Asymmetric total syntheses of naturally occurring α,β-enone-containing RALs, L-783290 and L-783277 through intramolecular base-mediated macrolactonization reaction

Article abstract of DOI:10.1039/d0ob00237b

Asymmetric total synthesis of two naturally occurring α,β-enone containing RALs, L-783290 and L-783277 is described in this article. An E-selective Horner-Wadsworth-Emmons (HWE) olefination was used as a key reaction to construct the C_7′-C_8′ olefinic unsaturation in L-783290. An enantiopure alkyne addition to the aldehyde followed by Z-selective partial reduction was employed to construct the C_7′-C_8′ olefinic unsaturation in L-783277. Biomimetic lactonization reaction was used to construct the macrolactone core in both the target molecules.

Full text of DOI:10.1039/d0ob00237b

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Asymmetric total syntheses of naturally occurring α,β-enone-containing RALs, L-783290
DOI: 10.1039/D0OB00237B
and L-783277 through intramolecular base-mediated macrolactonization reaction
Joy Chakraborty,1 Ankan Ghosh 1,2 and Samik Nanda*1
1 Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur.
2 Department of Chemistry, University of Texas at Austin, Austin, TX, USA
Abstract: Asymmetric total synthesis of two naturally occurring α,β-enone containing RALs,
L-783290 and L-783277 is described in this article. An E-selective Horner-Wadsworth-
Emmons (HWE) olefination was used as a key reaction to construct the C7´-C8´ olefinic
unsaturation in L-783290. An enantiopure alkyne addition to the aldehyde followed by Z-
selective partial reduction was employed to construct the C7´-C8´ olefinic unsaturation in L-
783277. Biomimetic lactonization reaction was used to construct the macrlactone core in both
the target molecules.
Introduction: Resorcylic acid lactones (RALs)1 are a unique class of fungal secondary
metabolites defined by the presence of a β-resorcylic acid ring and a 14-membered lactone
macrocycle with a methyl substituent at the C10'-position in its core structure.1 RALs have
received considerable attention, due to their diversified biological properties, which include
antifungal, cytotoxic, antimalarial, antiviral, antiparasitic, estrogenic, nematicidal, protein
tyrosine kinase, and ATPase inhibition activities.2 RALs containing an “α,β-enone” moiety in
its structure is susceptible to Michael addition reactions with the cysteine residue present in the
kinase nucleotide-binding site and thus serve as potent inhibitors of several protein kinases and
they, therefore, represent a unique pharmacophore.3 Some members of this family are LL-
Z1640-2 (3), which was first isolated as an anti protozoan from unidentified fungi by Ellestad
et al. 4 in 1978. L-783277 (1) was isolated from a Phoma sp (ATCC 74403) which came from
the fruit body of Helvella acetabulum, is a potent and specific inhibitor of MEK.5 L-783290
(2), the trans-isomer of L-783277 (1), was isolated from the same culture but RALs bearing
the cis-enone moiety such as hypothemycin (4), LL-Z1640-2 and L-783277 are more potent
than the trans-enone L-783290 (Figure 1).6 Pochonin C (5) and D (6) are also “α,β-enone”
containing RALs and isolated from the cultures of the clavicipitaceous hyphomycete Pochonia
chlamydosporia var. catenulata strain P 0297 in 2003 and found to possess antiviral activity
against HSV (Herpes Simplex Virus).7 The first example of a naturally occurring RAL,
1

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radicicol (8), was isolated from Monocillium nordinii in 1953 happened to contDaOinI: 1a0.n103“9α/D,0βO-B00237B
enone” moiety (E-enone) in its structure.8 Structurally similar to radicicol, another RAL
monocillin I (7) was also isolated from the same species and showed to exhibit moderate
antifungal and antibacterial activities. Cryptosporiopsin A (9) isolated from Cryptosporiopsis
sp, an endophytic fungus from healthy leaves, stems and branches of Zanthoxylum leprieurii,
having an E-enone functionality and a carbonyl group at C6ʹ position.9 Due to the broad
spectrum of bioactivity and the architecturally complex structure of these molecules, synthetic
organic chemist community has targeted these molecules for total synthesis and biosynthetic
study. The first synthesis of L-783277 was achieved by Altmann et al. in the year 2008, through
the successful exploration of Suzuki coupling and a late-stage macrolactonization reaction.10
Whereas Banwell’s group reported the first synthesis of L-783290 (the E-counterpart of L-
783277) through the exploitation of Heck coupling and intramolecular Weinreb ketone
synthesis followed by other synthetic manipulation.11 Subsequently, few other total syntheses
for the above two target molecules were reported in the literature.12 Our previous endeavor in
the asymmetric synthesis of several naturally occurring RALs, lead us to the total synthesis of
paecilomycin C, cochliomycin A, cochliomycin C, paecilomycin E, zeaenol etc. by the
successful exploration of several strategically important reactions such as ME-DKR (metal
enzyme combined dynamic kinetic resolution), Keck asymmetric allylation, E-selective Julia-
Kocienski olefination, RCM reaction, lactonization through intramolecular ring opening of an
epoxide and macrolactonization (Yamaguchi and Mitsunobu) protocol.13 Recent investigation
14
has revealed that biosynthesis of RALs involves a late-stage macrolactonization protocol.
Hence we argue that late-stage macrolactonization protocol for synthesizing RALs mimic the
biogenesis in true sense. Henceforth we would like to focus on the late-stage macrocyclization
protocol (-CO2H activation or -OH activation method) at the penultimate stage for the total
synthesis of RALs.
2

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8'
DOI: 10.1039/D0OB00237B
9'
OH
O
OH
O
7'
OH
O
10'
2
6'
5'
HO
1
O
O
O
O
3
4'
MeO
O
MeO
OH
4
MeO
OH
6
HO
2'
5
1'
3'
OH
LL-Z1640-2 (3)
TAK-1 inhibitor (8.1 nM)
O
L-783277 (1)
MEK-1 inhibitor (4 nM)
OH
L-783290 (2)
OH
O
OH
O
OH
O
O
O
O
O
Cl
HO
MeO
O
HO
HO
OH
OH
Cl
Cl
O
O
Hypothemycin (4)
MAP kinase inibitor (17-90 nM)
Pochonin C (5)
HSV inhibitor (6 mM)
Pochonin D (6)
HSP-90 inhibitor (80 nM)
OH
O
OH
O
OMe O
O
O
O
O
O
O
HO
HO
HO
Cl
Cl
O
O
O
Monocillin I (7)
Hsp90 inhibitor (0.34 mM)
Radicicol (8)
Hsp90 inhibitor (20 nM)
Cryptosporiopsin A (9)
Figure 1: RALs containing α,β-unsaturated ketone moiety and their bioactivities
Retrosynthetic analysis of target molecules L-783290 and L-783277:
In this current scenario, we fixed our objective is to describe a general and flexible synthetic
strategy for the asymmetric total synthesis of naturally occurring “α,β-enone” containing
RALs, L-783290 (2) and L-783277 (1). A careful structural investigation reveals that the C7´-
C8´olefinic unsaturation is “E” in the case of L-783290 (2) and “Z” for L-783277 (1). A
common intermediate 12 was visualized as a key precursor for accessing both the target RAL
molecules. The internal double bond (C7´-C8´) could be achieved by E-selective HWE
olefination of a properly substituted β-ketophosphonate (11) and an aldehyde for L-783290.
Such strategical disconnection by the execution of HWE olefination was never tried before for
RAL synthesis. The required β-ketophosphonate (required for HWE olefination) could be
achieved from an aldehyde and dimethyl methylphosphonate by aldol reaction followed by
oxidation of the aldol product. The “Z” internal olefinic unsaturation (C7´-C8´) for L-783277, is
proposed to be accessed through partial reduction of an alkyne functionality by hydrogenation
with Lindlar catalyst. The alkyne can be constructed from compound 12 as depicted in scheme
1. The key intermediate 12 could be accessed by JK (Julia-Kocienski) olefination between
sulfone 14 and aromatic aldehyde 15. Sulfone 14 and aromatic aldehyde 15 could be prepared
3

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from D-galactose and 2,4,6-trihydroxy benzoic acid respectively. De Brabander’s
DOI: 10.1039/D0OB00237B
15
intramolecular lactonization reaction was used in the late stage for the construction of the
core macrolactones in both the cases (Scheme 1).
O
O
O
O
O
O
O
OMe
O
E-selective
HWE olefination
MeO
O
P2O
OP1
P
P O
O1
MeO
OP1
OH
OP1
MeO
MeO
O
11
12
O
OP1
10
OP1
P1 = Acetonide; P2 = TBDPS; P3 = PMB
Brabander
lactonization
Alkyne addition followed by
hydrogenation with Lindlar catalyst
OH
O
P3O
O
O
OH
OH
O
O
P O
O1
8
HO
7
O
O
MeO
OH
1
2
MeO
OP1
5
MeO
OH
4
O
3
13
OH
L-783290 2
( )
L-783277 1
( )
O
O
TPO2S
O
O
P O
O1
OTBDPS
OH
OP1
O
O
O
MeO
14
MeO
CHO
15
12
JK-olefination
and hydrogenation
OH
OH
COOH
OH
HO
HO
OH
OH
HO
O
2,4,6-trihydroxy Benzoic acid
D-galactose
Scheme 1: Retrosynthetic disconnection for L-783290 and L-783277
Results and discussion:
Synthesis of Sulfone 14:
The synthesis was initiated with D-galactose, which on di-acetonide protection and subsequent
Appel reaction afforded the iodo compound 16 in 71% yield (in two steps).16 Reductive ring-
opening of compound 16 with Zn and ammonium chloride in the presence of Vitamin B12,
followed by LAH reduction, furnished the diol 17 in 73% yield (in two steps). Oxidative
cleavage of the diol 17 with NaIO4, followed by NaBH4 reduction in THF at 0 °C, afforded the
alcohol 18 in 80% yield (in two steps). Primary alcohol functionality in compound 18 was then
converted to its TBDPS (tert-butyl diphenylsilyl) ether by treatment of TBDPS-Cl and
4

