The first total synthesis of pectinolides D and e and total synthesis of pectinolides A and C

Article abstract of DOI:10.1055/s-0034-1378912

The first total synthesis of pectinolides D and E and total synthesis of pectinolides A and C was achieved from a hitherto unknown common key building block prepared from readily available d-mannitol. Key reactions involved in the synthesis are Red-Al reduction of an epoxy alcohol, enantioselective Noyori reduction of ynones, aldehyde-alkyne coupling, and Still-Genari cis-olefination.

Full text of DOI:10.1055/s-0034-1378912

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, 330–342
paper
330
G. Sabitha et al.
Paper
Synthesis
The First Total Synthesis of Pectinolides D and E and Total Synthesis
of Pectinolides A and C
Gowravaram Sabitha*
Praveen AnkiReddy
Sukant Kishore Das
D-mannitol
OBn
O
O
O
O
H
OTBS
Natural Products Chemistry Division, CSIR-Indian Institute of
O
O
H
OAc
OR OAc
OPMB
Chemical Technology, Hyderabad – 500 007, India
+
9
1
4
(
0
2
)
7
1
6
0
5
1
2
gowravaramsr@yahoo.com
sabitha@iict.res.in
OBn
OR
OR
key building block
OAc
R = H, pectinolide D
R = Ac, pectinolide A
R = H, pectinolide C
R = Ac, pectinolide E
Received: 06.06.2014
Accepted after revision: 06.10.2014
Published online: 14.11.2014
have recently reported the first synthesis of pectinolide F.11
With our ongoing studies on the efficient synthesis of δ-lac-
tones,12 we became interested in the synthesis of pectino-
lides by developing a more general and flexible approach.
We herein report a general strategy for the syntheses of
pectinolides A (1), C (3), D (4), and E (5) by employing D-
mannitol, a cost-effective and readily available starting ma-
terial. In this present approach, we plan a gram-scale syn-
thesis of a new key building block 9.
DOI: 10.1055/s-0034-1378912; Art ID: ss-2014-n0354-op
Abstract The first total synthesis of pectinolides D and E and total syn-
thesis of pectinolides A and C was achieved from a hitherto unknown
common key building block prepared from readily available D-mannitol.
Key reactions involved in the synthesis are Red-Al reduction of an epoxy
alcohol, enantioselective Noyori reduction of ynones, aldehyde–alkyne
coupling, and Still–Genari cis-olefination.
Retrosynthetically (Scheme 1), pectinolides 1, 3, 4, and
5 could be easily accessible from their precursors 10 and 11
through one-pot di-TBS deprotection followed by Lindlar
reduction and acetate formation. Compounds 10 and 11 in
turn could be made from 12 and 13 by successive transfor-
mations such as terminal olefin cleavage and cis-Wittig ole-
fination. We envisioned that compounds 12 and 13 would
be accessible from a common intermediate 9 by coupling
with respective aldehydes 14 and 15, whereas intermediate
9 could be made in gram quantities from D-mannitol.
The synthesis of intermediate 9 commenced from
known propargylic alcohol13 16 obtained from D-mannitol
in five steps as reported (Scheme 2). Protection of the sec-
ondary hydroxy group as its tert-butyldimethylsilyl (TBS)
ether 17 followed by acetonide deprotection gave diol 18.
Selective protection of the primary hydroxy group in com-
pound 18 produced pivaloyl ester 19. The secondary hy-
droxy group in 19 was mesylated using methanesulfonyl
chloride and triethylamine to provide secondary mesylate,
which on treatment with anhydrous potassium carbonate
in anhydrous methanol afforded inverted epoxide 20. The
epoxide on treatment with butyllithium and trimethylsul-
fonium iodide14 in tetrahydrofuran at –20 °C furnished the
allylic alcohol 21 in 78% yield. The hydroxy group of the al-
lylic alcohol was protected as its benzyl ether by treatment
Key words pectinolides, first synthesis, aldehyde–alkyne coupling,
Noyori reduction, Still–Genari cis-olefination
Pereda-Miranda and co-workers reported the isolation
of three pyrones, designated as pectinolides A–C1 (1–3)
(Figure 1) and a γ-lactone, pectinolide H2 (8) in 1993 and
2005, respectively, from the leaves of Hyptis pectinata col-
lected in the southeastern region of Mexico. Other three py-
rones, pectinolides D–F (4–6) (Figure 1) and a furan-2(5H)-
one, pectinolide G (7) were isolated by Tinto and co-work-
ers3 from the same plant. The structures of these lactones
were elucidated using extensive spectroscopic analysis. Hy-
purticin, a natural pyrone, was isolated in 1991 from Hyptis
urticoides by the group of Romo de Vivar and its structure
was revised in 20094 and found to correspond to that of
pectinolide E (5) that had been recently isolated from Hyp-
tis pectinata.3 Formulations of the Hyptis pectinata plant are
used as a remedy in the treatment of fevers, skin diseases,
gastric disturbances,5 and lung congestion.6a In Tanzania the
leaves are used to treat roundworms and coughs.6b Biologi-
cal tests revealed that pectinolides A–C exhibit significant
cytotoxic activity (ED50 <4 μg/mL) against a variety of tu-
mor cell lines and also show antimicrobial properties.6c
Only two synthetic studies, including our own, have
been published on pectinolide A7,8 and H9,10 despite their
appealing structures and promising biological activity. We
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G. Sabitha et al.
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Synthesis
O
O
O
OAc
O
OH
O
OAc
O
OH
O
OAc
O
OAc
O
pectinolide B (2)
pectinolide C (3)
pectinolide A (1)
OAc
OAc
OAc
O
OAc
O
OH
OAc
O
OMe
OAc
OAc
OAc
OAc
OAc
OAc
OH
pectinolide D (4)
pectinolide E (5)
pectinolide F (6)
OAc
OAc
OH
O
O
O
O
OAc
pectinolide G (7)
pectinolide H (8)
Figure 1 Natural pectinolides A–H
ethyl (S)-lactate
OH
OBn OH
OBn
OBn
O
OBn
O
OPMB
12
H
H
13
OTBS
OTBS
14
OPMB
15
OTBS
OBn
OTBS
OBn OTBS
OBn
OBn
key building block 9
OAc
ene-yne diol
11
10
TBSO
MeO
TBSO
MeO
O
O
O
O
D-mannitol
O
O
OR OAc
OAc
OR
OR
OAc
R = Ac, pectinolide A (1)
R = H, pectinolide C (3)
R = H, pectinolide D (4)
R = Ac, pectinolide E (5)
Scheme 1 Retrosynthetic analysis
with benzyl bromide in sodium hydride in tetrahydrofuran
to give the protected key building block, ene-yne diol 9 in
90% yield.
Alternatively, the key building block 9 can be synthe-
sized by a short route from a known enantiomerically pure
aldehyde 22, which was prepared in seven steps from D-
mannitol according to the reported procedure8b (Scheme 3).
This enantiomerically pure aldehyde 22 was subsequently
reacted with in situ metalated (trimethylsilyl)acetylene
(obtained by treating with EtMgBr) in the presence of mag-
nesium bromide–diethyl ether at –78 °C. This reaction pro-
ceeded with good stereoselectivity and afforded the
corresponding propargylic alcohol 23 in 75% yield as a mix-
ture of diastereomers (d.r. 88:12) favoring the syn isomer.
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G. Sabitha et al.
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Synthesis
PivCl, Et3N
DMAP
CH2Cl2, 0 °C
OR
OTBS
OH
CuCl2•2H2O
MeCN, 0 °C
ref. 13
OH
O
D-mannitol
87%
O
83%
18
TBSCl
imidazole
CH2Cl2, 0 °C
92%
16; R = H
17; R = TBS
OTBS
OTBS
Me3SI, n-BuLi
THF, –20 °C to r.t., 78%
OTBS
1. MsCl, Et3N
CH2Cl2, 0 °C
OPiv
O
2. K2CO3, MeOH
r.t., 78% (2 steps)
OH
OH
21
20
19
NaH
TBAI (cat.), THF
OTBS
BnBr, 0 °C to r.t.
90%
OBn
9
Scheme 2 Synthesis of key building block 9
The diastereomeric mixture of the product was determined
by HPLC analysis.15 Formation of the major diastereomeric
alcohol can be explained on the basis of chelation-con-
trolled (Cram-chelation model) addition of Grignard nucle-
ophile to the aldehyde. The syn-disposition of the protected
carbinols in 9 was unambiguously established by compar-
ing its data with the sample prepared from D-mannitol. Fi-
nally, silyl protection and removal of TMS group afforded 9
in 88% yield. The diastereomers 23 were separated after
protection of the hydroxy functionality as the TBS ether.
Synthesis of coupling partner 15 (Scheme 4) started
from a known epoxy alcohol 24, which was prepared from
ethyl (S)-lactate as previously reported.12a Subsequent pro-
tection of the primary alcohol in 1,3-diol 25 as the TBS
ether and the secondary hydroxy group as the benzyl ether
furnished compound 26. Next, deprotection of the primary
silyl ether resulted in free alcohol 27. Subsequent oxidation
of alcohol furnished the required aldehyde fragment 15 in
85% yield.
To complete the synthesis of target molecules 4 and 5,
the reaction between 9 and 15 was performed using butyl-
lithium, but this reagent was ineffective in realizing the ex-
pected product. However, generation of the anion of alkyne
9 using ethylmagnesium bromide and quenching with alde-
hyde at room temperature afforded compound 28 as an in-
separable mixture of diastereomers (Scheme 5). Oxidation
of 28 with Dess–Martin periodinane resulted in keto deriv-
ative 29 in 85% yield for two steps. The ketone functionality
OH
TMS
1.TBSCl, imidazole
CH2Cl2, 0 °C, 90%
OTBS
OHC
EtMgBr, THF
ref. 8b
D-mannitol
OBn
TMS
OBn
2. K2CO3, MeOH
r.t., 88%
MgBr2•Et2O
–78 °C
OBn
22
23
9
75%
Scheme 3 Alternate synthesis of 9
1. TBSCl, imidazole
CH2Cl2, 0 °C
85%
O
OH
O
ref. 12a
Red-Al
OEt
OH
OH
OH
THF, r.t., 90%
2. BnBr, NaH
TBAI (cat.)
THF, 0 °C to r.t., 87%
OPMB
OPMB
ethyl (S)-lactate
24
25
OBn
OBn
OBn
IBX, MeCN
heat, 85%
TBAF, THF
0 °C, 90%
CHO
OTBS
OH
OPMB
OPMB
OPMB
26
27
15
Scheme 4 Synthesis of aldehyde 15
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 330–342

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G. Sabitha et al.
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Synthesis
OBn
OH
OBn
O
DMP, CH2Cl2
NaHCO3, 0 °C
OTBS
EtMgBr
THF, r.t.
OBn
+
H
85% (2 steps)
OPMB
OPMB
OBn
OTBS
15
9
28
OBn
O
TBSCl
OBn OH
imidazole
CH2Cl2, 0 °C
OBn
OBn
Noyori reduction
OPMB
92%
OPMB
90%
95:5 dr
13
OTBS
OTBS
29
OBn OTBS
OBn OTBS
1. DDQ, CH2Cl2/H2O
9:1, 0 °C to r.t., 88%
OBn
1. OsO4
2. NaIO4
OBn
OPMB
2. Ac2O, Et3N
DMAP (cat.)
