Asymmetric Total Synthesis of the Putative Structure of Diplopyrone

Article abstract of DOI:10.1021/acs.joc.7b00086

The first asymmetric total synthesis of the putative structure of diplopyrone was achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation reac

Full text of DOI:10.1021/acs.joc.7b00086

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Article
Asymmetric Total Synthesis of Putative Structure of Diplopyrone
Saurabh Maity, Suresh Kanikarapu, Kanakaraju Marumudi, Ajit
C. Kunwar, Jhillu S. Yadav, and Debendra Kumar Mohapatra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00086 • Publication Date (Web): 07 Apr 2017
Downloaded from http://pubs.acs.org on April 7, 2017
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Asymmetric Total Synthesis of Putative Structure of Diplopyrone
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Saurabh Maity,†,‡ Suresh Kanikarapu,† Kanakaraju Marumudi,Ῑ Ajit C. Kunwar,Ῑ Jhillu S.
Yadav,†,‡ and Debendra K. Mohapatra*†,‡
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†Natural Products Chemistry Division, Centre for NMR and Structural Chemistry, CSIR-Indian
Ῑ
‡
Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and
Innovative Research (AcSIR, Mathura Road, New Delhi-110 025, India; mohapatra@iict.res.in
-
ennar
G
till
i
S
-
e ec ve
S l ti Ol fi ti
e
na on
Z
(
)
OH
H
H
H
H
O
OH
O
O
OTBDPS
PMB
OTBDPS
H
-
O
O
O
s mme r c
o
I
ne a a ze
A
t i
OPMB
y
di
C
t ly
d
/
H
-
-
m nox
a on
y
A i l ti
somer za on
ti
I
i
/
C O C C
ABSTRACT: The first asymmetric total synthesis of the putative structure of diplopyrone was
achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-
catalyzed tandem isomerization followed by C-O and C-C bond formation reaction strategy
developed by our own group to construct the trans-2,6-disubstituteddihydropyran ring,
asymmetric α-aminoxylation reaction, and Still-Gennari (Z)-selective olefination reactions.
1
13
Careful comparison of H and C NMR spectroscopic data as well as investigation of the UV
and circular dichroism (CD) spectrum in trifluoroethanol for compound 2, suggest that the the
putative structure proposed for diplopyrone {6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-
tetrahydropyran[3,2-b]pyran-2-one} requires revision.
______________________________________________________________________________
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INTRODUCTION
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5,6-Dihydropyran-2-one moiety containing natural products were isolated from many sources
such as bacteria, microbial plants and insects and is a key biosynthetic intermediate often
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1
involved in many different types of biological processes These compounds show interesting
biological activities such as neurotoxic, antibiotic, antifungal, immunosuppressive, anti-
inflammatory, cytotoxic, antitumor activities.2 It was postulated that some of these
pharmacological effects may be related to the presence of the conjugated double bond which acts
as a Michael acceptor.3 The important structural motif, pyranopyran occurs in active substance
like botcinin D (1; trans-fused),4 diplopyrone (2; cis-fused),5 and thyrsiferol (3; trans-fused)6
which were shown in Figure 1.
H
H
O
O
H
H
H
O
O
O
O
n
u
B
O
O
O
O
H
o c n n
B t i i D
o rone
Dipl py
1
( )
2
( )
H
H
O
H
H
O
O
O
H
O
O
O
H
H
r
B
rs ero
3
l
( )
Th if
y
Figure 1. Naturally occurring pyranopyrans moiety containing natural products.
_________________________________________________________________________
Diplopyrone (2), is a new phytotoxic monosubstituted tetrahydropyranpyran-2-one, isolated
from liquid culture filtrates of “Diplodia mutila”.5 This pathogenic fungus is responsible for coak
oak decline due to formation of canker disease. The fungus also can engross plants of different
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age, inducing signs very similar to those produced by tracheomycotic disease. Considering the
massive commercial use of cork, this causes heavy fiscal losses and environmental damages. On
tomato, a nonhost plant, diplopyrone also causes brown discoloration or simmering on the stem.
Diplopyrone (2) also acts as an antimicrobial agent. From the structural perspective, diplopyrone
contains a cis-fused bicyclic structure in which six-membered cyclic ether is fused with a six-
membered lactone. The stereochemistry of diplopyrone was proposed based on spectroscopic
and chemical methods as 6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-tetrahydropyran[3,2-
b]pyran-2-one (2) and the absolute stereochemistry of the chiral secondary hydroxy center in the
exocyclic tail was determined following modified Mosher’s ester method.2 As part of our
ongoing program on total synthesis of pyran containing natural products,7 herein, we report a
liner first total synthesis of diplopyrone (2) and assign the absolute stereochemistry.
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Retrosynthetic analysis for the synthesis of diplopyrone (2) is shown in Scheme 1.
Diplopyrone (2) could be obtained from ester 4 following deprotection and in situ lactonization.
cis-Ester moiety present in 4 would result from Still-Ginneri reaction and non-allylic secondary
hydroxyl group could be installed via asymmetric α-aminoxylation reaction starting from
compound 5. trans-Dihydropyran 5 could be prepared from δ-hydroxy-α,β-unsaturated aldehyde
6 by using our own strategy involving iodine-catalyzed tandem isomerization of enal, followed
by C-O and C-C bond formation reaction . Aldehyde 6 can be prepared through regioselective
opening of γ,δ-epoxy-α,β-unsaturated ester 7 which could be synthesized from easily available
and inexpensive cis-butene-1,4-diol (8).
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Scheme 1. Retrosynthetic Analysis
5
6
7
8
H
O
TB
H
O
S
5
O
H
H
4
H
O
9
3
a
4
6
7
10
a
8
e
M
CO2
PMB
O
9
2
O
O
8
H
1
10
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2
4
H
H
H
O
O
O
TBDP
O
S
TBDP
O
S
H
PMB
O
PMB
O
5
6
O
O
TBDP
O
S
H
O
H
O
Et
O
7
8
______________________________________________________________________________
RESULTS AND DISCUSSION
The synthesis was initiated with the synthesis of 9 from commercially available cis-butene-
1,4-diol 8 following a known literature protocol.8 Oxidation of the primary alcohol 9 under
Swern oxidation conditions9 followed by two carbon homologation using Witting olefination
reaction10 afforded the unsaturated epoxy ester 7 in 89% yield for two steps. Regioselective
opening of the epoxide in 7 with p-methoxybenzyl alcohol (PMB-OH) in presence of (PhO)3B
and catalytic amount of Pd(0)-catalyst gave the unsaturated ester 10 in 83% yield.11 Ester in 10
o
was reduced to the aldehyde 6 using DIBAL-H at −78 C in good yield. Using a protocol
developed in our group for the synthesis of dihydropyrans, treatment of the aldehyde 6 with
allyl-TMS in presence of catalytic amount of molecular iodine afforded the trans-dihydropyran 5
in 96:4 diastereomeric ratio in 87% yield (HPLC method) (Scheme 2).12
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Scheme 2. Synthesis of the Allylated Pyran Fragment 5
5
6
7
8
.