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imidazole to afford compound 19 in 95% yield, which was then subjected to hydroboration
DOI: 10.1039/D0OB00237B
with BH3.SMe2 and oxidation by NaOH and H2O2 to afford alcohol 20 in 80% yield.
Compound 20 was then transformed into the corresponding 1-phenyl-1H-tetrazol-5-yl sulfide
(21) through a Mitsunobu reaction, and subsequent Mo(IV)-catalyzed oxidation of sulfide
produced the desired sulfone 14 in a yield of 85% over two steps (Scheme 2).
O
OH
HO
OH
O
O
HO
OH
1. Zn,Vit B12, NH4Cl, MeOH
1. Acetone, H2SO4
2. I2, PPh3, imidazole
Toluene, MeCN, 90 oC
71%
2. LAH, THF, 73%
O
O
O
O
O
OH
16
I
OH
17
1. NaIO4, DCM:H2O
(3:2), rt, 2h
OH
OTBDPS
TBDPS-Cl, Imidazole
BH3 SMe2, NaOH, H2O2
THF, 80%
2. NaBH4,THF, 0 oC
1h, 80%
O
O
DCM, DMAP (cat.), rt
95%
O
O
N
N
18
= PT
19
N
N
Ph
HO
OTBDPS
OTBDPS
OTBDPS
TPS
(NH4)6Mo7O24 4H2O TPO2S
PTSH, PPh3, DIAD
-10 oC, THF, 90%
O
O
O
O
O
O
H2O2, EtOH, rt, 6h,
85% (two steps)
20
14
21
Scheme 2: Synthesis of sulfone 14 required for JK-olefination
Synthesis of aromatic aldehyde 15:
The aromatic fragment 15 can be prepared in 4 steps starting from 2,4,6- trihydroxy benzoic
acid as starting material.17 At first, one of the hydroxyl groups and the carboxylic acid group
of 2,4,6- trihydroxy benzoic acid has been protected to its acetonide by using acetone and acetic
anhydride in the presence of conc. H2SO4 to provide compound 22 in 70 % yield.
Regioselective monomethylation of one of the hydroxyl groups under the Mitsunobu condition
furnished compound 23 in 90% yield. Compound 23 was then converted to its triflate in the
18
presence of Tf2O and pyridine to provide compound 24 in 95% yield. Stille coupling of
triflate 24 and tributyl vinyltin in the presence of Pd(Ph3)4 furnished aromatic compound 25 in
85% yield. Oxidative cleavage of 25 under ozonolytic condition then furnished the aldehyde
15 in 90% yield (Scheme 3).
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DOI: 10.1039/D0OB00237B
OH
O
O
O
O
CO2H
OH
Acetone, (CH3CO)2O
O
TPP, DIAD, MeOH
THF, 0 oC, 90%
O
Conc. H2SO4, 0 oC,70%
HO
HO
OH
MeO
OH
2,4,6- trihydroxy
benzoic acid
22
23
O
O
O
O
O
O
O3, DCM, 78 oC
Tf2O, Pyridine
0 oC, 1.5h, 95%
TPP, 3h, 90%
SnBu3
(PPh3)4Pd, DMF, 85%
TPP, LiCl,
O
O
O
MeO
CHO
MeO
OTf
MeO
15
24
25
Scheme 3: Synthesis of aromatic aldehyde 15
Synthesis of keto phosphonate 11 required for HWE olefination (for L-783290): Sulfone
14 and aromatic aldehyde 15 was then subjected to JK-olefination 19 in the presence of KHMDS
and 18-c-6 ether in THF to furnish the ‘E’- olefin 26 in 78% yield. Compound 26 was then
allowed to react with TBAF in THF to furnish alcohol 27 in 88% yield. Alcohol 27 was then
subjected to hydrogenation with H2 in the presence of Pd-C in ethyl acetate solvent to afford
the corresponding hydrogenated alcohol 12 in 92% yield. The alcohol 12 on oxidation with
DMP in DCM furnished aldehyde 28 in 90% yield. Aldehyde 28 was then reacted with diethyl
methylphosphonate in the presence of n-BuLi in THF to give a diastereomeric mixture which
was then subjected to DMP oxidation in DCM at 0 °C to afford the β-ketophosphonate 11 in
58% yield in two steps (Scheme 4).20
O
O
TPO2S
O
O
OTBDPS
O
O
KHMDS, 18-c-6, THF
O
O
OP2
MeO
-78 oC to rt, 1h, 78%
MeO
CHO
O
26
P2 = TBDPS
O
15
14
O
O
O
O
TBAF, THF, rt
12h, 88%
H2, Pd-C, EtOAc, 3h, 92%
OH
O
DMP, NaHCO3, DCM
O
rt, 2h, 90%
OH
MeO
MeO
O
O
27
12
O
O
O
O
O
O
i. P(O)(Me)(OMe)2, n-BuLi
O
THF, -78 oC, 3h
O
O
O
P
MeO
O
ii. DMP, NaHCO3, DCM
0 oC, 2h, 58% (two steps)
O
28
O
MeO
OMe
O
OMe
11
O
Scheme 4: Synthesis of the β-keto phosphonate 11
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Synthesis of L-783290: Ketophosphonate 11 and known enantiopure aldehyde 29 21 wasVtiehweAnrticle Online
DOI: 10.1039/D0OB00237B
subjected to HWE olefination in the presence of Ba(OH)2 in THF: H2O (9:1) to afford the E
olefin 10 in 90% yield.22 The TBDPS group deprotection was then carried out by using HF-Py
in THF to furnish the lactone precursor 30 in 85% yield. Lactonization under Brabander
condition with NaH in THF was attempted, but unfortunately, we did not observe the desired
product and the starting material also got decomposed. Attempted hydrolysis of 10 with LiOH
as a base also failed. Such base mediated hydrolysis was earlier attempted on similar
systems,13c and found to be incompatible mainly due to depleted electrophilicity of the carbonyl
carbon of the ester functionality (due to presence of electron releasing 4-OMe group). Then we
also speculate that due to the presence of α,β-unsaturated ketone moiety in the system, side
reactions may have taken place (base can act as a nucleophile in Michael fashion). Forcefully
we had to reduce the α,β-unsaturated ketone functionality in 10 under Luche condition 23 and
subsequent MOM protection affords compound 31 in 81% yield (two steps). TBDPS group
deprotection was then done by using HF-Py in THF to afford the lactone precursor 32 in 90%
yield. Lactonization under Brabander condition using NaH in THF now proceeded smoothly
this time and furnished lactone 33 in 80% yield. Treatment of 33 with 2M HCl, deprotects the
acetonide as well as MOM ether group to afford the triol 34 in 90 % yield. Selective allylic
oxidation with Dess-Martin reagent 24 was then employed to furnish L-783290 in 73% yield as
a white solid (overall yield = 3.1% from D-galactose; Scheme 5). The characteristic spectral
13
data (1H and C-NMR) of our synthesized L-783290 matches well with that reported in the
literature.11
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DOI: 10.1039/D0OB00237B
O
O
O
O
Ba(OH)2,THF:H2O (9:1)
O
O
O
P
O P2O
+
P2O
O
rt, 2h, 90%
MeO
OMe
MeO
29
O
OMe
11
O
P2 = TBDPS
O
O
O
10
O
O
OH
O
O
HO
O
HF-Py, THF, 2h, 85%
MeO
X
i. NaH, THF
O
Conditions
MeO
or ii. LiOH, THF:H2O (3:1)
O
O
O
O
30
O
O
O
O
O
a) NaBH4.CeCl3,
MeOH, 2h, 90%
O
P2O
HF-Py, THF
O
HO
O
10
3h, 90%
MeO
b) MOM-Cl, DIPEA,
DCM, 12h, 90%
MeO
OMOM
OMOM
O
O
32
O
31
NaH, THF,
2h, 80%
OH
O
OH
O
OH
O
DMP, DCM,
10 min, 73%
O
O
O
HCl, THF:H2O (1:1)
MeO
OH
OH
MeO
OH
MeO
4h, 90%
OH
O
OMOM
O
L-783290 (2)
OH
34
O
33
Overall yield = 3.1% f rom D-galactose
Scheme 5: Completion of the synthesis of L-783290 (2)
Synthesis of L-783277: We have started the journey for the synthesis of L-783277 (1) with
the common intermediate aldehyde 28 which undergoes a nucleophilic addition reaction with
alkyne 35 (alkyne 35 was synthesized from ‘S’- propylene oxide in two steps 25) in presence of
n-BuLi and afforded compound 13 (inseparable diastereomer) in 82% yield. Alkyne 13 was
then converted to its corresponding ‘Z’-alkene 36 on restricted hydrogenation in the presence
of Lindlar catalyst in 90% yield. The free hydroxyl functionality in compound 36 was then
protected as its TBS-ether in the presence of TBS-Cl and imidazole to afford compound 37 in
88% yield. PMB group deprotection of compound 37 in the presence of DDQ in DCM: H2O
(19:1) afforded lactone precursor 38 in 85% yield. Compound 38 then underwent lactonization
under De Brabander condition with NaH in THF to furnish lactone 39 in 82% yield. The
diastereomers were then separated by column chromatography after lactonization. However,
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the determination of stereocenter at C6´- position was not necessary since this stereocenter was
DOI: 10.1039/D0OB00237B
going to be destroyed by the formation of an enone in the final natural product (Scheme 6).
OPMB
O
O
O
O
O
OH
, n-BuLi, THF,
O
35
OPMB
-78 °C, 82%
MeO
MeO
O
O
O
28
O
O
13
H2, Lindlar catalyst,
EtOAc, 3h, 90%
O
O
OPMB
O
O
OPMB
O
OH
O
OTBS
TBS-Cl, Imidazole,
DCM, rt, 3h, 88%
MeO
MeO
O
O
37
O
O
36
DDQ, DCM:H2O (19:1)
rt, 2h, 85%
O
O
OH
OH
O
O
OTBS
O
NaH, THF, 2h, 82%
MeO
MeO
OTBS
O
O
38
39
O
O
Scheme 6: Synthesis of macrolactone core of L-783277
Completion of the synthesis of L-783277: Lactone 39 was then reacted with HF-Py in THF
and underwent TBS deprotection to afford compound 40 in 90% yield. Oxidation with Dess-
Martin periodinane in DCM availed compound 41 in 70% yield. Then deprotection of
acetonide group was successfully carried out with PTSA in DCM: MeOH (1:1) to furnish the
desired L-783277 (1) in 75% yield as a white solid (overall yield = 3.35% from D-galactose;
13
Scheme 7). The characteristic spectral data (1H and C-NMR) of our synthesized L-783277
matches well with that reported in the literature.5a
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DOI: 10.1039/D0OB00237B
OH
O
OH
O
HF-Py, THF, rt, 3h, 90%
O
O
MeO
OTBS
MeO
OH
O
O
O
40
39
O
DMP, DCM,
rt, 2h, 70%
OH
O
OH
O
O
PTSA, DCM:MeOH (1:1)
3h, rt, 75%
O
MeO
O
MeO
O
HO
O
41
OH
O
L-783277
Overall yield = 3.35%f rom D-Galactose
Scheme 7: Completion of the synthesis of L-783277
Conclusion: In conclusion, we have successfully synthesized L-783290 in a convergent way
with 3.1% overall yield from D-galactose as a chiral pool material (in 23 linear steps). The
success of our strategy depends on an “E”-selective HWE olefination (for creation of C7´-C8´
olefinic unsaturation) and a late-stage De Brabender type lactonization reaction. We have also
accomplished the total synthesis of another naturally occurring RAL, L-783277 from an
advanced intermediate used in the synthesis of L-783290 in 3.35% overall yield from D-
galactose (in 22 linear steps). Alkyne addition on an aldehyde followed by Z-selective partial
reduction and nucleophilic macrolactonization under De Brabender condition is the main
highlight of the current synthesis for L-783277.
Experimental procedures and characterization data:
General procedures: All oxygen and/or moisture-sensitive reactions were carried out under
N2 atmosphere in glassware that had been flame-dried under vacuum (ca. 0.5 Torr) and purged
with N2 prior to use. Unless otherwise stated, materials were obtained from commercial
suppliers and used without further purification. THF, diethyl ether were distilled from sodium
benzophenone ketyl. Dichloromethane (DCM), hexane were distilled from calcium hydride.
Reactions were stirred magnetically using Teflon-coated magnetic stirring bars. Teflon-coated
magnetic stirring bars and syringe needles were dried in an oven at 120 °C for at least 12 h
prior to use then cooled in a desiccator cabinet over Drierite. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates with UV light,
ethanolic anisaldehyde, and phosphomolybdic acid/heat as developing agents. Silica gel 100-
200 mesh was used for column chromatography. Yields refer to chromatographically and
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spectroscopically homogeneous materials unless otherwise stated. NMR spectra wDeOreI: 1r0e.1c0o39r/dDe0dOB00237B
on 600, 400 and 200 MHz spectrometers at 25 °C in CDCl3 using TMS as the internal standard.
Chemical shifts are shown in δ. 13C NMR spectra were recorded with a complete proton
decoupling environment. Coupling constants (J) are reported in hertz (Hz), and the resonance
multiplicity abbreviations used are s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q,
quartet; m, multiplet; overlapping multiplets of magnetically non-equivalent protons. The mass
spectrometric analysis was performed in the CRF, IIT-Kharagpur (TOF analyzer).
(3aR,5S,5aR,8aS,8bR)-5-(iodomethyl)-2,2,7,7-tetramethyltetrahydro-5H-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (16):
Two batches of D-(+)-galactose (7 g, 38.85 mmol) in acetone (250 mL) were treated in parallel
with conc. H2SO4 (7.7 mL) at 0 °C. The reaction mixtures were stirred at room temperature for
3−5 h and then neutralized by the addition of a saturated solution of Na2CO3 until pH = 7.0.
The precipitate was then removed by filtration through a pad of Celite. The filtrates were
combined and concentrated under reduced pressure. The crude diacetonide protected D-(+)-
galactose (19 g, 98%) was used without further purification.
To an ice-cooled solution of crude isopropylidene galactose (18.8 g, 72.36 mmol) in toluene
(145 mL) and MeCN (70 mL) were added imidazole (9.85 g, 144.7 mmol), Ph3P (28.47 g,
108.6 mmol) and iodine (27.55 g, 108.6 mmol). The reaction mixture was then heated to 90 °C
and stirred for 2 h. The solution was subsequently cooled to 0 °C, and then Et2O (200 mL) was
added. The resultant precipitate was removed by filtration through a pad of Celite. The filtrate
was concentrated under reduced pressure and purified by flash chromatography (ethyl
acetate/hexane = 1:50) to provide iodide 16 (18.9 g, 71%) as a white solid. Rf = 0.6 (ethyl
acetate/hexane = 1:20). [α]D25 = ˗45 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ 5.54 (d, J =
5.0 Hz, 1H), 4.61 (dd, J = 7.8, 2.4 Hz, 1H), 4.40 (dd, J = 7.9, 1.8 Hz, 1H), 4.30 (dd, J = 5.0,
2.5 Hz, 1H), 3.94 (td, J = 7.0, 1.7 Hz, 1H), 3.26 (ddd, J = 24.0, 9.9, 7.0 Hz, 2H), 1.54 (s, 3H),
1.44 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 109.5, 108.8, 96.6, 71.5,
71.1, 70.5, 68.9, 26.0, 25.9, 24.9, 24.4, 2.3. HRMS (ESI) for C12H19O5INa [M+Na]+,
calculated: 393.0175, found: 393.0187.
(S)-1-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethane-1,2-diol (17):
A suspension of NH4Cl (9.74 g, 182.34 mmol) and zinc dust (11.9 g, 182.34 mmol) in MeOH
(55 mL) was treated with vitamin B12 (99 mg, 0.07 mmol, 0.2 mol%) at room temperature. The
reaction mixture was then stirred at ambient temperature for 15 min. Meanwhile, the
11

