Asymmetric total synthesis of dihydroisocoumarins: 6-methoxymellein, kigelin and fusarentin 6, 7 dimethyl ether by employing proline catalysed asymmetric α-aminoxylation

Article abstract of DOI:10.1016/j.tet.2020.131524

A concise asymmetric total synthesis of dihydroisocoumarins such as 6-methoxymellein, kigelin and fusarentin 6,7-dimethyl ether in high enantiopurity have been achieved from non-chiral aldehydes by employing proline catalysed asymmetric α-aminoxylation reaction. The required stereochemistry of hydroxyl group have been generated by alternating L or D proline as a organocatalyst in α-aminoxylation step and lactone ring is assembled by oxa-Pictet-Spengler cyclisation reaction as the key steps.

Full text of DOI:10.1016/j.tet.2020.131524

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric total synthesis of dihydroisocoumarins: 6-
methoxymellein, kigelin and fusarentin 6, 7 dimethyl ether by
employing proline catalysed asymmetric a-aminoxylation
Sachin B. Markad, Baliram B. Mane, Suresh B. Waghmode*
Department of chemistry, Savitribai Phule Pune University (Formerly University of Pune), Ganeshkhind, Pune, 411007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise asymmetric total synthesis of dihydroisocoumarins such as 6-methoxymellein, kigelin and
fusarentin 6,7-dimethyl ether in high enantiopurity have been achieved from non-chiral aldehydes by
Received 18 June 2020
Received in revised form
12 August 2020
Accepted 17 August 2020
Available online xxx
employing proline catalysed asymmetric
a-aminoxylation reaction. The required stereochemistry of
hydroxyl group have been generated by alternating L or D proline as a organocatalyst in
a
-aminoxylation
step and lactone ring is assembled by oxa-Pictet-Spengler cyclisation reaction as the key steps.
© 2020 Published by Elsevier Ltd.
Keywords:
Dihydroisocoumarins
Organocatalyst
a
-aminoxylation
HWE olefination
Oxa-Pictet-Spengler cyclisation
1. Introduction
fusarium larvarum [7] it shows various biological activities such as
antifungal, insecticidal, plant pathogenic properties and phytotoxic
The 3,4-dihydroisocoumarin is the fundamental scaffold of
various compounds those possess a wide spectrum of biological
activity [1]. Mellein (1) (pheromone) and its derivatives are most
common 3,4-dihydroisocoumarins and known to exhibit an array
of biological activities. Most of dihydroisocoumarins are isolated
from fungi and plants, mellein (1) [2] was isolated from various
fungi and several insects; it shows fungicidal, antibacterial, and
HCV protease inhibitory activities [3]. The derivatives of mellein, 6-
hydroxymellein (2) and 6-methoxymellein (3) were isolated from
phytopathogen, fungi or plant and displayed cytotoxicity, phyto-
toxicity, and phytoalexin activities [4] (see Fig. 1).
activity [8]. Due to their fascinating structural architecture and the
biological significance of this class of compounds there are several
total syntheses of these compounds has been reported in literature
[9e11]. Most of the reported methods are either based on use of
chiron approach, chiral auxiliary or chelation controlled synthesis
as well as racemic synthesis. Thus, the development of an efficient
organocatalytic stereo divergent protocol for the synthesis of 3,4-
dihydroisocoumarin skleton containing molecules from simple
staring material is demanding.
Since last few decades, proline and its derivatives have proven to
be versatile organocatalyst for the synthesis of structurally diverse
The (ꢀ)-kigelin (4) was isolated from the root heartwood of
Kigelia pinnata DC [5a] as well as extracted from fungus Aspergillus
terreus culture medium [5b]. Kiglin displays significant activity
against human pathogenic dermatophytes, Microsporum canis and
Trichophyton longifusus and exhibited potent xanthine oxidase in-
hibitor activity [6]. Fusarentin ethers (5) and (6) were isolated along
with 7-O-demethylmonocerin (9) and (þ)-monocerin (10) from
molecular architecture [12]. Asymmetric a-aminoxylation of alde-
hyde is effective method to incorporate hydroxyl group in highly
stereo selective fashion [13]. Further, aldehyde functionality was
transformed into diol or alkene through NaBH4 reduction and HWE
olefination [14]. As part of our research in asymmetric synthesis of
bioactive molecules and their key chiral intermediates using pro-
line catalysed reaction [15]. Herein we describe synthesis of 6-
methoxymellien 3, kigelin 4 and fusarentin 6,7-dimethyl ether 5
by employing proline catalysed a-aminoxylation to introduce chiral
hydroxyl group in enantioselective manner, HWE olefination or
Wittig olefination and oxa-Pictet Spengler reactions as key steps.
* Corresponding author.
E-mail addresses: suresh@chem.unipune.ac.in, suresh.waghmode@gmail.com
(S.B. Waghmode).
https://doi.org/10.1016/j.tet.2020.131524
0040-4020/© 2020 Published by Elsevier Ltd.
Please cite this article as: S.B. Markad, B.B. Mane and S.B. Waghmode, Asymmetric total synthesis of dihydroisocoumarins: 6-methoxymellein,
kigelin and fusarentin 6, 7 dimethyl ether by employing proline catalysed asymmetric
j.tet.2020.131524
a-aminoxylation, Tetrahedron, https://doi.org/10.1016/

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
Fig. 1. Structures of dihydroisomarines, 6-methoxymellein, kigelin and fusarentin
ether and their analogues.
Scheme 2. Asymmetric synthesis of 6-mehoxymellein and kigelin.
2. Result and discussion
arylpropanols were treated under oxa-Pictet -Spengler cyclisation
reaction conditions by using CH(OMe)3 and catalytic amount of
PTSA in dry DCM to achieve the desired intermediate cyclic acetal.
The resulting cyclic acetal subsequently without any purification
was treated with Jones reagent in acetone to give pyranolactones
16a and 16b in 79% and 81% yields over two steps.[11h] Finally the
selective demethylation of valerolactones were done by using BCl3
(1 M solution in heptane) in DCM at ꢀ10 ꢁC for 2h, afforded 6-
Our envisioned retrosynthetic analysis for dihydroisocoumarins
(3, 4 and 5) shows straightforward oxa-Pictet-Spengler cyclisation
of hydroxy compounds 11a, 11b and 13 to obtain target molecules.
These hydroxy compounds may be easily accessible through pro-
line catalysed a-aminoxylation of commercially available aldehydes
12a and 12b followed by reduction or HWE olefination or Wittig
olefination and functional group transformations (Scheme 1).
methoxmellein 3 ½a D20
ꢂ
¼ ꢀ54 (c 1, MeOH); lit.[9g] ½a D20
¼ ꢀ55 (c
ꢂ
0.23, MeOH) and kigelin
4
½
a 2D0
ꢂ
¼ ꢀ78 (c, 0.5), lit [5a].
