Stereoselective Total Synthesis of (+)-Anamarine and 8- epi -(-)-Anamarine from D-Mannitol

Article abstract of DOI:10.1055/s-0034-1380864

Stereoselective total synthesis of (+)-anamarine and the first synthesis of 8-epi-(-)-anamarine, its nonnatural diastereomer, were achieved from readily available d-mannitol. The key reactions involved were asymmetric dihydroxylation, cross-metathesis and ring-closing metathesis reactions. The approach is adoptable advantageously for the diversity-oriented synthesis of several related classes of natural products.

Full text of DOI:10.1055/s-0034-1380864

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, 2997–3008
paper
2997
R. Karnekanti et al.
Paper
Synthesis
Stereoselective Total Synthesis of (+)-Anamarine and 8-epi-(–)-
Anamarine from D-Mannitol
O
Rajender Karnekanti*a,b
Marumamula Hanumaiaha
Gangavaram V. M. Sharmaa
O
cross-
metathesis
OAc OAc
O
OAc OAc
+
O
OAc OAc
OH OH
OAc OAc
a Organic and Biomolecular Chemistry Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India
b Govt. Model Residential Polytechnic, Bhadrachalam,
Telangana 507 111, India
OH
(+)-anamarine
HO
O
O
OH OH
D-mannitol
O
cross-
metathesis
OAc OAc
OAc OAc
rajenderpoly@gmail.com
+
O
OAc OAc
OAc OAc
8-epi-(–)-anamarine
Received: 12.02.2015
Accepted after revision: 24.04.2015
Published online: 30.06.2015
O
O
1
O
OAc OAc
10S
O
OAc OAc
DOI: 10.1055/s-0034-1380864; Art ID: ss-2015-z0105-op
8R
S
R
5R
9S
S
R
R
11S
Abstract Stereoselective total synthesis of (+)-anamarine and the first
synthesis of 8-epi-(–)-anamarine, its nonnatural diastereomer, were
achieved from readily available D-mannitol. The key reactions involved
were asymmetric dihydroxylation, cross-metathesis and ring-closing
metathesis reactions. The approach is adoptable advantageously for
the diversity-oriented synthesis of several related classes of natural
products.
OAc OAc
(+)-anamarine (1)
OAc OAc
(–)-anamarine (2)
O
O
OAc OAc
R
R
Key words (+)-anamarine, 8-epi-(–)-anamarine, D-mannitol, asym-
S
R
R
metric dihydroxylation, cross-metathesis and ring-closing metathesis
OAc OAc
8-epi-(–)-anamarine (3)
Figure 1 Structures of anamarines 1, 2 and 3
The δ-lactone moiety is an important structural unit
found in various bioactive natural products, which show a
wide range of biological activities.1–4 The 5,6-dihydro-2H-
pyran-2-one-containing natural product (+)-anamarine (1)
was isolated from the flowers and leaves of a Peruvian hyp-
Similarly, the retrosynthetic analysis of 8-epi-(–)-ana-
marine (3) revealed that 8 (Scheme 1) is the late-stage in-
termediate. Olefin 8 could be realized from lactone 9 and
olefin 10 by a cross-metathesis reaction. The requisite lac-
tone 9 and olefin 10 could be prepared from D-mannitol as
common starting material.
Vinyl lactones 4 and 9 were prepared from alcohol 11
(Scheme 2). Accordingly, alcohol 11,12 obtained from D-
mannitol, was subjected to Mitsunobu inversion13 upon
treatment with p-nitrobenzoic acid, triphenylphosphane
and diisopropyl azodicarboxylate (DIAD) in tetrahydrofuran
to give 12 (74%), which on subsequent base hydrolysis
(K2CO3, MeOH) afforded 6 in 86% yield (Scheme 2). Reaction
of alcohol 6 with acryloyl chloride and triethylamine in di-
chloromethane furnished the acrylate 13 (82%), which on a
ring-closing metathesis (RCM) reaction with Grubbs I14 cat-
alyst gave α,β-unsaturated lactone 14 in 89% yield. Treat-
ment of 14 with copper(II) chloride dihydrate (CuCl2·2H2O)
in acetonitrile15 afforded the corresponding diol, which on
tis species.5 Lactone
1
contains five stereocenters
(5R,8R,9S,10S,11S), a trans double bond and an α,β-unsatu-
rated lactone moiety (Figure 1). Due to its biological impor-
tance, several syntheses6–10 have been reported for 1. In
continuation of our interest in the synthesis of biologically
active lactones,11 herein, we report a flexible route for the
synthesis of (+)-anamarine (1) and its nonnatural diaste-
reomer, 8-epi-(–)-anamarine (3), from D-mannitol as com-
mon starting material.
The retrosynthetic analysis of (+)-anamarine (1) re-
vealed that it could be obtained by an olefin cross-metathe-
sis reaction of the vinyl lactone 4 and tetraacetate 5, where-
in both, in turn, could be realized from D-mannitol through
6 and 7, respectively (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

2998
R. Karnekanti et al.
Paper
Synthesis
subsequent treatment with triphenylphosphane,16 iodine
O
and imidazole in dichloromethane furnished olefin 4 in 74%
O
yield {[α]D +93.8 (c 0.10, CHCl3); Lit.10 [α]D +90.4 (c 0.7,
CHCl3)}.
25
20
O
O
4
Likewise, alcohol 11 on treatment with acryloyl chloride
and triethylamine in dichloromethane furnished ester 15 in
82% yield (Scheme 2). The RCM reaction of 15 with Grubbs I
catalyst in dichloromethane gave the lactone 16 (81%). Hy-
drolysis of the acetonide in 16 (CuCl2·2H2O, MeCN) gave the
corresponding diol, which on further reaction with tri-
phenylphosphane, iodine and imidazole in dichlorometh-
6
OH
+
D-mannitol
1
OAc OAc
O
O
OAc OAc
O
O
5
7
25
ane afforded the olefin 9 in 70% yield {[α]D –87.5 (c 0.10,
CHCl3); Lit.17 [α]D25 –93.4 (c 0.10, CHCl3)}.
O
O
The diol 17 prepared from tri-O-isopropylidene-D-(+)-
mannitol,18 on treatment with triphenylphosphane, iodine
and imidazole in dichloromethane, gave olefin 18 in 78%
yield (Scheme 3). Selective deprotection of the 1,2-O-iso-
propylidene group in 18 using CuCl2·2H2O in acetonitrile
gave the diol 19 in 98% yield (with the recovery of starting
material). Reaction of 19 with benzoyl chloride in the pres-
ence of triethylamine and dibutyltin(IV) oxide19 in di-
chloromethane furnished the monobenzoate 20 selectively
in 70% yield. Alcohol 20 on further reaction with p-tosyl
chloride in the presence of triethylamine and catalytic 4-
(dimethylamino)pyridine in dichloromethane gave 21
O
O
O
OH 11
9
+
O
O
OTBDPS
3
O
OTBDPS
OH
O
D-mannitol
8
OH
O
10
Scheme 1 Retrosynthetic analysis of 1 and 3
O
O
a
b
c
O
O
O
O
O
O
O
O
NO2
OH
c
OH
6 (86%)
O
O
11
12 (74%)
13 (82%)
d
O
O
O
O
O
O
e,f
O
O
O
15 (82%)
4 (74%)
O
14 (89%)
d
O
O
O
e,f
O
O
O
16 (81%)
9 (70%)
Scheme 2 Reagents and conditions: a) p-nitrobenzoic acid, Ph3P, DIAD, THF, r.t., 5 h; b) K2CO3, MeOH, r.t., 1 h; c) acryloyl chloride, Et3N, DMAP (cat.),
CH2Cl2, 0 °C to r.t., 2 h; d) Grubbs I catalyst, CH2Cl2, reflux, 6 h; e) CuCl2·2H2O, MeCN, 0 °C, 30 min; f) I2, Ph3P, imidazole, CH2Cl2, 0 °C to r.t., 4 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

2999
R. Karnekanti et al.
Paper
Synthesis
subsequent treatment with acetic anhydride and pyridine
in dichloromethane gave the tetraacetate 510 in 90% yield
(Scheme 4).
O
O
HO
HO
a
b
O
O
O
O
O
O
O
O
O
O
17
18 (78%)
b, c
O
O
a
O
O
O
O
OH
O
c–e
f
OR1
25
26 (65%)
O
OR2
19 R1 = R2 = H
O
O
O
OH
O
22 (82%)
OH
20 R1 = Bz, R2 = H (70%)
21 R1 = Bz, R2 = Ts (90%)
O
O
O
OR
O
e
d
O
OH
OH
O
O
O
27 R = H (90%)
27a R = Ts
28 (80%)
O
X
O
OH
24
O
OH
O
HO
O
O
O
O
f
HO
O
23 (33%)
Scheme 3 Reagents and conditions: a) I2, Ph3P, imidazole, CH2Cl2, 0 °C
to r.t., 4 h; b) CuCl2·2H2O, MeCN, 0 °C, 15 min; c) BzCl, Et3N, n-Bu2SnO,
CH2Cl2, 0 °C to r.t., 1 h; d) p-TsCl, Et3N, DMAP (cat.), CH2Cl2, r.t., 5 h; e)
K2CO3, MeOH, 0 °C to r.t., 1 h; f) TMSI, n-BuLi, THF, –20 °C, 30 min.
O
O
O
O
29 (91%)
30 (98% based on
SM recovery)
O
O
OR OR
(90%), which on treatment with methanolic potassium car-
bonate at room temperature afforded the epoxide 22 in 82%
yield. Regioselective opening of the epoxide 22 with
trimethylsilyl iodide and n-butyllithium20 in tetrahydrofu-
ran at –20 °C furnished the allylic alcohol 23 (33%), which
on Sharpless asymmetric epoxidation under different reac-
tion conditions met with failure to give the expected epox-
ide 24, to introduce the C11 stereocenter of target 1.