CH2Cl2, 0 °C, 92%
OAc
3. cis-Wittig
THF, –78 °C
68% (2 steps)
30
OTBS
31
OTBS
OBn OTBS
OBn OH
Ac2O, Et3N
DMAP (cat.)
CH2Cl2, 0 °C
OBn
O
OBn
O
PTSA, CH2Cl2
r.t., 85%
OAc
OAc
90%
TBSO
MeO
O
32
11
OBn OAc
O
OBn
TiCl4, CH2Cl2
0 °C, 90%
Lindlar
reduction
O
OBn OAc
OAc
O
33
15 min, 82%
OBn
O
OAc
O
34
O
Ac2O, Et3N
DMAP (cat.)
CH2Cl2, 0 °C
Ts
Ph
Ph
N
O
O
OAc OAc
OH OAc
Ru
N
90%
H
OAc
OH
OAc
OAc
(S,S)-Noyori catalyst
pectinolide D (4)
Scheme 5 Synthesis of pectinolides D (4) and E (5)
pectinolide E (5)
was reduced with Noyori’s catalyst affording 13 in 90%
yield. The diastereomeric excess was determined to be 95%
by HPLC analysis.16 The secondary alcohol was silylated us-
ing tert-butylchlorodimethylsilane and imidazole to give
disilyl ether 30 followed by deprotection of the 4-methoxy-
benzyl (PMB) group and acetylation to give acetate 31. We
then focused on assembling the pyranone ring, keeping in
mind the results obtained in our previous report.12a The ox-
idative cleavage of olefin functionality in 31 was realized
with osmium tetroxide and N-methylmorpholine N-oxide
followed by sodium periodate to give the correct aldehyde
for cis-Wittig olefination. The aldehyde was subjected to
modified Still–Gennari olefination with bis(2,2,2-trifluoro-
ethyl) (methoxycarbonyl)methylphosphonate in tetrahy-
drofuran to furnish cis-olefinic ester 11. Treatment of 11
with catalytic 4-toluenesulfonic acid in dichloromethane at
room temperature resulting in a one-pot reaction via a
two-step sequence (di-TBS deprotection and lactonization)
to afford the lactone 32 (85%). The free alcohol was acetyl-
ated to produce 33 followed by partial reduction of the tri-
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G. Sabitha et al.
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Synthesis
ple bond to the Z-olefin with Lindlar catalyst resulting in 34
in 82% yield. Deprotection of benzyl groups was smoothly
achieved using titanium(IV) chloride to provide the target
lactone pectinolide D (4) in 90% yield, the spectral data of
which are identical with those reported in the literature.3
Whereas, acetylation of the free hydroxy groups produced
another target lactone, pectinolide E (5) in 90% yield. The
spectral data are in complete agreement with those report-
ed in the literature.4
After successful utilization of the intermediate 9 in the
total syntheses of pectinolides D and E, the key propargylic
compound 9 was further utilized for the synthesis of
pectinolides A and C (1 and 3), (Scheme 6), by utilizing pen-
tanal (14) as the coupling partner, following the same se-
quence of reactions as depicted in Scheme 5.
butyllithium and quenched with pentanal (14) furnished
35 in 85% yield. The remaining steps were similar to those
in Scheme 5 affording pectinolide C (3) and pectinolide A
(1). Spectroscopic data of synthetic 1 and 3 (1H and 13C
NMR spectra, HRMS) were fully consistent with the corre-
sponding data for the natural product1 and with the au-
thentic samples.8
In summary, we have demonstrated the accomplish-
ment of the first total synthesis of pectinolides D and E and
total synthesis of pectinolides A and C from a common key
building block 9. This flexible approach should enable the
synthesis of diverse pectinolides and their derivatives,
thereby facilitating the biological study of these promising
natural products. We are currently studying the divergent
and asymmetric synthesis of pectinolide analogues allow-
ing the key building block to serve as an intermediate from
which diverse members of this class of lactones can be pre-
pared.
However, in the first step, instead of anion generation
using Grignard reagent, butyllithium was used for anion
generation. Thus, alkyne intermediate 9 was treated with
OH
n-BuLi, THF
–78 °C
O
OTBS
OBn
+
H
85%
OBn
9
35
14
OTBS
O
Noyori
reduction
OH
IBX, CH2Cl2
DMSO, 0 °C
OBn
OBn
92%
80%
95:5 dr
36
12
OTBS
OTBS
OTBS
TBSCl
imidazole
OTBS
1. OsO4
2. NaIO4
OBn
OBn
CH2Cl2, 0 °C
90%
3. cis-Wittig
THF, –78 °C
67% (2 steps)
TBSO
MeO
37
10
OTBS
O
O
OH
O
PTSA, CH2Cl2
r.t., 86%
OR
Lindlar
reduction
OBn
O
85%
OBn
39, R = H
40, R = OAc
O
O
38
Ac2O, Et3N
DMAP (cat.)
CH2Cl2, 0 °C,
90%
O
Ac2O, Et3N
TiCl4, CH2Cl2
0 °C, 86%
DMAP (cat.)
CH2Cl2, 0 °C
O
O
OAc
OAc
90%
OAc
OH
pectinolide C (3)
Scheme 6 Synthesis of pectinolides A (1) and C (3)
pectinolide A (1)
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335
G. Sabitha et al.
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Synthesis
reaction was allowed to proceed for 4 h with gradual warming to r.t.
The mixture was diluted with CH2Cl2 and washed with sat. NaHCO3,
H2O, and brine. The organic layer was dried (anhyd Na2SO4) and con-
centrated in vacuo. The crude product was chromatographed (silica
gel (20% EtOAc–hexane) to give pure 19 (10.6 g, 83%) as a colorless liq-
uid; [α]D25 +33.0 (c 3.8, CHCl3).
All solvents and reagents were purified by standard techniques, reac-
tions were performed in oven-dried round-bottom flasks; crude
products were purified by column chromatography on silica gel (60–
120 mesh). TLC plates were visualized by exposure to UV light and/or
by exposure to methanolic acidic p-anisaldehyde solution on a hot
plate (~250 °C). Organic solutions were concentrated on a rotary
evaporator at 40–45 °C. IR spectra were recorded on Perkin-Elmer
683. 1H and 13C NMR spectra were recorded in CDCl3 on Varian Gemini
200, Bruker AV-300, and Varian Innova 500 NMR spectrometers. Opti-
cal rotations were measured on Perkin-Elmer-343. The diastereomer-
ic excess of the products was measured by HPLC using a Shimadzu LC-
20AT series with XDB C18, 150 × 4.6, 5U column. Mass spectra were
recorded on a Micro Mass VG-7070H mass spectrometer for ESI and
EI. HRMS (ESI) were obtained using either a TOF or a double focusing
spectrometer.
IR (KBr): 3310, 2958, 2932, 2859, 1735, 1255, 1162, 839 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.35 (dd, J = 5.0, 2.0 Hz, 1 H), 4.28–4.21
(m, 1 H), 4.17–4.09 (m, 1 H), 3.84–3.75 (m, 1 H), 2.41 (d, J = 2.0 Hz, 1
H), 1.15–1.12 (m, 9 H), 0.82 (s, 9 H), 0.07 (d, J = 9.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 178.6, 81.7, 74.6, 72.8, 64.3, 64.2, 27.1,
25.6, 18.0, –4. 6, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C16H31O4Na: 315.1986; found:
315.1987.
tert-Butyldimethyl{(S)-1-[(R)-2,2-dimethyl-1,3-dioxolan-4-
tert-Butyldimethyl{(S)-1-[(S)-oxiran-2-yl]prop-2-ynyloxy}silane
yl]prop-2-ynyloxy}silane (17)
(20)
To an ice-bath cooled solution of compound 16 (9.0 g, 57.6 mmol) and
imidazole (7.8 g, 115.2 mmol) in anhyd CH2Cl2 (80 mL) was added a
solution of TBSCl (9.58 g, 63.36 mmol) in anhyd CH2Cl2 (50 mL).The
mixture was stirred at 0 °C for 1 h, then diluted with H2O (50 mL) and
extracted with Et2O (5 × 30 mL). The combined organic phases were
washed with brine (30 mL), dried (anhyd Na2SO4), and concentrated.
The residue was purified by flash column chromatography (hexane–
EtOAc, 97:3) to give 17 (14.3, 92%) as a yellowish oil; Rf = 0.5 (hexane–
EtOAc, 9:1); [α]D25 +19.6 (c 2.5, CHCl3).
To a cooled (–80 °C) solution of 19 (10.4 g, 33.1 mmol) and Et3N (9.2
mL, 66.2 mmol) in anhyd CH2Cl2 (60 mL) was added MsCl (4.53 mL,
39.72 mmol) dropwise. The mixture was stirred for 15 min at this
temperature and kept in a freezer (–20 °C) overnight. The mixture
was diluted with more CH2Cl2 and washed with H2O and brine. The
CH2Cl2 layer was dried (anhyd Na2SO4) and concentrated on a rotary
evaporator. The crude yellow solid was dissolved in MeOH (60 mL)
and finely powdered K2CO3 (12.3 g, 31.3 mmol, 2.5 equiv based on
theoretical yield) was added, and the mixture was stirred vigorously
at r.t. for 2 h. MeOH was evaporated on a rotary evaporator. The resi-
due was taken up in H2O and extracted with Et2O, and the combined
organic layers were washed with brine, dried (anhyd Na2SO4), and
concentrated. The crude product was chromatographed (silica gel,
IR (KBr): 2956.1, 2933, 2859, 1255, 1076, 838 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.30 (dd, J = 6.1, 1.9 Hz, 1 H), 4.15–4.10
(m, 1 H), 4.07–4.02 (m, 1 H), 3.98–3.94 (m, 1 H), 2.43 (d, J = 2.1 Hz, 1
H), 1.42 (s, 3 H), 1.35 (s, 3 H), 0.89 (s, 9 H), 0.12 (s, 6 H).
25
10% EtOAc–hexane) to give 20 (5.45 g, 78%) as a colorless liquid; [α]D
+19.4 (c 1.0, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 109.9, 83.0, 78.6, 73.5, 65.9, 63.4, 26.6,
25.6, 25.3, 18.1, –4.5, –5.0.
HRMS (ESI): m/z [M + Na]+ calcd for C14H26O3NaSi: 293.1543; found:
293.1547.
IR (KBr): 2930, 2858, 1255, 1095, 839 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.22 (dd, J = 5.4, 2.0 Hz, 1 H), 3.21–3.15
(m, 1 H), 2.86–2.80 (m, 1 H), 2.78–2.74 (m, 1 H), 2.47 (d, J = 2.0 Hz, 1
H), 0.93 (s, 9 H), 0.15 (s, 6 H).
