Stereoselective Synthesis of the C1-C22 Carbon Framework of (-)-Amphidinolide K

Article abstract of DOI:10.1021/acs.joc.9b01248

Two stereoselective routes to the C7-C22 subunit of amphidinolide K are disclosed. Jacobsen's hydrolytic kinetic resolution and Sharpless' asymmetric dihydroxylation reactions have been employed for the construction of the tetrahydrofuran ring. The C10-C1

Full text of DOI:10.1021/acs.joc.9b01248

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Article
Stereoselective synthesis of the C1-C22
carbon framework of (-)-amphidinolide K
Somnath S. Chandankar, and Sadagopan Raghavan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01248 • Publication Date (Web): 04 Jul 2019
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Stereoselective synthesis of the C1-C22 carbon framework of (-)-
amphidinolide K
Somnath S. Chandankar and Sadagopan Raghavan*
Department of Organic Synthesis & Process Chemistry, Indian Institute of Chemical
Technology, Hyderabad 500007, India
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sraghavan@iict.res.in
Abstract: Two stereoselective routes to the C7-C22 subunit of amphidinolide K are
disclosed. Jacobsen's hydrolytic kinetic resolution and Sharpless' asymmetric dihydroxylation
reactions have been employed for the construction of the THF ring. The C10-C11, C16-C17,
C9-O and C18-O bonds have been created using α-chloro sulfide intermediates and [2,3]
sigmatropic rearrangement. Marshall's propargylation protocol is utilized to create the C4
stereogenic center and regioselective hydrozirconation/iodine quench afforded an alkenyl
iodide which is employed in the NHK coupling with the C7-C22 subunit. Oxonia-Cope
rearrangement resulted in the creation of the C18 carbinol stereogenic center and chain
elongation.
Introduction
Amphidinolide K (1, Figure 1) is a cytotoxic 19-membered macrolide isolated by
1
Kobayashi and co-workers from the cultured dinoflagellate Amphidinium sp. It displays
-1
cytotoxic activity against murine lymphoma L1210 (IC = 1.6 μg mL ) and epidermoic
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-1
2
carcinoma KB cells (IC = 2.9 μg mL ) in vitro. While amphidinolide H, a 26-membered
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macrolide stabilizes actin filaments (F-actin) and amphidinolide X, a 16-membered
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macrolide acts as a globulin actin (G-actin) assembly inhibitor, the biological target of the
common amphidinolides of intermediate ring sizes is not known. Williams and co-workers
assigned the relative and absolute stereochemistry of the natural product in the first report on
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the total synthesis of (+)-amphidinolide K. The groups of Lee and Villarasa reported the
synthesis of (-)-amphidinolide K.
OH
O
7
13
O
O
15
OH
10
15
19
O
22
O
O
O
1
7
HO
6
O
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OH
O
18
25
O
1
22
OH
4
8
1
O
O
Amphidinolide X
O
Amphidinolide K, 1
O
Amphidinolide H
Figure 1. Structures of Amphidinolides K, H and X.
The unique structure and potent bioactivity of amphidinolide has elicited considerable
7
interest and many reports detailing the synthesis of subunits have been published. We
disclose herein a convergent stereocontrolled synthesis of the entire carbon framework of
amphidinolide K taking advantage of Marshall's propargylation for C3-C4, NHK coupling for
C6-C7, α-chloro sulfide intermediates for forging the C10-C11 and C16-C17 bonds and
oxonia-Cope rearrangement for C18-C19 bond formation.
Results and discussion
The retrosynthetic disconnection is depicted in Scheme 1. Shina macrolactonization
of the hydroxy acid 2 followed by epoxidation would afford amphidinolide K. The hydroxy
acid 2 was envisaged to be obtained by NHK-coupling of iodo alkene 4 with aldehyde 3. Iodo
alkene 4 was traced to Roche ester 5 and mesylate 6. Aldehyde 3 was imagined to be
obtained from the reaction of an alkynylzinc bromide derived from alkyne 8 with the α-
chloro sulfide, obtained from sulfide 7, followed by [2,3] sigmatropic rearrangement of the
corresponding sulfoxide and further reduction of the ensuing ketone. Sulfide 7 was
envisioned to be obtained from the reaction of an aldehyde derived from sulfide 9 with the
homoallyl alcohol 10 by utilizing the oxonia-Cope rearrangement. Sulfide 9 can be traced to
glycidol ether 11.
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0
15
6
7
O
15
7
O
O
1
OH
PO
+
1 OP
HO 18
1
22
4
3
4
PO
22
OH
O
2
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OH
12
10
15
19
1
1
O
O
SPh
+
7
+
3
22
OP
SPh
OP
8
1
8
10
PO
7
9
6
MeO
3
1
OH
4
12
+
PO
4
P = Protecting group
5
O
11
O
6
OMs
Scheme 1. Retrosynthetic disconnection of amphidinolide K.
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The synthesis of sulfide 7 began from the known epoxide 11, Scheme 2, obtained by
Jacobsen's hydrolytic kinetic resolution, which on reaction with alkyne 12 following
9a
Yamaguchi's protocol yielded alkyne 13. Deprotection of the hydroxyl by cleavage of the
THP ether followed by reduction of the triple bond of the resulting propargylic alcohol 14,
employing Red-Al, afforded allyl alcohol 15. The sulfide 16, obtained cleanly using Hata's
protocol,10 was converted to the mesylate 17. Subjecting mesylate 17 to Sharpless'
asymmetric dihydroxylation11 conditions using (DHQD) PHAL ligand afforded the THF
2
derivative 18 via dihydroxylation (dr 7:3) followed by intramolecular displacement.12
1
3
Oxidation of the secondary hydroxyl to ketone 19 using IBX followed by Wittig olefination
furnished sulfide 20. Treatment of sulfide 20 with NCS afforded a chloro sulfide intermediate
1
4
which on reaction with vinylzinc bromide yielded allyl sulfide 9. The configuration at C16
was inconsequential since it was to be destroyed subsequently. Oxidation of the sulfide to
15
sulfoxide followed by Mislow-Evans rearrangement furnished the allyl alcohol 21, Scheme
1
6
3
, which was subjected to a redox reaction under Ru(IV) catalysis to yield aldehyde 22.
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Aldehyde 22 and the known homoallylic alcohol 10 underwent oxonia-Cope rearrangement17
in the presence of Sn(OTf)218 to yield the homoallyl alcohol 23 (dr >95: <5, 70%).9b
Protection of the hydroxyl group under standard conditions afforded the MOM-ether 24.
n-BuLi, BF .Et O,
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THF, add epoxide 11,
Red-Al, Et O,
2
o
OP
-78 C - rt, 2 h, 87%
0 oC - rt, 1 h, 95%
OTHP
OH
OH
R
12
PMBO
PMBO
1
3, P = THP
4, P = OH
15
16
PhSSPh, PBu3,
Toluene, rt,
, R = OH
, R = SPh
PPTS, MeOH,
o
50 C, 12 h, 93%
1
20 min, 80%
R
Ph PMeBr, KOtBu,
MsCl, Et N,
(DHQD) PHAL, 1 mol%,
2
3
3
o
R'
o
[
K OsO (OH) ], 1.37 mol%, K CO ,
THF, 0 C, 30 min,
CH Cl , 0 C,
2
2
4
2
3
2
2
o
K Fe(CN) , MeSO NH ,
then add 19, 0 C,
30 min, 97%
3
6
2
2
t-BuOH, H O, rt, 20 h, 63%
OMs
2
O
45 min, 95%
SPh
PMBO
PMBO
SPh
17
18, R = OH, R' = H
IBX, DMSO, CH Cl ,
2
2
rt, 2 h, 91%
19, R, R' = O
NCS, PhH,
rt, 30 min
PMBO
SPh
ZnBr
THF, 0 C - rt,
O
O
O
o
11
PMBO
SPh
PMBO
2
h, 81%
9
20
Scheme 2. Synthesis of sulfide 9.
1
9
Proceeding ahead, the alcohol was deprotected by cleavage of the PMB ether using DDQ to
furnish the compound 25. The sulfide 7 was obtained from alcohol 25 without incident
following Hata's protocol. The C10-C11 and the C9-O bonds were envisioned to be created
using an α-chloro sulfide intermediate. Thus reaction of chloro sulfide obtained from sulfide
7
with the alkynylzinc bromide prepared from homopropargylic ether 8 furnished the
1
4
20
propargylic sulfide 26. Oxidation followed by [2,3] sigmatropic rearrangement afforded
unsaturated ketone 27 which on reduction using (R)-CBS reagent21 yielded alcohol 28.9b
Protection of the alcohol as its MOM-ether afforded the compound 29. Deprotection of the
hydroxyl by removal of the PMB ether using DDQ furnished the alcohol 30 which on
22
oxidation using DMP yielded aldehyde 3, constituting the C7-C22 subunit.
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Ru cat., Cs2CO3,
THF, 80 oC,
mCPBA, CHCl3,
40 oC, 20 min
-
12 h, 87%
SPh
HN NMe
S
O
O
O
O
PMBO
Toluene, 60 oC,
PMBO
OH
PMBO
9
21
22
2
h, 80%
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DDQ, CH2Cl2,
pH 7 buffer, 0 oC - rt,
Sn(OTf)2, CHCl3,
rt, 1 h, 70%
NCS, PhH,
rt, 15 min
2 h, 80%
O
O
OH
BrZn
OPMB
PMBO
R
THF, 0 oC - rt,
2 h, 85%
PO
MOMO
10
MOM-Cl, iPrNEt2, 23, P = H
PhSSPh, PBu3,
Toluene, rt,
20 min, 87%
25, R = OH
7, R = SPh
CH2Cl2, 0 oC - rt,
2
4, P = OMOM
2
h, 96%
Cl
Ru Cl
Cl Ru
Cl
Ru-Cat.
mCPBA, CHCl3,
-
40 oC, 20 min
HN NMe
S
DDQ, CH2Cl2,
pH 7 buffer, 0 oC - rt,
h, 80%
2
R
O
PhS
O
O
Toluene, 60 oC,
OMOM
PMBO R R'
2
h, 80%
MOMO
MOMO
MOMO
26
(R)-CBS, BH3.Me2S,
THF, -78 oC, 2 h, 80%
30, R = CH2OH
3, R = CHO
27
,
R, R' = O
28, R = OH, R' = H
9, R = OMOM, R' = H
DMP, CH2Cl2,
0 oC, 1.5 h, 91%
PMBO
MOM-Cl, iPrNEt2,
CH2Cl2, 0 oC - rt,
2
2 h, 93%
Scheme 3. Synthesis of the C7-C22 subunit.
