1H), 6.22 – 6.14 (m, 1H), 5.72 (dt, J = 14.7, 7.1 Hz, 1H), 5.52 (dd, J =
5.5, 6.5 Hz, 1H), 4.42 (q, J = 6.0 Hz, 1H), 4.20 (q, J = 6.1 Hz, 1H), 2.42 – 2.38 (m, 2H),
1
3
.38 – 2.34 (m, 2H), 2.02 (t, J = 2.6 Hz, 1H), 1.13 (s, 9H). C NMR (125 MHz, CDCl ) δ
3
37.0, 136.0, 136.0, 134.3, 134.0, 133.5, 131.9, 130.1, 129.7, 129.6, 128.5, 128.5, 127.6,
27.5, 127.4, 126.4, 80.5, 74.0, 70.7, 70.6, 41.0, 27.4, 27.1, 19.4. HRMS (ESI) m/z: for
+
C H O SiNa[M + Na] , calculated: 503.2383; found: 503.2376.
3
2
36
2
(S)-1-((2S,3S)-3-((S,E)-2-(tert-butyldiphenylsilyloxy)-4-phenylbut-3-enyl)oxiran-2-
yl)but-3-yn-1-ol (22): A mixture of finely crushed 4 Å activated molecular sieves (1.5 g) and
CH Cl (20 mL) was cooled to −35 °C, and then Ti(OiPr) (0.46 mL, 1.56 mmol) and L-(+)-
2
2
4
DET (0.4 mL, 2.34 mmol) were added using a syringe. Afterward, the mixture was stirred at
35 °C for 30 min, and compound 21 (2.5 g, 5.2 mmol) in CH Cl (5 mL) was then added to
−
2
2
the reaction solution using a syringe, followed by addition of cumene hydroperoxide (1.16
mL, 7.8 mmol). The reaction mixture was then stirred at −35 °C for 1 h and then stirred at
−
20 °C for 35 h in a low temperature bath. Aqueous saturated Na SO (3 mL) was then added
2 4
and the mixture was diluted with Et O (20 mL). The reaction mixture was then stirred at
2
ambient temperature for 3 h, the resulting slurry was filtered through a pad of celite, and the
resulting solution was concentrated. The product was purified by silica gel chromatography
(EtOAc/hexane = 1:8) to obtain compound 22 (2.01 g, 4.05 mmol) in 78% yield as a colorless
2
5
1
oil. R = 0.3 (EtOAc/hexane = 1:8); [α]
= ‒21.6 (c 0.5, CHCl ). H NMR (600 MHz,
3
f
D
CDCl ) δ 7.76 – 7.71 (m, 2H), 7.71 – 7.67 (m, 2H), 7.49 – 7.44 (m, 1H), 7.40 (t, J = 7.2 Hz,
3
25

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3
1
2
–
1
6
5
H), 7.36 (t, J = 7.4 Hz, 2H), 7.32 – 7.27 (m, 3H), 7.26 – 7.21 (m, 3H), 6.30 (d, J = 16.0 Hz,
DOI: 10.1039/C9OB00399A
H), 6.18 (dd, J = 15.8, 6.8 Hz, 1H), 4.57 (q, J = 6.3 Hz, 1H), 3.65 (s, 1H), 3.11 (td, J = 5.9,
.2 Hz, 1H), 2.83 (dd, J = 4.3, 2.3 Hz, 1H), 2.50 – 2.41 (m, 2H), 2.01 (t, J = 2.7 Hz, 1H), 1.88
1
3
1.79 (m, 2H), 1.12 (s, 9H). C NMR (150 MHz, CDCl ) δ 136.7, 136.0, 135.9, 133.9,
3
33.8, 131.6, 130.3, 129.8, 129.6, 128.5, 127.6, 127.5, 127.5, 126.5, 79.6, 72.3, 71.0, 68.80,
+
0.4, 53.4, 40.4, 27.1, 24.6, 19.4. HRMS (ESI) m/z: for C H O SiNa[M + Na] , calculated:
3
2
36
3
19.2332; found: 519.2342.
