Convergent Synthesis of the Dihydropyran Core Containing the C1-C15 Subunit of Sorangicin A Employing Gold(I)-Catalyzed Cyclization of an Allenic Alcohol

Article abstract of DOI:10.1021/acs.joc.6b01743

A convergent route to the C1-C15 subunit of sorangicin A is disclosed. The key steps include carbon-carbon bond formation using an α-chloro sulfide, regioselective hydrozirconation of an internal alkyne for the preparation of a trisubstituted iodoalkene, allene formation using the Myers-Movassaghi protocol, stereoselective reduction of allylic and propargylic ketones using Noyori's catalyst, and gold(I)-catalyzed cyclization of a β-hydroxy allene to construct the dihydropyran ring.

Full text of DOI:10.1021/acs.joc.6b01743

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Article
Convergent Synthesis of the Dihydropyran Core Containing C1-C15 Subunit
of Sorangicin A Employing Gold(I)-Catalyzed Cyclization of an Allenic Alcohol
Sadagopan Raghavan, and Satyanarayana Nyalata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01743 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
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Convergent Synthesis of the Dihydropyran Core Containing C1-
C15 Subunit of Sorangicin A Employing Gold(I)-Catalyzed
Cyclization of an Allenic Alcohol
Sadagopan Raghavan* and Satyanarayana Nyalata
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Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad,
India
sraghavan@iict.res.in
Abstract: A convergent route to the C1ꢀC15 subunit of sorangicin A is disclosed. The key
steps include carbonꢀcarbon bond formation using an αꢀchlorosulfide, regioselective
hydrozirconation of an internal alkyne for the preparation of a trisubstituted iodo alkene,
allene formation using MyersꢀMovassaghi protocol, stereoselective reduction of allylic and
propargylic ketones using Noyori's catalyst and gold(I)ꢀcatalyzed cyclization of a βꢀhydroxy
allene to construct the dihydropyran ring.
INTRODUCTION
The isolation and structure elucidation of sorangicin A 1, obtained from a
fermentation broth of myxobacteria Sorangium cellulosum (strain So ce 12)1 was reported by
Jansen and coꢀworkers in 1985. Sorangicin A displayed potent antibiotic activity against both
Gramꢀpositive and Gramꢀnegative bacteria at concentrations of 0.01ꢀ0.3 and 3ꢀ25 µg/mL
respectively. The mechanism of action involves inhibition of DNAꢀdependant RNA
polymerase (RNAP) of bacteria, without affecting eukaryotic cells.2 Sorangicin A displayed
activity against rifampicin resistant microbes, too.
The structure assigned to sorangicin A was based on extensive NMR experiments and
mass spectrometry.3 Structurally, sorangicin A is comprised of C1ꢀC8 side chain with a
carboxyl group, attached to an unsaturated 31ꢀmembered macrocyclic lactone, possessing 15
stereocenters. A dioxabicyclo[3.2.1]octane, (Z,Z,E) trienoate linkage and diꢀ and
tetrahydropyran ring systems are contained in the macrocyclic ring.
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The challenging structure, potent antibiotic activity and novel mechanism of action
has led to widespread interest in sorangicin A among synthetic chemists. Smith and coꢀ
workers reported the first and only total synthesis of sorangicin A in 2009.4 Crimmins and coꢀ
workers have reported a formal synthesis5 and many groups have reported the synthesis of
subunits.6 By a retrosynthetic disconnection, sorangicin A was envisioned to be obtained by
the union of fragments 2ꢀ6, Scheme 1.
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O
O
OP
37
43
Ar(Het)O2S
O
8
29
O
16
O
H
H
8
+
15
5
O
4
O
19
PO
H
H
25
HO
1
15
2
OH
3
Ar(Het)S
22
1
19
PO
HO2C
HO
+
29
1
O
25
PO
O
OP
+
+
22
O
CO2Me
OHC
Bu3Sn
37
I
20
30
PO
4
6
5
OP
P = Protecting groups
Scheme 1. Retrosynthetic Disconnection of Sorangicin A.
Herein, we disclose a highly stereoselective route to the C1ꢀC15 subunit 2, of
sorangicin, utilizing an αꢀchlorosulfide intermediate for the C4ꢀC5 bond formation and goldꢀ
catalyzed 6ꢀendo cyclization of a βꢀhydroxy allene to construct the dihydropyran core. The
fragment 2 can be derived from βꢀhydroxy allene 7, which in turn can be obtained from the
union of a suitable nucleophile derived from iodoalkene 8 and allenic aldehyde 9. The iodo
alkene 8 can be obtained from sulfide 10 and alkyne 11. The aldehyde 9 was envisioned to be
obtained from propargylic alcohol 12 which in turn can be traced to chloro acetonide 13 and
Weinreb amide 14, Scheme 2.
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H
OP
OP
8
H
H
C
I
OP
O
H
C
H
H
O
HO
+
O
PO
2
7
9
8
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PO
OP
OH
PO
PO
PO
9
OBn
O
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PO
O
OP
OP
P = Protecting groups
+
OMe
+
PO
N
PO
SPh
10
Me
14
Cl
11
13
12
OP
Scheme 2. Retrosynthetic Analysis of Subunit 2.
RESULTS AND DISCUSSION
The synthesis began with the known sulfide 15,7 prepared from methallyl alcohol by a
chemoenzymatic route, which was converted readily into its benzyl ether 10. Treatment of 10
with Nꢀchlorosuccinimide yielded the αꢀchlorosulfide 16, which without isolation was reacted
with the alkynylzinc reagent prepared from 11, to furnish propargylic sulfide 17 as an
inconsequential mixture of diastereomers (4.5:5.5).8 Oneꢀpot reduction and hydrogenolysis
furnished alcohol 18. Oxidation using the Swern protocol9 yielded aldehyde 19, which on
subjecting to the OhiraꢀBestman protocol10 afforded the alkyne 20. Methylation of the lithio
acetylide furnished alkyne 21 that on reaction with an excess of Cp2ZrHCl in THF at 50 oC11
followed by quenching the resulting vinylzirconium species with iodine yielded iodo alkene
8, Scheme 3.
OTBS
11
OP
OBn
OBn
i-PrMgCl.LiCl, THF,
NCS,PhH
then ZnBr2
OTBS
BrZn
SPh
Cl
SPh
SPh
72%
15
, P = H
17
NaH, BnBr,
TBAI, THF,
90%
16
10, P = Bn
TBSO
X
O
O
P
R
I
OMe
Cp2ZrHCl, THF,
then I2, 80%
Ra-Ni, MeOH,
86%
OMe
N2
NaOMe, THF,
84%
TBSO
TBSO
TBSO
18, R = CH2OH
20, X = H
8
(COCl)2, DMSO,
Et3N, DCM, 90%
n-BuLi, THF,
DMPU, MeI,
95%
19, R = CHO
Scheme 3. Synthesis of Iodo Alkene 8.
21, X = Me
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The synthesis of aldehyde 9 commenced with (D)ꢀtartaric acid which was transformed
by a known sequence of four straight forward reactions12 into chloroacetonide 13. Alkynol
22, obtained by treatment of 13 with LiNH2,13 was protected using standard conditions as its
MOMꢀether 23. Reaction of the lithium acetylide derived from 23 with the Weinreb amide
14,14 furnished the ketone 24. Stereoselective reduction of the propargylic ketone using the
Noyori protocol15 afforded alcohol 12 (82%, 99% de). Alcohol 12 was converted to allene 27
using MyersꢀMovassaghi's protocol.16 Thus reaction of 12 with hydrazone 25 under
Mitsunobu conditions17 yielded hydrazone derivative 26 that on treatment with aq
trifluroethanol led to diazene formation and further rearrangement to afford allene 27.
Deprotection of the PMBꢀether using DDQ18 furnished the alcohol 28 that on oxidation using
DessꢀMartin periodinane19 furnished aldehyde 9, Scheme 4.
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Cl
OH
LiNH2, NH3,
90%
O
O
O
S N
O
Ru
OP
Seeref. 11
Steps
CO2H
NH2
HO2C
OH
D-Tartaric acid
OPMB
Cl
OPMB
13
22, P = H
MOM-Cl, i-Pr2NEt,
TBAI, DCM, 90%
Noyori Catalyst
23, P = MOM
NO2
OH
TBDPSO
O
TBDPSO
H
(S,S)-Noyori cat.,
HCO2Na, EtOAc,
H2O, 82%
N
S
N
i-PrMgCl.LiCl, THF,
then 14, 87%
25
O O
OMOM
OPMB
OMOM
OPMB
DEAD, PPh3,
Toluene
24
12
ArO2S
TBDPSO
N
H
H
N
OMOM
OMOM
OPMB
DDQ, DCM,
pH 7 Buffer,92%
H
C
H
C
CF3CH2OH, H2O,
83%
OMOM
OPMB
R
26
27
OTBDPS
OTBDPS
TBDPSO
O
28, R = CH2OH
DMP, NaHCO3,
DCM, 90%
Me
N
9, R = CHO
14 OMe
Scheme 4. Synthesis of Aldehyde 9.
The reaction of alkenyllithium derived from iodoalkene 8 with aldehyde 9 required
lots of experimentation. Attempted reaction of the aldehyde 9 with the alkenyllithium derived
o
from 8 at ꢀ78 C led to the competitive isomerization of the allenic aldehyde into a E,Zꢀ
mixture of diene aldehydes which further reacted to afford a complex mixture of products.
