Total synthesis of (±)-galanthamine from GABA through regioselective aryne insertion

Article abstract of DOI:10.1039/c8ob03123a

The total synthesis of (±)-galanthamine is achieved in ～5% overall yield using a key regioselective aryne insertion reaction into a GABA (γ-amino butyric acid) derivative. The strategy presented involves only two sub-critical temperature reactions and less than five chromatographic purifications to achieve the synthesis of galanthamine.

Full text of DOI:10.1039/c8ob03123a

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DOI: 10.1039/C8OB03123A
Total Synthesis of (±)-Galanthamine from GABA through
Regioselective Aryne Insertion
a,b
a,b
*a,b
Telugu Venkatesh, Prathama S. Mainkar, and Srivari Chandrasekhar
aDepartment of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
bAcademy of Scientific & Innovative Research (AcSIR), New Delhi 110020, India
Email: srivaric@iict.res.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Me
Cbz
N
O
N
PMB
OMe
OH
TMS
OTf
CHO
O
H
aryne insertion
OMe
OMe
(±)- Galanthamine
ABSTRACT: Total synthesis of (±)-galanthamine is achieved in ~5% overall yield using key
regioselective aryne insertion reaction into GABA (γ-Amino butyric acid) derivative. The strategy
presented involves only two sub critical temperature reactions and less than five chromatographic
purifications to achieve the synthesis of galanthamine.
KEYWORDS: Galanthamine, Total synthesis, Aryne insertion, Cycloaddition, GABA.
Total synthesis of scarcely available natural products is an ongoing process in research
community and has played an important role in understanding structure activity relationship (SAR)
1
of natural products and their analogues. More recently, the total syntheses of FDA approved drugs
2
of natural product origin have attracted equal attention, as many a times the supplies are
inconsistent and also depleting.
(-)-Galanthamine (1, Figure 1), an alkaloid belonging to Amaryllidaceae family, with
acetyl cholinesterase inhibitory activity, is one of the FDA approved drugs for symptomatic
1

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DOI: 10.1039/C8OB03123A
3
treatment of Alzheimer’s disease. This natural product has the ability to cross the blood-brain
barrier (BBB) and is also shown to act as nicotinic acetylcholine receptor.
Me
N
OH
O
H
OMe
(
-)- galanthamine (1)
Figure 1. Galanthamine structure.
The interesting and challenging scaffold of galanthamine has been classical target for
synthetic organic chemists. Several researchers have taken up the challenge of developing
4
a
4b
synthetic routes as compiled in a review by Hudlicky et al and Garcia et al. Syntheses that
5
p
5q
5o
appeared after the review include efforts of Banwell et al, Hudlicky et al, Nagase et al. Most
of the reported synthesis relied on at least one of the following strategies viz, oxidative cyclization,
chiron approach, noble metal catalyzed C-C bond formation, ring-closing metathesis and so on.
Our research group had synthesized the pruned versions of galanthamine to explore
6
a
whether a simpler analogue of galanthamine will be as effective as the natural product. In this
endeavour, we have also studied the literature describing total synthesis of galanthamine, for ways
to optimize the yields. This effort resulted in delineating a new strategy for this “age old target”
which avoids expensive metals, air sensitive reactions and also allows one to synthesize analogues.
Herein we report our findings. Our retrosynthetic dissection relied on the recently developed aryne
insertion reaction,7a,b wherein a β-keto ester adds onto aryne to create two C-C bonds through
cyclobutene. This strategy is exploited in synthesis of several natural products with ease.7a-h
Thus retrosynthesis of 1 revealed the benzofuranone 2 could be achieved using Pictet-
Spengler reaction and ketone-lactone condensation with ease. The required substituted benzene
ring 3 in turn can be synthesized from aryne precursor 4 and GABA derivative 5.
2