[(2R,3S)-3-(tert-Butyldimethylsiloxy)pent-4-yne-1,2-diol (18)
13C NMR (75 MHz, CDCl3): δ = 80.9, 73.8, 64.7, 54.6, 44.4, 25.6, 18.2,
To an ice-bath cooled solution of 17 (13 g, 48.0 mmol) in MeCN (60
mL) was added CuCl2·2 H2O (16.41 g, 96.28 mmol) as a solid. The mix-
ture was stirred at 0 °C for 1 h. The mixture was quenched with solid
NaHCO3 (20 g), and the resulting mixture was filtered. The filtrate was
concentrated under reduced pressure, and the crude product was pu-
rified by column chromatography (50% EtOAc–hexane) to afford diol
18 (9.6 g, 87%) as a colorless oil; [α]D25 +31.0 (c 0.37, CHCl3).
–4.8, –5.1.
HRMS (ESI): m/z [M + NH4]+ calcd for C11H24O2NSi: 230.1571; found:
230.1570.
(3S,4S)-4-(tert-Butyldimethylsiloxy)hex-1-en-5-yn-3-ol (21)
To a suspension of trimethylsulfonium iodide (28.86 g, 141.48 mmol)
in anhyd THF (150 mL) at –20 °C was added 2.5 M BuLi in hexane
(56.6 mL, 141.48 mmol) dropwise over 20 min and the mixture was
stirred for 30 min. Epoxide 20 (5.0 g, 24.0 mmol) in anhyd THF (25
mL) was added to this mixture, which was then slowly warmed to
0 °C over 1 h. The mixture was stirred at r.t. for 2 h and, after con-
sumption of the starting material, the reaction was quenched by the
addition of H2O (10 mL) and extracted with EtOAc (4 × 10 mL). The
combined extracts were washed with brine, dried (Na2SO4), and con-
centrated. Column chromatography of the crude product (PE–EtOAc,
IR (KBr): 3415, 2931, 1384, 1052, 772 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.47 (dd, J = 6.7, 2.0 Hz, 1 H), 3.90 (dd,
J = 11.5, 4.7 Hz, 1 H), 3.82–3.66 (m, 2 H), 2.88 (br s, 2 H), 2.5 (d, J = 2.0
Hz, 1 H), 0.89 (s, 9 H), 0.15 (d, J = 8.5 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 82.0, 74.98, 73.65, 65.5, 62.7, 25.5, 18.0,
–3.6, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C11H22O3NaSi: 253.1230; found:
293.1230.
25
70:30) gave 21 (4.1 g, 78%) as a colorless liquid; [α]D +20.2 (c 1.4,
CHCl3).
(2R,3S)-3-(tert-Butyldimethylsiloxy)-2-hydroxypent-4-ynyl Piva-
IR (KBr): 3433, 2954, 2926, 1455, 1224, 1105 cm–1
.
late (19)
To a solution of the diol 18 (9.4 g, 40.8 mmol) and DMAP (cat.) in an-
hyd CH2Cl2 (60 mL) was added Et3N (11.39 mL, 81.72 mmol) at 0 °C
under N2 atmosphere. This was followed by a dropwise addition of
pivaloyl chloride (5.58 mL, 44.94 mmol) with vigorous stirring. The
1H NMR (500 MHz, CDCl3): δ = 6.0–5.93 (m, 1 H), 5.39 (dt, J = 17.2, 1.5
Hz, 1 H), 5.28 (dt, J = 10.5, 1.4 Hz, 1 H), 4.35 (dd, J = 4.7, 2.1 Hz, 1 H),
4.16–4.12 (m, 1 H), 2.46 (d, J = 2.1 Hz, 1 H), 2.46–2.43 (br s, 1 H), 0.91
(s, 9 H), 0.17 (s, 3 H), 0.14 (s, 3 H).
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13C NMR (125 MHz, CDCl3): δ = 135.5, 117.6, 81.8, 75.4, 74.5, 66.6,
25.7, 18.1, –4.5, –4.1.
HRMS (ESI): m/z [M + NH4]+ calcd for C12H26O2NSi: 244.1727; found:
244.1733.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.30 (m, 5 H), 5.93–5.77 (m, 1 H),
5.50–5.34 (m, 2 H), 4.69 (d, J = 11.5 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1 H),
4.30 (d, J = 6.7 Hz, 1 H), 3.92–3.85 (m, 1 H), 0.17 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 136.8, 134.1, 128.4, 128.3, 127.9, 127.7,
127.6, 120.2, 103.1, 83.1, 82.1, 70.1, 65.6, –0.3.
HRMS (ESI): m/z [M + Na]+ calcd for C16H22O2NaSi: 297.1281; found:
[(3S,4S)-4-(Benzyloxy)hex-5-en-1-yn-3-yloxy]tert-butyldimethyl-
silane (9)
297.1281.
To a suspension of NaH (60%, 0.55 g, 23.1 mmol) in anhyd THF (10 mL)
was added dropwise a solution of alcohol 21 (3.5 g, 15.5 mmol) in
THF (25 mL) at 0 °C. To this mixture TBAI (cat.) and BnBr (2.02 mL,
16.94 mmol) were added sequentially and stirring was continued for
2 h at this temperature and 6 h at r.t. The mixture was quenched by
the addition of crushed ice flakes until a clear solution (biphasic)
formed. The mixture was extracted with EtOAc (2 × 60 mL). The or-
ganic extracts were washed with H2O (1 × 50 mL) and brine (1 × 50
mL) and dried (anhyd Na2SO4). Evaporation of the solvent followed by
column chromatography (hexane–EtOAc, 9:1) afforded the pure 9 (4.4
[(3S,4S)-4-(Benzyloxy)-1-(trimethylsilyl)hex-5-en-1-yn-3-
yloxy]tert-butyldimethylsilane (23a)
To an ice-bath cooled solution of compound 23 (4.8 g, 17.5 mmol) and
imidazole (2.38 g, 35.02 mmol) in anhyd CH2Cl2 (50 mL) was added a
solution of TBSCl (2.90 g, 19.26 mmol) in anhyd CH2Cl2 (15 mL). The
mixture was stirred at 0 °C for 1 h, then diluted with H2O (20 mL) and
extracted with Et2O (3 × 30 mL). The combined organic phases were
washed with brine (20 mL), dried (anhyd Na2SO4), and concentrated.
The residue was purified by flash column chromatography (hexane–
EtOAc, 97:3) to give 23a (5.6 g, 90%) as a yellowish oil; Rf = 0.5
(hexane–EtOAc, 9:1); [α]D25 +14.6 (c 2.23, CHCl3).
25
g, 90% yield) as a colorless liquid; Rf = 0.35 (hexane–EtOAc, 9:1); [α]D
+25.3 (c 1.62, CHCl3).
IR (KBr): 2954, 2931, 2858, 1466, 1254, 1105, 839 cm–1
.
IR (KBr): 2957.4, 2930.5, 2857.7, 1215.9, 1097.9, 842.3 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 6.07–6.0 (m, 1 H),
5.37 (dt, J = 17.2, 1.6 Hz, 1 H), 5.22 (dt, J = 10.5, 1.5 Hz, 1 H), 4.84 (d, J =
11.7 Hz, 1 H), 4.55 (dt, J = 11.9, 1.52 Hz, 1 H), 4.28–4.24 (m, 1 H), 3.98
(dd, J = 6.5, 2.1 Hz, 1 H), 2.47 (d, J = 2.1 Hz, 1 H), 0.90–0.87 (m, 9 H),
0.05–0.02 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 136.8, 128.2, 127.9, 127.6, 116.5, 80.3,
75.4, 74.9, 73.1, 70.8, 25.7, 18.2, –4.8.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.19 (m, 5 H), 5.94–5.81 (m, 1 H),
5.35–5.26 (m, 2 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H),
4.35 (d, J = 6.0 Hz, 1 H), 3.84–3.78 (m, 1 H), 0.94–0.85 (m, 9 H), 0.19–
0.06 (m, 15 H).
13C NMR (125 MHz, CDCl3): δ = 138.4, 134.5, 128.5, 127.7, 127.62,
127.33, 118.92, 104.64, 90.82, 82.96, 70.98, 66.82, 25.74, 18.29, –0.29,
–4.78, –4.86.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28O2NaSi: 339.1750; found:
339.1754.
HRMS (ESI): m/z [M + NH4]+ calcd for C22H40O2NSi2: 406.2592; found:
406.2598.
(S)-2-(Benzyloxy)but-3-enal (22)
[(3S,4S)-4-(Benzyloxy)hex-5-en-1-yn-3-yloxy]tert-butyldimethyl-
The diol8b (6.3 g, 28.8 mmol) was dissolved in 10% aq THF (60 mL) and
NaIO4 (9.7 g, 43.2 mmol) was added at 0 °C. After 30 min, H2O was
added and the aqueous layer was extracted with Et2O. The organic
layer was dried (anhyd Na2SO4) and solvent was removed under re-
duced pressure. The crude aldehyde 22 was used in the next step
without purification.
silane (9)
Compound 23a (5.5 g, 14.2 mmol) was dissolved in MeOH (55 mL),
and K2CO3 (2.7 g, 35.4 mmol) was added at r.t. After stirring for 2 h,
K2CO3 was filtered off and sat. NH4Cl was added to the mixture. After
evaporation of MeOH, the residue was extracted with EtOAc, dried
(Na2SO4), filtered, and concentrated in vacuo. Column chromatogra-
phy (hexane–EtOAc, 4:1 to 2:1) provided 9 (3.9 g, 88%) as a pale yel-
low oil; [α]D25 +25.0 (c 3.7, CHCl3).
(3S,4S)-4-(Benzyloxy)-1-(trimethylsilyl)hex-5-en-1-yn-3-ol (23)
IR (KBr): 2954, 2931, 2858, 1466, 1254, 1105, 839 cm–1
.
To a suspension of Mg (0.48 g, 20.0 mmol) in anhyd THF (10 mL) EtBr
(1.8 mL, 24.0 mmol) was added dropwise under N2 atmosphere at
0 °C and the mixture was allowed to stir for 30 min at r.t. To this
Grignard reagent, (trimethylsilyl)acetylene (1.98 g, 20.0 mmol) in an-
hyd THF (10 mL) was added at 0 °C and the mixture was stirred for 1 h
at r.t. In another round-bottom flask the crude aldehyde 22 (5.0 g,
28.4 mmol) dissolved in CH2Cl2 (50 mL) under N2 atmosphere was
added at 0 °C to a stirred suspension of MgBr2·Et2O (7.2 g, 28.4 mmol)
in CH2Cl2. After stirring for 20 min, the flask was cooled to –78 °C and
the alkyne Grignard generated above was added slowly at –78 °C and
the reaction was stirred further at this temperature for 1 h. The sol-
vent was then removed in vacuo, after which the residue was diluted
with CH2Cl2 and allowed to warm to 0 °C. Then, the mixture was
quenched with sat. aq NH4Cl and extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were washed with brine, dried (Na2SO4),
and the solvent was removed under reduced pressure. The compound
was purified by column chromatography (silica gel, 20% EtOAc–
hexane) to provide 23 (5.83 g, 75%) as a yellow oil; [α]D25 +8.4 (c 0.69,
CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 6.07–6.0 (m, 1 H),
5.37 (dt, J = 17.2, 1.6 Hz, 1 H), 5.22 (dt, J = 10.5, 1.5 Hz, 1 H), 4.84 (d, J =
11.7 Hz, 1 H), 4.55 (dt, J = 11.9, 1.5 Hz, 1 H), 4.28–4.24 (m, 1 H), 3.98
(dd, J = 6.5, 2.1 Hz, 1 H), 2.47 (d, J = 2.1 Hz, 1 H), 0.90–0.87 (m, 9 H),
0.05–0.02 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 136.7, 128.2, 127.9, 127.6, 116.5, 80.3,
75.4, 74.9, 73.0, 70.8, 25.7, 18.2, –4.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28O2NaSi: 339.1754; found:
339.1754.