2.1. Asymmetric synthesis of 6-methoxymellein and kigelin
½
a 2D0
ꢂ
¼ ꢀ79(c1, MeOH) in 69% and 70% yield, respectively. The op-
tical rotations and spectroscopic data were in good agreement with
literature reports.[5a, 9g]
Based on the above retrosynthetic analysis the total synthesis of
6-methoxymelien 3 and kigelin 4 started with commercially and
cheaply available aldehydes as shown in Scheme 2. Our synthesis
started from homologation of 3, 5-dimethoxyaldehydes 14a and
3,4,5-trimethoxybenzaldehyde 14 b through a 2C-Wittig olefina-
tion to obtain desired aldehydes 12a and 12b. The a,b-unsaturated
esters were reduced using H2/Pd/C followed by DIBAL-H reduction
to corresponding aldehydes 12a and 12b in quantitative yield (for
details see supporting information). Further D-proline catalysed a-
aminoxylation of aldehydes 12a and 12b was carried out with PhNO
as oxygen source in ACN at ꢀ20 ꢁC followed by NaBH4 reduction to
get aminoxylated alcohols, which was subjected to OeN bond
cleavage to afford enantiomerically pure diols 15a and 15b with 70%
and 71% yields, respectively [13c]. The selective monotosylation of
primary hydroxy group in diols 15a and 15b was carried out by
using p-TsCl (1.1 equiv.) and Et3N in presence of catalytic amount of
Bu2SnO [16] afforded monotosylated products, which was further
treated with LiAlH4 (3.5 equiv.) in THF to afford 2-aryl-propanals
11a and 11b in 81% and 83% yields, respectively. Further these 2-
Reagents
& Conditions (a) ethyl 2-(triphenylphosphor-
anylidene)acetate, DCM, rt, 12h, 98% yield, (b) i) H2, Pd/C, MeOH,
100 psi, rt,10h, ii) DIBAL-H, DCM, ꢀ78 ꢁC, 2h, 95% over 2 steps. (c)
D-
proline, PhNO, ACN, ꢀ20 ꢁC, 24h ii) NaBH4, MeOH, 0 ꢁC, 30 min, ii)
Cu(OAc)2, MeOH, rt, 12h,70% and 71% over 2 steps. (d) i) Bu2SnO, p-
TsCl, Et3N, DCM, 0 ꢁC,3h, ii) LiAlH4 (3.5 equiv.), THF, rt, 5h, 81% and
83% over 2 steps. (e) PTSA, CH(OMe)3, DCM, 0 ꢁC to rt, 2h, ii) Jones
oxidant, acetone, 0 ꢁC to rt, 1h, 79% and 81% over 2 steps. (f) BCl3,
DCM, ꢀ10 ꢁC, 69% and 70%, 2h.
2.2. Asymmetric synthesis of fusarentin 6,7 -dimethyl ether
After successful synthesis of the 6-methoxymellein 3 and
kigelin 4, we focused our attention towards the most challenging
target fusarentin ether, in which two iterative
a-aminoxylation
reactions were carried out to construct anti diol unit in highly
diastereoselective manner as shown in Scheme 3.
Reagents and conditions a) PhNO,
D
-proline, ACN, ꢀ20 ꢁC, 24 h,
then triethyl phosphonoacetate, DBU, LiCl, 0 ꢁC, 45 min, ii)
Cu(OAc)2, MeOH, 12h, rt, 71% b) TBDMSCl, imidazole, DMAP(cat),
DMF, rt, 12h, 92% c) i) NICl2 .6H2O, NaBH4, MeOH, 1h 0 ꢁC to rt, ii)
Scheme 1. Retrosynthetic analysis of dihydroisomarines: 6-methoxymellein, kigelin
and fusarentin ether.
Scheme 3. Asymmetric synthesis of fusarentin 6,7 dimethyl ether.
2

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
DIBAL-H, DCM, ꢀ78 ꢁC, 1h, 95% (d) i) PhNO,
L
-proline, ACN, ꢀ20 ꢁC,
3. Conclusion
24h, then NaBH4, MeOH, ii) Cu(OAc)2, MeOH, 12h, rt, 63% e)
PhCH(OMe)2, PPTS, benzene, reflux, 1h ii) DIBAL-H, DCM, 0 ꢁC, 12h,
83% f) i) oxalyl chloride, DMSO, DCM, Et3N, ꢀ78 ꢁC, 3h ii) ethyl-
triphenyl phosphonium bromide, n-BuLi, THF, 0 ꢁC to rt, 12h, 70% g)
TBAF, THF, rt, 6h, 91%, h) CH(OMe)3, TMSOTf, DCM, rt, 2h, ii) Jones
reagent, Acetone, rt, 1h, 85%, (i) H2, Pd (OH)2/C, 10h, rt, 97%, (j) BCl3,
DCM, ꢀ10 ꢁC, 69%.
In summary, we have successfully achieved synthesis of dihy-
droisocoumarins in high enantiopure form with good overall yield
from readily available starting materials. The dihydroiscoumarins
such as 6-methoxymellein and kigelin were synthesized in eight
steps with 29% and 31% overall yield, respectively. Whereas the
synthesis of fusarentin 6,7-dimethyl ether was achieved in 16 steps
with 11% yield from commercially available achiral aldehydes. Our
synthetic strategy involves use of organocatalyzed (proline)
Our synthetic endeavour (as shown in Scheme 3) began with
aldehyde 12b, which was converted into
using -proline catalysed -aminoxylation followed by HWE olefi-
nation in two steps in one pot sequences: i) reaction of aldehyde
g-hydroxy ester 17 by
D
a
asymmetric
group in highly stereoselective manner with required stereo-
chemistry just by choosing L or -proline, followed by HWE olefi-
a-aminoxylation reaction, which delivers hydroxyl
12b with PhNO as oxygen source using
D
-proline as a organo-
D
catalyst to introduce chirality in ACN at ꢀ20 ꢁC for 24h. Followed by
nation or Wittig olefination to construct required alkyl chain and
oxa-Pictet-Spengler cyclisation to construct lactones are the
salient feature of our synthesis. Use of simple, cheaply available
achiral starting materials, inexpensive chiral catalyst, simpler re-
action procedures are the salient features of our methodology.
Further current effort in our group is directed towards the expan-
sion of scope of this synthetic strategy for the preparation of
various other dihydroisocoumarins as well as other natural prod-
ucts containing lactone moiety.
addition of LiCl, triethylphosphonoacetate and DBU as base at 0 ꢁC,
to afford
g-aniloxy ester ii) subsequent OeN bond cleavage was
carried out using catalytic Cu(OAc)2 in MeOH yielded
g-hydroxyl
ester 17 in 71% yield over two steps and ee 99.67% was achieved.
The enantiomeric excess was determined by HPLC equipped with
Chiralpak IA column (4.6 ꢃ 250 nm). The hydroxyl functionality of
compound 17 was protected as a TBDMS ether using TBDMSCl and
imidazole as a base with catalytic amount of DMAP in DMF at rt for
6 h to afford compound 18 in 92% yield. The reduction of double
bond was attempted under hydrogenation condition using H2/
PdeC. In this step the deprotection of TBDMS group and its lacto-
nisaion product was obtained as a side product. Therefore the se-
lective double bond reduction was carried out using NiCl2.6H2O/
NaBH4 in MeOH to achieve saturated ester. The crude saturated
ester was further subjected for DIBAL-H reduction without further
purification to yield aldehyde 19 in 95% yield over two steps.