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DOI: 10.1039/C8OB03123A
Me
Cbz
PMB
N
N
O
Pictet-Spengler
OH
reaction
Me
O
O
H
ketone-lactone
condensation
O
OCH3
OCH3
(
±)- Galanthamine (1)
2
Michael
addition
PMB
Cbz
N
Cbz
TMS
OTf
N
aryne
insertion
PMB
O
CO2Me
OCH3
OCH3
CHO
5
CHO
OCH3
4
3
Scheme 1. Retrosynthetic analysis of (±)-galanthamine
Retrosynthetic analysis gave us a clue that GABA (γ-Amino butyric acid), an easily
available and clinically used neurotransmitter, would be an ideal starting material, which on simple
7
c
modifications could add on to aryne precursor 4 (Scheme 1). Aryne precursor can be prepared
from Guaiacol (2-methoxyphenol) in two easy steps. The ease of availability and commercial
feasibility of both the starting materials attracted our attention to focus on building galanthamine
8
skeleton. Thus protected GABA 6 was converted to corresponding ester 7 using SOCl /methanol
2
in 94% yield. The C-formylation of ester 7 under TiCl /NEt and methyl formate conditions
4
3
provided compound 5 in 92% yield. Thus formed β-formyl ester 5 on treatment with the methoxy
benzyne precursor 4, in presence of CsF, provided the trisubstituted aryl intermediate 3 in 62%
yield. The methoxy group on benzyne, through negative inductive effect, has provided us single
7
c
regioisomer, 3. The Baeyer-Villiger oxidation of 3 resulted in the GABA stitched catechol
derivative 8 in 86% yield. The hydrolysis of O-CHO group in 8 with 2M NaOH solution gave
phenol, which without purification was subjected to lactonisation using TsOH and yielded the
benzofuranone 9 in 65% yield for two steps (Scheme 2).
3

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DOI: 10.1039/C8OB03123A
Cbz
N
Cbz
Cbz
N
SOCl2
HCO2Me
N
PMB
O
MeOH PMB
O
TiCl4, NEt3 PMB
O
OH 0 oC, rt
h, 94%
CH2Cl2, 0 o
OMe
C
OMe
4
2 h, 92%
CHO
6
7
5
PMB
OMe
PMB
Cbz
Cbz
N
N
4
, CsF
m-CPBA
CH3CN
CO2Me
O Cs+
CH2Cl2
CO2Me
CHO
0 oC - rt, 6 h
6%
rt, 1 h
-
62%
8
OMe
A
3
PMB
Cbz
PMB
N
N
O
Cbz
i) 2M NaOH, 1,4-dioxane
0 oC, 0.5 h
CO2Me
OCHO
ii) TsOH, toluene
O
h, 90 o
5
C
OMe
OMe
65% (2 steps)
8
9
Scheme 2. Synthesis of benzofuranone 9
Having constructed this bicyclic frame of galanthamine, the next appendage was installed through
a simple Michael addition of 9 onto methyl vinyl ketone (MVK) under the influence of DIPEA to
furnish the α,α-disubstituted lactone 2. The PMB protection on amine 2 was removed by exposure
to CAN resulting in 82% yield of compound 10. The classical Pictet-Spengler reaction on 10 with
paraformaldehyde was achieved in 92% yield to get the tricyclic [6,5,7] membered core of
galanthamine 11. The intramolecular ketone-lactone condensation of 11, mediated by LDA at -78
o
5i
C, provided the tetracyclic lactol 12 in 90% yield. Reductive deoxygenation of 12 with Et SiH
3
promoted by BF .OEt resulted in 13 as a diastereomeric mixture, which without characterization,
3
2
was subjected to N-methylation using HCHO/HCOOH, the O-formyl group formed during the N-
methylation reaction was hydrolysed using potassium carbonate, and the free alcohol was oxidized
with SO .Py condition to yield compound 14 as a single diastereomer in 65% yield for 3 steps.
3
5
o
Compound 14 on treatment with LDA and PhSSPh followed by oxidative elimination produced
the (±)-narwedine 15 which is the biogenic precursor of galanthamine, in 45% yield.9
Diastereoselective reduction of (±)-narwedine 15 with LS-selectride furnished (±)-galanthamine
(1) in 96% yield, whose analytical data matched with literature values (Scheme 3).
4