Alternatively, olefin 5 was prepared as shown in Scheme
4, from the known epoxide 25.21 Accordingly, regioselective
opening of epoxide 25 with trimethylsilyl iodide and n-bu-
tyllithium in tetrahydrofuran at –20 °C gave the allylic alco-
hol 26 in 65% yield. The olefin 26 was subjected to asym-
metric dihydroxylation22 using AD-mix-β and methanesul-
fonamide in aqueous tert-butyl alcohol (1:1) at 0 °C to
afford the triol 27 in 90% yield (dr 9:1). Reaction of triol 27
with p-tosyl chloride, triethylamine and dibutyltin(IV) ox-
ide in dichloromethane furnished 27a, which on reduction
with lithium aluminum hydride in tetrahydrofuran gave
diol 28 in 80% yield. Treatment of 28 with 2,2-dimethoxy-
propane in acetone in the presence of catalytic p-toluene-
sulfonic acid furnished 29 (91%), which on selective depro-
tection (CuCl2·2H2O, MeCN) afforded the diol 30 (98% based
on starting material recovery). Reaction of 30 with triphen-
ylphosphane, iodine and imidazole in dichloromethane
gave olefin 7 in 74% yield. Reaction of 7 with trifluoroacetic
acid in dichloromethane furnished the tetrol 7a, which on
g
h, i
O
O
OR OR
7 (74%)
7a R = H
5 R = Ac (90%)
Scheme 4 Reagents and conditions: a) TMSI, n-BuLi, THF, –20 °C, 30
min; b) AD-mix-β, MsNH2, t-BuOH–H2O (1:1), 0 °C, 24 h; c) p-TsCl, Et3N,
n-Bu2SnO, CH2Cl2, 0 °C to r.t., 1 h; d) LAH, THF, 0 °C to r.t., 3 h; e) 2,2-
dimethoxypropane, PTSA (cat.), acetone, 0 °C to r.t., 1 h; f) CuCl2·2H2O,
MeCN, 0 °C, 15 min; g) I2, Ph3P, imidazole, CH2Cl2, 0 °C to r.t., 4 h; h)
TFA, CH2Cl2, 0 °C to r.t., 15 min; i) Ac2O, pyridine, DMAP (cat.), CH2Cl2,
r.t., 20 h.
For the synthesis of fragment 10, diol 17 was treated
with p-tosyl chloride, triethylamine and dibutyltin(IV) ox-
ide in dichloromethane to give tosylate 31, which on fur-
ther deoxygenation with lithium aluminum hydride in tet-
rahydrofuran furnished 32 in 74% yield (Scheme 5). Alcohol
32 on reaction with tert-butyldiphenylsilyl chloride and
imidazole in dichloromethane afforded 33 in 66% yield. Se-
lective deprotection of 33 (CuCl2·2H2O, MeCN) and subse-
quent tosylation (p-TsCl, Et3N, n-Bu2SnO) of diol 34 in di-
chloromethane gave 34a. Reaction of 34a with methanolic
potassium carbonate afforded the epoxide 35 (89%), which
on ring opening with trimethylsilyl iodide and n-butyllithi-
um in tetrahydrofuran at –20 °C furnished the allylic alco-
hol 10 in 70% yield. Exposure of 10 to trifluoroacetic acid in
dichloromethane and subsequent acetylation (Ac2O, pyri-
dine) of tetrol 10a in dichloromethane afforded the tetraac-
etate 36 in 82% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3000
R. Karnekanti et al.
Paper
Synthesis
For the synthesis of 8-epi-(–)-anamarine (3), vinyl lac-
O
O
tone 9 was reacted with olefin 10 in the presence of
Grubbs II catalyst in toluene at reflux to give 8 in 82% yield
(Scheme 7). Lactone 8 was treated with trifluoroacetic acid
in dichloromethane to give tetrol 8a, by the simultaneous
deprotection of the silyl and acetonide groups. Finally, reac-
tion of 8a with acetic anhydride and pyridine in dichloro-
methane furnished 8-epi-(–)-anamarine (3) in 84% yield,
O
O
a
O
b, c
O
17
OTs
O
OR
O
OH
32 R = H (74%)
31
33 R = TBDPS (66%)
O
HO
OH
O
25
RO
paving the way for its first synthesis {[α]D –9.0 (c 1.12,
f
d, e
CHCl3)}.
O
OTBDPS
Alternatively, cross-metathesis of olefins 9 and 36 using
Grubbs II catalyst afforded 8-epi-(–)-anamarine (3) in 84%
yield (Scheme 7). Though 3 could be obtained from this al-
ternative coupling, the yield was albeit less than the earlier
experiment. From these studies, it is evident that, in the ab-
sence of an acetyl group at the allylic position, the cross-
metathesis reaction is more facile and the yields are high.
O
OTBDPS
34 R = H
34a R = Ts
35 (89%)
O
OTBDPS
OR OR
g
h, i
OH
O
OR OR
10a R = H
36 R = Ac (82%)
O
10 (70%)
O
O
OTBDPS
a
Scheme 5 Reagents and conditions: a) p-TsCl, Et3N, n-Bu2SnO, CH2Cl2,
0 °C to r.t., 1 h; b) LAH, THF, 0 °C to r.t., 3 h; c) TBDPSCl, imidazole,
CH2Cl2, 0 °C to r.t., 1 h; d) CuCl2·2H2O, MeCN, 0 °C, 30 min; e) p-TsCl,
Et3N, n-Bu2SnO, CH2Cl2, r.t., 30 min; f) K2CO3, MeOH, r.t., 1 h; g) TMSI,
n-BuLi, THF, –20 °C, 30 min; h) TFA, CH2Cl2, 0 °C to r.t., 15 min; i) Ac2O,
pyridine, DMAP (cat.), CH2Cl2, r.t., 20 h.
O
O
OTBDPS
O
+
OH
O
9
OH
8 (82%)
O
10
O
O
OR OR
b, c
For the synthesis of (+)-anamarine (1), attempted cross-
metathesis of olefins 4 and 7 with the Grubbs II23 catalyst
met with failure to give the expected product 37 (Scheme
6). This may be attributed to the presence of the bulky ace-
tonide protection next to the olefin. Hence, vinyl lactone 4
was subjected to a cross-metathesis reaction with tetraace-
tate 5 using Grubbs II23 catalyst to give the target 1 in 68%
yield.
OR OR
8a R = H
3 R = Ac (84%)
O
OR OR
O
d
+
3 (84%)
OR OR
36 R = Ac
9
Scheme 7 Reagents and conditions: a) Grubbs II catalyst, toluene, re-
flux, 8 h; b) TFA, CH2Cl2, 0 °C to r.t., 15 min; c) Ac2O, pyridine, DMAP
(cat.), CH2Cl2, r.t., 20 h; d) Grubbs II catalyst, CH2Cl2, reflux, 5 h.
O
O
O
O
O
O
O
O
+
+
In conclusion, a general and efficient convergent syn-
thetic strategy has been developed for the synthesis of (+)-
anamarine and the first synthesis of its nonnatural diaste-
reomer 8-epi-(–)-anamarine from D-mannitol. Two enan-
tiomeric vinyl lactones and two olefinic acyclic fragments,
encompassing five stereocenters, were synthesized and
coupled to give this anamarine class of δ-lactones. This ap-
proach is adoptable for the diversity-oriented efficient syn-
thesis of related lactone classes of compounds.
O
O
4
O
O
7
37
O
O
OAc OAc
O
OAc OAc
O
a
OAc OAc
OAc OAc
1 (68%)
4
5
Scheme 6 Reagents and conditions: a) Grubbs II catalyst, CH2Cl2, reflux,
5 h.
Solvents were dried over standard drying agents and were freshly dis-
tilled prior to use. Chemicals were purchased and used without fur-
ther purification. All column chromatographic separations were per-
formed using silica gel (Acme, 60–120 mesh). Organic solutions were
dried over anhydrous Na2SO4 and concentrated below 40 °C under re-
duced pressure. 1H NMR (300 MHz and 500 MHz) and 13C NMR (75
The spectroscopic data of the synthetic 1 match the re-
ported5 values (see Supporting Information, Tables 1 and 2)
{[α]D +16.8 (c 0.3, CHCl3); Lit.7–9 [α]D +17.8 (c 0.3,
25
25
CHCl3)}.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3001
R. Karnekanti et al.
Paper
Synthesis
MHz and 125 MHz) spectra were measured with Bruker Avance 300
and Varian Unity Inova-500 instruments with tetramethylsilane as an
internal standard for solutions in CDCl3; J values are given in hertz. IR
spectra were recorded on Perkin-Elmer IR-683 and JASCO FT/IR-5300
spectrophotometers with NaCl and KBr optics. Optical rotations were
measured with a JASCO DIP 300 digital polarimeter. Mass spectra
were recorded on Bruker maXis, CEC-21-11013 or Finnigan Mat 1210
double-focusing mass spectrometers operating with a direct inlet sys-
tem or LC/MSD Trap SL (Agilent Technologies).
(R)-1-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}but-3-enyl Acrylate (13)
To a stirred solution of 6 (0.74 g, 3.49 mmol) in CH2Cl2 (7.5 mL) at
0 °C, Et3N (1.46 mL, 10.46 mmol) and DMAP (cat.) followed by acry-
loyl chloride (0.31 mL, 3.84 mmol) were added, and the mixture was
stirred at r.t. for 2 h. Then, it was diluted with CHCl3 (10 mL), washed
with water (10 mL) and brine (10 mL), and dried (Na2SO4). The solvent
was evaporated and the residue was purified by silica gel column
chromatography (EtOAc–PE, 5:95) to afford 13 (0.76 g, 82%) as a pale
yellow syrup.
[α]D25 +5.6 (c 0.30, CHCl3).
(R)-1-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}but-3-enyl 4-Nitroben-
zoate (12)
IR (neat): 3746, 3668, 3625, 3020, 2938, 2861, 2314, 1725, 1644,
1610, 1551, 1531, 1482, 1467, 1449, 1407, 1350, 1277, 1216, 1190,
To a stirred solution of 11 (1.2 g, 5.66 mmol) in THF (10 mL), Ph3P
(2.22 g, 8.49 mmol) and p-nitrobenzoic acid (1.42 g, 8.49 mmol) were
added, and the mixture was stirred for 20 min. DIAD (1.71 g, 8.49
mmol) was added at 0 °C and the reaction mixture was stirred at r.t.
for 5 h. Then, it was quenched with sat. aq NaHCO3 solution (10 mL)
and extracted with EtOAc (2 × 30 mL). The combined organic layers
were washed with water (10 mL) and brine (10 mL), and dried
(Na2SO4). The solvent was evaporated and the residue was purified by
silica gel column chromatography (EtOAc–PE, 1:9) to afford 12 (1.52 g,
74%) as a pale yellow syrup.
1164, 1101, 1049, 1018, 984, 925, 874, 844, 771, 668 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.43 (dd, J = 1.5, 17.4 Hz, 1 H, olefinic),
6.14 (dd, J = 10.2, 17.4 Hz, 1 H, olefinic), 5.85 (dd, J = 1.5, 10.4 Hz, 1 H,
olefinic), 5.80–5.69 (m, 1 H, olefinic), 5.16–5.04 (m, 2 H, olefinic), 4.44
(q, J = 7.2 Hz, 1 H, OCH), 4.27–4.16 (m, 1 H, OCH), 4.06–3.97 (m, 1 H,
OCH), 3.73 (m, 1 H, OCH), 2.52–2.31 (m, 2 H, allylic), 1.71–1.49 (m, 8
H, cyclohexyl), 1.48–1.30 (m, 2 H, cyclohexyl).
