Stereoselective synthesis of C13-C28 fragment of marinomycin A

Article abstract of DOI:10.1055/s-0034-1379697

Synthesis of the C13-C28 fragment of marinomycin A, consisting of all the five stereocenters, was achieved by asymmetric synthesis, starting from l-malic acid. The simple convergent approach utilized cross metathesis of two key olefinic fragments for the introduction of the C20-C21 double bond. Two of the five stereocenters, C19 and C27, were realized from l-malic acid, while, C17 and C23 are introduced by Sharpless asymmetric epoxidation and C25 by a selective allylation reaction.

Full text of DOI:10.1055/s-0034-1379697

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 845–853
845
paper
Synthesis
A. Rajesh et al.
Paper
Stereoselective Synthesis of C13–C28 Fragment of Marinomycin A
Akkapalli Rajesh*
OBn OPMB
Gangavaram V. M. Sharma
OTBDPS
OBn
OBn OPMB
Krishna Damera
PMBO
Grubbs II cat.
CH2Cl2, r.t.
PMBO
+
Organic and Biomolecular Chemistry Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India
rajesh.rjsiict@gmail.com
BnO
OBn
BnO
Received: 25.07.2014
Accepted after revision: 19.11.2014
Published online: 23.12.2014
revealed impressive and selective cancer cell cytotoxicity
against six of the eight melanoma cell lines in the NCI 60
cell line panel (IC50 = 0.2–2.7 μM). Interestingly, only ma-
DOI: 10.1055/s-0034-1379697; Art ID: ss-2014-z0466-op
rinomycin A, a C -symmetric macrodiolide, showed anti-
2
Abstract Synthesis of the C13–C28 fragment of marinomycin A, con-
sisting of all the five stereocenters, was achieved by asymmetric synthe-
sis, starting from L-malic acid. The simple convergent approach utilized
cross metathesis of two key olefinic fragments for the introduction of
the C20–C21 double bond. Two of the five stereocenters, C19 and C27,
were realized from L-malic acid, while, C17 and C23 are introduced by
Sharpless asymmetric epoxidation and C25 by a selective allylation re-
action.
fungal activity against Candida albicans (MIC90 = 10 μM).
The interesting biological activity and complex structural
features prompted the first total synthesis of marinomycin
2,3
A (1, Figure 1) by Nicolaou et al. recent total synthesis by
4
Evans et al., and a convergent synthesis of the monomeric
5
counterpart by Cossy group. In continuation of our interest
in the synthesis of natural products,6 herein we report the
synthesis of C13–C28 carbon framework 4, which consti-
tutes all the five stereocenters (17S,19S,23S,25S,27R), a syn-
,7
Key words marinomycins, stereoselective, cross-metathesis, Hoveyda–
Grubbs
1,3-diol (C17/19), and anti/anti-1,3-diols (C23/25 and
Marinomycins A–C are polyenic macrolides isolated by
Fenical et al. in 2006 from the saline culture of a new
group of marine actinomycetes, Marinispora strain CNQ-
40, cultured from the bottom of the ocean offshore of
La Jolla, CA (USA). These natural products display signifi-
cant antibiotic activity, with minimum inhibitory concen-
tration (MIC) values of 0.1–0.6 μM, against methicillin-
resistant Staphylococcus aureus and vancomycin-resistant
Enterococcus faecium. Further studies on marinomycins A–C
C25/C27) by a convergent approach.
1
Retrosynthetic strategy of 1, as shown in Scheme 1, re-
vealed that, 2 is the monomeric unit, while it could be real-
ized from Julia coupling with 3a and 3b. Fragment 4, the
C13–C28 unit of 1, could be synthesized by C–C bond for-
mation between olefins 5 and 6 by cross-metathesis, which
in turn could be envisaged from L-malic acid, by an asym-
metric synthetic approach.
1
OH
HO
OH
OH
OH
O
O
O
O
OH
OH
OH
OH
HO
1
Figure 1 Structure of marinomycin A
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Synthesis
A. Rajesh et al.
Paper
OH
O
HO
O
OH OH
OH
O
O
OH
OH OH
OH
HO
1
O
O
O
SO2Ar
3a
O
O
O
OBn OPMB
OBn OTBDPS
BnO
+
Julia
O
OBn OPMB
OBn OTBDPS
BnO
2
H
3b
OBn OPMB
PMBO
OBn OPMB
OBn OTBDPS
5
+
L-malic acid
PMBO
OBn OTBDPS
BnO
4
BnO
6
Scheme 1 Retrosynthetic strategy of marinomycin (1)
Synthesis of one of the sub-fragment 5 was initiated
from L-malic acid derived 1,3-diol 7 (Scheme 2). Accord-
treatment with p-anisaldehyde dimethyl acetal and pyri-
dinium 4-toluenesulfonate gave 17 (89%), which on ring
opening with diisobutylaluminum hydride at 0 °C to room
temperature for four hours afforded alcohol 18 in 88% yield.
Finally, alcohol 18 under Swern oxidation conditions fur-
nished the aldehyde 19, which, on further Wittig reaction
with methyltriphenylphosphonium bromide and butyllithi-
um in tetrahydrofuran afforded fragment 5 with a C17/C19
syn-1,3-diol system in 67% yield (from 18).
8
ingly, reaction of diol 7 with benzaldehyde dimethyl acetal
and pyridinium 4-toluenesulfonate gave benzylidene deriv-
ative 8 (86%), which on subsequent reductive ring opening
with diisobutylaluminum hydride at 0 °C to room tempera-
9
ture for one hour regioselectively afforded alcohol 9 in 80%
yield. Alcohol 9 on oxidation under Swern conditions fur-
nished aldehyde 10, which on subsequent reaction with
methylmagnesium iodide in diethyl ether gave the diaste-
reomeric mixture of alcohols 11 (58%). Oxidation of alco-
hols 11 with oxalyl chloride, dimethyl sulfoxide, and tri-
ethylamine afforded the ketone 12. Stereoselective olefina-
Accordingly, known alcohol 2011 on reaction with tert-
butyldiphenylsilyl chloride and imidazole afforded silyl
ether 21 (93%), which on ozonolysis in dichloromethane at
–78 °C for 15 minutes followed by treatment of resultant al-
dehyde 21a with (ethoxycarbonylmethylene)triphenyl-
phosphorane in benzene at reflux for one hour gave 22
(69%; Scheme 3). Reduction of ester 22 with diisobutylalu-
minum hydride at 0 °C for one hour afforded the allylic al-
cohol 23 (72%), which on Sharpless asymmetric epoxida-
tion with (–)-diisopropyl tartarate, titanium(IV) isopropox-
ide, and cumene hydroperoxide furnished epoxy alcohol 24
10
tion of ketone 12 with triethyl phosphonoacetate and
sodium hydride gave ester 13 (53%), which, on further re-
duction with diisobutylaluminum hydride at 0 °C to room
temperature for four hours furnished alcohol 14 in 69%
yield. Alcohol 14 on treatment with 4-methoxybenzyl bro-
mide and sodium hydride in tetrahydrofuran at 0 °C gave
1
5 (80%), which on reaction with copper(II) chloride dihy-
drate afforded diol 16 in 75% yield (Scheme 2). Diol 16 on
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Synthesis
A. Rajesh et al.
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Ph
OH
O
OBn
O
OH OBn
O
O
O
O
a
b, c
d
O
O
O
O
R
HO
7
8
9 R = CH2OH
0 R = CHO
11
1
O
OBn
O
O
OBn
O
OBn
O
c
b
O
e
O
O
O
HO
12
13
14
OBn
O
OBn OH
f
g
h
O
OH
PMBO
PMBO
15
16
PMP
OBn OPMB
X
OBn
O
OBn OPMB
c, i
b
PMBO
O
OH
PMBO
PMBO
1
5
9 X = O
X = CH2
17
18
Scheme 2 Reagents and conditions: (a) PhCH(OMe) , PPTS, CH Cl , 0 °C–r.t.; (b) DIBAL-H, CH Cl , 0 °C to r.t.; (c) (COCl) , DMSO, Et N, CH Cl , –78 °C;
2
2
2
2
2
2
3
2
2
(
(
d) MeI, Mg, Et O, 0 °C to r.t.; (e) triethyl phosphonoacetate, NaH, THF, 0 °C to r.t.; (f) PMBBr, NaH, THF, 0 °C to r.t.; (g) CuCl ·2 H O, MeCN, 0 °C to r.t.;
2
2
2
+
–
h) 4-MeOC H CH(OMe) , PPTS, CH Cl , 0 °C to r.t.; (i) MePh P Br , BuLi, THF, –10 °C.