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DOI: 10.1039/C8OB03123A
PMB
OMe
Cbz
Cbz
Cbz
O
PMB
OMe
Cbz
N
N
HN
O
Me
N
O
O
MVK, DIPEA
Me
CAN
Me
(CH2O)n
O
CH2Cl2, rt, 1 h
CH3CN:H2O (9:1)
rt, 8 h
TFA, 1,2-DCE
60 oC, 12 h
O
O
O
O
O
95%
O
82%
OMe
OMe
95%
9
2
10
11
i) HCHO/HCO2H
H2O, 70 oC, 12 h
Cbz
Me
N
H
N
N
then
LDA, -78 o
OH
O
C
O
BF3.Et2O, Et3SiH
CH2Cl2, 0 oC, 4 h
K CO , MeOH, H O
2
3
2
THF, 2 h
O
ii) SO3.Py, DMSO
DIPEA, CH2Cl2, 2 h
O
H
O
OH
86%
OMe
OMe
OMe
65% (3 steps)
12
13
14
i) LDA, THF, PhSSPh
78 o
-
C
Me
Me
ii) CSA, CH2Cl2, rt
N
N
then m-CPBA
O
OH
-
78 oC to -40 o
C
LS-selectride
iii) NaHCO3, toluene
10 o
5% (3 steps)
O
H
THF, -78 oC, 2 h
O
H
1
C
96%
OMe
OMe
4
15
(±)- galanthamine (1)
Scheme 3. Total synthesis of (±)-galanthamine
Another interesting feature of our synthetic route is the synthesis of 11 from 3 was achieved
in six-consecutive steps involving only one chromatographic purification. This has added to the
operational simplicity without any effect on the overall yield of the product. The conditions used
are mild, temperatures are moderate and purifications are minimal (Scheme 4).
1
. m-CPBA, CH2Cl2
0 oC - rt, 6 h
PMB
Cbz
2. 2M NaOH, 1,4-dioxane
0 oC, 0.5 h
Cbz
N
Me
O
N
3
. TsOH, toluene
9
0 oC, 5 h
CO2Me
CHO
O
4
5
6
. MVK, DIPEA, CH2Cl2
O
rt, 1 h
OMe
OMe
. CAN, CH3CN:H2O (9:1)
rt, 8 h
3
11
. (CH2O)n, TFA, 1,2-DCE
6
0 oC, 12 h
scalable
six steps
single column chromatography
Scheme 4. Practical simplicity for synthesis of 11 from 3
5

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In conclusion, synthesis of (±)-galanthamine (1), is achieved from GABA and aryne
precursor involving only two sub-critical temperature reactions and in less than five
chromatographic purifications in overall ~5% yield. This approach avoids expensive metals, air
sensitive reactions and also allows one to synthesize analogues.
EXPERIMENTAL SECTION
General information: Unless otherwise noted, all reagents were used as received from
commercial suppliers. All reactions were performed under nitrogen atmosphere and in a flame-
dried or oven-dried glassware with magnetic stirring. All solvents were dried before use following
the standard procedures. Reactions were monitored using thin-layer chromatography (SiO ). TLC
2
plates were visualized with UV light (254 nm), iodine treatment or using ninhydrin stain. Column
chromatography was carried out using silica gel (100-200 mesh) packed in glass columns. NMR
spectra were recorded at 300, 400, and 500 MHz (H) and at 75, 100, and 125 MHz (C),
respectively. Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCl (H:
3
δ = 7.26 and C: δ = 77.0 ppm) as internal standard, and coupling constants (J) are given in Hz.
HRMS were recorded using ESI-TOF techniques.
Methyl 4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)butanoate (7):
To N-protected γ-Amino butyric acid (GABA) 6 (25.0 g, 70 mmol, 1.0 equiv) in MeOH (200 mL)
o
was added SOCl (6.1 mL, 84 mmol, 1.2 equiv) at 0 C. The reaction was stirred for 1 h at same
2
temperature and monitored by TLC. After disappearance of starting material, MeOH was removed
under reduced pressure, and residue was extracted with EtOAc (3 x 100 mL). The organic layer
was washed with saturated aqueous NaHCO solution. The combined organic extracts were dried
3
over Na SO , concentrated under reduced pressure to give crude which was purified by silica gel
2
4
column chromatography (Hexane/EtOAc, 4:1) to afford 7 as a pale yellow oil (24.5 g, 94% yield);
1
H NMR (500 MHz, CDCl ) δ 7.45 – 7.25 (m, 5H), 7.12 (dt, J = 31.7, 15.9 Hz, 2H), 6.85 (d, J =
3
2
1.9 Hz, 2H), 5.17 (s, 2H), 4.43 (s, 2H), 3.77 (s, 3H), 3.62 (dd, J = 16.2, 11.3 Hz, 3H), 3.26 (d, J
1
3
=
22.6 Hz, 2H), 2.27 (d, J = 30.9 Hz, 2H), 1.83 (dd, J = 15.9, 6.5 Hz, 2H); C NMR (125 MHz,
CDCl ) δ 173.2, 158.8, 156.0, 136.5, 129.5, 129.1, 128.5, 128.3, 127.8, 127.7, 113.7, 67.0, 55.0,
3
5
1
1.3, 49.6, 49.3, 45.8, 44.9, 31.0, 23.1, 22.7; IR (neat): υmax 2949, 1735, 1694, 1612, 1585, 1511,
-1
455, 1433, 1416, 1300, 1243, 1173, 1030, 736, 697 cm ; HRMS (ESI) calcd for C H NO Na
2
1
25
5
+
[
M+Na] : 394.1630; found: 394.1626.
6