13C NMR (75 MHz, CDCl3): δ = 165.7, 133.0, 131.0, 128.3, 118.2, 110.1,
75.6, 72.7, 65.2, 35.7, 35.3, 34.9, 25.1, 23.9, 23.8.
[α]D25 +12.0 (c 0.62, CHCl3).
HRMS: m/z [M + Na]+ calcd for C15H22O4: 289.14103; found:
289.14129.
IR (neat): 3019, 2934, 2857, 2315, 1726, 1645, 1608, 1529, 1449,
1347, 1272, 1216, 1164, 1101, 1045, 1015, 925, 873, 846, 771, 721,
668 cm–1
.
(R)-6-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}-5,6-dihydro-2H-pyran-
2-one (14)
1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.1 Hz, 2 H, Ar-H), 8.23 (d,
J = 9.1 Hz, 2 H, Ar-H), 5.82 (ddd, J = 7.4, 10.2, 14.4 Hz, 1 H, olefinic),
5.26 (td, J = 5.3, 10.6 Hz, 1 H, OCH), 5.13 (dd, J = 1.5, 17.0 Hz, 1 H, ole-
finic), 5.07 (d, J = 10.2 Hz, 1 H, olefinic), 4.34 (q, J = 6.0 Hz, 1 H, OCH),
4.08 (dd, J = 6.6, 8.5 Hz, 1 H, OCH), 3.80 (dd, J = 6.0, 8.7 Hz, 1 H, OCH),
2.63–2.44 (m, 2 H, allylic), 1.74–1.48 (m, 8 H, cyclohexyl), 1.47–1.29
(m, 2 H, cyclohexyl).
To a stirred solution of 13 (0.05 g, 0.19 mmol) in CH2Cl2 (50 mL),
Grubbs I catalyst (10 mol%) was added, and the mixture was stirred at
reflux for 6 h. Most of the solvent was then distilled off and the con-
centrated solution was left to stir at r.t. for 2 h under a flow of air to
decompose the catalyst. The mixture was concentrated and the resi-
due was purified by silica gel column chromatography (EtOAc–PE,
3:7) to afford 14 (0.04 g, 89%) as a colorless syrup.
13C NMR (75 MHz, CDCl3): δ = 164.2, 150.5, 135.6, 132.6, 123.5, 118.6,
110.3, 75.6, 74.5, 65.2, 35.9, 35.4, 34.7, 25.0, 23.9, 23.8.
[α]D25 +61.0 (c 0.37, CHCl3).
HRMS: m/z [M + Na]+ calcd for C19H23NO6: 384.13935; found:
384.13366.
IR (neat): 3010, 2933, 2856, 2314, 1727, 1645, 1551, 1500, 1466,
1449, 1383, 1216, 1162, 1095, 1047, 928, 847, 816, 748, 667, 627 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.93 (ddd, J = 2.5, 6.0, 8.7 Hz, 1 H, ole-
finic), 6.03 (dd, J = 2.3, 9.8 Hz, 1 H, olefinic), 4.55 (td, J = 4.2, 12.1 Hz, 1
H, OCH), 4.33 (dt, J = 4.2, 6.2 Hz, 1 H, OCH), 4.13–4.00 (m, 2 H, OCH2),
2.63–2.47 (m, 1 H, allylic), 2.43–2.31 (m, 1 H, allylic), 1.75–1.52 (m, 8
H, cyclohexyl), 1.50–1.30 (m, 2 H, cyclohexyl).
13C NMR (75 MHz, CDCl3): δ = 165.0, 132.7, 117.8, 109.8, 75.5, 72.6,
65.4, 35.8, 35.1, 34.6, 24.8, 23.6, 23.5.
(R)-1-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}but-3-en-1-ol (6)
To a stirred solution of 12 (1.50 g, 4.16 mmol) in MeOH (10 mL) at
0 °C, K2CO3 (1.72 g, 12.47 mmol) was added, and the mixture was
stirred at r.t. for 1 h. Then, it was filtered through a pad of Celite®
which was then washed with EtOAc (3 × 15 mL). The combined organ-
ic layers were dried (Na2SO4) and concentrated, and the residue was
purified by silica gel column chromatography (EtOAc–PE, 8:92) to af-
ford 6 (0.76 g, 86%) as a colorless syrup.
HRMS: m/z [M + Na]+ calcd for C13H18O4: 261.10973; found:
261.10974.
[α]D25 +6.5 (c 0.20, CHCl3).
(R)-6-Vinyl-5,6-dihydro-2H-pyran-2-one (4)
IR (neat): 3396, 3018, 2936, 2860, 2314, 1644, 1551, 1433, 1367,
1334, 1281, 1216, 1164, 1101, 1045, 926, 848, 771, 668, 626 cm–1
.
To a stirred solution of 14 (0.3 g, 1.27 mmol) in MeCN (5 mL) at 0 °C,
CuCl2·2H2O (0.23 g, 1.38 mmol) was added, and the reaction mixture
was stirred at r.t. for 30 min. Then, it was quenched with sat. aq
NaHCO3 solution (1 mL), filtered through a pad of Celite® and the pad
was washed with EtOAc (10 mL). The organic layer was dried
(Na2SO4), concentrated and used as such for the next reaction.
1H NMR (300 MHz, CDCl3): δ = 5.87 (ddd, J = 7.2, 10.4, 14.2 Hz, 1 H,
olefinic), 5.21–5.07 (m, 2 H, olefinic), 4.08–3.97 (m, 2 H, OCH2), 3.80–
3.70 (m, 1 H, OCH), 3.59 (m, 1 H, OCH), 2.35 (br s, 1 H, OH), 2.25 (t, J =
6.4 Hz, 2 H, allylic), 1.70–1.51 (m, 8 H, cyclohexyl), 1.50–1.31 (m, 2 H,
cyclohexyl).
13C NMR (75 MHz, CDCl3): δ = 134.0, 117.7, 109.9, 78.0, 71.6, 65.7,
38.2, 36.2, 34.8, 25.1, 24.0, 23.7.
HRMS: m/z [M + Na]+ calcd for C12H20O3: 235.13047; found:
235.13033.
To a solution of the above diol (0.2 g, 1.27 mmol), Ph3P (1.33 g, 5.08
mmol) and imidazole (0.35 g, 5.08 mmol) in CH2Cl2 (5 mL) at 0 °C, I2
(0.97 g, 3.81 mmol) was added, and the mixture was stirred at r.t. for
4 h. Then, the reaction mixture was quenched with sat. aq NaOH solu-
tion (1 mL) and extracted with CHCl3 (3 × 5 mL). The organic layers
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3002
R. Karnekanti et al.
Paper
Synthesis
were washed with sat. aq Na2S2O3 (4 mL) and brine (4 mL), and dried
(Na2SO4). The solvent was evaporated and the residue was purified by
silica gel column chromatography (EtOAc–PE, 2:8) to give olefin 4
(0.12 g, 74%) as a colorless liquid.
(S)-6-Vinyl-5,6-dihydro-2H-pyran-2-one (9)
To a stirred solution of 16 (0.3 g, 1.27 mmol) in MeCN (5 mL) at 0 °C,
CuCl2·2H2O (0.23 g, 1.38 mmol) was added, and the reaction mixture
was stirred at r.t. for 30 min. Then, it was quenched with sat. aq
NaHCO3 solution (1 mL), filtered through a pad of Celite® and the pad
was washed with EtOAc (10 mL). The organic layer was dried
(Na2SO4), concentrated and used as such for the next reaction.
[α]D25 +93.8 (c 0.10, CHCl3) {Lit.10 [α]D20 +90.4 (c 0.7, CHCl3)}.
IR (neat): 3020, 2945, 2881, 2777, 1728, 1421, 1273, 1214, 1118,
1071, 1027, 928, 748, 667, 626 cm–1
.
To a stirred solution of the above diol (0.2 g, 1.27 mmol), Ph3P (1.33 g,
5.08 mmol) and imidazole (0.35 g, 5.08 mmol) in CH2Cl2 (10 mL) at
0 °C, I2 (0.97 g, 3.81 mmol) was added, and the mixture was stirred at
r.t. for 4 h. Workup as described for 4 and purification of the residue
by silica gel column chromatography (EtOAc–PE, 2:8) gave olefin 9
(0.11 g, 70%) as a colorless liquid.
1H NMR (300 MHz, CDCl3): δ = 6.87 (ddd, J = 3.4, 5.3, 8.7 Hz, 1 H, ole-
finic), 6.04 (td, J = 1.9, 9.6 Hz, 1 H, olefinic), 5.94 (m, 1 H, olefinic),
5.39 (d, J = 17.4 Hz, 1 H, olefinic), 5.28 (d, J = 10.6 Hz, 1 H, olefinic),
4.92 (m, 1 H, OCH), 2.45 (m, 2 H, allylic).
13C NMR (75 MHz, CDCl3): δ = 163.7, 144.3, 134.8, 121.6, 117.8, 77.7,
29.3.
[α]D25 –87.5 (c 0.10, CHCl3) {Lit.17 [α]D25 –93.4 (c 0.10, CHCl3)}.
HRMS: m/z [M + Na]+ calcd for C7H8O2: 147.0422; found: 147.0425.
IR (neat): 3016, 2943, 2882, 1726, 1426, 1382, 1215, 1160, 1108, 971,
819, 748, 703, 667, 609 cm–1
.
(S)-1-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}but-3-enyl Acrylate (15)
1H NMR (300 MHz, CDCl3): δ = 6.89 (ddd, J = 3.8, 5.3, 9.8 Hz, 1 H, ole-
finic), 6.10–5.90 (m, 2 H, olefinic), 5.42 (d, J = 17.4 Hz, 1 H, olefinic),
5.31 (d, J = 10.6 Hz, 1 H, olefinic), 4.94 (m, 1 H, OCH), 2.52–2.41 (m, 2
H, allylic).
13C NMR (75 MHz, CDCl3): δ = 163.7, 144.4, 134.8, 121.6, 117.8, 77.7,
29.3.
To a stirred solution of 11 (0.74 g, 3.49 mmol) in CH2Cl2 (7.5 mL) at
0 °C, Et3N (1.46 mL, 10.46 mmol), DMAP (cat.) and acryloyl chloride
(0.31 mL, 3.84 mmol) were added sequentially, and the mixture was
stirred at r.t. for 2 h. Workup as described for 13 and purification of
the residue by silica gel column chromatography (EtOAc–PE, 5:95) af-
forded 15 (0.76 g, 82%) as a pale yellow syrup.