6
4
2
2
2
3
in 83% yield. Regioselective reaction of epoxide 24 with
C19/C27 stereocenters were realized from the lone stereo-
center of L-malic acid, while, the C17/C23 stereocenters
were introduced by Sharpless asymmetric epoxidation.
12,13
Red-Al
2% yield, after removal of the 1,2-diol by sodium perio-
date.
Treatment of diol 25 with benzaldehyde dimethyl acetal
in tetrahydrofuran at 0 °C afforded 1,3-diol 25 in
7
and pyridinium 4-toluenesulfonate gave 26 (71%), which on
opening with diisobutylaluminum hydride at 0 °C to room
temperature for one hour afforded alcohol 27 in 75% yield.
Alcohol 27 on oxidation under Swern conditions furnished
the aldehyde 28, which on Wittig olefination with methyl-
triphenylphosphonium bromide and butyllithium in tetra-
hydrofuran furnished fragment 5 (52%).
Solvents were dried over standard drying agents or freshly distilled
prior to use. Chemicals were purchased and used without further pu-
rification. All column chromatographic separations were performed
using silica gel (Acme’s 60–120 mesh); PE = petroleum ether. Organic
solutions were dried over anhyd Na SO and concentrated below
2
4
4
0 °C in vacuo. 1H NMR (300 MHz, 500 MHz and 600 MHz) and, 13
C
NMR (75 MHz and 125 MHz) spectra were measured with a Bruker
Avance-300 MHz, Inova-500 MHz, and Bruker-600 MHz with TMS as
To establish the relative stereochemistry of 20, it was
treated with sodium in liquid ammonia to give 20a
internal standard for solutions in CDCl . IR spectra were recorded on
Perkin-Elmer IR-683 spectrophotometer with NaCl optics. Optical ro-
tations were measured with Jasco DIP 300 digital polarimeter at
3
(Scheme 4), which on further reaction with 2,2-dimethoxy-
25 °C. Mass spectra were recorded on direct inlet system or LC by
propane and 4-toluenesulfonic acid (cat.) in dichlorometh-
MSD trap SL (Agilent Technologies).
13
ane furnished acetonide 20b. The C NMR of 20b revealed
the presence of two peaks corresponding to the two methyl
groups of the acetonide at δ =25.04 and 24.97, characteris-
(S)-2-Benzyl-4-{[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,3-
dioxane (8)
14,15
tic of an anti-1,3-diol derivative.
To a stirred solution of 7 (5.0 g, 26.31 mmol) in CH Cl (90 mL), benz-
2
2
Finally, in a further study on the synthesis of 4 (Scheme
), olefins 5 and 6 were subjected to cross metathesis using
aldehyde dimethyl acetal (4.40 g, 28.94 mmol) and PPTS (cat.) were
added at 0 °C and stirred at r.t. for 3 h. The reaction mixture was neu-
5
Hoveyda–Grubbs II catalyst (10 mol%) in dichloromethane
tralized with Et N (3 mL) and extracted with CH Cl (3 × 20 mL). The
3
2
2
16,17
combined organic layers were washed with H O (50 mL), brine (50
to afford 4 in 57% yield.
2
mL) and dried (Na SO ). The solvent was evaporated and the residue
2
4
In conclusion, we have established a stereoselective
strategy for the synthesis of the advance stage key interme-
diate of marinomycin A. Synthesis of the C13–C28 fragment
of marinomycin with all the requisite five stereocenters
was achieved by a successful cross metathesis reaction to
introduce the requisite trans-C20–C21 double bond. The
was purified by column chromatography (60–120 mesh silica gel, 10%
25
EtOAc–PE) to give 8 (6.32 g, 86%) as a pale yellow oil; [α]D +74.0 (c
.6, CHCl3).
IR (neat): 3019, 2954, 2861, 1214, 1107, 1064, 748, 667, 627 cm–1
0
.
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Synthesis
A. Rajesh et al.
Paper
HO
OBn
TBDPSO
X
OBn
OH OBn
OH OH
a
a
b, c
20
21 X = CH2
1a X = O
20
20a
2
O
TBDPSO
OBn
TBDPSO
OBn
O
O
d
b
O
HO
20b
22
23
Scheme 4 Reagents and conditions: (a) Na–liq NH , THF, –78 °C; (b)
3
TBDPSO
BnO
OH OTBDPS
Me C(OMe) , TsOH, CH Cl , 0 °C to r.t.
2
2
2
2
O
e
f
HO
HO
OBn OTBDPS
BnO
OBn OPMB
24
25
a
PMBO
+
Ph
5
6
OBn OTBDPS
BnO
O
O
OTBDPS
d
g
HO
OBn OTBDPS
OBn OPMB
BnO
BnO
6
27
PMBO
2
4
OBn OTBDPS
BnO
h, i
Scheme 5 Reagents and conditions: (a) 10 mol% Hoveyda–Grubbs II cat-
X
alyst, CH Cl , r.t., 6 h.
2
2
BnO
2
8 X = O
X = CH2
IR (neat): 3424, 3019, 2930, 2858, 1247, 1214, 1175, 1034, 820, 748,
667, 629 cm .
–1
6
1
Scheme 3 Reagents and conditions: (a) TBDPSCl, imidazole, CH Cl , 0
H NMR (300 MHz, CDCl ): δ = 7.49–7.23 (m, 5 H, Ph), 5.46 (s, 1 H,
2
2
3
°
C to r.t.; (b) O , CH Cl , Me S, –78 °C; (c) Ph P=CHCO Et, benzene, re-
CHPh), 4.30–4.19 (dd, J = 15.8 Hz, 1 H, CH Ph), 4.04–3.85 (m, 2 H,
3
2
2
2
3
2
2
flux; (d) DIBAL-H, CH Cl , 0 °C to r.t.; (e) (–)-DIPT, Ti(Oi-Pr) , cumene
OCH ), 3.78–3.41 (m, 4 H, OCH), 2.14–2.01 (brs, 1 H, OH), 1.97–1.65
2
2
4
2
hydroperoxide, 4 Å molecular sieves, CH Cl , –20 °C; (f) 1. Red-Al, THF,
(m, 2 H, CH ), 1.55–1.23 (m, 2 H, CH ), 1.14 (d, J = 6.0 Hz, 6 H, CH ).
2
2
2
2
3
0
°C to r.t.; 2. NaIO , sat. NaHCO , CH Cl , 0 °C to r.t.; (g) PhCH(OMe) ,
4
3
2
2
2
13
C NMR (75 MHz, CDCl ): δ = 138.47, 128.8, 128.2, 127.9, 125.9, 73.7,
3
PPTS, CH Cl , 0 °C to r.t.; (h) (COCl) , DMSO, Et N, CH Cl , –78 °C; (i)
2
2
2
3
2
2
+
–
71.2, 67.0, 65.2, 63.7, 39.3, 36.8, 31.4.
MePh P Br , BuLi, THF, –78 °C.
3
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O Na: 303.1542; found:
4
303.1537.