Organic & Biomolecular Chemistry
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suspension lost its red color. Afterward, a solution of iodide 16 (13.5 g, 36.5 mmol) in MVeieOw HArticle Online
DOI: 10.1039/D0OB00237B
(18 mL) was added at 15 °C, and the red color reappeared. The suspension was then stirred at
ambient temperature for an additional 5 min, the red color got faded, and then ethyl acetate was
added to the reaction solution. After being stirred for several minutes at room temperature, the
resultant precipitate was removed by filtration through a pad of Celite. The filtrate was then
washed with water and brine solution (2×15 mL). The combined aqueous phases were
subsequently extracted with ethyl acetate (4×100 mL). The combined organic part were dried
over MgSO4 and concentrated under reduced pressure.
To an ice-cooled solution of the crude elimination product in THF (100 mL) was added LAH
(2.77 g, 73 mmol) in portions. The reaction mixture was stirred at 0 °C for 1.5 h and then
quenched by the addition of a saturated solution of Na2SO4. The resultant precipitate was
removed by filtration through a pad of Celite, and the precipitate was washed with ethyl acetate
(200 mL). The combined organic phases were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (ethyl acetate/hexane = 1:1) afforded
the diol 17 (5.0 g, 73%) as a clear oil. Rf = 0.45 (ethyl acetate). [α]D25 = +28.7 (c 1, CHCl3). 1H
NMR (200 MHz, CDCl3): δ 5.99 (td, J = 5.2, 4.2 Hz, 1H), 5.38 – 5.28 (m, 2H), 4.60 (t, J = 3.7
Hz, 1H), 4.17 (dd, J = 3.4, 2.4 Hz, 1H), 3.69 – 3.64 (m, 1H), 3.62 – 3.55 (m, 2H), 1.51 (s, 3H),
1.37 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 133.6, 119.7, 108.8, 78.9, 77.6, 69.8, 63.9, 27.2,
24.9. HRMS (ESI) for C9H16O4Na [M+Na]+, calculated: 211.0946, found: 211.0972.
tert-Butyl(((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methoxy)diphenyl silane (19):
To a stirring solution of the diol 17 (4.5 g, 23.75 mmol) in DCM: H2O = 3:1 (90 mL) at room
temperature was added NaIO4 (1.12 g, 47.5 mmol). The mixture was then stirred vigorously at
room temperature for 2 h. The reaction solution was then quenched by the addition of saturated
aq. Na2SO3 solution (18 mL) and further stirred for 20 min at room temperature. The reaction
mixture is then filtered through a Celite pad and washed with CH2Cl2 (150 mL). The organic
layer was separated, and the aqueous part was washed with CH2Cl2 (2×50 mL). The combined
organic layers were successively washed with 5% aq NaHCO3 solution, saturated aq Na2SO3,
and brine solution. The total organic solution was then dried over anhydrous MgSO4 and
concentrated under reduced pressure to furnish the crude aldehyde, which was used for the next
reaction without further purification. NaBH4 (550 mg, 14 mmol) was added to a stirring
solution the crude aldehyde in THF (65 mL) at 0 °C. After stirring for the next 40 minutes at
this temperature, the reaction mixture was quenched with the addition of a saturated solution
of NH4Cl (10 mL). THF was evaporated under reduced pressure, and the reaction mixture was
12

Page 13 of 31
Organic & Biomolecular Chemistry
diluted with the addition of ethyl acetate (100 mL). The layer was separated, andDtOhIe: 10a.q10u3V9ei/eoDwu0AOsrtiBc0le0O2n3li7nBe
part was washed with ethyl acetate (2×100 mL). The combined organic phases were dried over
MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (ethyl
acetate/hexane = 1:3) afforded alcohol 18 (3.0 g, 80% in two steps) as a clear oil. Rf = 0.45
(ethyl acetate/hexane = 1:1).
To a cooled (0 ºC) solution of alcohol 18 (3.0 g, 19 mmol) in dry CH2Cl2 (60 mL) was added
imidazole (1.94 g, 28.5 mmol), TBDPSCl (5.83 mL, 22.8 mmol) and catalytic amount of
DMAP. The mixture was stirred for 6 h at room temperature and then quenched with 10 mL of
water. The organic layer was separated and the aqueous part was extracted with CH2Cl2 (2×100
mL). The combined organic part was washed with saturated NaHCO3 solution (15 mL) and
brine solution (10 mL) and then dried over anhydrous MgSO4. The solution was then
concentrated in vacuo and purified by flash chromatography (EtOAc:hexane = 1:20) to yield
compound 19 (7.15 g, 95%) as a colorless oil. Rf = 0.30 (EtOAc/hexane, 1:15). [α]D25 = +18.3
(c 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.82 – 7.61 (m, 4H), 7.42 – 7.37 (m, 6H), 5.94
(ddd, J = 17.2, 10.3, 7.2 Hz, 1H), 5.41 – 5.31 (m, 1H), 5.22 (d, J = 10.2 Hz, 1H), 4.66 (t, J =
6.7 Hz, 1H), 4.29 (dd, J = 11.9, 6.4 Hz, 1H), 3.70 – 3.64 (m, 2H), 1.45 (s, 3H), 1.38 (s, 3H),
1.05 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 135.6, 133.7, 133.4, 129.7, 127.6, 118.0, 108.6,
78.8, 78.4, 62.8, 27.8, 26.8, 25.4, 19.2. HRMS (ESI) for C24H32O3SiNa [M+Na]+, calculated:
419.2018, found: 419.2037.
2-((4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-
1-ol (20):
To a stirring solution of olefin 19 (7.13 g, 18.05 mmol) in THF (70 mL) at 0 ºC was added
BH3•DMS (9.02 mL, 2 M solution) over 5 minute. After stirring for 2 h at the same temperature,
the reaction mixture was diluted with ethyl acetate (90 mL). Then the reaction mixture again
cooled to 0 ºC and was quenched by the addition of NaOH (37 mL, 3 N solution) and 30%
H2O2 (32 mL). After 1 h, the solution was poured into saturated aqueous NaCl (60 mL) and
then extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over
MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (ethyl
acetate/hexane = 1:3) afforded alcohol 20 (5.97 g, 80%) as a clear oil. Rf = 0.3 (ethyl
acetate/hexane = 1:1). [α]D25 = ˗5.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.64 – 7.68
(m, 4H), 7.49 – 7.30 (m, 6H), 4.38 (dt, J = 8.7, 5.5 Hz, 1H), 4.23 (dt, J = 7.8, 5.3 Hz, 1H), 3.89
– 3.77 (m, 2H), 3.73 (dd, J = 10.5, 7.9 Hz, 1H), 3.66 (dd, J = 10.5, 4.8 Hz, 1H), 1.95 – 1.86 (m,
2H), 1.37 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H). 13C NMR (50 MHz, CDCl3): δ 135.7, 133.3, 133.2,
13

Organic & Biomolecular Chemistry
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View Article Online
129.9, 127.9, 108.3, 77.8, 62.7, 61.4, 31.7, 28.2, 27.0, 25.7, 19.3. HRMS (ESI) for
DOI: 10.1039/D0OB00237B
C24H34O4SiNa [M+Na]+, calculated: 437.2124, found: 437.2145.
5-((2-((4S,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl)thio)-1-phenyl-1H-tetrazole (21):
To a stirring solution of compound 20 (5.97 g, 14.44 mmol) in anhydrous THF (45 mL) was
added triphenylphosphine (5.67 g, 21.6 mmol) and 1-phenyl-5-mercapto-1H-tetrazole (PT-SH;
3.85 g, 21.66 mmol) at ˗10 ºC. After stirring 15 minute at this temperature DIAD (4.26 mL,
21.66 mmol) in anhydrous THF (10 mL) was added drop wise and the reaction was left to stir
for 2 h. Water (20 mL) and EtOAc (60 mL) was added to this mixture and the organic layer
was separated. The aqueous part was then washed with EtOAc (2×100 mL). The combined
organic part was washed with saturated aq. NaHCO3 solution and brine solution (20 mL). The
organic solution was then dried over anhydrous MgSO4 and concentrated under reduced
pressure to furnish the crude product, which on purification by flash column chromatography
(EtOAc:hexane = 1:10) afforded compound 21 (6.02 g, 90%) as a colorless oil. Rf = 0.4
(EtOAc/hexane, 1:5). [α]D25 = ˗12.8 (c 0.5, CHCl3). IR (neat, ν cm˗1): 1357 (s), 1282 (s), 865
(s). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.6 Hz, 4H), 7.60 – 7.53 (m, 5H), 7.41 – 7.34
(m, 6H), 4.39 – 4.30 (m, 1H), 4.21 (q, J = 6.2 Hz, 1H), 3.69 (d, J = 6.3 Hz, 2H), 3.63 – 3.59
(m, 1H), 3.48 (dt, J = 13.3, 7.7 Hz, 1H), 2.35 – 2.24 (m, 1H), 2.10 – 2.05 (m, 1H), 1.37 (s, 3H),
13
1.32 (s, 3H), 0.99 (s, 9H). C NMR (50 MHz, CDCl3): δ 154.1, 135.7, 133.9, 133.2, 129.9,
128.0, 124.0, 123.8, 108.4, 78.4, 77.5, 75.9, 62.6, 30.6, 29.8, 28.2, 26.9, 25.7, 19.3. HRMS
(ESI) for C31H38N4O3SiSNa [M+Na]+, calculated: 597.2332, found: 597.2343.
5-((2-((4S,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole (14):
To a stirring solution of sulfide 21 (6.02 g, 13 mmol) in ethanol (80 mL) was added a mixture
of (NH4)6Mo7O24•4H2O (2.5 g, 1.95 mmol) and 30% H2O2 solution (9.3 mL) at 0 °C. The
mixture was then stirred at room temperature for 6 h, and after that the reaction mixture was
poured into 10% Na2S2O3 solution and extracted with ethyl acetate (2×100 mL). The organic
layer was washed with saturated NaHCO3 (10 mL) solution and brine (10 mL), dried over
anhydrous MgSO4 and concentrated in vacuo to afford the crude sulfone. The crude product
was then purified by flash column chromatography (EtOAc/hexane = 1:10) to furnish pure
sulfone 14 (5.6 g, 85%) as a colorless gummy oil. Rf = 0.4 (EtOAc/hexane, 1:5). [α]D25 = ˗14.5
(c 0.5, CHCl3). IR (neat, ν cm˗1): 1346 (s), 1150 (s), 702 (s). 1H NMR (400 MHz, CDCl3): δ
7.77 – 7.58 (m, 9H), 7.50 – 7.34 (m, 6H), 4.37 – 4.23 (m, 1H), 4.26 (dt, J = 7.7, 5.3 Hz, 1H),
14

