Hypervalent iodine(III) catalyzed radical hydroacylation of chiral alkylidenemalonates with aliphatic aldehydes under photolysis

Article abstract of DOI:10.1016/j.tet.2017.08.018

Hypervalent iodine(III) catalyzed diastereoselective radical hydroacylation of alkylidenemalonates bearing (?)-8-phenylmenthol as a chiral auxiliary with aliphatic aldehydes is realized under photolysis. This work represent the first example of diastereoselective addition of acyl radicals to olefins to afford chiral ketones in a highly stereoselective fashion. The reaction is initiated by the photolysis of hypervalent iodine(III) catalyst under mild and metal-free conditions. The synthetic potential of this methodology was demonstrated by the short formal synthesis of (?)-methyleneolactocin.

Full text of DOI:10.1016/j.tet.2017.08.018

Accepted Manuscript
Hypervalent iodine(III) catalyzed radical hydroacylation of chiral alkylidenemalonates
with aliphatic aldehydes under photolysis
Sermadurai Selvakumar, Qi-Kai Kang, Natarajan Arumugam, Abdulrahman I.
Almansour, Raju Suresh Kumar, Keiji Maruoka
PII:
S0040-4020(17)30838-4
10.1016/j.tet.2017.08.018
TET 28912
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 July 2017
Revised Date: 28 July 2017
Accepted Date: 10 August 2017
Please cite this article as: Selvakumar S, Kang Q-K, Arumugam N, Almansour AI, Kumar RS, Maruoka
K, Hypervalent iodine(III) catalyzed radical hydroacylation of chiral alkylidenemalonates with aliphatic
aldehydes under photolysis, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.018.
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Hypervalent Iodine(III) Catalyzed Radical
Hydroacylation of Chiral Alkylidene-
malonates with Aliphatic Aldehydes
under Photolysis
Leave this area blank for abstract info.
Sermadurai Selvakumar a, Qi-Kai Kang a, Natarajan Arumugam b, Abdulrahman I. Almansour b, Raju Suresh
Kumar b, Keiji Maruoka a, *

1
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Tetrahedron
journal homepage: www.elsevier.com
Hypervalent Iodine(III) Catalyzed Radical Hydroacylation of Chiral
Alkylidenemalonates with Aliphatic Aldehydes under Photolysis
Sermadurai Selvakumar a, Qi-Kai Kang a, Natarajan Arumugam b, Abdulrahman I. Almansour b, Raju
Suresh Kumar b, Keiji Maruoka a,
a Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa Oiwake-Cho, Kyoto, 606-8224, Japan
b Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Hypervalent
iodine(III)
catalyzed
diastereoselective
radical
hydroacylation
of
alkylidenemalonates bearing (–)-8-phenylmenthol as a chiral auxiliary with aliphatic aldehydes
is realized under photolysis. This work represent the first example of diastereoselective addition
of acyl radicals to olefins to afford chiral ketones in a highly stereoselective fashion. The
reaction is initiated by the photolysis of hypervalent iodine(III) catalyst under mild and metal-
free conditions. The synthetic potential of this methodology was demonstrated by the short
formal sythesis of (–)-methyleneolactocin.
Available online
Keywords:
Photolysis
Hydroacylation
Hypervalent iodine reagents
Chiral auxiliary
Radical reaction
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
ketones has also received greater attention in recent years.
Alternatively, radical hydroacylation6 through generation of acyl
radical from aldehydes also has the potential to become an
attractive atom economical method for the synthesis of ketones
(Scheme 1). However, this approach has been less investigated
due to the instability of acyl radical derived from branched
aldehydes under reaction condition. During the course of our
ongoing projects on the effective use of hypervalent iodine(III)
reagents under photolysis,6g,7 we investigated the hydroacylation
reaction of cyclohexanecarboxaldehyde 2a with ethyl crotonate
3a or diethyl ethylidenemalonate 3b under the influence of
various hypervalent iodine(III) reagents8 as catalyst (Table 1).
The in situ generation of acyl radicals from branched aldehydes
and its subsequent trapping with electrophiles have not been
previously developed to a synthetically useful level. To our
delight, catalytic use of DIB 1a under the irradiation of UV light
(365 nm) gave the hydroacylation product 4a or 4b in 11% or
81% yield respectively with high selectivity for ketone formation
(4a/5a = 5.8/1 and 4b/5b = 22.5/1; entry 1). Only trace amounts
of reaction products were detected in the absence of 1a or black
light under given conditions (entry 2 and 3). These results
strongly indicate that the reaction undergoes a radical pathway,
thereby generating desired acyl radicals9 in the reaction mixture.