(S,2E,6E)-5-(4-methoxybenzyloxy)-7-phenylhepta-2,6-dienal (23): The solution of
compound 9 (5 g, 17 mmol) in dry DCM (55 mL) was degassed with argon gas for 1 h at
room temperature, crotonaldehyde (3.5 mL, 42.5 mmol) and HG (II) catalyst (70 mg, 0.11
mmol) were added simultaneously. The reaction solution was then heated to reflux for 3 h.
After completion of the reaction, solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/hexane = 1:12) to afford
compound 23 (4.27 g, 13.26 mmol) in 78% yield as yellow oil. R = 0.4 (EtOAc/hexane =
f
:10); [α]D25 = ‒28.6 (c 2.0, CHCl ). H NMR (400 MHz, CDCl ) δ 9.50 (dd, J = 7.8, 2.1
1
1
3
3
Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.32 – 7.22 (m, 2H), 7.17 (d, J =
7
.9 Hz, 1H), 6.91 – 6.83 (m, 3H), 6.60 (d, J = 15.9 Hz, 1H), 6.20 – 6.10 (m, 2H), 4.60 (d, J =
1.3 Hz, 1H), 4.36 (d, J = 11.4 Hz, 1H), 4.09 (q, J = 6.9 Hz, 1H), 3.81 (s, Hz, 3H), 2.79 –
1
1
3
2
.55 (m, 2H), 2.36 (residual acetone), 1.6 (residual water). C NMR (100 MHz, CDCl ) δ
3
1
93.9, 159.3, 154.2, 136.0, 134.8, 133.4, 130.1, 129.4, 128.8, 128.7, 128.1, 126.6, 113.9,
+
7
7.9, 70.0, 55.3, 39.2. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated: 345.1467;
2
1
22
3
found: 345.1463.
(S,2E,6E)-5-(4-methoxybenzyloxy)-7-phenylhepta-2,6-dien-1-ol (24): To a solution of
compound 23 (4.2 g, 13.04 mmol) in dry DCM (50 mL) at ˗40 °C DIBAl-H in cyclohexane
26

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DOI: 10.1039/C9OB00399A
(
14.3 mL, 14.3 mmol) was added drop wise and the reaction mixture was stirred at the same
temperature for 2 h. After the completion of the reaction, it was quenched with saturated
solution of Rochelle salt (8 mL) and the mixture was allowed to warm at room temperature
and stirred for another 2 h at room temperature. The reaction mixture was then filtered
through a celite pad and washed with DCM (50 mL). The solvent was dried over anhydrous
Na SO and evaporated under reduced pressure. The residue was purified through column
2
4
chromatography (EtOAc/hexane = 1:7) to furnish compound 24 (3.59 g, 11.08 mmol) in 85%
2
5
1
yield. R = 0.3 (EtOAc/hexane = 1:7); [α] = ‒31.2 (c 1.0, CHCl ). H NMR (400 MHz,
f
D
3
CDCl ) δ 7.41 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (dd, J = 8.2, 2.8 Hz, 3H),
3
6
2
3
1
6
3
.89 (dd, J = 8.4, 2.5 Hz, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.16 – 6.12 (m, 1H), 5.83 – 5.57 (m,
H), 4.58 (dd, J = 11.5, 2.6 Hz, 1H), 4.36 (dd, J = 11.5, 2.6 Hz, 1H), 4.08 (d, J = 3.3 Hz, 2H),
1
3
.97 (t, J = 6.9 Hz, 1H), 3.81 (s, 3H), 2.52 – 2.36 (m, 2H). C NMR (100 MHz, CDCl ) δ
3
59.1, 136.5, 132.6, 131.6, 130.6, 129.9, 129.4, 128.6, 128.5, 127.8, 126.5, 113.8, 79.3, 69.8,
+
3.6, 55.3, 38.8. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated: 347.1623; found:
2
1
24
3
47.1626.