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The situation was no better using the less basic organomagnesium or organozinc reagents
prepared by transmetalation. Also trials involving inverse addition of alkenyllithium to
aldehyde afforded a complex mixture of products. Finally it was found that soon after
addition of the aldehyde to the alkenyllithium at ꢀ78 oC, warming to 0 oC and maintaining for
10 minutes led to a separable mixture of alcohols 7 and 29 in a 4:6 ratio and in 70%
combined yield.20 In an effort to improve the diastereoselectivity in favour of the desired
carbinol 7, the solution of an equimolar mixture of ZnCl2 and aldehyde 9 was added to the
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o
o
alkenyllithium at ꢀ78 C, warmed immediately to 0 C and quenched after 10 min. The
selectivity of 7:29 improved only slightly from 4:6 to 7:3 though at the cost of the yield
(60%). The alcohol 29 was oxidized using DessꢀMartin periodinane and reduced using
Noyori catalyst21 to furnish alcohol 7 (9:1 dr). The key transformation of the allenic alcohol
to dihydropyran proceeded cleanly using AuCl(PPh3)2 in the presence of AgSbF6 in toluene
to furnish the dihydropyran derivative 2.22 The structure of compound 2 was supported by
NOE studies that revealed NOE between C10H and C14H and absence of any NOE between
C9H and C13H, Scheme 5.
H
H
I
OMOM
OMOM
H
C
n-BuLi, THF,'
then 9, 70%
H
C
HO
+
HO
TBSO
TBDPSO
TBDPSO
7
29
8
DMP, NaHCO3,
DCM, 88%
TBSO
TBSO
(S,S)-Noyori cat.,
n-Bu4NBr, HCO2Na,
DCM, H2O, 85%
OMOM
Cl
O
S N
Ru
9
5 mol% (PPh3)2AuCl,
AgSbF6, Toluene, 62%
13
NH2
O
O
H
H
TBDPSO
2
Noyori Catalyst
TBSO
Scheme 5. Synthesis of the C1ꢀC15 Subunit 2.
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CONCLUSION
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In conclusion we have devised a highly stereoselective route to the C1ꢀC15 subunit of
sorangicin A comprising the transꢀ2,6ꢀdihydropyran core. The key features of the route
include the use of αꢀchlorosulfide for CꢀC bond formation, regioselective hydrozirconation of
an internal alkene, MyersꢀMovassaghi protocol for allene formation, Noyori reduction for the
creation of C9 and C13 carbinol stereocenters and goldꢀcatalyzed cyclization for the
preparation of dihydropyran core. The synthesis of the other subunits are in progress and
would be reported in due course.
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EXPERIMENTAL SECTION
Dry reactions were performed under an inert atmosphere using argon or nitrogen. All
glassware apparatus used for reactions were thoroughly ovenꢀdried. 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 used without purification. Column chromatography was carried out by using
silica gel (100−200 mesh). Analytical thinꢀlayer chromatography (TLC) was run on silica gel
60 F254 precoated plates (250 ꢁm 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. Highꢀresolution mass spectra
1
(HRMS; ESI+) were obtained using either a TOF or a doubleꢀfocusing spectrometer. H
NMR spectra were recorded at 300, 400, or 500 MHz and 13C 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.
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(S)-2-Methyl-3-(phenylthio)propan-1-ol 15: AIBN (2.56 g, 15.62 mmol) was added to a
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solution of methallyl alcohol (5.18 g, 72 mmol) in thiophenol (376 mL) at rt. The mixture
7
8
o
was heated to 80 C and stirred for 12 h. The mixture was cooled to rt. After dilution with
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Et2O (400 mL), the solution was washed successively with aq 5% NaOH solution (400 mL),
brine (2×400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography using 20%
EtOAc/hexanes (v/v) as the eluent to afford the racemic alcohol 15 (11.6 g, 63.7 mmol) in
88% yield as a liquid; TLC: Rf 0.25 (20% EtOAc/hexane); IR (neat): 3356, 2958, 2954, 2873,
1477, 1030, 739 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.37ꢀ7.33 (m, 2H), 7.30ꢀ7.25 (m, 2H),
7.19ꢀ7.15 (m, 1H), 3.63 (dd, J = 10.8, 5.5 Hz, 1H), 3.60 (dd, J = 10.8, 6.1 Hz, 1H), 3.07 (dd,
J = 13.0, 6.4 Hz, 1H), 2.84 (dd, J = 13.0, 6.9 Hz, 1H), 2.00ꢀ1.90 (m, 1H), 1.63 (brs, 1H), 1.05
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(d, J = 6.7 Hz, 3H); C NMR (125 MHz, CDCl3): δ 136.5, 128.5, 128.4, 125.4, 66.0, 36.8,
35.1, 16.0; MS (ESI): m/z 183 [M+H]+.
To a stirred solution of (±)ꢀalcohol 15 (11.61 g, 63.8 mmol) in anhydrous chloroform (90
mL) cooled at 0 °C was added vinyl acetate (16.3 g, 255 mmol) and Pseudomonas
fluorescens Amano Lipase (PFL) (0.7 g). The resulting solution was then stirred at 0 °C for 5
h. Monitoring by HPLC using a chiral column revealed the absence of (R)ꢀ15. (HPLC: ee =
99.0%, Chiralpak IC column, mobile phase: hexane/isopropanol 98/02, flow rate: 1 mL
min−1, temperature = 25 °C, detection: UV 220 nm, retention time (S)ꢀisomer = 25.47 min,
(R)ꢀisomer 23.76 min). The resulting reaction mixture was filtered through a pad of Celite,
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the
crude product. Purification of the crude residue by column chromatography using 20%
EtOAc/hexane (v/v) as the eluent afforded alcohol 15 (5.22 g, 28.71 mmol) in 45% yield as a
colorless liquid; TLC: Rf 0.25 (20% EtOAc/hexane). [α]20 = +15.45 (c 1.0, CHCl3); MS
D
(ESI): m/z 183 [M+H]+. HRMS (ESI): calcd for C10H15OS: 183.0838, found: 183.0834.
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(S)-(3-(Benzyloxy)-2-methylpropyl)(phenyl)sulfane 10: To a suspension of NaH (60% in
Nujol, 1.83 g, 45.7 mmol) in anhydrous THF (40 mL) cooled at 0 oC was added the solution
of alcohol 15 (5.2 g, 28.54 mmol) in anhydrous THF (90 mL). After the mixture was stirred
for 30 min, benzyl bromide (3.4 mL, 28.54 mmol) and TBAI (1.77 g, 4.81 mmol) were added
and the reaction mixture was stirred at rt for 2 h. After dilution with Et2O (50 mL), the
reaction mixture was cooled to 0 oC and treated with aq satd NH4Cl solution (50 mL). The aq
phase was extracted with Et2O (2×50 mL) and the combined organic extracts were washed
with brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue
was purified by flash column chromatography using 0.5ꢀ1% EtOAc/hexane (v/v) as the
eluent to afford the compound 10 (6.98 g, 25.7 mmol) in 90% yield as a colourless liquid;
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TLC: Rf 0.4 (hexane); [α]20 = –9.74 (c 1.0, CHCl3); IR (neat): 3060, 2856, 1477, 1364,
D
1
1094, 737 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.36ꢀ7.30 (m, 6H), 7.29ꢀ7.22 (m, 3H), 7.16ꢀ
7.12 (m, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 3.43 (dd, J = 10.5, 5.6 Hz,
1H), 3.42 (dd, J = 10.5, 5.6 Hz, 1H), 3.15 (dd, J = 13.0, 5.8 Hz, 1H), 2.79 (dd, J = 13.0, 7.5
Hz, 1H), 2.12ꢀ2.02 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 138.3,
137.0, 128.5, 128.4, 128.0, 127.2, 127.1, 125.2, 73.7, 72.7, 37.1, 33.6, 16.5; MS (ESI): m/z
273 [M+H]+. HRMS (ESI): calcd for C17H21OS: 273.1308, found: 273.1322.
(((6S)-7-(Benzyloxy)-6-methyl-5-(phenylthio)hept-3-yn-1-yl)oxy)(tert-butyl)
dimethylsilane 17: To a solution of (butꢀ3ꢀynꢀ1ꢀyloxy)(tertꢀbutyl)dimethylsilane (11) (10.5
g, 57.1 mmol) in anhydrous THF (57 mL) cooled at –10 °C was added iꢀPrMgCl·LiCl (1.5 M
in THF, 38.1 mL, 57.1 mmol) and stirred for 30 min at the same temperature. To the
generated Grignard reagent, a solution of ZnBr2 (1.5 M in THF, 41.9 mL, 62.8 mmol) was
added at 0 °C and stirred for 30 min. Separately in another rb flask the chlorosulfide 16 was
prepared by adding a solution of sulfide 10 (7.76 g, 28.5 mmol) in anhydrous benzene (145
mL) to NCS (3.81 g, 28.5 mmol) in anhydrous benzene (140 mL) and stirring for 45 min. To
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the organozinc reagent maintained at 0 °C was added a solution of chlorosulfide (28.5 mmol)
in benzene (285 mL). 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 chlorosulfide. The reaction mixture was cooled to 0 °C and quenched by the addition of
aq sat NH4Cl solution (50mL). It was allowed to warm to rt and diluted with Et2O (80 mL).