1
H NMR (300 MHz, CDCl ): δ = 7.50–7.27 (m, 5 H, Ph), 5.46 (s, 1 H,
(S)-4-(Benzyloxy)-5-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]pentan-2-
3
CHPh), 4.47–4.19 (m, 2 H, OCH), 4.15–3.88 (m, 3 H, OCH), 3.83–3.53
ol (11)
(
(
1
m, 1 H, OCH), 2.21–1.69 (m, 3 H, CH ), 1.65–1.50 (m, 1 H, CH ), 1.39
To a stirred solution of oxalyl chloride (2.39 mL, 27.32 mmol) in
CH Cl (20 mL), DMSO (3.87 mL, 54.64 mmol) was added at –78 °C
2
2
s, 3 H, CH ), 1.33 (s, 3 H, CH ).
3
3
2
2
3
and stirred at the same temperature for 0.5 h. A solution of 9 (5.1 g,
8.21 mmol) in CH Cl (40 mL) was added at –78 °C and stirred for an
C NMR (75 MHz, CDCl ): δ = 128.7, 128.3, 128.2, 125.9, 101.1, 76.5,
3
1
7
4.1, 72.2, 70.0, 69.3, 66.9, 39.2, 30.8, 26.8, 25.7.
2
2
additional 1 h at the same temperature. Et N (15.20 mL, 109.28
HRMS (ESI): m/z [M + Na]+ calcd for C16H22O Na: 301.1415; found:
3
3
4
mmol) was added at 0 °C and stirred for 15 min. The reaction mixture
was diluted with H O (50 mL) and extracted with CH Cl (2 × 75 mL).
01.1410.
2
2
2
The combined organic layers were washed with brine (50 mL), dried
Na SO ) and evaporated to give 10, which was used as such for the
next reaction.
(
S)-3-(Benzyloxy)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]butan-1-
(
2
4
ol (9)
To a solution of 8 (6.30 g, 22.50 mmol) in CH Cl2 (70 mL) at 0 °C,
2
To a suspension of magnesium turnings (1.76 g, 73.38 mmol) in Et O
2
DIBAL-H (13.50 mL, 27.0 mmol, 2 M solution in toluene) was added
dropwise and stirred for 1 h at r.t. MeOH (15 mL), followed by saturat-
ed aq. sodium potassium tartrate solution (15 mL) were added to the
reaction mixture, filtered through a pad of Celite and washed with
EtOAc (2 × 100 mL). The organic layers were dried (Na SO ), evaporat-
ed and the residue was purified by column chromatography (60–120
mesh silica gel; 15% EtOAc–PE) to furnish 9 (5.1 g, 80%) as a light yel-
low liquid; [α]D +17.5 (c 0.48, CHCl3).
(40 mL) under nitrogen atmosphere, a solution of MeI (4.73 mL, 73.38
mmol) in Et O (20 mL) was added and stirred at r.t. for 30 min. The
2
reaction mixture was cooled to 0 °C, a solution of aldehyde 10 (5.51 g,
1
8.34 mmol) in anhydrous Et O (45 mL) was added and stirred at r.t.
2
2
4
for 20 min. It was quenched with aq NH Cl (10 mL) at 0 °C and ex-
4
tracted with EtOAc (3 × 100 mL). The combined organic layers were
washed with H O (75 mL), brine (75 mL) and dried (Na SO ). The sol-
25
2
2
4
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Synthesis
A. Rajesh et al.
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vent was evaporated and the residue was purified by column chroma-
the residue was purified by column chromatography (60–120 mesh
tography (60–120 mesh silica gel, 7% EtOAc–PE) to afford 11 (3.12 g,
silica gel, 15% EtOAc–PE) afforded 14 (1.21 g, 69%) as a light yellow
liquid; [α]D +4.0 (c 0.27, CHCl3).
25
25
58%) as a colorless oil; [α]D +36.4 (c 0.83, CHCl3).
IR (neat): 3324, 3126, 2963, 1342, 1256, 1178, 1052, 820, 738, 668,
IR (neat): 3452, 3019, 2957, 2880, 1662, 1214, 1101, 1058, 745, 667,
–1
–1
629 cm
.
628 cm
.
1
1
H NMR (500 MHz, CDCl ): δ = 7.42 (d, J = 7.1 Hz, 2 H, ArH), 7.36–7.23
H NMR (300 MHz, CDCl ): δ = 7.49–7.19 (m, 5 H, Ph), 5.66–5.49 (m, 1
3
3
(m, 3 H, ArH), 5.44 ( d, J = 5.5 Hz, 1 H, CHPh), 4.56 (dd, J = 11.9 Hz, 1 H,
H, olefin), 5.40 (m, 1 H, CHPh), 4.42 (d, J = 1.7 Hz, 3 H, CH Ph), 4.29–
2
CHPh), 4.28–4.19 (m, 1 H, OCH ), 4.01–3.39 (m, 3 H, OCH), 3.35 (q, J =
3.76 (m, 6 H, OCH), 2.16–1.21 (m, 10 H, CH), 1.18–1.04 (m, 3 H, CH3).
2
5
1
.5 Hz, 1 H, OCH), 2.25 (br s, 1 H, OH), 1.93–1.76 (m, 2 H, CH ), 1.54–
13
2
C NMR (75 MHz, CDCl ): δ = 138.4, 137.1, 128.6, 128.1, 127.8, 125.9,
3
.22 (m, 2 H, CH ), 1.21–1.10 (m, 9 H, CH ).
2
3
101.0, 80.2, 74.2, 69.9, 58.9, 39.6, 30.9, 21.2, 10.9.
13
C NMR (75 MHz, CDCl ): δ = 133.4, 132.9, 130.0, 129.5, 78.7, 73.5,
+
3
HRMS (ESI): m/z [M + Na] calcd for C19H28O SiNa: 343.1825; found:
4
69.0, 66.0, 61.9, 38.7, 36.8, 23.2, 22.6, 19.1.
343.1822.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O Na: 317.1668; found:
4
317.1672.
(S)-4-[(S,E)-6-(4-Bethoxybenzyloxy)-2-(benzyloxy)-4-methylhex-
4-enyl]-2,2-dimethyl-1,3-dioxolane (15)
(
S,E)-Ethyl-5-(benzyloxy)-3-methyl-6-[(S)-2,2-dimethyl-1,3-diox-
To a stirred suspension of NaH (0.25 g, 10.50 mmol, 60% w/w disper-
sion in paraffin oil) in THF (5 mL) at 0 °C, a solution of 14 (1.12 g, 3.50
mmol) in THF (15 mL) was added and stirred for 30 min. PMBBr (0.76
mL, 3.85 mmol) was added to the reaction mixture and stirred for an
olan-4-yl]hex-2-enoate (13)
To a stirred solution of oxalyl chloride (1.38 mL, 15.81 mmol) in
CH Cl (10 mL), DMSO (2.24 mL, 31.63 mmol) was added at –78 °C
2
2
and stirred at the same temperature for 0.5 h. A solution of 11 (3.1 g,
0.54 mmol) in CH Cl (10 mL) was added at –78 °C and stirred for an
additional 6 h. The reaction mixture was quenched with aq NH Cl
solution (4 mL) and extracted with EtOAc (2 × 20 mL). The organic lay-
4
1
2
2
additional 2 h at the same temperature. Et N (8.87 mL, 63.24 mmol)
ers were washed with H O (2 × 10 mL), brine (10 mL) and dried
3
2
was added at 0 °C and stirred for 15 min. The reaction mixture was
diluted with H O (50 mL) and extracted with CH Cl (2 × 25 mL). The
(Na SO ). The solvent was evaporated under reduced pressure and the
2
4
residue was purified by column chromatography (60–120 mesh silica
gel; 15% EtOAc–PE) to afford 15 (1.24 g, 80%) as a yellow syrup; [α]D25
+6.13 (c 0.62, CHCl3).