(
(2S,3S)-3-((S,E)-2-(4-methoxybenzyloxy)-4-phenylbut-3-enyl)oxiran-2-yl)methanol
25): A mixture of finely crushed 4 Å activated molecular sieves (1.0 g) and CH Cl (30 mL)
(
2
2
was cooled to -35 °C, Ti(OiPr) (0.73 mL, 2.4 mmol) and (+)-DET (0.62 mL, 3.6 mmol) were
4
added through syringe. After that time, the reaction mixture was stirred at -35 °C for 30 min,
compound 24 (3.9 g, 12 mmol) was then added to the reaction solution by syringe, followed
by addition of cumenehydroperoxide (2.65 mL, 18 mmol). The reaction mixture was then
stirred at -35 °C for 1 h and then stirred at -20 °C for 35 h in a low temperature bath.
Aqueous saturated Na SO (3 mL) was then added and the mixture was diluted with Et O (30
2
4
2
mL). The reaction mixture was then stirred at ambient temperature for 3 h, the resulting
slurry was filtered through a pad of celite, and the resulting solution was concentrated. Excess
27

Organic & Biomolecular Chemistry
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cumene alcohol and cumene hydroperoxide were removed by flash chromatography
DOI: 10.1039/C9OB00399A
(EtOAc/hexane = 1:5) to provide compound 25 (3.34 g, 9.84 mmol) in 82% yield. R = 0.3
f
EtOAc/hexane = 1:5); [α]D25 = ‒15.6 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ 7.41 (d,
1
(
3
3
J = 7.8 Hz, 2H), 7.38 – 7.30 (m, 2H), 7.29 – 7.265 (m, 3H), 6.94 – 6.83 (m, 2H), 6.67 – 6.51
m, 1H), 6.18 – 6.12 (m, 1H), 4.60 (dd, J = 11.3, 1.9 Hz, 1H), 4.38 (dd, J = 11.3, 1.9 Hz, 1H),
(
4
1
.21 – 4.15 (m, 1H), 3.87 – 3.91 (m, 1H), 3.80 (s, 1H), 3.64 – 3.59 (m, 1H), 3.20 – 3.18 (m,
1
3
H), 2.98 – 2.95 (m, 1H), 2.12 – 1.93 (m, 1H), 1.81 – 1.67 (m, 1H). C NMR (100 MHz,
CDCl ) δ 159.2, 136.3, 132.6, 130.5, 129.6, 129.3, 128.6, 127.9, 126.6, 113.9, 76.7, 70.1,
3
+
6
3
1.7, 58.9, 55.3, 53.3, 38.6. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated:
2
1
24
4
63.1573; found: 363.1573.
(3R,5S,E)-5-(4-methoxybenzyloxy)-7-phenylhept-6-ene-1,3-diol (26): To a solution of
compound 25 (2.72 g, 8 mmol) in dry THF (32 mL), PhSiH (2.46 mL, 20 mmol) was added
3
at room temperature. Then to the reaction mixture TBAF (4 mL, 4 mmol) was added drop
wise at the same temperature and the reaction solution was stirred for 2 h. After complete
disappearance of the starting material, the reaction mixture was quenched with 2 (M) NaOH
solution (15 mL). And the mixture was stirred at room temperature for another 2 h. After that
time the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate.