HRMS: m/z [M + Na]+ calcd for C7H8O2: 147.0422; found: 147.0429.
[α]D25 +17.5 (c 0.30, CHCl3).
IR (neat): 2935, 2858, 2313, 1727, 1644, 1568, 1551, 1516, 1466,
(4S,4′R,5R)-2,2,2′,2′-Tetramethyl-5-vinyl-4,4′-bi(1,3-dioxolane)
(18)
1449, 1406, 1367, 1264, 1047, 925, 846, 807, 772, 669 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.41 (d, J = 17.4 Hz, 1 H, olefinic), 6.11
(dd, J = 10.2, 17.0 Hz, 1 H, olefinic), 5.88–5.69 (m, 2 H, olefinic), 5.15–
5.03 (m, 2 H, olefinic), 4.22–3.98 (m, 3 H, 3 × OCH), 3.82 (dd, J = 6.4,
7.9 Hz, 1 H, OCH), 2.55–2.33 (m, 2 H, allylic), 1.67–1.50 (m, 8 H, cyclo-
hexyl), 1.40–1.32 (m, 2 H, cyclohexyl).
13C NMR (75 MHz, CDCl3): δ = 165.4, 133.0, 131.1, 128.3, 118.1, 110.1,
75.8, 72.9, 65.7, 36.0, 35.3, 34.8, 25.1, 23.9, 23.8.
To a solution of diol 17 (6.48 g, 24.73 mmol), Ph3P (25.92 g, 98.93
mmol) and imidazole (6.73 g, 98.93 mmol) in CH2Cl2 (60 mL) at 0 °C,
I2 (18.84 g, 74.20 mmol) was added, and the mixture was stirred at r.t.
for 4 h. Workup as described for 4 and purification of the residue by
silica gel column chromatography (EtOAc–PE, 5:95) gave olefin 18
(4.39 g, 78%) as a pale yellow syrup.
[α]D25 –36.3 (c 0.16, CHCl3).
HRMS: m/z [M + Na]+ calcd for C15H22O4: 289.14103; found:
289.14077.
IR (neat): 2924, 2853, 1744, 1659, 1458, 1371, 1254, 1067, 1022, 793
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.88 (m, 1 H, olefinic), 5.37 (d, J = 17.2
Hz, 1 H, olefinic), 5.16 (d, J = 10.6 Hz, 1 H, olefinic), 4.31 (t, J = 6.2 Hz, 1
H, OCH), 4.09–4.00 (m, 2 H, OCH), 3.89 (m, 1 H, OCH), 3.60 (t, J = 7.6
Hz, 1 H, OCH), 1.38 (s, 6 H, 2 × Me), 1.37 (s, 3 H, Me), 1.31 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 135.8, 109.4, 109.2, 81.1, 80.3, 76.5,
66.9, 26.7, 26.5, 26.1.
(S)-6-{(R)-1,4-Dioxaspiro[4.5]decan-2-yl}-5,6-dihydro-2H-pyran-
2-one (16)
To a stirred solution of 15 (0.07 g, 0.27 mmol) in CH2Cl2 (50 mL),
Grubbs I catalyst (10 mol%) was added, and the mixture was stirred at
reflux for 6 h. Workup as described for 14 and purification of the res-
idue by silica gel column chromatography (EtOAc–PE, 3:7) afforded 16
(0.05 g, 81%) as a colorless syrup.
HRMS: m/z [M + Na]+ calcd for C12H20O4: 251.1259; found: 251.1251.
[α]D25 –59.0 (c 0.70, CHCl3).
(R)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]ethane-1,2-
diol (19)
IR (neat): 3020, 2314, 1727, 1711, 1663, 1569, 1551, 1533, 1483,
1467, 1215, 928, 742, 668 cm–1
.
To a stirred solution of 18 (2.8 g, 12.28 mmol) in MeCN (56 mL) at
0 °C, CuCl2·2H2O (1.88 g, 11.05 mmol) was added, and the reaction
mixture was stirred for 15 min. Then, it was quenched with sat. aq
NaHCO3 solution (4 mL), filtered through a pad of Celite® and the pad
was washed with EtOAc (40 mL). The organic layer was dried (Na2SO4)
and concentrated, and the residue was purified by silica gel column
chromatography (EtOAc–PE, 3:7) to afford 19 (1.40 g, 98% based on
starting material recovery) as a colorless syrup.
1H NMR (300 MHz, CDCl3): δ = 6.91 (m, 1 H, olefinic), 6.02 (dd, J = 2.0,
10.1 Hz, 1 H, olefinic), 4.30–4.24 (m, 1 H, OCH), 4.18–4.12 (m, 2 H,
OCH), 4.06–4.00 (m, 1 H, OCH), 2.61 (td, J = 5.0, 18.1 Hz, 1 H, allylic),
2.48 (td, J = 3.0, 10.1 Hz, 1 H, allylic), 1.65–1.53 (m, 8 H, cyclohexyl),
1.48–1.32 (m, 2 H, cyclohexyl).
13C NMR (75 MHz, CDCl3): δ = 163.1, 144.9, 121.3, 110.6, 78.1, 75.8,
66.7, 36.6, 34.5, 26.4, 25.0, 23.7.
HRMS: m/z [M + Na]+ calcd for C13H18O4: 261.1097; found: 261.1097.
[α]D25 +11.9 (c 0.12, CHCl3).
IR (neat): 3433, 2990, 2934, 2110, 1725, 1645, 1454, 1429, 1377,
1246, 1219, 1167, 1053, 926, 874 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3003
R. Karnekanti et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 5.87 (m, 1 H, olefinic), 5.39 (d, J = 17.2
Hz, 1 H, olefinic), 5.20 (d, J = 10.4 Hz, 1 H, olefinic), 4.38 (t, J = 7.2 Hz, 1
H, OCH), 3.77 (m, 1 H, OCH), 3.70–3.54 (m, 3 H, OCH), 3.49 (br s, 1 H,
OH), 3.26 (br s, 1 H, OH), 1.41 (s, 3 H, Me), 1.39 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 135.8, 118.4, 109.3, 80.8, 79.3, 72.2,
63.4, 26.8.
(4S,5R)-2,2-Dimethyl-4-[(S)-oxiran-2-yl]-5-vinyl-1,3-dioxolane
(22)
To a stirred solution of 21 (1.00 g, 2.23 mmol) in MeOH (5 mL) at 0 °C,
K2CO3 (0.92 g, 6.69 mmol) was added, and the mixture was stirred at
r.t. for 1 h. Then, it was treated with aq NH4Cl solution (3 mL), the
MeOH was evaporated below 40 °C under reduced pressure and the
residue was extracted with Et2O (3 × 10 mL). The organic layer was
washed with water (10 mL) and brine (10 mL), and dried (Na2SO4).
The solvent was evaporated and the residue was purified by silica gel
column chromatography (EtOAc–PE, 9:91) to afford 22 (0.32 g, 82%) as
a colorless syrup.
HRMS: m/z [M + Na]+ calcd for C9H16O4: 211.0940; found: 211.0946.
(R)-2-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-hy-
droxyethyl Benzoate (20)
To a stirred and cooled (0 °C) solution of 19 (0.71 g, 3.77 mmol) in
CH2Cl2 (5 mL), Et3N (0.53 mL, 3.18 mmol), n-Bu2SnO (0.018 g, 0.075
mmol) and BzCl (0.18 mL, 1.56 mmol) were sequentially added, and
the mixture was stirred at r.t. for 1 h. Then, it was diluted with CH2Cl2
(8 mL), washed with water (2 × 5 mL) and brine (2 × 5 mL), and dried
(Na2SO4). The solvent was evaporated and the residue was purified by
silica gel column chromatography (EtOAc–PE, 1:9) to furnish 20 (0.78
g, 70%) as a light yellow syrup.
[α]D25 –15.9 (c 0.29, CHCl3).
IR (neat): 2928, 2852, 1722, 1611, 1513, 1462, 1370, 1301, 1240,
1214, 1175, 1089, 1031, 924, 878, 817, 750 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.82 (m, 1 H, olefinic), 5.39 (d, J = 17.0
Hz, 1 H, olefinic), 5.25 (d, J = 11.0 Hz, 1 H, olefinic), 4.31 (t, J = 8.0 Hz, 1
H, OCH), 3.52 (dd, J = 4.0, 8.0 Hz, 1 H, OCH), 2.95 (m, 1 H, epoxide),
2.73 (t, J = 5.0 Hz, 1 H, epoxide), 2.65 (dd, J = 3.0, 6.0 Hz, 1 H, epoxide),
1.39 (s, 3 H, Me), 1.38 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 135.8, 118.4, 109.3, 80.8, 79.3, 72.2,
63.4, 26.8.
[α]D25 +19.8 (c 0.38, CHCl3).
IR (neat): 3478, 3069, 2988, 2936, 1719, 1713, 1603, 1452, 1375,
1273, 1069, 932, 874, 810, 712 cm–1
.
HRMS: m/z [M + Na]+ calcd for C9H14O3: 193.0847; found: 193.1001.
1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J = 7.4 Hz, 2 H, Ar-H), 7.53 (t,
J = 7.4 Hz, 1 H, Ar-H), 7.41 (t, J = 7.4 Hz, 2 H, Ar-H), 5.89 (m, 1 H, ole-
finic), 5.41 (d, J = 17.4 Hz, 1 H, olefinic), 5.20 (d, J = 10.4 Hz, 1 H, ole-
finic), 4.47 (m, 2 H, OCH), 4.34 (dd, J = 6.9, 11.9 Hz, 1 H, OCH), 4.06 (m,
1 H, OCH), 3.76 (t, J = 6.9 Hz, 1 H, OCH), 2.61 (d, J = 4.0 Hz, 1 H, OH),
1.42 (s, 3 H, Me), 1.41 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 166.7, 135.8, 133.2, 129.6, 128.4, 118.4,
109.4, 80.5, 79.2, 70.6, 66.1, 26.9.
HRMS: m/z [M + Na]+ calcd for C16H20O5: 315.1208; found: 315.1203.
(S)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]prop-2-en-
1-ol (23)
To a stirred solution of TMSI (0.30 g, 1.48 mmol) in THF (5 mL) at
–20 °C, 2.5 M n-BuLi in hexane (0.86 mL, 2.15 mmol) was added, and
the mixture was stirred at –20 °C for 30 min. A solution of 22 (0.50 g,
2.90 mmol) in THF (5 mL) was added and stirring was continued at
–20 °C for an additional 30 min. The reaction mixture was quenched
with aq NH4Cl solution (2 mL) and extracted with EtOAc (2 × 10 mL).