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Methyl 4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-2-formylbutanoate (5):
TiCl (11.78 mL, 161.72 mmol) and Et N (18.75 mL, 134.77 mmol) were successively added
4
3
dropwise to a stirred solution of a methyl ester 7 (20.0 g, 53.90 mmol) and methyl formate (9.90
o
mL, 161.72 mmol) in CH Cl (250 mL) at 0 C under nitrogen atmosphere, and the mixture was
2
2
stirred at the same temperature for 1 h and at room temperature for 1 h. Water was added to the
mixture, which was extracted twice with EtOAc. The combined organic phase was washed with
brine, dried over with Na SO , and concentrated. The obtained crude oil was purified by column
2
4
chromatography to give the α–formylated ester 5 (both aldehyde and enol mixture 6:4) as yellow
1
oil (19.78 g, 92% yield); H NMR (300 MHz, CDCl ) δ 11.36 (t, J = 12.8 Hz, 0.5H), 9.75 – 9.10
3
(m, 0.2H), 7.64 (s, 0.3H), 7.47 – 6.71 (m, 9H), 5.15 (d, J = 3.1 Hz, 2H), 4.53 – 4.33 (m, 2H), 3.82
1
3
–
1
1
1
3.52 (m, 6H), 3.25 (d, J = 6.3 Hz, 2H), 2.61 – 2.09 (m, 2H); C NMR (100 MHz, CDCl ) δ
3
96.1, 172.3, 169.1, 161.9, 159.1, 156.6, 129.9, 129.8, 129.4, 128.9, 128.5, 128.0, 127.9, 114.0,
13.9, 101.6, 67.3, 67.2, 55.2, 52.5, 51.3, 50.3, 47.0, 46.2, 26.5, 25.8; IR (neat): υmax 3020, 1684,
-1
613, 1512, 1442, 1215, 1120, 1035, 741, 668 cm ; HRMS (ESI) calcd for C H NO Na
2
2
25
6
+
[
M+Na] : 422.1580; found: 422.1577.
Methyl 4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-2-(2-formyl-3-methoxyphenyl)b-
utaneate (3):
A flame-dried round bottom flask equipped with a magnetic stir bar was charged with 5 (15.0 g,
3
8 mmol, 1.0 equiv) in acetonitrile (200 mL). Methoxy aryne precursor 4 (15.0 g, 46 mmol, 1.2
equiv) and cesium fluoride (14.0 g, 95 mmol, 2.5 equiv) were sequentially added to the flask at
room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at same
temperature, completion of the reaction was monitored by TLC. The mixture was extracted with
water (150 mL). The aqueous layer was back-extracted with ethyl acetate (3 x 100 mL). The
organic layers were combined and dried over Na SO . After filtration, the residue was concentrated
2
4
under reduced pressure and the crude was purified on silica gel column chromatography
1
(
Hexane/EtOAc, 6:4) to give insertion product 3 as yellow oil (12 g, 62% yield); H NMR (500
MHz, CDCl ) δ 10.57 (d, J = 12.2 Hz, 1H), 7.49 – 6.90 (m, 9H), 6.81 (d, J = 8.2 Hz, 3H), 5.15 (s,
3
2
3
H), 4.69 (s, 1H), 4.47 (d, J = 14.8 Hz, 1H), 4.37 (d, J = 15.2 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H),
1
3
.59 (d, J = 28.9 Hz, 3H), 3.24 (d, J = 19.5 Hz, 2H), 2.31 (s, 1H), 1.93 (d, J = 36.8 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 192.2, 173.7, 163.3, 158.9, 156.5, 156.1, 141.3, 136.8, 135.0, 130.0,
3
1
29.9, 129.4, 128.8, 128.4, 127.8, 122.5, 121.0, 120.7, 113.8, 110.5, 67.1, 55.9, 55.2, 52.2, 49.8,
7