Page 15 of 31
Organic & Biomolecular Chemistry
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4.08 – 4.0 (m, 1H), 3.90 (ddd, J = 15.1, 10.3, 5.3 Hz, 1H), 3.76 – 3.66 (m, 2H), 2.45 – 2.41 (m,
DOI: 10.1039/D0OB00237B
1H), 2.33 – 2.26 (m, 1H), 1.40 (s, 3H), 1.33 (s, 3H), 1.01 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 153.4, 135.5, 133.0, 132.9, 132.8, 131.4, 129.9, 129.7, 127.8, 127.8, 125.0, 108.8, 77.1, 75.2,
61.9, 53.7, 27.9, 26.7, 25.5, 23.4, 19.1. HRMS (ESI) for C31H38N4O5SiSNa [M+Na]+,
calculated: 629.2230, found: 629.2263.
5,7-Dihydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (22):
A 100 mL round-bottomed flask equipped with a magnetic stirring bar was charged with 2,4,6-
trihydroxy benzoic acid (6.8 g, 40 mmol), acetic anhydride (7 mL), and anhydrous acetone (40
mL). The mixture was cooled to 0 °C and catalytic amount of concentrated H2SO4 was added
to the stirring mixture. The flask was kept stirring at 0 °C for 12 h. After that time a saturated
solution of aqueous NaHCO3 was poured into the reaction mixture, and extracted with ethyl
acetate (3 × 80 mL). The combined extracts were washed with water and brine, dried over
anhydrous MgSO4, filtered and concentrated to give brown solid. Chromatography of the crude
solid over silica gel using EtOAc/petroleum ether (1:10) gave acetonide 22 (5.88 g, 70%) as
white solid. Rf = 0.5 (EtOAc/hexane = 1:5). 1H NMR (600 MHz, CDCl3): δ 10.47 (s, 1H), 6.10
13
(d, J = 2.3 Hz, 1H), 5.98 (d, J = 2.2 Hz, 1H), 1.76 (s, 6H). C NMR (150 MHz, CDCl3): δ
165.1, 164.1, 163.2, 157.3, 106.9, 97.6, 95.5, 93.2, 25.6.
5-Hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (23):
Diethyl azodicarboxylate (6.27 mL, 39.33 mmol) was added to a magnetically stirred solution
of phenol 22 (5.88 g, 28.12 mmol) and triphenylphosphine (8.1 g, 30.97 mmol) in THF (45
mL) containing CH3OH (1.26 mL, 30.97 mmol) and the reaction solution was then maintained
at 0 °C under a nitrogen atmosphere. After 4 h the reaction mixture was concentrated under
reduced pressure, and the residue thus obtained was subjected to flash chromatography
(EtOAc/hexane = 1:10) to afford compound 23 (5.67 g, 90%) as a white crystalline solid. Rf =
0.6 (EtOAc/hexane = 1:5). 1H NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 6.13 (d, J = 2.3 Hz,
1H), 5.99 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 1.72 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.6,
165.1, 163.1, 156.8, 106.9, 95.7, 94.6, 93.0, 55.7, 25.6.
7-Methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesulfonate
(24):
Trifluoromethanesulfonic anhydride (6.0 mL, 35.4 mmol) was added to a magnetically stirred
mixture of phenol 23 (5.6 g, 25.3 mmol) and pyridine (46 mL) maintained at 0 °C under a
15

Organic & Biomolecular Chemistry
Page 16 of 31
nitrogen atmosphere. The ensuing mixture was stirred at 0 °C for 1.5 h and thenDdOiIl:u10te.1d03V9wi/eDwi0tAhOrtiBc0le0O2n3li7nBe
ethyl acetate (160 mL), and the resulting solution was washed with CuSO4 (3 × 100 mL of a
saturated aqueous solution), water (1 × 100 mL), and brine (1 × 70 mL) before being dried over
MgSO4, filtered, and concentrated under reduced pressure. The resulting light yellow oil was
subjected to flash chromatography (EtOAc/hexane = 1:5) to afford compound 24 (8.55 g, 95%)
as a white solid. Rf = 0.3 (EtOAc/hexane = 1:5). 1H NMR (400 MHz, CDCl3): δ 6.49 (dd, J =
13
10.0, 2.4 Hz, 2H), 3.86 (s, 3H), 1.71 (s, 6H). C NMR (100 MHz, CDCl3): δ 165.6, 158.8,
157.1, 149.8, 123.5, 120.3, 117.1, 113.9, 106.6, 105.3, 101.1, 100.8, 56.3, 25.4.
7-Methoxy-2,2-dimethyl-5-vinyl-4H-benzo[d][1,3]dioxin-4-one (25):
To a stirred solution of 24 (8.55 g, 24.03 mmol) in DMF (70 mL) was added triphenylphosphine
(450 mg, 1.6 mmol) and LiCl (3.1 g,71.8 mmol) at room temp. Then the reaction mixture was
de-gassed for 10 min and to this was added vinyl n-tributyltin (7.7 mL, 22 mmol) and Pd(PPh3)4
(450 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 4 h and extracted
with EtOAc (2 × 120 mL). The combined extracts was washed with water (3 × 100 mL) and
brine solution (50 mL), dried over anhydrous MgSO4 and concentrated. The product was
purified by silica gel chromatography (EtOAc/hexane = 1:10) to yield 25 as a white solid (4.78
g, 85%). m.p = 144–147°C (uncorrected). Rf = 0.6 (EtOAc/hexane = 1:5). 1H NMR (400 MHz,
CDCl3): δ 7.70 (ddd, J = 17.3, 10.8, 1.6 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.38 (d, J = 2.4 Hz,
1H), 5.68 (dd, J = 17.4, 1.4 Hz, 1H), 5.40 (dd, J = 11.0, 1.4 Hz, 1H), 3.85 (s, 3H), 1.70 (s, 6H).
13C NMR (100 MHz, CDCl3): δ 164.9, 160.1, 158.7, 144.1, 135.5, 117.6, 108.5, 105.13, 103.9,
100.7, 55.6, 25.6.
7-Methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxine-5-carbaldehyde (15):
To a stirring solution of compound 25 (2.8 g, 12.1 mmol) in DCM (25 mL) at –78 °C was
applied a flow of Ozone from an Ozone generator (flow rate 2 L/min) for 15 minute. Then after
consumption of all the starting materials as monitored by TLC, TPP (3.8 g, 14.5 mmol) was
added to the stirring mixture at –40 °C and allowed to stir at room temperature for 2 h. After
completion of the reaction, the solution was concentrated under reduced pressure and the crude
product was purified by flash column chromatography (EtOAc /hexane = 1:10) to afford
aldehyde 15 (2.54 g, 90%) as a white solid. m.p = 102–104°C (uncorrected). Rf = 0.4
(EtOAc/hexane = 1:5). 1H NMR (200 MHz, CDCl3): δ 10.88 (s, 1H), 7.21 (d, J = 2.6 Hz, 1H),
6.67 (d, J = 2.6 Hz, 1H), 3.90 (s, 3H), 1.77 (s, 6H). 13C NMR (50 MHz, CDCl3): δ 191.6, 165.5,
159.8, 158.8, 140.3, 109.6, 106.3, 106.1, 56.2, 25.7. HRMS (ESI) for C12H12O5Na [M+Na]+,
calculated: 259.0582, found: 259.0593.
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Organic & Biomolecular Chemistry
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5-((E)-3-((4S,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-diDoOxI:o1l0a.1n03-94/D-0OB00237B
yl)prop-1-en-1-yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (26):
Sulfone 14 (3.96 g, 6.55 mmol) was dissolved in anhydrous THF (25 mL) and the solution was
cooled to ˗78 ºC. To this solution KHMDS (0.5 M in toluene, 15.7 mL) was added drop wise
and stirred for 40 min. Aldehyde 15 (1.85 g , 7.86 mmol) in anhydrous THF (7 mL) was then
added to the reaction solution at ˗78 ºC and the temperature was allowed to attain room
temperature slowly. The reaction solution was then quenched with saturated NH4Cl (5 mL) and
extracted with diethyl ether (3×100 mL). The combined organic layer was washed with brine
solution and dried with anhydrous MgSO4 and concentrated in vacuo to furnish the crude
olefin. The crude product was then purified by flash column chromatography (EtOAc/hexane
= 1:15) to give E-olefin 26 (3.1 g, 78%) as a colorless gummy oil. Rf = 0.60 (EtOAc/hexane,
1:5). [α]D25 = ˗30.2 (c 0.8, CHCl3). IR (neat, ν cm˗1): 1732 (s), 1635 (s), 1246 (s). 1H NMR (400
MHz, CDCl3): δ 7.69 – 7.65 (m, 4H), 7.55 (d, J = 15.8 Hz, 1H), 7.44 – 7.35 (m, 6H), 6.77 (d,
J = 2.5 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 6.28 (dt, J = 15.7, 6.9 Hz, 1H), 4.34 (dt, J = 9.5, 4.8
Hz, 1H), 4.30 – 4.20 (m, 1H), 3.83 (s, 3H), 3.78 (dd, J = 10.7, 7.3 Hz, 1H), 3.71 (dd, J = 10.7,
5.0 Hz, 1H), 2.72 – 2.60 (m, 1H), 2.62 – 2.51 (m, 1H), 1.70 (s, 6H), 1.41 (s, 3H), 1.35 (s, 3H),
13
1.06 (s, 9H). C NMR (50 MHz, CDCl3): δ 164.9, 160.3, 158.9, 144.0, 135.8, 133.5, 133.5,
131.4, 130.4, 129.9, 127.9, 108.5, 108.3, 105.1, 104.0, 100.5, 77.9, 77.3, 62.9, 55.8, 33.5, 28.3,
27.1, 25.9, 25.8, 19.4. HRMS (ESI) for C36H44O7SiNa [M+Na]+, calculated: 639.2754, found:
639.2772.
5-((E)-3-((4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-en-1-yl)-7-
methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (27):
To a stirred solution of compound 26 (3.1 g, 5.11 mmol) in THF (20 mL) was added tetra butyl
ammonium fluoride (1 M in THF, 6.1 mL) at 0 °C and the reaction mixture was allowed to stir
at room temperature for 2 h. After completion of the reaction as monitored by TLC, the solvent
was evaporated under reduced pressure. Ethyl acetate (80 mL) and water (7 mL) was added to
the crude reaction mixture and the aqueous layer was extracted with ethyl acetate (2×80 mL).
The combined organic layer was washed with brine and dried over MgSO4. The organic part
was evaporated under reduced pressure and the crude material was purified through flash
column chromatography (EtOAc/hexane = 1:3) to afford alcohol 27 (1.7 g, 88%) as a clear oil.
25
21
Rf = 0.25 (EtOAc/hexane = 1:3). [α]D = ˗34.8 (c 1, CHCl3) {Lit.19 [α]D = ˗32.7 (c 0.94,
CHCl3)}. IR (neat, ν cm˗1): 1722 (s), 1694 (s), 1161 (s). 1H NMR (400 MHz, CDCl3): δ 7.48
(d, J = 15.8 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 6.20 (ddd, J = 15.8,
7.7, 6.0 Hz, 1H), 4.36 (dt, J = 7.3, 5.9 Hz, 1H), 4.25 (td, J = 6.5, 4.6 Hz, 1H), 3.84 (s, 3H), 3.72
17

