A Stereoselective Synthesis of the Carbon Backbone of Phoslactomycin B

Article abstract of DOI:10.1002/ejoc.201700379

A convergent synthesis of the entire carbon framework of phoslactomycin B is disclosed. An initial route aimed to create the C-8 tetrasubstituted stereocentre through regioselective intermolecular coupling between an internal alkyne and an allyl silyl ether, adopting Trost's protocol, followed by [2,3] sigmatropic rearrangement. But this was not successful. In a second approach, a propargylic sulfide was rearranged to give an unsaturated ketone. This was then treated with lithio acetonitrile to create the C-8 stereocentre selectively. The C-4 and C-5 stereocentres were introduced by a non-Evans syn-aldol reaction using Crimmins's protocol. The C-9 and C-11 carbinol centres were created by asymmetric transfer hydrogenation. The (Z,Z)-diene moiety was introduced by partial reduction of a diyne following Hansen's modification of the Boland reduction reaction.

Full text of DOI:10.1002/ejoc.201700379

A Journal of
Accepted Article
Title: A Stereoselective Synthesis of the Cabon Backbone of
Phoslactomycin B
Authors: Sadagopan Raghavan and Javed Patel
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700379
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700379
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
A Stereoselective Synthesis of the Cabon Backbone of
Phoslactomycin B
a,b
a,b
Sadagopan Raghavan* , Javed Sardar Patel,
a
Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad,
b
India, Academy of Scientific and Innovative Research, Indian Institute of Chemical
Technology, Hyderabad, India.
Email:sraghavan@iict.res.in
Abstract: A convergent synthesis of the entire carbon framework of phoslactomycin B is
disclosed. The first route aimed at creating the C8 tetrasubstituted stereocenter by a
regioselective intermolecular coupling between an internal alkyne and allyl silyl ether,
adopting Trost's protocol followed by [2,3] sigmatropic rearrangement was not successful. In
the second approach, a propargylic sulfide was rearranged to an unsaturated ketone which
was further reacted with lithio acetonitrile to create the C8 stereocenter selectively. The C4
and C5 stereocenters were introduced by the non-Evans syn-aldol reaction using Crimmins'
protocol. The C9 and C11 carbinol centers were created by asymmetric transfer
hydrogenation. The (Z,Z)-diene moiety was introduced by a partial reduction of a diyne
following Hansen's modification of Boland reduction reaction.
Inroduction
Phoslactomycins A-F, (Figure 1) isolated in 1989 from a strain of Streptomyces
nigrescens, were found to exhibit potent activity against phytopathogenic fungi.[1] These
compounds possess common structural characteristics including an ,-unsaturated -
lactone, an alkene with (E)-configuration (C6-C7), a tertiary alcohol at C8 substituted by a 2-
amino ethyl chain, a phosphate at C9, a secondary hydroxyl at C11 and conjugated (Z,Z)
diene (C12-C15) with a cyclohexyl group at C15 and a variety of substituents at C18 on the
cyclohexane ring. Phoslactomycin-B was also isolated from the fermentation broth of
Streptomyces hygroscopicus and was reported to be active against L1210, P388 and EL4
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
[2]
murine cancer cell lines. The structurally related leustroducsins A-C were isolated from the
culture broth of Streptomyces platensis[3] (SANK 60191) and were shown to possess
[
4]
bioactivities such as antibacterial, antifungal and antitumor activity. The mode of action of
phoslactomycins[5] and leuctroducsins was shown to be via inhibition of serine-threonine
[
6]
phosphatase 2A, an enzyme involved in the regulation of several biological events.
Figure-1. Phoslactomycins (PLMs) A-F and Leustroducsins A-C.
To date, five formal/total synthesis of PLMs[7,8,9,10] have been reported. Similarly,
leuctroducsin B has been a target of interest for the synthetic community.[11] Evans aldol,[7,10]
[
8]
[9]
Brown-type pentenylation and [2,3]-Wittig rearrangement have been employed to control
the configuration at C4 and C5 stereocenters. The 1,2-diol at C8-C9 has been installed by
Sharpless' asymmetric dihydroxylation[8,10] or chelation controlled addition to a ketone,[7,9]
and in all the syntheses, the C13-C14 bond is constructed by a Stille coupling.
Herein, we report a new convergent approach to the entire carbon chain of PLM B,
using a unique protocol employing an -chloro sulfide for C-C bond formation and Mislow-
Evans rearrangement for C-O bond formation to create the C6-C7 bond and C8 stereocenter.
The initial retrosynthetic analysis is depicted in Scheme 1.
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European Journal of Organic Chemistry
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Scheme 1. Retrosynthetic Analysis of PLM B.
PLM B was envisaged to be obtained from the key intermediate 2 by elaboration of
C13-C14 bond by reaction with alkenyl stannane 3, phosphorylation of C9 OH, oxidation to
lactone and global deprotection. The intermediate 2 was expected to be obtained by a [2,3]
sigmatropic rearrangement of the sulfoxide, derived eventually from allylic sulfide 4, which
in turn was envisioned to be obtained by an ambitious regioselective intermolecular coupling
between alkyne 5 and allyl ether 6 employing Trost’s protocol[12] using Ru(II) catalyst. The
propargylic sulfide 5 was imagined to be obtained from the reaction of the -chloro sulfide
derived from sulfide 7 with alkynylzinc bromide derived from alkyne 8.
Result and discussion
In keeping with the above retrosynthetic analysis, since the eventual creation of the
C8 stereocenter rested on the successful and regioselective intermolecular coupling of a
densely functionalised internal alkyne 5 with an alkene such as 6, it was deemed prudent to
assess the practicality of the proposal on a simpler model substrate 22, the synthesis of which
is detailed in Scheme 2.
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European Journal of Organic Chemistry
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Scheme 2. Synthesis of Model Alkyne 22.
The synthesis of alkyne 22 began with the diol 9, obtained by hydrolytic kinetic
resolution of rac-epichlorohydrin,[13] that on selective monoprotection furnished chlorohydrin
1
0. Displacement of chlorine by thiophenol in the presence of DBU yielded sulfide 11 which
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
was protected as its TBS ether under standard conditions to afford compound 12. The sulfide
2 on treatment with N-chlorosuccinimide afforded the -chloro sulfide 13, which on
1
reaction with alkynylzinc bromide, prepared from TMS acetylene,[14] afforded propargylic
sulfide 14 stereoselectively.[15] The observed diastereoselectivity can be rationalized by the
reaction proceeding through a putative transition state I wherein the sulfenium ion is eclipsed
by the OTBS group and the alkynylzinc reagent appoaches it from the face away from the
bulky CH
2
OTBDPS group. Deprotection of the TMS group with catalytic quantity of K
2
CO
3
in methanol afforded alkyne 15. The synthesis of aldehyde 20 began from commercially
available -chloroketo ester 16 which was converted to the p-methoxybenzyl ether 17
following literature precedent.[16] Asymmetric hydrogenation[17] employing Noyori’s catalyst
yielded alcohol 18 (99% ee) which was protected as its MOM ether 19. Selective reduction of
the ester to aldehyde 20 proceeded cleanly using DIBAL-H at low temperature. Reaction of
aldehyde 20 with the lithium acetylide prepared from alkyne 15 yielded an inseparable
mixture of epimeric alcohols 21 and 22 in a 1:1 ratio. Oxidation using DMP, furnished the
ketone 23 in good yield. Stereoselective transfer hydrogenation of ketone 23 using Noyori’s
protocol[18] delivered alcohol 22.
With the internal alkyne 22 becoming available, the enyne coupling was attempted
with the silyl ether 6. The product expected from the reaction was a silyl enol ether which
was expected to be chemoselectively oxidized to an aldehyde[19] (eventually to be converted
to the aminoethyl side chain) in the presence of the other double bond (C6-C7). In the event,
reaction of 22 with silyl ether 6 resulted in only recovery of starting material under a variety
of reaction conditions.
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
Scheme 3. Attempted Enyne Coupling.
The reaction of 22 with a less hindered alkene 25, proceeded in a low yield 25% and poor
regioselectivity (1:1) to furnish the trisubstituted alkenes 26 and 27, Scheme 3. The above
result illustrated that the intermolecular enyne coupling was not a viable disconnection to
construct the trisubstituted alkene 4.
An alternate retrosynthetic disconnection of PLM B is depicted in Scheme 4. PLM B
1
, was envisaged to be obtained from tetraene derivative 28.
Scheme 4. Revised Retrosynthetic Analysis.