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4
8
9.5, 45.0, 44.3, 43.8, 31.3, 30.8; IR (neat): υmax 2986, 1737, 1449, 1373, 1233, 1100, 1044, 930,
-1
+
47, 781 cm ; HRMS (ESI) calcd for C H NO Na [M+Na] : 528.1998; found: 528.1997.
2
9
31
7
Methyl 4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-2-(2-(formyloxy)-3-methoxyphe-
nyl)butanoate (8):
The GABA inserted aryl aldehyde 3 (10.0 g, 20 mmol, 1.0 equiv) was dissolved in CH Cl (125
2
2
o
mL) at 0 C and then m-CPBA (~76%, 6.7 g, 30 mmol, 1.5 equiv) was added portion-wise under
nitrogen atmosphere. The mixture was stirred for 5 h at room temperature and monitored by TLC.
After disappearance of starting material, the reaction was quenched with sat. NaHCO solution
3
and extracted with CH Cl (3 x 75 mL). The combined organic layers were dried over Na SO .
2
2
2
4
After filtration, the filtrate was concentrated under reduced pressure and the residue was purified
on silica gel column chromatography (Hexane/EtOAc, 3:2) to give insertion product 8 as yellow
1
oil (8.87 g, 86% yield); H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 23.1 Hz, 1H), 7.40 – 7.26 (m,
3
5
3
H), 7.22 – 6.65 (m, 7H), 5.15 (s, 2H), 4.39 (dt, J = 23.8, 14.8 Hz, 2H), 3.84 (d, J = 21.6 Hz, 3H),
.80 – 3.66 (m, 4H), 3.57 (d, J = 19.6 Hz, 3H), 3.17 (d, J = 6.0 Hz, 2H), 2.31 (s, 1H), 1.93 (s, 1H);
1
3
C NMR (125 MHz, CDCl ) δ 172.9, 168.7, 158.9, 158.8, 156.5, 151.0, 137.0, 136.7, 134.6,
3
1
1
4
1
5
33.5, 131.9, 131.3, 130.2, 129.8, 129.6, 129.4, 128.8, 128.5, 128.2, 127.9, 127.9, 127.2, 120.1,
19.9, 113.9, 111.8, 111.3, 107.4, 77.3, 77.0, 76.8, 67.3, 56.0, 55.7, 55.4, 55.2, 52.2, 49.7, 44.9,
4.0, 42.4, 42.2, 30.2, 29.7; IR (neat): υmax 3020, 2404, 2356, 1738, 1692, 1606, 1512, 1473, 1216,
-1
+
172, 1116, 912, 740, 669 cm ; HRMS (ESI) calcd for C H NO [M+H] : 522.2128; found:
2
9
32
8
22.2107.
Benzyl (2-(7-methoxy-2-oxo-2,3-dihydrobenzofuran-3-yl)ethyl)(4-methoxybenzyl)carbam-
ate (9):
To a solution of 8 (8.0 g, 15.35 mmol, 1.0 equiv) in 1,4-dioxane (60 mL) was added 2M NaOH
o
solution (40 mL) at 0 C and the resulting mixture was stirred at same temperature for 0.5 h. The
reaction mixture was neutralized by the addition of 2N HCl and extracted with EtOAc (3 x 100
mL). The combined organic extracts were dried over Na SO and concentrated to give a crude oil,
2
4
which was used for the next step without any further purification. To a solution of crude oil in
anhydrous toluene (100 mL) was added TsOH (0.26 g, 1.53 mmol, 0.1 equiv) at room temperature.
The mixture was stirred at 90 °C for 5 h, quenched by the addition of saturated aqueous solution
of NaHCO at 0 °C, and extracted with EtOAc (3 x 50 mL). The combined organic layers were
3
dried over Na SO , concentrated under reduced pressure and the crude was purified on silica gel
2
4
8