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(t, J = 5.9 Hz, 2H), 2.67 – 2.46 (m, 1H), 1.70 (s, 6H), 1.50 (s, 3H), 1.38 (s, 3H). 13C NMRV(i1ew0A0rticle Online
DOI: 10.1039/D0OB00237B
MHz, CDCl3): δ 164.8, 160.3, 158.7, 143.6, 130.6, 130.1, 108.5, 108.2, 105.1, 103.7, 100.3,
77.8, 76.3, 61.6, 55.6, 33.0, 28.1, 25.7, 25.6, 25.4. HRMS (ESI) for C20H26O7Na [M+Na]+,
calculated: 401.1576, found: 401.1571.
5-(3-((4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-
dimethyl-4H-benzo[d][1,3]dioxin-4-one (12):
Olefin 27 (1.69 g, 4.5 mmol) was taken in a glass vessel with dry EtOAc (15 mL) in argon
medium followed by the addition of Pd/C (65 mg, 10%). The vessel was then placed in a Parr
hydrogenataion apparatus and the reaction was continued for 3 h at 60 psi at room temperature.
After completion of the reaction the solution was filtered through a Celite pad. The Celite pad
was washed with EtOAc (150 mL). Combined organic filtrate was then evaporated in vacuo
and the residue was purified by flash column chromatography (EtOAc/hexane = 1:3) to furnish
compound 12 (1.54 g, 92%) as a clear oil. Rf = 0.25 (EtOAc/hexane = 1:3). [α]D25 = ˗28.7 (c 1,
CHCl3). IR (neat, ν cm˗1): 1725 (s), 1610 (s), 1159 (s). 1H NMR (400 MHz, CDCl3): δ 6.46 (d,
J = 2.4 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.23 – 4.06 (m, 2H), 3.80 (s, 3H), 3.59 (d, J = 5.7
Hz, 2H), 3.11 – 3.08 (m, 1H), 3.04 – 3.00 (m, 1H), 1.85 – 1.74 (m, 1H), 1.67 (s, 6H), 1.62 –
1.55 (m, 3H), 1.44 (s, 3H), 1.33 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 164.8, 160.1, 159.1,
149.3, 112.2, 108.0, 104.8, 104.7, 99.4, 77.9, 76.8, 61.7, 55.5, 34.4, 28.8, 28.2, 27.9, 25.6, 25.5.
HRMS (ESI) for C20H28O7Na [M+Na]+, calculated: 403.1733, found: 403.1747.
(4S,5R)-5-(3-(7-methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)propyl)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde (28):
The alcohol 12 (1.5 g, 3.95 mmol) in CH2Cl2 (15 mL) was taken in a single neck round bottom
flask and cooled to 0 °C. NaHCO3 (1.6 g, 19.5 mmol) was added to the above mixture followed
by the addition of Dess-Martin periodinane (2.6 g, 6.24 mmol) at the same temperature. The
reaction mixture was then stirred for 2 h. After completion of the reaction it was diluted with
CH2Cl2 (200 mL). The organic part was then successively washed with saturated NaHSO3 (20
mL), NaHCO3 (20 mL, 5%) and then with brine solution (10 mL). The organic layer was then
dried over anhydrous MgSO4 and evaporated in vacuo. Purification by flash column
chromatography (EtOAc /hexane = 1:5) afforded aldehyde 28 (1.34 g, 90%) as a clear oil. Rf =
0.4 (EtOAc/hexane = 1:3). [α]D25 = ˗23.8 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.61
(d, J = 3.3 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.38 (td, J = 7.5, 4.3 Hz,
1H), 4.26 (dd, J = 7.0, 3.3 Hz, 1H), 3.80 (s, 3H), 3.04 (t, J = 7.3 Hz, 2H), 1.87 – 1.75 (m, 2H),
1.67 (s, 6H), 1.66 – 1.59 (m, 2H), 1.55 (s, 3H), 1.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
202.2, 165.0, 160.2, 159.3, 149.1, 112.5, 110.6, 105.1, 104.8, 99.6, 82.2, 78.6, 55.7, 34.4, 29.6,
18

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Organic & Biomolecular Chemistry
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27.9, 27.8, 25.8, 25.5. HRMS (ESI) for C20H26O7Na [M+Na]+, calculated: 401.1576, found:
DOI: 10.1039/D0OB00237B
401.1582.
Dimethyl
2-((4S,5S)-5-(3-(7-methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-
yl)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxoethylphosphonate (11):
To a solution of dimethyl methylphosphonate (1.54 g, 12.5 mmol) in THF (15 mL) at –78 °C
was added n-butyllithium (1.6 M in hexanes, 7.8 mL, 12.5 mmol) and the reaction mixture was
stirred at –78 °C for 1 h, then aldehyde 28 (935.3 mg, 2.5 mmol) in THF (5 mL) was added
dropwise. The resultant mixture was stirred at –78 °C for 2 h, then saturated aq. NH4Cl solution
(8 mL) was added. The mixture was extracted with EtOAc (3×100 mL), then the combined
organic extracts were dried over anhydrous MgSO4 and evaporated in vacuo to give an oil,
which was dissolved in CH2Cl2 (20 mL). To this solution at 0 °C was added NaHCO3 (2.1g, 25
mmol) followed by Dess–Martin periodinane (1.9 g, 4.5 mmol) and the reaction mixture was
stirred at room temperature for 2 h, then saturated aq. Na2S2O3 solution (10 mL) was added
and the resultant mixture was stirred at room temperature for 30 min. The mixture was extracted
with CH2Cl2 (3×80 mL) and the combined organic extracts were dried over anhydrous MgSO4
and concentrated. Purification by flash column chromatography (EtOAc /hexane = 1:2)
afforded β-ketophosphonate 11 (720 mg, 58%) as a clear oil. Rf = 0.3 (EtOAc/hexane = 1:1).
25
1
[α]D = ˗18.9 (c 0.5, CHCl3). IR (neat, ν cm˗1): 2810 (m), 1665 (s), 1258 (s). H NMR (600
MHz, CDCl3): δ 6.48 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 4.49 (d, J = 7.7 Hz, 1H),
4.43 (ddd, J = 10.7, 7.7, 3.3 Hz, 1H), 3.84 (s, 3H), 3.83 (d, J = 6.4 Hz, 3H), 3.81 (d, J = 6.3 Hz,
3H), 3.49 (dd, J = 21.0, 15.2 Hz, 1H), 3.11 – 3.03 (m, 3H), 1.89 – 1.77 (m, 4H), 1.71 (s, 6H),
1.61 (s, 3H), 1.39 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 202.8, 164.8, 160.0, 159.1, 149.2,
112.2, 110.2, 104.9, 104.7, 99.4, 82.6, 82.6, 78.1, 55.5, 53.2, 53.1, 52.9, 52.9, 38.4, 37.5, 34.2,
30.0, 27.8, 27.0, 25.7, 25.6, 24.8. HRMS (ESI) for C23H33O10PNa [M+Na]+, calculated:
523.1709, found: 523.1699.
5-(3-((4S,5S)-5-((S,E)-5-((tert-Butyldiphenylsilyl)oxy)hex-2-enoyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (10):
To a solution of aldehyde 29 (130.4 mg, 0.40 mmol) and β-ketophosphonate 11 (166 mg, 0.33
mmol) in THF (3.8 mL) and H2O (0.20 mL) at room temperature was added Ba(OH)2 (52 mg,
0.161 mmol) and the reaction mixture was stirred at room temperature for 2 h, then saturated
aq. NH4Cl solution (2 mL) was added. The mixture was then extracted with EtOAc (3×50 mL)
and the combined organic extracts were dried over anhydrous MgSO4 and concentrated under
reduced pressure. Purification by flash column chromatography (EtOAc /hexane = 1:10)
afforded E- olefin 10 (210 mg, 90%) as a colourless gummy oil. Rf = 0.6 (EtOAc/hexane =
19

Organic & Biomolecular Chemistry
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1:5). [α]D25 = +16.7 (c 1, CHCl3). IR (neat, ν cm˗1): 2830 (m), 1680 (s), 870 (s). 1H NMR V(i6ew0A0rticle Online
DOI: 10.1039/D0OB00237B
MHz, CDCl3): δ 7.68 (d, J = 7.4 Hz, 4H), 7.48 – 7.36 (m, 6H), 6.93 (dt, J = 15.2, 7.4 Hz, 1H),
6.47 (d, J = 15.8 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 4.57 (d, J = 7.5
Hz, 1H), 4.42 (td, J = 7.2, 3.8 Hz, 1H), 4.01 (q, J = 6.0 Hz, 1H), 3.81 (s, 3H), 3.05 (dd, J = 9.9,
5.6 Hz, 1H), 3.00 (dd, J = 9.8, 5.6 Hz, 1H), 2.38 (t, J = 6.8 Hz, 2H), 1.85 – 1.77 (m, 1H), 1.69
(s, 6H), 1.68 – 1.64 (m, 1H), 1.60 (s, 3H), 1.54 – 1.50 (m, 1H), 1.47 – 1.42 (m, 1H), 1.39 (s,
3H), 1.11 (d, J = 6.1 Hz, 3H), 1.07 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 197.5, 164.8, 160.0,
159.1, 149.4, 145.2, 135.8, 135.8, 134.3, 133.9, 129.7, 129.6, 128.0, 127.6, 127.5, 112.1, 109.8,
104.8, 104.7, 99.4, 82.0, 78.0, 68.4, 55.5, 42.6, 34.2, 30.3, 27.7, 27.2, 27.0, 25.7, 25.6, 25.1,
23.2, 19.2. HRMS (ESI) for C41H52O8SiNa [M+Na]+, calculated: 723.3329, found: 723.3357.
5-(3-((4S,5S)-2,2-dimethyl-5-((9S,E)-9,12,12-trimethyl-11,11-diphenyl-2,4,10-trioxa-11-
silatridec-6-en-5-yl)-1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (31):
To a stirring solution of enone 10 (82.8 mg, 0.12 mmol) in methanol (2 mL) at 0 ºC was added
CeCl3 (47.2 mg, 0.125 mmol) and then NaBH4 (4.8 mg, 0.125 mmol). The reaction mixture
was stirred at room temperature for 2 h, then saturated aq. NH4Cl solution (2 mL) was added.
The mixture was extracted with EtOAc (3×30 mL) and the combined organic extracts were
dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash
column chromatography (EtOAc /hexane = 1:5) afforded alcohol (74.8 mg, 90%) as a colorless
oil. Rf = 0.3 (EtOAc/hexane = 1:5).
To a stirring solution of the above alcohol (74.8 mg, 0.11 mmol) in dry CH2Cl2 (1.5 mL) was
added diisopropylethylamine (0.18 mL, 1.08 mmol) at 0 °C. After 15 min of stirring MOM-Cl
(methoxymethyl chloride; 0.05 mL, 0.64 mmol) was added and the reaction solution was stirred
for further 12 h at room temperature. The reaction was diluted with CH2Cl2 (50 mL) and
washed with saturated NaHCO3 (5 mL), H2O (5 mL) and brine (5 mL). The combined organic
part was dried over anhydrous MgSO4 and then concentrated in vacuo. The crude material was
then purified by flash column chromatography (EtOAc/hexane = 1: 20) to afford compound 31
(70 mg, 90%) as a colourless liquid. Rf = 0.6 (EtOAc/hexane = 1:5). IR (neat, ν cm˗1): 1665 (s),
1170 (s). 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.59 (m, 4H), 7.46 – 7.33 (m, 6H), 6.46 (d, J =
2.5 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 5.75 (dt, J = 14.9, 7.2 Hz, 1H), 5.27 (dd, J = 15.5, 7.0
Hz, 1H), 4.71 (d, J = 6.7 Hz, 1H), 4.57 (d, J = 6.7 Hz, 1H), 4.07 – 3.99 (m, 3H), 3.89 (q, J =
5.9 Hz, 1H), 3.80 (s, 3H), 3.37 (s, 3H), 3.03 (dt, J = 8.5, 5.5 Hz, 2H), 2.21 (t, J = 6.6 Hz, 2H),
1.86 – 1.79 (m, 1H), 1.68 (s, 6H), 1.59 – 1.53 (m, 3H), 1.44 (s, 3H), 1.35 (s, 3H), 1.07 (d, J =
6.5 Hz, 3H), 1.05 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 164.9, 160.1, 159.2, 149.8, 135.9,
20