The organic part was washed with brine, dried over anhydrous Na SO and concentrated
2
4
under reduced pressure. The product was purified by flash column chromatography
EtOAc/hexane = 1:2.5) to have the compound 26 (2.52 g, 7.36 mmol) in 92% yield as
(
2
5
1
colorless oil. R = 0.2 (EtOAc/hexane = 1:3); [α] = ‒18.2 (c 0.5, CHCl ). H NMR (600
f
D
3
MHz, CDCl ) δ 7.44 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.34 – 7.27 (m, 3H), 6.98 –
3
6
1
.86 (m, 2H), 6.63 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.7 Hz, 1H), 4.62 (d, J = 11.4 Hz,
H), 4.38 (dd, J = 11.4, 4.3 Hz, 1H), 4.30 – 4.30 (m, 1H), 4.25 – 4.21 (m, 1H), 3.87 – 3.84
1
3
(
m, 2H), 3.83 (s, 3H), 1.91 – 1.82 (m, 2H), 1.79 – 1.64 (m, 2H). C NMR (150 MHz,
28

Page 29 of 41
Organic & Biomolecular Chemistry
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CDCl ) δ 159.4, 136.3, 132.6, 130.1, 129.5, 129.2, 128.7, 128.0, 126.6, 114.0, 77.4, 70.2,
3
DOI: 10.1039/C9OB00399A
+
6
3
9.1, 61.6, 55.3, 42.4, 38.5. HRMS (ESI) m/z: for C H O Na[M + Na] , calculated:
21 26 4
65.1729; found: 365.1762.
(R)-5-((S,E)-2-(4-methoxybenzyloxy)-4-phenylbut-3-enyl)-2,2,3,3,9,9,10,10-octamethyl-
4
,8-dioxa-3,9-disilaundecane (27): To a solution of compound 26 (2.0 g, 5.84 mmol) in dry
DCM (20 mL), immidazole (1.19 g, 17.53 mmol) was added at 0 °C and stirred for 10 min.
TBS-Cl (2.19 g, 14.61 mmol) was then added to the reaction mixture at the same temperature
and the reaction solution was allowed to warm at room temperature and stirred for further 8
h. After completion of the reaction, it was quenched with water and extracted with DCM. The
organic layer was washed with brine and dried over anhydrous Na SO . The solution was
2
4
then concentrated under reduced pressure and the residue was purified through flash column
chromatography (EtOAc/hexane = 1:20) to yield the compound 27 (2.93 g, 5.14 mmol) in
2
5
1
8
8% yield as colorless oil. R = 0.4 (EtOAc/hexane = 1:20); [α] = ‒32.4 (c 1.0, CHCl ). H
f D 3
NMR (400 MHz, CDCl ) δ 7.41 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.30 – 7.23 (m,
3
3
4
H), 6.87 (d, J = 8.2 Hz, 2H), 6.55 (dd, J = 16.3, 4.1 Hz, 1H), 6.13 (dd, J = 15.8, 8.2 Hz, 1H),
.54 (d, J = 11.1 Hz, 1H), 4.30 (dd, J = 11.4, 3.1 Hz, 1H), 4.08 (tq, J = 7.9, 4.9 Hz, 2H), 3.80
(d, J = 3.1 Hz, 3H), 3.68 (t, J = 6.8 Hz, 2H), 1.9 – 1.86 (m, 1H), 1.72 (h, J = 6.9, 6.1 Hz, 3H),
1
3
0
.91 (d, J = 2.7 Hz, 7H), 0.87 (d, J = 3.3 Hz, 11H), 0.05 (d, J = 14.2 Hz, 11H). C NMR
(
100 MHz, CDCl ) δ 159.0, 136.6, 132.1, 130.9, 129.3, 129.2, 128.6, 127.7, 126.5, 113.7,
3
7
7.2, 69.8, 66.4, 59.5, 55.2, 44.3, 40.9, 25.9, 18.2, 18.1, -4.4, -5.3. HRMS (ESI) m/z: for
+
C H O Si Na[M + Na] , calculated: 593.3459; found: 593.3461.
3
3
54
4
2
(
3R,5S,E)-3-(tert-butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-7-phenylhept-6-en-1-ol
28): The compound 27 (2.5 g, 4.38 mmol) was dissolved in dry DCM-MeOH (1:1, 16 mL)
(
and stirred at -30 °C. CSA (102 mg, 0.438 mmol) was then added to the reaction mixture, and
it was stirred at -30 °C for another 2 h. The reaction solution was then quenched with Et N
3
29