O
e
R f
S
8
(
)
TBDP
O
S
H
O
H
H
O
O
S
(
)9
8
9
.
,
l
,
1
l
)
DM
Et3N
10
11
12
13
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COC
(
SO
2
O
-
,
O
H
C
78 o
2C 2
C
TBDP
O
S
Et
O
.
,
=
2 Ph3P
H
%
Et H
C CO2 C6
6
7
,
re ux
over s e s
2
t
p
fl
89
,
H
O
O
PMB H Ph 3B
Pd PPh
O
O
THF
-
(
)
)
,
,
DIBAL H
H
l
C
2C 2
TBDP
O
S
(
3 4
Et
O
-
o
,
,
0 oC 83
7
1
%
8 C 9
%
PMB
-
O
10
H
H
H
O
O
,
O
Allyl TM I2
S
TBDP
O
S
TBDP
O
S
H
, ,
r
THF t
7
%
8
PMB
O
PMB
O
5
6
___________________________________________________________________________
Selective oxidative cleavage of the terminal double bond following Jin’s protocol13 with
OsO4, 2,6-lutidine, NaIO4 furnished the aldehyde 11 in 73% yield. α-Aminohydroxylation of the
aldehyde 11 with L-proline and nitrosobenzene in dry DMSO, followed by in situ reduction of
the aldehyde with NaBH4 and the cleavage of resulting ‘O-N’ bond by CuSO4 produced the diol
12 in 62% yield over 2 steps with moderate diastereoselectivity (dr =7:3, determined by
HPLC).14 The diastereomers were not separated at this stage by silica gel column
chromatography and was used in the next step. Following the Forsyth protocol,15 exposure of
diol 12 with NaH and tosylimidazole furnished the epoxide 13 in 83% combined yield (7:3
ratio). At this stage, diastereomers were easily separated by silica gel column chromatography.
The major diastereomer was taken forward. Treatment of epoxide 13 with super-hydride in
anhydrous THF furnished alcohol 14 in good yield (Scheme 3).16
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Scheme 3. Synthesis of the Key Fragment 14
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9
H
H
H
H
-
, ,
O
O
s
u
ne
x n
O
2 6 l tidi
O O4
TBDP
O
S
TBDP
O
S
-
, ,
a
o a e
H
N I
1 4 di
O4
PMB
O
PMB
O
,
r
10
11
12
13
14
15
16
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t 7
3
%
5
11
-
,
H
O
ro ne
a
PhN L P li
O
DM
H
H
-
,
,
m
,
a
r s
N H T i yl i id THF
H
O
O
N BH4
SO
TBDP
O
S
,
,
,
0 o 83
C
e
u
r
M
H
t
O
C SO4
%
PMB
O
62
%
12
=
r
:
3
7
d
(
)
H
O
H
H
-
O
H
H
u er
S p
r eTM
hyd id
,
O
O
TBDP
O
S
TBDP
O
S
,
THF 0 o 79
C
%
PMB
O
PMB
O
14
13
___________________________________________________________________________
Absolute stereochemistry of the newly generated secondary hydroxy bearing carbon center
(C7) was determined by modified Mosher’s ester analysis.17 Esterification of the alcohol 14 with
both (S)- and (R)-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) showed positive
chemical shift difference [(Δδ = δS – δR) × 103] for protons on C6 through C8, while protons on
C10 showed negative chemical shift differences, which is the indicative of C9 bearing an S-
configuration (Figure 2).
<
>
∆
0
∆
0
δ
δ
∆δ < 0
∆δ > 0
MTPA
OMTPA
O
H
H
H
H
4
4
10
10
O
O
+
10
+10
9
9
a
H
TBDP
S
C
O
4
6
6
H33C
4a
OTBDPS
-
90
-90
7
7
a
8
8a
+
70
+70
8
8
PMB
OPMB
O
H
H
+
22
+22
Figure 2. Δδ = (δS – δR) × 103 for R and S-MTPA ester of alcohol 14.
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Having secured the stereochemistry of the newly generated center of the secondary hydroxy
group present in 14, the hydroxy group was protected as its TBS-ether 15 using tert-
butyldimethylsilyl trifluoromethanesulfonate and 2,6-lutidine as base in CH2Cl2 in 93% yield.
Primary silylether in 15 was selectively deprotected in presence of NH4F in MeOH at room
temperature to afford the primary alcohol 16 in 85% yield.18 Treatment of alcohol 16 with 2-
10
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o
iodoxybenzoic acid (IBX) in acetonitrile at 80 C, furnished the corresponding aldehyde in
quantitative yield.19 Following Still-Gennari conditions,20 treatment of the crude aldehyde with
bis-(trifluoroethyl)methyl phosphonate in the presence of NaH in THF at −78 °C provided (Z)-
α,β-unsaturated ester 4 in 78% yield. PMB-group was deprotected with DDQ21 in CH2Cl2/buffer
(pH = 7) (9:1) to afford the, which was lactonized using a catalytic amount of PTSA in benzene
to furnish the lactone 17 in 86% yield over two steps. Deprotection of the TBS group in lactone
17 under usual conditions (TBAF/THF or CSA/MeOH) led to intractable mixture of products.
Pleasingly, treatment of lactone 17 with HF.pyridine22 in dry THF led to clean deprotection of
TBS-ether to furnish diplopyrone 2 in 90% yield (Scheme 4).
Scheme 4. Completion of the Total Synthesis of Diplopyrone (2)
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6
H
O
TB
O
S
-
-
, ,
O
u
ne
Tf 2 l tidi
6
TB
S O
O
TBDP
S
O
TBDP
O
S
, ,
r
t 93
2C 2
%
H
l
C
PMB
O
7
PMB
O
8
9
14
15
.
TB
O
10
11
12
13
14
15
16
17
18
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S
,
,
i IBX
H
N
C
3C 80 oC
,
e
NH4F M
H
O
O
.
H
O
e
ii
F
3C
H
a
P
)
2
H
M
O C 2CO2
( )
C
O
(
2
,
r
t
5
8
-
-
o
%
,
,
r
t
N H THF 7
8 C
PMB
O
v r
o e s e s
7
8
2 t
p
%
16
.
,
=
H
:
,
TB
O
S
1 DD
H
2C 2
l P
7
TB
O S
C
Q
,
o
u er
:
O
b ff
10 1 0 C
)
O
(
) (
.
,
,
e
M
z n
en e e
r
t
CO2
2 PT A b
S
%
O
O
PMB
v
O
o er s e s
86
2
t
p
4
17
H
O
.
,
r
ne
O
HF py idi
-
THF
o
,
r
t
0 C 90
%
O
O
2
____________________________________________________________________________
1
13
However, comparison of the H and CNMR spectra (Table 1) of the synthetic sample with
that of the natural product displayed discrepancies concerning the resonances of some of the
protons and carbons.