2
2
2
combined organic layers were washed with brine (50 mL), dried
Na SO ) and evaporated to give 12, which was used as such for the
(
2
4
next reaction.
IR (neat): 3063, 3033, 2964, 2924, 2854, 1611, 1512, 1247, 1174,
1100, 1069, 1030, 820, 752, 698, 646 cm .
–1
To a cooled (0 °C) solution of triethyl phosphonoacetate (2.52 mL,
1
2.73 mmol) in THF (20 mL), NaH (0.38 g, 15.92 mmol) was added,
1
H NMR (500 MHz, CDCl ): δ = 7.57–7.19 (m, 7 H, ArH), 6.89 (d, J = 8.9
3
stirred for 30 min and treated with a solution of 12 (3.1 g, 10.61
mmol) in THF (20 mL). After 1 h, the reaction mixture was quenched
with aq NH Cl solution (8 mL) and extracted with EtOAc (2 × 40 mL).
The organic layers were washed with H O (2 × 10 mL), brine (10 mL)
Hz, 2 H, ArH), 5.67 (m, 1 H, olefin), 5.44 (m, 1 H, CHPh), 4.56–4.40 (m,
3
(m, 7 H, CH ), 1.0 (m, 6 H, CH ).
H, CH Ar), 4.34–3.86 (m, 6 H, OCH), 3.80 (s, 3 H, OCH ), 1.94–1.43
2
3
4
2
2
2
13
C NMR (75 MHz, CDCl ): δ = 159.1, 138.7, 137.6, 134.1, 129.2, 128.1,
3
and dried (Na SO ). The solvent was evaporated under reduced pres-
2
4
1
6
27.8, 125.9, 124.9, 113.7, 101.0, 80.35, 74.2, 71.7, 69.9, 67.9, 66.9,
5.9, 55.1, 40.0, 39.7, 30.9, 23.4, 21.1, 10.9.
sure and the residue was purified by column chromatography (60–
20 mesh silica gel, 15% EtOAc–PE) to furnish 13 (2.02 g, 53%) as a yel-
1
25
HRMS (ESI): m/z [M + Na]+ calcd for C27
63.2445.
low syrup; [α]D +25.13 (c 0.51, CHCl3).
H O Na: 463.2455; found:
36 5
4
IR (neat): 2972, 2926, 2855, 1714, 1648, 1275, 1218, 1152, 1101,
–1
1031, 875, 754, 698, 668 cm .
(E,2S,4S)-4-(Benzyloxy)-8-(4-methoxybenzyloxy)-6-methyloct-6-
1
H NMR (300 MHz, CDCl ): δ = 7.49–7.20 (m, 5 H, Ph), 5.94–5.77 (q, J =
3
ene-1,2-diol (16)
14.3 Hz, 1 H, olefin), 5.40 (s, 1 H, CHPh), 4.45 (d, J = 11.1 Hz, 1 H,
To a stirred solution of 15 (1.2 g, 2.72 mmol) in MeCN (10 mL), CuCl ·2
H O (0.51 g, 3.0 mmol) was added at 0 °C and the mixture was stirred
at this temperature for 30 min. The mixture was quenched with aq
NaHCO3 (5 mL), filtered through a pad of Celite, and washed with
EtOAc (2 × 50 mL). The combined extracts were dried (Na SO ) and
evaporated; the residue was purified by column chromatography (sil-
ica gel, 30% EtOAc–PE) to give 16 (0.82 g, 75%) as a colorless oil;
[α]D –41.95 (c 1.0, CHCl3).
CH Ph), 4.30–3.74 (m, 6 H, OCH), 3.48 (quint, J = 6.0 Hz, 1 H, OCH)
2
2
2.12 (d, J = 14.3 Hz, 3 H, CH ), 2.06–1.58 (m, 2 H, CH ), 1.54–1.19 (m, 4
2
3
2
H, CH ), 1.13 (dd, J = 9.0 Hz, 6 H, CH ).
2
3
13
C NMR (75 MHz, CDCl ): δ = 166.4, 138.6, 128.6, 127.8, 125.9, 118.0,
3
2
4
117.3, 101.0, 73.8, 69.2, 66.9, 59.8, 40.0, 23.3, 21.2, 14.2, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H30O Na: 385.1985; found:
5
2
5
385.1978.
IR (neat): 3395, 2967, 2926, 2857, 1611, 1513, 1248, 1214, 1174,
(
S,E)-5-(Benzyloxy)-3-methyl-6-[(S)-2,2-dimethyl-1,3-dioxolan-4-
–1
1035, 820, 749, 667 cm
.
yl]hex-2-en-1-ol (14)
1
H NMR (300 MHz, CDCl ): δ = 7.41–7.21 (m, 7 H, H ), 6.90 (d, J = 8.4
3
Ar
To a solution of 13 (1.96 g, 5.41 mmol) in CH Cl (20 mL) at 0 °C,
2
2
Hz, 2 H, H ), 5.82–5.53 (m, 1 H, olefin), 4.53–4.41 (m, 4 H, CH Ar),
A
r
2
DIBAL-H (3.24 mL, 6.49 mmol, 2 M solution in toluene) was added
dropwise and stirred for 1 h at r.t. MeOH (5 mL), followed by saturated
aq sodium potassium tartrate solution (5 mL) were added to the reac-
tion mixture, filtered through a pad of Celite and washed with EtOAc
4
.40–3.94 (m, 6 H, OCH), 3.81 (s, 3 H, OCH ), 1.97–1.4 (m, 7 H, CH ).
3 2
13
C NMR (75 MHz, CDCl ): δ = 159.1, 138.5, 137.5, 133.2, 129.3, 128.4,
3
1
1
27.8, 125.6, 124.5, 78.1, 71.9, 69.5, 68.2, 65.8, 61.1, 40.7, 38.6, 20.8,
1.2.
(2 × 50 mL). The organic layers were dried (Na SO ), evaporated and
2 4
HRMS (ESI): m/z [M + Na]+ calcd for C24H32O Na: 423.2142; found:
5
423.2141.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 845–853

8
50
Synthesis
A. Rajesh et al.
Paper
+
–
(S)-2-(4-Methoxybenzyl)-4-[(S,E)-6-(4-methoxybenzyloxy)-2-
To a stirred solution of MePh P Br (2.89 g, 8.1 mmol) in THF (10 mL),
3
(
benzyloxy)-4-methylhex-4-enyl]-1,3-dioxolane (17)
1.6 M BuLi in hexane (4.21 mL, 6.75 mmol) was added and the mix-
ture was stirred at –10 °C for 1 h. A solution of 19 (0.7 g, 1.35 mmol)
in THF (10 mL) was added dropwise and the mixture was stirred at r.t.
To a stirred solution of 16 (0.8 g, 1.54 mmol) in CH Cl (90 mL), p-an-
2
2
isaldehyde dimethyl acetal (0.3 g, 1.69 mmol) and PPTS (cat.) were
added at 0 °C and stirred at r.t. for 3 h. The reaction mixture was neu-
tralized with Et N (0.5 mL) and extracted with CH Cl (3 × 10 mL). The
combined organic layers were washed with H O (20 mL), brine (20
mL) and dried (Na SO ). The solvent was evaporated and the residue
for 1 h. The mixture was quenched with aq NH Cl solution (2 mL),
4
treated with water (10 mL), and extracted with EtOAc (2 × 20 mL). The
combined organic layers were washed with water (20 mL) and brine
3
2
2
2
(
20 mL) and dried (Na SO ). The solvent was evaporated and the resi-
2 4
2
4
due was purified by column chromatography (silica gel, 10% EtOAc–
was purified by column chromatography (60–120 mesh silica gel, 10%
25
EtOAc–PE) afforded 17 (0.92 g, 89%) as a pale yellow oil; [α]D25 +5.18
PE) to furnish 5 (0.47 g, 67%) as a pale yellow liquid; [α]D +2.13 (c
1
.1, CHCl3).