Having sufficient quantity of aldehyde 19 in hand, our next aim
4. Experimental section
4.1. General experimental details
All reagents were obtained from commercial suppliers unless
otherwise stated and solvents were used as received with the
following exceptions. Tetrahydrofuran (THF) was distilled from
benzophenone and sodium immediately prior to use. All moisture
sensitive reactions were carried out under a nitrogen atmosphere
with dry solvents under anhydrous conditions, unless otherwise
noted. Reactions were magnetically stirred and monitored by
analytical thin-layer chromatography (TLC) E. Merck 0.25 mm silica
gel 60 F254. TLC plates were visualized by exposure to ultraviolet
light (UV, 254 nm) and/or exposure to an aqueous solution of po-
tassium permanganate (KMnO4), an acidic solution of Ninhydrin or
a solution of PMA followed by heating with a heat gun. Chroma-
tography was performed using silica gel (100e200 mesh) with
solvents distilled prior to use. Yields refer to chromatographically
and spectroscopically (1H and 13C NMR) pure material. All spectra
were recorded at 25 ꢁC. 1H NMR spectra were recorded on 500 MHz
and 400 MHz spectrometers and 13C NMR spectra were obtained at
500 NMR (126 MHz) and 400 (101 MHz) spectrometer using CDCl3
as solvent. Tetramethylsilane (0.00 ppm) served as an internal
standard in 1H NMR and CDCl3 (77.0 ppm) in 13C NMR. Chemical
shifts were recorded in ppm, and coupling constants (J) were in Hz.
HRESIMS were taken on Bruker Impact HD quadrupole plus ion
trap at CIF, S. P. Pune University. Infrared spectra were recorded on a
Nicolet Nexus 470 FT-IR spectrometer. Optical rotations were
measured on a digital polarimeter. The following abbreviations are
used for the multiplicities: s: singlet, d: doublet, t: triplet, m:
multiplet, bs: broad singlet dd: doublet of doublet for proton
spectra.
was to perform second
an organocatalyst to introduce hydroxyl group with required ste-
reochemistry. Second -aminoxylation was carried out over alde-
hyde 19 using PhNO as an oxidant and -proline as organocatalyst,
a-aminoxylation reaction using L-proline as
a
L
followed by reduction with NaBH4 in MeOH to get crude aniloxy
alcohol, which was subjected to OeN bond cleavage by using
Cu(OAc)2 in MeOH afforded diol 20 in 63% yield over two steps with
high diasteroselectivity [13c]. Diasteromerically pure diol func-
tionality of compound 20 was subjected for protection of benzal-
dehyde dimethyl acetal using catalytic amount of PPTS in benzene
under reflux condition afforded 1,2-benzylidine acetal. The crude
acetal was further subjected to regioselective reductive opening
with DIBAL-H at 0 ꢁC led to desired alcohol 21 in 83% over two steps
[17]. The oxidation of primary alcohol to aldehyde under Swern
reaction conditions and subsequent treatment of corresponding
intermediate aldehyde with Wittig reagent generated from ethyl-
triphenyl phosphonium bromide and n-BuLi as a base, to produce
alkene 22 as cis isomer in 70% yield. The TBDMS deprotection of
alkene 22 was carried out using TBAF in THF to afford free alcohol
13 in 92% yield. After successful construction of monoprotected anti
1,3 diol functionality 13 was subjected for oxa-Pictet-Spengler re-
action using CH(OMe)3 in presence of catalytic amount of TMSOTf,
followed by Jones oxidation protocol afforded g-valerolactone 23 in
85% yield.[11h] The global double bond reduction and benzyl
deprotection was smoothly carried out under hydrogenation con-
ditions using Pd(OH)2 at 100 psi to afford compound 24 in 97%
yield. Finally the selective demethylation was carried out using BCl3
to achieve target molecule fusarentin 6,7-dimethyl ether
4.2. General procedure for preparation of aldehydes
Aldehyde (2.5 g, 12.5 mmol)) in DCM was added ethyl 2-(tri-
phenylphosphoranylidene)acetate (5.2 g, 15 mmol) and reaction
mixture was stirred at rt for 12h after completion of reaction, sol-
vent was evaporated under vacuo and purified by using silica gel
chromatography using hexane: EtOAc (9:1) gave olefin as white
solid in 98% yield.
(5) ½a 2D0
ꢂ
¼ ꢀ26.9 (c 1.0, CHCl3); lit.[11h] ½a D20
¼ ꢀ25.8 (c 1.0, CHCl3);
ꢂ
lit [7]. ½a 2D0
¼ ꢀ29 (c 1.0, CHCl3) as single anti diastereomer in 69%
ꢂ
yield. The physical and spectroscopic data were in full agreement
with reported compound documented in literature.[7, 11h]
To a stirred solution of above olefin (1.0 equiv.) in MeOH (50 mL)
3

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
was added Pd/C (0.25g,10%) and reaction mixture was stirred about
10h under hydrogen pressure (100 psi). after completion of reaction
(checked on TLC), reaction mass filtered through a celite pad, and
MeOH was evaporated under vacuo afforded crude saturated ester.
The crude ester was dissolved in DCM (35 mL) and cooled
to ꢀ78 ꢁC. At this temperature DIBAL-H (13.7 mL, 13.7 mmol, 1 M
solution in toluene) was added to the reaction mixture and stirred
for 2h. After 2h, reaction was quenched with sat. tartaric acid so-
lution and extracted with DCM (3 x 50 mL). The combined organic
layers were dried over Na2SO4, evaporated on rotavapour and the
crude was purified by column chromatography using pet ether:
ethyl acetate (9:1) afforded aldehydes 98% yield as colourless liquid.
J ¼ 16, 4.0 Hz, 1H), 2.64 (m, dd, J ¼ 12, 4.0 Hz, 1H); 1.77 (s, 1H), 1.26
(d, J ¼ 8.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 160.9, 140.1, 107.3,
98.4,
68.7,
46.1,
22.8.
HRMS
(ESIþ)[MþNa]þ:
found
219.0997C11H16NaOþ3 requires 219.0992.
4.2.3. (R)-6, 8-dimethoxy-3-methylisochroman-1-one16a
To a stirred solution of 2-arylpropanol 11a (0.5g, 2.5 mmol) in
DCM (10 mL), was added CH(OMe)3 (2 mL) and PTSA
(0.095g,0.5 mmol) at 0 ꢁC and stirred for 2 h at rt. After 2h, reaction
mixture was quenched with sat. NaHCO3 and extracted with DCM
(3 x 25 mL). The combined organic layers were dried over Na2SO4,
concentrated under vacuo to obtain crude material. Jones oxidant
(2 mL, 6 mmol, and 3 M solution) was added to the stirred solution
of above crude acetal in acetone at 0 ꢁC and reaction mixture was
stirred for 2h at same temperature. After2 h, reaction mixture was
quenched with sat. NaHCO3 solution and extracted with EtOAc (3 x
20 mL). The combined organic layer was washed with water and
brine, dried over Na2SO4 and concentrated on rotavapour to obtain
crude compound. The crude was purified by column chromatog-
raphy using hexane: EtOAc (65:35) afforded compound 16a as
Aldehyde 12a: 1H NMR (400 MHz, CDCl3)
d
9.84 (t, J ¼ 1.3 Hz,
1H), 6.37 (d, J ¼ 2.2 Hz, 2H), 6.34 (d, J ¼ 2.2 Hz,1H), 3.80 (s, 6H), 2.92
(t, J ¼ 7.5 Hz, 2H), 2.78 (dd, J ¼ 10.8, 4.2 Hz, 2H); 13C NMR (101 MHz,
CDCl3)
d 201.4, 160.9, 142.7, 106.4, 98.1, 55.2, 45.0, 28.4.