1
13
Table 1: Comparison of H and C NMR of Natural Product with Synthetic 2 in CDCl3
(500 MHz)
1H NMR
Natural
1H NMR
Synthetic 2
13C NMR
Natural
13C NMR
Synthetic 2
Position
2
3
162.7
124.8
161.73
123.28
6.23 (d, J = 9.8
Hz)
6.88 (dd, J = 9.8,
5.8 Hz)
6.07 (dd, J = 10.0,
1.6 Hz)
6.88 (ddd, J =
10.0, 3.1, 1.0 Hz)
140.0
64.9
78.9
144.24
64.90
74.79
4
4.09 (dd, J = 5.8, 4.92 (ddd, J = 5.6,
4a
6
2.8 Hz)
3.1, 1.6 Hz)
4.16 (br s)
4.08 (ddt, J = 4.2,
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2.6, 2.6, 1.6 Hz)
5
6
7
8
6.18 (d, J = 9.8
6.06 (td, J = 10.5,
1.6, 1.6 Hz )
6.04 (td, J = 10.5,
2.6, 2.6 Hz)
4.97 (m, J = 5.6,
2.6, 2.6, 1.6, 1.0
Hz)
3.96 (dd, J = 6.4,
4.2 Hz )
1.25 (d, J = 6.4
Hz)
132.6
129.57
124.68
70.0
7
8
Hz)
6.14 (ddd, J =
10.4, 4.6, 1.8 Hz)
4.65 (ddd, J =
4.6, 3.5, 2.8 Hz)
123.0
69.7
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8a
3.92 (dq, 6.5, 4.2
Hz)
1.21 (d, J = 6.5
Hz)
69.03
17.8
69.66
18.72
9
10
Extensive NMR studies on the synhtetic sample of (obtained above) diplopyrone (2) were carried
out in CDCl3 solvent with the help of 2-D Double Quantum Filtered Correlation Spectroscopy
(DQFCOSY), Nuclear Overhauser Effect Spectroscopy (NOESY), Hetero-Nuclear Single
Quantum Correlations (HSQC), Hetero-Nuclear Multiple Bond Correlation (HMBC) and
extensive decoupling experiments. The olefinic protons of α,β-unsaturated δ-lactone (H-3 and H-
4), displayed very distinctive pattern at 6.88 (ddd, 10.0, 3.1, 1.0 Hz) and 6.07 (dd, 10.0, 1.6 Hz)
ppm in the 1H NMR spectrum. In addition, these two protons displayed HMBC correlation with
lactone carbonyl carbon (161.73 ppm). The other group of (Z)-olefinic protons H-7 and H-8 (3JH-
= 10.5 Hz) resonated at 6.06 and 6.04 ppm, resulting in a somewhat complicated spectral
7/H-8
pattern. Further assignments were completed with the help of DQF-COSY and NOESY
experiments. The very distintive dq at 3.96 ppm assigned as H-9 due to adjacent correlations
with coupled Me-10 (1.25 ppm) and proton H-6 (4.08 ppm) in the DQF-COSY spectrum. The
DQF-COSY spectrum showed H-4 coupled to adjacent bridged proton H-4a, which resonated as
ddd at 4.92 ppm (3JH-4/H-4a = 3.1 Hz). Further H-4a coupled to another bridged proton H-8a,
3
appeared as ddd at 4.97 ppm with coupling constant, JH-4/H-8a = 5.6 Hz, justifying a syn-
orientation of bridged protons (H-4a and H-8a) (Table 1). The stereochemistry of bicyclic
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compound was assigned with the help of couplings discussed above and NOE correlations, H-
4/H-6, H-6/Me-10 and H-7/Me-10. The energy minimized structure adequately supported the
proposed structure of diplopyrone (2) (Figure 3). The sign of the specific rotation of the synthetic
compound was same {[α]D25 = +49.0 (c = 0.28, CHCl3); lit.5 [α]D25 +67.6 (c = 0.25, CHCl3)}, but
the value was showing little deviation from that reported for the natural product. However,
comparison of the UV and CD spectra of the natural product (Figure 3) and the synthetic sample
(Figure 4) in trifluoroethanol, showed reasonable agreement with the pattern as well as the
values for the cotton effects studied by Evdente et al indicating that the functionalties present in
the molecule are similar.5b Considering the above extenisive NMR studies, it is suggested that
the putative structure proposed for diplopyrone requires revision.
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H
O
OH
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Diplopyrone ( )
( )
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Figure 3: Energy minimized structure of diplopyrone (2) along with the characteristic NOE
correlations shown with double-headed arrows.
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Figure 4. Absorption (UV) and circular dichroism (CD) spectra of natural diplopyrone in
trifluoroethanol (taken from Evidente et al. J. Org. Chem. 2005, 70, 7-13)
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Figure 5. Absorption (UV) and circular dichroism (CD) spectra of synthetic diplopyrone (2) in
trifluoroethanol.
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CONCLUSIONS
In summary, the first asymmetric total synthesis of the proposed structure of diplopyrone was
achieved in 17 linear steps starting from commercially available stating material cis-1,4-butene-
diol. Palladium-catalyzed epoxide ring opening reaction, iodine-catalyzed tandem isomerization
followed by C-O and C-C bond formation reaction developed by our own group, asymmetric α-
aminoxylation reaction, super-hydride reaction and Still-Gennari-(Z)-selective olefination
reactions were used as key steps. It was found that there are serious discrepancies with the
spectral values for the synthetic and natural samples, which suggest that the structure proposed
for the natural product requires revision.
EXPERIMENTAL SECTION
General methods: Experiments which required an inert atmosphere were carried out under
argon in flame-dried glassware. TBME and THF were freshly distilled from
sodium/benzophenone ketyl and transferred via syringe. Dichloromethane was freshly distilled
from CaH2. Tertiary amines were freshly distilled over KOH. Commercially available reagents
were used as received. Unless detailed otherwise, "work-up" means pouring the reaction mixture
into brine, followed by extraction with the solvent indicated in parenthesis. If the reaction
medium was acidic (basic), an additional washing with saturated aqueous NaHCO3 solution
(saturated aqueous NH4Cl solution) was performed. Washing with brine, drying over anhydrous
Na2SO4 and evaporation of the solvent under reduced pressure followed by chromatography on a
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silica gel column (60-120 mesh) with the indicated eluent furnished the corresponding products.
Where solutions were filtered through a Celite pad, the pad was additionally washed with the
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same solvent used, and the washings incorporated to the main organic layer. H and C NMR
chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J)
are reported in hertz (Hz). High resolution mass spectra were run by the electron impact mode
(ESIMS, 70 eV) or by the FAB mode (m-nitrobenzyl alcohol matrix), using an orbitrap mass
analyzer. IR data were measured with oily films on NaCl plates (oils) or KBr pellets (solids).
Specific optical rotations [α]D are given in 10−1 deg cm2 g−1 and were measured at 29 °C or
otherwise mentioned. The following abbreviations are used to designate signal multiplicity: s =
singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, br = broad.