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134.6, 134.4, 133.3, 129.7, 129.6, 128.3, 127.7, 127.6, 112.2, 108.4, 104.9, 104.9, 99.3, 93.3,
DOI: 10.1039/D0OB00237B
80.0, 74.8, 69.1, 55.6, 55.6, 42.5, 34.6, 29.9, 28.2, 27.7, 27.1, 26.2, 25.7, 22.9, 19.3. HRMS
(ESI) for C43H58O9SiNa [M+Na]+, calculated: 769.3748, found: 769.3773.
(3aS,8S,17aS,E)-11-hydroxy-13-methoxy-4-(methoxymethoxy)-2,2,8-trimethyl-
3a,4,7,8,15,16,17,17a-octahydro-10H-benzo[c][1,3]dioxolo[4,5-h][1]oxacyclotetradecin-
10-one (33):
Compound 31 (45 mg, 0.06 mmol) was dissolved in anhydrous THF (2 mL) in a polyethylene
vessel and HF-pyridine (400 μL ) was added to it at 0 ºC. The mixture was then stirred for 2 h
at room temperature followed by addition of EtOAc (40 mL) and brine solution (5 mL). The
organic layer was separated and the aqueous layer was twice washed with EtOAc (50 mL). The
combined organic part was washed with brine (5 mL) and the solution was dried over
anhydrous MgSO4 and concentrated in vacuo. The crude material was then purified by flash
column chromatography (EtOAc /hexane = 1:1) to afford 32 (28 mg, 90%) as a colourless oil.
Rf = 0.25 (EtOAc/hexane = 1:1).
To a stirring solution of NaH (60%, 14 mg, 0.33 mmol) in dry THF (4 mL) at 0 °C, compound
32 (28 mg, 0.055 mmol) in dry THF (2 mL) was slowly added. Then the reaction mixture was
stirred at room temperature for 2 h. After completion of the reaction as monitored by TLC,
saturated aq. NH4Cl solution (5 mL) was added. The mixture was extracted with EtOAc (3×40
mL). The combined organic part was washed with brine (5 mL) and the solution was dried over
anhydrous MgSO4 and concentrated in vacuo. The crude material was then purified by flash
column chromatography (EtOAc /hexane = 1:5) to afford 33 (20 mg, 80%) as a colourless oil.
Rf = 0.5 (EtOAc/hexane = 1:3). IR (neat, ν cm˗1): 1655 (s), 1270 (s), 1148 (s). 1H NMR (400
MHz, CDCl3): δ 11.49 (s, 1H), 6.33 (d, J = 2.7 Hz, 1H), 6.29 (d, J = 2.7 Hz, 1H), 5.83 (ddd, J
= 15.7, 8.6, 5.4 Hz, 1H), 5.47 (dt, J = 15.0, 4.5 Hz, 1H), 5.41 – 5.33 (m, 1H), 4.75 (d, J = 6.9
Hz, 1H), 4.58 (d, J = 6.9 Hz, 1H), 4.09 – 4.05 (m, 2H), 4.03 – 3.96 (m, 1H), 3.79 (s, 3H), 3.39
(s, 3H), 3.23 – 3.12 (m, 1H), 2.86 (dt, J = 12.6, 6.3 Hz, 1H), 2.68 – 2.61 (m, 1H), 2.46 (dt, J =
15.8, 8.3 Hz, 1H), 1.71 – 1.65 (m, 3H), 1.54 – 1.46 (m, 1H), 1.45 (s, 3H), 1.44 (d, J = 8 Hz,
13
3H), 1.33 (s, 3H). C NMR (100 MHz, CDCl3): δ 170.4, 164.8, 163.9, 147.3, 132.7, 128.9,
110.6, 107.4, 105.8, 99.2, 92.9, 79.2, 77.2, 74.9, 71.7, 55.6, 55.2, 38.5, 33.7, 28.5, 28.2, 28.1,
25.7, 19.9. HRMS (ESI) for C24H34O8Na [M+Na]+, calculated: 473.2151, found: 473.2165.
(3S,8S,9S,E)-7,8,9,16-tetrahydroxy-14-methoxy-3-methyl-3,4,7,8,9,10,11,12-octahydro-
1H-benzo[c][1]oxacyclotetradecin-1-one (34):
21