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column chromatography (Hexane/EtOAc, 1:1) afforded 9 as a pale yellow oil (4.6 g, 65% yield (2
1
steps)); H NMR (400 MHz, CDCl ) δ 7.33 (s, 5H), 7.23 – 6.86 (m, 4H), 6.86 – 6.51 (m, 3H), 5.21
3
–
3
2
1
5.11 (m, 2H), 4.53 (d, J = 15.2 Hz, 1H), 4.29 (d, J = 15.2 Hz, 1H), 3.93 – 3.87 (m, 3H), 3.81 –
.75 (m, 3H), 3.70 (ddd, J = 46.5, 19.6, 6.5 Hz, 1H), 3.60 – 3.13 (m, 2H), 2.15 (d, J = 22.7 Hz,
1
3
H); C NMR (125 MHz, CDCl ) δ 176.1, 159.0, 156.3, 144.0, 141.9, 136.5, 129.5, 128.9, 128.5,
3
28.1, 127.9, 124.8, 116.2, 115.7, 114.0, 112.7, 67.4, 56.3, 55.3, 50.2, 49.9, 43.8, 42.9, 41.3, 29.1;
-1
IR (neat): υmax 2985, 1805, 1737, 1618, 1455, 1372, 1234, 1112, 1044, 930, 846, 775 cm ; HRMS
+
(
ESI) calcd for C H NO Na [M+Na] : 484.1736; found: 484.1727.
2
7
27
6
Benzyl (2-(7-methoxy-2-oxo-3-(3-oxobutyl)-2,3-dihydrobenzofuran-3-yl)ethyl)(4-methoxy-
benzyl)carbamate (2):
To a stirred solution of 9 (4.0 g, 8.7 mmol, 1.0 equiv) in anhydrous CH Cl (35 mL) at room
2
2
temperature were added DIPEA (7.56 mL, 43.39 mmol, 5.0 equiv) followed by methyl vinyl
ketone (1.07 mL, 13.1 mmol, 1.5 equiv) dropwise, the reaction mixture was stirred for 1 h at room
temperature. After completion of the starting material, monitored by TLC, the reaction was
quenched with water (2 mL), extracted with CH Cl (3 x 30 mL). The combined organic layers
2
2
were washed with 1N HCl (2 x 10 mL) and dried over Na SO . After filtration, the residue was
2
4
concentrated under reduced pressure and the residue was purified on silica gel column
1
chromatography (Hexane/EtOAc, 1:1) to give product 2 as yellow oil (4.37 g, 95% yield); H NMR
(
400 MHz, CDCl ) δ 7.34 (d, J = 19.2 Hz, 5H), 6.99 (ddd, J = 47.1, 17.7, 10.0 Hz, 4H), 6.82 –
3
6
.31 (m, 3H), 5.10 (q, J = 12.3 Hz, 2H), 4.39 (t, J = 17.0 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 3.90
1
3
(
s, 3H), 3.78 (s, 3H), 3.08 (s, 0.5H), 2.90 – 2.78 (m, 1.5H), 2.34 – 1.90 (m, 9H); C NMR (100
MHz, CDCl ) δ 206.6, 178.1, 159.1, 155.9, 144.1, 141.1, 136.5, 129.8, 129.7, 129.6, 129.4, 128.9,
3
1
3
1
28.5, 128.1, 127.9, 125.4, 115.2, 114.9, 114.0, 112.7, 56.2, 55.3, 50.2, 49.8, 42.9, 42.1, 38.0, 35.7,
5.0, 32.0, 29.9; IR (neat): υmax 2923, 2850, 1799, 1697, 1620, 1503, 1455, 1424, 1363, 1286,
-1
223, 1174, 1133, 1030, 917, 876, 818, 737, 699, 629 cm ; HRMS (ESI) calcd for C H NO Na
3
1
33
7
+
[
M+Na] : 554.2155; found: 554.2153.
Benzyl (2-(7-methoxy-2-oxo-3-(3-oxobutyl)-2,3-dihydrobenzofuran-3-yl)ethyl)carbamate
10):
(
To a suspension of 2 (4.0 g, 7.53 mmol) in CH CN : water (9:1, 40 mL) at room temperature was
3
added portion-wise ceric ammonium nitrate (12.38 g, 22.59 mmol, 3.0 equiv), the resultant mixture
was stirred for 8 h at room temperature. After consumption of starting material, the reaction was
9