The layers were separated and the aq layer was extracted with Et2O (3×80 mL). The
combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over
anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford a crude
compound which was purified by column chromatography using 1ꢀ2% EtOAc/hexanes (v/v)
as the eluent to afford the pure product 17 as a 4.5:5.5 mixture of diastereomers at the newly
created stereocentre (8.35 g, 18.39 mmol) in 72% yield as a light yellow liquid. TLC: Rf 0.2
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(1% EtOAc/hexane); [α]20 = +15.26 (c 1.0, CHCl3); IR (neat): 3061, 2930, 1472, 1253,
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1102, 836 cmꢀ1; 1H NMR (diastereomers with 0.9:1 ratio and the minor isomer denoted with
asterisk, 500 MHz, CDCl3): δ 7.50ꢀ7.45 (m, 4H), 7.35ꢀ7.20 (m, 16H), 4.47 (s, 2H)*, 4.46 (s,
2H), 4.25 (dt, J = 4.3, 2.1 Hz, 1H)*, 4.02 (dt, J = 4.9, 2.3 Hz, 1H), 3.69 (dd, J = 9.3, 6.4 Hz,
1H)*, 3.63 (t, J = 7.3 Hz, 2H)*, 3.62 (t, J = 7.3 Hz, 2H), 3.48 (dd, J = 9.3, 5.2 Hz, 1H), 3.46
(dd, J = 9.3, 3.0 Hz, 1H), 3.41 (dd, J = 9.3, 5.3 Hz, 1H)*, 2.40ꢀ2.36 (m, 4H), 2.23ꢀ2.11 (m,
2H), 1.14 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H)*, 0.89 (s, 9H)*, 0.88 (s, 9H), 0.05 (s,
12H); 13C NMR (diastereomers with 0.9:1 ratio and the minor isomer denoted with asterisk,
100 MHz, CDCl3): δ 138.35, 138.30*, 135.1, 134.9*, 132.0*, 131.5, 128.62*, 128.60, 128.57,
128.16, 128.13*, 127.39*, 127.31, 126.9, 126.8*, 82.9*, 82.0, 79.8*, 77.6, 72.9, 72.8, 72.3*,
61.8, 42.7*, 41.3, 38.3, 37.2*, 25.8, 23.1, 18.1, 14.7, 12.6*, –5.3; MS (ESI): m/z 477
[M+Na]+. HRMS (ESI): calcd for C27H38NaO2SSi: 477.2254, found: 477.2266.
(R)-7-((tert-Butyldimethylsilyl)oxy)-2-methylheptan-1-ol 18: To a solution of compound
17 (8.3 g, 18.3 mmol) in methanol (152 mL) was added freshly prepared W2 RaneyꢀNickel
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(suspension in methanol, 32 g) and the above mixture was stirred for 16 h under hydrogen
atmosphere. The reaction mixture was filtered through a pad of Celite and washed with
methanol (2×30 mL). The combined organic layers were concentrated under reduced
pressure, and the residue was purified by column chromatography using 10ꢀ12%
EtOAc/hexanes (v/v) as the eluent to afford the pure product 18 (4.1 g, 15.7 mmol) in 86%
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yield as a colourless liquid. TLC: Rf 0.15 (5% EtOAc/hexane); [α]20 = +4.80 (c 1.0,
D
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CHCl3); IR (neat): 3352, 2930, 1466, 1253, 1100, 836 cmꢀ1; H NMR (400 MHz, CDCl3): δ
3.60 (t, J = 6.6 Hz, 2H), 3.51 (dd, J = 10.5, 5.7 Hz, 1H), 3.41 (dd, J = 10.5, 6.5 Hz, 1H), 1.66ꢀ
1.56 (m, 2H), 1.56ꢀ1.47 (m, 2H), 1.45ꢀ1.36 (m, 1H), 1.36ꢀ1.23 (m, 3H), 1.16ꢀ1.04 (m, 1H),
0.91 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 67.9,
63.1, 35.5, 33.0, 32.6, 26.6, 26.0, 25.8, 18.2, 16.4, –5.3; MS (ESI): m/z 261 [M+H]+. HRMS
(ESI): calcd for C14H33O2Si: 261.2244, found: 261.2235.
(R)-7((tert-Butyldimethylsilyl)oxy)-2-methylheptanal 19: Dimethylsulfoxide (4.42 mL,
62.4 mmol) was added drop wise to a solution of oxalyl chloride (2.72 mL, 31.2 mmol) in
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anhydrous dichloromethane (142 mL) cooled at ‒78 C and the solution was maintained
under a nitrogen atmosphere. After 0.5 h a solution of alcohol 18 (4.06 g, 15.6 mmol) in
anhydrous dichloromethane (16 mL) was added dropwise. After a further 45 min,
triethylamine (17.4 mL, 124.8 mmol) was added and the mixture was warmed to rt over 1 h.
Water (100 mL) was added and the layers were separated. The aq phase was extracted with
dichloromethane (3x100 mL). The combined organic extracts were washed with water (80
mL), brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to give a yellow colour liquid. The residue was purified by column chromatography
using 5ꢀ8 % EtOAc/hexanes (v/v) as the eluent to afford the pure aldehyde 19 (3.66 g, 14.1
mmol) in 90% yield as a colourless liquid. TLC: Rf 0.25 (5% EtOAc/hexane); [α]20D = –7.04
(c 1.0, CHCl3); IR (neat): 2932, 2858, 1708, 1466, 1253, 1100, 835, 775 cmꢀ1; 1H NMR (400
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MHz, CDCl3): δ 9.61 (d, J = 2 Hz, 1H), 3.59 (t, J = 6.5 Hz, 2H), 2.37ꢀ2.27 (m, 1H), 1.77ꢀ1.64
(m, 1H), 1.56ꢀ1.45 (m, 2H), 1.42ꢀ1.28 (m, 5H), 1.09 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (100 MHz, CDCl3): δ 205, 62.9, 46.1, 32.5, 30.4, 26.8, 25.8, 25.7, 18.2, 13.2,
–5.3; MS (ESI): m/z 259 [M+H]+. HRMS (ESI): calcd for C14H31O2Si: 259.2087, found:
259.2073.
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(R)-tert-Butyldimethyl((6-methyloct-7-yn-1-yl)oxy)silane 20: To a solution of Ohiraꢀ
Bestman reagent (5.4 g, 28 mmol) in anhydrous THF (40 mL) cooled at ‒78 °C was added
NaOMe (5.4 M in MeOH, 4.66 mL, 25.2 mmol) diluted with anhydrous THF (24 mL) over a
period of 10 min. A solution of aldehyde 19 (3.6 g, 14 mmol) in anhydrous THF (24 mL) was
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added to the above solution at ‒78 C and the reaction mixture was warmed to 0 °C and
stirred for a further 30 min. The mixture was quenched with aq sat Rochelleꢀsalt solution (30
mL). The layers were separated and the aq layer was extracted with Et2O (3x25 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by column chromatography using hexanes
as the eluent to afford the pure product 20 (2.99 g, 11.76 mmol) in 84% yield as a clear
colourless liquid. TLC: Rf 0.3 (hexane); [α]20 = –11.26 (c 1.0, CHCl3); IR (neat): 3311,
D
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2932, 2113, 1253, 1100, 837 cmꢀ1; H NMR (500 MHz, CDCl3): δ 3.60 (t, J = 6.5 Hz, 2H),
2.46ꢀ2.37 (m, 1H), 2.03 (d, J = 2.4 Hz, 1H), 1.56ꢀ1.48 (m, 3H), 1.48ꢀ1.38 (m, 3H), 1.38ꢀ1.28
(m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
89.1, 68.0, 63.1, 36.7, 32.7, 27.0, 25.9, 25.6, 20.9, 18.3, –5.2; MS (ESI): m/z 255 [M+H]+.
HRMS (ESI): calcd for C15H31OSi: 255.2138, found: 255.2133.
Note!!: The amount of base has to be less than the amount of the OhiraꢀBestman reagent in
order to avoid epimerisation of the aldehyde.
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(R)-tert-Butyldimethyl((6-methylnon-7-yn-1-yl)oxy)silane 21: To a solution of 20 (2.95 g
11.65 mmol) in anhydrous THF (58 mL) cooled at ‒78 °C was added nꢀBuLi (2.5 M in
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Hexane, 14 mL, 35.0 mmol). Stirring was continued for 1 h at ‒78 C and then additionally
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for 15 min without dry ice bath. The lithium acetylide solution was again cooled down to ‒78
°C and treated with methyl iodide (4.4 mL, 70 mmol) and freshly distilled DMPU (4.2 mL,
35.0 mmol). The reaction mixture was stirred at ‒78 °C for 2 h and warmed to rt and stirred
for 12 h. The reaction was quenched with aq sat NH4Cl (40 mL). The layers were separated
and the aq layer was extracted with Et2O (3×60 mL). The combined organic extracts were
dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure the crude
product was purified by flash column chromatography using 1% EtOAc/hexanes (v/v) as the
eluent to afford methylated product 21 (2.97 g, 11.1 mmol) in 95% yield as a colourless
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liquid. TLC: Rf 0.3 (hexane); [α]20 = ‒14.34 (c 1.0, CHCl3); IR (neat): 2930, 2859, 1253,
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1100, 836 cmꢀ1; H NMR (500 MHz, CDCl3): δ 3.60 (t, J = 6.5 Hz, 2H), 2.39ꢀ2.30 (m, 1H),
1.79 (d, J = 2.4 Hz, 3H), 1.56ꢀ1.49 (m, 2H), 1.49ꢀ1.41 (m, 1H), 1.41ꢀ1.24 (m, 5H), 1.12 (d, J
= 7.0 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 83.9, 75.3, 63.1,
37.2, 32.7, 27.1, 25.9, 25.8, 25.6, 21.4, 18.3, 3.4, –5.2; MS (ESI): m/z 269 [M+H]+. HRMS
(ESI): calcd for C16H33OSi: 269.2295, found: 269.2285.