(
c 0.72, CHCl3).
IR (neat): 3067, 2966, 2927, 2855, 1640, 1612, 1512, 1247, 1214,
1174, 1068, 1035, 820, 751, 667 cm .
IR (neat): 3072, 3010, 2972, 2850, 1214, 1100, 1033, 745, 667, 626
–1
–1
cm
.
1
1
H NMR (300 MHz, CDCl ): δ = 7.39–7.13 (m, 9 H, H ), 6.78 (m, 4 H,
3 Ar
H NMR (300 MHz, CDCl ): δ = 7.46–7.21 (m, 9 H, ArH), 6.94–6.82 (m,
3
H ), 5.92–5.70 (m, 1 H, olefin), 5.66–5.45 (m, 1 H, olefin), 5.15–4.97
4
H, ArH), 5.82–5.55 (m, 1 H, olefin), 5.41 (m, 1 H, CHAr), 4.53–4.39
Ar
(
m, 2 H, olefin), 4.58–4.28 (m, 6 H, CH Ar), 4.26–3.87 (m, 2 H, OCH),
(
m, 4 H, CH Ar), 4.31–3.84 (m, 5 H, OCH), 3.80 (d, J = 1.5 Hz, 6 H,
2
2
3.80 (d, J = 3.8 Hz, 6 H, OCH ), 3.70–3.34 (m, 2 H, OCH), 2.42–2.20 (m,
3
OCH ), 3.70–3.46 (m, 1 H, OCH), 2.19–1.95 (m, 2 H, CH ), 1.93–1.44
3
2
2
H, CH ), 2.08–1.79 (m, 1 H, CH ), 1.76–1.49 (m, 4 H, CH ).
(m, 5 H, CH2).
2
2
2
13
13
C NMR (75 MHz, CDCl ): δ = 159.0, 138.9, 137.8, 134.5, 129.3, 128.2,
C NMR (75 MHz, CDCl ): δ = 159.7, 159.1, 131.9, 129.3, 127.8, 127.2,
3
3
1
3
27.8, 126.0, 125.0, 117.2, 113.6, 79.0, 75.4, 71.7, 70.4, 65.9, 55.2,
8.2, 21.2, 10.9.
1
2
13.7, 113.5, 100.9, 80.3, 74.1, 69.9, 66.9, 65.9, 55.2, 42.0, 39.7, 30.9,
3.4, 21.1, 11.0.
HRMS (ESI): m/z [M + Na]+ calcd for C33H40O Na: 539.2768; found:
HRMS (ESI): m/z [M + Na]+ calcd for C32H38O Na: 541.2560; found:
5
6
539.2768.
541.2557.
[
(4R,6R)-6-(Benzyloxy)hept-1-en-4-yloxy](tert-butyl)diphenylsi-
lane (21)
To a stirred solution of 20 (3.16 g, 14.36 mmol) in CH Cl (30 mL), im-
(
E,2S,4S)-4-(Benzyloxy)-2,8-bis(4-methoxybenzyloxy)-6-methyl-
oct-6-en-1-ol (18)
To a solution of 17 (0.84 g, 1.62 mmol) in CH Cl (10 mL) at 0 °C, 2 M
2
2
2
2
idazole (2.93 g, 43.09 mmol) and TBDPSCl (4.51 mL, 17.23 mmol)
were sequentially added at 0 °C and stirred at r.t. for 5 h. The reaction
mixture was washed with H O (40 mL), brine (40 mL) and dried
DIBAL-H in toluene (0.97 mL, 1.94 mmol) was added dropwise and
the mixture was stirred for 1 h at r.t. First MeOH (2 mL) and then sat.
aq sodium potassium tartrate solution (2 mL) were added to the mix-
ture, which was filtered through a pad of Celite and washed with
EtOAc (2 × 50 mL). The combined organic layers were dried (Na SO )
2
(Na SO ). The solvent was evaporated and the residue was purified by
2 4
column chromatography (60–120 mesh silica gel, 5% EtOAc–PE) to
furnish 20 (6.12 g, 93%) as a pale yellow oil; [α]D –12.36 (c 0.86, CHCl3).
2
4
25
and evaporated; the residue was purified by column chromatography
silica gel, 15% EtOAc–PE) to give 18 (0.74 g, 88%) as a light yellow liq-
(
IR (neat): 3070, 3019, 2930, 2856, 1678, 1214, 1109, 1061, 739, 667,
608 cm
25
–1
uid; [α]D –33.33 (c 0.72, CHCl3).
.
1
IR (neat): 3393, 3063, 3020, 2924, 2854, 1602, 1277, 1214, 1115,
H NMR (300 MHz, CDCl ): δ = 7.77–7.61 (m, 4 H, ArH), 7.48–7.11 (m,
3
–1
1067, 747, 667 cm
.
11 H, ArH), 5.84–5.64 (m, 1 H, olefin), 5.01–4.81 (m, 2 H, olefin), 4.38
1
(d, 1 H, J = 11.5 Hz, CHPh), 4.09 (d, J = 11.5 Hz, 1 H, CHPh), 4.02 (m, 1
H NMR (300 MHz, CDCl ): δ = 7.40–7.14 (m, 9 H, H ), 6.96–6.81 (m,
3
Ar
H, CH), 3.60 (m, 1 H, CH), 2.26–2.12 (m, 2 H, CH ), 1.85–1.73 (m, 1 H,
4
3
1
H, H ), 5.70–5.49 (m, 1 H, olefin), 4.56–4.34 (m, 6 H, CH Ar), 4.26–
2
Ar
2
CH ), 1.59–1.48 (m, 1 H, CH ), 1.09–0.99 (m, 12 H, CH ).
.95 (m, 4 H, OCH), 3.93–3.46 (m, 8 H, OCH ), 2.19–1.83 (m, 1 H, CH ),
2
2
3
3
2
13
.84–1.51 (m, 6 H, CH2).
C NMR (75 MHz, CDCl ): δ = 135.8, 134.7, 129.5, 128.1, 127.6, 127.1,
3
1
3
117.0, 72.1, 70.2, 70.0, 44.2, 42.0, 26.9, 26.5, 19.8, 19.3.
C NMR (75 MHz, CDCl ): δ = 159.2, 139.3, 129.5, 127.8, 127.5, 124.3,
3
+
1
13.8, 71.8, 70.3, 68.1, 65.9, 60.1, 55.2, 38.2, 35.8, 23.4, 21.1, 11.2.
HRMS (ESI): m/z [M + Na] calcd for C30H38O SiNa: 481.2538; found:
2
HRMS (ESI): m/z [M + Na]+ calcd for C32H40O Na: 543.2717; found:
481.2561.
6
543.2709.
(5R,7R,E)-Ethyl 7-(Benzyloxy)-5-(tert-butyldiphenylsilyloxy)oct-2-
enoate (22)
[
(E,5S,7S)-5-(Benzyloxy)-1,7-bis(4-methoxybenzyloxy)-3-methyl-
nona-2,8-diene (5)
A solution of 21 (6.0 g, 13.10 mmol) in CH Cl (50 mL) was cooled to
2
2
–78 °C and subjected to ozonolysis for 15 min and quenched with di-
To a stirred solution of oxalyl chloride (0.17 mL, 2.01 mmol) in CH Cl
2
2
methylsulfide (2 mL). The solvent was evaporated, the residue was
dissolved in benzene (30 mL), treated with (ethoxycarbonylmeth-
ylene)triphenyl phosphorane (6.56 g, 19.65 mmol) and heated at re-
flux for 2 h. The solvent was evaporated and the residue was purified
by column chromatography (60–120 mesh silica gel, 5% EtOAc–PE) to
(
5 mL), DMSO (0.28 mL, 4.03 mmol) was added at –78 °C and the mix-
ture was stirred at this temperature for 0.5 h. A solution of 18 (0.7 g,
.34 mmol) in CH Cl (10 mL) was added at –78 °C and the mixture
1
2
2
was stirred a further 1 h at this temperature. Et N (1.69 mL, 12.06
mmol) was added at 0 °C and the mixture was stirred for 15 min
more. The reaction mixture was diluted with H O (10 mL) and ex-
tracted with CH Cl (2 × 25 mL). The combined organic layers were
3
25
furnish 22 (4.81 g, 69%) as a yellow syrup; [α]D –33.77 (c 0.75,
CHCl3).