The organic layers were washed with water (10 mL) and brine (10
mL), and dried (Na2SO4). The solvent was evaporated and the residue
was purified by silica gel column chromatography (EtOAc–PE, 12:88)
to afford 23 (0.18 g, 33%) as a pale yellow syrup.
(R)-2-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-(tosyl-
oxy)ethyl Benzoate (21)
To a stirred and cooled (0 °C) solution of 20 (0.75 g, 2.55 mmol) in
CH2Cl2 (5 mL), Et3N (0.24 mL, 1.72 mmol) followed by DMAP (cat.) and
p-TsCl (0.26 g, 1.37 mmol) were added, and the mixture was stirred at
r.t. for 5 h. Workup as described for 20 and purification of the residue
by silica gel column chromatography (EtOAc–PE, 7:93) afforded 21
(1.03 g, 90%) as a colorless syrup.
[α]D25 –13.1 (c 0.13, CHCl3).
IR (neat): 3453, 3086, 2986, 2926, 2859, 1728, 1647, 1453, 1429,
1373, 1246, 1217, 1167, 1113, 1057, 928, 877 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.87 (m, 3 H, olefinic), 5.44 (dd, J =
10.1, 17.0 Hz, 1 H, olefinic), 5.21 (dd, J = 10.0, 17.0 Hz, 2 H, olefinic),
4.41–4.31 (m, 2 H, OCH), 4.03 (br s, 1 H, OH), 3.64 (dd, J = 4.0, 8.0 Hz, 1
H, OCH), 1.42 (s, 3 H, Me), 1.41 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 137.1, 135.2, 119.3, 116.8, 109.5, 83.0,
78.8, 71.3, 27.1, 26.9.
[α]D25 +53.3 (c 1.60, CHCl3).
IR (neat): 3745, 3701, 3609, 3020, 2926, 2854, 2313, 1726, 1645,
1629, 1586, 1551, 1532, 1499, 1451, 1371, 1272, 1216, 1177, 1115,
1096, 1070, 988, 924, 874, 772, 668, 627 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 7.2 Hz, 2 H, Ar-H), 7.74 (d,
J = 8.3 Hz, 2 H, Ar-H), 7.57 (t, J = 7.4 Hz, 1 H, Ar-H), 7.42 (m, 2 H, Ar-H),
7.18 (d, J = 8.1 Hz, 2 H, Ar-H), 5.84 (m, 1 H, olefinic), 5.47 (d, J = 17.0
Hz, 1 H, olefinic), 5.30 (d, J = 10.4 Hz, 1 H, olefinic), 4.99 (m, 1 H, OCH),
4.58–4.35 (m, 3 H, 3 × OCH), 4.01 (dd, J = 5.1, 7.9 Hz, 1 H, OCH), 2.31
(s, 3 H, Me), 1.40 (s, 3 H, Me), 1.36 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 163.9, 142.9, 132.6, 131.6, 131.2, 127.7,
127.2, 126.3, 125.7, 117.7, 108.2, 75.4, 75.0, 74.5, 60.9, 24.8, 24.6,
19.6.
HRMS: m/z [M + Na]+ calcd C10H16O3: 207.0997; found: 207.1091.
(S)-1-[(4R,4′R,5R)-2,2,2′,2′-Tetramethyl-4,4′-bi(1,3-dioxolan)-5-
yl]prop-2-en-1-ol (26)
To a stirred solution of TMSI (1.85 g, 8.13 mmol) in THF (25 mL) at
–20 °C, 2.5 M n-BuLi in hexane (4.71 mL, 11.78 mmol) was added, and
the mixture was stirred at –20 °C for 30 min. A solution of 25 (0.34 g,
2.03 mmol) in THF (15 mL) was added and stirring was continued for
an additional 30 min. Workup as described for 23 and purification of
the residue by silica gel column chromatography (EtOAc–PE, 8:92) af-
forded 26 (0.23 g, 65%) as a pale yellow syrup.
HRMS: m/z [M + Na]+ calcd for C23H26O7S: 469.12914; found:
469.12911.
[α]D25 +1.6 (c 1.60, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3004
R. Karnekanti et al.
Paper
Synthesis
IR (neat): 3451, 2988, 2833, 2801, 1476, 1371, 1251, 1215, 1155,
1127, 1069, 1000, 932, 836, 773, 669 cm–1
13C NMR (75 MHz, CDCl3): δ = 109.8, 109.6, 79.9, 77.3, 77.2, 72.3, 70.1,
67.9, 27.1, 26.8, 26.6, 25.2, 19.7.
.
1H NMR (300 MHz, CDCl3): δ = 6.06–5.93 (m, 1 H, olefinic), 5.44–5.37
(td, J = 1.5, 17.4 Hz, 1 H, olefinic), 5.28–5.23 (td, J = 1.5, 10.6 Hz, 1 H,
olefinic), 4.33 (br s, 1 H, OH), 4.22–4.12 (m, 2 H, OCH2), 4.11–4.00 (m,
3 H, OCH), 3.91–3.84 (m, 1 H, OCH), 1.43 (s, 3 H, Me), 1.41 (s, 3 H, Me),
1.38 (s, 3 H, Me), 1.35 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 137.4, 116.0, 110.0, 109.6, 82.4, 77.3,
76.9, 70.8, 67.7, 27.1, 27.0, 26.5, 25.2.
HRMS: m/z [M + Na]+ calcd for C13H24O6: 299.14651; found:
299.14634.
(4S,4’R,4”R,5S,5’R)-2,2,2’,2’,2”,2”,5-heptamethyl-4,4’,5’,4”-ter(1’,3’-
dioxolane) (29)
To a stirred and cooled (0 °C) solution of 28 (0.85 g, 3.08 mmol) in
acetone (4 mL), 2,2-dimethoxypropane (0.83 mL, 6.78 mmol) and
PTSA (cat.) were added. After the reaction mixture was stirred at r.t.
for 1 h, it was quenched with Et3N (3 mL) and extracted with CH2Cl2
(15 mL). The extract was washed with water (10 mL) and brine (10
mL), and dried (Na2SO4). The solvent was evaporated and the residue
was purified by silica gel column chromatography (EtOAc–PE, 6:94) to
furnish 29 (0.89 g, 91%) as a light yellow syrup.
HRMS: m/z [M + Na]+ calcd for C13H22O5: 281.13649; found:
281.13646.
(1S,2S)-1-[(4R,4′R,5R)-2,2,2′,2′-Tetramethyl-4,4′-bi(1,3-dioxolan)-
5-yl]propane-1,2,3-triol (27)
A stirred solution of AD-mix-β (7.78 g, 10.0 mmol) in t-BuOH–H2O
(1:1, 5 mL) was treated with MsNH2 (0.47 g, 5.0 mmol) at r.t. After 30
min, the clear yellow solution was cooled to 0 °C and 26 (1.3 g, 5.0
mmol) was added. The reaction mixture was stirred vigorously at 0 °C
for 24 h, then quenched with solid Na2SO3 (1.5 g) and warmed to r.t.
After 1 h, it was extracted with EtOAc (3 × 10 mL), and the combined
organic layer was dried (Na2SO4) and concentrated. The residue was
purified by silica gel column chromatography (EtOAc–PE, 8:2) to af-
ford 27 (1.32 g, 90%) as a pale yellow syrup; dr 9:1.
[α]D25 –7.0 (c 0.50, CHCl3).
IR (neat): 2988, 2925, 2854, 2312, 1711, 1678, 1663, 1610, 1568,
1551, 1533, 1379, 1219, 1071, 847, 772, 670 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.39 (dd, J = 6.0, 13.0 Hz, 1 H, OCH),
4.19 (d, J = 6.0 Hz, 1 H, OCH), 4.13 (dd, J = 3.0, 6.0 Hz, 1 H, OCH), 4.07–
4.00 (m, 1 H, OCH), 3.96 (dd, J = 3.0, 5.0 Hz, 1 H, OCH), 3.90 (t, J = 8.0
Hz, 1 H, OCH), 3.84 (d, J = 8.0 Hz, 1 H, OCH), 1.42–1.38 (m, 12 H, 4 ×
Me), 1.35 (s, 6 H, 2 × Me), 1.33 (d, J = 6.0 Hz, 3 H, Me).
[α]D25 +9.4 (c 0.70, CHCl3).
13C NMR (125 MHz, CDCl3): δ = 109.7, 109.6, 108.0, 79.1, 77.5, 77.4,
IR (neat): 3760, 3642, 3561, 3432, 2924, 2854, 2311, 1727, 1694,
1645, 1586, 1568, 1551, 1533, 1500, 1380, 1219, 1155, 1068, 846,
76.1, 72.9, 68.0, 27.2, 27.0, 26.8, 26.6, 25.5, 25.3, 15.2.
HRMS: m/z [M + Na]+ calcd for C16H28O6: 339.17781; found:
339.17835.
772, 668 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.94–4.78 (br s, 2 H, 2 × OH), 4.26–4.13
(m, 2 H, OCH2), 4.12–3.94 (m, 5 H, 5 × OCH), 3.86–3.70 (m, 2 H,
CH2OH), 2.34 (br s, 1 H, OH), 1.43 (s, 6 H, 2 × Me), 1.40 (s, 3 H, Me),
1.35 (s, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 110.0, 109.5, 82.0, 79.8, 76.4, 72.7, 70.2,
67.7, 63.8, 43.2, 26.9, 26.7, 26.4, 25.1.
(R)-1-[(4S,4′S,5R,5′S)-2,2,2′,2′,5′-Pentamethyl-4,4′-bi(1,3-dioxol-
an)-5-yl]ethane-1,2-diol (30)
To a stirred solution of 29 (0.85 g, 2.69 mmol) in MeCN (10 mL) at
0 °C, CuCl2·2H2O (0.41 g, 2.68 mmol) was added, and the mixture was
stirred at 0 °C for 15 min. Workup as described for 19 and purification
of the residue by silica gel column chromatography (EtOAc–PE, 3:7)
afforded 30 (0.65 g, 98% based on starting material recovery) as a col-
orless syrup.
HRMS: m/z [M + Na]+ calcd for C13H24O7: 315.14197; found:
315.14140.
[α]D25 +16.8 (c 1.30, CHCl3).