Alternate shorter route to aldehyde 3
It was reasoned that if the THF subunit corresponding to aldehyde 22 constituting the
C11-C18 fragment could be prepared with the C11 atom decorated with the sulfide, the
synthetic steps, required for elaboration from an epoxide, similar to 11, to sulfide 7 could be
reduced. Towards this objective an alternate route was designed as depicted in Scheme 4. The
8
9a
synthesis began with (S)-epichlorohydrin 31, which on reaction with the lithium acetylide
derived from pentynol ether 32 afforded chlorohydrin 33. Nucleophilic displacement of
chlorine by an acetate using KOAc in DMSO yielded primary acetate 34 along with a small
quantity of the secondary acetate. Treatment of the mixture of acetates with LAH furnished
the homoallyl alcohol 35 by deprotection and reduction of the triple bond. The primary
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hydroxyl was selectively converted to the sulfide 369b and the secondary hydroxyl was
converted to the mesylate 37. Sharpless' asymmetric dihydroxylation (dr 7:3) using
2
3
(DHQD) PHAL ligand afforded the THF derivative 38. Oxidation of the alcohol to the
2
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ketone 39 and Wittig olefination furnished exocyclic alkene 40. Deprotection of the hydroxyl
group by cleavage of the THP ether and oxidation of the resulting alcohol 41 yielded
aldehyde 42. Oxonia-Cope rearrangement using the homoallylic alcohol 43 derived from (+)-
1
7
9b
menthol yielded the alcohol 44 which on protection using MOM-Cl furnished compound
7
.
n-BuLi, BF3.Et2O,
THF, add epoxide
31, -78 oC - rt, 2 h,
89%
LAH, THF,
Toluene, 0 - 90 oC,
12 h, 95%
OH
OH
32
OTHP
R
OTHP
R
OTHP
3
3, R = Cl
4, R = OAc
35, R = OH
36, R = SPh
PhSSPh, PBu3,
Toluene, rt,
30 min, 87%
KOAc, DMSO,
20 oC, 6 h, 91%
Cl
1
3
O
31
R
Ph PMeBr, KOtBu,
3
(
DHQD)2PHAL, 1 mol%,
THF, 0 oC, 30 min,
MsCl, Et3N,
R'
[K2OsO2(OH)4], 1.37 mol%, K2CO3,
K3Fe(CN)6, MeSO2NH2,
CH2Cl2, 0 oC,
then add 39, 0 oC,
30 min, 97%
30 min, 91%
t-BuOH, H2O, rt, 20 h, 65%
O
OMs
37
SPh
OTHP
SPh
OTHP
38, R = OH, R' = H
39, R, R' = O
IBX, DMSO, CH2Cl2,
rt, 2 h, 90%
IBX, DMSO, CH2Cl2,
rt, 2 h, 86%
NCS, PhH,
rt, 15 min
PTSA, CH2Cl2,
rt, 12 h, 78%
O
O
O
BrZn
iPr
OTBDPS
O
THF, 0 oC - rt,
4 h, 85%
SPh
OP
SPh
SPh
43
OH
4
2
PO
4
0, P = THP
PTSA, MeOH,
rt, 12 h, 95%
4
1, P = OH
MOM-Cl, iPrNEt2, 44, P = H
CH2Cl2, 0 oC - rt,
7
, P = OMOM
2
h, 96%
mCPBA, CHCl3,
-40 oC, 20 min
TBAF, THF,
0 oC, 2 h, 98%
HN NMe
PhS
S
O
O
O
Toluene, 60 oC,
OH OMOM
MOMO
R R'
2
h, 80% TBDPSO
MOMO
45
MOMO
46, R, R' = O
7, R = OH, R' = H
30
(R)-CBS, BH .Me S,
THF, -78 oC, 1 h, 80%
3
2
OTBDPS
4
MOM-Cl, iPrNEt2,
CH2Cl2, 0 oC - rt,
48, R = OMOM, R' = H
2
h, 93%
Scheme 4. Alternate route to alcohol 30.
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Reaction of the chloro sulfide derived from sulfide 7 with the alkynylzinc bromide obtained
from the homopropargyl alcohol protected as its silyl ether furnished sulfide 45 which was
subjected to the same two-step one-pot procedure as shown in Scheme 3 (26 to 27) to yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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5
5
5
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0
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9b
ketone 46. Stereoselective reduction to alcohol 47 and protection furnished compound 48.
The silyl ether was deprotected in nearly quantitative yield to furnish alcohol 30, Scheme 4.
The synthesis of iodo alkene 4 began from Roche ester 5 which was converted by a
2
4
known sequence of reactions into aldehydes 49 and 50. Reaction of aldehyde 49, Scheme 5,
2
5
with mesylate 6 following Marshall's protocol afforded alkyne 51. Deoxygenation of the
2
6
mesylate 53 using LAH afforded alkyne 55 which on hydrozirconation followed by iodine
quench yielded iodo alkene 4. An identical sequence of reactions afforded iodo alkene 57
starting from aldehyde 50.
Pd(PPh3)2Cl2, 6,
Et2Zn, THF,
0 oC - rt, 1.5 h
MsCl, Et N,
3
CH Cl , 0 oC,
2
2
See Ref. 24
MeO
OH
H
OP
OP
30 min
O
O
OH
1, P = PMB, 75%
52, P = TBDPS, 72%
5
4
5
9, P = PMB, 87% overall
0, P = TBDPS, 87% overall
5
6
OMs
I
OP
LAH, Et2O,
0 oC - rt, 1 h, 80%
Cp2ZrHCl, THF,
OP
0 oC - rt, 1 h,
OMs
then cool to -78 oC,
OP
5
3, P = PMB, 95%
I2 quench, 30 min
5
5
5, P = PMB, 80%
4, P = PMB, 83%
54, P = TBDPS, 90%
6, P = TBDPS, 75%
57, P = TBDPS, 85%
Scheme 5. Synthesis of iodo alkenes 4 and 56.
The union of iodo alkene 4 with aldehyde 3 adopting NHK-coupling conditions27
afforded an inseparable epimeric mixture of alcohols 58. Oxidation using DMP furnished the
ketone 60 which on subjecting to Wittig olefination afforded alkene 62. The stage was set for
macrolactonization. Towards this end, attempted deprotection of the alcohol by removal of
the PMB ether using DDQ furnished a complex mixture of products probably arising from
allylic oxidation of the conjugated diene. We were therefore compelled to prepare iodo
alkene 57. The epimeric mixture of alcohols 59, Scheme 6, resulting from the NHK coupling
of aldehyde 3 and iodo alkene 57 was elaborated by the same sequence of reactions to yield
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compound 63. Deprotection of the hydroxyl group by cleavage of the silyl ether proceeded
without incident using TBAF to furnish the primary alcohol 64. Oxidation using DMP
2
8
followed by Pinnick oxidation of the ensuing aldehyde afforded acid 65. It only remained to
0
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9
0
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deprotect the alcohol by removal of the MOM ether to effect the macrolactonization.
2
9
Disappointingly, attempted deprotection using TMS-Br or ZnBr in the presence of butane
2
3
0
thiol afforded a complex mixture of products. At this stage we ran out of sample to attempt
the deprotection of the MOM-ether under different conditions and therefore the synthesis of
amphidinolide K could not be completed.
I
DMP, CH2Cl2,
0 oC, 1.5 h
O
HO
OP
4/56
MOMO
O
OMOM
O
CrCl2, NiCl2,
MOMO
OMOM
THF, DMF,
0 oC - rt, 12 h
OP
3
5
8, P = PMB, 81%
59, P = TBDPS, 73%
TBAF, THF,
0 oC, 2 h, 98%
O
O
R
MOMO
MOMO
OMOM
OMOM
R
OP
1
. DMP, CH2Cl2,
6
0, R = O, P = PMB, 84%
64, R = CH OH
2
NaHCO , 0 oC, 1 h
6
1, R = O, P = TBDPS, 78%
3
Ph3P=CH2, THF,
-30 oC, 20 min
2
. NaClO2, 2-Me-2-butene,
6
2, R = CH , P = PMB, 75%
2
2
65, R = CO H
6
3, R = CH , P = TBDPS, 75%
2
NaH PO , tBuOH, H O,
2
4
2
0 oC - rt, 1.5 h, 60%
Scheme 6. Synthesis of acid 65 constituting the entire carbon framework of amphidinolide K.
Conclusion
Stereoselective routes to the C7-C22 subunit of amphidinolide K are disclosed. The
C10-C11, C16-C17, C18-O and C9-O bonds are created using α-chloro sulfide intermediates.
The C1-C6 subunit was synthesized using Marshall's propargylation as the key step. NHK-
coupling was employed for coupling the C1-C6 with C7-C22 subunit. Oxonia-Cope
rearrangement, [2,3] sigmatropic rearrangement, Ru(IV)-catalyzed redox rearrangement,
Jacobsen's hydrolytic kinetic resolution and Sharpless' asymmetric dihydroxylation with
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concomitant cyclization constitute the unique features of the synthesis. The potential of α-
chloro sulfides for stereoselective carbon-carbon bond formation is elegantly demonstrated.
Experimental
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31
(
S)-2-(((4-Methoxybenzyl)oxy)methyl)oxirane 11 : The catalyst (R,R)-salen-Co(II) (454
mg, 0.75 mmol) was dissolved in dichloromethane (5 mL) and treated with acetic acid (285
μL, 5 mmol). The solution was allowed to stir at rt in open air for 30 min over which time the
color changed from orange-red to dark brown. The solution was concentrated in vacuo to
yield a crude brown solid, which was dissolved in THF (2.5 mL) and then racemic epoxide
(29.1 g, 150 mmol) was added to the solution. The reaction mixture was cooled at 0 °C and
H O (1.5 mL, 82.5 mmol) was added dropwise over a 5 min period. The reaction mixture was
2
allowed to warm to rt and stirred for 12 h. Direct purification by flash chromatography on
silica gel using 5% EtOAc/hexane as the eluent provided the enantioenriched epoxide 11
(7.66 g, 63 mmol) in 42% yield as a colourless oil. TLC: R 0.3 (10% EtOAc/Hexane); [α]2
0
f
D
-1
1
-
3.5 (c 1.0, CHCl ); IR (Neat) 2925, 2856, 1727, 1085, 994, 810 cm ; H NMR (500 MHz,
3
CDCl ) δ 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.54 (d, J = 11.5 Hz, 1H), 4.48
3
(d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.72 (dd, J = 11.4, 3.1 Hz, 1H), 3.41 (dd, J = 11.4, 5.8 Hz,
1
3
1
1
H), 3.19 – 3.15 (m, 1H), 2.81 – 2.76 (m, 1H), 2.60 (dd, J = 5.0, 2.7 Hz, 1H); C{ H} NMR
(
100 MHz, CDCl ) δ 159.3, 130.0, 129.5, 113.8, 73.0, 70.6, 55.3, 50.9, 44.4; MS (ESI-TOF)
3
+
m/z: 217 [M+Na]+. HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na: 217.0841;
11 14
3
found: 217.0848.