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((2S,3S)-3-((tert-Butyldiphenylsilyloxy)methyl)oxiran-2-yl)methanol (9): L-(+)-DET (0.71 mL,
4.17 mmol) and Ti(OiPr)4 (1.08 mL, 3.68 mmol) were added subsequently to a stirred solution of flame
dried 4Å powdered molecular sieve (4.9 g) in dry CH2Cl2 (65 mL) at −20 °C and stirred for 30 min. The
corresponding trans-allyl alcohol (8.0 g, 24.5 mmol) in dry CH2Cl2 (15 mL) was added to the reaction
mixture and stirred for another 30 min at the same temperature. TBHP (76.5 M in toluene, 5 mL, 49
mmol) was added and the resulting mixture was stirred at the same temperature for overnight. It was then
warmed to 0 °C, quenched with water (21 mL), followed by 20% aqueous NaOH solution (5 mL) and
stirred until clear separation of two layers occurred. It was filtered through a Celite pad. The filtrate was
extracted with CH2Cl2 (3 × 100 mL) and washed with brine (2 × 50 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:4) to get pure epoxy alcohol 9 (7.1 g, 85%) as a yellowish oil.
Rf = 0.46 (SiO2, 20% ethyl acetate in hexane). [α]D29 = −7.1 (c = 0.05, CHCl3); IR (neat) νmax = 3349,
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3071, 2932, 2860, 1468, 1428, 1110 cm–1; H NMR (300 MHz, CDCl3): δ = 7.70–7.67 (m, 4H), 7.46–
7.36 (m, 6H), 3.95 (m, 1H), 3.88 (dd, J = 11.8, 3.0 Hz, 1H), 3.72 (dd, J = 12.1, 4.3 Hz, 1H), 3.63 (m, 1H),
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3.17 (m, 1H), 3.08 (m, 1H), 1.05 (s, 9H); C NMR (75 MHz, CDCl3): δ = 135.6, 135.5, 129.8, 127.7,
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63.2, 61.2, 55.7, 55.6, 26.7, 19.2; HRMS (ESI): m/z calcd. for C20H26O3NaSi [M + Na]+: 365.1543; found
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365.1546.
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(E)-Ethyl 3-((2S,3S)-3-((tert-butyldiphenylsilyloxy)methyl)oxiran-2-yl)acrylate (7): To a solution
of oxalyl chloride (2.6 mL, 30.7 mmol) in CH2Cl2 (60 mL), was added DMSO (3.6 mL, 51.2 mmol) at –
78 °C under nitrogen atmosphere and stirred for 20 min. A solution of epoxy alcohol 9 (7.0 g, 20.4 mmol)
in CH2Cl2 (15 mL) was added and stirred for 45 min. Then triethylamine (11.3 mL, 81.9 mmol) was
added, and the stirring continued for 20 min. The mixture was allowed to warm to 0 °C. After completion
of reaction (as monitored by TLC), it was quenched with water (30 mL). The reaction mixture was
extracted with CH2Cl2 (3 × 100 mL), and the combined extract was washed with water (100 mL) and
brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude
aldehyde was used for the next step immediately without further purification. To a stirred solution of the
crude aldehyde in benzene (50 mL) was added ethoxycarbonylmethylene triphenylphosphorane (7.83 g,
22.5 mmol) at room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced
pressure and purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to afford the
desired unsaturated ester compound 7 (7.4 g, 89%) as yellowish viscous liquid. Rf = 0.45 (SiO2, 10%
ethyl acetate in hexane); [α]D29 = −14.2 (c = 0.48, CHCl3); IR (neat) νmax = 3071, 2958, 2933, 2859, 1722,
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1658, 1266, 1137, 1110 cm–1; H NMR (500 MHz, CDCl3): δ = 7.70–7.65 (m, 4H), 7.47–7.37 (m, 6H),
6.66 (dd, J = 15.8, 7.2 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.83 (d, J = 3.7 Hz,
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2H), 3.36 (dd, J = 7.1, 1.6 Hz, 1H), 3.08 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H); C NMR (100
MHz, CDCl3): δ = 165.6, 144.0, 135.5, 132.9, 129.8, 127.8, 124.0, 62.9, 60.8, 60.6, 53.8, 26.7, 19.2, 14.2;
HRMS (ESI): m/z calcd. for C24H30O4NaSi [M + Na]+: 433.1805; found 433.1819.
(4S,5S,E)-Ethyl-6-(tert-butyldiphenylsilyloxy)-5-hydroxy-4-(4-methoxybenzyloxy)hex-2-enoate
(10): To a solution of an α,β-unsaturated γ,δ-epoxy ester 7 (5.5 g, 13.4 mmol) in THF (15 mL) was added
triphenyl borate (5.83 g, 20.1 mmol)), PMB-OH (6.3 mL, 60.3 mmol), and catalytic amount of Pd(PPh3)4
(1.34 g, 10 mol%) and the resulting reaction mixture was stirred at 0 °C for 2 h. After completion of the
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reaction (as monitored by TLC), it was passed through a short silica gel column by the aid of ethyl acetate
(100 mL) and the eluent was concentrated under reduced pressure to furnish the crude product. The crude
product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:10) to afford 10 (6.1
g, 83%) as pale yellow oil. Rf = 0.52 (SiO2, 20% ethyl acetate in hexane); [α]D29 = +5.3 (c = 0.92, CHCl3);
IR (neat) νmax = 3517, 2933, 2859, 1719, 1514, 1250, 1110 cm–1; 1H NMR (300 MHz, CDCl3): δ = 7.65–
7.63 (m, 4H), 7.45–7.35 (m, 6H), 7.20 (d, J = 8.6 Hz, 2H), 6.94 (dd, J = 15.8, 6.6 Hz, 1H), 6.87 (d, J =
8.6 Hz, 2H), 6.11 (d, J = 15.8 Hz, 1H), 4.58 (d, J = 11.1 Hz, 1H), 4.31 (d, J = 11.1 Hz, 1H), 4.23 (q, J =
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7.2 Hz, 3H), 3.79 (s, 3H), 3.73–3.67 (m, 3H), 2.50 (br s, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.03 (s, 9H); C
NMR (75 MHz, CDCl3): δ = 165.8, 159.4, 144.8, 135.5, 132.9, 129.8, 129.6, 129.5, 127.7, 123.8, 113.8,
77.5, 73.5, 71.3, 63.8, 60.5, 55.2, 26.8, 19.2, 14.2; HRMS (ESI): m/z calcd. for C32H40O6NaSi [M + Na]+:
571.2486; found 571.2479.