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
It was decided to incorporate the (Z,Z)-diene moiety even in the early stage of the synthesis,
since intramolecular enyne coupling was no more an issue unlike the previous retrosynthetic
disconnection wherein an intermolecular enyne coupling was envisaged. The C8 stereocenter
in 28 was expected to be introduced by a stereoselective addition of a two-carbon nucleophile
to the unsaturated ketone that would result from a [2,3] sigmatropic rearrangement of
propargylic sulfide 29. The sulfide 29 was envisioned to be obtained from sulfide 30 and
aldehyde 31. The aldehyde 31 itself can be obtained from diyne 32. On the other hand,
sulfide 30 can be traced back to thiazolidinethione 33 and aldehyde 34.[20]
The synthesis of sulfide 30 began with non-Evans syn-aldol reaction[21] of
thiazolidinethione 33 with phenylthio acetaldehyde 34, obtained by oxidation of phenylthio
ethanol with IBX, to yield compound 35. Protection of the hydroxyl as its TBS ether yielded
compound 36. Removal of the auxiliary using DIBAL-H afforded aldehyde 37 that upon
HWE olefination following Ando’s protocol[22] furnished (Z)-alkene 39 (95:5). Acid
treatment resulted in TBS deprotection followed by cyclisation to afford -lactone 7, Scheme
5
.
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
Scheme 5. Synthesis of Sulfide 30.
The C-C bond formation reaction using the -chloro sulfide, derived from 7, was
attempted using the alkynylzinc bromide derived from TMS-acetylene. A complex mixture of
products resulted, probably as a consequence of elimination.[23] Pleasingly though, the
reaction proceeded cleanly with -chloro sulfide generated from sulfide 38 to yield the
propargylic sulfide 40.[15] The trimethylsilyl and t-butyldimethyl silyl groups of compound 40
were deprotected using TBAF to furnish alkynol 41. Lactonisation to yield 42 proceeded
cleanly in the presence of catalytic amount of titanium tetraisopropoxide in refluxing
benzene.[7] Reduction of lactone to lactol using DIBAL-H followed by reaction with iso-
propanol in presence of PPTS yielded acetal 30 as one of the key intermediates.
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
Scheme 6. Synthesis of Aldehyde 31.
The synthesis of aldehyde 31 is depicted in Scheme 6. Commercially available
ethynylcyclohexane 43 was converted to bromoalkyne 44 by treatment with N-
bromosuccinimide in presence of silver nitrate. Cadiot-Chodkiewicz cross coupling[24] of
compound 44 with 2-methyl-3-butyn-2-ol 45 furnished diyne 46. Treatment with KOH
yielded diyne 32.[25] The lithio derivative of 32 was reacted with ethyl chloroformate to
afford ester 47. Further reaction of ester 47 with the anion of ethyl acetate furnished the keto
ester 48. Asymmetric transfer hydrogenation using Noyori’s protocol[18] yielded alcohol 49.
The diyne was stereoselectively reduced to the Z,Z-diene 50 using Hansen’s modification[26]
to the Boland protocol.[27] Protection of the hydroxyl as its silyl ether 51 and reduction of the
ester using DIBAL-H furnished aldehyde 31 constituting the C9-C21 subunit.
With both the partners being available the creation of the C8-C9 bond was explored.
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
The lithio anion of alkyne 30 was reacted with aldehyde 31 to furnish an inseparable mixture
of alcohols 52 and 53.
Scheme 7. Synthesis of Ketone 55.
Oxidation of the epimeric alcohols using DMP[28] yielded the ketone 54 which was
stereoselectively reduced by asymmetric transfer hydrogenation using Noyori’s catalyst
following Spur’s protocol[29] to yield alcohol 53. Protection employing standard conditions
afforded TES ether 29. Oxidation of the sulfide in 29 with m-CPBA afforded an equimolar
mixture of sulfoxides which without isolation was subjected to [2,3] sigmatropic
rearrangement[30] in the presence of 2-mercapto-1-methylimidazole[31] as a thiophilic agent, to
yield unsaturated ketone 55, Scheme 7.
The amino ethyl side chain was introduced by way of reaction of lithio acetonitrile
with ketone 55 to afford a 4:1 mixture of tertiary alcohols 56 and 57. The structure of the
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
major isomer 56 was unambiguously assigned by NOE studies on the acetonide 58, obtained
by selective deprotection of the TES ether and reaction of the ensuing diol with 2,2-
dimethoxypropane. NOE between C9H and CH
2
CN supported the structural assignment to
compound 56.
Scheme 8. Synthesis of Carbon Backbone of PLM-B.
The formation of 56 can be rationalized by a Felkin-Anh model wherein the acetonitrile anion
attacks the carbonyl group from the face away from the OTES moiety. Reduction of the
nitrile in 56 with LAH afforded the primary amine with concomitant deprotection of the TES
ether. The primary amine was protected as its allyl carbamate 59 to provide the all carbon
containing subunit of PLM-B, Scheme 8.
Conclusion
In conclusion, we have developed a new strategy to the entire carbon framework of
PLM-B. The key steps include non-Evans syn aldol reaction to forge the C4 and C5
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
stereogenic centers, utilization of an α-chloro sulfide for the preparation of a propargylic
sulfide, [2,3] sigmatropic rearrangement of a sulfoxide to prepare an unsaturated ketone and
stereoselective introduction of the C8 stereocenter using lithio acetonitrile. Also unlike earlier
reports the (Z,Z)-diene is introduced early in the synthesis. The C9 and C11 carbinols are
stereoselectively introduced by transfer hydrogenation. The disclosed strategy would prove
useful in the synthesis of related natural products.
Acknowledgements
J. S. Patel 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 (SR/S1/OC-5/2011) and CSIR, New Delhi for funding under the XII five
year plan programme entitled ORIGIN (CSC-108).
Experimental section
(R)-1-((tert-Butyldiphenylsilyl)oxy)-3-chloropropan-2-ol (10)
A 250 mL flask equipped with a stir bar and a thermometer was charged with (R,R)-Co(salen)
o
complex (1.47 g, 2.15 mmol). The catalyst was dissolved in THF (13 mL) and cooled to 4 C.
The flask was charged with (±-epichlorohydrin (8.45 mL, 108.0 mmol) followed by the
addition of H
2
O (901 L, 50 mmol) over 1.5 h via syringe pump. The reaction mixture was
o
o
stirred at 4 C for 24 h. It was then cooled to –78 C and diluted with CH
2
Cl
O (75 mL) was added. The aqueous
(15 mL x 2). The remaining catalyst was removed
2
(250 mL). The
solution was transferred to a separating funnel and H
layer was separated, extracted with CH Cl
2
2
2
by filtration. The filtrate was concentrated in vacuo to give 5.96 g of (R)-3-chloro-1,2-
1
propanediol (54 mmol, 50% yield). H NMR (300 MHz, CDCl
3
): 5.41-4.41 (bs, OH), 3.99-
3
.82 (m, 1H), 3.81-3.49 (m, 4H).
o
To a stirred solution of above diol (5.96 g, 54.0 mmol) in CH
2
Cl
2
(200 mL) cooled to 0 C
was added imidazole (7.3 g, 108.0 mmol) followed by TBDPSCl (14.2 mL, 53.0 mmol)
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
dropwise over the period of 15 minutes. The reaction mixture was allowed to warm to room
temperature and stirred for 4 h. The reaction mixture was quenched by the addition of H
150 mL) and diluted with CH Cl (100 mL). The layers were separated and the organic layer
was washed with brine (100 mL), dried over Na SO , filtered and the solvent evaporated
2
O
(
2
2
2
4
under reduced pressure. The residual oil was purified by flash chromatography on silica gel
using 5% EtOAc/hexane (v/v) as the eluent to give pure monoprotected silyl ether 10 (15.9 g,
8
5% yield) as a clear oil. TLC: R
neat): 3550, 2856, 1510, 1402, 1262, 1066, 1152, 805 cm ; H NMR (500 MHz, CDCl
7.70-7.63 (m, 4H), 7.46-7.38 (m, 6H), 3.95-3.88 (m, 1H), 3.78 (dd, J = 10.3, 4.8 Hz, 1H),
.73 (dd, J = 10.2, 5.1 Hz, 1H), 3.68 (dd, J = 10.9, 5.4 Hz, 1H), 3.63 (dd, J = 11.1, 5.5 Hz,
f
0.2 (5% EtOAc/hexane); [α]25
D
= –15.2 (c 1, CHCl
3
); IR
-1 1
(
3
):

3
1
1
1
3
H), 2.51 (d, J = 5.9 Hz, 1H), 1.07 (s, 9H); C NMR (75 MHz, CDCl ):  135.4, 132.7,
3
+
29.8, 127.7, 71.4, 64.3, 45.7, 26.8, 19.2; MS (ESI): m/z 371 [M+Na] . HRMS (ESI): calcd.
for C19
H
25ClNaO
2
Si 371.1205, Found 371.1223.