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quenched by adding water (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic
layers were dried over Na SO , concentrated under reduced pressure and the crude was purified
2
4
on silica gel column chromatography (Hexane/EtOAc, 1:1) to give product 10 as yellow oil (2.53
1
g, 82% yield); H NMR (400 MHz, CDCl ) δ 7.53 – 7.19 (m, 5H), 7.14 (t, J = 7.7 Hz, 1H), 6.89
3
(t, J = 15.9 Hz, 1H), 6.84 – 6.54 (m, 1H), 5.00 (d, J = 11.8 Hz, 2H), 4.70 (d, J = 51.2 Hz, 1H), 3.92
1
3
(
s, 3H), 3.12 – 2.77 (m, 2H), 2.35 – 1.93 (m, 9H); C NMR (100 MHz, CDCl ) δ 206.6, 178.7,
3
1
56.0, 144.2, 141.2, 136.4, 129.8, 128.5, 128.1, 128.0, 125.5, 115.1, 112.9, 66.6, 56.2, 49.9, 38.0,
3
7.6, 37.2, 32.0, 29.9; IR (neat): υmax 3341, 2019, 2928, 2853, 1802, 1713, 1604, 1512, 1455, 1257,
-1
+
1
170, 1034, 883, 844, 767, 701 cm ; HRMS (ESI) calcd for C H NO Na [M+Na] : 434.1580;
23 25 6
found: 434.1568.
Benzyl 7-methoxy-5-oxo-4a-(3-oxobutyl)-3,4,4a,5-tetrahydrobenzofuro[4,3-cd]azepine-2(1-
H)-carboxylate (11):
To a solution of 10 (2.3 g, 5.59 mmol, 1.0 equiv) in 1,2-dichloroethane (30 mL) were added
paraformaldehyde (0.83 g, 27.98 mmol, 5.0 equiv) and TFA (4.28 mL, 55.96 mmol, 10.0 equiv)
at room temperature. The mixture was stirred at 60 °C for 12 h, quenched with saturated aqueous
NaHCO at 0 °C and extracted with CH Cl (3 x 30 mL). The organics were combined and dried
3
2
2
over Na SO . After filtration, the solvent was concentrated under reduced pressure and the crude
2
4
was purified on silica gel column chromatography (Hexane/EtOAc, 3:2) which afforded 11 as a
1
yellow oil (2.44 g, 95% yield) in 1:1 ratio of isomers; H NMR (500 MHz, CDCl ) δ 7.38 – 7.26
3
(m, 3.5H), 7.26 – 7.17 (m, 1.5H), 7.04 (d, J = 8.4 Hz, 0.5H), 6.82 (d, J = 8.0 Hz, 0.5H), 6.80 (d, J
=
7.4 Hz, 0.5H), 6.72 (d, J = 8.4 Hz, 0.5H), 5.11 (d, J = 12.3 Hz, 0.5H), 5.01 (td, J = 12.4, 7.7 Hz,
1
1
0
2
1
1
3
1
H), 4.97 – 4.89 (m, 0.5H), 4.80 (d, J = 15.3 Hz, 0.5H), 4.67 (d, J = 15.6 Hz, 0.5H), 4.43 (d, J =
4.8 Hz, 0.5H), 4.32 (d, J = 15.2 Hz, 0.5H), 4.23 (d, J = 15.6 Hz, 0.5H), 4.15 (d, J = 15.2 Hz,
.5H), 3.93 (s, 1.5H), 3.92 (s, 1.5H), 3.55 (ddd, J = 26.8, 20.2, 7.5 Hz, 1H), 2.74 – 2.63 (m, 1H),
1
3
.46 – 2.33 (m, 1H), 2.19 – 1.83 (m, 7H); C NMR (125 MHz, CDCl ) δ 206.4, 178.3, 178.1,
3
55.3, 155.2, 143.4, 140.8, 140.8, 136.5, 129.5, 129.1, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8,
24.8, 124.3, 112.3, 112.0, 67.4, 67.3, 56.4, 56.3, 50.8, 50.3, 50.2, 45.6, 45.2, 37.7, 33.4, 32.4,
0.1, 27.8, 27.6; IR (neat): υmax 3506, 3542, 2950, 1803, 1701, 1635, 1599, 1512, 1427, 1363,
-1
281, 1231, 1171, 1138, 1068, 1013, 920, 817, 738, 700 cm ; HRMS (ESI) calcd for
+
C H NO Na [M+Na] : 446.1580; found: 446.1573.
2
4
25
6
1
0