2S)-1-((4-Methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)oxy)hex-4-yn-2-ol 13: To a
(
stirred solution of alkyne 12 (9.1 g, 65 mmol) in anhydrous THF (150 mL) was added n-BuLi
(2.5 M in THF, 26 mL, 65 mmol) under N at -78 ºC. After 30 min the solution of the
2
epoxide 11 (9.7 g, 50 mmol) in anhydrous THF (50 mL) was added over a period of 15
o
minutes, followed by BF .Et O (10.4 mL, 84 mmol). The mixture was stirred at -78 C for 1 h
3
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o
and was allowed to warm to rt over period of 1 h. The reaction mixture was cooled to 0 C
and quenched with satd aq NH Cl (100 ml). The layers were separated and the aq layer
4
extracted with EtOAc (3x100mL). The combined organic layers were washed with water
0
1
2
3
4
5
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9
0
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(
100 mL), brine (100 mL), dried over Na SO and concentrated. The residue was purified by
2 4
column chromatography using 10% EtOAc/Hexane (v/v) to afford the alcohol 13 (14.52 g,
2
0
4
3.5 mmol) in 87% yield as a colourless liquid. TLC: R 0.2 (10%EtOAc/Hexane); [α] -1.6
f D
-
1 1
(
c 1, CHCl ); IR (Neat) 3421, 2941, 2866, 1607, 1513, 1251, 1115, 1024, 816, 771 cm ; H
3
NMR (400 MHz, CDCl ) δ 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.78 (t, J = 3.3
3
Hz, 1H), 4.49 (s, 2H), 4.32 – 4.16 (m, 2H), 3.97 – 3.91 (m, 1H), 3.88 – 3.82 (m, 1H), 3.81 (s,
3H), 3.57 (dd, J = 9.6, 3.9 Hz, 1H), 3.54 – 3.49 (m, 1H), 3.46 (dd, J = 9.5, 6.6 Hz, 1H), 2.61
13
1
(
s, 1H), 2.52 – 2.44 (m, 2H), 1.89 – 1.69 (m, 3H), 1.66 – 1.50 (m, 3H); C{ H} NMR (100
MHz, CDCl ) δ 159.3, 129.9, 129.4, 113.8, 96.8, 82.2, 78.2, 73.1, 72.6, 68.9, 62.0, 55.2, 54.6,
3
+
+
30.2, 25.3, 23.9, 19.1; MS (ESI-TOF) m/z: 357 [M+Na] . HRMS (ESI-TOF) m/z: [M + Na]
calcd for C H O Na: 357.1688; found: 357.1672.
1
9
26
5
General procedure for the preparation of mandelate ester:
o
To a solution of the alcohol (30 μmol, 1 eq) in dichloromethane (0.5 mL) cooled at 0 C was
added (R)-methoxyphenylacetic acid (39 μmol, 1.3 eq), DMAP (1 mg, 20 mol%) and
EDC.HCl (45 μmol, 1.5 eq). The reaction mixture was stirred at rt for 2 h. After complete
consumption of starting material, the reaction mixture was diluted with dichloromethane (2
mL) and H O (2 mL). The layers were separated and the aq layer was extracted with
2
dichloromethane (2x5 mL). The combined organic layers were sequentially washed with satd
aq NaHCO (5 mL), 1N HCl (5 mL), H O (2x5 mL), brine (10 mL), dried over Na SO and
3
2
2
4
concentrated under reduced pressure to afford the ester.
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PMBO
Ph
H
O
R OMe
S
H
THPO
O
1
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(
2R)-(2S)-1-((4-methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)oxy)hex-4-yn-2-yl 2-
methoxy-2-phenylacetate I: Following the general procedure, alcohol 13 (17 mg, 50 μmol)
on reaction with (R)-methoxyphenylacetic acid (11 mg, 65 μmol) afforded ester I (23 mg, ,
1
4
7
1
7 μmol) in 95% yield as a liquid. H NMR (400 MHz, CDCl ) δ 7.48 – 7.42 (m, 2H), 7.37 –
3
.31 (m, 3H), 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.18 – 5.09 (m, 1H), 4.78 (s,
H), 4.72 (dd, J = 6.5, 3.3 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.12
(dt, J = 15.4, 2.0 Hz, 1H), 4.04 (dt, J = 15.4, 2.0 Hz, 1H), 3.85 – 3.77 (m, 4H), 3.62 (d, J =
.9 Hz, 2H), 3.55 – 3.47 (m, 1H), 3.42 (s, 3H), 2.55 – 2.40 (m, 2H), 1.84 – 1.49 (m, 6H).
4
PMBO
Ph
H
O
S OMe
S
THPO
H
O
(
2S)-(2S)-1-((4-methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)oxy)hex-4-yn-2-yl 2-
methoxy-2-phenylacetate II: Following the general procedure, alcohol 13 (17 mg, 50 μmol)
on reaction with (S)-methoxyphenylacetic acid (11 mg, 65 μmol) afforded ester II (23 mg, 47
1
μmol) in 94% yield as a liquid. H NMR (400 MHz, CDCl ) δ 7.50 – 7.41 (m, 2H), 7.36 –
3
7
.30 (m, 3H), 7.09 (d, J= 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.20 – 5.11 (m, 1H), 4.80 (s,
H), 4.77 (t, J = 3.3 Hz, 1H), 4.29 (d, J = 11.6 Hz, 1H), 4.26 – 4.11 (m, 3H), 3.87 – 3.81 (m,
1
1H), 3.80 (s, 3H), 3.55 – 3.44 (m, 3H), 3.42 (s, 3H), 2.70 – 2.52 (m, 2H), 1.86 – 1.50 (m, 6H).
Note: The configuration of alcohol 13 was unambiguously established as ‘S’ by comparison
1
of the H NMR spectra of both (R) & (S)-mandelate esters. Thus the propargylic protons
appeared upfield in the R-mandelate compared to the S-mandelate while the CH OPMB
2
appeared downfield in the R-mandelate ester compared to the S-diastereomer.
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(
S)-6-((4-Methoxybenzyl)oxy)hex-2-yne-1,5-diol 14: To solution of alkyne 13 (14 g, 42
mmol) in methanol (42 mL) was added PPTS (105 mg, 1 mol%) and the mixture stirred at 50
oC for 12 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (100
0
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mL) and washed with satd aq NaHCO (50 mL), water (50 mL), brine (50 mL) and dried over
3
anhydrous Na SO . After filtration, the solvent was evaporated under reduced pressure and
2
4
the crude product was purified by flash column chromatography using 10-20%
EtOAc/Hexane (v/v) as the eluent to afford the primary alcohol 14 (9.76 g, 39.1 mmol) in
2
0
9
3% yield as a colorless oil. TLC: R 0.2 (30% EtOAc/Hexane); [α] +7.1 (c 1.1, CHCl3);
f D
-1 1
IR (Neat) 3388, 2912, 2864, 1612, 1513, 1247, 1100, 1030, 820 cm ; H NMR (400 MHz,
CDCl ) δ 7.25 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.48 (s, 2H), 4.21 (t, J = 2.2 Hz,
3
2
H), 3.98 – 3.90 (m, 1H), 3.80 (s, 3H), 3.54 (dd, J = 9.6, 4.0 Hz, 1H), 3.45 (dd, J = 9.6, 6.6
1
3
1
Hz, 1H), 2.45 (dt, J = 6.1, 2.2 Hz, 2H); C{ H} NMR (100 MHz, CDCl ) δ 159.2, 129.7,
3
129.4, 113.7, 81.8, 80.7, 73.0, 72.6, 68.7, 55.2, 50.8, 23.8; MS (ESI-TOF) m/z: 273 [M+Na]+.
+
HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na: 273.1112; found: 273.1103.
1
4
18
4
(S,E)-6-((4-Methoxybenzyl)oxy)hex-2-ene-1,5-diol 15: The solution of alkyne 14 (9.5 g, 38
mmol) in anhydrous Et O (40 mL) was added dropwise to sodium bis-(2-
2
methoxyethoxy)aluminium hydride (60 wt% in toluene, 35 mL, 116 mmol) in anhydrous
o
Et O (40 mL) maintained at 0 C in a rb flask. The reaction mixture was gradually warmed to
2
o
rt, stirred at the same temperature for 1 h and then cooled to 0 C. The reaction mixture was
quenched with aq 1M HCl solution (40 mL). The layers were separated and the aq layer was
extracted with Et O (3x80 mL). The combined organic layers were dried over Na SO and
2
2
4
concentrated. The residue was purified by column chromatography using 20-30%
EtOAc/Hexane (v/v) as the eluent to give pure compound 15 (9.1 g, 36.1 mmol) in 95% yield
20
as a colourless liquid. TLC: R 0.2 (40% EtOAc/Hexane); [α]
+1.4 (c 0.95, CHCl ); IR
3
f
D
-1 1
(
Neat) 3421, 2931, 2863, 1612, 1513, 1247, 1090, 1032, 819, 771 cm ; H NMR (500 MHz,
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CDCl ) δ 7.25 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.79 – 5.61 (m, 2H), 4.47 (s, 2H),
3
4
.07 (d, J = 4.3 Hz, 2H), 3.90 – 3.82 (m, 1H), 3.81 (s, 3H), 3.46 (dd, J = 9.5, 3.4 Hz, 1H),
1
3
1
3.33 (dd, J = 9.5, 7.4 Hz, 1H), 2.28 – 2.15 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
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2
3
4
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6
7
8
9
0
1
59.2, 132.1, 129.9, 129.4, 128.0, 113.8, 73.6, 72.9, 69.7, 63.1, 55.2, 36.1; MS (ESI-TOF)
+
+
m/z: 275 [M+Na] . HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na: 275.1250;
1
4
20
4
found: 275.1254.