(R)-1-((tert-Butyldiphenylsilyl)oxy)-3-(phenylthio)propan-2-ol (11)
To a stirred mixture of DBU (1.88 mL, 12.60 mmol) and thiophenol (1.28 mL, 12.60 mmol)
o
in toluene (24 mL) cooled to 0 C was added a solution of chloro alcohol 10 (4.38 g, 12.60
mmol) in toluene (8 mL) dropwise over 5 min. The resulting reaction mixture was stirred at
room temperature for 12 h. The precipitated DBU·HCl salt was removed by filtration. The
filtrate was washed with H
2
O (8 mL) and dried over anhydrous Na
2
SO . Toluene was
4
evaporated in vacuo and the residue was purified by column chromatography using 1% ethyl
acetate/hexane (v/v) as the eluent to furnish sulfide 11 (4.14 g, 78% yield) as a colorless
liquid. TLC: R
f
0.2 (5% EtOAc/hexane); [α]25
D
= –37.0 (c 1, CHCl
3
); IR (neat): 3448, 2936,
865, 1610, 1523, 1276, 1054, 1161, 800 cm ; H NMR (400 MHz, CDCl ): 7.66-7.62 (m,
H), 7.47-7.33 (m, 8H), 7.29-7.24 (m, 2H), 7.21-7.17 (m, 1H), 3.85-3.80 (m, 1H), 3.75-3.72
-1 1
2
4
3
(m, 2H), 3.15 (dd, J = 13.7, 5.6 Hz, 1H), 3.03 (dd, J = 13.7, 5.6 Hz, 1H), 2.65 (bs, 1H), 1.07
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
1
3
(
s, 9H); C NMR (125 MHz, CDCl
3
):  135.5, 134.7, 132.9, 129.8, 129.4, 128.9, 127.7,
+
1
26.2, 70.2, 66.1, 37.1, 26.8, 19.2; MS (ESI): m/z 445 [M+Na] . HRMS (ESI): calcd. for
C
25
H30NaO
2
SSi 445.1628, Found 445.1629.
(R)-2,2,3,3,9,9-Hexamethyl-8,8-diphenyl-5-((phenylthio)methyl)-4,7-dioxa-3,8-
disiladecane (12)
To a stirred solution of alcohol 11 (8.44 g, 20.0 mmol) in anhydrous CH
2
Cl (70 mL) cooled
2
to 0 °C was added imidazole (2.72 g, 40.0 mmol) followed by TBS-Cl (3 g, 20 mmol). The
reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction
mixture was quenched by the addition of H
layers were separated and the organic layer was washed with H
and dried over Na SO . The solvent was evaporated under reduced pressure to afford the
2
O (40 mL) and diluted with CH
2
Cl (80 mL). The
2
2
O (80 mL), brine (40 mL)
2
4
crude product which was purified by column chromatography using pure hexane to afford
0.7 (5% EtOAc/hexane); [α]25
=
silyl ether 12 (10.18 g, 95% yield) as a gummy oil. TLC: R
f
D
-
1 1
–
12.0 (c 1, CHCl
3
); IR (neat): 2936, 2856, 1502, 1322, 1445, 1275, 1024, 1161, 800 cm ; H
): 7.69-7.64 (m, 4H), 7.45-7.40 (m, 2H), 7.39-7.34 (m, 6H), 7.26-
.22 (m, 2H), 7.17-7.13 (m, 1H), 3.88-.84 (m, 1H), 3.68 (dd, J = 10.2 Hz, J = 4.6 Hz, 1H),
.64 (dd, J = 10.2, 6.7 Hz, 1H), 3.41 (dd, J = 13.6, 4.6 Hz, 1H), 2.97 (dd, J = 13.6, 6.7 Hz,
NMR (500 MHz, CDCl
3
7
3
1
1
–
1
3
H), 1.05 (s, 9H), 0.81 (s, 9H), –0.01 (s. 3H), –0.11 (s, 3H); C NMR (75 MHz, CDCl ): 
3
35.5, 133.3, 133.2, 129.6, 128.7, 128.6, 127.7, 125.5, 72.0, 66.7, 38.0, 26.8, 25.8, 19.2, 18.0,
+
4.6, –4.7; MS (ESI): m/z 559 [M+Na] . HRMS (ESI): calcd. for C31
H44NaO
2
SSi 559.2493,
2
Found 559.2512.
(R)-2,2,3,3,9,9-Hexamethyl-8,8-diphenyl-5-((R)-1-(phenylthio)-3-(trimethylsilyl)prop-2-
yn-1-yl)-4,7-dioxa-3,8-disiladecane (14)
To a solution of trimethylsilylacetylene (4.15 mL, 30.0 mmol) in anhydrous THF (30 mL)
cooled to 0 °C was added i-PrMgCl·LiCl (1.5 M in THF, 20 mL, 30 mmol) and the mixture
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
stirred for 30 minutes at the same temperature. To the alkynyl Grignard reagent so generated
was added a solution of ZnBr (1.5 M in THF, 22 mL, 33 mmol) at 0 °C and the mixture
2
stirred for 30 min. Separately, in another round-bottom flask, the -chloro sulfide 13 was
prepared by adding a solution of sulfide 12 (8 g, 15 mmol) in anhydrous benzene (75 mL) to
o
NCS (1.99 g, 15.0 mmol) in anhydrous benzene (75 mL) and stirred for 45 min at 0 C. To
the organozinc reagent maintained at 0 °C the solution of -chloro sulfide in benzene was
added via canula and the reaction mixture was stirred for 10 h gradually, allowing it to attain
room temperature. The reaction mixture was cooled to 0 °C and quenched by the addition of
an aqueous saturated solution of NH Cl (30 mL). It was allowed to warm to room
4
temperature and diluted with ethyl acetate (50 mL). The layers were separated and the
aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layer was
washed with H
2
O (80 mL), brine (80 mL), dried over anhydrous Na
2
SO and the solvent was
4
evaporated under reduced pressure to afford a crude compound which was purified by
column chromatography using hexane as the eluent to afford the pure product compound 14
(
7.34 g, 80% yield) as a light yellow liquid. TLC: R
c 1, CHCl ); IR (neat): 2933, 2856, 2239, 1510, 1448, 1276, 1161, 800 cm ; H NMR (500
): 7.70-7.61 (m, 4H), 7.59-7.54 (m, 2H), 7.45-7.34 (m, 6H), 7.30-7.20 (m, 3H),
.29 (d, J = 2.8 Hz, 1H), 4.05-3.92 (m, 2H), 3.65 (dd, J = 9.6, 4.3 Hz, 1H), 1.05 (s, 9H), 0.85
f
0.8 (5% EtOAc/hexane); [α]25
D
= +75.0
-1 1
(
3
MHz, CDCl
3
4
1
3
(
s. 9H), 0.11 (s, 9H), 0.05 (s, 3H), –0.10 (s, 3H); C NMR (75 MHz, CDCl
3
):  135.6, 135.5,
1
1
6
33.3, 133.1, 132.4, 129.7, 128.5, 127.6, 127.0, 105.0, 89.2, 74.9, 64.7, 44.1, 26.8, 25.7, 19.1,
+
8.0, –0.1, –4.5, –4.7; MS (ESI): m/z 633 [M+H] . HRMS (ESI): calcd. for C36
H
53
O
2
SSi
3
33.3069, Found 633.3086.