(R,E)-tert-Butyl((8-iodo-6-methylnon-7-en-1-yl)oxy)dimethylsilane 8: To a solution of
Cp2ZrHC1 (5.62 g, 21.8 mmol) in anhydrous THF (24 mL) was added the solution of alkyne
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21 (2.92 g, 10 mmol) in anhydrous THF (30 mL) and the mixture was stirred at 50 C under
nitrogen atmosphere in the absence of light for 50 min resulting in a bloodꢀred reaction
mixture. This reaction mixture was cooled to rt and stirred for 5 min when it turned to an
orange yellow solution. A solution of iodine (5.6 g, 21.8 mmol) in THF (22.0 mL) was added
via a cannula and this reaction mixture was stirred for 30 min at ‒78 oC. The temperature was
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raised to 0 C and stirring was continued for 1h. The reaction was quenched with aq sat
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Na2S2O3 (20 mL). The organic layer was separated and the aq layer was extracted with ethyl
acetate (4×40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The crude product was purified by flash column
chromatography using 0.5% EtOAc/hexanes (v/v) as the eluent to afford pure product 8 (3.45
g, 8.7 mmol) in 80% yield as a yellow colour liquid. TLC: Rf 0.42 (hexane); [α]20D = –19.08
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(c 1.0, CHCl3); IR (neat): 2929, 2857, 1463, 1252, 1099, 835, 774 cmꢀ1; H NMR (500
MHz, CDCl3): δ 5.93 (dq, J = 9.7, 1.4 Hz, 1H), 3.59 (t, J = 6.5 Hz, 2H), 2.41ꢀ2.33 (m, 1H),
2.36 (d, J = 1.5 Hz, 3H), 1.54ꢀ1.46 (m, 2H), 1.35ꢀ1.19 (m, 6H), 0.94 (d, J = 6.7 Hz, 3H), 0.89
(s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 147.4, 92.3, 63.1, 36.9, 35.6, 32.7, 27.7,
27.1, 25.9, 25.8, 20.4, 18.3, –5.2; MS (ESI): m/z 397 [M+H]+. HRMS (ESI): calcd for
C16H34OISi: 397.1418, found: 397.1400.
Preparation of Chloroacetonide 13: The chloroacetonide was prepared in a four step
sequence from (D)ꢀtartaric acid.
(4S,5S)-Dimethyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate I: In a 50 mL, oneꢀ
necked, rb flask fitted with a reflux condenser and a magnetic stirring bar under nitrogen, a
mixture of Dꢀtartaric acid (3.0 g, 20 mmol), 2,2ꢀdimethoxypropane (5.67 mL, 46 mmol),
methanol (1.2 mL) and pꢀtoluenesulfonic acid monohydrate (12 mg, 0.06 mmol) was warmed
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to 102 C with occasional swirling until a darkꢀred homogeneous solution is obtained.
Additional 2,2ꢀdimethoxypropane (2.8 mL, 22.88 mmol) and cyclohexane (13.5 mL) are
added and the flask was fitted with a 30ꢀcm Vigreux column and a variable reflux distilling
head. The mixture was heated to reflux with internal stirring and the acetone–cyclohexane
and methanol–cyclohexane azeotropes are slowly removed. Additional 2,2ꢀ
dimethoxypropane (0.18 mL, 1.44 mmol) was added and the mixture was heated under reflux
for 15 min. After the mixture was cooled it to rt, anhydrous potassium carbonate (27 mg, 0.2
mmol) was added and the mixture was stirred until the reddish colour had abated. Volatile
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material was removed under reduced pressure (water aspirator) and the residue was
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fractionally distilled under vacuum to afford the product I (3.8 g, 17.6 mmol) in 88% yield as
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a paleꢀyellow oil, bp 94–101 °C (0.5 mm Hg). TLC: Rf 0.25 (15% EtOAc/hexane); [α]20
=
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+44.93 (c 1.0, CHCl3); [lit.12d[α]20 = +48.8O (c 1.0, MeOH)]; IR (neat): 2995, 2355, 1757,
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1214, 1110, 859 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 4.80 (s, 2H), 3.82 (s, 6H), 1.48 (s, 6H);
13C NMR (75 MHz, CDCl3): δ 169.4, 113.1, 76.3, 52.0, 25.6; MS (ESI): m/z 241 [M+Na]+.
HRMS (ESI): calcd for C9H14O6Na: 241.0682, found: 241.0667.
((4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol II: To a suspension of LiAlH4
(1.7 g, 43.8 mmol) in anhydrous THF (45 mL) cooled at 0 °C was added a solution of
compound I (3.82 g, 17.5 mmol) in anhydrous THF (18 mL) dropwise over a period of 30
min. The reaction mixture was stirred for an additional 30 min at 0 °C and it was warmed to
rt and stirred for 2 h. The reaction mixture was diluted with ether (60 mL) and quenched with
ice pieces. The reaction mixture was stirred at room temperature for 1 h, and the resulting
reaction mixture was filtered through a pad of Celite, and the filter cake was washed with
EtOAc (3×100 mL) and MeOH (200 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was
purified by column chromatography using 60ꢀ70% EtOAc/hehane (v/v) as the eluent to afford
diol II (2.55 g, 15.75 mmol) in 90% yield as a colourless liquid. TLC: Rf 0.25 (60%
EtOAc/hexane); [α]20 = +6.21 (c 1.0, CHCl3); IR (neat): 3404, 2935, 2882, 1377, 1217,
D
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1056, 844 cmꢀ1; H NMR (500 MHz, CDCl3): δ 4.00ꢀ3.95 (m, 2H), 3.77 (ddd, J = 11.7, 2.6,
1.4 Hz, 2H), 3.70 (ddd, J = 11.7, 2.4, 1.2 Hz, 2H), 2.83ꢀ2.66 (brs, 2H), 1.41 (s, 6H); 13C
NMR (75 MHz, CDCl3): δ 108.5, 77.8, 61.5, 26.2; MS (ESI): m/z 185 [M+Na]+. HRMS
(ESI): calcd for C7H14O4Na: 185.0784, found: 185.0776.
((4R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol
III: To a solution of diol II (2.53 g, 15.6 mmol) in anhydrous benzene (26 mL) maintained
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under nitrogen was added 4ꢀmethoxybenzyl chloride (1.5 mL, 14.51 mmol) and KOH (0.84
g, 14.98 mmol). The reaction mixture was refluxed for 9 h and then filtered. The solvent was
removed under reduced pressure, and the crude product was purified by flash column
chromatography using 30ꢀ40% EtOAc/hexane (v/v) as the eluent to afford alcohol III (3.6 g,
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12.8 mmol) in 82% yield as a colourless oil. TLC: Rf 0.28 (30% EtOAc/hexane); [α]20
=
D
‒9.94 (c 1.0, CHCl3); [lit. 12b[α]23 = ‒8.44 (c 1.08, CHCl3)]; IR (neat): 3454, 2932, 1612,
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1513, 1375, 1248, 1082, 843 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.24 (d, J = 8.7 Hz, 2H),
6.88 (d, J =8.7 Hz, 2H), 4.53 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.02 (ddd, J =
8.2, 5.9, 5.2 Hz, 1H), 3.91 (dt, J = 8.2, 4.4 Hz, 1H), 3.80 (s, 3H), 3.75 (dt, J = 11.6, 4.3 Hz,
1H), 3.70ꢀ3.64 (m, 2H), 3.51 (dd, J = 9.8, 5.9 Hz, 1H), 2.33 (dd, J = 7.6, 4.0 Hz, 1H), 1.41 (s,
3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 158.7, 129.2, 128.8, 113.3, 108.8, 79.0,
76.2, 72.6, 69.6, 61.9, 54.6, 26.4; MS (ESI): m/z 305 [M+Na]+. HRMS (ESI): calcd for
C15H23O5: 283.1530, found: 283.1533
(4S,5R)-4-(Chloromethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane
13: To a stirred solution of III (3.58 g, 12.7 mmol) in CCl4 (64 mL) was added triphenyl
phosphine (6.7 g, 25.4 mmol) at rt and the mixture was heated at reflux for 12 h. The reaction
mixture was cooled to 0 °C, diluted with hexanes (64 mL) and stirred for 30 min. The
precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography using 3% EtOAc/hexane (v/v) as the eluent to afford
compound 13 (3.24 g, 10.79 mmol) in 85% yield as a colourless liquid. TLC : Rf 0.25 (5%
EtOAc/hexane); [α]20 = ‒1.13 (c 1.0, CHCl3); IR (neat): 2989, 2865, 1610, 1513, 1248,
D
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1084, 828 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz,
2H), 4.52 (s, 2H), 4.08ꢀ4.05 (m, 2H), 3.81 (s, 3H), 3.69ꢀ3.56 (m, 4H), 1.44 (s, 3H), 1.43 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 158.7, 129.3, 128.6, 113.1, 109.2, 77.6, 77.2, 72.5, 69.5,
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54.4, 43.9, 26.5, 26.4; MS (ESI): m/z 323 [M+Na]+. HRMS (ESI): calcd for C15H21O4ClNa:
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323.1020, found: 323.1001.