S,E)-1-((4-Methoxybenzyl)oxy)-6-(phenylthio)hex-4-en-2-ol 16: To a solution of alcohol
5 (8.32 g, 33 mmol) in toluene (57 mL) at rt was added diphenyl disulfide (7.91 g, 36.3
(
1
mmol) followed by tri-n-butylphosphine (16.3 mL, 66 mmol). The reaction mixture was
stirred at ambient temperature for 20 min. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography on silica gel using 10%
EtOAc/Hexane (v/v) as the eluent to afford sulfide 16 as colorless oil (9.87 g, 28.7 mmol) in
2
0
87% yield. TLC: R 0.3 (10% EtOAc/Hexane); [α] +8.0 (c 0.75, CHCl ): IR (Neat) 3450,
f
D
3
-1
1
2
907, 2859, 1611, 1511, 1246, 1089, 1031, 967, 819, 741, 691 cm ; H NMR (400 MHz,
CDCl ) δ 7.34 – 7.31 (m, 2H), 7.28 – 7.25 (m, 2H), 7.24 (d, J= 8.7 Hz, 2H), 7.21 – 7.15 (m,
3
1
1
H), 6.88 (d, J = 8.7 Hz, 2H), 5.61 – 5.45 (m, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.75 – 3.68 (m,
H), 3.55 – 3.49 (m, 2H), 3.34 (dd, J = 9.5, 3.5 Hz, 1H), 3.22 (dd, J = 9.5, 7.2 Hz, 1H), 2.17
1
3
1
(
t, J = 6.3 Hz, 2H); C{ H} NMR (125 MHz, CDCl ) δ 159.2, 135.7, 130.1, 130.0, 129.33,
3
1
29.25, 128.7, 128.3, 126.2, 113.8, 73.3, 72.9, 69.7, 55.2, 36.3; MS (ESI-TOF) m/z: 367
+
+
[M+Na] . HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O NaS: 367.1338; found:
2
0
24
3
3
67.1349.
(S,E)-1-((4-Methoxybenzyl)oxy)-6-(phenylthio)hex-4-en-2-yl
methanesulfonate
17:
Triethylamine (8.6 mL, 61.6 mmol) and methanesulfonyl chloride (2.6 mL, 33.6 mmol) were
added successively to a solution of alcohol 16 (9.63 g, 28 mmol) in anhydrous CH Cl (56
2
2
mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min before it was quenched by
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the addition of satd aq NaHCO (50 mL) at 0 °C. After the mixture was warmed to 25 °C, the
3
organic layer was separated and the aq layer was extracted with CH Cl (2x70 mL). The
2
2
combined organic extracts were washed with water (100 mL), brine (100 mL), dried over
0
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8
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0
1
2
3
4
5
6
7
8
9
0
Na SO , filtered and concentrated to afford mesylate 17 (11.46 g, 27.16 mmol) in 97% yield
2
4
as a pale yellow oil, which was used in the next step without further purification. TLC: R 0.3
f
(
10% EtOAc/Hexane); [α]20 +14.2 (c 1, CHCl ); IR (Neat) 2935, 2866, 1612, 1513, 1248,
D 3
-
1 1
1
2
1
174, 1095, 917, 818, 743 cm ; H NMR (500 MHz, CDCl ) δ 7.33 – 7.29 (m, 2H), 7.27 (m,
3
H), 7.21 (d, J = 8.7 Hz, 2H), 7.20 – 7.16 (m, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.62 (dt, J =
5.2, 6.8 Hz, 1H), 5.49 (dt, J = 15.2, 7.1 Hz, 1H), 4.74 – 4.65 (m, 1H), 4.42 (d, J = 11.4 Hz,
1H), 4.37 (d, J = 11.4 Hz, 1H), 3.80 (s, 3H), 3.51 (d, J = 6.9 Hz, 2H), 3.43 (d, J = 5.2 Hz,
13
1
2
1
H), 2.95 (s, 3H), 2.47 – 2.36 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ 159.3, 135.6,
3
29.9, 129.7, 129.4, 129.3, 128.8, 126.7, 126.2, 113.8, 80.9, 72.9, 70.3, 55.2, 38.5, 35.9, 34.8;
+
+
MS (ESI-TOF) m/z: 445 [M+Na] . HRMS (ESI-TOF) m/z: [M+H] calcd for C H O S :
2
1
27
5 2
4
23.1294; found: 423.1306.
(2S,3R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2-((phenylthio)methyl)tetrahydrofuran-
3
-ol 18: To a stirred solution of K CO (11.2 g, 81 mmol), K [Fe(CN) ] (26.5 g, 81 mmol)
2 3 3 6
and hydroquinine 1,4-phthalazinediyl diether [(DHQD) PHAL, 110 mg, 0.14 mmol] in
2
tBuOH/H O (100 mL, 1:1) were added methane sulfonamide (2.6 g, 27 mmol) and
2
K2
OsO
2
(OH) (10 mg, 0.027 mmol) at rt and the solution was stirred for 15 min. The reaction
4
mixture was cooled to 0 °C and a solution of mesylate 17 (11.4 g, 27 mmol) in tBuOH/H O
2
(35 mL, 1:1) was added. The resultant mixture was stirred at the same temperature for 10 h.
The reaction mixture was then warmed to rt and stirred for 10 h. Upon completion (monitored
by TLC), the reaction mixture was quenched with a satd solution of Na SO (80 mL). The aq
2
3
layer was separated and then extracted with EtOAc (3x100 mL). The combined organic
extracts were washed with brine, dried with anhydrous Na SO and concentrated under
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reduced pressure. The crude residue was purified by silica gel column chromatography using
1
0% EtOAc/Hexane (v/v) as the eluent to give tetrahydrofuran derivative 18 (6.12 g, 17.0
2
0
mmol) in 63% yield as a viscous liquid; TLC: R 0.2 (10% EtOAc/Hexane); [α] -30.1 (c
f
D
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
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4
5
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7
8
9
0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
1
.5, CHCl ); IR (Neat) 3436, 2925, 1612, 1512, 1246, 1175, 1076, 1033, 820, 744 cm ; H
3
NMR (400 MHz, CDCl ) δ 7.39 – 7.35 (m, 2H), 7.30 – 7.23 (m, 4H), 7.19 – 7.12 (m, 1H),
3
6.88 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.25 (dq, J =
10.3, 2.0 Hz, 1H), 4.10 (bs, 1H), 4.06 – 3.96 (m, 1H), 3.82 (td, J = 6.6, 2.4 Hz, 1H), 3.79 (s,
3H), 3.69 (dd, J = 10.3, 2.0 Hz, 1H), 3.38 (dd, J = 10.3, 2.0 Hz, 1H), 3.25 (dd, J = 13.3, 6.7
Hz, 1H), 3.19 (dd, J = 13.3, 6.6 Hz, 1H), 2.31 (ddd, J = 14.1, 10.4, 5.1 Hz, 1H), 1.94 (dd, J =
1
3
1
14.1, 2.7 Hz, 1H); C{ H} NMR (125 MHz, CDCl ) δ 159.4, 136.5, 129.5, 129.0, 128.8,
3
1
28.7, 125.7, 113.8, 82.7, 76.7, 73.3, 71.3, 71.1, 55.1, 36.9, 32.2; MS (ESI-TOF) m/z: 383
+
+
[
M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O NaS: 383.1286; found:
20 24 4
383.1288.
(2S,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2- ((phenylthio)methyl)dihydrofuran-3(2H)-
one 19: To a stirred solution of 2-iodoxybenzoic acid (7.14 g, 25.5 mmol) in anhydrous
o
DMSO (34 mL) cooled at 0 C was added a solution of alcohol 18 (6.12 g, 17 mmol) in
anhydrous dichloromethane (52 mL) and the reaction mixture was stirred for a period of 2 h
at rt. After completion of the reaction, the mixture was filtered through a small pad of Celite
pad and the filtrate was diluted with CH Cl (80 mL), washed with water (200mL), brine
2
2
(100 mL) and dried over Na SO . The solvent was evaporated under reduced pressure to
2
4
afford the residue which was purified by column chromatography using 5% EtOAc/Hexane
(v/v) as the eluent to give the pure ketone 19 (5.54 g, 15.47 mmol) in 91% yield as a
colourless liquid. TLC: R 0.2 (7% EtOAc/Hexane); [α]20D +116.6 (c 1.65, CHCl ); IR (Neat)
f
3
-1
1
2
908, 2862, 1758, 1611, 1512, 1247, 1173, 1089, 1031, 820, 743, 693 cm ; H NMR (300
MHz, CDCl ) δ 7.44 – 7.33 (m, 2H), 7.30 – 7.21 (m, 4H), 7.17 (tt, J = 8.3, 2.2 Hz, 1H), 6.86
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(
d, J = 8.6 Hz, 2H), 4.48 (s, 2H), 4.45 – 4.35 (m, 1H), 4.07 (dd, J = 6.3, 3.6 Hz, 1H), 3.79 (s,
3
H), 3.65 (dd, J = 10.5, 3.6 Hz, 1H), 3.56 (dd, J = 10.5, 4.9 Hz, 1H), 3.38 (dd, J = 14.0, 3.6
Hz, 1H), 3.13 (dd, J = 14.0, 6.4 Hz, 1H), 2.54 (dd, J = 18.2, 6.6 Hz, 1H), 2.44 (dd, J = 18.2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
9
1
.0 Hz, 1H); C{ H} NMR (125 MHz, CDCl ) δ 213.3, 159.2, 135.9, 129.7, 129.5, 129.2,
3
28.8, 126.2, 113.7, 79.9, 75.2, 73.1, 71.2, 55.1, 39.4, 35.1; MS (ESI-TOF) m/z: 381
+
+
[M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O NaS: 381.1136; found:
20 22 4
3
81.1139.
(
2S,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylene-2-
(phenylthio)methyl)tetrahydrofuran 20: Methyltriphenylphosphonium bromide (26.8 g,
(
75 mmol) was suspended in THF (120 mL) and a solution of potassium tert-butoxide solution
in THF (8.4 g, 75 mmol) was added dropwise at 0 °C. After addition, the resultant yellow
solution was stirred for 45 min and was added to the solution of ketone 19 (5.37 g, 15 mmol)
in THF (30 mL) at 0 °C. The reaction mixture was stirred for 45 min and then quenched with
H O (50 mL). The mixture was extracted with EtOAc (3x100 mL). The combined organic
2
extracts were washed with brine (100 mL), dried over anhydrous Na SO , filtered, and
2
4
concentrated. The residue was purified by silica gel column chromatography using 3%
EtOAc/Hexanes (v/v) as the eluent to afford the pure compound 20 (5.1 g, 14.25 mmol) in
2
0
9
5% yield as a colourless oil. TLC: R 0.3 (5% EtOAc/Hexane); [α] +87.7 (c 0.95, CHCl3);
f D
-1 1
IR (Neat) 2903, 2860, 1611, 1512, 1247, 1175, 1087, 1033, 819, 741, 692 cm ; H NMR
(300 MHz, CDCl ) δ 7.38 (d, J = 7.3 Hz, 2H), 7.30 – 7.22 (m, 4H), 7.15 (t, J = 7.3 Hz, 1H),
3
6
4
.86 (d, J = 8.6 Hz, 2H), 5.1 – 4.95 (m, 2H), 4.58 – 4.52 (m, 1H), 4.50 (d, J = 11.7 Hz, 1H),
.46 (d, J = 11.7 Hz, 1H), 4.19 – 4.08 (m, 1H), 3.79 (s, 3H), 3.51 (d, J = 5.0 Hz, 2H), 3.17
1
3
1
(dd, J = 5.5, 1.0 Hz, 2H), 2.60 (dd, J = 15.5, 6.1 Hz, 1H), 2.53 – 2.40 (m, 1H); C{ H} NMR
(100 MHz, CDCl ) δ 159.1, 149.5, 136.8, 130.2, 129.3, 129.0, 128.8, 125.8, 113.7, 106.4,
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+
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9.5, 77.8, 73.0, 71.9, 55.2, 39.3, 35.9; MS (ESI-TOF) m/z: 379 [M+Na] . HRMS (ESI-TOF)
+
m/z: [M+Na] calcd for C H O NaS: 379.1344; found: 379.1341.