(4S,5S,E)-6-(tert-Butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy)hex-2-ene-1,5-diol (6): DIBAL-H
(25 wt% in toluene, 14.3 mL, 25.1 mmol) was added slowly to a stirred solution of α,β-unsaturated ester
10 (4.6 g, 8.4 mmol) in CH2Cl2 (30 mL) at −78 °C and stirring was continued for 30 min. After
completion of the reaction, it was quenched by slow addition of methanol (5 mL) and followed by
saturated aqueous solution of sodium potassium tartrate (50 mL), diluted with CH2Cl2 (150 mL) and
allowed to stir at room temperature to get separated layers. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 70 mL). The combined organic layers were washed with
brine (2 × 75 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude
product on silica gel column chromatography (ethyl acetate/hexane = 3:7) afforded aldehyde 6 (3.86 g,
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91%) as light yellowish oil. Rf = 0.35 (SiO2, 40% ethyl acetate in hexane); [α]D = +13.5 (c = 1.6,
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CHCl3); IR (neat) νmax = 3448, 2927, 2855, 1690, 1614, 1513, 1248, 1109, 1035 cm–1; H NMR (300
MHz, CDCl3): δ = 9.54 (d, J = 7.9 Hz, 1H), 7.66–7.60 (m, 4H), 7.47–7.35 (m, 6H), 7.18 (d, J = 8.5 Hz,
2H), 6.86 (d, J = 8.5 Hz, 2H), 6.79 (dd, J = 15.9, 5.8 Hz, 1H), 6.32 (dd, J = 15.9, 7.9 Hz, 1H), 4.56 (d J =
11.3 Hz, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.33 (m, 1H), 3.80 (s, 3H), 3.76–3.68 (m, 3H), 2.52 (br s, 1H),
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1.05 (s, 9H); C NMR (125 MHz, CDCl3): δ = 193.0, 159.4, 153.6, 135.5, 133.5, 132.8, 129.8, 129.6,
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129.1, 127.7, 113.9, 77.5, 73.4, 71.7, 63.8, 55.2, 26.8, 19.1; HRMS (ESI): m/z calcd. for C30H36O5NaSi
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[M + Na]+: 527.2224; found 527.2225.
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(((2S,3S,6S)-6-Allyl-3-(4-methoxybenzyloxy)-3,6-dihydro-2H-pyran-2-yl)methoxy)(tert-butyl)
diphenylsilane (5): To a stirred solution of δ-hydroxy α,β-unsaturated aldehyde 6 (3.0 g, 5.9 mmol) and
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o
allyltrimethylsilane (2.37 mL, 14.8 mmol) in THF (25 mL) was added iodine (0.30 g, 1.2 mmol) at 0 C
and allowed to warm to room temperature. After completion of the reaction (as indicated by TLC), it was
quenched with saturated solution of Na2S2O3 (10 mL) and diluted with diethyl ether (40 mL). The
aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic layers were washed
with brine (2 × 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to obtain
the cyclized product 5 (2.73 g, 87%) as light yellow oil. Rf = 0.45 (SiO2, 10% ethyl acetate in hexane);
[α]D29 = +21.0 (c = 1.2, CHCl3); IR (neat) νmax = 3100, 2922, 2853, 1731, 1640, 1513, 1464, 1429, 1360,
1247, 1120, 1036 cm–1; 1H NMR (300 MHz, CDCl3): δ = 7.73–7.66 (m, 4H), 7.42–7.34 (m, 6H), 7.17 (d,
J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.91–5.89 (m, 2H), 5.79 (m, 1H), 5.07–4.99 (m, 2H), 4.54 (d, J
= 11.5 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.24 (m, 1H), 3.98–3.80 (m, 4H), 3.79 (s, 3H), 2.34 (m, 1H),
2.20 (m, 1H), 1.07 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 159.1, 135.6, 134.8, 134.5, 133.2, 130.8, 129.6,
129.3, 127.6, 124.3, 117.1, 113.6, 72.5, 71.9, 70.6, 67.8, 62.5, 55.2, 37.3, 26.9, 19.2. HRMS (ESI): m/z
calcd. for C33H40O4SiNa [M + Na]+: 551.2588, found 551.2601.
2-((2S,5S,6S)-6-((tert-Butyldiphenylsilyloxy)methyl)-5-(4-methoxybenzyloxy)-5,6-dihydro-2H-
pyran-2-yl)acetaldehyde (11): To a stirred solution of cyclized compound 5 (2.4 g, 4.5 mmol) in 1,4-
dioxane (25 mL), was added 2,6-lutidine (2.1 mL, 18.2 mmol), NaIO4 (3.87 g, 18.2 mmol) and OsO4 (1
M solution in toluene, 0.1 mL, 0.45 mmol) and stirring was continued at room temperature. After
completion, the reaction was quenched with solid NaHSO3 (15 mL). 1,4-Dioxane was removed under
reduced pressure and the aqueous layer was extracted with ethyl acetate (3 × 60 mL). The combined
organic layer was washed with 1N HCl (2 × 50 mL) to remove excess 2,6-lutidine, dried over anhydrous
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Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column
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chromatography (ethyl acetate/hexane = 1:8) to give aldehyde 11 (1.75 g, 73%) as a light yellowish
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liquid. Rf = 0.40 (SiO2, 20% ethyl acetate in hexane). [α]D = +37.0 (c = 0.55, CHCl3); IR (neat) νmax
=
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3448, 3069, 2930, 2856, 1725, 1612, 1512, 1248, 1109, 1033 cm–1; 1H NMR (500 MHz, CDCl3): δ = 9.74
(t, J = 1.9 Hz, 1H), 7.68–7.65 (m, 4H), 7.45–7.32 (m, 6H), 7.15 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz,
2H), 5.99–5.83 (m, 2H), 4.78 (m, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.97–3.81 (m,
4H), 3.79 (s, 3H), 2.66 (ddd, J = 16.4, 8.7, 2.6 Hz, 1H), 2.46 (ddd, J = 16.4, 4.9, 1.9 Hz, 1H), 1.06 (s, 9H);
13C NMR (75 MHz, CDCl3): δ = 200.5, 159.1, 135.6, 133.5, 131.7, 130.4, 129.7, 129.3, 127.7, 125.4,
113.7, 72.8, 70.6, 67.6 (d), 62.2, 55.2, 46.2, 26.8, 19.2; HRMS (ESI): m/z calcd. for C32H38O5NaSi [M +
Na]+: 553.2380; found 553.2410.
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(S)-1-((2R,5S,6S)-6-((tert-Butyldiphenylsilyloxy)methyl)-5-(4-methoxybenzyloxy)-5,6-dihydro-
2H-pyran-2-yl)ethane-1,2-diol (12): To a stirred solution of aldehyde 11 (1.0 g, 1.88 mmol) in dry
DMSO (6 mL), nitroso benzene (0.20 g, 1.8 mmol) was added under nitrogen atmosphere and stirred for
five minutes. L-proline (43 mg, 0.37 mmol) was added and stirred until color changed from green to deep
orange. Then methanol (10 mL) was added to the reaction mixture and cooled to 0 oC. NaBH4 (0.10 g, 2.8
mmol) was added portion wise and further stirred for 30 min. After complete disappearance of the starting
material (as monitored by TLC), methanol was removed under reduced pressure and the reaction mixture
was quenched with saturated aqueous solution of NH4Cl (20 mL). The aqueous layer was extracted with
ethyl acetate (3 × 60 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give
deep orange colored syrup. The crude mass was dissolved in methanol and CuSO4.5H2O (0.08 g, 0.3
mmol) was added at room temperature and stirred overnight. After removal of methanol from the reaction
mixture, saturated aqueous solution of NH4Cl (30 mL) was added and extracted with ethyl acetate (3 × 50
mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by using silica gel column chromatography (ethyl
acetate/hexane = 1:1) to afford diol 12 (0.55 g, 62% over 2 steps) as a yellowish oil. Rf = 0.2 (SiO2, 60%
ethyl acetate in hexane). [α]D29 = +31.4 (c = 0.4, CHCl3); IR (neat) νmax = 3446, 2931, 2857, 1612, 1512,
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1248, 1108 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.71–7.65 (m, 4H), 7.46–7.35 (m, 6H), 7.09 (d, J = 8.7
Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.14–5.89 (m, 2H), 4.46 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 11.6 Hz,
1H), 4.16 (m, 1H), 3.95–3.68 (m, 10H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 159.1, 135.6, 133.3,
130.4, (130.2), 129.7, (129.6), 129.3, 127.7, 125.9, 125.4, 113.7, 74.2 (74.0), (73.5) 72.9, 72.4 (71.2),
70.4, 67.8 (67.4), 64.4, (63.2), 62.5, 55.2, 26.8, 19.1; HRMS (ESI): m/z calcd. for C32H40O6NaSi [M +
Na]+: 571.2486; found 571.2475.