Organic & Biomolecular Chemistry
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To a solution of 33 (14 mg, 0.03 mmol) in THF (1 mL) was added HCl (2 N, 40 µL) and stViirerweAdrticle Online
DOI: 10.1039/D0OB00237B
for 4 h at room temperature. The reaction solution was then quenched with saturated aqueous
NaHCO3 solution (1 mL) and extracted with EtOAc (3×30 mL). The organic layers were
combined and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure
to afford the crude product. The crude product was then purified on flash column
chromatography (EtOAc /hexane = 1:1) to provide 34 (10 mg, 90%) as a white powder. m.p =
114–117°C (uncorrected). IR (KBr, ν cm˗1): 3335 (br), 2905 (m), 1645 (s), 1253 (s). 1H NMR
(600 MHz, CDCl3): δ 11.52 (s, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 5.96 –
5.88 (m, 1H), 5.69 (dd, J = 15.5, 8.6 Hz, 1H), 5.31 (ddd, J = 9.1, 6.2, 3.1 Hz, 1H), 4.17 (t, J =
8.8 Hz, 1H), 3.82 (s, 4H), 3.69 (dd, J = 9.1, 2.2 Hz, 1H), 3.09 – 3.02 (m, 1H), 2.95 – 2.90 (m,
1H), 2.61 (d, J = 15.4 Hz, 1H), 2.57 – 2.49 (m, 1H), 1.90 – 1.86 (m, 1H), 1.72 (ddd, J = 11.8,
6.9, 3.3 Hz, 2H), 1.52 – 1.48 (m, 1H), 1.46 (d, J = 6.2 Hz, 3H). 13C NMR (150 MHz, CDCl3):
δ 171.2, 164.8, 163.9, 146.8, 132.2, 131.9, 109.6, 106.1, 98.9, 76.1, 72.4, 71.8, 71.4, 55.3, 38.6,
33.7, 30.9, 25.8, 20.1. HRMS (ESI) for C19H26O7Na [M+Na]+, calculated: 389.1576, found:
389.1589.
(3S,8S,9S,E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10,11,12-hexahydro-1H-
benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (L-783290):
To the solution of compound 34 (8 mg, 0.02 mmol) in DCM (1 mL) at 0 °C was added Dess–
Martin periodinane (9.8 mg, 0.02 mmol) and the reaction mixture was stirred at room
temperature for 10 min, then saturated aq. Na2S2O3 solution (0.5 mL) was added and the
resultant mixture was stirred at room temperature for 5 min. The mixture was extracted with
CH2Cl2 (3×15 mL) and the combined organic extracts were dried over anhydrous MgSO4 and
concentrated. Purification by flash column chromatography (EtOAc /hexane = 1:1) afforded
L-783290 (5.5 mg, 0.015 mmol, 73%) as a white powder, m.p = 134–138 °C (uncorrected). Rf
= 0.25 (EtOAc/hexane = 1:1). [α]D25 = +8.9 (c 0.25, CHCl3). IR (KBr, ν cm˗1): 2822 (m), 1680
1
(s), 1245 (s). H NMR (500 MHz, CD2Cl2): δ 11.83 (s, 1H), 7.03 (dt, J = 15.3, 7.4 Hz, 1H),
6.45 – 6.29 (m, 3H), 5.69 –5.62 (m, 1H), 4.69 (s, 1H), 3.96 (s, 1H), 3.83 (s, 3H), 3.13 (ddd, J
= 15.1, 11.8, 3.5 Hz, 1H), 2.93 – 2.83 (m, 1H), 2.62 – 2.57 (m, 2H), 1.77 – 1.69 (m, 2H), 1.65
(s, 1H), 1.49 (d, J = 6.5 Hz, 3H), 1.39 – 1.30 (m, 1H). 13C NMR (125 MHz, CD2Cl2): δ 199.3,
171.3, 166.2, 164.7, 147.7, 143.7, 131.5, 109.5, 104.9, 99.3, 77.3, 73.3, 71.3, 55.7, 38.0, 36.2,
32.8, 26.9, 19.2.
HRMS (ESI) for C19H24O7Na [M+Na]+, calculated: 387.1420, found: 387.1434.
(S)-5-(trimethylsilyl)pent-4-yn-2-ol (SI-1):
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To a solution of trimethylsilylacetylene (2.2 mL, 15.5 mmol) in dry THF (20 mL), n-BuLi
DOI: 10.1039/D0OB00237B
(11.2 mL, 1.6 M in hexane, 18.06 mmol) was added at -78 °C. The reaction mixture was then
stirred at the same temperature for 1 h and then ‘S’- propylene oxide (1.2 mL, 17.2 mmol) in
THF and BF3•Et2O (2.4 mL, 18.9 mmol) were added simultaneously. The reaction mixture was
stirred at 0 °C for 4 h and then allowed to warm at room temperature. After 4 h the reaction
solution was quenched with saturated NH4Cl (5 mL) and extracted with Et2O (3×100 mL). The
organic layers were combined and dried over anhydrous MgSO4 and concentrated under
reduced pressure to yield the crude product. The crude product was then purified through flash
column chromatography (EtOAc /hexane = 1:10) to provide SI-1 (2.1 g, 80%) as a gummy oil.
Rf = 0.3 (EtOAc/hexane; 1:10). 1H NMR (400 MHz, CDCl3) δ 3.91 (d, J = 5.3 Hz, 1H), 2.37
(qd, J = 16.7, 5.9 Hz, 2H), 1.23 (d, J = 6.1 Hz, 3H), 0.13 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 103.2, 87.4, 66.2, 30.4, 22.2, 0.04. HRMS (ESI) for C8H16OSiNa [M+Na]+, calculated:
179.0868, found: 179.0875.
(S)-1-methoxy-4-((pent-4-yn-2-yloxy)methyl)benzene (35):
To a suspension of NaH (60%, 338.4 mg, 8.46 mmol) in dry THF (20 mL), compound SI-1
(1.2 g, 7.69 mmol) in dry THF (7 mL) was added drop wise at 0 °C. After that the reaction
mixture was stirred for 25 minute at room temperature, it was then cooled to 0 °C and freshly
prepared PMB-Br (1.7 g, 8.46 mmol) in dry THF (5 mL) was added to the reaction mixture.
The reaction mixture was stirred at room temperature for 2 h and the reaction solution was
quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and the
aqueous part was washed with ethyl acetate (2×150 mL). Combined organic layer was washed
with brine (20 mL) and dried over anhydrous MgSO4. The solvent was then evaporated under
reduced pressure and the crude residue was purified by flash column chromatography
(EtOAc/hexane = 1:30) to furnish compound 35 (1.33 g, 85%) as a colorless oil. Rf = 0.4
(EtOAc/hexane; 1:20). 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.6
Hz, 2H), 4.53 (s, 2H), 3.82 (s, 3H), 3.70 (td, J = 6.4, 5.7 Hz, 1H), 2.51 (ddd, J = 16.6, 4.9, 2.7
Hz, 1H), 2.37 (ddd, J = 16.7, 7.1, 2.7 Hz, 1H), 2.02 (t, J = 2.7 Hz, 1H), 1.32 (d, J = 6.2 Hz,
3H). 13C NMR (150 MHz, CDCl3): δ 159.2, 130.6, 129.2, 113.8, 81.3, 72.9, 70.3, 69.8, 55.3,
26.0, 19.5. HRMS (ESI) for C13H16O2Na [M+Na]+, calculated: 227.1048, found: 227.1056.
5-(3-((4S,5S)-5-((5S)-1-Hydroxy-5-((4-methoxybenzyl)oxy)hex-2-yn-1-yl)-2,2-dimethyl-
1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (13):
To a solution of 35 (61.2 mg, 0.3 mmol) in THF (2 mL) at –78 °C was added n-butyllithium
(1.6 M in hexanes, 0.21 mL, 0.325 mmol) and the reaction mixture was stirred at –78 °C for 1
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h, then aldehyde 28 (95 mg, 0.25 mmol) in THF (0.5 mL) was added dropwise. Then the
DOI: 10.1039/D0OB00237B
reaction was allowed to come to room temperature and saturated aq. NH4Cl solution (2 mL)
was added. The mixture was extracted with EtOAc (3×60 mL), then the combined organic
extracts were dried over anhydrous MgSO4 and evaporated in vacuo to afford the crude
product. The crude residue was purified by flash column chromatography (EtOAc/hexane =
1:3) to furnish the inseparable diastereomeric mixture of compound 13 (120 mg, 82%) as a
colorless oil. Rf = 0.25 (EtOAc/hexane; 1:3). IR (neat, ν cm˗1): 1725 (s), 1610 (s), 1576 (s),
1
1157 (s). H NMR (600 MHz, CDCl3): δ 7.28 (d, J = 6.1 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H),
6.49 (s, 1H), 6.31 (s, 1H), 4.49 (s, 2H), 4.32 (d, J = 7.6 Hz, 1H), 4.27 – 4.19 (m, 1H), 4.08 (dt,
J = 13.4, 6.2 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.68 (q, J = 6.3 Hz, 1H), 3.18 – 3.10 (m, 1H),
3.09 – 2.99 (m, 1H), 2.56 (dd, J = 16.6, 4.9 Hz, 1H), 2.38 (dd, J = 16.6, 7.5 Hz, 1H), 1.89 –
1.81 (m, 4H), 1.70 (s, 6H), 1.49 (s, 3H), 1.37 (s, 3H), 1.29 (d, J = 6.3 Hz, 3H). 13C NMR (150
MHz, CDCl3): δ 164.8, 160.0, 159.1, 159.1, 149.4, 130.6, 129.2, 129.2, 113.7, 112.2, 108.4,
104.8, 99.3, 84.0, 80.4, 79.6, 77.1, 73.0, 70.3, 61.3, 55.5, 55.2, 34.4, 29.1, 28.1, 28.0, 26.3,
25.6, 25.6, 25.4, 19.7. HRMS (ESI) for C33H42O9Na [M+Na]+, calculated: 605.2727, found:
605.2756.
5-(3-((4S,5S)-5-((5S,Z)-1-Hydroxy-5-((4-methoxybenzyl)oxy)hex-2-en-1-yl)-2,2-
dimethyl-1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (36):
Lindlar catalyst (4 mg) was added to the compound 13 (105.2 mg, 0.18 mmol) dissolved in
ethyl acetate (6 mL). The mixture was then stirred under H2 atmosphere (through H2 balloon)
for 3 h. After completion of the reaction (TLC analysis) it was filtered through a Celite pad.
The Celite pad was then washed with EtOAc (100 mL). The combined organic filtrate was
evaporated in vacuo and the residue was purified by flash column chromatography
(EtOAc/hexane = 1: 3) to afford compound 36 (95 mg, 90%) as a clear oil. Rf = 0.30
1
(EtOAc/hexane, 1: 3). IR (neat, ν cm˗1): 1727 (s), 1619 (s), 1204 (s). H NMR (600 MHz,
CDCl3) δ 7.27 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 2.8 Hz, 1H), 6.30 (d,
J = 2.5 Hz, 1H), 5.74 – 5.62 (m, 1H), 5.55 (dt, J = 10.2, 8.8 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H),
4.44 – 4.37 (m, 2H), 4.13 – 4.08 (m, 1H), 3.97 (t, J = 6.1 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H),
3.61 (q, J = 6.0 Hz, 1H), 3.15 – 3.08 (m, 1H), 3.03 – 2.97 (m, 1H), 2.45 – 2.38 (m, 1H), 2.39 –
2.32 (m, 1H), 1.85 – 1.78 (m, 2H), 1.69 (s, 6H), 1.63 – 1.56 (m, 2H), 1.50 (s, 3H), 1.36 (s, 3H),
13
1.22 (d, J = 6.2 Hz, 3H). C NMR (151 MHz, CDCl3): δ 164.8, 160.0, 159.1, 159.1, 149.5,
130.8, 130.7, 130.4, 130.3, 130.3, 129.3, 129.3, 113.7, 112.2, 112.2, 108.1, 107.9, 104.8, 104.7,
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99.3, 99.3, 80.6, 77.1, 77.1, 73.7, 73.4, 70.1, 70.1, 65.6, 65.3, 55.5, 55.2, 35.3, 34.9, 34.4, 34.4,
DOI: 10.1039/D0OB00237B
29.5, 29.4, 28.0, 28.0, 27.9, 27.8, 25.7, 25.6, 25.6, 25.6, 25.4, 19.6, 19.3. HRMS (ESI) for
C33H44O9Na [M+Na]+, calculated: 607.2883, found: 607.2892.
5-(3-((4S,5S)-5-((5S,Z)-1-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)hex-2-
en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (37):
Imidazole (18.4 mg, 0.27 mmol) was added to a solution of 36 (95 mg, 0.16 mmol) in
anhydrous CH2Cl2 (1.5 mL) at room temperature. After stirring for 15 min TBS-Cl (51.7 mg,
0.34 mmol) was added to the reaction vessel and stirred for 3 h. After completion of the
reaction, water (3 mL) and CH2Cl2 (40 mL) was added to the reaction mixture and the organic
layer was washed with excess water and brine. The organic layer was dried over MgSO4 and
evaporated to dryness to afford the crude silylated compound, which was purified by silica gel
chromatography (EtOAc/hexane = 1:10) to get the compound 37 (99.8 mg, 88%). Rf = 0.6
1
(EtOAc/hexane; 1:3). IR (neat, ν cm˗1): 1722 (s), 1632 (s), 1170 (s). H NMR (600 MHz,
CDCl3): δ 7.27 (d, J = 11.2 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 2.5 Hz, 1H), 6.31 (d,
J = 2.6 Hz, 1H), 5.61 – 5.50 (m, 2H), 4.54 – 4.46 (m, 2H), 4.42 (t, J = 9.8 Hz, 1H), 4.05 – 4.01
(m, 1H), 3.94 (dq, J = 12.0, 6.4, 5.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.60 – 3.55 (m, 1H),
3.16 – 3.12 (m, 1H), 3.06 – 2.98 (m, 1H), 2.40 – 2.31 (m, 1H), 2.28 (dt, J = 14.2, 6.7 Hz, 1H),
1.80 (ddd, J = 15.5, 8.1, 4.3 Hz, 2H), 1.70 (s, 6H), 1.68 – 1.63 (m, 2H), 1.47 (s, 3H), 1.32 (s,
13
3H), 1.23 (d, J = 6.1 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H). C NMR (150 MHz,
CDCl3): δ 164.7, 159.9, 159.1, 159.0, 149.7, 131.6, 130.9, 129.2, 129.1, 127.6, 113.7, 112.1,
107.8, 104.7, 99.3, 81.6, 77.4, 74.2, 70.1, 68.0, 55.5, 55.2, 35.3, 34.5, 29.4, 28.0, 27.5, 25.9,
25.7, 25.6, 19.8, 18.2, -3.9, -4.4. HRMS (ESI) for C39H58O9SiNa [M+Na]+, calculated:
721.3748, found: 721.3762.
5-(3-((4S,5S)-5-((5S,Z)-1-((tert-butyldimethylsilyl)oxy)-5-hydroxyhex-2-en-1-yl)-2,2-
dimethyl-1,3-dioxolan-4-yl)propyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (38):
Compound 37 (63.9 mg, 0.09 mmol) was dissolved in CH2Cl2/phosphate buffer (pH = 7.0;
19:1, 2 mL) and the solution was cooled to 0 ºC. DDQ (24.5 mg, 0.108 mmol) was added
portion wise to the solution and the mixture was stirred at this temperature for 2 h. After
completion, the reaction mixture was passed through a pad of Celite and the residue was then
washed with CH2Cl2 (100 mL). The combined organic fraction was washed with water and
brine solution. The organic layer was then dried over anhydrous MgSO4 and evaporated in
25