Aldehyde 12b: 1H NMR (400 MHz, CDCl3)
d 9.84 (s, 1H), 6.42 (s,
2H), 3.86 (s, 6H), 3.83 (s, 3H), 2.92 (t, J ¼ 7.4 Hz, 2H), 2.80 (t,
J ¼ 7.4 Hz, 2H); 13C NMR (101 MHz, CDCl3)
d 201.4, 153.2, 136.4,
136.1, 105.2, 60.8, 56.1, 45.3, 28.4.
yellowish sticky liquid (0.44 g, 79% yield over two steps). ½a D20
¼ -
ꢂ
153.89 (c, 0.22), FTIR cmꢀ1 2969, 2927, 1703, 1595, 1245, 1111; 1H
4.2.1. (S)-3-(3, 5-dimethoxyphenyl)propane-1,2-diol 15a
NMR (400 MHz, CDCl3)
d 6.41 (s, 1H), 6.31 (s, 1H), 4.62e4.28 (m,
To stirred solution of PhNO (0.7g, 6.5 mmol) and aldehyde 12a
1H), 3.92 (s, 3H), 3.86 (s, 3H), 2.84 (dd, J ¼ 15.9, 7.0 Hz, 2H), 1.46 (d,
(1.51g, 7.8 mmol) in ACN (30 mL) was added
D-proline (0.15g,
J ¼ 4Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 164.3, 163.1, 162.7, 143.8,
1.3 mmol) at ꢀ20 ꢁC, and the reaction mixture was stirred for 24h to
same temperature. After 24h warmed to 0 ꢁC and, diluted with
MeOH, then NaBH4 was added portion wise to the reaction mixture
at 0 ꢁC and stirred it for 30 min. After 30 min reaction mixture
quenched with sat. NH4Cl solution and extracted with EtOAc (2 x
100 mL). The combined organic layers were washed with water,
brine dried over Na2SO4 and concentrated on rotavapour. The crude
was dissolved in MeOH (50 mL), Cu(OAc)2 (0.03 equiv.) was added
reaction mixture was stirred for 12h. After completion of reaction,
reaction mixture was concentrated on rotavapour. The crude ob-
tained was purified by silica gel column chromatography using
Hexane: EtOAc (40:60) afforded diol 15a as brownish thick liquid
106.8, 103.8, 97.7, 73.5, 56.1, 55.5, 36.5, 20.6. HRMS (ESIþ)[MþH]þ:
found 223.0961C12H15Oþ4 requires 223.0965.
4.2.4. (R)-8-hydroxy-6-methoxy-3-methylisochroman-1-one (6-
methoxymellein) 3
To the solution of valerolactone 16a (0.22g, 1 mmol) in anhy-
drous DCM was added BCl3 (1.2 mL, 1.2 mmol, 1 M in heptane)
at ꢀ10 ꢁC and reaction mixture was stirred for 2h, and then
quenched with sat. NaHCO3 and extracted with DCM (3 x 15 mL)
and concentrated on rotavapour. The crude was purified by silica
gel chromatography in hexane: EtOAc (65:35) afforded 6-
(0.97 g, 70%) yield. ½a D20
ꢂ
¼ ꢀ22.64 (c, 0.78) FTIR cmꢀ1 3368, 2935,
methoxymellein
3
as white solid (0.159 g, 70% yield).
mp ¼ 76e77 ꢁC, ½a 2D0
ꢂ
¼ ꢀ54 (c, 0.5), lit.[9g] ½a D20
¼ ꢀ55 (c 0.23,
ꢂ
2839, 1593, 1258, 1202, 1148; 1H NMR (400 MHz, CDCl3)
d 6.39 (d,
J ¼ 2.2 Hz, 2H), 6.37 (d, J ¼ 2.2 Hz, 1H), 4.04 (ddd, J ¼ 8.1, 6.2, 4.7 Hz,
MeOH); 1H NMR (400 MHz, CDCl3)
d
11.25 (s, 1H), 6.37 (d, J ¼ 4 Hz,
1H), 3.80 (s, 6H), 2.84 (s, 2H), 2.71 (m, 2H). 13C NMR (101 MHz,
1H), 6.26 (d, J ¼ 4 Hz, 1H), 4.67 (dd, J ¼ 13.9, 6.8 Hz, 1H), 3.83 (s, 3H),
CDCl3)
d
160.9, 140.8, 107.3, 98.4, 72.9, 65.9 55.2, 40.6, HRMS (ESIþ)
2.87 (d, J ¼ 7.2 Hz, 2H); 1.51 (d, J ¼ 4 Hz, 3H) 13C NMR (101 MHz,
[MþH]þ: found 213.1125C11H17Oþ4 requires 213.1121.
CDCl3) d 169.8, 165.8, 164.5, 140.9, 106.1, 101.5, 99.4, 75.5, 55.5, 34.8,
20.6; HRMS (ESIþ)[MþNa]þ: found 231.0618C11H12NaOþ4 requires
231.0628.
4.2.2. (R)-1-(3, 5-dimethoxyphenyl) propan-2-ol 11a
To a stirred solution of diol 15a (0.8 g, 3.3 mmol) and Bu2SnO
(0.08g, 0.3 mol) in DCM was added p- TsCl (0.7g, 3.6 mmol), Et3N
(0.92 mL, 6.6 mmol) and DMAP (0.04g, 0.3 mmol) sequentially at
0 ꢁC and stirred at rt for 3h. After completion of reaction (checked
on TLC) reaction mixture was quenched with cold water and
extracted with EtOAc (3x 40 mL). The combined organic layers
washed with brine, dried over Na2SO4 and concentrated under
vacuo to obtain crude product, which was subjected to next step
without further purification. To the suspension of LiAlH4 (0.44 g,
11.5 mmol) in THF (20 mL) was added above crude monotosylated
compound in THF (10 mL) at 0 ꢁC slowly and reaction mixture was
stirred for 5h at room temperature. After completion of reaction,
reaction mixture was quenched with aq. NH4Cl, filtered over celite
and extracted with EtOAc (2 x 40 mL). The combined organic layers
dried over Na2SO4 and concentrated on rotavapour. The crude was
purified by silica gel chromatography using hexane: EtOAc (75:25)
to obtain alcohol 11a as yellowish liquid (0.59 g, 81% yield over two
4.2.5. (S)-3-(3, 4, 5-trimethoxyphenyl) propane-1,2-diol 15b
Diol 15b was synthesized from aldehyde 12b by using same
experimental procedure as used for 15a. 0.7 g scale (PhNO) afforded
diol 15b as brownish liquid (1.12 g, 71%). ½a D20
¼ ꢀ18.64 (c, 0.4); FTIR
ꢂ
cmꢀ1 3383, 2931, 2834, 1591, 1122, 1029, 922, 894; 1H NMR
(400 MHz, CDCl3)
d 6.44 (s,1H), 3.94e3.83 (m, 1H), 3.82 (s, 6H), 3.82
(s, 3H), 3.71e3.68 (m,1H), 3.67e3.49 (m,1H), 2.98 (s, 2H), 2.77e2.64
(m, 2H); 13C NMR (101 MHz, CDCl3)
66.0, 60.8, 56.1, 40.1; HRMS
243.1219C12H19Oþ5 requires 243.1227.