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tert-Butyl(((2S,3S,6R)-3-(4-methoxybenzyloxy)-6-((S)-oxiran-2-yl)-3,6-dihydro-2H-pyran-2-yl)
methoxy)diphenylsilane (13): Diol compound 12 (0.54 g, 0.99 mmol) in THF (10 mL) was added
dropwise to a stirred suspension of NaH (60 wt% dispersion in mineral oil, 0.06 g, 1.50 mmol) in dry
THF (15 mL) at 0 oC. After 30 min stirring, tosyl-imidazole (0.26 g, 1.2 mmol) was added to the reaction
mixture and stirring was continued for another 1 h. The reaction was quenched by addition of water. The
reaction mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (ethyl acetate/hexane = 1:8) to afford required epoxy compound 13
(0.301 g, 58.1%) and the other isomer (0.129g, 24.9%) as a pale yellow liquid. Rf = 0.45 (SiO2, 20% ethyl
acetate in hexane). [α]D29 = +61.2 (c = 0.4, CHCl3); IR (neat) νmax = 3450, 2925, 2854, 1736, 1613, 1512,
1248, 1109, 1036 cm–1; 1H NMR (300 MHz, CDCl3): δ = 7.71–7.65 (m, 4H), 7.46–7.32 (m, 6H), 7.16 (d,
J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.07 (ddd, J = 10.1, 4.7, 2.1 Hz, 1H ), 5.92 (dd, J = 10.4, 3.0
Hz, 1H ), 4.54 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.13 (m, 1H), 4.01–3.83 (m, 4H), 3.79 (s,
3H), 3.02 (m, 1H), 2.74 (dd, J = 4.9, 4.1 Hz, 1H), 2.60 (dd, J = 4.9, 2.6 Hz, 1H), 1.07 (s, 9H); 13C NMR
(75 MHz, CDCl3): δ = 159.7, 135.6, 133.5, 129.6, 129.4, 128.8, 127.6, 127.2, 126.6, 113.7, 74.5, 72.5,
70.7, 67.3, 62.7, 55.2, 52.3, 44.8, 26.9, 19.2; HRMS (ESI): m/z calcd. for C32H38O5NaSi [M + Na]+:
553.2380; found 553.2381.
(S)-1-((2R,5S,6S)-6-((tert-Butyldiphenylsilyloxy)methyl)-5-(4-methoxybenzyloxy)-5,6-dihydro-
2H-pyran-2-yl)ethanol (14): To a stirred solution of epoxide 13 (0.37 g, 0.69 mmol) in dry THF (10
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mL), was added super-hydrideTM (1 M solution in THF, 3.49 mL, 3.49 mmol) dropwise at 0 C. After
completion of the reaction (as monitored by TLC), it was quenched by slow addition of water (5 mL) and
extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product was purified by column chromatography on
silica gel (ethyl acetate/hexane = 1:7) to afford compound 14 (0.29 g , 79%) as a yellowish oil. Rf = 0.5
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(SiO2, 30% ethyl acetate in hexane). [α]D = +52.0 (c = 0.8, CHCl3); IR (neat) νmax = 3449, 2928, 2856,
1615, 1252, 1104, 1034 cm–1; H NMR (300 MHz, CDCl3): δ = 7.72–7.65 (m, 4H), 7.45–7.35 (m, 6H),
1
7.10 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 6.05–5.92 (m, 2H), 4.50 (d, J = 12.1 Hz, 1H), 4.40 (d, J
= 12.1 Hz, 1H), 3.94–3.89 (m, 3H), 3.86–3.80 (m, 2H), 3.78 (s, 3H), 3.71 (m, 1H), 1.21 (d, J = 6.0 Hz,
3H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 159.1, 135.6, 133.6, 130.3, 129.6, 129.3, 128.7, 127.6,
126.6, 113.7, 74.7, 74.4, 70.6, 69.4, 68.6, 61.6, 55.2, 26.9, 19.2, 18.0; HRMS (ESI): m/z calcd. for
C32H40O5NaSi [M + Na]+: 555.2537; found 555.2520.
(S)-(S)-1-((2R,5S,6S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-((4-methoxybenzyl)oxy)-5,6-
dihydro-2H-pyran-2-yl)ethyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (14a): To a solution of
(R)-(–)-α-methoxy-α-trifluoromethylphenylacetic acid [(R)-MTPA] (17 mg, 74 μmol) in dry toluene (1.5
mL) at 0 °C were added Et3N (20 μL, 150 μmol) and 2,4,6-Cl3C6H2COCl (30 μL, 112 μmol). The reaction
mixture was stirred at room temperature for 30 min. Then the alcohol 14 (20 mg, 37 μmol) in toluene (0.5
mL) and DMAP (2 mg) were added to the reaction mixture at 0 °C. The resulting solution was stirred at
room temperature for 3 h and the progress of the reaction was monitored by TLC. After complete
consumption of starting material, the reaction mixture was directly concentrated under reduced pressure
and purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to afford (R)-MTPA ester
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14a (19 mg, 70%) as a light yellowish liquid. H NMR (500 MHz, CDCl3): δ 7.70–7.66 (m, 4H), 7.52–
7.49 (m, 2H), 7.44–7.35 (m, 9H), 7.10 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.89 (ddd, J = 10.5,
4.7, 2.1 Hz, 1H), 5.62 (dd, J = 10.5, 2.4 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 11.6 Hz, 1H),
4.03 (m, 1H), 3.86–3.79 (m, 3H), 3.78 (s, 3H), 3.73 (m, 1H), 3.60 (q, J = 7.2 Hz, 1H), 3.55 (s, 3H), 1.39
(d, J = 6.3 Hz, 3H), 1.06 (s, 9H).