(3R,4S)-4-(4-Methoxybenzyloxy)pentene-1,3-diol (25)
To a cold (0 °C) solution of epoxide 24 (5.5 g, 23.1 mmol) in THF (40
mL) was added Red-Al (8.56 mL, 70 wt% in toluene, 30.03 mmol)
dropwise. After 19 h at 0 °C, the mixture was quenched carefully by
dropwise addition of sat. aq Na2SO4 (Caution: vigorous evolution of H2
may result). EtOAc was added and the mixture was allowed to warm
to r.t. The organic layer was washed with brine and the combined
aqueous layers were extracted several times with EtOAc. The com-
IR (KBr): 3445, 2958, 2925, 1456, 1250, 1067, 848 cm–1
.
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bined organic extracts were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The residue was chromatographed (silica gel,
hexane–EtOAc, 1:1 to 1:2) to provide diol 25 (4.99 g, 90%) as a color-
less oil; Rf = 0.15 (hexane–EtOAc, 1:1); [α]D25 +18 (c 3.3, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C26H40O4NaSi: 467.2588; found:
467.2597.
(3R,4S)-3-(Benzyloxy)-4-(4-methoxybenzyloxy)pentan-1-ol (27)
IR (KBr): 3390, 2935, 1515, 1248, 1034, 823 cm–1
.
To a stirred solution of 26 (5.3 g, 11.9 mmol) in anhyd THF, 1 M TBAF
in THF (14.19 mL, 14.31 mmol) was added slowly at 0 °C. After com-
pletion of the reaction as indicated by TLC, the mixture was concen-
trated under reduced pressure and purified by column
chromatography (30% EtOAc–hexane) to yield 27 (3.54 g, 90%) as a
colorless liquid; [α]D25 +22.2 (c 3.2, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.24 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6
Hz, 2 H), 4.53 (d, J = 11.3 Hz, 1 H), 4.41 (d, J = 11.6 Hz, 1 H), 3.87–3.82
(m, 1 H), 3.80–3.72 (m, 5 H), 3.48–3.43 (m, 1 H), 1.69–1.59 (m, 2 H),
1.16 (d, J = 6.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 158.9, 130.2, 129.1, 113.1, 77.2, 72.4,
70.2, 60.4, 55.0, 33.8, 13.9.
IR (KBr): 3426, 2932, 2872, 1513, 1247, 1036, 747 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.27 (m, 7 H), 6.87 (d, J = 8.7 Hz, 2
H), 4.70 (d, J = 11.5 Hz, 1 H), 4.58–4.54 (m, 2 H), 4.50 (d, J = 11.4 Hz, 1
H), 3.80 (s, 3 H), 3.77–3.64 (m, 4 H), 1.90–1.73 (m, 2 H), 1.23 (d, J = 6.2
Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H20O4Na: 263.1253; found:
263.1255.
(3R,4S)-1-(tert-Butyldimethylsiloxy)-4-(4-methoxybenzyl-
oxy)pentane-3-ol (25a)
13C NMR (75 MHz, CDCl3): δ = 158.9, 138.2, 130.4, 129.0, 128.5, 127.7,
127.5, 113.6, 80.3, 75.8, 72.1, 70.5, 59.9, 55.0, 32.8, 15.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H26O4Na: 353.1723; found:
353.1728.
To an ice-bath-cooled solution of 25 (4.5 g, 18.7 mmol) and imidazole
(2.55 g, 37.5 mmol) in anhyd CH2Cl2 (35 mL) was added a solution TB-
SCl (3.10 g, 20.62 mmol) in anhyd CH2Cl2 (15 mL).The mixture was
stirred at 0 °C for 1 h, then diluted with H2O (25 mL) and extracted
with Et2O (3 × 20 mL). The combined organic phases were washed
with brine (20 mL), dried (anhyd Na2SO4), and concentrated. The resi-
due was purified by flash column chromatography (hexane–EtOAc,
97:3) to give 25a (5.64 g, 85%) as a yellowish oil; Rf = 0.2 (hexane–
EtOAc, 9:1); [α]D25 +12.5 (c 2.4, CHCl3).
(2S,3R,8S,9S)-3,9-Bis(benzyloxy)-8-(tert-butyldimethylsiloxy)-2-
(4-methoxybenzyloxy)undec-10-en-6-yn-5-one (29)
To an ice-cooled solution of 2-iodoxybenzoic acid (3.1 g, 10.9 mmol)
in anhyd MeCN (20 mL) was added a solution of alcohol 27 (2.4 g, 7.2
mmol). The mixture was refluxed for 1 h, and then allowed to cool to
r.t. The solvent was removed under reduced pressure and the unstable
crude aldehyde product 15 was used directly in the next step without
further purification.
IR (KBr): 3416, 2932, 2857, 1612, 1513, 1249, 1035, 835, 776 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 7.4 Hz, 2 H), 6.87 (d, J = 7.9
Hz, 2 H), 4.56 (d, J = 11.2 Hz, 1 H), 4.4 (d, J = 11.4 Hz, 1 H), 3.89–3.75
(m, 6 H), 3.49–3.42 (m, 1 H), 1.80–1.73 (m, 1 H), 1.69–1.60 (m, 1 H),
1.19 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.06 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 158.9, 130.6, 129.1, 113.6, 77.2, 73.0,
70.2, 61.8, 55.0, 34.2, 25.7, 18.0, 14.4, –5.6, –5.6.
To a suspension of Mg (0.065 g, 2.76 mmol) in anhyd THF (10 mL) was
added dropwise EtBr (0.21 mL, 2.76 mmol) under N2 atmosphere at
0 °C. The mixture was stirred for 30 min at r.t. To this Grignard re-
agent, alkyne compound 9 (0.88 g, 2.76 mmol) in anhyd THF (10 mL)
was added at r.t. The mixture was stirred for 2 h at r.t., the aldehyde
compound 15 (1.0 g, 3.04 mmol) was added to the mixture, which
was then refluxed to afford the alcohol 28 as diastereomers in ap-
proximately 80% yield. The mixture was quenched with sat. NH4Cl
solution (7 mL) and filtered through a Celite pad. The mixture was ex-
tracted with EtOAc and dried (Na2SO4). The organic layer was concen-
trated to give a crude non-separable diastereomeric mixture, which
was used directly in the next step.
HRMS (ESI): m/z [M + Na]+ calcd for C19H34O4NaSi: 377.2118; found:
377.2126.
[(3R,4S)-3-(Benzyloxy)-4-(4-methoxybenzyloxy)pentyloxy]tert-
butyldimethylsilane (26)
To a suspension of NaH (0.5 g, 21.18 mmol) in anhyd THF (10 mL) was
added dropwise a solution of alcohol 25a (5 g, 14.12 mmol) in THF
(30 mL) at 0 °C. To this mixture TBAI (cat.) and BnBr (1.83 mL, 15.5
mmol) were added sequentially and stirring was continued for 2 h at
this temperature and 6 h at r.t. The mixture was quenched by the ad-
dition of crushed ice flakes until a clear solution (biphasic) formed.
The mixture was extracted with EtOAc (2 × 60 mL). The combined or-
ganic extracts were washed with H2O (1 × 50 mL) and brine (1 × 50
mL) and dried (anhyd Na2SO4). Evaporation of the solvent followed by
column chromatography (hexane–EtOAc, 9:1) afforded the pure 26
To a stirred solution of 28 (1.6 g, 2.5 mmol) in CH2Cl2 (10 mL), Dess–
Martin periodinane (1.58 g, 3.72 mmol) was added at 0 °C and the
mixture was stirred at this temperature for 3 h. When the reaction
was complete, it was quenched with aq Na2S2O3 (4 mL) and sat. aq
NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (2 × 10 mL),
dried (anhyd Na2SO4), and concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel, EtOAc–hexane, 4:6) to
afford 29 (1.35 g, 85%) as a yellow liquid; [α]D25 +9.0 (c 3.7, CHCl3).
25
(5.45 g, 87%) as a colorless liquid; Rf = 0.5 (hexane–EtOAc, 9:1); [α]D
IR (KBr): 2931, 2858, 1678, 1511, 1460, 1251, 1101, 840 cm–1
.
+14.2 (c 3.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.39–7.17 (m, 12 H), 6.85 (d, J = 8.9 Hz,
2 H), 5.91–5.77 (m, 1 H), 5.39–5.29 (m, 2 H), 4.68–4.42 (m, 8 H), 4.10–
4.02 (m, 1 H), 3.79 (s, 3 H), 3.60 (dd, J = 6.2, 4.53 Hz, 1 H), 2.91–2.81
(m, 2 H), 1.18 (d, J = 6.4 Hz, 3 H), 0.89 (s, 9 H), 0.1 (d, J = 10.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 185.3, 159.1, 138.3, 134.4, 133.8, 130.6,
129.3, 128.2, 127.7, 127.6, 127.5, 120.0, 113.7, 90.9, 84.7, 82.4, 78.6,
75.5, 72.8, 71.0, 70.7, 66.2, 55.3, 47.4, 25.7, 18.2, 16.1, –4.7, –4.9.
IR (KBr): 3448, 2930, 2857, 1513, 1250, 1091, 834 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.22 (m, 7 H), 6.86 (d, J = 8.6 Hz, 2
H), 4.58–4.46 (m, 4 H), 3.79 (s, 3 H), 3.75–3.60 (m, 3 H), 3.54 (q, J = 6.9
Hz, 1 H), 1.86–1.66 (m, 2 H), 1.20 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.04
(s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 158.9, 138.5, 130.9, 129.0, 128.3,
128.2, 127.7, 127.6, 127.4, 127.3, 113.6, 78.4, 76.5, 72.6, 70.5, 65.6,
55.1, 34.3, 25.9, 18.2, 15.1, –5.3, –5.35.
HRMS (ESI): m/z [M + Na]+ calcd for C39H50O6NaSi: 665.3268; found:
665.3280.
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(2S,3R,5S,8S,9S)-3,9-Bis(benzyloxy)-8-(tert-butyldimethylsiloxy)-
2-(4-methoxybenzyloxy)undec-10-en-6-yn-5-ol (13)
which was purified by column chromatography (5% EtOAc–hexane) to
provide the desired alcohol 30a (0.7 g, 88%) as a colorless oil; [α]D
25
+13.3, (c 1.6, CHCl3).