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(S)-1-((4-Methoxybenzyl)oxy)but-3-yn-2-ol 22: To freshly prepared LiNH2 (prepared in
situ by dissolving lithium metal (65 mg atom) in liq NH3 (160 mL) at ‒33 °C was added the
solution of chloride 13 (2.2 g, 10.7 mmol) in anhydrous THF (11 mL) during 3 min. After 30
min, solid NH4Cl (11 g) was added and ammonia was warmed to rt to evaporate. The residue
was partitioned between water (50 mL) and ether (50 mL). The organic layer was separated
and the aq layer was extracted with Et2O (2×50 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue
was purified by flash column chromatography using 20ꢀ25% EtOAc/hexanes (v/v) as the
eluent to afford pure product 22, (1.98 g, 9.63 mmol) in 90% yield as a colourless liquid.
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TLC: Rf 0.2 (20% EtOAc/hexane); [α]20 = +4.66 (c 1.0, CHCl3); IR (neat): 3412, 3284,
D
2909, 2115, 1512, 1246, 1030 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.27 (d, J = 8.7 Hz, 2H),
6.89 (d, J = 8.7 Hz, 2H), 4.56 (d, J = 11.6 Hz, 1H), 4.54ꢀ4.51 (m, 1H), 4.52 (d, J = 11.6 Hz,
1H), 3.80 (s, 3H), 3.62 (dd, J = 9.9, 3.7 Hz, 1H), 3.55 (dd, J = 9.9, 7.2 Hz, 1H), 2.74ꢀ2.70
(brs, 1H), 2.45 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 158.7, 129.2, 129.0,
113.3, 81.9, 73.3, 72.7, 72.4, 60.7, 54.7; MS (ESI): m/z 229 [M+Na]+. HRMS (ESI): calcd
for C12H14O3Na: 229.0835, found: 229.0821.
(S)-1-Methoxy-4-(((2-(methoxymethoxy)but-3-yn-1-yl)oxy)methyl)benzene 23: To
a
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cooled (0 C) solution of compound 22 (1.96 g, 9.53 mmol) and iꢀPr2NEt (4.9 mL, 28.6
mmol) in anhydrous dichloromethane (48 mL) was added MOMꢀCl (1.1 mL, 14.3 mmol)
slowly followed by TBAI (0.35 g, 0.95 mmol) and the mixture was stirred for 6 h at rt. After
completion of the reaction as monitored by TLC, H2O (20 mL) was added and the reaction
mixture was extracted with dichloromethane (3×30 mL) and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure to give a crude residue, which was purified
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23 (2.14 g, 8.58 mmol) in 90% yield as a light yellow liquid. TLC: Rf 0.3 (10%
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EtOAc/hexane); [α]20 = +49.67 (c 1.0, CHCl3); IR (neat): 3281, 2897, 2114, 1512, 1247,
D
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1030, 822 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz,
2H), 4.93 (d, J = 6.8 Hz, 1H) 4.68 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.54 (d, J =
11.7 Hz, 1H), 4.53 (td, J = 6.6, 2.1 Hz, 1H), 3.80 (s, 3H), 3.67ꢀ3.64 (m, 2H), 3.40 (s, 3H),
2.44 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 158.9, 129.6, 129.0, 113.5, 94.0,
79.8, 74.3, 72.7, 71.7, 64.8, 55.3, 54.8; MS (ESI): m/z 273 [M+Na]+. HRMS (ESI): calcd for
C14H18O4Na: 273.1097, found: 273.1080.
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3-((tert-Butyldiphenylsilyl)oxy)-N-methoxy-N-methylpropanamide 14: Mono TBDPS
protected 1,3ꢀpropane diol (6.2 g, 20 mmol) was dissolved in acetone (80 mL) and cooled at
o
0 C. Jones reagent (12.5 mL) (prepared by dissolution of 26.72 g CrO3 in 23 mL of conc.
H2SO4 and dilution to 100 mL with H2O) was added slowly. The reaction mixture was stirred
at the same temperature for 10 min, then the acetone was removed in vacuo. Ethyl acetate
(100 mL) was added and this solution was washed several times with H2O and once with
brine. The solution was dried over anhydrous Na2SO4 and was then evaporated in vacuo to
afford the corresponding acid (6.2 g, 19 mmol) in 95% yield as viscous oil which was used in
the next step without further purification. A solution of the acid (6.2 g, 19 mmol) in CH2Cl2
(95 mL) was cooled to 0 °C in a flameꢀdried flask. 1,1’ꢀCarbonyl diimidazole (3.7 g, 22.8
mmol) was added to the reaction mixture at this temperature. After stirring for 30 min, N,Oꢀ
dimethyl hydroxylamine hydrochloride (2.2 g, 22.8 mmol) was added and the reaction was
warmed to rt. After 4 h the salts were filtered through a cotton plug and the filtrate was
washed with aq HCl (1 M, 50 mL) and brine (50 mL). The organic layer was dried with
anhydrous Na2SO4 and concentrated to obtain Weinreb amide 14 (6.22 g, 16.7 mmol) in 88%
yield as a light yellow oil. TLC: Rf 0.2 (15% EtOAc/hexane); IR (neat): 3070, 2933, 2757,
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1664, 1426, 1109, 704 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.70ꢀ7.66 (m, 4H), 7.45ꢀ7.35 (m,
6H), 4.01 (t, J = 6.7 Hz, 2H), 3.66 (s, 3H), 3.18 (s, 3H), 2.71 (t, J = 6.7 Hz, 2H), 1.05 (s, 9H);
13C NMR (125 MHz, CDCl3): δ 172.0, 135.3, 133.4, 129.4, 127.4, 61.0, 59.9, 34.7, 31.7,
26.6, 18.9; MS (ESI): m/z 394 [M+Na]+. HRMS (ESI): calcd for C21H30NO3Si: 372.1989,
found: 372.1996.
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(S)-5-(((4-Methoxybenzyl)oxy)methyl)-13,13-dimethyl-12,12-diphenyl-2,4,11-trioxa-12-
silatetradec-6yn-8-one 24: To a stirred solution of alkyne 23 (2.12 g, 8.49 mmol) in THF
o
(28 mL) was added i-PrMgCl (2.0 M in THF, 4.24 mL, 8.5 mmol) at 0 C under nitrogen
atmosphere. After stirring at the same temperature for 1 h, the mixture was transferred to the
o
solution of Weinreb amide 14 (2.4 g, 6.53 mmol) in THF (38 mL) via cannula at 0 C under
nitrogen atmosphere. Then the mixture was warmed to rt and stirred for 8 h. The reaction was
quenched by adding aq sat NH4Cl (30 mL) and the reaction mixture was diluted with EtOAc
(25 mL). After separation of the two layers, the aq layer was extracted with EtOAc (3×25
mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous
Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash
column chromatography using 15% EtOAc/hexane (v/v) as the eluent to afford compound 24
(3.18 g, 5.68 mmol) in 87% yield as a pale yellow liquid. TLC: Rf 0.4 (15% EtOAc/hexane);
[α]20 = + 42.09 (c 1.0, CHCl3); IR (neat): 3069, 2933, 2213, 1680, 1248, 1107, 1031, 705
D
1
cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.68ꢀ7.63 (m, 4H), 7.45ꢀ7.35 (m, 6H), 7.26 (d, J = 8.5
Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.86 (d, J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.65 (d,
J = 6.1 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.51 (d, J = 11.8 Hz, 1H), 4.00 (t, J = 6.1 Hz, 2H),
3.80 (s, 3H), 3.69ꢀ3.63 (m, 2H), 3.39 (s, 3H), 2.78 (t, J = 6.1 Hz, 2H), 1.02 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 185.3, 159.2, 135.4, 133.1, 129.6, 129.5, 129.2, 127.6, 113.7, 94.7,
87.8, 84.4, 73.0, 71.0, 65.1, 59.0, 55.6, 55.1, 48.0, 26.6, 19.0; MS (ESI): m/z 578 [M+NH4]+.
HRMS (ESI): calcd for C33H44O6NSi: 578.2932, found: 578.2951.
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(5S,8S)-5-(((4-Methoxybenzyl)oxy)methyl)-13,13-dimethyl-12,12-diphenyl-2,4,11-trioxa-
12-silatetradec-6-yn-8-ol 12: A solution of compound 24 (4.1 g, 7.23 mmol) in ethyl acetate
(144 mL) was added to a suspension of [(S,S)ꢀTsDPEN]Ruꢀ(pꢀcymene)Cl (91mg, 0.144
mmol), sodium formate (9.0 g, 115.6 mmol) and 1ꢀbutylꢀ3ꢀmethylimidazolium
tetrafluoroborate (163 mg, 0.72 mmol) in water (144 mL). The reaction mixture was stirred
for 12 h at rt. The phases were separated and the aq phase was extracted with ethyl acetate
(2×100 mL). The combined organic layers were washed with brine (40 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product obtained was
purified by column chromatography using 20ꢀ25% EtOAc/hexane (v/v) as the eluent to afford
compound 12 (3.33 g, 5.93 mmol) in 82% yield as liquid. TLC : Rf 0.25 (20%
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EtOAc/hexane); [α]20 = +45.45 (c 1.0, CHCl3); IR (neat): 3448, 3070, 2932, 2116, 1513,
D
1248, 1107, 704 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.70ꢀ7.64 (m, 4H), 7.46ꢀ7.37 (m, 6H),
7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.91 (d, J = 6.7 Hz, 1H), 4.75ꢀ4.70 (m,
1H), 4.65 (d, J = 6.7 Hz, 1H), 4.59 (ddd, J = 6.8, 4.5, 1.5 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H),
4.51 (d, J = 11.7 Hz, 1H), 4.01 (ddd, J = 11.9, 7.9, 3.9 Hz, 1H), 3.84ꢀ3.78 (m, 4H), 3.66ꢀ3.60
(m, 2H), 3.38 (s, 3H), 3.29 (d, J = 5.2 Hz, 1H), 2.05ꢀ1.98 (m, 1H), 1.94ꢀ1.85 (m, 1H), 1.04
(s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.1, 135.4, 132.8, 129.8, 129.7, 129.1, 127.7,
113.6, 94.2, 86.9, 80.7, 72.8, 72.0, 65.2, 61.5, 61.1, 55.5, 55.1, 38.8, 26.6, 18.9; MS (ESI):
m/z 580 [M+NH4]+. HRMS (ESI): calcd for C33H46O6NSi: 580.3088, found: 580.3103.