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(R)-(S)-1-((2R,5S,6S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-((4-methoxybenzyl)oxy)-5,6-
dihydro-2H-pyran-2-yl)ethyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (14b): To a solution of
(S)-(–)-α-methoxy-α-trifluoromethylphenylacetic acid [(S)-MTPA] (8 mg, 37 μmol) in dry toluene (1.0
mL) at 0 °C were added Et3N (10 μL, 75 μmol) and 2,4,6-Cl3C6H2COCl (15 mL, 56 μmol), and the
resulting mixture was stirred at room temperature for 30 min. Then the alcohol 14 (10 mg, 18 μmol) in
toluene (0.5 mL) and DMAP (1 mg) were added to the reaction mixture at 0 °C. The resulting solution
was stirred at room temperature for 3 h and the progress of the reaction was monitored by TLC. After
complete consumption of the starting material, the reaction mixture was directly concentrated under
reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to
afford (S)-MTPA ester 14b (11 mg, 75%) as a light yellowish liquid. Rf = 0.6 (SiO2, 10% ethyl acetate in
hexane); 1H NMR (500 MHz, CDCl3): δ 7.69–7.66 (m, 4H), 7.53–7.49 (m, 2H), 7.41–7.35 (m, 9H), 7.12
(d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.96 (ddd, J = 10.5, 4.2, 2.1 Hz, 1H), 5.84 (dd, J = 10.5, 2.1
Hz, 1H), 4.46 (d, J = 11.4 Hz, 1H), 4.40 (d, J = 11.4 Hz, 1H), 4.11 (m, 1H), 3.90–3.80 (m, 3H), 3.79 (s,
3H), 3.60 (q, J = 7.2 Hz, 2H), 3.51 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.06 (s, 9H).
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tert-Butyl(((2S,3S,6R)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxybenzyloxy)-3,6-
dihydro-2H-pyran-2-yl)methoxy)diphenylsilane (15): To a stirred solution of alcohol 14 (0.25 g, 0.47
mmol) in CH2Cl2 (10 mL) under nitrogen atmosphere, was added 2,6-lutidine (0.08 mL, 0.70 mmol)
o
followed by TBSOTf (0.13 mL, 0.56 mmol) dropwise at 0 C and allowed to stir for 30 min. After
completion of the reaction (monitored by TLC), it was quenched with water (20 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 25 mL) and washed with 1 N HCl (2 × 25 mL) to remove excess 2,6-
lutidine. The organic layer was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, evaporated
to dryness under reduced pressure to obtain the crude product which on purification by silica gel column
chromatography (ethyl acetate/hexane = 1:19) furnished the desired TBS-ether 15 (0.28 g, 93%) as a
yellowish liquid. Rf = 0.35 (SiO2, 5% ethyl acetate in hexane); [α]D29 = +93.0 (c = 0.55, CHCl3); IR (neat)
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ν
max= 2930, 2853, 1725, 1615, 1400, 1255, 1084 cm–1; H NMR (500 MHz, CDCl3): δ = 7.69–7.67 (m,
4H), 7.44–7.33 (m, 6H), 7.15 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 6.17 (dd, J = 10.5, 2.9 Hz,
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1H), 5.94 (ddd, J = 10.4, 4.6, 2.1 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 3.90 (dd, J
= 10.5, 5.7 Hz, 1H), 3.84–3.70 (m, 8H), 1.19 (d, J = 6.1 Hz, 3H), 1.07 (s, 9H), 0.88 (s, 9H), 0.05 (s, 3H),
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0.02 (s, 3H); C NMR (75 MHz, CDCl3): δ = 159.1, 135.7, 133.6, 132.3, 130.8, 129.6, 129.4, 127.7,
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124.2, 113.7, 76.6, 73.8, 70.4, 69.5, 67.5, 62.8, 55.3, 26.9, 25.8, 21.4, 19.2, 18.0, −4.2, −4.8; HRMS
(ESI): m/z calcd. for C38H54O5NaSi2 [M + Na]+: 669.3402; found 669.3429.
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((2S,3S,6R)-6-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-(4-methoxybenzyloxy)-3,6-dihydro-2H-
pyran-2-yl)methanol (16): NH4F (0.07 g, 1.85 mmol) was added to a stirred solution of 15 (0.20 g, 0.31
mmol) in anhydrous MeOH (6 mL) at room temperature. The reaction mixture was allowed to stir
overnight. After complete consumption of stating material (monitored by TLC), MeOH was removed
under vacuum and quenched by saturated aqueous solution of NH4Cl (10 mL). The aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (5 mL),
dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by
silica gel column chromatography (ethyl acetate/hexane = 1:6) to yield alcohol 16 (0.11 g, 85%) as a
colorless liquid. Rf = 0.2 (SiO2, 20% ethyl acetate in hexane); [α]D29 = +71.4 (c = 0.55, CHCl3); IR (neat)
ν
max = 3450, 2925, 2854, 1728, 1614, 1461, 1250 cm–1; 1H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 8.7
Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.07 (ddd, J = 10.5, 4.1, 2.6 Hz, 1H), 5.97 (dd, J = 10.5, 2.6 Hz, 1H),
4.61 (d, J = 11.4 Hz, 1H), 4.48 (d, J = 11.4 Hz, 1H), 4.19 (m, 1H), 4.10 (ddd, J = 8.7, 4.9, 3.9 Hz, 1H),
3.95–3.84 (m, 3H), 3.80 (s, 4H), 1.16 (d, J = 6.3 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 159.3, 131.9, 130.1, 129.4, 123.6, 113.9, 76.5, 72.9, 70.2, 69.6, 68.5, 62.4,
55.3, 25.8, 21.2, 17.9, −4.3, −4.8; HRMS (ESI): m/z calcd. for C22H36O5NaSi [M + Na]+: 431.2224; found
431.2225.
(Z)-Methyl-3-((2S,3S,6R)-6-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-((4-methoxybenzyl)oxy)-
3,6-dihydro-2H-pyran-2-yl)acrylate (4): IBX (0.15 g, 0.55 mmol) was added to a stirred solution of
alcohol 16 (0.09 g, 0.22 mmol) in CH3CN (9 mL) and refluxed for 3 h. After complete consumption of
the starting material (as monitored by TLC), the reaction mixture was diluted with tert-butylmethyl ether
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(30 mL) and the solid precipitates were filtered using Celite bed. The residue was washed with tert-
butylmethyl ether (2 × 30 mL). The colorless filtrate was washed with saturated aqueous NaHCO3
solution (2 × 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to get crude aldehyde
as a yellow liquid which was directly used for the next reaction without further purification.