2
1
24
3
(2S,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylene-2-(1-
phenylthio)allyl)tetrahydrofuran 9: To a solution vinyl magnesium bromide (1M in THF,
6 mL, 36 mmol) cooled at 0 °C was added a solution of ZnBr (1.5 M in THF, 36 mL, 54
1
1
1
1
1
1
1
1
1
1
2
2
2
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2
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5
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5
5
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5
6
0
1
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9
0
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9
0
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2
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8
9
0
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2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3
2
mmol) at 0 °C and the mixture stirred for 30 min. Separately, in another rb flask, the chloro
sulfide was prepared by adding a solution of sulfide 20 (4.27 g, 12 mmol) in anhydrous
benzene (60 mL) to NCS (1.67 g, 12.6 mmol) in anhydrous benzene (60 mL) and stirring for
4
5 min. To the organozinc reagent maintained at 0 °C was added a solution of chloro sulfide
(12 mmol) in benzene (120 mL). The reaction mixture was stirred gradually, allowing it to
attain rt and stirred further for a period of 2 h when TLC examination indicated complete
consumption of the chloro sulfide. The reaction mixture was cooled to 0 °C and quenched by
the addition of aq satd NH Cl solution (50 mL). It was allowed to warm to rt and diluted with
4
EtOAc (80 mL). The layers were separated and the aq layer was extracted with EtOAc (3x80
mL). The combined organic layers were washed with H O (100 mL), brine (100 mL) and
2
dried over anhydrous Na SO .The solvent was evaporated under reduced pressure to afford a
2
4
crude compound that was purified by column chromatography using 1−2% EtOAc/hexanes
v/v) as the eluent to afford the pure product 9 (3.66 g, 9.6 mmol) in 81% yield as a light
(
2
0
yellow liquid. TLC: R 0.3 (5% EtOAc/Hexane); [α] +51.3 (c 0.5, CHCl ); IR (Neat) 2903,
f
D
3
-1 1
2861, 1611, 1512, 1247, 1175, 1088, 1034, 821, 743, 693 cm ; H NMR (500 MHz, CDCl )
3
δ 7.41 – 7.37 (m, 2H), 7.30 – 7.22 (m, 4H), 7.22 – 7.09 (m, 1H), 6.88 (d, J = 8.7 Hz, 2H), 5.9
(
ddd, J = 17.1, 10.2, 9.0 Hz, 1H), 5.15 – 5.12 (m, 2H), 5.03 (d, J =10.2 Hz, 1H), 5.01 (d, J =
16.5 Hz, 1H), 4.63 – 4.59 (m, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.16
–
2
4.09 (m, 1H), 3.79 (s, 3H), 3.52 (dd, J = 10.4, 6.3 Hz, 1H), 3.16 (dd, J = 10.4, 4.3 Hz, 1H),
1
3
1
.60 (dd, J = 15.5, 6.1 Hz, 1H), 2.48 – 2.39 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ
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59.1, 148.1, 135.6, 135.0, 132.2, 130.3, 129.3, 128.7, 126.9, 117.0, 113.7, 107.0, 82.8, 78.3,
+
3.0, 71.9, 57.7, 55.2, 37.0; MS (ESI-TOF) m/z: 405 [M+Na] . HRMS (ESI-TOF) m/z:
+
[M+Na] calcd for C H O NaS: 405.1500; found: 405.1502.
2
3
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(E)-3-((2R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylenetetrahydrofuran-2-
yl)prop-2-en-1-ol 21: To a solution of sulfide 9 (3.1 g, 8.1 mmol) in CHCl (16 mL) cooled
3
at -40 °C was added mCPBA (70%, 2 g, 8.1 mmol) and the reaction mixture stirred at the
same temperature for 20 min. Toluene (32 mL) and 2-mercapto-1-methyl-imidazole (1.4 g,
1
2.2 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h and then quenched
by the addition of satd aq NaHCO (50 mL). The mixture was diluted with CH Cl (50 mL)
3
2
2
and the layers were separated. The combined organic layers were washed successively with
water (80 mL), brine (50 mL) and dried over Na SO . The solvent was evaporated under
2
4
reduced pressure to furnish the crude compound which was purified by column
chromatography using 20% EtOAc/hexanes (v/v) as the eluent to afford the product 21 (1.88
20
g, 6.5 mmol) in 80% yield as a liquid. TLC: R 0.2 (20% EtOAc/hexanes); [α] +54.7 (c 0.5,
f
D
-1
1
CHCl ); IR (Neat) 3417, 2924, 2858, 1614, 1512, 1247, 1175, 1094, 1030, 820 cm ; H
3
NMR (400 MHz, CDCl ) δ 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.91 (dt, J =
3
1
5.4, 5.3 Hz, 1H), 5.69 – 5.60 (m, 1H), 5.03 – 4.99 (m, 1H), 4.85 – 4.81 (m, 1H), 4.74 – 4.68
(m, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.20 – 4.12 (m, 3H), 3.80 (s,
1
3
1
3
H), 3.56 – 3.46 (m, 2H), 2.65 (dd, J = 16.2, 6.8 Hz, 1H), 2.45 – 2.35 (m, 1H); C{ H} NMR
(125 MHz, CDCl ) δ 159.2, 149.8, 132.6, 130.5, 130.2, 129.4, 113.7, 106.5, 81.9, 77.3, 73.1,
3
+
+
7
2.0, 62.9, 55.3, 35.4; MS (ESI-TOF) m/z: 313 [M+Na] . HRMS (ESI-TOF) m/z: [M+Na]
calcd for C H O Na: 313.1416; found: 313.1419.
1
7
22
4
3-((2R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylenetetrahydrofuran-2-
yl)propanal 22: To solution of alcohol 21 (1.74 g, 6 mmol) in THF (12 mL) contained in a
pressure tube bis(allyl)-ruthenium(IV) dimer (13 mg, 0.3 mol%), CS CO (12 mg, 0.6 mol%)
2
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o
were introduced and reaction mixture was stirred at 80 C for 12 h under nitrogen
atmosphere. The resulting solution was quenched with satd NaCl (10 mL). The layers were
separated and the aq layer was extracted with dichloromethane (3x20 mL). The combined
organic exactrats were washed with water (30 mL), brine (30 mL), dried over Na SO ,
1
1
1
1
1
1
1
1
1
1
2
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2
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0
1
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7
8
9
0
1
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3
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5
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8
9
0
1
2
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8
9
0
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4
5
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7
8
9
0
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3
4
5
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7
8
9
0
2
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concentrated and purified by column chromatography over silica gel using 7%
EtOAc/Hexane (v/v) as the eluent to furnish compound 22 (1.51 g, 5.22 mmol) in 87% yield
2
0
as a yellow oil. TLC: R 0.3 (10% EtOAc/Hexane); [α] +72.2 (c 0.55, CHCl ); IR (Neat)
f
D
3
-1 1
2
930, 2856, 1724, 1610, 1513, 1251, 1174, 1094, 1030, 836, 776 cm ; H NMR (500 MHz,
CDCl ) δ 9.77 (t, J = 1.7 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.03 –
3
4.99 (m, 1H), 4.87 – 4.84 (m, 1H), 4.53 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.41
–
2
4.36 (m, 1H), 4.11 – 4.05 (m, 1H), 3.81 (s, 3H), 3.51 – 3.47 (m, 2H), 2.63 – 2.47 (m, 3H),
1
3
1
.33 – 2.28 (m, 1H), 2.18 – 2.10 (m, 1H), 1.86 – 1.78(m, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 202.6, 159.1, 149.9, 130.1, 129.3, 113.6, 105.2, 79.8, 77.3, 73.0, 71.8, 55.2, 39.4,
3
+
+
3
6.0, 27.1; MS (ESI-TOF) m/z: 313 [M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for
C H O Na: 313.1416; found: 313.1422.
1
7
22
4
(
S,E)-1-((2R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylenetetrahydrofuran-2-
yl)hept-5-en-3-ol 23: Tin(II) triflate (25 mg, 0.06 mmol) was added in one portion to a
solution of homoallyl alcohol 10 (1.62 g, 10 mmol) and aldehyde 22 (1.45 g, 5 mmol) in
CHCl (50 mL; passed through a pad of basic Al O before use) at rt and the mixture was
3
2
3
stirred for 1 h. Subsequently, the mixture was diluted with CH Cl (50 mL), washed with a
2
2
satd NaHCO solution (2x50 mL), water (50 mL) and brine (50 mL). The organic layer was
3
dried over sodium sulfate and the solvents were removed in vacuum. The crude compound
was purified by column chromatography using 10-20% EtOAc/Hexanes (v/v) as the eluent to
afford the alcohol 5 (1.21 g, 3.5 mmol) in 70% yield as a liquid. TLC: R 0.3 (10%
f
EtOAc/Hexane); [α]20 +58.4 (c 0.5, CHCl ); IR (Neat) 3447, 2922, 2858, 1611, 1512, 1247,
D
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175, 1035, 970, 821 cm ; H NMR (500 MHz, CDCl ) δ 7.27 (d, J = 8.6 Hz, 2H), 6.87 (d, J
3
=
8.7 Hz, 2H), 5.59 – 5.50 (m, 1H), 5.49 – 5.40 (m, 1H), 5.0 – 4.95 (m, 1H), 4.86 – 4.82 (m,
1H), 4.54 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.36 – 4.29 (m, 1H), 4.09 (ddd, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
1.5, 10.1, 5.7 Hz, 1H), 3.80 (s, 3H), 3.67 – 3.59 (m, 1H), 3.52 – 3.49 (m, 2H), 2.6(dd, J =
5.7, 6.7 Hz, 1H), 2.41 – 2.31 (m, 1H), 2.27 (bs, 1H), 2.24 – 2.15 (m, 1H), 2.14 – 2.06 (m,
H), 1.93 – 1.83 (m, 1H), 1.68 (dd, J = 6.2, 1.1 Hz, 3H), 1.66 – 1.58 (m, 2H), 1.57 – 1.48 (m,
1
3
1
H); C{ H} NMR (125 MHz, CDCl ) δ 159.2, 150.7, 130.2, 129.3, 128.4, 127.4, 113.7,
3
04.8, 81.3, 77.1, 73.0, 71.9, 70.9, 55.2, 40.7, 36.0, 32.7, 31.3, 18.1; MS (ESI-TOF) m/z: 369
+
+
[
M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O Na: 369.2042; found:
21 30 4
369.2039.