We also investigated other iodine(III) catalysts 1b-e (entries
4~7), and found that 1d gave a satisfactory result (entry 6).
Among the screened iodine(III) catalysts 1d shows higher
Research in the last few decades has witnessed an
incredible development of new methods for the C-C bond
formation via radical chemistry.1 Atom economical reaction
between aldehyde and olefin namely hydroacylation represent
one of the synthetically useful transformation for the construction
O
R
H
[M]
NHC
I(III)
OH
O
O
X
R
R
[M]
R
X
H
This work
R'
R''
O
H
R
R''
R'
Scheme 1. Hydroacylation of olefins with aldehydes
of ketones. Metal catalyzed hydroacylation2 and N-heterocyclic
carbenes (NHCs)3 catalyzed Stetter reaction are most widely used
approach for the addition of aldehydes to olefins (Scheme 1). In
addition, the development of asymmetric metal catalyzed
hydroacylation4 and chiral N-heterocyclic carbenes (NHCs)
5
———
catalyzed asymmetric Stetter reactions to synthesize chiral
Corresponding author. Tel./fax: +81-75-753-4041; e-mail address: maruoka@kuchem.kyoto-u.ac.jp (K. Maruoka)

COX*
COX*
O
O
COX*
cat. 1d
*
Alkyl
H
Alkyl
COX*
365 nm, RT
R1
R1
X* = Chiral auxiliary
α-chiral ketone
2
Tetrahedron
solubility in CH3CN solvent. Evaluation of different solvents
Scheme 2. Hypervalent iodine(III) catalyzed diastereo-
selective radical hydroacylation of chiral olefins with
aldehydes.
ACCEPTED MANUSCRIPT
revealed CH3CN as best solvent for this reaction. The
concentration of the reaction mixture is also crucial for obtaining
the high yield as well as selectivity, and indeed use of a more
concentrated CH3CN (1.0 M or 1.6 M) solution including catalyst
1d significantly enhanced both the selectivity (6.4/1 and >25/1)
and the yield (>99%) for 4a and 4b respectively (entries 8 and 9).
Lowering the catalyst loading of 1d decelerates the reaction
progress, however high yield was obtained with prolonged
reaction time (entry 10).
2. Results and discussion
At the outset, we first investigated the effect of chiral auxiliary
for the diastereoselctive radical hydroacylation between
cyclohexanecarboxaldehyde 2a with various chiral alkenes 6a-h.
Chiral crotyl esters derived from alcohols such as (–)-menthol, (–
)-8-phenylmenthol,
(–)-borneol,
(+)-fenchol
afforded
hydroacylated product 7a-h in good yield with poor
diastereoslectivity. Crotyl imides 6e derived from (S)-4-benzyl-2-
oxazolidinone also gave hydroacylated product in 1:1
diastereoselectivity. Interestingly, crotyl amide 6f derived from
(R)-(–)-1-phenylethylamine was found to remain unreactive
under standard condition (Table 2).