d 153.2, 136.5, 133.6,106.2, 73.0,
(ESIþ)[MþH]þ:
found
4.2.6. ((R)-1-(3, 4, 5-trimethoxyphenyl) propan-2-ol 11b
The compound 11b was synthesized according to procedure
used for synthesis of compound 11a. From diol 15b (1.0 g scale)
afforded 11b as yellowish liquid (0.88 g, 83% yield). ½a D20
¼ -2.17 (c,
ꢂ
0.32); FTIR cmꢀ1 3409, 2933, 2837, 1588, 1235, 1119; 1H NMR
steps). ½a 2D0
ꢂ
¼ ꢀ13.94(c, 0.62), FTIR cmꢀ1 3384, 2964, 2839, 1593,
(400 MHz, CDCl3)
d 6.44 (s, 2H), 4.05e4.00 (m, 1H), 3.87 (s, 6H),
1201, 1148, 1053; 1H NMR (400 MHz, CDCl3)
d
6.39 (d, J ¼ 2.2 Hz,
3.84 (s, 3H), 2.75 (dd, J ¼ 13.5, 4.3 Hz, 1H), 2.61 (dd, J ¼ 13.5, 8.3 Hz,
2H), 6.35 (d, J ¼ 2.2 Hz,1H), 4.06e4.03 (m,1H), 3.80 (s, 6H), 2.74 (dd,
1H), 1.90 (s, 1H), 1.28 (d, J ¼ 6.2 Hz, 1H); 13C NMR (101 MHz, CDCl3)
4

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
d
153.2, 136.6, 134.2, 106.1, 68.8, 60.8, 56.0, 46.1, 22.8. HRMS (ESIþ)
with EtOAc (200 mL) and washed with cold water several times
then brine and dried over Na2SO4 and concentrated under vacuo.
The obtained crude was purified using silica gel column chroma-
tography using hexane: EtOAc (9:1) to afford compound 18 (2.4 g,
[MþNa]þ: found 249.1090C12H18NaOþ4 requires 249.1097.
4.2.7. ((R)-6, 7, 8-trimethoxy-3-methylisochroman-1-one 16b
Valerolactone 16b was synthesized according to procedure used
for 16a. From diol 16b (0.5 g scale) afforded 16b as yellowish liquid
92% yield) as colourless liquid. ½a D20
¼ ꢀ27.2 (c 0.20, MeOH); FTIR
ꢂ
cmꢀ1 1717, 1590, 1298, 1159,834,776; 1H NMR (400 MHz, CDCl3)
(0.45 g, 81% yield). ½a D20
ꢂ
¼ -109.35 (c, 0.24); FTIR cmꢀ1 2966, 2841,
d
6.99 (dd, J ¼ 15.5, 4.6 Hz,1H), 6.41 (s, 2H), 6.00 (dd, J ¼ 15.5,1.6 Hz,
1704, 1587,1255,1110; 1H NMR (400 MHz, CDCl3)
d 6.50 (s, 1H), 4.54
1H), 4.48e4.45 (m, 1H), 4.21 (q, J ¼ 7.1, 2H), 3.86 (s, 6H), 3.84 (s, 3H),
2.81 (dd, J ¼ 13.4, 5.0 Hz, 1H), 2.70 (dd, J ¼ 13.4, 7.7 Hz, 1H), 1.31 (t,
(ttd, J ¼ 12.6, 6.3, 3.6 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H),
J ¼ 7.1 Hz, 3H), 0.89e0.85 (m, 9H), ꢀ0.04 (s, 3H), ꢀ0.17 (s, 3H); 13
C
2.91e2.76 (m, 2H), 1.48 (d, J ¼ 6.3 Hz, 3H); 13C NMR (101 MHz,
NMR (101 MHz, CDCl3)
d 166.58, 152.99, 150.19, 136.87, 133.37,
CDCl3)
d 162.2, 157.5, 156.3, 142.1, 137.0, 111.7, 105.7, 73.9, 61.8, 61.1,
56.1, 36.0, 20.6. HRMS (ESIþ)[MþH]þ: found 253.1075C13H17O5þ
120.18, 106.97, 73.07, 60.87, 60.37, 56.09, 44.62, 25.78, 25.64, 18.13,
14.24, 14.19, ꢀ4.84, ꢀ5.31; HRMS (ESIþ)[MþNa]þ: found
447.2178C22H36NO6Si requires 447.2173.
requires 253.1071.
4.2.8. (R)-8-hydroxy-6,7-dimethoxy-3-methylisochroman-1-one
(kigelin) 4
4.2.11. (R)-4-((tert-butyldimethylsilyl)oxy)-5-(3,4,5-trimethoxy
phenyl)pentanal 19
Same experimental procedure used for the synthesis of kigelin 4
as per procedure used for 6-methoxymellein 3. From diol 16b
(0.25 g scale) afforded kigelin 4 as pale yellow solid (0.165 g, 70%
To a stirred solution of compound 18 (2 g, 4.71 mmol) in
methanol (30 mL) was added NiCl2$6H2O (0.220 g, 0.94 mmol),
NaBH4 (0.350 g, 9.43 mmol) portion wise subsequently at 0 ꢁC, and
stirred at room temperature for 1 h. After completion of the reac-
tion, the reaction mixture was filtered over celite; solvent was
evaporated under vacuo. The crude was diluted with water and
extracted into EtOAc (3 x 25 mL). The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The crude product was subjected to DIBAL-H reduction without
yield. mp ¼ 143e144 ꢁC; ½a D20
¼ ꢀ78 (c 1, MeOH) lit [5a].
ꢂ
½
a 2D0
ꢂ
¼ ꢀ79 (c 1, MeOH); FTIR cmꢀ1 2929, 2857, 2356.58, 1655, 1511,
272,1113, 755; 1H NMR (400 MHz, CDCl3)
d 11.15 (s,1H), 6.30 (s,1H),
4.68 (dt, J ¼ 8.7, 6.2 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.86 (d,
J ¼ 8.0 Hz, 2H), 1.52 (d, J ¼ 4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
169.8, 158.4, 156.1, 135.4, 135.3, 102.8, 102.0, 75.8, 60.7, 56.1, 34.6,
20.7; HRMS (ESIþ)[MþNa]þ: found 261.0726C12H14NaOþ5 requires
further purification. 1H of crude; 1H NMR (400 MHz, CDCl3)
d 6.41
261.0733.
(s, 2H), 4.14 (q, J ¼ 7.1 Hz, 2H), 3.94 (dd, J ¼ 6.1, 5.0 Hz, 1H), 3.86 (s,
6H), 3.83 (s, 3H), 2.68 (d, J ¼ 6.2 Hz, 2H), 2.41 ((td, J ¼ 7.4, 1.6 Hz,
2H)), 1.89e1.70 (m, 2H), 1.27 (t, J ¼ 7.1 Hz, 3H), 0.88 (s, 9H), 0.02 (s,
3H), ꢀ0.13 (s, 3H).
4.2.9. (S,E)-ethyl 4-hydroxy-5-(3,4,5-trimethoxyphenyl)pent-2-
enoate 17
To a stirred solution of PhNO (2 g, 18.8 mmol) and aldehyde 12b
A solution of crude ester (2.0 g, 1 eq.) in DCM (30 mL) was cooled
to e 78 ꢁC. At ꢀ78C, DIBAL-H (5.1 mL of a 1 M solution in toluene,
5.1 mmol) was added dropwise and stirred for 1h. After 1h, the
reaction mixture was quenched with sat. tartaric acid solution
(20 mL) at - 78 ꢁC, warmed to rt and extracted with DCM (3 x
15 mL). The combined organic layers were washed with water,
brine and dried over Na2SO4 and concentrated under vacuo. The
crude was purified by silica gel column chromatography using pet
ether: ethyl acetate (92: 8) afforded pure aldehyde 19 (1.8 g, 95%) as
(4.7 g, 20.5 mmol) in ACN (50 mL) was added D-proline (0.430 mg,
3.75 mmol) at -20 ꢁC and stirred for 24 h at the same temperature.