2
2
2
washed with brine (10 mL) and dried (Na SO ). The solvent was evap-
orated to give 19, which was used directly in the next reaction.
IR (neat): 3019, 2930, 2856, 1699, 1646, 1214, 1110, 1001, 742, 667,
608 cm .
2
4
–1
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 845–853

8
51
Synthesis
A. Rajesh et al.
Paper
1
+
H NMR (300 MHz, CDCl ): δ = 7.76–7.62 (m, 5 H, ArH), 7.49–7.21 (m,
HRMS (ESI): m/z [M + Na] calcd for C31H40O SiNa: 527.2588; found:
3
4
9
H, ArH), 7.14 (dd, J = 7.7 Hz, 1 H, ArH), 6.91 (m, 1 H, olefin), 5.69 (d,
527.2561.
J = 15.6 Hz, 1 H, olefin), 4.43–4.34 (d, J = 11.3 Hz, 1 H, CH Ar), 4.21–
2
4
1
.03 (m, 4 H, OCH), 3.56 (m, 1 H, OCH), 2.38–2.17 (m, 2 H, CH), 1.79–
.51 (m, 2 H, CH ), 1.28 (t, J = 7.1 Hz, 3 H, CH ), 1.10 (d, J = 6.7 Hz, 12 H,
(
3S,5R,7R)-7-(Benzyloxy)-5-(tert-butyldiphenylsilyloxy)octane-
2
3
1,3-diol (25)
CH3).
To a stirred solution of epoxide 24 (2.50 g, 4.96 mmol) in THF (25 mL),
Red-Al (19.56 mL, 69.15 mmol, 70% w/w in toluene) was added at 0
13
C NMR (75 MHz, CDCl ): δ = 166.3, 145.1, 135.9, 134.7, 129.6, 127.6,
3
127.5, 123.5, 72.0, 70.0, 69.7, 60.1, 44.7, 40.4, 26.9, 26.5, 19.9, 14.2.
°C. After 4 h, the reaction mixture was quenched with sat. Na SO4
2
+
solution (10 mL) and filtered through a pad of Celite and washed with
EtOAc (2 × 100 mL). The organic layer was concentrated, then NaIO4
HRMS (ESI): m/z [M + Na] calcd for C33H42O SiNa: 553.2750; found:
4
553.2772.
(1.26 g, 5.95 mmol) was added to a solution of the compound in
CH Cl (25 mL) at 0 °C. After 4 h, the mixture was extracted with
2
2
(
5R,7R,E)-7-(Benzyloxy)-5-(tert-butyldiphenylsilyloxy)oct-2-en-1-
CH Cl (2 × 100 mL). The organic layers were dried (Na SO ), evaporat-
2
2
2
4
ol (23)
ed, and the residue was purified by column chromatography (60–120
To a solution of 22 (4.70 g, 8.867 mmol) in CH Cl (70 mL) at 0 °C,
2
2
mesh silica gel, 40% EtOAc–PE) to afford 25 (1.81 g, 72%) as a colorless
DIBAL-H (5.32 mL, 10.64 mmol, 2 M solution in toluene) was added
dropwise and stirred for 1 h at r.t. MeOH (14 mL), followed by saturat-
ed aq sodium potassium tartrate solution (14 mL) were added to the
reaction mixture. The mixture was filtered through a pad of Celite
and washed with EtOAc (2 × 100 mL). The organic layers were dried
25
oil; [α]D –16.28 (c 0.7, CHCl3).
IR (neat): 3395, 3068, 3031, 2926, 2855, 1714, 1275, 1109, 1064, 740,
–1
7
03, 610 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.73–7.65 (m, 4 H, ArH), 7.47–7.34 (m,
3
(
Na SO ), evaporated and the residue was purified by column chro-
6 H, ArH), 7.32–7.20 (m, 3 H, ArH), 7.16 (d, J = 6.7 Hz, 2 H, Ar), 4.36 (d,
J = 11.4 Hz, 1 H, CHPh), 4.19–4.06 (m, 2 H, OCH), 4.01 (d, J = 11.4 Hz, 1
H, CHPh), 3.75–3.67 (m, 2 H, OCH), 3.27–3.18 (m, 1 H, OCH), 1.99–
2
4
matography (60–120 mesh silica gel, 15% EtOAc–PE) afforded 23 (3.12
g, 72%) as a light yellow liquid; [α]D –47.97 (c 0.55, CHCl3).
25
IR (neat): 3426, 3042, 2926, 1687, 1207, 1142, 1055, 743, 667 cm–1
.
1.40 (m, 6 H, CH
13C NMR (75 MHz, CDCl
2.4, 71.2, 70.0, 69.1, 61.5, 43.5, 42.2, 26.9, 19.4, 19.1.
2
), 1.11–1.01 (m, 12 H, CH
3
).
1
3
): δ = 135.9, 129.9, 128.2, 127.6, 127.5, 127.4,
H NMR (300 MHz, CDCl ): δ = 7.71–7.63 (m, 4 H, ArH), 7.44–7.21 (m,
3
7
9
H, ArH), 7.16 (d, J = 6.8 Hz, 2 H, ArH), 5.56–5.40 (m, 2 H, olefin), 4.40
+
(d, J = 11.4 Hz, 1 H, CHPh), 4.11 (d, J = 11.3 Hz, 1 H, CHPh), 4.03 (quint,
HRMS (ESI): m/z [M + Na] calcd for C31H42O SiNa: 529.2750; found:
4
J = 4.4 Hz, 1 H, OCH), 3.94 (d, J = 5.3 Hz, 2 H, OCH), 3.66–3.59 (m, 1 H,
529.2725.
OCH), 2.16 (t, J = 6.2 Hz, 2 H, CH ), 1.80–1.72 (sept, J = 13.9 Hz, 1 H,
2
CH ), 1.61–1.53 (m, 1 H, CH ), 1.07 (d, J = 6.0 Hz, 3 H, CH ), 1.04 (s, 9 H,
CH3).
2
2
3
{(2S,4R)-4-(Benzyloxy)-1-[(4S)-2-phenyl-1,3-dioxan-4-yl]pentan-
2-yloxy}tert-butyldiphenylsilane (26)
13
C NMR (75 MHz, CDCl ): δ = 135.9, 131.5, 128.8, 128.1, 127.5, 72.2,
To a stirred solution of 25 (1.70 g, 3.35 mmol) in CH Cl (20 mL),
3
2
2
7
0.1, 70.4, 63.6, 44.6, 40.5, 26.9, 19.8, 19.3.
benzaldehyde dimethyl acetal (0.61 g, 4.03 mmol) and PPTS (cat.)
were added at 0 °C and the mixture was stirred at r.t. for 3 h. The reac-
+
HRMS (ESI): m/z [M + Na] calcd for C31H40O SiNa: 511.2644; found:
3
tion mixture was neutralized with Et N (1 mL) and extracted with
511.2663.