Table 1. Hydroacylation of cyclohexanecarboxaldehyde with
ethyl crotonate or diethyl ethylidenemalonate by hypervalent
iodine(III) catalystsa
O
CO2Et
O
CO2Et
1a e (10 mol%)
365 nm
R'
H
R'
Me
Me
CH3CN, Ar
RT, 12 h
4a (R' = H)
4b (R' = CO2Et)
Table 2. Diasteroselective Hydroacylation of chiral crotonates
2a
3a (R' = H)
3b (R' = CO2Et)
and alkylidenemalonatesa
O
O
R1
R1
Me
1a (R = Me)
1b (R = CF3)
1d (20 mol%)
R(O)CO
OC(O)R
CO2Et
I
H
R2
7a-h
R2
6a-h
1c (R = Ph)
CH3CN
365 nm, RT
Me
Me
R'
1d (R = 4-t-BuC6H4)
1e (R = 3,5-(t-Bu)2C6H3
2a
1a e
5a (R' = H)
5b (R' = CO2Et)
6a
6b
6c
Entry
1
Catalyst
1a
Yield (%)b
11
4a/5ac
5.8/1
n.d
Yield (%)b
4b/5bc
O
O
R1 =
R1
=
R1 =
81
22.5/1
n.d
O
O
O
Ph
R2 = H 90% (62:38)
O
2
none
1a
trace
trace
trace
32
trace
trace
31
R2 = H 75% (58:42)
R2 = H 98% (52:48)
3d
4
n.d
n.d
O
O
6d
6e
6f
O
Ph
1b
ND
12.6/1
23.2/1
25/1
R1
=
R1
=
O
N
R1
=
O
N
Me
5
1c
3.0/1
4.8/1
ND
67
Me
O
6
1d
24
83
Ph
R2 = H 82% (62:38)
R2 = H
R2 = H 93% (50:50)
NR
7
1e
trace
95
40
14/1
6g
R1, R2 =
6h
8 e
9 f
10 g
1d
5.2/1
6.4/1
6.6/1
99(95)h
88
25/1
O
O
O
R1, R2
=
O
1d
99(97)h
95 f
17.4/1
25/1
50% (60:40)
98% (82:18)
99e
Ph
1d
Yield% (dr)b
aThe reaction of 2a (0.225 mmol) and 6 (0.15 mmol) was
conducted in the presence of 1d (20 mol%) in CH3CN (2.4 M)
aUnless otherwise specified, reaction of 2a (0.75 mmol) and 3a
(0.5 mmol) was conducted in the presence of 1 (10 mol%) in
CH3CN (0.5 M) with irradiation of UV light (λ = 365nm).
bDetermined by 1H NMR analysis using 1,1’,2,2’-
b
with irradiation by UV light (λ = 365nm). Yield of isolated
1
product and diastereoselectivity was determined by H NMR
analysis of crude reaction mixture.
c
1
tetrachloroethane as internal standard. Determined by H NMR
e
analysis of crude mixture. dReaction in the dark. Reaction in 1.0
Then we turned our attention to use chiral alkylidenemalonates as
substrate. Since the crotyl ester derived from (–)-8-
phenylmenthol 6b shows higher reactivity and better selectivity
f
g
M CH3CN. Reaction in 1.6 M CH3CN. Reaction performed for
18 h using 5 mol% of 1d. hYield of isolated product.
among
other
chiral
auxiliaries,
the
corresponding
To further demonstrate the synthetic potential of this approach,
we have become interested in testing the possibility of adding
acyl radical to chiral alkenes for the diastereoselective radical
hydroacylation. Our approach also enables the use of various
linear and branched aliphatic aldehydes, which have rarely been
used with success in either metal catalyzed hydroacylation or
NHC-catalyzed Stetter reaction.10 Herein, we report the first
diastereoselctive radical hydroacylation11 of alkenes with
aliphatic aldehydes for the stereoselective synthesis of chiral
ketones (Scheme 2).
alkylidenemalonate12 was synthesized and subjected to standard
reaction condition. To our surprise, diastereoselectivity of the
reaction increased significantly to 82:18 d.r. and afforded the

3
corresponding ketone 7g in high yield. It is worth mentioning
ACCEPTED MANUSCRIPT
here that with analogous (–)-menthol derived alkylidenemalonate
6h diastereoselectivity of the hydroacylated product dropped
drastically to 60:40 and afforded the corresponding ketone 7h in
moderate yield. Having identified the best chiral auxiliary for this
reaction, we turned our attention to optimize other reaction
parameter.
diastereoselective
A
series of solvents was screened for the
radical hydroacylation between
cyclohexanecarboxaldehyde 2a and (–)-8-phenylmenthol derived
benzylidenemalonate 8b (Table 3).
Table 3. Optimization of reaction conditiona
efficiently with benzylidene malanote 8b to give the
corresponding ketones 9j-n13 with excellent yields and
diastereoselectivities.