(R)-2,2,3,3,9,9-Hexamethyl-8,8-diphenyl-5-((R)-1-(phenylthio)prop-2-yn-1-yl)-4,7-
dioxa-3,8-disiladecane (15)
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
To a stirred solution of alkyne 14 (6.1 g, 10.0 mmol) in methanol (40 mL) was added
potassium carbonate (27 mg, 2 mmol) and reaction mixture stirred ar room temperature for
3
0 minutes. Methanol was evaporated under reduced pressure. The residue was dissolved in
ethyl acetate (20 mL) and H O (10 mL). The layers were separated, the aqueous layer was
extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine
10 mL), dried over Na SO and concentrated under reduced pressure to furnish the crude
product which was purified by flash chromatography on silica gel using 2% EtOAc/hexane
2
(
2
4
(v/v) as the eluent to afford the alkyne 15 as colourless oil (5.5 g, 98% yield). TLC: R
f
0.7
(
5% EtOAc/hexane); [α]25
D
= +112.0 (c 1, CHCl ); IR (neat): 3320, 2935, 2855, 2235, 1540,
3
-
1 1
1
7
4
1
3
8
442, 1274, 1027, 1168, 808 cm ; H NMR (500 MHz, CDCl ): 7.66-7.63 (m, 4H), 7.55-
3
.53 (m, 2H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 4H), 7.32-7.27 (m, 2H), 7.26-7.23 (m, 1H),
.27 (t, J = 2.9 Hz, 1H), 4.05-4.00 (m, 1H), 3.97 (dd, J = 10.0, 7.4 Hz, 1H), 3.65 (dd, J =
0.0, 4.0 Hz, 1H), 2.35 (d, J = 2.6 Hz, 1H), 1.02 (s, 9H), 0.84 (s, 9H), 0.04 (s, 3H), –0.10 (s,
1
3
H); C NMR (125 MHz, CDCl
3
):  135.5, 133.2, 131.4, 129.8, 129.7, 128.7, 127.6, 126.9,
3.4, 75.0, 72.6, 64.6, 43.2, 26.7, 25.7, 19.1, 18.0 –4.6, –4.7; MS (ESI): m/z 583 [M+Na]+.
HRMS (ESI): calcd. for C33
H44NaO
2
SSi 583.2493, Found 583.2504.
2
Ethyl 4-((4-methoxybenzyl)oxy)-3-oxobutanoate (17)
p-Methoxybenzyl alcohol (4.4 g, 31.9 mmol) was added dropwise to a stirred suspension of
sodium hydride (60% in Nujol, 2.67 g, 66.80 mmol) in anhydrous THF (20 mL), occasional
cooling was required with an ice bath to maintain ambient temperature. After hydrogen
evolution ceased, the thick slurry was allowed to stir for 2 h. Ethyl 4-chloro-acetoacetate 16
(
5 g, 30 mmol) was then added dropwise within 3 h, and the reaction mixture was stirred for
6 h. The reaction mixture was carefully added into 5% HCl solution (20 mL) cooled to 5 °C
and extracted with EtOAc (10 mL x 3). The organic layer was washed with an aqueous
saturated solution of NaHCO (6 mL x 2), brine (6 mL), dried over anhydrous Na SO ,
1
3
2
4
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
filtered, and concentrated in vacuo. The crude product was purified by flash chromatography
on silica gel using 10% EtOAc/hexane (v/v) as the eluent to give 17 (7.26 g, 91% yield) as
pale yellow oil. TLC: R 0.5 (20% EtOAc/hexane); IR (neat): 2933, 2856, 1735, 1710, 1448,
f
-
1 1
1
8
1
1
276, 1161, 800 cm ; H NMR (500 MHz, CDCl
3
):  7.26 (d, J = 8.5 Hz, 2H), 6.89 (d, J =
.5 Hz, 2H), 4.52 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 4.11 (s, 2H), 3.81 (s, 3H), 3.51 (s, 2H),
1
3
.25 (t, J = 7.1 Hz, 3H); C NMR (125 MHz, CDCl
3
):  201.7, 166.9, 159.4, 129.5, 128.8,
+
13.8, 74.4, 73.0, 61.3, 52.2, 45.9, 14.0; MS (ESI): m/z 289 [M+Na] . HRMS (ESI): calcd.
for C14
H18NaO
5
289.1046, Found 289.1069.
R)-Ethyl 3-hydroxy-4-((4-methoxybenzyl)oxy)butanoate (18)
Catalyst Preparation: A 50 mL pressure tube was charged with a stir bar, (RuC1
39.0 mg, 0.13 mmol), (S)-2,2’-bis(diphenylphosphino)-l,l’-binaphthyl (100.0 mg, 0.16
(
2
.COD)
n
(
mmol), triethylamine (0.28 mL, 0.20 mmol), and toluene (4 mL). The tube was capped
o
securely and then heated at 140 C in an oil bath until the solution was clear homogeneous
red in colour (4 h). The contents of the flask were transferred to a 100 ml, round-bottom flask
with toluene (40 mL). The toluene was removed in vacuo, and the resulting red oil was taken
up in anhydrous THF (10 mL). The brown THF suspension was divided into five x 2 mL
portions, which were stored in stoppered vials under N
Under N , a hydrogen reactor was charged with absolute EtOH (50 mL), -keto ester 17 (26.6
g, 100.0 mmol), the catalyst as prepared above (4 mL, from 40 mg BINAP), and the
autoclave was closed under N . Hydrogen was introduced three times and released each time
through a valve into a ventilated hood. The pressure reactor was then filled with H (50 bar)
2
.
2
2
2
and heated to 80 °C (inner temperature), and the contents were stirred for 6 h. The reactor
was cooled to room temperature. TLC analysis indicated consumption of the starting
material. The reaction solution was concentrated in a rotary evaporator and the purification
by flash chromatography on silica gel using 16% EtOAc/hexane (v/v) as the eluent yielded
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
the title compound 18 (25.7 g, 96% yield) as yellow coloured oil with enantiomeric purity of
9
1
9% as determined using chiral HPLC. TLC: R
, CHCl
f
0.3 (20% EtOAc/hexane); [α]25
D
= +52.0 (c
-1
1
3
); IR (neat): 3450, 2935, 2856, 1735, 1710, 1452, 1262, 1158, 803 cm ; H NMR
(
500 MHz, CDCl
.18 (m, 1H), ), 4.15 (q, J = 7.0 Hz, 2H), 3.80 (s, 3H), 3.49 (dd, J = 9.6, 4.4 Hz, 1H), 3.44
dd, J = 9.6, 6.1 Hz, 1H), 3.02 (d, J = 3.9 Hz, 1H), 2.52 (d, J = 6.2 Hz, 2H), 1.25 (t, J = 7.1
3
): 7.25 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.49 (s, 2H), 4.24-
4
(
13
Hz, 3H); C NMR (125 MHz, CDCl
3
):  171.8, 159.0, 129.7, 129.1, 113.5, 72.8, 72.7, 66.9,
+
6
2
0.4, 54.9, 38.1, 13.9; MS (ESI): m/z 291 [M+Na] . HRMS (ESI): calcd. for C14
H20NaO
5
91.1203, Found 291.1227.
General procedure for the esterification: To a solution of an alcohol 18 (1.0 eq) in CH Cl
2
2
(
10 mL/mmol) were added DCC (1.2 eq), DMAP (0.2 eq) and (R)- or (S)-
methoxyphenylacetic acid (1.5 eq). The mixture was stirred overnight at room temperature
and the cloudy solution was filtered on cotton. The filtrate was diluted with H O (10 mL), the
layers were separated, the aqueous layer was extracted with CH Cl (10 mL x 2) and the
combined organic layer was washed with saturated aqueous solutions of NaHCO (10 mL),
and concentrated under reduced pressure. The crude
2
2
2
3
brine (10 mL), dried over Na
2
SO
4
1
product was characterised by H NMR spectroscopy.
(R)-Ethyl 3-((R)-2-methoxy-2-phenylacetoxy)-4-((4-methoxybenzyl)oxy)butanoate (60)
Following the procedure detailed above alcohol 18 (27.0 mg, 0.1 mmol), was reacted with
R)-methoxyphenylacetic acid (24.0 mg, 0.15 mmol) to afford ester 60 (35 mg, 85% yield).
(
TLC: R
f
0.4 (20% EtOAc/hexane); IR (neat): 2935, 2854, 1740, 1448, 1272, 1172, 1052, 803
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
-1 1
cm ; H NMR (500 MHz, CDCl
3
): 7.37-7.34 (m, 2H), 7.28-7.22 (m, 3H), 7.01 (d, J = 8.5
Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 5.41-5.36 (m, 1H), 4.69 (s, 1H), 4.21 (d, J = 11.5 Hz, 1H),
4
3
3
.18 (d, J = 11.5 Hz, 1H), 4.02-3.95 (m, 2H), 3.72 (s, 3H), 3.40 (dd, J = 10.8, 5.1 Hz, 1H),
.34 (s, 3H), 3.32 (dd, J = 11.4, 4.2 Hz, 1H), 2.60 (d, J = 6.2 Hz, 2H), 1.12 (t, J = 7.1 Hz,
H).
(R)-Ethyl 3-((S)-2-methoxy-2-phenylacetoxy)-4-((4-methoxybenzyl)oxy)butanoate (61)
Following the procedure detailed above alcohol 18 (27.0 mg, 0.1 mmol), was reacted with
S)-methoxyphenylacetic acid (24.0 mg. 0.15 mmol) to afford ester 61 (34 mg, 83% yield).