IR (KBr): 3453, 2955, 2930, 2857, 1464, 1359, 1253, 1077, 838 cm–1
To a mixture of propargyl ketone 29 (1.25 g, 1.94 mmol) in formic
acid (0.75 mL, 19.4 mmol) and Et3N (1.07 mL, 7.76 mmol) was added
at r.t. 0.1 M RuCl[N-tosyl-1,2-diphenylethylenediamine)(p-cymene)]
complex in CH2Cl2 (0.8 mL, 0.08 mmol, from stock solution). The mix-
ture was stirred at r.t. overnight. The reaction was quenched with sat.
aq NaHCO3, and extracted with CH2Cl2. The combined extracts were
dried (anhyd Na2SO4) and concentrated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
EtOAc–hexane, 4:6) to afford 13 (1.125 g, 90%) as a light-yellow-
colored liquid; [α]D25 +12.0 (c 1, CHCl3).
.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 10 H), 5.94–5.81 (m, 1
H), 5.38–5.27 (m, 2 H), 4.68–4.58 (m, 2 H), 4.54–4.41 (m, 4 H), 4.00–
3.88 (m, 1 H), 3.84–3.75 (m, 1 H), 3.62–3.54 (m, 1 H), 2.06–1.93 (m, 1
H), 1.90–1.80 (m, 1 H), 1.15 (d, J = 6.6 Hz, 3 H), 0.91–0.87 (m, 18 H),
0.14–0.06 (m, 12 H).
13C NMR (125 MHz, CDCl3): δ = 138.4, 134.9, 134.5, 128.4, 128.3,
127.6, 127.5, 127.4, 127.3, 119.4, 119.1, 85.8, 83.8, 83.2, 80.7, 72.2,
70.1, 67.6, 65.9, 60.9, 38.0, 25.8, 25.7, 18.2, 18.1, 17.9, –4.5, –4.6, –4.9,
–5.1.
IR (KBr): 3449, 2928, 2856, 1512, 1460, 1249, 1088, 1034, 839 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.20 (m, 12 H), 6.86 (d, J = 8.5 Hz,
2 H), 5.95–5.80 (m, 1 H), 5.38–5.27 (m, 2 H), 4.73–4.39 (m, 8 H), 3.84–
3.61 (m, 6 H), 2.99 (br s, 1 H), 2.15–2.02 (m, 1 H), 1.87 (dq, J = 13.9, 3.7
Hz, 1 H), 1.21 (d, J = 6.2 Hz, 3 H), 0.89 (s, 9 H), 0.19 (d, J = 10.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 159.0, 138.2, 134.4, 129.1, 128.3,
128.1, 127.7, 127.6, 127.3, 127.5, 126.9, 119.0, 113.7, 86.6, 83.7, 82.9,
80.3, 75.9, 72.4, 70.9, 71.0, 70.7, 66.0, 60.7, 55.2, 38.8, 25.7, 18.2, 15.5,
–4.6, –4.9.
HRMS (ESI): m/z [M + Na]+ calcd for C37H58O5NaSi2: 661.3715; found:
661.3725.
(2S,3R,5S,8S,9S)-3,9-Bis(benzyloxy)-5,8-bis(tert-butyldimethyl-
siloxy)undec-10-en-6-yn-2-yl Acetate (31)
To a stirred solution of 30a (0.6 g, 0.94 mmol) in anhyd CH2Cl2 (10 mL)
were added Et3N (0.26 mL, 1.88 mmol) followed by Ac2O (0.14 mL,
1.41 mmol) and DMAP (cat.) at 0 °C. The mixture was stirred for 1 h
and then diluted with CH2Cl2 (5 mL). The organic layer was washed
with 5% NaHCO3 (2 × 3 mL) and brine (2 × 3 mL) and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
crude residue was purified by column chromatography (silica gel, 30%
HRMS (ESI): m/z [M + Na]+ calcd for C39H52O6NaSi: 665.3425; found:
667.3437.
(2S,3R,5S,8S,9S)-3,9-Bis(benzyloxy)-5,8-bis(tert-butyldimethyl-
siloxy)-2-(4-methoxybenzyloxy)undec-10-en-6-yne (30)
25
EtOAc–hexane) to provide 31 (0.585 g, 92%) as a colorless oil; [α]D
+9.4 (c 0.6, CHCl3).
IR (KBr): 2954, 2931, 2857, 1738, 1463, 1367, 1246, 1074, 838 cm–1
To an ice-bath cooled solution of 13 (1.0 g, 1.6 mmol) and imidazole
(0.21 g, 3.1 mmol) in anhyd CH2Cl2 (15 mL) was added a solution of
TBSCl (0.25 g, 1.70 mmol) in anhyd CH2Cl2 (5 mL). The mixture was
stirred at 0 °C for 1 h, then diluted with H2O (5 mL) and extracted
with Et2O (3 × 20 mL). The combined organic phases were washed
with brine (20 mL), dried (anhyd Na2SO4), and concentrated. The resi-
due was purified by flash column chromatography (hexane–EtOAc,
.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.20 (m, 10 H), 5.90–5.82 (m, 1
H), 5.35–5.28 (m, 2 H), 5.14–5.07 (m, 1 H), 5.14–5.07 (m, 1 H), 4.67–
4.56 (m, 3 H), 4.49–4.41 (m, 3 H), 3.82–3.78 (m, 1 H), 3.71 (dt, J = 9.6,
3.2 Hz, 1 H), 2.04 (s, 3 H), 1.96–1.89 (m, 1 H), 1.22 (d, J = 6.5 Hz, 3 H),
0.9–0.86 (m, 18 H), 0.12–0.06 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 138.5, 138.4, 134.5, 128.3, 128.2,
127.6, 127.5, 127.3, 125.9, 119.0, 86.3, 83.8, 83.2, 78.6, 72.8, 71.4,
71.0, 66.0, 60.9, 39.9, 25.7, 25.7, 21.3, 18.2, 18.1, 15.1, –4.5, –4.6, –4.9,
–5.1.
25
97:3) to give 30 (1.08 g, 92%) as a yellowish oil; [α]D +13.6 (c 1.16,
CHCl3).
IR (KBr): 2954, 2930, 2857, 1613, 1513, 1463, 1250, 1086, 837 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.22 (m, 12 H), 6.85 (d, J = 8.6 Hz,
2 H), 5.91–5.83 (m, 1 H), 5.34–5.26 (m, 2 H), 4.67–4.59 (m, 3 H), 4.53–
4.45 (m, 4 H), 4.42 (dd, J = 6.5, 1.6 Hz, 1 H), 3.80–3.78 (m, 4 H), 3.74
(dt, J = 9.1, 3.0 Hz, 1 H), 3.66–3.60 (m, 1 H), 2.01–1.93 (m, 1 H), 1.87–
1.80 (m, 1 H), 1.18 (d, J = 6.4 Hz, 3 H), 0.93–0.83 (m, 18 H), 0.13–0.06
(m, 12 H).
13C NMR (125 MHz, CDCl3): δ = 159.0, 139.0, 138.5, 134.6, 131.0,
129.1, 128.2, 128.2, 127.7, 127.6, 127.4, 119.1, 113.1, 86.8, 83.6, 83.3,
79.5, 76.3, 72.8, 71.0, 70.6, 66.1, 55.3, 40.4, 25.8, 25.8, 18.2, 18.2, 15.4,
–4.4, –4.5, –4.8, –5.0.
HRMS (ESI): m/z [M + Na]+ calcd for C39H60O6NaSi2: 703.3820; found:
703.3831.
Methyl (4S,5S,8S,10R,11S,Z)-11-Acetoxy-4,10-bis(benzyloxy)-5,8-
bis(tert-butyldimethylsiloxy)dodec-2-en-6-ynoate (11)
NMO (0.12 g, 1.01 mmol) and alkene 31 (0.53 g, 0.77 mmol) were dis-
solved in acetone–H2O (4:1, 15 mL). 0.02 M OsO4 in toluene (0.39 mL,
0.007 mmol) was added, and the mixture was stirred for 1 d at r.t.,
then cooled in an ice bath. The reaction was quenched by the addition
of sat. Na2SO3 (3 mL). Most of the acetone was removed by a rotary
evaporator, and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined extracts were concentrated under reduced pres-
sure, and the residue was purified by column chromatography (40%
EtOAc–hexane) to give the corresponding diol as a viscous liquid.
HRMS (ESI): m/z [M + NH4]+ calcd for C45H70O6NSi2: 776.4736; found:
776.4758.
(2S,3R,5S,8S,9S)-3,9-Bis(benzyloxy)-5,8-bis(tert-butyldimethyl-
siloxy)undec-10-en-6-yn-2-ol (30a)
To a solution of 30 (0.95 g, 1.25 mmol) in CH2Cl2 (10 mL) and H2O (1
mL), DDQ (0.42 g, 1.87 mmol) was added at 0 °C and the mixture was
allowed to stir for 2 h at r.t. The mixture was quenched with sat.
NaHCO3 (5 mL) and diluted with CH2Cl2 (10 mL). The two layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine (2 × 10
mL), dried (anhyd Na2SO4), and evaporated to give the crude product
The diol was dissolved in 10% aq THF (10 mL) and NaIO4 (0.23 g, 1.07
mmol) was added at 0 °C. After 30 min, H2O was added and the aque-
ous layer was extracted with Et2O. The organic layer was dried (anhyd
Na2SO4) and the solvent was removed under reduced pressure. With-
out purification the crude aldehyde was subjected to the next step.
A solution of bis[2,2,2-(trifluoromethyl)] (ethoxycarbonyl)methyl-
phosphonate (0.25 g, 0.79 mmol) in THF (10 mL) was added slowly to
a stirred solution of NaH (0.03 g, 1.31 mmol) in THF (5 mL) at 0 °C un-
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339
G. Sabitha et al.
Paper
Synthesis
der N2; the mixture was stirred at 0 °C for 30 min. Then the mixture
was cooled to –78 °C and the above crude aldehyde in THF (10 mL)
was added dropwise over 10 min. The resulting mixture was stirred at
–78 °C for 30 min. Then the mixture was quenched with sat. NH4Cl
(10 mL) and the product was extracted with EtOAc (3 × 10 mL). The
combined organic extracts were dried (Na2SO4), the solvent was re-
moved under reduced pressure, and the crude product was purified
by using column chromatography (silica gel, 10% EtOAc–hexane) to
afford (Z)-olefin ester 11 (0.39 g, 68% from 3 steps) as a colorless liq-
uid; [α]D25 +15.0 (c 0.3, CHCl3).
IR (KBr): 2924, 2854, 1738, 1457, 1371, 1234, 1024, 818 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 10 H), 6.76 (dd, J = 10.0,
2.9 Hz, 1 H), 6.05 (dd, J = 10.0, 1.4 Hz, 1 H), 5.61 (dd, J = 9.7, 5.3 Hz, 1
H), 5.23–5.21 (m, 1 H), 5.16–5.11 (m, 1 H), 4.72–4.61 (m, 3 H), 4.40 (d,
J = 10.9 Hz, 1 H), 4.33–4.30 (m, 1 H), 3.68 (dt, J = 10.0, 3.0 Hz, 1 H),
2.05–2.02 (m, 7 H), 1.94–1.88 (m, 1 H), 1.20 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.3, 169.4, 161.3, 144.6, 137.9,
136.7, 128.6, 128.4, 128.3, 127.9, 127.8, 127.7, 121.6, 85.8, 79.2, 77.9,
72.5, 72.1, 69.9, 69.1, 61.8, 35.3, 21.2, 20.8, 15.2.