PMBO
Ph
R
R
H
O
O
R OMe
S
H
O
(R)-(S,E)-1-((2R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-3-methylenetetrahydrofuran-2-
yl)hex-4-en-3-yl 2-methoxy-2-phenylacetate (III): Following the general procedure,
alcohol 23 (11 mg, 30 μmol) on reaction with (R)-methoxyphenylacetic acid afforded ester
1
III (13 mg, 26 μmol) in 89% yield as a liquid. TLC: R 0.4 (10% EtOAc/hexanes); H NMR
f
(
300 MHz, CDCl ) δ 7.48 – 7.40 (m, 2H), 7.37 – 7.28 (m, 3H), 7.25 (d, J = 8.7 Hz, 2H), 6.87
3
(
d, J = 8.7 Hz, 2H), 5.51 – 5.38 (m, 1H), 5.37 – 5.24 (m, 1H), 4.97 – 4.85 (m, 1H), 4.85 –
4
.80 (m, 1H), 4.72 (s, 1H), 4.52 (d, J = 11.8 Hz, 1H), 4.48 – 4.42 (m, 2H), 4.10 – 4.01 (m,
1H), 4.03 – 3.94 (m, 1H), 3.80 (s, 3H), 3.48 – 3.42 (m, 2H), 3.41 (s, 3H), 2.51 (dd, J = 15.7,
5
1
.8 Hz, 1H), 2.33 – 2.13 (m, 3H), 1.76 – 1.65 (m, 1H), 1.59 (dd, J = 6.1, 1.0 Hz, 3H), 1.56 –
.30 (m, 2H), 1.23 – 1.07 (m, 1H).
PMBO
Ph
R
H
R
O
O
S OMe
S
H
O
2
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(
S)-(S,E)-1-((2R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-3-methylenetetrahydrofuran-2-
yl)hex-4-en-3-yl 2-methoxy-2-phenylacetate (IV): Following the general procedure, alcohol
23 (11 mg, , 30 μmol mmol) on reaction with (S)-methoxyphenylacetic acid afforded ester IV
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
4
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0
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0
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7
8
9
0
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2
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6
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8
9
0
1
(13.6 mg, , 27 μmol) in 92% yield. H NMR (400 MHz, CDCl ) δ 7.43 (dd, J = 7.8, 1.5 Hz,
3
2
1
1
1
2
H), 7.37 – 730 (m, 3H), 7.26 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.20 (dq, J =
5.6, 6.3 Hz, 1H), 5.07 – 4.97 (m, 1H), 4.97 – 4.91 (m, 2H), 4.75 – 4.72 (m, 1H), 4.72 (s,
H), 4.55 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.31 – 4.24 (m, 1H), 4.1 – 4.02 (m,
H), 3.80 (s, 3H), 3.53 – 3.45 (m, 2H), 3.40 (s, 3H), 2.56 (dd, J = 15.6, 6.0 Hz, 1H), 2.35 –
.25 (m, 1H), 2.09 (t, J = 6.8 Hz, 2H), 1.72 – 1.58 (m, 4H),1.43 (dd, J = 6.4, 1.2 Hz, 3H).
Note: The configuration of alcohol 23 was unambiguously established as a ‘S’ by comparison
1
of the H NMR spectra of (R) & (S)-mandelate esters. Thus the terminal olefinic protons
appeared upfield in the R-mandelate compared to the S-mandelate while the CH CHCHCH
2
3
appeared downfield in the R-mandelate ester compared to the S-diastereomer.
2R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2-((S,E)-3-(methoxymethoxy)hept-5-en-1-
yl)-3-methylenetetrahydrofuran 24: To a solution of the alcohol 23 (1 g, 2.9 mmol) and
iPr NEt (1 mL, 5.8 mmol) in dichloromethane (6 mL) cooled to 0 °C, MOM-Cl (0.33 mL,
(
2
4
.35 mmol) was added at 0 °C and the resulting reaction mixture was stirred at rt for 2 h. The
reaction was quenched with satd aq NH Cl (10 mL) and the mixture was extracted with
4
CH Cl (3×30 mL). The combined organic layers were washed with brine (30 mL), dried
2
2
over Na SO and concentrated under reduced pressure. The crude product was purified by
2
4
flash chromatography on silica gel using 5-10% EtOAc/Hexane (v/v) as the eluent to afford
the MOM ether 24 (984 mg, 2.52 mmol) in 96% yield as a colourless liquid. TLC: R 0.3
f
(10% EtOAc/Hexane); [α]20 +57.1 (c 0.5, CHCl ); IR (Neat) 2928, 1612, 1513, 1248,
D
3
-1
1
1
147,1095,1038, 969, 821 cm ; H NMR (400 MHz, CDCl ) δ 7.27 (d, J = 8.7 Hz, 2H), 6.87
3
(d, J = 8.7 Hz, 2H), 5.54 – 5.38 (m, 2H), 4.97 – 4.94 (m, 1H), 4.84 – 4.81 (m, 1H), 4.66 (d, J
2
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=
6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H),
4
.33 – 4.26 (m, 1H), 4.12 – 4.03 (m, 1H), 3.80 (s, 3H), 3.63 – 3.54 (m, 1H), 3.52 (dd, J =
10.2, 5.7 Hz, 1H), 3.49 (dd, J = 10.2, 4.5 Hz, 1H), 3.37 (s, 3H), 2.58 (dd, J = 15.7, 6.0, Hz,
0
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H), 2.38 – 2.28 (m, 1H), 2.22 (t, J = 5.6 Hz, 2H), 1.88 – 1.78 (m, 1H), 1.74 – 1.67 (m, 1H),
1
3
1
.65 (dd, J = 5.8, 0.9 Hz, 3H), 1.61 – 1.45 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ
3
59.1, 151.0, 130.3, 129.3, 127.6, 127.0, 113.7, 104.5, 95.3, 81.2, 77.2, 77.1, 73.0, 72.1, 55.5,
+
5.2, 37.6, 36.2, 31.0, 29.8, 18.0; MS (ESI-TOF) m/z: 413 [M+Na] . HRMS (ESI-TOF) m/z:
+
[M+Na] calcd for C H O Na: 413.2304; found: 413.2303.
2
3
34
5
((2R,5R)-5-((S,E)-3-(Methoxymethoxy)hept-5-en-1-yl)-4-methylenetetrahydrofuran-2-
yl)methanol 25: To a solution of PMB ether 24 (0.94 g, 2.4 mmol) in anhydrous
dichloromethane (19.8 mL) and pH 7 buffer (2.2 mL) cooled to 0 °C was added DDQ (0.75
g, 3.3 mmol). The reaction mixture was stirred at the same temperature for 2 h and then
diluted with water (20 mL). The aq phase was extracted with CH Cl (3x50 mL). The
2
2
combined organic layers were washed with water (50 mL), brine (50 mL), dried over
anhydrous Na SO and concentrated under reduced pressure. Flash column chromatography
2
4
using 15% EtOAc/Hexane (v/v) as the eluent afforded alcohol 25 (518 mg, 1.92 mmol) in
2
0
8
0% yield as a colorless oil. TLC: R 0.3 (15% EtOAc/Hexane); [α] +51.3 (c 0.5, CHCl3);
f D
-1 1
IR (Neat) 3447, 2932, 2857, 1621, 1462, 1388, 1254, 1051, 834, 772 cm ; H NMR (400
MHz, CDCl ) δ 5.55 – 5.38 (m, 2H), 5.0 – 4.95 (m, 1H), 4.85 – 4.81 (m, 1H), 4.68 (d, J = 6.9
3
Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.34 – 4.29 (m, 1H), 4.06 – 3.98 (m, 1H), 3.80 (dd, J =
1
1.8, 3.0 Hz, 1H), 3.66 – 3.59 (m, 1H), 3.54 (dd, J = 11.8, 5.1 Hz, 1H), 3.38 (s, 3H), 2.57 –
.43 (m, 2H), 2.22 (t, J= 6.2 Hz, 2H), 1.89 – 1.78 (m, 1H), 1.74 – 1.68 (m, 1H), 1.67 (dd, J =
2
1
3
1
5.9, 1.1 Hz, 3H), 1.65 – 1.49 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ 151.1, 127.7,
3
1
26.9, 104.8, 95.3, 81.3, 78.2, 77.1, 64.2, 55.5, 37.7, 34.4, 30.9, 30.0, 18.0; MS (ESI-TOF)
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+
+
m/z: 293 [M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O Na: 293.1729; found:
1
5
26
4
2
93.1735.
(2R,5R)-2-((S,E)-3-(Methoxymethoxy)hept-5-en-1-yl)-3-methylene-5-
(phenylthio)methyl)tetrahydrofuran 7: Following the procedure detailed for the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
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4
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4
4
4
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5
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5
5
5
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5
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0
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(
preparation of sulfide 16 from alcohol 15, alcohol 25 (351 mg, 1.3 mmol) was treated with
diphenyl disulfide (312 mg, 1.4 mmol) followed by tri-n-butylphosphine (0.64 mL, 2.6
mmol) to afford sulfide 7 (409 mg, 1.13 mmol) in 87% yield as a colourless oil. TLC: R 0.3
f
(
10% EtOAc/Hexane); [α]20 +68.2 (c 0.5, CHCl ); IR (Neat) 2924, 2858, 1648, 1451, 1259,
D
3
-1
1
1
088, 1031, 800, 741 cm ; H NMR (400 MHz, CDCl ) δ 7.40 – 7.35 (m, 2H), 7.31 – 7.25
3
(m, 2H), 7.21 – 7.13 (m, 1H), 5.55 – 5.38 (m, 2H), 5.0 – 4.94 (m, 1H), 4.85 – 4.80 (m, 1H),
4
.67 (d, J = 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.32 – 4.26 (m, 1H), 4.11 – 4.03 (m, 1H),
.61 – 3.53 (m, 1H), 3.37 (s, 3H), 3.23 (dd, J = 13.3, 5.1 Hz, 1H), 3.00 (dd, J = 13.3, 7.1 Hz,
3
1H), 2.71 (dd, J = 15.5, 6.5 Hz, 1H) 2.42 – 2.32 (m, 1H), 2.22 (t, J = 5.7 Hz, 2H), 1.86 –
1
.77 (m, 1H), 1.66 (dd, J = 5.8, 0.9 Hz, 3H), 1.64 – 1.56 (m, 1H), 1.54 – 1.44 (m, 2H);
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 150.8, 136.3, 129.2, 128.8, 127.6, 126.9, 126.0, 104.8,
3
9
5.3, 81.3, 77.1, 76.8, 55.5, 38.7, 38.5, 37.6, 31.2, 29.8, 18.0; MS (ESI-TOF) m/z: 385
+
+
[
M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O NaS: 385.1813; found:
21 30 3
3
85.1811.