O
COX*
COX*
O
COX*
COX*
1d (20 mol%)
H
Table 4. Diasteroselective Hydroacylation of alkylidene-
solvent
365 nm, RT
Ph
9b
Ph
malonate derivatives with various aliphatic aldehydesa
2a
8b
O
COX*
O
1d (20 mol%),
CH3CN/CH2Cl2,
COX*
X* = (–)-8-phenylmenthyloxy
R2
Entry Solvent
Time (h)
12
Yield (%)b
d.r.c
R1
COX*
R1
H
O
COX*
2
R2
8
365nm, RT
COX*
9a-n
X* = (−)-8-phenylmenthyloxy
COX*
COX*
1
2
CH3CN
98
80
98
98
98
98
96
92
91
65
82:18
87:13
87:13
91:9
O
O
COX*
CH2Cl2
12
cHex
cHex
COX*
cHex
COX*
3
None
16
CF3
Ph
p-CH3-C6H4
4
Benzene
Toluene
12
9a: 48% (84:16)
9b: 83% (92:8)
9c: 65% (89:11)
5
18
90:10
90:10
90:10
90:10
92:8
O
COX*
COX*
O
COX*
O
COX*
COX*
6
o-Xylene
C6F6
18
cHex
cHex
p-Cl-C6H4
9e: 65% (89:11)
COX*
p-F-C6H4
TsN
Ph
7
12
9d: 91% (88:12)
9f: 48% (86:14)
8
CF3C6H5
CH3CN/CH2Cl2
CH3CN/CH2Cl2
12
9
12
O
COX*
O
COX*
COX*
O
COX*
COX*
Et
10d
12
87:13
cHex
COX*
COOtBu
9g: 90% (82:18)
Et
Ph
Ph
aThe reaction of 2a (0.225 mmol) and 8b (0.15 mmol) was
conducted in the presence of 1d (20 mol%) in solvent (2.4 M)
9h: 82% (90:10)b
9i: 87% (90:10)
b
1
with irradiation of UV light (λ = 365nm). Determined by H
O
COX*
COX*
O
COX*
COX*
O
COX*
COX*
NMR analysis using 1,1’,2,2’-tetrachloroethane as internal
c
1
Et
n-Pr
n-Bu
standard. Determined by H NMR analysis of crude mixture.
dReaction performed with irradiation of visible light (λ = 400nm).
Ph
Ph
Ph
9j: 93% (90:10)
9k: 80% (88:12)
9l: 85% (89:11)
Non-polar solvents afforded hydroacylated product in high
diastereoselectivity and yield than polar solvents such as CH3CN
(Table 3, entries 4-7 vs. entry 1). Interestingly, mixed solvent
system CH3CN/CH2Cl2 gave the corresponding product in higher
diastereoselectivity (Table 3, entry 9). Slightly lowered yield and
diastereoselectivity was observed, when the reaction performed
under visible light (λ = 400nm) irradiation (Table 3, entry 10).
O
COX*
O
COX*
COX*
n-C8H17
COX*
n-Pentyl
Ph
Ph
Yield % (dr)c
9n: 84% (86:14)
9m: 93% (92:8)
aThe reaction of 2 (0.225 mmol) and 8 (0.15 mmol) was
conducted in the presence of 1 (20 mol%) in 1:1 CH3CN/CH2Cl2
(2.4 M) with irradiation by UV light (λ = 365nm). b4 equivalents
of 2h were used without solvent for 48 h. Yield of isolated
product and diastereoselectivity was determined by H NMR
To demonstrate the scope of the reaction, a series of aldehydes
were hydroacylated with alkenes 8, providing the corresponding
ketones 9 in uniformly good yield and high diastereoselectivity
(Table 4). When employing β-trifluoromethyl alkylidene-
malonates 8a as substrate, α-trifluoromethylated chiral ketone 9a
was obtained in moderate yield with 84:16 d.r. In the case on
benzylidenemalonates, introduction of electron-withdrawing and
electron-donating susbtituents on the aryl ring of 8b did not
affect the yield and diastereoselectivities (Table 4, 9c-e).
Introduction of heteroatom into the cyclohexane ring of aldehyde
altered the reactivity and stereochemical outcome of the reaction
(Table 2, 9b vs 9f). The reaction of ethene tricarboxylates 8g
with cyclohexanecarboxaldehyde 2a proceeded efficiently to
afford the corresponding ketones 9g in good yield and
diastereoselectivity (Table 2). In addition to α-branched and β
branched aldehydes, various linear aldehydes 2l-o were reacted
c
1
analysis of crude mixture.
The further synthetic utility of the present diastereselective
radical hydroacylation was successfully demonstrated in the short
formal synthesis of (–)-methyleneolactocin (Scheme 3),14-16
which exhibits potent antibacterial and antitumor activities.