After 24 h reaction warmed to 0 ꢁC, LiCl (1.190 g, 28.2 mmol),
triethyl phosphonoacetate (4.20 g, 28.2 mmol) and DBU (3.42 g,
22.5 mmol) was added sequentially at 0 ꢁC and stirred for addi-
tional 1h. After completion of reaction, the reaction mixture was
quenched with saturated NH4Cl solution and extracted with EtOAc
(2 x 200 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated under vacuo to give a crude
aminoxy olefinic ester.
a-
colourless oil. ½a D20
ꢂ
¼ ꢀ23.44 (c 0.25, MeOH); FTIR cmꢀ1 2855, 2716,
1723, 1238, 1125, 831, 774 1H NMR (400 MHz, CDCl3)
d 9.80 (t,
To a stirred solution of crude a-aminoxy olefinic ester in MeOH
J ¼ 1.6 Hz,1H), 6.40 (s, 2H), 3.96 (dd, J ¼ 6.2, 4.7 Hz,1H), 3.87 (s, 6H),
3.84 (s, 3H), 2.74e2.64 (m, 2H), 2.55 (td, J ¼ 7.4, 1.6 Hz, 2H), 1.86
(ddd, J ¼ 12.2, 7.1, 4.6 Hz, 1H), 1.75 (dt, J ¼ 13.9, 7.3 Hz, 1H), 0.88 (m,
(50 mL) was added Cu(OAc)2 (1.1 g, 0.3 equiv.) and reaction mixture
was stirred at rt for 12 h. After completion of the reaction (moni-
tored by TLC), the solvent was evaporated under vacuo and crude
material was purified by silica gel column chromatography using
9H), 0.03 (s, 3H), ꢀ0.11 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 202.42,
153.05, 136.68, 134.37, 106.66, 72.40, 60.88, 56.12, 44.12, 39.65,
28.95, 25.84, 18.01, ꢀ4.67, ꢀ4.79. HRMS (ESIþ)[MþH]þ: found
405.2074C20H35O5Si requires 405.2068.
hexane: EtOAc (7:3) as eluents to afford
71% yield) as brown liquid. ½a D20
g-hydroxy ester 17 (3.3 g,
ꢂ
¼ þ19.59 (c 0.34, MeOH); FTIR
cmꢀ1 3470, 1712 1589, 1237, 1122, 1036, 1005. 1H NMR (400 MHz,
CDCl3)
d
7.03 (dd, J ¼ 15.6, 4.5 Hz,1H), 6.45 (s, 2H), 6.09 (dd, J ¼ 15.7,
4.2.12. (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-5-(3,4,5trimeth
oxyphenyl)pentane-1,2-diol 20
Diol 20 was synthesized by using same experimental procedure
as used for 15a. From aldehyde 19 (1.5 g scale) afforded diol 20 as
1.7 Hz, 1H), 4.54 (dtd, J ¼ 6.2, 4.6, 1.7 Hz, 1H), 4.22 (q, J ¼ 7.1 Hz, 2H),
3.86 (s, 6H), 3.84 (s, 3H), 2.91 (dd, J ¼ 13.7, 4.6 Hz, 1H), 2.73 (dd,
J ¼ 13.7, 8.4 Hz, 1H), 2.03 (s, 1H), 1.31 (t, J ¼ 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) d, 166.45, 153.35, 148.80, 136.93, 132.46, 120.66,
106.36, 71.63, 60.85, 60.49, 56.11, 43.64, 14.24; HRMS (ESIþ)
red viscous liquid (0.99 g, 63% yield) (note: L-proline used as
[MþH]þ: found 311.1491C16H23O6 requires 311.1489.
organocatalyst) ½a D20
ꢂ
¼ þ 13.84 (c 0.25, MeOH); FTIR cmꢀ1 3468,
2931, 2885, 1238, 1124, 1047,831, 773; 1H NMR (400 MHz, CDCl3)
4.2.10. (S,E)-ethyl 4-((tert-butyldimethylsilyl)oxy)-5-(3,4,5tri
methoxyphenyl)pent-2-enoate 18
d 6.40 (s, 2H), 4.27e4.22 (m, 1H), 4.18e4.14 (m, 1H), 3.85 (s, 6H),
3.83 (s, 3H), 3.62 (dd, J ¼ 11.1, 3.4 Hz, 1H), 3.46 (dd, J ¼ 11.1, 6.4 Hz,
1H), 2.87 (dd, J ¼ 13.6, 7.1 Hz,1H), 2.79 (dd, J ¼ 13.5, 6.3 Hz,1H), 2.09
(s, 1H), 2.06 (s, 1H), 1.76 (ddd, J ¼ 14.4, 10.5, 3.8 Hz, 1H), 1.52 (ddd,
To a stirred solution of g-hydroxy ester 17 (2.00 g, 6.45 mmol) in
DMF (25 mL) were added Imidazole (0.65g, 9.65 mmol), TBDMSCl
(1.45 g, 9.65 mmol) and DMAP (catalytic) Sequentially at 0 ꢁC and
reaction mixture was stirred at rt for overnight. After completion of
the reaction (monitored by TLC), the reaction mixture was diluted
J ¼ 14.4, 4.8, 2.3 Hz, 1H), 0.89 (s, 9H), 0.07 (s, 3H), ꢀ0.12 (s, 3H). 13
C
NMR (101 MHz, CDCl3) d 153.13,136.77, 134.26, 106.66, 72.68, 69.02,
67.11, 60.87, 56.13, 43.42, 37.60, 25.80, 17.92, ꢀ4.92, ꢀ5.02; HRMS
5

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
(ESIþ)[MþNa]þ: found 423.2179C20H36NaO6Si requires 423.2173.