(
2R,5R)-5-(5-((4-Methoxybenzyl)oxy)-1-(phenylthio)pent-2-yn-1-yl)-2-((S,E)-3-
(methoxymethoxy)hept-5-en-1-yl)-3-methylenetetrahydrofuran 26: To a solution of
alkyne 8 (456 mg, 2.4 mmol) in anhydrous THF (0.8 mL) cooled at 0 °C was added
iPrMgCl·LiCl (1.5 M in THF, 1.6 mL, 2.4 mmol) and the mixture stirred for 30 min at the
same temperature. To the so generated Grignard reagent was added a solution of ZnBr (1.5
2
M in THF, 2.4 mL, 3.6 mmol) at 0 °C and the mixture stirred for 30 min. Separately, in
another rb flask, the chloro sulfide was prepared by adding a solution of sulfide 7 (290 mg,
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.8 mmol) in anhydrous benzene (8 mL) to NCS (65 mg, 0.49 mmol) in anhydrous benzene
(8 mL) and stirring for 15 min. To the organozinc reagent maintained at 0 °C was added a
solution of chloro sulfide in benzene. The reaction mixture was stirred gradually allowing it
to attain rt, and stirred further for a period of 2 h when TLC examination indicated complete
consumption of the chloro sulfide. The reaction mixture was cooled to 0 °C and quenched by
0
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0
the addition of satd aq NH Cl solution (20 mL). It was allowed to warm to rt and diluted with
4
EtOAc (20 mL). The layers were separated and the aq layer was extracted with EtOAc (3x20
mL). The combined organic layers were washed with H O (40 mL), brine (40 mL) and dried
2
over anhydrous Na SO . The solvent was evaporated under reduced pressure to afford a crude
2
4
compound that was purified by column chromatography using 5% EtOAc/Hexane (v/v) as the
eluent to give the pure product 26 (374 mg, 0.68 mmol) in 85% yield as a colourless liquid.
2
0
TLC: R 0.3 (10% EtOAc/Hexane); [α]
+19.8 (c 0.5, CHCl ); IR (Neat) 2897, 2114,
3
f
D
-1 1
1648,1614, 1512, 1247, 1030, 925, 860, 741, 503 cm ; H NMR (400 MHz, CDCl ) δ 7.54 –
3
7
.48 (m, 2H), 7.30 – 7.22 (m, 5H), 6.88 (d, J = 6.7 Hz, 2H), 5.53 – 5.37 (m, 2H), 5.0 – 4.95
(m, 1H), 4.85 – 4.80 (m, 1H), 4.65 (d, J = 6.7 Hz, 1H) 4.63 (d, J = 6.7 Hz, 1H), 4.43 (s, 2H),
4
2
.37 – 4.29 (m, 1H), 4.06 – 3.94 (m, 2H), 3.80 (s, 3H), 3.63 – 3.53 (m, 1H), 3.51 – 3.44 (m,
H), 3.35 (s, 3H), 2.74 – 2.64 (m, 2H), 2.51 – 2.43 (m, 2H), 2.25 – 2.16 (m, 2H), 1.83 – 1.77
1
3
1
(m, 1H), 1.75 – 1.66 (m, 1H), 1.64 (d, J = 5.7 Hz, 3H), 1.63 – 1.51 (m, 2H); C{ H} NMR
(100 MHz, CDCl ) δ 159.2, 150.5, 133.8, 130.2, 129.3, 128.7, 128.6, 127.6, 127.0, 113.8,
3
104.9, 95.3, 83.2, 81.7, 81.4, 79.0, 77.2, 72.6, 68.1, 55.5, 55.3, 43.7, 37.6, 36.6, 31.2, 29.6,
+
+
2
0.2, 18.1; MS (ESI-TOF) m/z: 573 [M+Na] . HRMS (ESI-TOF) m/z: [M+NH ] calcd for
4
C H NO S: 568.3097; found: 568.3102.
3
3
46
5
(E)-5-((4-Methoxybenzyl)oxy)-1-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-1-yl)-
4
-methylenetetrahydrofuran-2-yl)pent-1-en-3-one 27: To a solution of sulfide 26 (275 mg,
0
.5 mmol) in CHCl (1 mL) cooled at -40 °C was added mCPBA (70% 123 mg, 0.5 mmol)
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and the reaction mixture was stirred at the same temperature for 20 min. Toluene (2 mL) and
2
-mercapto-1-methyl-imidazole (86 mg, 0.75 mmol) were added. The reaction mixture was
stirred at 60 °C for 2 h and then quenched by the addition of satd aq NaHCO (5 mL). The
3
1
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0
mixture was diluted with CH Cl (10 mL) and the layers were separated. The combined
2
2
organic layers were washed successively with water (20 mL), brine (30 mL) and dried over
Na SO . The solvent was evaporated under reduced pressure to furnish the crude compound
2
4
which was purified by column chromatography using 5-10% EtOAc/Hexanes (v/v) as the
eluent to afford the product 27 (183 mg, 0.4 mmol) in 80% yield as a liquid. TLC: R 0.3
f
(
15% EtOAc/Hexane); [α]20 +33.2 (c 0.5, CHCl ); IR (Neat) 2926, 2854, 1675, 1614, 1512,
D 3
−
1 1
1451, 1249, 1096, 1035, 813, 749 cm ; H NMR (400 MHz, CDCl ) δ 7.24 (d, J = 8.7 Hz,
3
2
5
H), 6.87 (d, J = 8.7 Hz, 2H), 6.82 (dd, J = 15.9, 5.3 Hz, 1H), 6.33 (dd, J = 15.9, 1.4 Hz, 1H),
.57 – 5.39 (m, 2H), 5.02 – 4.98 (m, 1H), 4.88 – 4.85 (m, 1H), 4.68 (d, J = 6.9 Hz, 1H), 4.64
(d, J = 6.9 Hz, 1H), 4.49 – 4.45 (m, 1H), 4.44 (s, 2H), 4.38 – 4.30 (m, 1H), 3.80 (s, 3H), 3.76
t, J = 6.5 Hz, 2H), 3.64 – 3.55 (m, 1H), 3.38 (s, 3H), 2.87 (t, J = 6.4 Hz, 2H), 2.75 (dd, J =
(
1
1
5.5, 6.2 Hz, 1H), 2.41 – 2.30 (m, 1H), 2.23 (t, J = 6.0 Hz, 2H), 1.90 – 1.80 (m, 1H), 1.76 –
1
3
1
.68 (m, 1H), 1.66 (dd, J = 5.9, 1.0 Hz, 3H), 1.62 – 1.48 (m, 2H); C{ H} NMR (125 MHz,
CDCl ) δ 198.4, 159.2, 150.2, 145.2, 130.3, 129.3, 129.1, 127.7, 126.8, 113.7, 105.1, 95.3,
3
8
1.4, 77.0, 76.8, 72.9, 65.0, 55.5, 55.2, 40.5, 39.3, 37.6, 31.1, 29.8, 18.0; MS (ESI-TOF) m/z:
+
+
4
81 [M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O Na: 481.2566; found:
27 38 6
481.2570.
(S,E)-5-((4-Methoxybenzyl)oxy)-1-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-1-
yl)-4-methylenetetrahydrofuran-2-yl)pent-1-en-3-ol 28: A solution of (R)-(-)-2-methyl-
CBS-oxazaborolidine (1 M solution in toluene, 60 μL, 0.06 mmol) in THF (0.4 mL) was
treated with BH ·DMS (57 μL, 0.6 mmol) at -5 ºC. After 1 h the reaction mixture was cooled
3
to -78 ºC. A solution of enone 27 (138 mg, 0.3 mmol) in THF (0.8 mL) was then added
2
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slowly and stirred for 2 h at the same temperature. The reaction was quenched with satd aq
NH Cl solution (5 mL). The aq layer was extracted with EtOAc (3x15 mL), the combined
4
organic layers were washed with water (20 mL), brine (20 mL), dried over Na SO and
2
4
0
1
2
3
4
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concentrated. Purification of the residue by column chromatography using 10-20%
EtOAc/Hexane (v/v) as the eluent furnished pure alcohol 28 (110 mg, 0.24 mmol) in 80%
2
0
yield as a colourless oil. TLC: R 0.2 (10% EtOAc/hexanes); [α] +35.6 (c 0.5, CHCl ); IR
f
D
3
(Neat) 3421, 2926, 2854, 1675, 1614, 1512, 1451, 1249, 1096, 1035, 922, 813, 749, 502
−
1 1
cm ; H NMR (500 MHz, CDCl ) δ 7.25 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.82 –
3
5
.71 (m, 2H), 5.54 – 5.38 (m, 2H), 5.01 – 4.93 (m, 1H), 4.86 – 4.80 (m, 1H), 4.67 (d, J = 6.9
Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.44 (s, 2H), 4.35– 4.32 (m, 1H), 4.30 – 4.24 (m, 2H), 3.80
s, 3H), 3.71 – 3.64 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 (s, 3H), 2.65 (dd, J = 15.5, 5.8 Hz,
H), 2.38 – 2.27 (m, 1H), 2.22 (t, J = 5.8 Hz, 2H), 1.91 – 1.76 (m, 3H), 1.74 – 1.67 (m, 1H),
(
1
1
3
1
1.65 (dd, J = 5.9, 1.0 Hz, 3H), 1.63 – 1.49 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ
3
1
7
59.3, 151.4, 134.8, 130.3, 129.9, 129.3, 127.7, 126.9, 113.8, 104.4, 95.3, 81.0, 78.4, 77.2,
2.9, 71.2, 68.1, 55.5, 55.2, 40.0, 37.6, 36.3, 31.2, 29.8, 18.0; MS (ESI-TOF) m/z: 483
+
+
[
M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O Na: 483.2723; found:
27 40 6
4
83.2727.