(S)-(5S,8S)-5-(((4-Methoxybenzyl)oxy)methyl)-13,13-dimethyl-12,12-diphenyl-2,4,11-
trioxa-12-silatetradec-6-yn-8-yl-2-methoxy-2-phenylacetate IV: To a solution of the
alcohol 12 (14 mg, 0.025 mmol) in anhydrous CH2Cl2 (2 mL) were added (S)ꢀOꢀmethyl
mandelic acid (4.2 mg, 0.025 mmol), DCC (6.2 mg, 0.03 mmol) and a few crystals of DMAP
and the mixture was stirred for 45 min. The solvent was removed under vacuum and the
residue was purified by flash column chromatography on silica gel using 10ꢀ12%
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EtOAc/hexane (v/v) as the eluent to afford a esters IV (14.5 mg, 0.02 mmol) in 82% yield as
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a colourless oil. H NMR (400 MHz, CDCl3): δ 7.69ꢀ7.54 (m, 4H), 7.45ꢀ7.33 (m, 9H), 7.32ꢀ
7
8
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7.27 (m, 2H), 7.23 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.72 (td, J = 7.6, 1.2 Hz,
1H), 4.71 (s, 1H), 4.7 (d, J = 6.7 Hz, 1H), 4.53 (d, J = 6.7 Hz, 1H), 4.51ꢀ4.41 (m, 3H), 3.80
(s, 3H), 3.75ꢀ3.62 (m, 2H), 3.49 (dd, J = 10.7, 7.4 Hz, 1H), 3.44 (dd, J = 10.7, 4.0 Hz, 1H),
3.39 (s, 3H), 3.31 (s, 3H), 2.10ꢀ1.90 (m, 2H), 1.02 (s, 9H).
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(R)-(5S,8S)-5-(((4-Methoxybenzyl)oxy)methyl)-13,13-dimethyl-12,12-diphenyl-2,4,11-
trioxa-12-silatetradec-6-yn-8-yl-2-methoxy-2-phenylacetate V: To a solution of the
alcohol 12 (14 mg, 0.025 mmol) in anhydrous CH2Cl2 (2 mL) were added (R)ꢀOꢀmethyl
mandelic acid (4.2 mg, 0.025 mmol), DCC (6.2 mg, 0.03 mmol) and a few crystals of DMAP
and the mixture was stirred for 45 min. The solvent was removed under vacuum and the
residue was purified by flash column chromatography on silica gel using 10ꢀ12%
EtOAc/hexane (v/v) as the eluent to afford a esters V (14 mg, 0.02 mmol) in 80% yield as a
colourless oil. 1H NMR (500 MHz, CDCl3): δ 7.73ꢀ7.67 (m, 2H), 7.59ꢀ7.50 (m, 4H), 7.44ꢀ
7.32 (m, 8H), 7.29ꢀ7.23 (m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 5.71 (t, J = 7.6 Hz, 1H), 4.82 (d, J
= 6.7 Hz, 1H), 4.74 (s, 1H), 4.60 (d, J = 6.7 Hz, 1H), 4.55ꢀ4.47 (m, 3H), 4.26ꢀ4.17 (m, 2H),
3.79 (s, 3H), 3.60ꢀ3.53 (m, 2H), 3.44ꢀ3.33 (m, 8H), 1.96ꢀ1.82 (m, 2H), 0.98 (s, 9H).
(5S,7S)-5-(((4-Methoxybenzyl)oxy)methyl)-13,13-dimethyl-12,12-diphenyl-2,4,11-trioxa-
12-silatetradeca-6,7-diene 27: DEAD (1.1 mL, 7.1 mmol) was added dropwise to a solution
containing the mixture of NꢀisopropylideneꢀN'ꢀ2ꢀnitrobenzenesulfonylhydrazine (25)(1.83 g,
7.14 mmol), alcohol 12 (3.32 g, 5.9 mmol) and triphenylphosphine (1.87 g, 7.14 mmol) in
anhydrous toluene (137 mL) cooled at 0 °C under nitrogen atmosphere. After 5 min, the
reaction mixture was warmed to rt. After 20 min a mixture of trifluoroethanol and water (1:1,
67.5 mL) was added to the reaction mixture to enable formation of the allylic diazene
intermediate. After 3 h, the reaction mixture was partitioned between diethyl ether (60 mL)
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and water (60 mL) and the aq layer was extracted with diethyl ether (2×100 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chromatography using 5%
EtOAc/hexane (v/v) as the eluent to afford allene 27 (2.67 g, 4.9 mmol) in 83% yield as a
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colourless liquid. TLC: Rf 0.3 (5% EtOAc/hexane); [α]20 = +79.84 (c 1.0, CHCl3); IR
D
1
(neat): 3069, 2932, 1964, 1513, 1248, 1152, 1107, 1033, 704 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 7.69ꢀ7.64 (m, 4H), 7.45ꢀ7.35 (m, 6H), 7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 5.25 (qd, J = 7.3, 1.5 Hz, 1H), 5.10ꢀ5.03 (m, 1H), 4.74 (d, J = 6.7 Hz, 1H), 4.60 (d, J =
6.7 Hz, 1H), 4.50 (s, 2H), 4.31ꢀ4.24 (m, 1H), 3.80 (s, 3H), 3.73 (td, J = 6.8, 1.7 Hz, 2H),
3.55ꢀ3.51 (m, 2H), 3.35 (s, 3H), 2.29 (qd, J = 6.8, 2.7 Hz, 2H), 1.05 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 205.2, 158.9, 135.3, 133.6, 130.1, 129.4, 129.0, 127.4, 113.5, 94.0, 88.9,
73.4, 72.7, 72.5, 63.3, 55.1, 55.0, 32.0, 26.7, 19.0; MS (ESI): m/z 569 [M+Na]+. HRMS
(ESI): calcd for C33H42O5Na Si: 569.2693, found: 569.2701.
(2S,4S)-7-((tert-Butyldiphenylsilyl)oxy)-2-(methoxymethoxy)hepta-3,4-dien-1-ol 28: To a
solution of the PMB ether 27 (2.65 g, 4.85 mmol) in a mixture of dichloromethane (30 mL)
and pH 7 phosphate buffer (3 mL) was added DDQ (1.65 g, 7.28 mmol). The reaction
mixture was stirred for 1.5 h at ambient temperature and then diluted with Et2O (20 mL). The
organic solution was washed with water (2×10 mL) and sat aq NaHCO3 (15 mL). The
combined aq layers were extracted with Et2O (2×25 mL). The combined organic layers were
dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography using 20ꢀ25% EtOAc/hexane (v/v) as
the eluent to afford alcohol 28 (1.9 g, 4.46 mmol) in 92% yield as a clear, colourless liquid.
TLC: Rf 0.25 (20% EtOAc/hexane); [α]20D = +81.49 (c 1.0, CHCl3); IR (neat): 3450, 3070,
1
2931, 1964,
1427, 1106, 1030, 704 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.29ꢀ7.64 (m,
4H), 7.45ꢀ7.35 (m, 6H), 5.28 (qd, J = 7.1, 1.6 Hz, 1H), 5.07ꢀ5.01 (m, 1H), 4.75 (d, J = 6.7
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Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.13 (tdd, J = 7.2, 3.7, 1.6 Hz, 1H), 3.73 (td, J = 6.7, 0.8
Hz, 2H), 3.69ꢀ3.54 (m, 2H), 3.37 (s, 3H), 2.35 (dd, J = 8.3, 4.7 Hz, 1H), 2.29 (qd, J = 6.7, 2.8
Hz, 2H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 205.2, 135.4, 133.6, 129.5, 127.5,
94.5, 89.3, 88.4, 76.4, 65.4, 63.2, 55.4, 32.0, 26.7, 19.1; MS (ESI): m/z 449 [M+Na]+. HRMS
(ESI): calcd for C25H34O4NaSi: 449.2118, found: 449.2096.
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(2S,4S)-7-((tert-Butyldiphenylsilyl)oxy)-2-(methoxymethoxy)hepta-3,4-dienal 9: To a
solution of alcohol 28 (1.87 g, 4.4 mmol) in dichloromethane (44 mL) was added sodium
bicarbonate (5.55 g, 66 mmol) and DessꢀMartin periodinane (2.8 g, 6.6 mmol). The mixture
was stirred at ambient temperature for 1.5 h and then quenched with aq sat Na2S2O3 (20 mL).