HRMS (ESI): m/z [M + Na]+ calcd for C30H32O8Na: 543.1989; found:
543.1994.
IR (KBr): 2954, 2930, 2857, 1732, 1462, 1368, 1247, 1071, 837 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.23 (m, 10 H), 6.21 (dd, J = 9.4,
11.7 Hz, 1 H), 6.00 (d, J = 11.8 Hz, 1 H), 5.2–5.05 (m, 2 H), 4.66–4.52
(m, 5 H), 4.42 (d, J = 11.1 Hz, 1 H), 3.76–3.63 (m, 4 H), 2.08–1.73 (m, 5
H), 1.20 (d, J = 6.4 Hz, 3 H), 0.90–0.83 (m, 18 H), 0.14–0.04 (m, 12 H).
(2S,3R,5S,Z)-3-(Benzyloxy)-7-[(2S,3S)-3-(benzyloxy)-6-oxo-3,6-di-
hydro-2H-pyran-2-yl]hept-6-ene-2,5-diyl Diacetate (34)
A suspension of 33 (70 mg, 0.13 mmol), Lindlar catalyst (0.020 mg,
300 wt%), and quinoline (cat.) in EtOAc (3 mL) was stirred at r.t. under
a H2 atmosphere (1 atm) until partially reduced product appeared on
TLC. The mixture was filtered through a pad of Celite with EtOAc (5
mL). The filtrate was concentrated under reduced pressure and the
crude product was purified by column chromatography (silica gel,
40% EtOAc–hexane) to afford 34 (57 mg, 82%) as a colorless liquid;
[α]D25 +60.5 (c 0.4, CHCl3).
13C NMR (125 MHz, CDCl3): δ = 170.3, 166.0, 144.9, 138.5, 138.3,
128.2, 128.1, 128.1, 127.8, 127.7, 127.5, 127.4, 123.5, 86.5, 83.4, 78.6,
76.3, 72.8, 71.6, 71.3, 65.4, 60.9, 51.2, 39.8, 25.8, 25.6, 21.3, 18.137,
18.137, 15.1, –4.5, –4.7, –5.1, –5.1.
HRMS (ESI): m/z [M + Na]+ calcd for C41H62O8NaSi2: 761.3875; found:
761.3879.
IR (KBr): 2926, 1737, 1453, 1371, 1238, 1056, 821 cm–1
.
(2S,3R,5S)-3-(Benzyloxy)-7-[(2S,3S)-3-(benzyloxy)-6-oxo-3,6-dihy-
dro-2H-pyran-2-yl]-5-hydroxyhept-6-yn-2-yl Acetate (32)
1H NMR (500 MHz, CDCl3): δ = 7.38–7.21 (m, 10 H), 6.43 (dd, J = 9.7,
5.1 Hz, 1 H), 6.03 (d, J = 9.7 Hz, 1 H), 5.68–5.58 (m, 3 H), 5.29 (dd, J =
8.7, 3.0 Hz, 1 H), 5.12–5.07 (m, 1 H), 4.69–4.65 (m, 1 H), 4.49 (d, J =
12.0 Hz, 1 H), 4.43–4.38 (m, 2 H), 4.19 (d, J = 11.7 Hz, 1 H), 3.43 (dt, J =
9.0, 3.6 Hz, 1 H), 2.05 (s, 3 H), 2.0 (s, 3 H), 1.94–1.86 (m, 1 H), 1.78–
1.73 (m, 1 H), 1.22 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.2, 169.4, 162.5, 142.3, 137.8,
136.7, 131.7, 128.6, 128.5, 128.3, 127.8, 127.6, 127.5, 127.0, 123.5,
121.5, 77.8, 75.8, 72.5, 72.0, 69.8, 69.1, 61.7, 34.7, 21.2, 20.8, 15.2.
A stirred solution of 11 (0.30 g, 0.40 mmol) in CH2Cl2 (5 mL) was
treated with PTSA (0.38 g, 2.0 mmol) for 3 h at r.t. When the reaction
was complete (TLC), mixture was diluted with CH2Cl2 (5 mL) and solid
NaHCO3 (0.34 g, 4.0 mmol) was added and the mixture was stirred for
a further 15 min. The mixture was then filtered through a short pad
of Celite and the Celite pad was washed with CH2Cl2 (3 × 10 mL). Evap-
oration of solvent gave a residue that was subjected to column chro-
matography (silica gel, 30% EtOAc–hexane) to yield 32 (0.11 g, 85%) as
a colorless oil; Rf = 0.4; [α]D25 +23.0 (c 0.2, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C30H34O8Na: 545.2145; found:
545.2154.
IR (KBr): 3447, 2926, 1735, 1455, 1373, 1244, 1056, 820 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.28 (m, 10 H), 6.77 (dd, J = 10.0,
3.5 Hz, 1 H), 6.04 (dd, J = 9.9, 1.3 Hz, 1 H), 5.24–5.22 (m, 1 H), 5.19–
5.13 (m, 1 H), 4.74–4.64 (m, 4 H), 4.43 (d, J = 11.1 Hz, 1 H), 4.33–4.30
(m, 1 H), 3.71 (dt, J = 10.0, 3.2 Hz, 1 H), 2.07 (s, 3 H), 1.94–1.80 (m, 2
H), 1.22 (d, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.4, 161.4, 144.7, 137.6, 136.7, 128.6,
128.5, 128.3, 128.0, 127.9, 127.8, 121.5, 89.1, 79.3, 78.1, 72.4, 70.5,
69.9, 69.2, 60.9, 37.8, 21.3, 14.9.
(2S,3R,5S,Z)-3-Hydroxy-7-[(2S,3S)-3-hydroxy-6-oxo-3,6-dihydro-
2H-pyran-2-yl]hept-6-ene-2,5-diyl Diacetate (4)
To a stirred solution of 34 (30 mg, 0.05 mmol) in anhyd CH2Cl2 (5 mL),
TiCl4 (0.01 mL, 0.05 mmol) was added at 0 °C and the mixture was
stirred at this temperature for 1 h. The mixture was quenched with
solid NaHCO3 and filtered. The solvent was removed under reduced
pressure. The residue was purified by column chromatography (silica
gel, 50% EtOAc–hexane) to afford 4 (17 mg, 90%) as a colorless oil;
[α]D25 +95.6 (c 0.5, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C28H30O7Na: 501.1883; found:
501.1891.
IR (KBr): 3545, 1735, 1635, 1341 cm–1
.
(2S,3R,5S)-3-(Benzyloxy)-7-[(2S,3S)-3-(benzyloxy)-6-oxo-3,6-dihy-
dro-2H-pyran-2-yl]hept-6-yne-2,5-diyl Diacetate (33)
1H NMR (500 MHz, CDCl3 + 2 drops CD3OD): δ = 6.97 (dd, J = 9.8, 5.0
Hz, 1 H), 6.11 (d, J = 9.9 Hz, 1 H), 5.84 (dd, J = 11.6, 7.3 Hz, 1 H), 5.72
(dd, J = 10.2, 4.2 Hz, 1 H), 5.61 (ddd, J = 11.3, 10.0, 1.1 Hz, 1 H), 5.41
(dd, J = 7.3, 3.6 Hz, 1 H), 4.90–4.87 (m, 1 H), 4.49–4.44 (m, 1 H), 3.73
(dt, J = 6.9, 3.2 Hz, 1 H), 2.09 (s, 3 H), 2.05 (s, 3 H), 1.94–1.87 (m, 1 H),
1.77–1.71 (m, 1 H), 1.24 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3 + 2 drops CD3OD): δ = 171.2, 170.7, 162.9,
145.3, 132.2, 127.7, 121.7, 78.1, 73.9, 69.7, 68.5, 62.7, 36.1, 21.2, 21.2,
15.1.
To a stirred solution of lactone 32 (90 mg, 0.18 mmol) in anhyd CH2Cl2
(5 mL) were added Et3N (0.05 mL, 0.36 mmol) followed by Ac2O (0.03
mL, 0.27 mmol) and DMAP (cat.) at 0 °C. The mixture was stirred for 1
h and then diluted with CH2Cl2 (5 mL). The organic layer was washed
with 5% NaHCO3 (2 × 3 mL) and brine (2 × 3 mL) and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
crude residue was purified by column chromatography (silica gel, 30%
25
EtOAc–hexane) to provide 33 (88 mg, 90%) as a colorless oil; [α]D
HRMS (ESI): m/z [M + Na]+ calcd for C16H22O8Na: 365.1206; found:
+15.0 (c 0.4, CHCl3).
365.1212.
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340
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Synthesis
(2S,3R,5S,Z)-7-[(2S,3S)-3-Acetoxy-6-oxo-3,6-dihydro-2H-pyran-2-
(5S,8S,9S)-9-(Benzyloxy)-8-(tert-butyldimethylsiloxy)undec-10-
yl]hept-6-ene-2,3,5-triyl Triacetate (5)
en-6-yn-5-ol (12)
To a stirred solution of lactone 4 (6 mg, 0.017 mmol) in anhyd CH2Cl2
(2 mL) were added Et3N (0.01 mL, 0.06 mmol) followed by Ac2O (0.007
mL, 0.06 mmol) and DMAP (cat.) at 0 °C. The mixture was stirred for 1
h and then diluted with CH2Cl2 (5 mL), The organic layer was washed
with 5% NaHCO3 (2 × 3 mL) and brine (2 × 3 mL) and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
crude residue was purified by column chromatography (silica gel, 30%
To a mixture of propargyl ketone 36 (1.1 g, 2.75 mmol) in formic acid
(1.06 mL, 27.5 mmol) and Et3N (1.53 mL, 11 mmol) were added at r.t.
0.1
M
RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-cymene)]
complex in CH2Cl2 (0.68 mL, 0.068 mmol, from stock solution). The
mixture was stirred at r.t. overnight. The reaction was quenched with
sat. aq NaHCO3 and extracted with CH2Cl2. The combined organic ex-
tracts were dried (anhyd Na2SO4) and concentrated under reduced
pressure. The crude product was purified by column chromatography
(silica gel, EtOAc–hexane, 4:6) to afford chiral 12 (1.02 g, 92%) as a
light-yellow-colored liquid; [α]D25 +8.9 (c 1.26, CHCl3).
25
EtOAc–hexane) to provide 5 (6.7 mg, 90%) as a colorless oil; [α]D
+128.2 (c 0.5, CHCl3).
IR (KBr): 1732, 1716, 1654, 1470, 1240 cm–1
.
IR (KBr): 3421, 2956, 2860, 1641, 1469, 1102, 838 cm–1
.