(1S,2S)-1-[(4R,4′R,5R)-2,2,2′,2′-Tetramethyl-4,4′-bi(1,3-dioxolan)-
5-yl]propane-1,2-diol (28)
IR (neat): 3745, 3702, 3642, 3561, 2987, 2924, 2854, 2312, 1765,
1727, 1710, 1693, 1663, 1610, 1551, 1533, 1500, 1381, 1219, 1168,
To a stirred solution of 27 (1.2 g, 4.11 mmol) in CH2Cl2 (10 mL) at 0 °C,
Et3N (0.72 mL, 5.14 mmol), n-Bu2SnO (0.03 g, 0.10 mmol) and then p-
TsCl (0.78 g, 4.11 mmol) were added, and the mixture was stirred at
r.t. for 1 h. Workup as described for 20 gave the tosylate 27a, which
was used in the next step without any further purification.
1064, 991, 931, 873, 772, 672 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.21–4.16 (dd, J = 6.5, 12.5 Hz, 1 H,
OCH), 4.10 (d, J = 5.5 Hz, 2 H, OCH2), 3.82 (d, J = 8.0 Hz, 1 H, OCH),
3.74–3.72 (m, 3 H, OCH), 2.77 (br s, 1 H, OH), 2.02 (br s, 1 H, OH),
1.43–1.41 (m, 12 H, 4 × Me), 1.32 (d, J = 6.5 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 109.6, 108.6, 81.0, 77.3, 77.2, 73.2, 72.8,
63.8, 27.4, 27.2, 26.7, 26.5, 17.8.
To a stirred suspension of LAH (0.16 g, 4.11 mmol) in THF (5 mL) at
0 °C, a solution of 27a (1.90 g, 4.24 mmol) in THF (5 mL) was added
dropwise under nitrogen atmosphere. The reaction mixture was
stirred at r.t. for 3 h, cooled to 0 °C, treated with sat. aq Na2SO4 solu-
tion (10 mL) and filtered. The aqueous layer was extracted EtOAc (50
mL) and dried (Na2SO4). The solvent was evaporated and the residue
was purified by silica gel column chromatography (EtOAc–PE, 3:7) to
furnish 28 (0.91 g, 80%) as a colorless oil.
HRMS: m/z [M + Na]+ calcd for C13H24O6: 299.14651; found:
299.14674.
(4S,4′S,5S,5′R)-2,2,2′,2′,5-Pentamethyl-5′-vinyl-4,4′-bi(1,3-dioxol-
ane) (7)
[α]D25 +14.7 (c 2.40, CHCl3).
To a stirred solution of 30 (0.62 g, 2.25 mmol), Ph3P (2.35 g, 8.99
mmol) and imidazole (0.60 g, 8.85 mmol) in CH2Cl2 (10 mL) at 0 °C, I2
(1.71 g, 6.74 mmol) was added, and the mixture was stirred at r.t. for
4 h. Workup as described for 4 and purification of the residue by silica
gel column chromatography (EtOAc–PE, 6:94) gave olefin 7 (0.40 g,
74%) as a pale yellow syrup.
IR (neat): 3745, 3460, 2987, 2925, 2854, 2313, 1727, 1678, 1629,
1551, 1455, 1374, 1216, 1155, 1066, 887, 846, 772, 663 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.18–4.12 (m, 2 H, 2 × OCH), 4.07 (m, 1
H, OCH), 4.00–3.94 (m, 1 H, OCH), 3.87 (m, 1 H, OCH), 3.60–3.54 (dd,
J = 5.3, 6.0 Hz, 2 H, OCH), 1.43 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.39 (s, 3
H, Me), 1.35 (s, 3 H, Me), 1.31 (d, J = 6.8 Hz, 3 H, Me).
[α]D25 –20.0 (c 0.30, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3005
R. Karnekanti et al.
Paper
Synthesis
IR (neat): 3020, 2925, 2854, 2314, 1728, 1678, 1646, 1610, 1568,
1551, 1450, 1216, 929, 722, 668, 626 cm–1
13C NMR (75 MHz, CDCl3): δ = 110.1, 109.1, 84.4, 80.8, 76.4, 68.5, 26.8,
26.7, 26.5, 25.1, 19.5.
.
1H NMR (300 MHz, CDCl3): δ = 5.84 (m, 1 H, olefinic), 5.44 (d, J = 16.6
Hz, 1 H, olefinic), 5.30 (d, J = 9.8 Hz, 1 H, olefinic), 4.45 (t, J = 8.3 Hz, 1
H, OCH), 4.34–4.05 (m, 3 H, 3 × OCH), 1.49–1.38 (m, 12 H, 4 × Me),
1.30 (d, J = 6.2 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 134.5, 120.0, 109.9, 108.8, 81.3, 77.5,
77.4, 73.4, 27.6, 27.4, 26.9, 26.7, 18.0.
HRMS: m/z [M + Na]+ calcd for C12H22O5: 269.1364; found: 269.1353.
tert-Butyldiphenyl{(1R)-1-[(4R,4′R,5S)-2,2,2′,2′-tetramethyl-4,4′-
bi(1,3-dioxolan)-5-yl]ethoxy}silane (33)
To a stirred solution of alcohol 32 (13.80 g, 56.09 mmol) in CH2Cl2 (68
mL), imidazole (11.44 g, 168.29 mmol), TBDPSCl (17.61 mL, 67.31
mmol) and DMAP (cat.) were added sequentially, and the mixture
was stirred at r.t. for 1 h. Then, it was treated with water (25 mL) and
extracted with CH2Cl2 (2 × 100 mL). The combined organic layers
were washed with brine (65 mL) and dried (Na2SO4). The solvent was
evaporated and the residue was purified by silica gel column chroma-
tography (EtOAc–PE, 5:95) to afford 33 (18.20 g, 66%) as a colorless
syrup.
HRMS: m/z [M + Na]+ calcd for C13H22O4: 265.15182; found:
265.15209.
(2S,3S,4S,5R)-Hept-6-ene-2,3,4,5-tetrayl Tetraacetate (5)
A solution of 7 (0.10 g, 0.41 mmol) in CH2Cl2 (1 mL) at 0 °C was treat-
ed with TFA (0.5 mL), and the mixture was stirred at r.t. for 15 min.
The solvent was evaporated and the crude tetrol 7a was used as such
for the next reaction.
[α]D25 +4.4 (c 0.10, CHCl3).
IR (neat): 2930, 2859, 1659, 1462, 1428, 1379, 1240, 1152, 1111,
A solution of the above tetrol 7a dissolved in pyridine (3 mL) was
cooled (0 °C) and treated with Ac2O (1 mL) and DMAP (cat.); the reac-
tion mixture was stirred at r.t. for 20 h. Then, it was quenched with
solid NaHCO3 (0.2 g), diluted with EtOAc (3 mL) and filtered through a
pad of Celite®. The solvent was evaporated and the residue was puri-
fied by silica gel column chromatography (EtOAc–PE, 1:9) to give
tetraacetate 5 (0.13 g, 90%) as a light yellow oil.
1057, 845, 739, 702 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.69 (m, 4 H, Ar-H), 7.36 (m, 6 H, Ar-
H), 4.06–3.92 (m, 3 H, 3 × OCH), 3.88–3.75 (m, 3 H, 3 × OCH), 1.32 (s, 6
H, 2 × Me), 1.24 (s, 6 H, 2 × Me), 1.06 (d, J = 6.04 Hz, 3 H, Me), 1.06 (s, 9
H, 3 × Me).
13C NMR (75 MHz, CDCl3): δ = 135.9, 134.4, 133.9, 129.6, 129.5, 127.5,
127.4, 109.5, 109.3, 84.4, 78.3, 76.9, 69.8, 66.8, 27.3, 27.2, 27.0, 26.4,
25.3, 19.3, 18.6.
[α]D25 +10.9 (c 0.16, CHCl3).
IR (neat): 2993, 2881, 2780, 1747, 1426, 1370, 1217, 1059, 1034, 949,
851, 771, 668 cm–1
.
HRMS: m/z [M + Na]+ calcd for C28H40O5Si: 507.2542; found:
507.2533.
1H NMR (300 MHz, CDCl3): δ = 5.80–5.69 (m, 1 H, olefinic), 5.34 (d, J =
2.3 Hz, 1 H, olefinic), 5.33 (d, J = 3.0 Hz, 1 H, olefinic), 5.28 (d, J = 2.3
Hz, 1 H, OCH), 5.16 (d, J = 6.0 Hz, 1 H, OCH), 5.09 (t, J = 5.3 Hz, 1 H,
OCH), 5.00 (t, J = 6.0 Hz, 1 H, OCH), 2.10 (s, 3 H, OAc), 2.09 (s, 3 H,
OAc), 2.08 (s, 3 H, OAc), 2.04 (s, 3 H, OAc), 1.20 (d, J = 6.0 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 170.0, 169.8, 169.5, 131.3, 119.8, 72.5,
72.03, 71.6, 71.0, 20.9, 20.8, 20.6, 16.3.
(R)-1-{(4R,5R)-5-[(R)-1-(tert-Butyldiphenylsilyloxy)ethyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}ethane-1,2-diol (34)
To a stirred solution of 33 (18.0 g, 37.11 mmol) in MeCN (360 mL) at
0 °C, CuCl2·2H2O (5.69 g, 33.40 mmol) was added, and the mixture
was stirred at 0 °C for 30 min. Workup as described for 19 and purifi-
cation of the residue by silica gel column chromatography (EtOAc–PE,
3:7) afforded 34 (9.0 g, 98% based on starting material recovery) as a
colorless syrup.
HRMS: m/z [M + Na]+ calcd for C15H22O8: 353.12069; found:
353.12072.
[α]D25 –14.6 (c 1.0, CHCl3).
(R)-1-[(4R,4′R,5R)-2,2,2′,2′-Tetramethyl-4,4′-bi(1,3-dioxolan)-5-
IR (neat): 3335, 3073, 2934, 2859, 1721, 1590, 1474, 1429, 1381,
1319, 1252, 1159, 1113, 1082, 1024, 949, 912, 872, 822, 743, 702,
yl]ethanol (32)
To a stirred solution of 17 (21.0 g, 80.15 mmol) in CH2Cl2 (210 mL) at
0 °C, Et3N (13.94 mL, 100.19 mmol), then n-Bu2SnO (0.50 g, 2.00
mmol) and p-TsCl (15.28 g, 80.15 mmol) were added. The reaction
mixture was stirred at r.t. for 1 h. Workup as described for 20 afforded
31, which was used as such for the next step.
612, 500 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.74–7.67 (m, 4 H, Ar-H), 7.43–7.35
(m, 6 H, Ar-H), 3.90–3.78 (m, 3 H, 3 × OCH), 3.71–3.43 (m, 3 H, 3 ×
OCH), 2.69 (d, J = 4.5 Hz, 1 H, OH), 1.95 (t, J = 5.3 Hz, 1 H, OH), 1.34 (s,
3 H, Me), 1.28 (s, 3 H, Me), 1.08 (d, J = 5.3 Hz, 3 H, Me), 1.05 (s, 9 H, 3 ×
Me).