After stirring for an additional 10 min, the mixture was then diluted with Et2O (20 mL) and
aq sat NH4Cl (20 mL). The layers were separated and the aq layer was extracted with Et2O
(2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was purified by flash column
chromatography using 20% EtOAc/Hexane (v/v) as the eluent to afford compound 9 (1.68 g,
3.96 mmol) in 90% yield, as a colourless liquid. TLC: Rf 0.4 (20% EtOAc/hexane); [α]20
=
D
+49.24 (c 1.0, CHCl3); IR (neat): 3070, 2932, 2858, 1964, 1734, 1427, 1108, 704 cmꢀ1; 1H
NMR (400 MHz, CDCl3): δ 9.52 (d, J = 1.3 Hz, 1H), 7.68ꢀ7.63 (m, 4H), 7.45ꢀ7.35 (m, 6H),
5.41 (qd, J = 7.1, 1.9 Hz, 1H), 5.10ꢀ5.03 (m 1H), 4.76 (d, J = 6.7 Hz, 1H), 4.66 (d, J = 6.7
Hz, 1H), 4.46 (dt, J = 7.2, 1.7 Hz, 1H), 3.73 (td, J = 6.6, 1.6 Hz, 2H), 3.37 (s, 3H), 2.31 (qd, J
= 6.6, 2.7 Hz, 2H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 206.6, 198.1, 135.4, 133.6,
129.5, 127.6, 94.9, 90.7, 85.4, 79.3, 63.1, 55.7, 31.8, 26.7, 19.1; MS (ESI): m/z 447
[M+Na]+. HRMS (ESI): calcd for C25H32O4SiNa: 447.1962, found: 447.1965.
(8S,10S,11R,14R,E)-10-(Methoxymethoxy)-2,2,12,14,21,21,22,22-octamethyl-3,3-
diphenyl-4,20-dioxa-3,21-disilatricosa-7,8,12-trien-11-ol 29 and (8S,10S,11S,14R,E)-10-
(Methoxymethoxy)-2,2,12,14,21,21,22,22-octamethyl-3,3-diphenyl-4,20-dioxa-3,21-
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disilatricosa-7,8,12-trien-11-ol 7: nꢀBuLi (2.5 M in Hexane, 0.96 mL, 2.4 mmol) was added
dropwise to a stirred solution of vinyl iodide 8 (990 mg, 2.5 mmol) in Et2O (17 mL) cooled at
‒78 °C. The reaction mixture was stirred at ‒78 °C for 20 min and at 0 °C for 10 min before
being reꢀcooled to ‒78 °C. A solution of aldehyde 9 (424 mg, 1.0 mmol) in Et2O (7 mL) was
added dropwise and the reaction mixture was warmed to 0 oC immediately and stirred at 0 °C
for 20 min. The reaction was quenched with aq sat NH4Cl (5 mL). The organic layer was
separated and the aq layer was extracted with Et2O (4×8 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purification by flash column chromatography using 10% EtOAc/Hexane
(v/v) as the eluent to afford alcohol 7 (194 mg, 0.28 mmol) in 28% yield and alcohol 29 (291
mg, 0.42 mmol) in 42% yield as a separable mixture of diastereomers (dr = 1:1.5
respectively).
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Compound 29: TLC: Rf 0.3 (10% EtOAc/hexane); IR (neat): 3469, 3070, 2930, 1964, 1467,
1
1253, 1104, 704 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.68ꢀ7.63 (m, 4H), 7.44ꢀ7.35 (m, 6H),
5.27 (d, J = 9.6 Hz, 1H), 5.20 (q, J = 6.7 Hz, 1H), 5.04ꢀ4.99 (m, 1H), 4.71 (d, J = 6.6 Hz,
1H), 4.51 (d, J = 6.6 Hz, 1H), 4.12 (dd, J = 8.4, 5.0 Hz, 1H), 4.09ꢀ4.07 (m, 1H), 3.73 (t, J =
6.7 Hz, 2H), 3.57 (t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 2.42ꢀ2.33 (m, 1H), 2.29 (qd, J = 6.7, 2.4
Hz, 2H), 1.61 (d, J = 1.2 Hz, 3H), 1.51ꢀ1.44 (m, 2H), 1.33ꢀ1.19 (m, 6H), 1.04 (s, 9H), 0.92
(d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 206.4, 135.5,
134.3, 133.7, 131.1, 129.5, 127.5, 93.7, 88.3, 87.3, 78.0, 76.7, 63.4, 63.2, 55.5, 37.4, 32.8,
32.2, 31.9, 27.2, 26.8, 25.9, 20.9, 20.8, 19.1, 18.3, 13.0, ‒5.2; MS (ESI): m/z 717 [M+Na]+.
HRMS (ESI): calcd for C41H66O5Si2Na: 717.4341, found: 717.4347.
Compound 7: TLC: Rf 0.25 (10% EtOAc/hexane); [α]20 = +84.07 (c 0.6, CHCl3); IR
D
1
(neat): 3452, 2926, 2856, 1964, 1463, 1102, 1028, 703 cmꢀ1; H NMR (500 MHz, CDCl3): δ
7.68ꢀ7.64 (m, 4H), 7.44ꢀ7.35 (m, 6H), 5.22ꢀ5.14 (m, 2H), 4.87ꢀ4.82 (m, 1H), 4.75 (d, J = 6.5
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Hz, 1H), 4.54 (d, J = 6.5 Hz, 1H), 4.03 (t, J = 8.2 Hz, 1H), 3.87 (d, J = 7.9 Hz, 1H), 3.72 (t, J
= 6.8 Hz, 2H), 3.56 (t, J = 6.5 Hz, 2H), 3.36 (s, 3H), 2.40ꢀ2.32 (m, 1H), 2.28 (qd, J = 6.8, 2.7
Hz, 2H), 1.60 (d, J = 1.2 Hz, 3H), 1.50ꢀ1.43 (m, 2H), 1.33ꢀ1.21 (m, 5H), 1.21ꢀ1.14 (m, 1H),
1.04 (s, 9H), 0.93 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 205.9, 136.8, 135.5, 133.7, 131.3, 129.5, 127.5, 94.1, 88.53, 88.50, 80.5, 77.7,
63.3, 63.2, 55.7, 37.4, 32.8, 32.1, 31.9, 29.6, 27.1, 26.7, 25.9, 20.8, 19.1, 18.3, 12.0, –5.2; MS
(ESI): m/z 717 [M+Na]+. HRMS (ESI): calcd for C41H66O5Si2Na: 717.4341, found:
717.4356.
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Mandelate esters of the mixtutre of alcohols 7 and 29 (VI): To a solution of the mixture of
alcohols 7 and 29 (16 mg, 0.023 mmol) in anhydrous CH2Cl2 (2 mL) were added (R)ꢀOꢀ
methyl mandelic acid (4 mg, 0.023 mmol), DCC (6 mg, 0.028 mmol) and a few crystals of
DMAP were added and the mixture was stirred for 45 min. The solvent was removed under
vacuum and the residue was purified by flash column chromatography on silica gel using 5ꢀ
7% EtOAc/hexane (v/v) as the eluent to afford esters VI (15.5 mg, 0.018 mmol) in 80% yield
1
as a colourless oil. The data for the ester of alcohol 29 is denoted with an asterisk. H NMR
(500 MHz, CDCl3): δ 7.68ꢀ7.62 (m, 8H), 7.46ꢀ7.29 (m, 22H), 5.24 (d, J = 9.2 Hz, 1H)*, 5.20ꢀ
5.10 (m, 4H), 5.06 (d, J = 9.5 Hz, 1H), 4.82ꢀ4.74 (m, 4H), 4.65 (d, J = 6.7 Hz,1H), 4.45 (d, J
= 6.7 Hz, 1H), 4.39 (d, J = 6.7 Hz, 1H)*, 4.20 (d, J = 6.7 Hz, 1H)*, 4.19 (t, J = 7.2 Hz, 1H),
4.10 (t, J = 8 Hz, 1H) *, 3.74ꢀ3.66 (m, 4H), 3.55 (t, J = 6.6 Hz, 2H)*, 3.54 (t, J = 6.6 Hz, 2H),
3.42 (s, 3H), 3.41 (s, 3H)*, 3.40 (s, 3H)*, 3.30 (s, 3H), 2.30ꢀ2.21 (m, 4H), 1.97ꢀ1.90 (m, 2H),
1.74ꢀ1.67 (m, 4H), 1.66ꢀ1.56 (m, 8H), 1.55 (d, J = 1.2 Hz, 3H)*, 1.46ꢀ1.38 (m, 4H), 1.29 (d, J
= 1.2 Hz, 3H), 1.04 (s, 9H), 1.03 (s, 9H)*, 0.89 (s, 9H)*, 0.88 (brs, 12H), 0.77 (d, J = 6.6 Hz,
3H)*,
0.02
(s,
12H).
(8S,10S,14R,E)-10-(Methoxymethoxy)-2,2,12,14,21,21,22,22-octamethyl-3,3-diphenyl-
4,20-dioxa-3,21-disilatricosa-7,8,12-trien-11-one VII: To a solution of alcohol 29 (278 mg,
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0.4 mmol) in dichloromethane (8 mL) was added sodium bicarbonate (504 mg, 6 mmol) and
DessꢀMartin periodinane (254 mg, 0.6 mmol). The mixture was stirred for 1.5 h at ambient
temperature and then quenched with aq sat Na2S2O3 (5 mL). After stirring for an additional
10 min, the mixture was then diluted with Et2O (5 mL) and aq sat NH4Cl (5 mL). The layers
were separated and the aq layer was extracted with Et2O (2×5 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography using 5ꢀ8% EtOAc/Hexane
(v/v) as the eluent to afford compound VII (243 mg, 0.35 mmol) in 88% yield as light yellow
liquid. TLC: Rf 0.15 (5% EtOAc/hexane); [α]20D = +109.76 (c 0.33, CHCl3); IR (neat): 2930,
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2858, 1964, 1680, 1466, 1105, 1033, 704; H NMR (500 MHz, CDCl3): δ 7.68ꢀ7.63 (m, 4H),
7.45ꢀ7.35 (m, 6H), 6.43 (dq, J = 9.7, 1.2 Hz, 1H), 5.32ꢀ5.23 (m, 2H), 5.19ꢀ5.13 (m, 1H), 4.76
(d, J = 6.8 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 3.72 (td, J = 6.6, 0.6 Hz, 2H), 3.58 (t, J = 6.5
Hz, 2H), 3.33 (s, 3H), 2.59ꢀ2.52 (m, 1H), 2.30 (qd, J = 6.7, 2.6 Hz, 2H), 1.79 (d, J = 1.2 Hz,
3H), 1.52ꢀ1.45 (m, 2H), 1.43ꢀ1.34 (m, 1H), 1.34ꢀ1.21 (m, 5H), 1.04 (s, 9H), 1.00 (d, J = 6.5
Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 206.2, 197.4, 150.3,
135.4, 133.7, 133.6, 129.5, 127.6, 94.3, 89.9, 89.0, 75.0, 63.2, 63.1, 55.8, 36.7, 33.5, 32.7,
31.9, 27.2, 26.7, 25.9, 25.8, 20.0, 19.1, 18.3, 11.8, –5.2; MS (ESI): m/z 715 [M+Na]+. HRMS
(ESI): calcd for C41H64O5Si2Na: 715.4184, found: 715.4181.