3
CH Cl (3 × 10 mL). The combined organic layers were washed with
2
2
H O (30 mL), brine (30 mL) and dried (Na SO ). The solvent was evap-
orated and purification of the residue by column chromatography
2
2
4
{
(2R,3R)-3-[(2S,4R)-4-(Benzyloxy)-2-(tert-butyldiphenylsilyl-
oxy)pentyl]oxiran-2yl} methanol (24)
(
60–120 mesh silica gel, 10% EtOAc–PE) gave 26 (1.42 g, 71%) as a pale
To a stirred suspension of (–)-DIPT (0.28 g, 1.22 mmol) in CH Cl (10
25
2
2
yellow oil; [α]D +9.06 (c 0.55, CHCl3).
mL) at –20 °C containing 4 Å MS (2 g), sequentially Ti(Oi-Pr)4 (0.17
mL, 0.61 mmol) and cumene hydroperoxide (1.36 mL, 9.22 mmol)
were added and stirred for 20 min. A solution of allylic alcohol 23 (3.0
g, 6.4 mmol) in CH Cl (15 mL) was added and stirred for 5 h at –20 °C.
IR (neat): 3068, 3033, 2927, 2855, 1455, 1373, 1213, 1108, 1063,
–1
1
027, 821, 741, 700, 611 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.72–7.63 (m, 4 H, H ), 7.43–7.14 (m,
2
2
3
Ar
The reaction mixture was quenched with 10% NaOH solution (1.50 g
in 15 mL brine) and stirred for 3 h. It was filtered through a pad of
Celite and washed with CH Cl (50 mL). The organic layer was dried
16 H, H ), 5.13 (s, 1 H, CHPh), 4.35 (d, J =11.5 Hz, 1 H, CHPh), 4.24 (d,
1 H, OCH), 4.12 (dd, J = 15.6 Hz, 1 H, OCH), 4.04 (d, J = 11.1 Hz, 1 H,
CHPh), 3.94 (t, J = 8.7 Hz, 1 H, OCH), 3.73 (t, J = 12.2 Hz, 1 H, OCH),
Ar
2
2
(
Na SO ), evaporated and the residue was purified by column chro-
3.48–3.40 (m, 1 H, OCH), 1.86–1.72 (m, 2 H, CH ), 1.72–1.55 (m, 2 H,
2
4
2
matography (60–120 mesh silica gel, 20% EtOAc–PE) to give 24 (2.57
CH ), 1.32–1.19 (m, 2 H, CH ), 1.10–0.99 (m, 12 H, CH ).
2
2
3
25
g, 83%) as a colorless oil; [α]D
–9.44 (c 0.15, CHCl3).
13
C NMR (75 MHz, CDCl ): δ = 138.8, 138.7, 135.9, 134.4, 134.2, 129.5,
3
IR (neat): 3457, 2921, 2852, 1722, 1611, 1513, 1461, 1246, 1214,
128.4, 128.0, 127.5, 127.4, 127.2, 126.0, 100.7, 73.0, 72.4, 70.0, 67.6,
66.9, 45.9, 44.3, 31.4, 26.9, 19.5.
–1
1174, 1031, 816, 749, 667 cm .
1
+
H NMR (300 MHz, CDCl ): δ = 7.74–7.62 (m, 4 H, ArH), 7.47–7.20 (m,
HRMS (ESI): m/z [M + NH ] calcd for C38H54O NSi: 612.3509; found:
3
4
4
9
H, ArH), 7.20–7.12 (m, 2 H, ArH), 4.40 (d, J = 11.7 H, 1 Hz, CHPh),
612.3535.
4.12 (d, J = 7.1 Hz, 2 H, CH), 4.05 (d, J = 11.3 Hz, 1 H, CHPh), 3.80–3.70
(
m, 1 H, OCH), 3.63–3.41 (m, 2 H, OCH), 2.97–2.91 (td, J = 7.9, 1.8 Hz, 1
(
1
3S,5S,7R)-3,7-Bis(benzyloxy)-5-(tert-butyldiphenylsiloxy)octan-
-ol (27)
H, OCH), 2.68–2.62 (quint, J = 1.8 Hz, 1 H, CH), 1.86–1.48 (m, 2 H,
CH ), 1.35–1.22 (m, 2 H, CH ), 1.09–1.00 (m, 12 H, CH ).
2
2
3
A 2 M DIBAL-H in toluene solution (1.34 mL, 2.68 mmol) was added
dropwise to a solution of 26 (1.34 g, 2.24 mmol) in CH Cl (15 mL) at
1
3
C NMR (75 MHz, CDCl ): δ = 135.9, 129.6, 128.2, 127.5, 127.3, 72.2,
3
2
2
70.1, 69.3, 61.4, 58.4, 52.9, 45.2, 39.8, 26.9, 19.78, 19.38.
0 °C and the mixture was stirred for 1 h at r.t. MeOH (3 mL) and then
sat. aq sodium potassium tartrate solution (3 mL) were added to the
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 845–853

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Synthesis
A. Rajesh et al.
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mixture, which was then filtered through a pad of Celite and washed
with EtOAc (2 × 50 mL). The combined organic layers were dried
[(2R,4S,6S)-2,6-Bis(benzyloxy)non-8-en-4-yloxy]tert-butyldiphe-
nylsilane (6)
(
Na SO ) and evaporated; the residue was purified by column chro-
2 4
To a stirred solution of oxalyl chloride (0.19 mL, 2.25 mmol) in CH Cl2
2
matography (silica gel, 15% EtOAc–PE) to give 27 (1.01 g, 75%) as a
light yellow liquid; [α]D
(
5 mL), DMSO (0.32 mL, 4.51 mmol) was added at –78 °C and the mix-
ture was stirred at this temperature for 0.5 h. A solution of 27 (0.9 g,
1.50 mmol) in CH Cl (10 mL) was added at –78 °C and the mixture
was stirred for a further 1 h at this temperature. Et N (1.26 mL, 9.0
25
–53.81 (c 0.55, CHCl3).
IR (neat): 3421, 3053, 3019, 2967, 2855, 1270, 1113, 1068, 742, 667,
6
2
2
–1
27 cm
.
3
1
mmol) was added at 0 °C and the mixture was stirred for 15 min
H NMR (500 MHz, CDCl ): δ = 7.72–7.62 (m, 4 H, H ), 7.44–7.10 (m,
3
Ar
more. The reaction mixture was diluted with H O (10 mL) and ex-
2
1
6 H, H ), 4.41 (d, J =11.3 Hz, 1 H, CHPh), 4.36–4.22 (q, J = 10.1 Hz, 2
Ar
tracted with CH Cl (2 × 15 mL). The combined organic layers were
2
2
H, OCH), 4.11–3.98 (m, 2 H, OCH), 3.72–3.36 (m, 4 H, OCH), 2.13 (br s,
H, OH), 2.01–1.19 (m, 6 H, CH ), 1.10–0.97 (m, 12 H, CH ).
washed with brine (20 mL) and dried (Na SO ), and evaporation of the
2
4
1
2
3
solvent gave 28, which was used directly in the next reaction.
13
C NMR (75 MHz, CDCl ): δ = 135.9, 34.1, 129.6, 128.3, 128.1, 127.2,
3
+
–
To a stirred suspension of MePh P Br (3.22 g, 9.03 mmol) in THF (10
3
7
6.0, 72.4, 70.7, 68.8, 60.2, 45.6, 42.6, 35.6, 26.9.
mL), 1.6 M BuLi in hexane (4.7 mL, 7.52 mmol) was added and the
mixture stirred at –10 °C for 10 min. A solution of 28 (0.9 g, 1.50
mmol) in THF (10 mL) was added dropwise and the mixture was
stirred for 1 h at r.t. Workup as described for 5 and purification of the
residue by column chromatography (silica gel, 10% EtOAc–PE) afford-
HRMS (ESI): m/z [M + H]+ calcd for C38H49O Si: 597.3400; found:
5
4
97.3393.
(2R,4R)-Hept-6-ene-2,4-diol (20a)
25
A solution of alcohol 20 (0.20 g, 0.91 mmol) in THF (2 mL) was added
ed 6 (0.47 g, 52%) as a pale yellow liquid; [α]
D
–4.32 (c 1.41, CHCl ).