13C NMR (75 MHz, CDCl3): δ = 135.9, 135.8, 133.7, 133.1, 129.9, 129.8,
127.7, 127.7, 109.6, 83.9, 79.5, 73.0, 71.6, 63.8, 27.1, 26.9, 19.9, 19.2.
To a stirred suspension of LAH (2.92 g, 76.92 mmol) in THF (50 mL) at
0 °C, a solution of 31 (32.0 g, 76.92 mmol) in THF (100 mL) was added
dropwise under nitrogen atmosphere, and the mixture was stirred at
r.t. for 3 h. Workup as described for 28 and purification of the residue
by silica gel column chromatography (EtOAc–PE, 2:8) furnished 32
(13.9 g, 74%) as a light yellow syrup.
HRMS: m/z [M + Na]+ calcd for C25H36O5Si: 467.2229; found:
467.2233.
[α]D25 +6.4 (c 0.20, CHCl3).
tert-Butyl{(1R)-1-[(4S,5R)-2,2-dimethyl-5-{(R)-oxiran-2-yl}-1,3-
dioxolan-4-yl]ethoxy}diphenylsilane (35)
IR (neat): 3470, 3434, 2990, 2936, 2890, 1597, 1460, 1373, 1306,
1252, 1217, 1179, 1069, 938, 841, 710, 667, 554, 513, 490 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.15 (q, J = 5.7 Hz, 1 H, OCH), 4.05–4.00
(m, 2 H, OCH), 3.71 (m, 1 H, OCH), 3.67–3.57 (m, 2 H, OCH), 2.47 (br s,
1 H, OH), 1.44 (s, 3 H, Me), 1.35 (s, 6 H, 2 × Me), 1.34 (s, 3 H, Me), 1.24
(d, J = 6.0 Hz, 3 H, Me).
To a stirred solution of 34 (1.10 g, 2.46 mmol) in CH2Cl2 (10 mL) at
0 °C, Et3N (0.39 mL, 2.81 mmol), then n-Bu2SnO (cat.) and p-TsCl (0.43
g, 2.25 mmol) were added, and the mixture was stirred at r.t. for 30
min. Workup as described for 20 afforded 34a, which was used as
such for the next reaction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3006
R. Karnekanti et al.
Paper
Synthesis
To a stirred solution of 34a (1.35 g, 2.24 mmol) in MeOH (4 mL) at
0 °C, K2CO3 (0.93 g, 6.74 mmol) was added, and the mixture was
stirred at r.t. for 1 h. Workup as described for 22 and purification of
the residue by silica gel column chromatography (EtOAc–PE, 15:85)
afforded 35 (0.86 g, 89%) as a colorless syrup.
1H NMR (300 MHz, CDCl3): δ = 5.71 (m, 1 H, olefinic), 5.40–5.17 (m, 5
H, 2 × olefinic, 3 × OCH), 4.94 (m, 1 H, OCH), 2.09 (s, 3 H, OAc), 2.04 (s,
6 H, 2 × OAc), 2.01 (s, 3 H, OAc), 1.18 (d, J = 6.0 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 170.0, 169.8, 169.6, 132.3, 120.8, 71.7,
71.1, 69.8, 67.0, 29.7, 21.0, 20.7, 16.3.
[α]D25 +18.0 (c 0.20, CHCl3).
HRMS: m/z [M + Na]+ calcd for C15H22O8: 353.12069; found:
IR (neat): 3073, 3052, 2984, 2934, 2894, 2859, 1809, 1760, 1588,
1474, 1428, 1374, 1308, 1256, 1213, 1159, 1113, 1069, 868, 822, 741,
353.12072.
704 cm–1
.
(2S,3S,4S,5R,E)-7-[(R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]hept-6-
1H NMR (300 MHz, CDCl3): δ = 7.68 (m, 4 H, Ar-H), 7.44–7.31 (m, 6 H,
Ar-H), 3.98–3.87 (m, 2 H, 2 × OCH), 3.76 (m, 1 H, OCH), 2.97 (m, 1 H,
epoxide), 2.75 (t, J = 5.3 Hz, 1 H, epoxide), 2.68 (dd, J = 2.6, 5.3 Hz, 1 H,
epoxide), 1.36 (s, 3 H, Me), 1.33 (s, 3 H, Me), 1.05 (s, 9 H, 3 × Me), 1.04
(d, J = 5.3 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 135.9, 129.7, 129.6, 127.6, 127.5, 109.6,
85.1, 82.7, 69.9, 52.3, 44.8, 27.4, 27.0, 19.9, 19.3.
ene-2,3,4,5-tetrayl Tetraacetate [(+)-Anamarine, 1]
To a solution of 4 (0.04 g, 0.36 mmol) and 5 (0.03 g, 0.09 mmol) in
CH2Cl2 (2 mL) under nitrogen atmosphere, Grubbs II catalyst (0.01 g,
0.01 mmol) was added, and the mixture was stirred at reflux for 5 h.
Workup as described for 14 and purification of the residue by silica
gel column chromatography (EtOAc–PE, 1:3) afforded 1 (0.03 g, 68%)
as a white solid; mp 109–111 °C (Lit.9 109–111 °C).
[α]D25 +16.8 (c 0.3, CHCl3) {Lit.9 [a]D25 +17.8 (c 0.3, CHCl3)}.
HRMS: m/z [M + Na]+ calcd for C25H34O4Si: 449.2124; found:
449.2107.
IR (neat): 3870, 3761, 3642, 3610, 3023, 2923, 2853, 2314, 1743,
1711, 1694, 1663, 1645, 1551, 1533, 1483, 1451, 1415, 1373, 1218,
1028, 929, 772, 668 cm–1
.
(R)-1-{(4R,5S)-5-[(R)-1-(tert-Butyldiphenylsilyloxy)ethyl]-2,2-di-
1H NMR (300 MHz, CDCl3): δ = 6.88 (ddd, J = 3.5, 5.2, 9.9 Hz, 1 H, ole-
finic), 6.06 (ddd, J = 1.7, 1.7, 9.9 Hz, 1 H, olefinic), 5.88–5.74 (m, 2 H,
olefinic), 5.36 (dd, J = 5.2, 7.2 Hz, 1 H, OCH), 5.30 (dd, J = 3.5, 7.2 Hz, 1
H, OCH), 5.17 (dd, J = 3.5, 7.0 Hz, 1 H, OCH), 4.96 (m, 1 H, OCH), 4.90
(dq, J = 6.4, 6.4 Hz, 1 H, OCH), 2.45 (m, 2 H, allylic), 2.11 (s, 3 H, OAc),
2.07 (s, 3 H, OAc), 2.06 (s, 3 H, OAc), 2.03 (s, 3 H, OAc), 1.17 (d, J = 6.4
Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): δ = 170.0, 169.9, 169.7, 169.5, 163.4, 144.5,
133.0, 125.6, 121.5, 75.9, 71.9, 71.5, 70.4, 67.5, 29.5, 21.0, 20.9, 20.8,
20.7, 15.9.
methyl-1,3-dioxolan-4-yl}prop-2-en-1-ol (10)
To a stirred solution of TMSI (0.48 g, 2.34 mmol) in THF (5 mL) at
–20 °C, 2.5 M n-BuLi in hexane (1.36 mL, 3.39 mmol) was added, and
the mixture was stirred for 30 min. A solution of 35 (0.25 g, 0.58
mmol) in THF (3 mL) was added and stirring was continued for 30
min at –20 °C. Workup as described for 23 and purification of the res-
idue by silica gel column chromatography (EtOAc–PE, 1:9) afforded 10
(0.18 g, 70%) as a colorless syrup.
[α]D25 +27.0 (c 0.10, CHCl3).
IR (neat): 3464, 3075, 2932, 2859, 1468, 1428, 1379, 1242, 1165,
1108, 822, 741, 704, 436 cm–1
.
HRMS: m/z [M + Na]+ calcd for C20H26O10
: 449.14198; found:
449.14240.
1H NMR (300 MHz, CDCl3): δ = 7.75–7.65 (m, 4 H, Ar-H), 7.45–7.33
(m, 6 H, Ar-H), 5.81 (m, 1 H, olefinic), 5.26 (d, J = 17.0 Hz, 1 H, olefin-
ic), 5.14 (d, J = 10.6 Hz, 1 H, olefinic), 4.07 (q, J = 4.5 Hz, 1 H, OCH),
3.90–3.78 (m, 3 H, 3 × OCH), 1.35 (s, 3 H, Me), 1.29 (s, 3 H, Me), 1.07
(d, J = 5.3 Hz, 3 H, Me), 1.06 (s, 9 H, 3 × Me).
(S)-6-[(R,E)-3-{(4R,5S)-5-[(R)-1-(tert-Butyldiphenylsilyloxy)ethyl]-
2,2-dimethyl-1,3-dioxolan-4-yl}-3-hydroxyprop-1-enyl]-5,6-dihy-
dro-2H-pyran-2-one (8)
13C NMR (75 MHz, CDCl3): δ = 136.5, 135.9, 134.1, 133.4, 129.9, 129.7,
127.7, 127.6, 117.4, 109.5, 82.6, 81.4, 73.9, 71.3, 27.2, 27.1, 27.0, 19.8,
19.3.
HRMS: m/z [M + Na]+ calcd for C26H36O4Si: 463.2280; found:
463.2273.
To a mixture of olefins 9 (0.08 g, 0.64 mmol) and 10 (0.14 g, 0.32
mmol) in toluene (1 mL) under nitrogen atmosphere, Grubbs II cata-
lyst (0.01 g, 0.01 mmol) was added, and the mixture was stirred at re-
flux for 8 h. Workup as described for 14 and purification of the resi-
due by silica gel column chromatography (EtOAc–PE, 35:65) afforded
8 (0.14 g, 82%) as a light yellow syrup.
[α]D25 –68.0 (c 0.20, CHCl3).
(2R,3R,4R,5R)-Hept-6-ene-2,3,4,5-tetrayl Tetraacetate (36)
IR (neat): 3020, 2314, 1765, 1728, 1694, 1645, 1569, 1551, 1516,
A solution of 10 (0.10 g, 0.22 mmol) in CH2Cl2 (1 mL) at 0 °C was treat-
ed with TFA (0.5 mL), and the mixture was stirred at r.t. for 15 min.
Workup as described for 7a gave tetrol 10a, which was used as such
for the next reaction.