TLC: R 0.5 (20% EtOAc/hexane); IR (neat): 2937, 2850, 1738, 1457, 1270, 1162, 1055, 800
cm ; H NMR (500 MHz, CDCl ): 7.44-7.40 (m, 2H), 7.36-7.30 (m, 3H), 7.21 (d, J = 8.5
Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.46-5.41 (m, 1H), 4.74 (s, 1H), 4.48 (d, J = 11.6 Hz,
H), 4.40 (d, J = 11.6 Hz, 1H), 3.90 (dq, J = 10.8, 7.1 Hz, 1H), 3.82-3.76 (m, 4H), 3.59 (dd, J
10.7, 4.9 Hz, 1H), 3.55 (dd, J = 10.7, 4.4 Hz, 1H), 3.38 (s, 3H), 2.58 (d, J = 6.2 Hz, 2H),
.07 (t, J = 7.1 Hz, 3H).
(
f
-1 1
3
1
=
1
Note: A comparison of the NMR of esters 60 and 61 unambiguously proves the configuration
of the newly created stereocenter in compound 18 as 'R' based on the report of Trost and co-
workers.
(R)-Ethyl 4-((4-methoxybenzyl)oxy)-3-(methoxymethoxy)butanoate (19)
To a stirred solution of alcohol 18 (13.4 g, 50.0 mmol) and i-Pr
2
NEt (21 mL, 120 mmol) in
o
o
CH
2
Cl
2
(200 mL) cooled to 0 C was added MOMCl (4.5 mL, 60.0 mmol) at 0 C and
resulting reaction mixture was stirred at room temperature. After stirring for 4 h, the reaction
was quenched with an aqueous saturated solution of NH Cl (100 mL) and extracted with
4
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
CHCl
3
(50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over
and concentrated under reduced pressure. The crude product was purified by flash
Na SO
2
4
chromatography on silica gel using 5% EtOAc/hexane (v/v) as the eluent to afford the MOM
0.6 (20% EtOAc/hexane); [α]25
=
ether 19 (14.8 g, 95% yield) as a colourless oil. TLC: R
f
D
-
1 1
+
72.0 (c 1, CHCl
500 MHz, CDCl
d, J = 11.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 4.21-4.16 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H),
3
); IR (neat): 2937, 2855, 1735, 1448, 1276, 1044, 1161, 805 cm ; H NMR
(
(
3
): 7.18 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.70 (s, 2H), 4.49
3
2
1
.80 (s, 3H), 3.55 (dd, J = 9.9, 5.0 Hz, 1H), 3.49 (dd, J = 9.9, 5.0 Hz, 1H), 3.32 (s, 3H), 2.64-
1
3
.55 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl
3
):  171.0, 159.0, 129.9,
29.0, 113.5, 96.2, 73.2, 72.7, 71.3, 60.2, 55.3, 55.0, 37.6, 14.0; MS (ESI): m/z 313 [M+H]+.
HRMS (ESI): calcd. for C16
H
25
O
6
313.1646, Found 313.1662.
(R)-4-((4-Methoxybenzyl)oxy)-3-(methoxymethoxy)butanal (20)
To a stirred solution of ester 19 (3.12 g, 10.0 mmol) in anhydrous CH
2
Cl (60 mL) cooled to
2
o
–
78 C was added DIBAL-H (1.25 M in toluene 8 mL) dropwise over a period of 10 minutes,
TLC examination soon after addition revealed consumption of starting material, the reaction
o
mixture was quenched at –78 C by adding a saturated solution of sodium potassium tartrate
(
20 mL). The reaction mixture was warmed to room temperature and stirred for 2 h. The
organic layer was separated and extracted with CHCl (10 mL x 3). The combined organic
layer was washed with brine (10 mL), dried over Na SO , filtered and the solvent evaporated
3
2
4
under reduced pressure. The residual oil was purified by flash chromatography on silica gel
using 3% EtOAc/hexane (v/v) as the eluent to afford aldehyde 20 (2.62 g, 98% yield) as a
colourless oil. TLC: R 0.5 (20% EtOAc/hexane); IR (neat): 2933, 2856, 2239, 1725, 1448,
f
-
1 1
1
8
4
276, 1161, 800 cm ; H NMR (500 MHz, CDCl ): 9.77 (t, J = 2.5 Hz, 1H), 7.23 (d, J =
3
.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.73 (d, J = 7.0 Hz, 1H), 4.67 (d, J = 7.0 Hz, 1H),
.49 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.26 (quint, J = 5.3 Hz, 1H), 3.80 (s,
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
3
2
5
(
H), 3.55 (dd, J = 9.9, 4.8 Hz, 1H), 3.51 (dd, J = 9.9, 4.8 Hz, 1H), 3.35 (s, 3H), 2.70-2.66 (m,
1
3
H); C NMR (75 MHz, CDCl
3
):  200.6, 159.2, 129.8, 129.2, 113.7, 96.1, 73.0, 71.7, 71.3,
5.5, 55.2, 46.5.
5R,7R,10R,11R)-11-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-
5,15-dimethyl-14,14-diphenyl-10-(phenylthio)-2,4,13-trioxa-14-silahexadec-8-yn-7-ol
21) and (5R,7S,10R,11R)-11-((tert-butyldimethylsilyl)oxy)-5-(((4-
1
(
methoxybenzyl)oxy)methyl)-15,15-dimethyl-14,14-diphenyl-10-(phenylthio)-2,4,13-
trioxa-14-silahexadec-8-yn-7-ol (22)
To a solution of compound 15 (2.8 g, 5.0 mmol) in anhydrous THF (30 mL) cooled to –78
oC was added n-BuLi (2.5 M in hexane, 2 mL, 5 mmol) dropwise and stirred at the same
temperature for 40 min. A solution of aldehyde 20 (1.4 g, 5.5 mmol) in THF (2 mL) was
o
added to the above lithio alkyne. The reaction mixture was warmed gradually to 0 C over a
o
period of 1 h. The reaction mixture was quenched at 0 C with an aqueous saturated solution
of NH
acetate (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over
Na SO and concentrated under reduced pressure to furnish the crude compound. Purification
4
Cl (5 mL). The layers were separated, the aqueous layer was extracted with ethyl
2
4
by flash chromatography on silica gel using 15% EtOAc/hexane (v/v) as the eluent furnished
alcohol 21 and 22 as an inseparable epimeric mixture in equimolar amounts as a yellow oil
(
3.82 g, 93% yield). TLC: R 0.2 (20% EtOAc/hexane); IR (neat): 3452, 2933, 2856, 2250,
f
-
1 1
1
7
4
510, 1455, 1279, 1027, 11612, 810 cm ; H NMR (500 MHz, CDCl ): 7.68-7.63 (m, 8H),
3
.54-7.50 (m, 4H), 7.45-7.34 (m, 12H), 7.30-7.19 (m, 10H), 6.89-6.85 (m, 4H), 4.71-4.60 (m,
H), 4.49-4.42 (m, 4H), 4.58-4.52 (m, 2H), 4.36-4.33 (m, 2H), 4.05-3.94 (m, 5H), 3.90-3.85
(m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.65 (m, 2H), 3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.33 (s,
3
5
H), 2.0 (dt, J = 14.2, 5.4 Hz, 1H), 1.96-1.90 (m, 1H), 1.89-1.83 (m, 1H), 1.78 (dt, J = 14.5,
1
3
.0 Hz, 1H), 1.04 (s, 18H), 0.85 (s, 18H), 0.05 (s, 6H), –0.08 (s, 6H); C NMR (125 MHz,
):  159.1, 135.4, 133.1, 133.0, 131.6, 131.5, 129.7, 129.6, 129.2, 129.1, 128.6, 127.6,
13.6, 96.7, 96.0, 85.2, 85.1, 84.0, 83.9, 75.1, 75.0, 74.2, 72.9, 72.8, 72.2, 71.9, 64.7, 64.6,
CDCl
3
1
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
6
4
8
0.2, 59.4, 55.6, 55.5, 55.1, 43.3, 43.2, 40.3, 39.6, 26.7, 25.6, 19.0, 17.9, –4.5, –4.6, –4.7, –
+
.8; MS (ESI): m/z 851 [M+Na] . HRMS (ESI): calcd. for C47
H64NaO
7
SSi 851.3803, Found
2
51.3805.