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To a stirred suspension of NaH (60 wt% dispersion in mineral oil, 5 mg, 135 μmol) in THF (5 mL) at 0
°C under argon atmosphere, was added bis(2,2,2-trifluroethyl)methylphosphonate (43 mg, 135 μmol) and
stirred for 30 min at the same temperature. The reaction mixture was cooled to −78 °C and a solution of
crude aldehyde (50 mg, 123 μmol) in THF (2 mL) was added dropwise. After the mixture was stirred for
1 h, the reaction was quenched by slow addition of water (5 mL) at 0 oC and extracted with ethyl acetate
(3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:12) to obtain unsaturated ester 4 (44 mg, 78%) as a colorless
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liquid. Rf = 0.3 (SiO2, 10% ethyl acetate in hexane); [α]D = +88.0 (c = 0.16, CHCl3); IR (neat) νmax
=
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2928, 2856, 1732, 1636, 1515, 1250, 1178 cm–1; H NMR (500 MHz, CDCl3): δ = 7.21 (d, J = 8.7 Hz,
2H), 6.84 (d, J = 8.7 Hz, 2H), 6.43 (dd, J = 11.9, 7.6 Hz, 1H), 6.19 (dd, J = 10.5, 3.5 Hz, 1H), 5.98 (ddd, J
= 10.5, 4.6, 2.1 Hz, 1H), 5.91 (dd, J = 11.7, 1.4 Hz, 1H), 5.36 (ddd, J = 7.6, 3.2, 1.4 Hz, 1H), 4.49 (ABq,
J = 11.7 Hz, ∆ν = 17.4 Hz, 2H), 4.06 (m, 1H), 3.91–3.82 (m, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 1.19 (d, J =
13
5.8 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); C NMR (125 MHz, CDCl3): δ = 166.2, 159.1,
147.5, 131.2, 130.5, 129.4, 124.5, 120.2, 113.6, 76.6, 70.7, 69.9, 69.6, 69.0, 55.2, 51.3, 25.8, 21.3, 17.9,
−4.3, −4.8; HRMS (ESI): m/z calcd. for C25H38O6NaSi [M + Na]+: 485.2329; found 485.2344.
(4aS,6R,8aS)-6-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-6,8a-dihydropyrano[3,2-b]pyran-
2(4aH)-one (17): To a stirred solution of compound 4 (35 mg, 75 μmol) in CH2Cl2 (5 mL) and pH =7
buffer (0.5 mL) was added DDQ (20 mg, 90 μmol) at 0 oC and allowed to stir at same temperature. After
completion of the reaction (as monitored by TLC), it was quenched with saturated aqueous solution of
NaHCO3 (15 mL). Aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The combined organic layer
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was washed with brine (2 × 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure. As the product was unstable, we proceeded for next step without purification and
characterization. PTSA (2 mg, 13.4 μmol) was added to a stirred solution of crude compound (23 mg, 67
μmol) dissolved in dry benzene (5 mL) at room temperature and stirred for 1 h. The reaction mixture was
quenched by aqueous solution of NaHCO3 (5 mL) and extracted with ethyl acetate (3 × 10 mL). The
combined organic layer was washed with brine (2 × 15 mL) and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 3:7) to
obtain lactone 17 (20 mg, 86% over 2 steps) as a colorless liquid. Rf = 0.5 (SiO2, 20% ethyl acetate in
hexane); [α]D29 = +41.0 (c = 0.19, CHCl3); IR (neat) νmax = 2926, 2854, 1732, 1463, 1371, 1253, 1099 cm–
1; 1H NMR (500 MHz, CDCl3): δ = 6.85 (dd, J = 10.0, 3.9 Hz, 1H), 6.23 (ddd, J = 10.5, 2.3, 1.3 Hz, 1H),
6.10 (dd, J = 10.0, 1.5 Hz, 1H), 6.00 (ddd, J = 10.5, 3.7, 2.3 Hz, 1H), 4.83 (m, 1H), 4.70 (m, 1H), 3.92
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(m, 1H), 3.87 (q, J = 6.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); C
NMR (100 MHz, CDCl3): δ = 162.2, 143.5, 132.0, 123.5, 122.4, 76.1, 70.2, 69.8, 63.7, 25.7, 20.7, 17.9,
−4.3, −4.8; HRMS (ESI): m/z calcd. for C16H27O4Si [M + H]+: 311.1673; found 311.1658.
(4aS,6R,8aS)-6-((S)-1-Hydroxyethyl)-6,8a-dihydropyrano[3,2-b]pyran-2(4aH)-one (2):
To a stirred solution 17 (15 mg, 48 μmol) in dry THF (5 mL) in a polypropylene vial, was added
HF.pyridine complex (70% solution, 0.02 mL) at 0 °C. The reaction mixture was slowly raised to
room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), it
was cautiously poured into saturated aqueous NaHCO3 (5 mL), diluted with ethyl acetate (10
mL) and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with
ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated aqueous
CuSO4 (5 mL), water (5 mL), brine (5 mL) and dried over Na2SO4. The crude product was
purified by silica gel column chromatography (ethyl acetate/hexane = 3:7) to afford compound 2
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(8.5 mg, 90%) as a light yellowish liquid. Rf =0.3 (SiO2, 40% ethyl acetate in hexane). [α]D
=
+49.0 (c = 0.28, CHCl3); lit.5 [α]D25 +67.6 (c = 0.25, CHCl3)}; IR (neat) νmax = 3418, 2922, 2853,
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1716, 1633, 1461, 1377, 1256, 1058 cm–1; 1H NMR (500 MHz, CDCl3): δ = 6.88 (ddd, J = 10.0,
3.1, 1.0 Hz, 1H), 6.07 (dd, J = 10.0, 1.6 Hz, 1H), 6.06 (td, J = 10.5, 1.6, 1.6 Hz, 1H), 6.04 (td, J =
10.5, 2.6, 2.6 Hz, 1H), 4.97 (m, J = 5.6, 2.6, 2.6, 1.6, 1.0 Hz, 1H), 4.92 (ddd, J = 5.6, 3.1, 1.6 Hz,
1H), 4.08 (ddt, J = 4.2, 2.6, 2.6, 1.6 Hz, 1H), 3.96 (dd, J = 6.4, 4.2 Hz, 1H), 1.25 (d, J = 6.4 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ = 161.7, 144.2, 129.6, 124.7, 123.3, 74.8, 70.0, 69.7, 64.9,
18.7; HRMS (ESI): m/z calcd. for C10H13O4 [M + H]+: 197.0808; found 197.0798.
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Acknowledgments. The authors thank Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial support as part of the XII Five Year plan programme under the
title ORIGIN (CSC-0108). S.M. and S.K. thank the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for financial assistance in the form of fellowship.
Supporting Information Available: Copies of 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
(2) (a) Jewers, J. R.; Davies, J. B.; Dougan, J.; Manchanda, A. H.; Blunden, G.; Kyi, A.;
Wetchainan, S. Phytochemistry 1972, 11, 2025. (b) Hoffmann, H. M. R; Rabe, J. Angew.
Chem. Int. Ed. 1985, 24, 94. (c) Pihie, A. H. L.; Stanslas, J.; Din, L. B. Anticancer Res.
1998, 18, 1739. (d) Hawariah, A.; Stanslas, J. Anticancer Res. 1998, 18, 4383. (e) Tanaka,
S.; Yoichi, S.; Ao, L.; Matumoto, M.; Morimoto, K.; Akimoto, N.; Honda, G.; Tabata, M.;
Oshima, T.; Masuda, T.; Asmawi, M. Z.; Ismail, Z.; Yusof, S. M.; Din, L. B.; Said, I. M.
Phytother. Res. 2001, 15, 681.
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