Exposure of ketone 9m with 0.6 equivalent of LiBH4 leads to the
formation of γ-butyrolactone 10 which upon subsequent base
hydrolysis with KOH followed by decarboxylation upon
refluxing in toluene afforded γ-butyrolactone 11 in 36% overall
yield. The lactone 11 can be converted to (–)-methyleneolactocin
in two steps using literature known method.16a Though the

4
Tetrahedron
ACCEPTED MANUSCRIPT
stereoselectivity of the product was slightly decreased, γ-
= triplet, q = quartet, m = multiplet, br = broad, and app =
butyrolactone 11 was obtained in only three steps from ketone
9m. It is worth mentioning here that during this transformation,
(–)-8-phenylmenthol was successfully recovered in 83% yield.
apparent), and coupling constants (Hz). 13C NMR spectra were
recorded on JEOL JNM-ECA500 (125 MHZ) spectrometer with
complete proton decoupling. Chemical shifts were reported in
ppm from the residual solvent as an internal standard.
Photochemical reactions (365 nm) were carried out using VBL-
F30 LED lamp (VBL-F30L-U (365)-3W-H28). High
performance liquid chromatography (HPLC) was performed on
Shimadzu 20A instruments using chiral columns. The high-
resolution mass spectra (HRMS) were performed on Bruker
microTOF. Optical rotations were measured on a JASCO DIP-
1000 digital polarimeter. For thin layer chromatography (TLC)
analysis throughout this work, Merck precoated TLC plates
(silica gel 60 GF254, 0.25 mm) were used. The products were
purified by flash column chromatography on neutral silica gel
60N (Kanto Chemical Co. Inc., 40-50mm). Other simple
chemicals were purchased and used as such.
O
O
COX*
Ph
X*
LiBH4 (0.6 equiv.),
THF, -78 °C - rt
n-Pr
COX*
Ph
9m (d.r. = 92:8)
O
O
n-Pr
10
1. 2M KOH, EtOH,
0 °C, 12 h
2. Toluene, 120 °C,
18 h
X* = (–)-8-phenylmenthyloxy
Me
Ph
HOOC
ref. 16a
n-Pr
O
O
O
OH
O
n-Pr
(–)-methyleneolactocin
83%
Ph
11 36% (3 steps)
(e.r. = 82:18)
4.2. General procedure for the radical hydroacylation
Scheme 3. Formal total synthesis of (–)-methyleneolactocin.
Based on the observed stereochemistry, transition state models
can be proposed as shown in Figure 1. During the radical
addition step, the in situ generated acyl radical will prefer
sterically less congested face of alkenes. However, Re face of the
alkene is effectively shielded by the phenyl group of one of the
chiral auxiliary, which would explain the low diastereoselectivity
achieved when using 6h. As a result, Si face addition of radical
occurs to provide S isomer predominantly.
4.2.1.Bis(1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-
yl)cyclohexyl)2-((S)-2-Cyclohexyl-2-oxo-1-phenylethyl)malonate
(9b)
In a reaction tube containing alkylidene malonate 8b (0.15
mmol), hypervalent iodine (III) catalyst 1d (0.03 mmol) and
cyclohexanecarboxaldehyde (0.225 mmol) were mixed in
CH3CN:CH2Cl2 (1:1) (2.4 M) under argon atmosphere. The
mixture was irradiated by UV light (365 nm) with stirring for 12
h. After completion of reaction, solvent was removed under
reduced pressure. The diastereoselectivity of hydroacylated
products were calculated from 1H NMR spectra of crude
products. Purification by flash column chromatography (eluting
with hexane/ethyl acetate = 20:1 to 4:1) gave the corresponding
H
H
O
O
O
O
O
O
O
O
O
O
hydroacylated product 9b (91.1 mg, 0.124 mmol, 83% yield). dr
1
R
= 92:08; [a]23 = 137.97 (c 1.3, CHCl3); H NMR (500 MHz,
R'
R'
R
D
CDCl3) d 7.32-7.07 (15H, m), 4.80 (1H, dt, J = 11.0, 4.5 Hz),
4.72 (0.08H, m), 4.55 (1H, dt, J = 11.0, 4.5 Hz), 4.47 (0.92H, d, J
= 11.5 Hz), 3.95 (1H, m), 2.43 (1H, m), 2.12 (1H, m), 1.94 (1H,
m), 1.78 (2H, m), 1.64-1.45 (6H, m), 1.42-1.05 (24H, m), 0.97-
0.86 (2H, m), 0.82 (3H, d, J = 6.5 Hz), 0.67 (1H, m), 0.60 (3H, d,
J = 6.5 Hz), 0.52-0.43 (1H, m); 13C NMR (125 MHz, CDCl3)
(data given for major isomer) d 210.4, 168.4, 167.6, 150.6, 150.4,
134.1, 129.8, 128.9, 128.1, 126.1, 126.0, 125.5, 125.3, 76.6, 76.2,
56.3, 55.4, 50.8, 50.3, 49.9, 41.1, 40.6, 40.3, 34.6, 34.2, 31.5,
31.3, 31.0, 29.5, 28.8, 28.6, 27.2, 27.1, 26.0, 25.8, 25.4, 25.1,
23.1, 21.8, 21.5; IR (neat) 2929, 1739, 1707, 1594, 1264 cm-1;
HRMS (ESI-TOF) Calcd. for C49H64NaO5: 755.4646 ([M +
Na]+), Found: 755.4653 ([M + Na]+).