dry THF (10 mL) was added TBAF (0.9 mmol, 0.9 mL, 1 M solution in
THF) and stirred for 6 h at rt. After completion of reaction, reaction
mixture was quenched with aq. NH4Cl and extracted with EtOAc
(3x 20 mL). The combined organic layer were washed with brine,
dried over Na2SO4 and concentrated under vacuo to obtain crude
material. The crude was purified using by silica gel column chro-
matography using hexane: EtOAc (80:20) to obtain pure hydroxyl
4.2.13. (2R,4S)-2-(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-5-
(3,4,5-trimethoxyphenyl)pentan-1-ol 21
To a stirred solution of diol 20 (0.6, g 1.5 mmol) in benzene
(50 mL) were added PhCH(OMe)2 (0.25 g, 1.65 mmol) and PPTS
(38 mg, 0.15 mmol) and reaction mixture was refluxed for 1h with a
DeaneStark apparatus. After 1 h, reaction was quenched with Et3N
(0.2 mL) and the solvent was removed under vacuo to get crude
acetal. To the crude solution of acetal in DCM (25 mL), was added
DIBAL-H (4.5 mmol, 4.5 ml, 1 M in toluene) at 0 ꢁC and stirred for
12 h at same temperature. After completion of reaction, reaction
mixture was quenched with MeOH (1 mL) and saturated tartaric
acid solution (5 mL), and extracted with DCM (3 x 50 mL). The
combined organic layers were concentrated under vacuo to afford
crude compound. The crude was purified by silica gel column
chromatography using hexane: EtOAc (85: 15) to afford pure
compound 13 (0.245g, 91%) as colourless liquid. ½a D20
¼ - 22.69 (c
ꢂ
0.23, MeOH); FTIR cmꢀ1 3485, 1588, 1237, 1124, 1HNMR (400 MHz,
CDCl3)
d 7.36e7.29 (m, 5H), 6.43 (s, 2H), 1e5.68 (m, 1H), 5.50 (ddd,
J ¼ 10.9, 9.2, 1.7 Hz, 1H), 4.63 (d, J ¼ 11.7 Hz, 1H), 4.56 (td, J ¼ 8.5,
3.6 Hz, 1H), 4.36 (d, J ¼ 11.7 Hz, 1H), 4.17 (ddd, J ¼ 11.8, 8.0, 2.8 Hz,
1H), 3.86 (s, 6H), 3.85 (s, 3H), 2.70 (d, J ¼ 6.2 Hz, 2H, and 1H (OH)
merged together), 1.84 (ddd, J ¼ 14.4, 8.2, 2.7 Hz, 1H), 1.70 (dd,
J ¼ 8.9, 3.7 Hz, 1H), 1.66 (dd, J ¼ 7.0, 1.7 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d 153.15, 138.36, 136.48, 134.49, 130.96, 128.43, 127.99,
127.77, 127.71, 106.18, 71.43, 70.11, 69.55, 60.84, 56.06, 44.34, 41.63,
13.38; HRMS (ESIþ)[MþNa]þ: found 409.1990C23H30NaO5Si re-
quires 409.1985.
compound 21 as a colourless oil (0.60 g, 83%) ½a D20
¼ þ 7.87 (c 0.26,
ꢂ
MeOH); FTIR cmꢀ1 3468, 2931, 2885, 1238, 1124, 1047,831, 773; 1
H
NMR (500 MHz, CDCl3)
d 7.33e7.26 (m, 5H), 6.36 (s, 2H), 4.52 (d,
4.2.16. (S)-3-((R,Z)-2-(benzyloxy)pent-3-en-1-yl)-6,7,8-trimeth
oxyisochroman-1-one 23
The title compound was synthesized by using same experi-
mental procedure as used for 16a. From compound 13 (0.200 g
scale) afforded lactone 23 (0.181 g, 85% yield for two steps) as pale
yellow oil: ((Note: TMSOTF used as catalyst instead of PTSA)
J ¼ 4.1 Hz, 2H), 4.05e4.01 (m, 1H), 3.80e3.69 (m, 10H), 3.68e3.60
(m, 1H), 3.51 (dd, J ¼ 11.7, 5.1 Hz, 1H), 2.74e2.66 (m, 2H), 2.06 (s,
1H), 1.83 (ddd, J ¼ 14.4, 7.2, 4.5 Hz, 1H), 1.54 (ddd, J ¼ 14.4, 7.4,
5.0 Hz, 1H), 0.85 (s, 9H), ꢀ0.00 (s, 3H), ꢀ0.11 (s, 3H); 13C NMR
(101 MHz, CDCl3)
d 153.00, 138.38, 136.62, 134.39, 128.49, 127.76,
127.53, 106.72, 76.71, 71.08, 70.98, 64.39, 60.87, 56.07, 44.84, 38.95,
25.91, 18.04, ꢀ4.42, ꢀ4.56 HRMS (ESIþ) [MþNa]þ: found
513.2649C27H46NaO6Si requires 513.2642.
½
a 2D0
ꢂ
¼ ꢀ42.81 (c 0.32, MeOH); FTIR cmꢀ1 2937, 1716, 1592, 1254,
1105. 1H NMR (400 MHz, CDCl3)
d 7.33e7.26 (m, 5H), 6.48 (s, 1H),
5.79e5.71 (m, 1H), 5.39 (ddd, J ¼ 11.0, 6.4,1.8 Hz,1H), 4.75e4.71 (m,
1H), 4.64 (td, J ¼ 8.1, 4.2 Hz, 1H), 4.58 (d, J ¼ 11.3 Hz, 1H), 4.37 (d,
J ¼ 11.3 Hz, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 2.93e2.77 (m,
2H), 1.94e1.91 (m, 2H), 1.75 (dd, J ¼ 7.0, 1.8 Hz, 3H). 13C NMR
4.2.14. (((2S,4R,Z)-4-(benzyloxy)-1-(3,4,5-trimethoxyphenyl) hept-
5-en-2-yl)oxy)(tert-butyl)dimethylsilane 22
IBX (0.430 g, 1.53 mmol) was added to the solution of compound
21 (0.5 g, 1.02 mmol) in DMSO (6 mL) and stirred for 4 h at room
temperature. After completion of the reaction as observed in TLC,
the reaction was quenched with saturated NaHCO3 solution (25 mL)
and was extracted with EtOAc (2 x 20 mL). The combined organic
phases were washed with brine (30 mL) and dried over Na2SO4,
concentrated under vacuo to obtained crude aldehyde.
To the Wittig salt (1.51 g, 4.08 mmol) in dry THF (10 mL) was
added n-BuLi (1.6 mL, 2.5 M in hexane) very slowly at 0 ꢁC and
stirred for 30 min at 0 ꢁC to generate Wittig reagent. After 30 min,
crude aldehyde in THF (5 mL) was added to the above reaction
mixture at 0 ꢁC and stirred at rt for overnight. After completion of
reaction mixture, (checked on TLC), quenched with sat. NH4Cl and
extracted with EtOAc (3x 50 mL), the combined organic layer was
washed with brine, and concentrated under vacuo to obtain crude
material. The crude was purified by silica gel column chromatog-
raphy using hexane: EtOAc (96:4) to afford olefin 22 (0.36 g, 70%
(101 MHz, CDCl3)
d 162.28, 157.53, 156.30, 142.09, 138.61, 137.23,
130.88, 128.33, 128.28, 127.86, 127.56, 111.97, 105.70, 74.37, 70.31,
70.01, 61.87, 61.17, 56.13, 41.13, 34.95, 13.60. HRMS (ESIþ)[MþH]þ:
found 413.1962C24H29O6 requires 413.1958.