3
to a stirred suspension of Na in liquid NH at –78 °C and stirred at the
same temperature for 10 min. The reaction was quenched with solid
3
IR (neat): 3050, 3016, 2967, 2879, 1624, 1215, 1152, 1072, 822, 749,
–1
667, 629 cm
.
NH Cl (2 g) until disappearance of the blue color, then the mixture
4
1
H NMR (300 MHz, CDCl ): δ = 7.77–7.61 (m, 4 H, H ), 7.48–7.06 (m,
3
Ar
was extracted with EtOAc (2 × 10 mL). The organic layer was dried
1
4
2
6 H, H ), 5.79–5.59 (m, 1 H, olefin), 5.05–4.89 (m, 2 H, olefin), 4.44–
Ar
(
Na SO ) and evaporated, and the residue was purified by column
2 4
.28 (m, 3 H, CHPh), 4.21–3.98 (m, 2 H, CH ), 3.64–3.45 (m, 2 H, CH),
2
chromatography (60–120 mesh silica gel, 25% EtOAc–PE) to afford 20a
.21–2.08 (m, 2 H, CH ), 1.96–1.51 (m, 2 H, CH ), 1.35–1.21 (m, 2 H,
25
2
2
(
0.11 g, 69%) as a yellow syrup; [α]D +16.13 (c 0.62, CHCl3).
CH ), 1.13–0.96 (m, 12 H, CH ).
2
3
IR (neat): 3363, 3033, 2964, 1611, 1512, 1247, 1174, 1100, 1069, 1030
13
C NMR (75 MHz, CDCl ): δ = 139.0, 135.9, 134.7, 129.4, 128.1, 127.4,
–1
3
cm
.
127.1, 116.9, 75.3, 72.3, 70.6, 70.0, 69.1, 45.3, 42.2, 38.3, 29.6, 27.0,
1
H NMR (300 MHz, CDCl ): δ = 5.86–5.71 (m, 1 H, olefin), 5.19–4.97
3
19.3.
(m, 2 H, olefin), 3.92 (m, 1 H, OCH), 3.82 (m, 1 H, OCH), 2.52 (br s, 1 H,
+
HRMS (ESI): m/z [M + Na] calcd for C39H48O SiNa: 615.3264; found:
3
OH), 2.22–2.12 (m, 2 H, CH ), 1.64–1.53 (m, 2 H, CH ), 1.22 (d, J = 6.6
2
2
615.3266.
Hz, 3 H, CH3).
13
C NMR (75 MHz, CDCl ): δ = 135.2, 118.3, 73.2, 66.5, 46.2, 42.5, 24.1.
3
tert-Butyldiphenyl[(2R,4S,6S,8E,10S,12S,14E)-2,6,12-tris(benzyl-
oxy)-10,16-bis(4-methoxybenzyloxy)-14-methylhexadeca-8,14-
dien-4-yloxy]silane (4)
+
MS (ESI): m/z (%) = 153 [M + Na] (100).
(4R,6R)-4-Allyl-2,2,6-trimethyl-1,3-dioxane (20b)
To a stirred solution of 5 (0.031 g, 0.06 mmol) and 6 (0.042 g, 0.072
To a stirred solution of 20a (0.07 g, 0.54 mmol) in CH Cl (20 mL), 2,2-
mmol) in CH
mmol) was added and the mixture was allowed to stir at r.t. for ca. 6 h
under N . The mixture was directly adsorbed on silica gel and purified
by column chromatography (60–120 mesh silica gel, 20% EtOAc–PE)
2
Cl (1 mL), Hoveyda–Grubbs II catalyst (3.1 mg, 0.06
2
2
2
dimethoxypropane (0.06 g, 0.65 mmol) and PPTS (cat.) were added at
°C and stirred at r.t. for 3 h. The reaction mixture was neutralized
with Et N (0.5 mL) and extracted with CH Cl (3 × 10 mL). The com-
0
2
3
2
2
25
bined organic layers were washed with H O (10 mL) and brine (10
to afford 4 (0.037 g, 57%) as a colorless syrupy liquid; [α]
1.0, CHCl ).
D
+1.10 (c
2
mL), then dried (Na SO ). The solvent was evaporated and the residue
3
2
4
was purified by column chromatography (60–120 mesh silica gel, 10%
IR (neat): 3053, 2926, 2855, 1678, 1642, 1611, 1247, 1107, 1060,
EtOAc–PE) gave 20b (0.06 g, 67%) as a pale yellow oil; [α]D2 +7.14 (c
5
–1
1039, 903, 820, 771, 726, 648, 609 cm
.
0
.59, CHCl3).
1
H NMR (300 MHz, CDCl ): δ = 7.76–7.60 (m, 4 H, H ), 7.46–7.08 (m,
3
Ar
IR (neat): 3019, 2972, 1247, 1214, 1109, 749 cm–1
.
2
5 H, H ), 6.85 (d, J = 8.4 Hz, 4 H, H ), 5.66 (m, 1 H, olefin), 5.41 (dd,
A
r
A
r
1
H NMR (300 MHz, CDCl ): δ = 5.90–5.70 (m, 1 H, olefin), 5.15–4.89
J = 16.2, 1.5 Hz, 1 H, olefin), 5.39 (dt, J = 15.6, 1.7 Hz, 1 H, olefin), 4.64
(d, J = 11.7 Hz, 1 H, CHAr), 4.54–4.44 (m, 9 H, CH Ar), 4.05 (m, 2 H,
CH), 3.87 (m, 2 H, CH), 3.83–3.77 (s, 6 H, CH), 3.70 (m, 1 H, CH), 3.55
(m, 2 H, CH), 2.58–2.27 (m, 2 H, CH ), 2.17–1.97 (m, 2 H, CH ), 1.80–
1.48 (m, 9 H, CH ), 1.26 (s, 12 H, CH ).
13C NMR (75 MHz, CDCl
): δ = 135.9, 134.7, 130.7, 129.6, 128.2, 127.4,
125.9, 121.8, 121.2, 113.7, 75.0, 72.7, 70.5, 70.0, 69.6, 55.2, 36.8, 35.1,
2.0, 31.8, 9.6, 29.3, 26.5, 23.4, 22.6, 22.1, 2 × 19.2, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C70H85O Si: 1081.6008; found:
3
(
m, 2 H, olefin), 4.04–3.79 (m, 2 H, OCH), 2.38–2.25 (m, 1 H, CH2),
2
2
1
.24–2.15 (m, 1 H, CH ), 1.92–1.49 (m, 2 H, CH ), 1.36 (s, 3 H, CH ),
2
2
3
.25 (s, 3 H, CH ), 1.19 (d, J = 6.2 Hz, 3 H, CH ).
2
2
3
3
13
2
3
C NMR (75 MHz, CDCl ): δ = 134.4, 116.7, 100.1, 66.1, 62.7, 40.1,
3
39.4, 24.9, 21.6.
3
HRMS (ESI): m/z [M + Na]+ calcd for C10H18O Na: 193.1204; found:
2
3
193.1210.
8
1081.6010.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 845–853

8
53
Synthesis
A. Rajesh et al.
Paper
Acknowledgement
(7) Rajesh, A.; Sharma, G. V. M.; Damera, K. Tetrahedron Lett. 2014,
55, 4067.
All the authors are thankful for financial support from MLP-0008 of
CSIR, New Delhi. A.R. is thankful to CSIR, New Delhi for a fellowship.
(8) Sharma, G. V. M.; Reddy, S. V.; Ramakrishna, K. V. S. Org. Biomol.
Chem. 2012, 10, 3689.
(9) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Dolle, R. E.
J. Am. Chem. Soc. 1981, 103, 6967.
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5
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 845–853