(8S,10S,11S,14R,E)-10-(Methoxymethoxy)-2,2,12,14,21,21,22,22-octamethyl-3,3-
diphenyl-4,20-dioxa-3,21-disilatricosa-7,8,12-trien-11-ol 7: To a solution of ketone VII
(235 mg, 0.34 mmol) in 1:1 mixture of dichloromethane/water (1.8 mL) were added sodium
formate (231 mg, 3.4 mmol) and nꢀBu4NBr (32.8 mg, 0.102 mmol). The biphasic reaction
mixture was vigorously stirred and (S,S)ꢀNoyori catalyst (5.4 mg, 2.5 mol%) was added.
After stirring for 15 h, an additional 1 mol% of catalyst was added and the reaction mixture
was stirred for an additional 12 h. The layers were separated and the aq layer was extracted
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with dichloromethane (2×5 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under the reduced pressure to afford a separable mixture
of alcohol 7 and 29 (200 mg, 0.289 mmol) in 85% combined yield as 9:1 mixture of isomers
respectively.
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tert-Butyl(2-((2S,5S,6S)-6-((R,E)-9-((tert-butyldimethylsilyl)oxy)-4-methylnon-2-en-2-yl)-
5-(methoxymethoxy)-5,6-dihydro-2H-pyran-2-yl)ethoxy)diphenylsilane 2: To a solution
of the allene 7 (160 mg, 0.23 mmol) in anhydrous toluene (3 mL) under nitrogen was added
(PPh3)2AuCl (5.9 mg, 5 mol%) and AgSbF6 (4.1 mg, 5 mol%) The mixture was stirred at rt
for 6 h. The mixture was filtered through Celite, and the filtrate was concentrated under
reduced pressure. The crude product was purified by flash column chromatography using 5ꢀ
6% EtOAc/Hexane (v/v) as the eluent to afford compound 2 (99 mg, 0.14 mmol) in 62%
yield as a light yellow liquid. TLC: Rf 0.3 (5% EtOAc/hexane); [α]20 = +35.08 (c 0.22,
D
CHCl3); IR (neat): 2927, 2856, 1741, 1636, 1103, 1041, 768 cmꢀ1; 1H NMR (400 MHz,
CDCl3): δ 7.69ꢀ7.64 (m, 4H), 7.44ꢀ7.33 (m, 6H), 6.04ꢀ5.94 (m, 2H), 5.36 (dt, J=9.5, 1.2 Hz,
1H), 4.72ꢀ4.66 (m, 2H), 4.58 (d, J = 6.8 Hz, 1H), 3.99 (s, 1H), 3.89 (dd, J = 5.0, 2.2 Hz, 1H),
3.88ꢀ3.83 (m, 1H), 3.73ꢀ3.67 (m, 1H), 3.57 (t, J = 6.6 Hz, 2H), 3.35 (s, 3H), 2.43ꢀ2.35 (m,
1H), 1.92ꢀ1.81 (m, 1H), 1.75ꢀ1.65 (m, 4H), 1.51ꢀ1.40 (m, 2H), 1.34ꢀ1.17 (m, 6H), 1.04 (s,
9H), 0.93 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
135.5, 134.1, 133.9, 132.4, 130.0, 129.5, 127.6, 124.4, 95.7, 74.0, 70.0, 68.7, 63.3, 60.4, 55.4,
37.4, 34.4, 32.8, 31.8, 29.6, 27.3, 26.8, 25.9, 20.9, 19.2, 18.3, 13.8, –5.2; MS (ESI): m/z 717
[M+Na]+. HRMS (ESI): calcd for C41H66O5Si2Na: 717.4341 found: 717.4354.
Supporting Information
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HPLC chromatogram, H and C NMR spectroscopic characterization data. This material is
available free of charge via the internet at http://pubs.acs.org.
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ACKNOWLEDGEMENT
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N. Satyanarayana is thankful to Council of Scientific and Industrial Research (CSIR)ꢀNew
Delhi for fellowship. S. R is grateful to the Department of Science and Technology, New
Delhi for funding the project (EMR/2014/000753) and CSIR, New Delhi for funding under
the XII five year plan programme entitled ORIGIN (CSCꢀ108).
REFERENCES
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(1) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Hofle, G. Tetrahedron Lett. 1985, 26,
6031.
(2) Irschik, H.; Jansen, R.; Gerth, K.; Hofle, G.; Reichenbach, H. J. Antibiot. 1987, 40, 7.
(3) Jansen, R.; Irschik, H.; Reichenbach, H.; Schomburg, D.; Wray, V.; Hofle, G. Liebigs
Ann. Chem. 1989, 111.
(4) Smith, A. B., III; Dong, S.; Brenneman, J. B.; Fox, R. J. J. Am. Chem. Soc. 2009, 131,
12109 and references cited therein.
(5) Crimmins, M. T.; Haley, M. W.; O’Bryan, E. A. Org. Lett. 2011, 13, 4712 and references
cited therein.
(6) (a) Smith, A. B., III; Dong, S. Org. Lett. 2009, 11, 1099 and references cited therein. (b)
Lee, K.; Kim, H.; Hong, J. Eur. J. Org. Chem. 2012, 1025. (c) Sridhar, Y.; Srihari, P. Org.
Biomol. Chem. 2013, 11, 4640 and references cited therein. (d) Michaelis, L.; Schinzer, D.
Synlett. 2014, 25, 951 and references cited therein
(7) Raghavan, S.; Rajendar, S. Org. Biomol. Chem. 2016, 14, 131. Addition of thiophenol to
methallyl alcohol in the presence of catalytic amount of AIBN yielded the racemic alcohol
15, which was resolved using Amano lipase to furnish the (S)ꢀalcohol in 45% yield and 99%
ee.
(8) (a) Dilworth, B. M.; McKervey, M. A. Tetrahedron. 1986, 42, 3731. (b) Raghavan, S.;
Vinoth Kumar, V.; Raju Chowhan, L. Synlett 2010, 1807.
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(9) Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem.1979, 44, 4148 and references
cited therein
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9
(10) (a) Ohira, S.; Synth. Commun. 1989, 19, 561. (b) Muller, S, J.; Liepold, B.; Roth, G. J.;
Bestmann, H, J. Synlett. 1996, 521.
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(11) Panek, S. J.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(12) (a) Kim, B. M.; Bae, S. J.; So, S. M.; Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang, J. Org.
Lett. 2001, 3, 2349. (b) Roulland, E. Angew. Chem. Int. Ed. 2008, 47, 3762. (c) Lo, H. J.;
Chang, Y. K.; Yan, T. H. Org. Lett. 2012, 14, 5896. (d) Li, B.; Yang, X.; Yang , K.; Fu, E.
Synth. Commun. 2005, 35, 2603.
(13) Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett. 1988, 29, 2737.
(14) The amide 14 was prepared by Jones oxidation of the monoꢀprotected silyl ether of 1,3ꢀ
propanediol followed by treatment of the resulting acid with carbonyldiimidazole and N,Oꢀ
dimethylhydroxylamine hydrochloride. For related preparation, see: Ng, S.M.; Bader, S.J.;
Snaper, M. L. J. Am. Chem. Soc. 2006, 128, 7315.
(15) (a) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 1912. (b) Matsumara, K.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738.
(16) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (b) Movassaghi, M.;
Ahmad, O. K. J. Org. Chem. 2007, 72, 1838.
(17) Fukuyama, T.; Jow, C.ꢀK.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373 and references
cited therein.
(18) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(19) Meyer, S. D.; Schreiber, S. J. Org. Chem. 1994, 59, 7549 and references cited therein.
(20) Attemted reaction of aldehyde 9 with the alkenylzinc species, obtained from 21 by
reaction with Schwartz reagent followed by transmetalation with diethylzinc, did not furnish
any desired product, instead a complex mixture of products resulted. For transmetalation of
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alkenylzirconium to alkenylzinc species and addition to aldehyde, see: Wipf, P.; Xu, W.
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Tetrahedron Lett. 1994, 35, 5197.
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(21) (a) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.;
Walsgroveb, T.; Willsa, M. Tetrahedron. 2006, 62, 1864. (b) Nicolaou, K. C.; Adsool, V. A.;
Hale, C. R. H. Angew. Chem. Int. Ed. 2011, 50, 5149.
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(22) Gockel, B.; Krause. N. Org. Lett. 2006, 8, 4485.
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