Re-face attack
Si-face attack
COX*
O
O
H
COX*
COX*
R
COX*
R
H
R'
R'
favoured
unfavoured
X* = (−)-8-phenylmenthol
Figure 1. Proposed transition state model for stereochemical
outcome.
3. Conclusions
In summary, we have developed a mild and efficient method for
the synthesis of chiral ketones via diastereoselective radical
hydroacylation of (–)-8-phenylmenthol derived chiral
alkylidenemalonates with aldehydes in highly stereoselective
fashion. The reaction proceeds with low catalyst loading of
hypervalent iodine(III) reagent under UV-light irradiation.
Furthermore, the synthetic utility of this transformation has been
demonstrated in the concise formal synthesis of (–)-
methyleneolactocin.
4.2.2. Synthesis of (4S, 5S)-5-Pentyl-4-phenyldihydrofuran-
2(3H)-one (11)
To a solution of ketone 9m (0.228 mmol) in dry THF (2 mL)
was added a 3.0 M THF solution of LiBH4 (0.1368 mmol, 45.5
mL) at –78 °C. The reaction mixture was gradually warmed to
room temperature within 3 h and continued to stir overnight. The
reaction mixture was carefully quenched with saturated aq NH4Cl
solution and extracted with ethyl acetate (3x10 mL). The
combined organic extracts were washed with brine (20 mL), then
dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude compound was purified by flash column chromatography
on silica gel (eluting with hexane/AcOEt = 5/1) to give
diastereomeric mixture of γ-butyrolactone 10 and 8-phenyl
menthol, which was subjected to next step without further
purification. To a solution of 10 (0.164 mmol) in EtOH (2 mL)
was added a 3M aqueous solution of KOH (500 mL) at 0 °C. The
reaction mixture was allowed to stir at same temperature for 12 h.
4. Experimental section
4.1. General
Infrared (IR) spectra were recorded on a Thermo Scientific
Nicolet iS5 spectrometer. H NMR spectra were measured on
JEOL JNM-ECA500 (500 MHZ) spectrometer. Chemical shits
were reported in ppm from tetramethylsilane (in the case of
CDCl3) as an internal standard. Data were reported as follows:
chemical shift, integration, multiplicity (s = singlet, d = doublet, t
1

5
6. (a) Esposti, S.; Dondi, D.; Fagnoni, M.; Albini, A. Angew.
It was then poured into mixture of 2N HCl and brine solution.
Aqueous layer was then extracted with ethyl acetate (3x10 mL).
The combined organic extracts were washed with brine (20 mL),
then dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude product was then dissolved in toluene (3 mL) and
heated to reflux for 3 h. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The crude compound was
purified by flash column chromatography on silica gel (eluting
with hexane/AcOEt = 5/1) to give γ-butyrolactone 11 (18.2 mg,
0.082 mmol, 36% yield).
ACCEPTED MANUSCRIPT
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Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research from the MEXT (Japan). The authors extend
their appreciation to the International Scientific Partnership
Program ISPP at King Saud University for funding this research
work through ISPP#0072.
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