(5R,10R,11R)-11-((tert-Butyldimethylsilyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-15,15-
dimethyl-14,14-diphenyl-10-(phenylthio)-2,4,13-trioxa-14-silahexadec-8-yn-7-one (23)
To a solution of the epimeric mixture of alcohols 21 and 22 (3.3 g, 4.0 mmol) in anhydrous
o
CH
2
Cl
2
(30 mL) cooled to 0 C was added Dess-Martin periodinane (2.2 g, 5.2 mmol) in one
portion and the reaction mixture stirred at the same temperature for 1 h. The reaction was
o
quenched at 0 C by the addition of a 1:1 mixture of saturated aqueous solutions of Na
2
S
2
O
3
and NaHCO
layers were separated, the aqueous layer was extracted with CH
combined organic layer was washed with brine (10 mL), dried over Na
3
(10 mL). The reaction mixture was stirred at room temperature for 1 h. The
Cl (10 mL x 3) and the
SO and concentrated
2
2
2
4
under reduced pressure to afford the crude compound. Purification by flash chromatography
on silica gel using 2-5% EtOAc/hexane (v/v) as the eluent afforded propargylic ketone 23
(
3.1 g, 95% yield) as a yellow oil. TLC: R
CHCl ); IR (neat): 2935, 2852, 2245, 1705, 1510, 1420, 1270, 1168, 805 cm ; H NMR (500
MHz, CDCl ): 7.67-7.61 (m, 4H), 7.54 (d, J = 8 Hz, 2H), 7.44-7.34 (m, 6H), 7.31-7.21 (m,
H), 6.87 (d, J = 8 Hz, 2H), 4.66 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.47 (d, J =
f
0.5 (20% EtOAc/hexane); [α]25
D
= +89.0 (c 1,
-1 1
3
3
5
1
4
1
9
1
1
1.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 5.8 Hz, 1H), 4.27-4.21 (m, 1H), 4.08-
.03 (m, 1H), 3.98 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.62 (d, J = 9.0 Hz, 1H), 3.51 (dd, J =
0.0, 4.9 Hz, 1H), 3.45 (dd, J = 9.8, 5.0 Hz, 1H), 3.30 (s, 3H), 2.85-2.73 (m, 2H), 1.02 (s,
1
3
H), 0.82 (s, 9H), 0.03 (s, 3H), –0.12 (s, 3H); C NMR (75 MHz, CDCl ):  184.6, 159.1,
3
35.4, 134.6, 133.0, 132.9, 132.2, 130.0, 129.8, 129.7, 129.2, 128.9, 127.8, 127.7, 127.5,
13.7, 96.4, 92.2, 83.6, 74.4, 72.9, 72.4, 71.4, 64.2, 55.5, 55.2, 48.2, 43.7, 26.7, 25.6, 19.1,
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
+
1
8
79, –4.6, -4.8; MS (ESI): m/z 849 [M+Na] . HRMS (ESI): calcd. for C47
H62NaO
7
SSi
2
49.3647, Found 849.3622.
(
1
(
5R,7R,10R,11R)-11-((tert-Butyldimethylsilyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-
5,15-dimethyl-14,14-diphenyl-10-(phenylthio)-2,4,13-trioxa-14-silahexadec-8-yn-7-ol
22)
To a solution of ketone 23 (826 mg, 1 mmol) in ethyl acetate (15 mL) was added sodium
formate (1.36 g, 20.0 mmol), (R,R)-Noyori catalyst (7.0 mg, 0.01 mmol), distilled H O (15
2
mL), finally catalytic amounts of hexadecyltrimethylammonium bromide and the reaction
mixture was stirred at room temperature for 24 h. The layers were separated, the aqueous
layer was extracted with ethyl acetate (10 mL x 3) and the combined organic layer was
washed with brine (10 mL), dried over Na
2
SO and concentrated under reduced pressure to
4
furnish the crude compound. Purification by flash chromatography on silica gel using 10%
EtOAc/hexane (v/v) as the eluent provided alcohol 22 (695 mg, 84% yield) as a yellow
coloured oil. TLC: R
f
0.2 (20% EtOAc/hexane); [α]25
D
= +68.0 (c 1, CHCl
3
); IR (neat): 3445,
): 7.68-7.62 (m,
-1 1
2
4
4
930, 2848, 2239, 1423, 1279, 1158, 804 cm ; H NMR (300 MHz, CDCl
3
H), 7.52 (d, J = 8 Hz, 2H), 7.46-7.32 (m, 6H), 7.30-7.18 (m, 5H), 6.88 (d, J = 8 Hz, 2H),
.71 (d, J = 6.6 Hz, 1H), 4.65 (d, J = 6.6 Hz, 1H), 4.60-4.50 (m, 1H), 4.43 (s, 2H), 4.37-4.32
(m, 1H), 4.05-3.86 (m, 3H), 3.80 (s, 3H), 3.62 (dd, J = 9.8, 4.3 Hz, 1H), 3.50-3.40 (m, 2H),
3
0
1
7
.35 (s, 3H), 2.93 (d, J = 6.2 Hz, 1H), 2.01-1.83 (m, 1H), 1.82-1.71 (m, 1H), 1.00 (s, 9H),
1
3
.83 (s, 9H), 0.04 (s, 3H), –0.10 (s, 3H); C NMR (125 MHz, CDCl ):  159.1, 135.6, 135.5,
3
33.2, 133.1, 131.6, 129.7, 129.6, 129.1, 128.6, 127.6, 126.7, 113.7, 96.8, 85.1, 84.0, 75.0,
4.3, 72.9, 72.2, 64.7, 59.5, 55.7, 55.2, 43.3, 39.6, 26.7, 25.7, 19.1, 18.0, –4.5, –4.7; MS
+
(
ESI): m/z 851 [M+Na] . HRMS (ESI): calcd. for C47
H64NaO
7
SSi 851.3803, Found
2
8
51.3807.
(
2E,5Z,6R,8R)-5-((2R,3R)-3-((tert-Butyldimethylsilyl)oxy)-4-((tert-
butyldiphenylsilyl)oxy)-2-(phenylthio)butylidene)-9-((4-methoxybenzyl)oxy)-8-
methoxymethoxy)non-2-ene-1,6-diol (26)
(
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
To a solution of mixture of alkyne 22 (528.0 mg, 0.64 mmol) and homoallyl alcohol (92.0
mg, 1.24 mmol) in acetone (1 mL) was added [CpRu(CH CN) ]PF (28.0 mg, 0.064 mmol)
and stirred at room temperature for 2 h. Acetone was evaporated the residue taken in to Et
2 mL) and H O (2 mL). The aqueous layer was extracted with Et O (2 mL x 2). The
combined organic layer was dried over Na SO , filtered and concentrated. The crude residue
3
3
6
2
O
(
2
2
2
4
was purified by flash chromatography using 30% EtOAc/hexane (v/v) as the eluent to afford
readily separable regioisomers 26 and 27 in (1:1 ratio) in a combined yield of 25% (143 mg).
TLC: R
f
0.3 (40% EtOAc/hexane); [α]25
239, 1610, 1524, 1448, 1345, 1266, 1162, 803 cm ; H NMR (500 MHz, CDCl
.66 (m, 4H), 7.53 (d, J = 8.6 Hz, 2H), 7.45-7.35 (m, 6H), 7.25-7.20 (m, 5H), 6.86 (d, J = 8.6
D
= +44.0 (c 1, CHCl
3
); IR (neat): 3449, 2933, 2856,
-1 1
2
7
3
): 7.74-
Hz, 2H), 5.62 (dt, J = 15.2, 4.7 Hz, 1H), 5.59 (dt, J = 15.2, 5.3 Hz, 1H), 5.43 (d, J = 11.1 Hz,
1
1
H), 4.62 (d, J = 6.5 Hz, 1H), 4.53- 4.49 (m, 2H), 4.40 (s, 2H), 4.30 (dd, J = 10.5, 2.7 Hz,
H), 4.07 (d, J = 4.1 Hz, 2H), 4.02 (dd, J = 10.0, 5.8 Hz, 1H), 3.84-3.75 (m, 6H), 3.55 (dd, J
=
10.0, 4.8 Hz, 1H), 3.34 (d, J = 5.0 Hz, 1H), 3.24 (s, 3H), 2.81 (dd, J = 16.9, 5.2 Hz, 1H),
2
9
1
9
1
9
.67 (dd, J = 16.9, 5.9 Hz, 1H), 1.54-1.47 (m, 1H), 1.36-1.30 (m, 1H), 1.08 (s, 9H), 0.84 (s,
1
3
H), –0.03 (s, 3H), –0.16 (s, 3H); C NMR (75 MHz, CDCl ):  159.1, 140.2, 135.6, 134.5,
3
33.3, 133.2, 131.2, 130.9, 129.8, 129.7, 129.2, 128.8, 128.6, 127.7, 127.4, 126.6, 113.7,
6.7, 75.2, 73.8, 72.9, 72.8, 66.1, 65.3, 63.6, 55.5, 55.2, 51.7, 37.5, 34.3, 26.9, 25.8, 19.2,
+
8.0, –4.3, –4.8; MS (ESI): m/z 923 [M+Na] . HRMS (ESI): calcd. for C51
H72NaO
8
SSi
2
23.4378, Found 923.4372.