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vacuo. Purification by flash column chromatography (EtOAc/hexane = 1:D3O)I: 1a0.f1f0o39r/dDe0dOB00237B
compound 38 (45 mg, 85%) as a colorless oil. Rf = 0.25 (EtOAc/hexane = 1:3). IR (neat, ν
cm˗1): 1675 (s), 1224 (s). 1H NMR (600 MHz, CDCl3): δ 6.51 (d, J = 2.7 Hz, 1H), 6.32 (s, 1H),
5.65 (dt, J = 10.5, 7.6 Hz, 1H), 5.56 (dt, J = 11.1, 7.6 Hz, 1H), 4.59 (dd, J = 9.5, 5.1 Hz, 1H),
4.12 (q, J = 3.8 Hz, 1H), 4.04 (t, J = 5.6 Hz, 1H), 3.86 (d, J = 6.9 Hz, 1H), 3.84 (s, 3H), 3.17 –
3.13 (m, 1H), 3.08 – 2.99 (m, 1H), 2.40 – 2.30 (m, 1H), 2.28 – 2.18 (m, 1H), 1.87 – 1.76 (m,
4H), 1.71 (s, 6H), 1.47 (s, 3H), 1.34 (s, 3H), 1.26 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H),
0.07 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 164.8, 160.1, 159.1, 149.7, 132.2, 128.2, 112.2,
107.9, 104.8, 104.7, 99.4, 80.9, 77.6, 67.8, 67.3, 55.5, 38.1, 34.5, 29.6, 28.1, 27.4, 25.9, 25.9,
25.7, 25.6, 23.1, 18.1, -4.0, -4.5. HRMS (ESI) for C31H50O8SiNa [M+Na]+, calculated:
601.3173, found: 601.3195.
(3aS,8S,17aS,Z)-4-((tert-Butyldimethylsilyl)oxy)-11-hydroxy-13-methoxy-2,2,8-
trimethyl-3a,4,7,8,15,16,17,17a-octahydro-10H-benzo[c][1,3]dioxolo[4,5-
h][1]oxacyclotetradecin-10-one (39):
To a stirring solution of NaH (60%, 18 mg, 0.45 mmol) in dry THF (5 mL) at 0 °C, compound
38 (43.4 mg, 0.075 mmol) in dry THF (2 mL) was slowly added. Then the reaction mixture
was stirred at room temperature for 2 h. After completion of the reaction as monitored by TLC,
saturated aq. NH4Cl solution (3 mL) was added. The mixture was extracted with EtOAc (3×40
mL). The combined organic part was washed with brine (5 mL) and the solution was dried over
anhydrous MgSO4 and concentrated in vacuo. The crude material was then purified by flash
column chromatography (EtOAc /hexane = 1:10) to afford 39 (32 mg, 82%) as a colourless oil.
High polar Rf = 0.45 (EtOAc/hexane = 1:5). Less polar (major isomer) Rf = 0.5 (EtOAc/hexane
25
1
= 1:5). [α]D = +19.8 (c 1, CHCl3). IR (neat, ν cm˗1): 1645 (s), 1253 (s), 1160 (s). H NMR
(600 MHz, CDCl3) δ 12.08 (s, 1H), 6.35 (d, J = 2.8 Hz, 1H), 6.28 (d, J = 2.8 Hz, 1H), 5.55
(ddd, J = 12.0, 6.3, 2.7 Hz, 1H), 5.48 (td, J = 11.0, 2.3 Hz, 1H), 5.37 (td, J = 10.6, 2.7 Hz, 1H),
4.44 (t, J = 9.4 Hz, 1H), 3.91 (dd, J = 8.7, 5.6 Hz, 1H), 3.84 (d, J = 5.4 Hz, 1H), 3.81 (s, 3H),
3.27 (dt, J = 12.3, 7.5 Hz, 1H), 2.91 – 2.81 (m, 1H), 2.48 (ddd, J = 12.9, 8.1, 5.2 Hz, 1H), 2.36
(dq, J = 16.0, 2.7 Hz, 1H), 1.82 – 1.74 (m, 1H), 1.68 (dt, J = 13.1, 4.1 Hz, 1H), 1.63-1.58 (m,
2H), 1.49 (s, 3H), 1.47 (d, J = 6.2 Hz, 3H), 1.33 (s, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 171.4, 165.8, 164.0, 147.9, 131.5, 128.9, 110.6, 107.5, 105.0,
99.1, 81.8, 77.4, 72.0, 67.9, 55.3, 35.9, 35.5, 31.5, 31.3, 28.2, 25.8, 25.5, 21.1, 18.3, -4.2, ˗4.3.
HRMS (ESI) for C28H44O7SiNa [M+Na]+, calculated: 543.2754, found: 543.2763.
(3aS,8S,17aS,Z)-4,11-dihydroxy-13-methoxy-2,2,8-trimethyl-3a,4,7,8,15,16,17,17a-
octahydro-10H-benzo[c][1,3]dioxolo[4,5-h][1]oxacyclotetradecin-10-one (40):
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Compound 39 (23.1 mg, 0.044 mmol) was dissolved in anhydrous THF (2 mL) in a
DOI: 10.1039/D0OB00237B
polyethylene vessel and HF-pyridine (300 μL) was added to it at 0 ºC. The mixture was then
stirred for 3 h at room temperature followed by addition of EtOAc (25 mL) and brine solution
(5 mL). The organic layer was separated and the aqueous layer was washed with (2×30 mL)
EtOAc. The combined organic part was washed with brine (5 mL) and the solution was dried
over anhydrous MgSO4 and concentrated in vacuo. The crude material was then purified by
flash column chromatography (EtOAc /hexane = 1:3) to afford 40 (17.23 mg, 90%) as a
colourless oil. High polar Rf = 0.3 (EtOAc/hexane = 1:1). Less polar (major isomer) Rf = 0.35
(EtOAc/hexane = 1:1). [α]D25 = +26.6 (c 1, CHCl3). IR (neat, ν cm˗1): 1642 (s), 1252 (s), 1040
(s).1H NMR (600 MHz, CDCl3) δ 11.99 (s, 1H), 6.36 (d, J = 2.7 Hz, 1H), 6.29 (d, J = 2.7 Hz,
1H), 5.67 – 5.58 (m, 2H), 5.33 – 5.23 (m, 1H), 4.37 (t, J = 9.6 Hz, 1H), 4.07 (q, J = 6.3 Hz,
1H), 3.81 (s, 3H), 3.76 (dd, J = 9.3, 5.3 Hz, 1H), 3.31 (dt, J = 12.6, 7.4 Hz, 1H), 2.96 – 2.86
(m, 1H), 2.56 – 2.49 (m, 1H), 2.49 – 2.44 (m, 1H), 1.81 – 1.76 (m, 1H), 1.71 (ddd, J = 15.3,
7.5, 4.3 Hz, 1H), 1.68 – 1.59 (m, 2H), 1.53 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.39 (s, 3H). 13C
NMR (150 MHz, CDCl3): δ 171.3, 165.6, 163.9, 147.3, 131.8, 130.7, 110.7, 107.8, 105.3, 99.1,
79.9, 77.8, 71.6, 64.6, 55.3, 35.7, 35.4, 29.9, 29.0, 28.2, 25.6, 21.0. HRMS (ESI) for
C22H30O7Na [M+Na]+, calculated: 429.1889, found: 429.1896.
(3aS,8S,17aS,Z)-11-Hydroxy-13-methoxy-2,2,8-trimethyl-7,8,15,16,17,17a-hexahydro-
4H-benzo[c][1,3]dioxolo[4,5-h][1]oxacyclotetradecine-4,10(3aH)-dione (41):
To the solution of compound 40 (17.23 mg, 0.04 mmol) in DCM (1.5 mL) at 0 °C was added
Dess–Martin periodinane (18.6 mg, 0.05 mmol) and the reaction mixture was stirred at room
temperature for 2 h, then saturated aq. Na2S2O3 solution (0.5 mL) was added and the resultant
mixture was stirred at room temperature for 30 min. The mixture was extracted with CH2Cl2
(3×30 mL) and the combined organic extracts were dried over anhydrous MgSO4 and
concentrated. Purification by flash column chromatography (EtOAc /hexane = 1:10) afforded
enone 41 (12 mg, 0.03 mmol, 70%) as a white powder. m.p = 120–122 °C (uncorrected). Rf =
0.4 (EtOAc/hexane = 1:5). [α]D25 = +5.7 (c 0.5, CHCl3). IR (KBr, ν cm˗1): 1645 (s), 1614 (s),
1255 (s), 1168 (s).1H NMR (600 MHz, CDCl3) δ 11.99 (s, 1H), 6.43 – 6.40 (m, 1H), 6.36 (d, J
= 2.7 Hz, 1H), 6.27 (d, J = 2.7 Hz, 1H), 6.15 (d, J = 11.8 Hz, 1H), 5.56 (ddd, J = 10.9, 6.1, 2.6
Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.35 (ddd, J = 10.1, 6.7, 3.7 Hz, 1H), 3.82 (s, 3H), 3.24 (td,
J = 11.7, 4.7 Hz, 1H), 2.40 – 2.32 (m, 3H), 2.10 – 2.01 (m, 1H), 1.90 – 1.86 (m, 1H), 1.79 (dt,
J = 14.0, 3.8 Hz, 2H), 1.65 (s, 3H), 1.44 (d, J = 6.2 Hz, 3H), 1.39 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ 201.1, 171.3, 165.8, 164.1, 147.8, 145.3, 126.5, 110.9, 109.4, 104.7, 99.2, 81.9, 77.3,
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72.4, 55.2, 36.8, 36.4, 30.4, 27.0, 26.1, 24.1, 20.9. HRMS (ESI) for C22H28O7Na [M+Na]+,
DOI: 10.1039/D0OB00237B
calculated: 427.1733, found: 427.1748.
(3S,8S,9S,Z)-8,9,16-Trihydroxy-14-methoxy-3-methyl-3,4,9,10,11,12-hexahydro-1H-
benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (L-783277):
Compound 41 (0.01 mmol, 4.3 mg) was dissolved in DCM:MeOH (1:1) in an one neck round
bottled flask and p-toluenesulfonic acid (1 mg, 0.005 mmol) was added to it at 0 °C. Then the
reaction mixture was stirred for 3 h at room temperature and then saturated NaHCO3 (50 µL)
solution was added. The resultant reaction mixture was stirred at room temperature for
additional 15 minute. The mixture was extracted with EtOAc (3×15 mL) and the combined
organic extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (EtOAc /hexane = 1:3) afforded L-783277 (3
mg, 0.008 mmol, 75%) as a white powder. m.p = 144-147 °C (uncorrected). Rf = 0.35
25
(EtOAc/hexane = 1:1). [α]D = +10.2 (c 0.5, CHCl3). IR (KBr, ν cm˗1): 2932 (m), 1662 (s),
1248 (s). 1H NMR (600 MHz, CD2Cl2) δ 12.22 (s, 1H), 6.37 (dd, J = 11.5, 3.1 Hz, 1H), 6.31
(d, J = 2.5 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 6.24 (td, J = 11.2, 2.5 Hz, 1H), 5.42 – 5.38 (m,
1H), 4.58 (d, J = 3.1 Hz, 1H), 3.82 – 3.77 (m, 1H), 3.79 (s, 3H), 3.32 (dt, J = 17.3, 11.3 Hz,
1H), 2.95 (ddd, J = 15.3, 11.8, 3.7 Hz, 1H), 2.55 – 2.50 (m, 1H), 2.42 – 2.36 (m, 1H), 1.75 –
1.68 (m, 1H), 1.50 – 1.47 (m, 1H), 1.46 – 1.39 (m, 1H), 1.41 (d, J = 5.9 Hz, 3H), 1.13 – 1.02
13
(m, 1H). C NMR (150 MHz, CD2Cl2): δ 200.3, 172.2, 166.7, 164.8, 148.0, 146.6, 126.6,
109.7, 105.0, 99.4, 81.5, 74.0, 73.5, 55.8, 37.5, 37.0, 33.4, 29.4, 21.1.
1H NMR (600 MHz, CDCl3): δ 12.18 (s, 1H), 6.39 (dd, J = 11.6, 3.2 Hz, 1H), 6.35 (d, J = 2.4
Hz, 1H), 6.29 (m, 2H), 5.44 (m, 1H), 4.55 (d, J = 2.1 Hz, 1H), 3.83 (bs, 1H), 3.82 (s, 3H), 3.67
(d, J = 4.3 Hz, 1H), 3.37 (dt, J = 17.5, 11.3 Hz, 1H), 2.95 (t, J = 13.0 Hz, 1H), 2.57 (d, J = 17.2
Hz, 1H), 2.51 – 2.45 (m, 1H), 2.07 – 2.02 (m, 2H), 1.75 (d, J = 8.7 Hz, 1H), 1.44 (d, J = 6.0
Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 199.6, 171.6, 166.5, 164.3, 147.0, 146.4, 126.1, 109.5,
104.9, 99.0, 80.8, 73.2, 73.2, 55.3, 37.1, 36.5, 33.0, 28.8, 20.9.
HRMS (ESI) for C19H24O7Na [M+Na]+, calculated: 387.1420, found: 387.1442.
Conflicts of Interest
The authors declare no competing financial interest.
Acknowledgments
Financial support from CSIR (Grant No: 02(0244)/15/EMR-II), India, is gratefully
acknowledged. One of the authors, JC is thankful to DST-India for a research fellowship. DST-
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India is thanked for the 500 MHz NMR machine (Grant No: SR/FST/ CSII-026/D2O0I:1130.)10a39t/Dth0OeB00237B
Department of Chemistry, IIT-KGP.
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