1H NMR (500 MHz, CDCl3 + 2 drops CD3OD): δ = 6.98 (dd, J = 9.7, 5.8
Hz, 1 H), 6.24 (d, J = 9.7 Hz, 1 H), 5.79 (dd, J = 11.6, 8.8 Hz, 1 H), 5.61
(ddd, J = 11.1, 9.9, 1.06 Hz, 1 H), 5.52–5.45 (m, 2 H), 5.31 (dd, J = 5.8,
2.9 Hz, 1 H), 5.01–4.93 (m, 2 H), 2.09 (s, 3 H), 2.08 (s, 3 H), 2.04 (s, 3
H), 2.04 (s, 3 H), 2.0 (ddd, J = 14.0, 8.3, 5.8 Hz, 1 H), 1.9 (ddd, 14.0, 7.3,
2.8 Hz, 1 H), 1.21 (d, J = 6.4 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 5.92–5.84 (m, 1 H),
5.36–5.29 (m, 2 H), 4.67 (d, J = 12.0 Hz, 2 H), 4.43 (dt, J = 6.2, 1.5 Hz, 1
H), 4.40–4.35 (m, 1 H), 3.84–3.80 (m, 1 H), 1.72–1.64 (m, 2 H), 1.46–
1.40 (m, 2 H), 1.35–1.30 (m, 2 H), 0.92–0.89 (m, 12 H), 0.1 (d, J = 12.8
Hz, 6 H).
13C NMR (125 MHz, CDCl3 + 2 drops CD3OD): δ = 170.5, 170.3, 169.8,
169.7, 162.1, 140.2, 132.2, 127.1, 124.9, 74.8, 71.1, 70.5, 66.7, 63.7,
35.0, 21.1, 21.0, 20.9, 20.5, 14.7.
13C NMR (75 MHz, CDCl3): δ = 135.0, 134.4, 128.2, 127.7, 119.2, 87.1,
83.1, 82.9, 70.9, 66.1, 62.4, 37.3, 26.1, 25.7, 23.3, 18.3, 14.1, –4.7, –4.8.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38O3NaSi: 425.2482; found:
425.2491.
HRMS (ESI): m/z [M + NH4]+ calcd for C20H30O10N: 444.1879; found:
444.1879.
(5S,8S,9S)-9-(Benzyloxy)-5,8-bis(tert-butyldimethylsiloxy)undec-
(8S,9S)-9-(Benzyloxy)-8-(tert-butyldimethylsiloxy)undec-10-en-6-
10-en-6-yne (37)
yn-5-one (36)
To an ice-bath cooled solution of 12 (0.9 g, 2.23 mmol) and imidazole
(0.3 g, 4.4 mmol) in anhyd CH2Cl2 (20 mL) was added a solution of
TBSCl (0.4 g, 2.64 mmol) in anhyd CH2Cl2 (5 mL).The mixture was
stirred at 0 °C for 1 h, then diluted with H2O (5 mL) and extracted
with Et2O (3 × 20 mL). The combined organic extracts were washed
with brine (20 mL), dried (anhyd Na2SO4), and concentrated. The resi-
due was purified by flash column chromatography (hexane–EtOAc,
97:3) to give 37 (1.03 g, 90%) as a yellowish oil; Rf = 0.5 (hexane–
EtOAc, 9:1); [α]D25 +12.5 (c 1.0, CHCl3).
To a stirred solution of alkyne 9 (1.5 g, 4.7 mmol) in anhyd THF (12
mL) was slowly added 2.5 M BuLi in hexanes (2.3 mL, 5.7 mmol) at
–78 °C under N2. The mixture was stirred for 30 min at –78 °C and a
solution of pentanal (0.48 g, 5.68 mmol) in anhyd THF (10 mL) was
added dropwise. The mixture was kept at –78 °C for 2 h and then al-
lowed to warm to r.t. for 2 h. The reaction was quenched with sat. aq
NH4Cl and extracted with EtOAc. The combined organic extracts were
dried (anhyd Na2SO4) and concentrated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
20% EtOAc–hexane) to afford alcohol 35 (1.6 g, 85%) as a diastereo-
meric mixture.
IR (KBr): 2956, 2931, 2858, 1642, 1466, 1253, 1085, 837 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H), 5.92–5.84 (m, 1 H),
5.36–5.29 (m, 2 H), 4.64 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H),
4.43–4.40 (m, 1 H), 4.38–4.33 (m, 1 H), 3.81 (t, J = 6.8 Hz, 1 H), 1.67–
1.60 (m, 2 H), 1.41–1.27 (m, 4 H), 0.93–0.86 (m, 21 H), 0.12–0.07 (m,
12 H).
13C NMR (125 MHz, CDCl3): δ = 135.0, 134.6, 128.2, 127.6, 127.3,
119.0, 87.6, 83.4, 78.9, 71.0, 66.3, 63.0, 38.4, 27.3, 25.8, 22.4, 18.2,
14.0, –4.4, –4.7, –5.0, –5.2.
The alcohol 35 (1.6 g, 4.0 mmol) in anhyd CH2Cl2 (5 mL) was added
dropwise at 0 °C to an ice-cooled solution of 2-iodoxybenzoic acid
(1.7 g, 5.97 mmol) in DMSO (0.6 mL, 11.94 mmol). The mixture was
stirred at r.t. for 2 h and then filtered through a Celite pad and washed
with Et2O. The combined organic filtrates were washed with H2O and
brine, dried (anhyd Na2SO4), and concentrated under reduced pres-
sure. The crude product was purified by column chromatography (sil-
ica gel, 10% EtOAc–hexane) to afford 36 (1.27 g, 80%) as a yellow-
colored liquid; [α]D25 +15.7 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + NH4]+ calcd for C30H56O3NSi2: 534.3769; found:
534.3792.
IR (KBr): 2958, 2932, 1721, 1677, 1456, 1253, 839 cm–1
.
Methyl (4S,5S,8S,Z)-4-(Benzyloxy)-5,8-bis(tert-butyldimethyl-
siloxy)dodec-2-en-6-ynoate (10)
1H NMR (300 MHz, CDCl3): δ = 7.38–7.30 (m, 5 H), 5.90–5.82 (m, 1 H),
5.40–5.33 (m, 2 H), 4.67 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 6.2 Hz, 1 H),
4.51–4.47 (m, 1 H), 3.90–3.86 (m, 1 H), 2.53 (t, J = 7.3 Hz, 2 H), 1.68–
1.61 (m, 2 H), 1.38–1.31 (m, 2 H), 0.92–0.89 (m, 12 H), 0.11 (d, J = 16.4
Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 187.8, 133.8, 128.3, 127.8, 127.6, 120.0,
90.4, 82.6, 73.5, 71.0, 66.2, 45.2, 27.1, 25.6, 22.5, 18.3, 13.9, –4.8, –5.0.
NMO (0.26 g, 2.26 mmol) and the alkene 37 (0.9 g, 1.74 mmol) were
dissolved in acetone–H2O (4:1, 15 mL). 0.02 M OsO4 in toluene solu-
tion (0.88 mL, 0.0174 mmol) was added, and the mixture was stirred
for 1 d at r.t., then cooled in an ice bath. The reaction was quenched by
the addition of sat. Na2SO3 (3 mL). Most of the acetone was removed
by a rotary evaporator, and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined extracts were concentrated under
reduced pressure, and the residue was purified by column chroma-
tography (40% EtOAc–hexane) to give the corresponding diol as a vis-
cous liquid.
HRMS (ESI): m/z [M + Na]+ calcd for C24H36O3NaSi: 423.2325; found:
423.2324.
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The diol was dissolved in 10% aq THF (10 mL) and NaIO4 (0.58 g, 2.72
mmol) was added at 0 °C. After 30 min, H2O was added. The aqueous
layer was extracted with Et2O. The organic layer was dried (anhyd
Na2SO4) and solvent was removed under reduced pressure. Without
purification the crude aldehyde was subjected to the next step.
EtOAc (5 mL). The filtrate was concentrated under reduced pressure
and the crude product was purified by column chromatography (sili-
ca gel, 40% EtOAc–hexane) to afford lactone 39 (0.11 g, 85%) as a col-
orless liquid; [α]D25 +62.1 (c 0.4, CHCl3).
IR (KBr): 3448, 2927, 1725, 1051 cm–1
.
A solution of bis[2,2,2-(trifluoromethyl)] (ethoxycarbonyl)methyl-
phosphonate (0.51 g, 1.60 mmol) in THF (10 mL) was added slowly to
a stirred solution of NaH (0.06 g, 2.66 mmol) in THF (10 mL) at 0 °C
under N2. The mixture was stirred at 0 °C for 30 min. Then the mix-
ture was cooled to –78 °C and the crude aldehyde in THF (10 mL) was
added dropwise over 10 min. The resulting mixture was stirred at
–78 °C for 30 min. Then the mixture was quenched with sat. NH4Cl (5
mL) and the product was extracted with EtOAc (3 × 10 mL). The com-
bined organic extracts were dried (Na2SO4) and the solvent was re-
moved under reduced pressure. The crude product was purified by
column chromatography (silica gel, 10% EtOAc–hexane) to afford (Z)-
olefin ester 10 (0.65 g, 67%) as a colorless liquid; [α]D25 +19.5 (c 0.77,
CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H), 6.88 (dd, J = 9.8, 5.3
Hz, 1 H), 6.13 (d, J = 9.1 Hz, 1 H), 5.93–5.75 (m, 2 H), 5.34 (dd, J = 7.7,
3.1 Hz, 1 H), 4.66–4.59 (m, 2 H), 4.45–4.37 (m, 1 H), 4.07–4.02 (m, 1
H), 1.73–1.57 (m, 2 H), 1.38–1.27 (m, 4 H), 0.89 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.5, 143.1, 138.7, 136.8, 128.8, 128.0,
127.6, 123.7, 123.0, 75.5, 71.6, 68.5, 68.0, 36.5, 27.3, 22.4, 13.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H24O4Na: 339.1674; found:
339.1580.
(S,Z)-1-[(2S,3S)-3-(Benzyloxy)-6-oxo-3,6-dihydro-2H-pyran-2-
yl]hept-1-en-3-yl Acetate (40)
To a stirred solution of 39 (80 mg, 0.25 mmol) in anhyd CH2Cl2 (3 mL)
were added Et3N (0.068 mL, 0.5 mmol) followed by Ac2O (0.034 mL,
0.37 mmol) and DMAP (cat.) at 0 °C. The mixture was stirred for 1 h
and then diluted with CH2Cl2 (10 mL), The organic layer was washed
with 5% NaHCO3 (2 × 3 mL) and brine (2 × 3 mL) and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
crude residue was purified by column chromatography (silica gel, 10%
IR (KBr): 2955, 2930, 1728, 1653, 1465, 1253, 1082, 837 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 6.22 (dd, J = 11.5,
9.4 Hz, 1 H), 6.0 (d, J = 11.7 Hz, 1 H), 5.20–5.16 (m, 1 H), 4.6–4.58 (m, 2
H), 4.57–4.53 (m, 1 H), 4.37–4.34 (m, 1 H), 3.67 (s, 3 H), 1.67–1.60 (m,
2 H), 1.44–1.27 (m, 4 H), 0.90–0.86 (m, 21 H), 0.11–0.05 (m, 12 H).
13C NMR (125 MHz, CDCl3): δ = 166.1, 145.2, 128.1, 127.7, 127.4,
127.3, 123.2, 82.0, 77.5, 76.6, 71.7, 65.6, 63.0, 51.3, 38.3, 27.3, 25.8,
25.7, 22.3, 18.2, 14.0, –4.4, –4.6, –4.7, –5.0.
25
EtOAc–hexane) to provide 40 (81 mg, 90%) as a colorless liquid; [α]D
+25.5 (c 0.3, CHCl3).