4.2.17. (S)-3-((S)-2-hydroxypentyl)-6,7,8-trimethoxyiso chroman-
1-one
To the stirred solution of lactone 23 (150 mg, 0.35 mmol) in
EtOAc (20 mL), was added Pd(OH)2 (30 mg, 20%) and reaction
mixture was stirred at rt under hydrogen pressure (100 psi) in Parr
reactor for overnight. After complete consumption of starting ma-
terial (checked on TLC) reaction mixture was filtered on celite and
filtrate was concentrated under vacuo to obtain crude material. The
crude material was purified by silica gel column chromatography
using hexane: EtOAc (65:35), afforded compound 24 (114 mg, 97%)
as yellow liquid. ½a D20
ꢂ
¼ - 64.8 (c 1, CHCl3); FTIR cmꢀ1 3422, 2934,
2872, 1705, 1592, 1257, 1110; 1H NMR (400 MHz, CDCl3)
d 6.50 (s,
yield) as yellow oil. ½a D20
ꢂ
¼ þ 44.91 (c 0.22, MeOH); FTIR cmꢀ1 2930,
2855, 1588, 1238. 1126, 1066, 832, 774; 1H NMR (400 MHz, CDCl3)
1H), 4.75e4.69 (m, 1H), 4.08e4.04 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H),
3.86 (s, 3H), 2.86 (ddd, J ¼ 19.1, 16.1, 7.4 Hz, 2H), 2.20 (s, 1H), 1.94
(ddd, J ¼ 14.3, 9.6, 2.2 Hz, 1H), 1.71e1.65 (m, 1H), 1.52e1.38 (m, 4H),
d
7.35e7.29 (m, 5H), 6.41 (s, 2H), 5.77e5.69 (m, 1H), 5.38 (ddd,
J ¼ 11.0, 9.3, 1.8 Hz, 1H), 4.56 (d, J ¼ 11.4 Hz, 1H), 4.42 (td, J ¼ 8.8,
4.0 Hz,1H), 4.33 (d, J ¼ 11.4 Hz,1H), 4.15 (dd, J ¼ 5.9, 4.1 Hz,1H), 3.83
(s, 3H), 3.82 (s, 6H), 2.72 (ddd, J ¼ 20.2, 13.7, 6.0 Hz, 2H), 1.86 (ddd,
J ¼ 13.6, 8.8, 4.6 Hz, 1H), 1.73 (dd, J ¼ 7.0, 1.7 Hz, 3H), 1.54 (ddd,
0.94 (t, J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 162.39, 157.59,
156.29, 142.03, 137.33,111.78, 105.73, 74.81, 67.11, 61.84, 61.15, 56.13,
42.24, 40.19, 34.94, 18.74, 14.06.; HRMS (ESIþ)[MþH]þ: found
325.1643, C17H25O6 requires 325.1646.
J ¼ 14.0, 7.3, 4.4 Hz, 1H), 0.89 (s, 9H), 0.04 (s, 3H), ꢀ0.10 (s, 3H); 13
C
NMR (101 MHz, CDCl3) d, 152.88, 138.95, 136.49, 134.77, 131.99,
4.2.18. (S)-8-hydroxy-3-((S)-2-hydroxypentyl)-6,7-dimethoxy
isochroman-1-one (5)
The title compound was synthesized by using same experi-
mental procedure used for compound 3. From compound 24 (0.1g
scale) afforded fusarentin 6,7 dimethyl 5 (66 mg, 70% yield) as a
128.28, 127.67, 127.39, 127.24, 106.75, 71.04, 70.18, 69.72, 60.84,
56.00, 44.84, 43.46, 25.88, 18.00, 13.43, ꢀ4.55, ꢀ4.72; HRMS (ESIþ)
[MþNa]þ: found 523.2855C29H44NaO5Si requires 523.2850.
4.2.15. (2S,4R,Z)-4-(benzyloxy)-1-(3,4,5-trimethoxyphenyl) hept-5-
en-2-ol 13
white solid. mp ¼ 101e103 ꢁC; ½a D25
ꢂ
¼ ꢀ26.9 (c 1, CHCl3); ½a D20
¼ -
ꢂ
To the stirred solution of compound 22 (0.35 g, 0.69 mmol) in
25.8 (c 1, CHCl3); FTIR cmꢀ1 3461, 3388, 2923, 2854, 1650, 1630,
6

S.B. Markad, B.B. Mane and S.B. Waghmode
Tetrahedron xxx (xxxx) xxx
1511, 1272, 1117; 1H NMR (400 MHz, CDCl3)
d 11.08 (s, 1H), 6.28 (s,
[9] For the Synthesis of Mellein and its Derivatives (a) C. Dimitriadis, M. Gill,
M.F. Harte, Tetrahedron Asymmetry 8 (1997) 2153;
1H), 4.88e4.81 (m, 1H), 4.07e4.03 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H),
2.97e2.83 (m, 2H), 1.98 (ddd, J ¼ 14.5, 9.6, 2.3 Hz, 1H), 1.70 (ddd,
J ¼ 14.5, 10.2, 3.0 Hz, 1H), 1.52e1.41 (m, 4H), 0.95 (t, J ¼ 7.0 Hz, 3H);
(b) B.H. Bhide, A.J. Kalaria, B.M. Panchal, J. Heterocycl. Chem. 39 (2002) 623;
(c) R. Cordova, B. Snider, Tetrahedron Lett. 25 (1984) 2945;
(d) A.C. Regan, J. Staunton, J. Chem. Soc., Chem. Commun. (1983) 764;
(e) K. Mori, A.K. Gupta, Tetrahedron 41 (1985) 5295;
(f) K.M. Pietrusiewicz, I. Salamonczyk, J. Org. Chem. 53 (1988) 2837;
(g) M.S. Islam, K. Ishigami, H. Watanabe, Tetrahedron 63 (2007) 1074;
13C NMR (101 MHz, CDCl3)
d 169.7, 158.5, 156.2, 135.6, 135.4, 103.0,
102.1, 76.5, 67.1, 60.7, 56.1, 42.3, 40.2, 33.6, 18.7, 14.0; HRMS (ESIþ)
[MþH]þ: found 311.1485, C16H23O6 requires 311.1489.
ꢀ
ꢀ
(h) J. Mangas-Sanchez, E. Busto, V. Gotor- Fernandez, V. Gotor, Catal. Sci.
Technol. 2 (2012) 1590.
[10] For the Synthesis of Kigelin (a) N.S. Narasimhan, C.P. Bapat, J. Chem. Soc.
Perkin Trans. I (1982) 2099;
Declaration of Competing Interest
(b) M.P. Sibi, M.A.J. Miah, V. Snieckus, J. Org. Chem. 49 (1984) 737;
(c) A. Saeed, S. Ehsan, J. Braz. Chem. Soc. 16 (4) (2005) 739.
[11] For the synthesis of fusarentin ether and its analogues a) M.P. Dillon,
T.J. Simpson, J.B. Sweeney, Tetrahedron Lett. 33 (1992) 7569e7572;
(b) McNicholas, T.J. Simpson, N.J. Willett, Tetrahedron Lett. 37 (1996)
8053e8056;
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(c) P.J. Reddy, A.S. Reddy, J.S. Yadav, B.V.S. Reddy, Tetrahedron Lett. 53 (2012)
4051e4053;
Acknowledgments
(d) T.N. Trotter, A.M.M. Albury, M.P. Jennings, J. Org. Chem. 77 (2012)
7688e7692;
(e) J.H. Cassidy, C.N. Farthing, S.P. Marsden, A. Pedersen, M. Slater, G. Stemp,
Org. Biomol. Chem. 4 (2006) 4118e4126;
(f) M. Fujita, K. Mori, M. Shimogaki, T. Sugimura, Org. Lett. 14 (2012)
1294e1297;
SBM and BBM thank CSIR New Delhi, India for research fel-
lowships and BCUD, SPPU and UPE phase II Pune 411007 for
financial support (Ref. No. O.S.D./B.C.U.D./83).
(g) H.K. Kwon, Y.E. Lee, E. Lee, Org. Lett. 10 (2008) 2995e2996;
(h) B. Fang, X. Xie, C. Zhao, P. Jing, H. Li, Z. Wang, J. Gu, X. She, J. Org. Chem. 78
(2013) 6338;
Appendix A. Supplementary data
(i) G. Kumaraswamy, K. Ankamma, N. Raghu, D. RamBabu, Eur. J. Org Chem.
(2014) 2168e2173.
[12] (a) N.S. Chowdari, D.B. Ramachary, C.F. Barbas, III Org. Lett. 5 (2003) 1685;
(b) G. Zhong, Chem. Commun. (2004) 606;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131524.
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