(
2E,5Z,7R,9R)-5-((1R,2R)-2-((tert-Butyldimethylsilyl)oxy)-3-((tert-
butyldiphenylsilyl)oxy)-1-(phenylthio)propyl)-10-((4-methoxybenzyl)oxy)-9-
methoxymethoxy)deca-2,5-diene-1,7-diol (27)
(
TLC: R
f
0.3 (40% EtOAc/hexane); [α]25
D
= +32.0 (c 1, CHCl
3
); IR (neat): 3448, 2935, 2846,
): 7.70 (d,
-1 1
2
299, 1615, 1528, 1438, 1335, 1246, 1130, 803 cm ; H NMR (500 MHz, CDCl
3
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.45-7.34 (m, 6H), 7.26-7.19
m, 5H), 6.88 (d, J = 8.6 Hz, 2H), 5.86 (d, J = 11.1 Hz, 1H), 5.48-5.41 (m, 1H), 5.21-5.15 (m,
(
1
1
3
3
9
H), 4.74 (d, J = 6.7 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H), 4.48 (d, J = 11.7 Hz, 2H), 4.47 (d, J =
1.7 Hz, 2H), 4.35 (dd, J = 10.9, 2.2 Hz, 1H), 4.19-4.16 (m, 1H), 4.10-4.07 (m, 1H), 3.94-
.89 (m, 1H), 3.84-3.78 (m, 6H), 3.56 (dd, J = 10.0, 4.7 Hz, 1H), 3.47 (d, J = 5.0 Hz, 2H),
.37 (s, 3H), 2.56-2.50 (m, 1H), 2.47-2.41 (m, 1H), 1.39-1.36 (m, 2H), 1.06 (s, 9H), 0.85 (s,
+
H), 0.07 (s, 3H), –0.14 (s, 3H); MS (ESI): m/z 923 [M+Na] . HRMS (ESI): calcd. for
C
51
H72NaO
8
SSi
2
923.4378, Found 923.4364.
(S)-1-(4-Benzyl-2-thioxothiazolidin-3-yl)butan-1-one (33)
To a stirred solution of 4-benzyl-2-thioxothiazolidine (2.3 g, 11.0 mmol) in anhydrous
o
CH
2
Cl
2
(22 mL) cooled to 0 C was added Et
3
N (2.0 mL, 14.3 mmol) followed by n-butyryl
chloride (1.25 mL, 12 mmol). The reaction mixture was stirred for 1 h at room temperature
and quenched with an aqueous saturated solution of NH Cl (5 mL). The aqueous layer was
extracted with CH Cl (25 mL x 3). The combined organic layer was dried over anhydrous
Na SO , concentrated to dryness under reduced pressure, and purified by silica gel
4
2
2
2
4
chromatography using 1% EtOAc/hexane (v/v) as the eluent to afford compound 33 (2.9 g ,
o
0.80 (5% EtOAc/hexane); [α]25
9
5% yield) as a solid. M.P. = 101 C. TLC: R
f
D
= –204.0 (c 1,
):
1
CHCl3); IR (KBr): 2958, 2925, 1694, 1162, 1062, 1034 cm-1; H NMR (500 MHz, CDCl
3
7.36-725 (m, 5H), 5.40-5.35 (m, 1H), 3.41-3.31 (m, 2H), 3.22 (dd, J = 13.1, 3.6 Hz, 1H),
1
3
3
.15-3.10 (m, 2H), 2.88 (d, J = 11.6 Hz, 1H), 1.80-1.65 (m, 2H), 098 (t, J = 7.4 Hz, 3H); C
3
NMR (125 MHz, CDCl ):  200.9, 173.8, 136.4, 129.3, 128.7, 127.0, 68.4, 40.2, 36.6, 31.8,
+
1
8.0, 13.5; MS (ESI): m/z 280 [M+H] . HRMS (ESI): calcd. for C14
H18NO
2
S 280.0825,
2
Found 280.0824.
(2R,3R)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-2-ethyl-3-hydroxy-4-
(phenylthio)butan-1-one (35)
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
o
To a solution of thiazolidine thione 33 (2.79 g, 10.0 mmol) in CH
2
Cl
2
(60 mL) cooled to 0 C,
maintained under N atmosphere was added, titanium (IV) chloride (20.0 mmol, 2.2 mL)
2
dropwise and the mixture stirred for 5 min. To the resulting yellow slurry
diisopropylethylamine (1.9 mL, 11.0 mmol) was added. The dark red titanium enolate was
stirred for 20 min at 0 °C and then was cooled to –78 °C. Freshly prepared 2-phenylthio
acetaldehyde 34 (1.67 g, 11.0 mmol) was added dropwise. The resulting mixture was stirred
for 1 h at –78 °C and then was warmed to 0 °C. The reaction was quenched with an aqueous
saturated solution of NH
dried over anhydrous Na
by silica gel chromatography using 8% EtOAc/hexane (v/v) as the eluent to furnish the
4
Cl (60 mL) and the layers were separated. The organic layer was
2
SO , concentrated to dryness under reduced pressure and purified
4
yellow coloured compound 35 (3.62 g, 84% yield). TLC: R
f
0.20 (10% EtOAc/hexane);
[
α]25
D
= +62.0 (c 1, CHCl ); IR (neat): 3448, 2933, 2856, 2239, 1710, 1448, 1276, 1161, 800
3
-1 1
cm ; H NMR (500 MHz, CDCl
3
): 7.43-7.20 (m, 10H), 5.41-5.32 (m, 1H), 4.85 (dt, J =
9
2

3
4
.4, 4.7 Hz, 1H), 4.16-4.07 (m, 1H), 3.36 (dd, J = 11.5, 6.9 Hz, 1H), 3.28-2.98 (m, 4H),
1
3
.96-2.87 (m, 2H), 1.95-1.65 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ):
3
201.6, 175.8, 136.1, 135.2, 129.2, 129.1, 128.8, 128.6, 127.0, 126.0, 69.5, 68.6, 48.9, 38.4,
+
6.7, 32.2, 21.4, 11.3; MS (ESI): m/z 454 [M+Na] . HRMS (ESI): calcd. for C22
2 3
H25NNaO S
54.0940, Found 454.0930.
(2R,3R)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-((tert-butyldimethylsilyl)oxy)-2-
ethyl-4-(phenylthio)butan-1-one (36)
o
To a stirred solution of alcohol 35 (6.4 gm, 15.0 mmol) in CH
2
Cl (60 mL) cooled at –78 C
2
was added 2,6-lutidine (3.8 mL, 33.0 mmol), followed by addition of TBSOTf (3.7 mL, 16.5
mmol). After 1 h, the reaction was quenched by addition of an aqueous saturated solution of
NaHCO
3
(30 mL). The layers were separated and the aqueous layer was extracted with
CH Cl
2
2
(40 mL x 2).The combined organics were washed with 10% NaHSO (40 mL), dried
4
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
and concentrated under reduced pressure. The crude product was purified by column
chromatography using 2% EtOAc/hexane (v/v) as the eluent to provide the product 36 (7.6 g,
9
4% yield) as bright yellow oil. TLC: R
f
0.6 (10% EtOAc/hexane); [α]25
= +98.9 (c 1,
D
CHCl ); IR (neat): 3061, 3027, 2955, 2930, 2882, 2856, 1688, 1564, 1461, 1340, 1258, 1191,
3
-
1 1
1
4
161, 837,776 cm ; H NMR (500 MHz, CDCl
3
): 7.37-7.22 (m, 10H), 5.35-5.29 (m, 1H),
.93-4.88 (m, 1H), 4.33 (dd, J = 12.3, 6.7 Hz, 1H), 3.32-3.23 (m, 3H), 3.16 (dd, J = 13.7, 5.3
Hz, 1H), 3.04-2.98 (m, 1H), 2.86 (d, J = 12.3 Hz, 1H), 1.90-1.70 (m, 2H), 0.94-0.85 (m,
1
3
1
1
1
5
2H), 0.07 (s, 3H), 0.05 (s, 3H); C NMR (125 MHz, CDCl ):  200.9, 175.5, 136.7, 136.6,
3
29.5, 129.3, 128.9, 128.8, 127.1, 126.0, 72.0, 69.2, 50.0, 40.6, 36.5, 31.7, 25.9, 23.5, 18.1,
+
1.0, –4.0, –4.4; MS (ESI): m/z 568 [M+Na] . HRMS (ESI): calcd. for C28
H
39NNaO
2
3
S Si
68.1804, Found 568.1809.