IR (KBr): 1731, 1242, 1052 cm–1
.
HRMS (ESI): m/z [M + NH4]+ calcd for C32H58O5NSi2: 592.3859; found:
592.3862.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 6.88 (dd, J = 9.8, 4.9
Hz, 1 H), 6.17 (d, J = 10.1 Hz, 1 H), 5.93 (dd, J = 10.5, 8.9 Hz, 1 H), 6.65
(td, J = 11.1, 1.1 Hz, 1 H), 5.46–5.32 (m, 2 H), 4.60 (ABq, J = 17.7, 12.1
Hz, 2 H), 3.94 (dd, J = 4.9, 3.6 Hz, 1 H), 2.03 (s, 3 H), 1.73–1.53 (m, 2 H),
1.36–1.18 (m, 4 H), 0.88 (t, J = 6.8 Hz, 3 H).
(5S,6S)-5-(Benzyloxy)-6-[(S)-3-hydroxyhept-1-ynyl]-5,6-dihydro-
2H-pyran-2-one (38)
A stirred solution of 10 (0.50 g, 0.87 mmol) in CH2Cl2 (5 mL) was
treated with PTSA (0.80 g, 4.39 mmol) for 3 h at r.t. When the reaction
was complete (TLC), the mixture was diluted with CH2Cl2 (5 mL) and
solid NaHCO3 (0.73 g, 8.7 mmol) was added and it was stirred for a
further 15 min. The mixture was then filtered through a short pad of
Celite and the Celite pad was washed with CH2Cl2 (3 × 10 mL). The sol-
vent was evaporated and the residue was purified by column chroma-
tography (silica gel, EtOAc) to yield 38 (0.23 g, 86%) as a colorless oil;
Rf = 0.4; [α]D25 +26.4 (c 0.5, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 170.0, 162.3, 142.4, 137.0, 132.4, 128.4,
128.0, 127.6, 127.2, 123.5, 75.9, 71.4, 69.1, 69.0, 34.0, 27.0, 22.3, 21.0,
13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H26O5Na: 381.1780; found:
381.1691.
(S,Z)-1-[(2S,3S)-3-Hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-
yl]hept-1-en-3-yl Acetate (3)
IR (KBr): 3447, 2930, 1733, 1053 cm–1
.
To a stirred solution of 40 (50 mg, 0.139 mmol) in anhyd CH2Cl2 (5
mL), TiCl4 (0.01 mL, 0.139 mmol) was added at 0 °C and the mixture
was stirred at this temperature for 1 h. The mixture was quenched
with solid NaHCO3 and filtered. The solvent was removed under re-
duced pressure. The residue was purified by column chromatography
(silica gel, 50% EtOAc–hexane) to afford 3 (32 mg, 86%) as a colorless
oil; [α]D25 +70.4 (c 0.5, MeOH).
1H NMR (500 MHz, CDCl3): δ = 7.39–7.32 (m, 5 H), 6.79 (dd, J = 9.9, 3.3
Hz, 1 H), 6.07 (dd, J = 10.0, 0.9 Hz, 1 H), 5.26–5.24 (m, 1 H), 4.77–4.70
(m, 2 H), 4.45–4.41 (m, 1 H), 4.35–4.32 (m, 1 H), 1.76–1.66 (m, 2 H),
1.46–1.38 (m, 2 H), 1.37–1.29 (m, 2 H), 0.9 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.5, 144.5, 136.8, 128.6, 128.3,
127.9, 127.9, 121.6, 90.0, 77.6, 72.1, 70.0, 69.2, 37.1, 27.1, 22.2, 13.9.
IR (KBr): 3443, 2928, 1725, 1245, 1039 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C19H22O4Na: 337.1518; found:
337.1570.
1H NMR (300 MHz, CDCl3): δ = 7.00 (dd, J = 9.8, 5.3 Hz, 1 H), 6.14 (d, J =
9.8 Hz, 1 H), 5.77–5.62 (m, 2 H), 5.49 (ddd, J = 9.8, 7.5, 6.0 Hz, 1 H),
5.30 (dd, J =6.1, 2.3 Hz, 1 H), 4.14 (dd, J = 5.4, 2.3 Hz, 1 H), 2.04 (s, 3 H),
1.68–1.56 (m, 2 H), 1.38–1.27 (m, 4 H), 0.90 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.1, 162.7, 144.2, 134.0, 125.6, 122.8,
77.9, 70.9, 63.2, 34.2, 27.2, 22.4, 21.2, 13.9.
(5S,6S)-5-(Benzyloxy)-6-[(S,Z)-3-hydroxyhept-1-enyl]-5,6-dihy-
dro-2H-pyran-2-one (39)
A suspension of 38 (0.13 g, 0.413 mmol), Lindlar catalyst (0.026 g, 300
wt%), and quinoline (catalytic amount) in EtOAc (3 mL) was stirred at
r.t. under H2 atmosphere (1 atm) until partially reduced product ap-
peared on TLC. The mixture was filtered through a pad of Celite with
HRMS (ESI): m/z [M + Na]+ calcd for C14H20O5Na: 291.1310; found:
291.1250.
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342
G. Sabitha et al.
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Synthesis
(S,Z)-1-[(2S,3S)-3-Acetoxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]hept-
1-en-3-yl Acetate (1)
(5) Martinez, M. Las Plantas Medicinales de Mexico; Editorial Botas:
Mexico, 1989, 508–517.
(6) (a) Malan, K.; Pelissier, Y.; Marion, C.; Blaise, A.; Blessiere, J.
Planta Med. 1988, 54, 531. (b) Pullaiah, T. Encyclopaedia of
World Medicinal Plants; Vol. 3; Regency Publications: New
Delhi, 2006, 1134. (c) Hjelmgaard, T.; Persson, T.; Rasmussen, T.
B.; Givskov, M.; Nielsen, J. Bioorg. Med. Chem. 2003, 11, 3261.
(7) Yadav, J. S.; Mandal, S. S. Tetrahedron Lett. 2011, 52, 5747.
(8) (a) Sabitha, G.; Das, S. K.; AnkiReddy, P.; Yadav, J. S. Tetrahedron
Lett. 2013, 54, 1097. (b) Kamal, A.; Reddy, P. V.; Prabhakar, S.
Tetrahedron: Asymmetry 2009, 20, 1120.
To a stirred solution of the lactone 3 (15 mg, 0.05 mmol) in anhyd
CH2Cl2 (2 mL) were added Et3N (0.015 mL, 0.10 mmol) followed by
Ac2O (0.01 mL, 0.10 mmol) and DMAP (cat.) at 0 °C. The mixture was
stirred for 1 h and then diluted with CH2Cl2 (10 mL). The organic layer
was washed with 5% NaHCO3 (2 × 3 mL) and brine (2 × 3 mL) and
dried (anhyd Na2SO4). The solvent was removed under reduced pres-
sure and the crude residue was purified by column chromatography
(silica gel, 30% EtOAc–hexane) to provide 1 (15 mg, 90%) as a colorless
oil; [α]D25 +190.6 (c 0.4, MeOH).
(9) Ramesh, D.; Shekhar, V.; Chantibabu, D.; Rajaram, S.; Ramulu,
U.; Venkateswarlu, Y. Tetrahedron Lett. 2012, 53, 1258.
(10) Sabitha, G.; AnkiReddy, P.; Das, S. K.; Yadav, J. S. Synthesis 2013,
45, 651.
(11) Sabitha, G.; Gurumurthy, Ch.; Yadav, J. S. Synthesis 2014, 46,
1757.
IR (KBr): 2925, 2856, 1739, 1373, 1225, 1029, 771 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.96 (dd, J = 9.6, 5.7 Hz, 1 H), 6.25 (d, J =
9.8 Hz, 1 H), 5.73 (dd, J = 11.1, 8.3 Hz, 1 H), 5.67–5.56 (m, 2 H), 5.40–
5.30 (m, 1 H), 5.17 (dd, J = 5.7, 2.8 Hz, 1 H), 2.09 (s, 3 H), 2.05 (s, 3 H),
1.79–1.51 (m, 2 H), 1.36–1.12 (m, 4 H), 0.91 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.2, 169.6, 162.1, 139.8, 133.2, 126.2,
125.0, 75.0, 69.3, 64.2, 34.0, 27.2, 22.4, 21.1, 20.4, 13.7.
(12) For our recent contributions to δ-lactone-containing natural
products: (a) Sabitha, G.; Rao, A. S.; Sandeep, A.; Yadav, J. S. Eur.
J. Org. Chem. 2014, 455. (b) Sabitha, G.; Sandeep, A.; Rao, A. S.;
Yadav, J. S. Eur. J. Org. Chem. 2013, 6702. (c) Sabitha, G.;
Shankaraiah, K.; Yadav, J. S. Eur. J. Org. Chem. 2013, 4870.
(d) Sabitha, G.; Raju, A.; Reddy, C. N.; Yadav, J. S. RSC Adv. 2014,
4, 1496. (e) Sabitha, G.; Reddy, D. V.; Reddy, S. S. S.; Yadav, J. S.;
Kumar, C. G.; Sujitha, P. RSC Adv. 2012, 2, 7241. (f) Sabitha, G.;
Reddy, S. S. S.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 2407.
(g) Sabitha, G.; Reddy, S. S. S.; Raju, A.; Yadav, J. S. Synthesis
2011, 1279. (h) Sabitha, G.; Reddy, C. N.; Raju, A.; Yadav, J. S. Tet-
rahedron: Asymmetry 2011, 22, 493. (i) Sabitha, G.; Reddy, C. N.;
Gopal, P.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5736.
(j) Sabitha, G.; Bhikshapathi, M.; Ranjith, N.; Ashwini, N.; Yadav,
J. S. Synthesis 2011, 821.
HRMS (ESI): m/z [M + Na]+ calcd for C16H22O6Na: calcd 333.1413;
found: 333.1319.
Acknowledgement
P.A.R. thanks CSIR and S.K.D. thanks UGC, New Delhi for the award of
fellowships. All the authors thank CSIR, New Delhi for financial
support as part of XII Five Year plan programme under title ORIGIN
(CSC-0108).
Supporting Information
(13) Ghosh, S.; Pradhan, T. K. Synlett 2007, 2433.
(14) (a) Trygstad, T. M.; Pang, Y.; Forsyth, C. J. J. Org. Chem. 2009, 74,
910. (b) Yu, P.; Li, C.; Guozhu, Z.; Liming, Z. J. Am. Chem. Soc.
2009, 131, 5062.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378912.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(15) The diastereomeric ratio of the product was determined by
HPLC [Shimadzu HPLC system, chiral HPLC column (Chiralcel
OD), UV detector, λ = 225 nm, Zorbax SBC 18 250 × 4.6 mm, 5μ
(column), MeCN–H2O (7:3), flow rate: 1.0 mL/min]: tR = 6.1 and
6.3 min.
(16) The diastereomeric excess of the product was determined by
HPLC [Shimadzu HPLC system, chiral HPLC column (Chiralcel
OD), UV detector, λ = 225 nm, Atlantis DC18 150 × 4.6 mm, 5μ
(column), MeCN–H2O (3:1), flow rate: 1.0 mL/min]: tR = 21.17
and 24.34 min.
References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 330–342