1500, 1467, 1449, 1430, 1216, 929, 743, 668, 626 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.73 (dd, J = 7.3, 20.1 Hz, 4 H, Ar-H),
7.49–7.37 (m, 6 H, Ar-H), 6.87 (m, 1 H, olefinic), 6.05 (d, J = 9.8 Hz, 1
H, olefinic), 5.99 (dd, J = 4.9, 15.6 Hz, 1 H, olefinic), 5.91 (dd, J = 5.4,
15.6 Hz, 1 H, olefinic), 4.94 (q, J = 5.9 Hz, 1 H, OCH), 4.15 (m, 1 H,
OCH), 3.94–3.80 (m, 3 H, OCH), 2.5 (br s, 1 H, OH), 2.4 (m, 2 H, allylic),
1.37 (s, 3 H, Me), 1.30 (s, 3 H, Me), 1.09 (d, J = 5.8 Hz, 3 H, Me), 1.07 (s,
9 H, 3 × Me).
13C NMR (125 MHz, CDCl3): δ = 163.8, 144.5, 135.9, 133.9, 133.2,
132.6, 130.0, 129.8, 128.8, 127.8, 127.6, 121.6, 109.7, 83.1, 81.5, 77.2,
72.5, 71.6, 29.7, 29.6, 27.1, 27.0, 20.1, 19.2.
The above tetrol 10a dissolved in pyridine (3 mL) was cooled to 0 °C
and treated with Ac2O (1 mL) and DMAP (cat.); the mixture was
stirred at r.t. for 20 h. Workup as described for 5 and purification of
the residue by silica gel column chromatography (EtOAc–PE, 1:9) gave
tetraacetate 36 (0.61 g, 82%) as a light yellow oil.
[α]D25 +22.0 (c 1.70, CHCl3).
IR (neat): 2924, 2853, 2813, 2314, 1747, 1646, 1586, 1551, 1512,
1483, 1450, 1371, 1218, 1059, 1034, 989, 948, 772, 668 cm–1
.
HRMS: m/z [M + Na]+ calcd for C31H40O6Si: 559.2486; found:
559.2487.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3007
R. Karnekanti et al.
Paper
Synthesis
(2R,3R,4R,5R,E)-7-[(S)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]hept-6-
ene-2,3,4,5-tetrayl Tetraacetate [8-epi-(–)-Anamarine, 3]
(c) Hagen, S. E.; Vara-Prasad, J. V. N.; Tait, B. D. Adv. Med. Chem.
2000, 5, 159. (d) Aristoff, P. A. Drugs Future 1998, 23, 995.
(e) Romines, K. R.; Chrusciel, R. A. Curr. Med. Chem. 1995, 2, 825.
(f) Chan, K. M.; Rajab, N. F.; Ishak, M. H. A.; Ali, A. M.; Yusoff, K.;
Din, L. B.; Inayat-Hussain, S. H. Chem.-Biol. Interact. 2006, 159,
129. (g) Inayat-Hussain, S. H.; Annuar, B. O.; Din, L. B.; Ali, A. M.;
Ross, D. Toxicol. in Vitro 2003, 17, 433. (h) Inayat-Hussain, S. H.;
Annuar, B. O.; Din, L. B.; Taniguchi, N. Toxicol. Lett. 2002, 131,
153. (i) Veena, B.; Sharma, G. V. M. Synlett 2014, 25, 1283.
(4) Marco, J. A.; Carda, M. Recent Advances in the Field of Naturally
Occurring 5,6-Dihydropyran-2-ones, In Natural Lactones and
Lactams, Synthesis, Occurrence and Biological Activity; Janecki,
T., Ed.; Wiley-VCH: Weinheim, 2013, 51–100.
A solution of 8 (0.05 g, 0.09 mmol) in CH2Cl2 (1 mL) at 0 °C was treat-
ed with TFA (0.3 mL), and the mixture was stirred at r.t. for 15 min.
Evaporation of the solvent gave tetrol 8a, which was used as such for
the next reaction.
To a solution of the above tetrol 8a in pyridine (2 mL) at 0 °C, Ac2O
(0.5 mL) and DMAP (cat.) were added, and the mixture was stirred at
r.t. for 20 h. Workup as described for 5 and purification of the residue
by silica gel column chromatography (EtOAc–PE, 3:7) gave tetraace-
tate 3 (0.03 g, 84%) as a gummy liquid.
[α]D25 –9.0 (c 1.12, CHCl3).
(5) Alemany, A.; Márquez, C.; Pascual, C.; Valverde, S.; Martínez-
Ripoll, M.; Fayos, J.; Perales, A. Tetrahedron Lett. 1979, 3583.
(6) (a) Lorenz, K.; Lichtenthaler, F. W. Tetrahedron Lett. 1987, 28,
6437. (b) Diaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco,
J. A. Tetrahedron 2004, 60, 2979.
(7) Gao, D.; Doherty, G. A. O. J. Org. Chem. 2005, 70, 9932.
(8) Sabitha, G.; Reddy, C. N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett.
2010, 51, 5736.
(9) Kumar, K. S.; Reddy, C. S. Org. Biomol. Chem. 2012, 10, 2647.
(10) (a) Prasad, K. R.; Kumar, S. M. Tetrahedron 2014, 70, 4552.
(b) Reddy, B. V. S.; Reddy, V. V.; Praneeth, K. Tetrahedron Lett.
2014, 55, 1398.
(11) (a) Sharma, G. V. M.; Mallesham, S.; Chandramouli, C. Tetrahe-
dron: Asymmetry 2009, 20, 2513. (b) Mallesham, S.; Sharma, G.
V. M. Tetrahedron: Asymmetry 2010, 21, 2646. (c) Sharma, G. V.
M.; Chary, D. H.; Chandramouli, N.; Achrainer, F.; Patrudu, S.;
Zipse, H. Org. Biomol. Chem. 2011, 9, 4079. (d) Sharma, G. V. M.;
Sai Reddy, P. Eur. J. Org. Chem. 2012, 2414. (e) Sharma, G. V. M.;
Reddy, S. V.; Ramakrishna, K. V. S. Org. Biomol. Chem. 2012, 10,
3689. (f) Rajesh, A.; Sharma, G. V. M.; Damera, K. Tetrahedron
Lett. 2014, 55, 4067. (g) Rajesh, A.; Sharma, G. V. M.; Damera, K.
Tetrahedron Lett. 2014, 55, 6474. (h) Veena, B.; Sharma, G. V. M.
Synlett 2014, 25, 2039. (i) Sharma, G. V. M.; Doddi, V. R. Macro-
lactones, In Natural Lactones and Lactams: Synthesis, Occurrence
and Biological Activity; Janecki, T., Ed.; Wiley-VCH: Weinheim,
2013, 229–272.
IR (neat): 2924, 2853, 2313, 1744, 1679, 1646, 1630, 1552, 1500,
1450, 1372, 1220, 1031, 772, 686 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.90 (ddd, J = 3.1, 5.1, 9.4 Hz, 1 H, ole-
finic), 6.06 (td, J = 1.9, 9.8 Hz, 1 H, olefinic), 5.95 (dd, J = 5.2, 15.7 Hz, 1
H, olefinic), 5.75 (dd, J = 8.4, 15.9 Hz, 1 H, olefinic), 5.33 (m, 1 H, OCH),
5.30–5.23 (m, 2 H, 2 × OCH), 4.99–4.91 (m, 2 H, 2 × OCH), 2.49–2.35
(m, 2 H, allylic), 2.12 (s, 3 H, OAc), 2.07 (s, 3 H, OAc), 2.06 (s, 3 H, OAc),
2.03 (s, 3 H, OAc), 1.21 (d, J = 6.5 Hz, 3 H, Me).
13C NMR (125 MHz, CDCl3): δ = 170.2, 170.1, 169.9, 169.6, 163.6,
144.5, 133.0, 127.1, 121.5, 76.2, 70.7, 70.4, 69.6, 66.8, 29.4, 22.7, 21.1,
21.0, 20.8, 16.2.
HRMS: m/z [M + Na]+ calcd for C20H26O10
:
449.14182; found:
449.14196.
(2R,3R,4R,5R,E)-7-[(S)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]hept-6-
ene-2,3,4,5-tetrayl Tetraacetate [8-epi-(–)-Anamarine, 3]
To a stirred solution of olefins 36 (0.15 g, 0.48 mmol) and 9 (0.12 g,
0.96 mmol) in CH2Cl2 (2 mL) under nitrogen atmosphere, Grubbs II
catalyst (0.01 g, 0.01 mmol) was added, and the mixture was heated
at reflux for 5 h. Workup as described for 14 and purification of the
residue by silica gel column chromatography (EtOAc–PE, 1:3) afforded
3 (0.16 g, 84%), whose spectroscopic data were comparable with 3
synthesized from 8.
(12) (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60,
585. (b) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104.
(13) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Ahn, C.; Correia, R.;
Deshong, P. J. Org. Chem. 2002, 67, 1751. (c) Swamy, K. C. K.;
Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev.
2009, 109, 2551.
Acknowledgment
All the authors thank the UGC and CSIR, New Delhi, India for financial
support.
(14) (a) Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942.
(b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(c) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110,
1746.
(15) Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tet-
rahedron Lett. 1998, 39, 3091.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380864.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(16) (a) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 813. (b) Garegg,
P. J. Pure Appl. Chem. 1984, 56, 845.
References
(1) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007,
63, 2929.
(17) Ramesh, P.; Meshram, H. M. Tetrahedron Lett. 2012, 53, 4008.
(18) Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 5232.
(19) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, P. Org. Lett. 1999, 1, 447.
(20) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.;
Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
(21) Regeling, H.; Chitenden, G. J. F. Carbohydr. Res. 1989, 190, 313.
(22) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7568.
(2) Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.; Amagai, A.;
Kubohara, Y.; Ohsima, Y. Bioorg. Med. Chem. 2004, 12, 3203.
(3) (a) Agrawal, V. K.; Singh, J.; Mishra, K. C.; Khadikar, P. V.;
Jaliwala, Y. A. ARKIVOC 2006, (ii), 162. (b) Hagen, S. E.;
Domagala, J. M.; Gajda, C.; Lovdahl, M.; Tait, B. D.; Wise, E.;
Holler, T.; Hupe, D.; Nouhan, C.; Urumov, A.; Zeikus, G.; Zeikus,
E.; Lunney, E. A.; Pavlovsky, A.; Gracheck, S. J.; Saunders, J. M.;
VanderRoest, S.; Brodfuehrer, J. J. Med. Chem. 2001, 44, 2319.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008

3008
R. Karnekanti et al.
Paper
Synthesis
(23) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(e) Nolen, E. G.; Kurish, A. J.; Wong, K. A.; Orlando, M. D. Tetra-
hedron Lett. 2003, 44, 2449. (f) Grubbs, R. H. Tetrahedron 2004,
60, 7117.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2997–3008