(
2R,3R)-3-((tert-Butyldimethylsilyl)oxy)-2-ethyl-4-(phenylthio)butanal (37)
DIBAL-H (1.25 M in toluene, 8 mL, 10 mmol,) was added dropwise to a solution of TBS
compound 36 (2.72 g, 5.0 mmol) in anhydrous CH Cl (40 mL) cooled to –78 °C and stirred
2
2
for 30 minutes at the same temperature. The yellow colour of reaction mixture turned to
colourless and TLC examination revealed consumption of starting material. The reaction
mixture was then quenched by adding saturated aqueous sodium potassium tartrate solution
o
(
25 mL) at –78 C followed by vigorous stirring for 1 h at room temperature. The aqueous
phase was then extracted with CH
washed with brine (30 mL), dried over anhydrous Na
The crude product was purified by column chromatography using 5% EtOAc/hexane (v/v) as
2
Cl
2
(30 mL x 3) and the combined organic layer was
2
SO and the solvent removed in vacuo.
4
the eluent to yield aldehyde 37 (1.54 g, 89% yield) as a colourless oil. TLC: R
f
0.7 (10%
EtOAc/hexane); [α]25
= +32.9 (c 1, CHCl ); IR (neat): 3060, 2930, 2874, 1720, 1687, 1583,
D
3
-
1 1
1
1
438, 1362, 1341, 1258, 1137, 1035, 793 cm ; H NMR (300 MHz, CDCl ): 9.75 (d, J =
3
.5 Hz, 1H), 7.36-7.18 (m, 5H), 4.20 (dt, J = 6.7, 3.0 Hz, 1H), 3.05-3.0 (m, 2H), 2.60-2.52
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
(m, 1H), 1.84-1.72 (m, 1H), 1.55-1.40 (m, 1H), 0.89 (t, J = 7.5 Hz, 3H), 0.84 (s, 9H), 0.04 (s,
1
3
3
5
H), –0.02 (s, 3H); C NMR (100 MHz, CDCl
3
):  204.3, 135.6, 129.6, 128.9, 126.4, 70.8,
+
7.4, 38.5, 25.6, 17.8, 16.6, 12.2, –4.3, –4.9; (ESI): m/z 361 [M+Na] . HRMS (ESI): calcd.
for C18
H30NaO
2
SSi 361.1628, Found 361.1623.
(4S,5R,Z)-Ethyl 5-((tert-butyldimethylsilyl)oxy)-4-ethyl-6-(phenylthio)hex-2-enoate (39)
To the suspension of NaH (60% in Nujol, 480 mg, 12 mmol) in anhydrous THF (30 mL)
o
cooled to –78 C was added Ando’s reagent 38 (3.84 g, 12.0 mmol) in anhydrous THF (20
mL) after 15 minutes, the aldehyde 37 (3.38 g, 10.0 mmol) in THF (5 mL) was added and the
o
resulting mixture was gradually warmed to –20 C over 1-2 h. The reaction was quenched
with an aqueous saturated solution of NH
4
Cl (30 mL). The aqueous layer was extracted with
EtOAc (30 mL x 2).The combined organic layer was washed with brine (30 mL), dried over
anhydrous Na
2
SO
4
and concentrated to dryness under reduced pressure. After determining
1
Z/E ratio of the crude mixture by H NMR the product was purified by silica gel
chromatography using 1% EtOAc/hexane (v/v) as the eluent to afford compound 39 (3.59 g,
8
8% yield). TLC: R
930, 2857, 1720, 1645, 1585, 1472, 1414, 1388, 1255, 1185, 1094, 1040, 836 cm ; H
): 7.37-7.32 (m, 2H), 7.28-7.24 (m, 2H), 7.18-7.14 (m, 1H), 6.06
dd, J = 11.7, 10.8 Hz, 1H), 5.86 (d, J = 11.7 Hz, 1H), 4.20-4.14 (m, 2H), 3.86-3.81 (m, 1H),
f
0.6 (2% EtOAc/hexane); [α]25
D
= +18.7 (c 1, CHCl
3
); IR (neat): 2959,
-1
1
2
NMR (500 MHz, CDCl
3
(
3
.76-3.69 (m, 1H), 3.14 (dd, J = 13.1, 6.2 Hz, 1H), 2.97 (dd, J = 13.1, 6.2 Hz, 1H), 1.68-1.60
(m, 1H), 1.35-1.25 (m, 4H), 0.88 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H), 0.03 (s, 3H), –0.02 (s, 3H);
13C NMR (100 MHz, CDCl
):  166.0, 151.1, 136.8, 129.4, 128.7, 125.8, 121.1, 74.1, 59.8,
3
+
4
4.1, 39.0, 25.8, 21.4, 18.0, 14.2, 11.6, –4.6, –4.1; (ESI): m/z 431 [M+Na] . HRMS (ESI):
calcd. for C22
H36NaO
3
SSi 431.2047, Found 431.2053.
(5S,6R)-5-Ethyl-6-((phenylthio)methyl)-5,6-dihydro-2H-pyran-2-one (7)
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European Journal of Organic Chemistry
10.1002/ejoc.201700379
o
To a stirred solution of ester 38 (818 mg, 2 mmol) in methanol (20 mL) cooled to 0 C was
added 1 N HCl in methanol (2 mL, 2 mmol) and the reaction mixture stirred at room
temperature for 1 day. Methanol was evaporated under reduced pressure to afford a residue
which was diluted with EtOAc (10 mL). The organic layer was washed with aqueous
saturated solution of NaHCO
3
(5 mL), brine (10 mL), dried over anhydrous Na
2
SO and
4
concentrated to dryness under reduced pressure. The crude product was purified by column
chromatography using 10% EtOAc/hexane (v/v) as the eluent to provide the lactone 7 (357
mg, 72% yield) as a colourless oil. TLC: R
f
0.4 (10% EtOAc/hexane); [α]25
= +36.5 (c 1,
D
CHCl ); IR (neat): 3066, 3022, 2945, 2872, 2850, 1690, 1620, 1451, 1330, 1250, 1189, 1166,
3
1
1
8
9
3
0
1
37 cm ; H NMR (400 MHz, CDCl ): 7.41-7.36 (m, 2H), 7.33-7.20 (m, 3H), 7.02 (dd, J =
3
.7, 6.2 Hz, 1H), 6.03 (d, J = 9.7 Hz, 1H), 4.54-4.48 (m, 1H), 3.35 (dd, J = 13.8, 5.7 Hz, 1H),
.11 (dd, J = 13.9, 9.1 Hz, 1H), 2.62-2.55 (m, 1H), 1.70-1.61 (m, 1H), 1.55-1.45 (m, 1H),
1
3
.95 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl
3
):  163.8, 150.3, 134.3, 130.0, 129.1,
+
26.9, 120.7, 78.2, 36.4, 34.1, 20.1, 10.6; (ESI): m/z 271 [M+Na] . HRMS (ESI): calcd. for
C
14
H
16NaO Si 271.0764, Found 271.0775.
2
(4S,5R,6R,Z)-Ethyl 5-((tert-butyldimethylsilyl)oxy)-4-ethyl-6-(phenylthio)-8-
(trimethylsilyl)oct-2-en-7-ynoate (40)
Compound 40 was prepared following the procedure detailed earlier for the preparation of
compound 14. The sulfide 39 (6.12 g, 15.0 mmol) afforded the compound 40 (5.89 g, 78%
yield) as a yellow oil. TLC: R
f
0.6 (2% EtOAc/hexane); [α]25
D
= +52.1 (c 1, CHCl ); IR
3
(neat): 2959, 2931, 2898, 2857, 2171, 1721, 1643, 1466, 1414, 1252, 1183, 1101, 1031, 840
-1 1
cm ; H NMR (500 MHz, CDCl
0.8 Hz, 1H), 5.86 (d, J = 11.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.0-3.91 (m, 1H), 3.90-3.85
m, 2H), 1.99-1.92 (m, 1H), 1.34-1.27 (m, 1H), 1.25 (t, J = 7.4 Hz, 3H), 0.94 (s, 9H), 0.86 (t,
3
): 7.52-7.47 (m, 2H), 7.28-7.22 (3H), 6.0 (dd, J = 11.6,
1
(
1
3
J = 7.4 Hz, 3H), 0.19 (s, 3H), 0.11 (s, 9H), 0.08 (s, 3H); C NMR (125 MHz, CDCl ): 
3
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