OPMB
S
Ph
R
H
R
O
OMOM
MeO R
O
S
O
H
(R)-(S,E)-5-((4-Methoxybenzyl)oxy)-1-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-
1
-yl)-4-methylenetetrahydrofuran-2-yl)pent-1-en-3-yl 2-methoxy-2-phenylacetate (V):
Following the general procedure, alcohol 28 (5 mg, 11 μmol) on reaction with (R)-
methoxyphenylacetic acid (3 mg, 16 μmol) afforded ester V (6 mg, 10 μmol) in 91% yield as
1
a liquid. TLC: R 0.3 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl ) δ 7.49 – 7.40 (m,
f
3
2
H), 7.38 – 7.31 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.76 (dd, J =
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5.6, 5.8 Hz, 1H), 5.69 (dd, J = 15.6, 6.1 Hz, 1H), 5.61 – 5.38 (m, 3H), 4.98 – 4.94 (m, 1H),
.85 – 4.80 (m, 1H), 4.73 (s, 1H), 4.67 (d, J = 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.34 –
4.19 (m, 2H), 4.09 (s, 2H), 3.79 (s, 3H), 3.62 – 3.55 (m, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 3.20
1
1
1
1
1
1
1
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0
1
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9
0
1
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9
0
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9
0
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2
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8
9
0
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4
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8
9
0
–
2
2
3.12 (m, 1H), 3.04 – 2.95 (m, 1H), 2.61 (dd, J = 15.7, 5.7 Hz, 1H), 2.37 – 2.25 (m, 1H),
.22 (t, J = 5.6 Hz, 2H), 1.92 – 1.68 (m, 4H), 1.65 (dd, J = 5.9, 1.1 Hz, 3H) 1.57 – 1.47 (m,
H).
OPMB
S
H
R
Ph
R
O
OMOM
MeO S
O
S
O
H
(S)-(S,E)-5-((4-methoxybenzyl)oxy)-1-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-
-yl)-4-methylenetetrahydrofuran-2-yl)pent-1-en-3-yl 2-methoxy-2-phenylacetate (VI):
1
Following the general procedure, alcohol 28 (5 mg, 11 μmol) on reaction with (S)-
methoxyphenylacetic acid (3 mg, 0.016 mmol) afforded ester VI (5.9 mg, 9.6 μmol) in 88%
1
yield as a liquid. TLC: R 0.35 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl ) δ 7.49 –
f
3
7
.40 (m, 2H), 7.38 – 7.31 (m, 3H), 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.59 –
.39 (m, 5H), 4.95 – 4.90 (m, 1H), 4.83 – 4.77 (m, 1H), 4.73 (s, 1H), 4.67 (d, J = 6.9 Hz, 1H),
5
4.63 (d, J = 6.9 Hz, 1H), 4.32 (s, 2H), 4.27 – 4.19 (m, 1H), 4.15 – 4.07 (m, 1H), 3.79 (s, 3H),
3
2
.62 – 3.55 (m, 1H), 3.45 – 3.38 (m, 5H), 3.37 (s, 3H), 2.48 (dd, J = 15.7, 5.7 Hz, 1H), 2.38 –
.28 (m, 1H), 2.21 (t, J = 5.6 Hz, 2H), 1.96 – 1.86 (m, 2H), 1.67 (d, J = 5.9 Hz, 3H), 1.58 –
1.44 (m, 4H). Note: The configuration of alcohol 28 was unambiguously established as a ‘S’
1
by comparison of the H NMR spectra of both (R) & (S)-mandelate esters. Thus the olefinic
protons appeared downfield in the R-mandelate compared to the S-mandelate while the
signals for CH CH OPMB appeared upfield in the R-mandelate ester compared to the S-
2
2
diastereomer.
(
2R,5R)-5-((S,E)-5-((4-Methoxybenzyl)oxy)-3-(methoxymethoxy)pent-1-en-1-yl)-2-
(S,E)-3-(methoxymethoxy)hept-5-en-1-yl)-3-methylenetetrahydrofuran 29: Following
(
2
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the procedure detailed for the preparation of compound 24 from alcohol 23, alcohol 28 (92
mg, 0.2 mmol) was treated with iPr NEt (77 μL, 0.44 mmol) and MOM-Cl (12 μL, 0.15
2
mmol) to afford MOM ether 29 (93 mg, 0.18 mmol) in 93% yield as a colourless liquid.
0
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20
TLC: R 0.2 (5% EtOAc/Hexane); [α]
-9.8 (c 0.5, CHCl ); IR (Neat) 2897, 1622, 2114,
3
f
D
−
1 1
1
512, 1247, 1030, 822 cm ; H NMR (400 MHz, CDCl ) δ 7.26 (d, J = 8.7 Hz, 2H), 6.88 (d,
3
J = 8.7 Hz, 2H), 5.73 (dd, J = 15.5, 6.6 Hz, 1H), 5.59 (dd, J = 15.5, 7.6 Hz, 1H), 5.54 – 5.35
m, 2H), 5.00 – 4.93 (m, 1H), 4.85 – 4.80 (m, 1H), 4.68 (d, J = 6.9 Hz, 2H), 4.64 (d, J = 6.7
Hz, 1H), 4.51 (d, J = 6.7 Hz, 1H), 4.42 (s, 2H), 4.34 – 4.25 (m, 2H), 4.24 – 4.18 (m, 1H),
.80 (s, 3H), 3.63 – 3.54 (m, 2H), 3.54 – 3.48 (m, 1H), 3.37 (s, 3H), 3.34 (s, 3H), 2.65 (dd, J
= 15.4, 5.7 Hz, 1H), 2.35 – 2.25 (m, 1H), 2.22 (t, J = 5.7 Hz, 2H), 1.94 – 1.78 (m, 3H), 1.75 –
(
3
13
1
1
.68 (m, 1H), 1.65 (dd, J = 5.9, 0.9 Hz, 3H), 1.60 – 1.47 (m, 2H); C{ H} NMR (125 MHz,
CDCl ) δ 159.1, 151.3, 133.3, 131.8, 130.5, 129.3, 127.6, 126.9, 113.7, 104.4, 95.3, 93.8,
3
81.0, 78.1, 77.1, 73.2, 72.6, 66.3, 55.5, 55.4, 55.2, 40.1, 37.6, 35.7, 31.2, 29.8, 18.0; MS
+
+
(
ESI-TOF) m/z: 527 [M+Na] . HRMS (ESI-TOF) m/z: [M+Na] calcd for C H O Na:
29 44 7
5
27.2985; found: 527.2998.
S,E)-3-(Methoxymethoxy)-5-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-1-yl)-4-
(
methylenetetrahydrofuran-2-yl)pent-4-en-1-ol 30: Following the procedure detailed for
the preparation of compound 25 from PMB ether 24, compound 29 (70 mg, 0.14 mmol) was
treated with DDQ (48 mg, 0.21 mmol) to afford alcohol 30 (43 mg, 0.11 mmol) in 80% yield
2
0
as a colourless liquid. TLC: R 0.2 (20% EtOAc/Hexane); [α]
-27.1 (c 0.3, CHCl ); IR
3
f
D
−1
1
(
Neat) 3281, 2897, 1615, 1512, 1247, 1030, 822 cm ; H NMR (500 MHz, CDCl ) δ 5.75
3
(dd, J = 15.5, 6.6 Hz, 1H), 5.63 (dd, J = 15.5, 7.2 Hz, 1H), 5.54 – 5.37 (m, 2H), 4.99 – 4.95
(m, 1H), 4.89 – 4.78 (m, 1H), 4.69 (d, J = 6.7 Hz, 1H), 4.67 (d, J = 6.9 Hz, 1H), 4.64 (d, J =
6
1
.9 Hz, 1H), 4.53 (d, J = 6.7 Hz, 1H), 4.33 – 4.25 (m, 3H), 3.83 – 3.77 (m, 1H), 3.74 (dt, J =
1.1, 5.5 Hz, 1H), 3.58 (dt, J = 11.5, 5.7 Hz, 1H), 3.39 (s, 3H), 3.37 (s, 3H), 2.68 (dd, J =
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5.4, 5.8 Hz, 1H), 2.36 – 2.28 (m, 1H), 2.22 (t, J = 6.1 Hz, 2H), 1.87 – 1.79 (m, 3H), 1.73 –
1
3
1
1
.67 (m, 1H), 1.65 (dd, J = 5.9, 0.9 Hz, 3H), 1.63 – 1.49 (m, 2H); C{ H} NMR (100 MHz,
CDCl ) δ 151.1, 133.4, 131.4, 127.6, 126.9, 104.6, 95.3, 93.9, 81.1, 78.0, 77.1, 75.0, 59.9,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
6
7
8
9
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3
4
5
6
7
8
9
0
+
5
5.6, 55.5, 40.0, 37.7, 37.6, 31.1, 29.8, 18.0; MS (ESI-TOF) m/z: 407 [M+Na] . HRMS (ESI-
+
TOF) m/z: [M+Na] calcd for C H O Na: 407.2410; found: 407.2418.
2
1
36
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(S,E)-3-(Methoxymethoxy)-5-((2R,5R)-5-((S,E)-3-(methoxymethoxy)hept-5-en-1-yl)-4-
methylenetetrahydrofuran-2-yl)pent-4-enal 3: To a solution of alcohol 30 (35 mg, 90
o
μmol) in dichloromethane (2 mL) cooled at 0 C was added Dess−Martin periodinane (60
mg, 0.14 mmol). The mixture was stirred at same temperature for 1.5 h. The reaction was
quenched with aq satd Na S O (2 mL). After being stirred for an additional 10 min, the
2
2
3
mixture was diluted with CH Cl (20 mL) and aq satd NH Cl (20 mL). The layers were
2
2
4
separated and the aq layer was extracted with CH Cl (2x10 mL). The combined organic
2
2
layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na SO ,
2
4
filtered, and concentrated under reduced pressure. The crude residue was purified by flash
column chromatography using 15% EtOAc/Hexane (v/v) as the eluent to afford compound 3
(21 mg, 50 μmol) in 91% yield as a colorless liquid. TLC: R 0.5 (15% EtOAc/Hexane);
f
α]20 -37.2(c 0.5, CHCl ); IR (Neat) 2897, 17.25, 1615, 1512, 1247, 1030, 822, 502 cm ; H
−1 1
[
D
3
NMR (400 MHz, CDCl ) δ 9.77 (t, J = 2.6 Hz, 1H), 5.82 (dd, J = 15.5, 6.5 Hz, 1H), 5.66 (dd,
3
J = 15.5, 7.4 Hz, 1H), 5.54 – 5.36 (m, 2H), 4.99 – 4.93 (m, 1H), 4.85 – 4.80 (m, 1H), 4.68 (d,
J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.62 – 4.57 (m, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.45
(d, J = 6.8 Hz, 1H), 4.33 – 4.25 (m, 2H), 3.59 – 3.48 (m, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 2.77
–
2.63 (m, 2H), 2.61 – 2.54 (m, 1H), 2.36 – 2.26 (m, 1H), 2.21 (t, J = 5.7 Hz, 2H), 1.88 – 1.78
1
3
1
(m, 1H), 1.75 – 1.67 (m, 1H), 1.65 (d, J = 5.7 Hz, 3H), 1.62 – 1.47 (m, 2H); C{ H} NMR
(100 MHz, CDCl ) δ 200.3, 150.9, 134.2, 130.0, 127.6, 126.9, 104.7, 95.3, 93.9, 81.1, 77.8,
3
2
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