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Benzyl 7-methoxy-5-oxo-4a-(3-oxobutyl)-3,4,4a,5-tetrahydrobenzofuro[4,3-cd]azepine-
(1H)-carboxylate (12):
2
o
To a stirred solution of 11 (0.2 g, 0.47 mmol, 1.0 equiv) in anhydrous THF (10 mL) at -78 C was
added LDA (2.5M, 0.2 mL, 0.47 mmol, 1.0 equiv) under argon atmosphere and the mixture was
stirred at the same temperature for 0.5 h. Then another portion of LDA (2.5M, 0.1 mL, 0.24 mmol,
o
0
.5 equiv) was added and the reaction mixture was stirred at -78 C for 1 h. The reaction was
quenched with 1N HCl, and extracted by EtOAc (3 x 10 mL). The combined organic layers were
washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The
2
4
crude material was purified by silica gel column chromatography (Hexane/EtOAc, 1:1) to afford
1
compound 12 as a foamy solid (0.172 g, 86% yield) in 2:3 ratio of isomers; H NMR (500 MHz,
CDCl ) δ 7.39 – 7.27 (m, 3.8H), 7.24 – 7.14 (m, 1.2H), 6.87 (d, J = 8.2 Hz, 0.4H), 6.71 (d, J = 8.2
3
Hz, 0.4H), 6.65 (d, J = 8.2 Hz, 0.6H), 6.58 (d, J = 8.2 Hz, 0.6H), 5.11 (dd, J = 19.2, 8.9 Hz, 0.4H),
4
.99 – 4.85 (m, 1.4H), 4.76 (d, J = 15.8 Hz, 0.6H), 4.64 (t, J = 12.3 Hz, 0.6H), 4.44 (br.s, 1H) 4.37
(
dd, J = 14.1, 10.6 Hz, 1H), 4.13 (dd, J = 30.7, 15.5 Hz, 1H), 3.82 (s, 1.2H), 3.72 (s, 1.8H), 3.39
t, J = 13.7 Hz, 0.4H), 3.30 (t, J = 13.5 Hz, 0.6H), 3.04 (dd, J = 20.8, 17.2 Hz, 1H), 2.84 (dd, J =
(
1
1
7.2, 10.7 Hz, 1H), 2.54 – 2.40 (m, 1H), 2.39 – 2.29 (m, 1.4H), 2.25 (t, J = 8.3 Hz, 0.6H), 2.08 –
1
3
.96 (m, 1H), 1.95 – 1.85 (m, 1H), 1.77 (dd, J = 14.4, 2.6 Hz, 1H); C NMR (125 MHz, CDCl )
3
δ 207.1, 206.9, 155.4, 155.3, 145.5, 145.2, 144.1, 136.6, 136.4, 130.7, 130.5, 128.8, 128.4, 128.4,
1
28.0, 127.8, 122.4, 121.5, 111.4, 111.0, 110.2, 109.7, 67.3, 67.1, 56.0, 55.8, 51.5, 51.4, 51.0, 46.9,
4
6.6, 45.8, 45.2, 35.1, 34.0, 33.3, 30.4; IR (neat): υmax 3329, 3020, 2352, 1805, 1689, 1510, 1432,
-1
+
1
218, 1163, 1073, 914, 746, 667 cm ; HRMS (ESI) calcd for C H NO Na [M+Na] : 446.1580;
24 25 6
found: 446.1578.
(
4aS,8aR)-3-Methoxy-11-methyl-4a,5,7,8,9,10,11,12-octahydro-6H-benzo[2,3]benzofuro-
4,3-cd]azepin-6-one (14):
[
o
To a stirred solution of 12 (2.0 g, 4.72 mmol, 1.0 equiv) in anhydrous CH Cl (15 mL) at 0 C was
2
2
o
added Et SiH (7.53 mL, 47.28 mmol, 10 equiv). After stirring at 0 C for 10 min, BF ·Et O (3.48
3
3
2
o
mL, 28.368 mmol, 6 equiv) was added to it. The reaction was kept at 0 C for 0.5 h and then
allowed to reach room temperature and stirred for 3 h. The reaction was quenched with saturated
Na CO and extracted by EtOAc (3 x 25 mL). The organic layers were combined, washed with
2
3
brine and dried over anhydrous Na SO . The solvent was removed under reduced pressure and the
2
4
residue 13 was used for the next step without any further purification. To a stirred solution of 13
1
1

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(
0.88 g, 1.0 equiv) in CHCl (20 mL) was added formaldehyde (37% in water, 5.76 mL, 20 equiv)
3
o
and formic acid (12.8 mL, 100 equiv). Then the reaction was heated to 60 C and stirred overnight.
The reaction was quenched with saturated Na CO and extracted with EtOAc (3 x 25 mL). The
2
3
combined organic phases were washed with brine and dried over anhydrous Na SO . The solvent
2
4
was removed under reduced pressure. The residue was dissolved in MeOH/H O (6/1, 8 mL) and
2
K CO (0.92 g, 2 equiv) was added to it. The mixture was stirred at room temperature for 2 h, and
2
3
solvent was evaporated residue was dissolved in EtOAc. The organic phase was combined, washed
with brine and dried over anhydrous Na SO . The solvent was removed under reduced pressure
2
4
and the residue (1.04 g, 3.04 mmol) was dissolved in anhydrous CH Cl (10 mL). To the solution
2
2
o
at 0 C were added DMSO (1.28 mL, 18.24 mmol, 6 equiv), DIPEA (5.28 mL, 30.44 mmol, 10
equiv) and SO .Py (1.44 g, 9.12 mmol 3 equiv) respectively, the reaction mixture stirred for 2 h at
3
0 oC. After completion of starting material monitored by TLC, reaction was quenched with adding
excess water, and extracted with CH Cl (3 x 15 mL). The combined organic extracts was dried
2
2
over Na SO and concentrated to give a crude, which on column chromatography (CHCl /CH OH,
2
4
3
3
1
9
:1) afforded 14 as a white solid (0.88 g, 65% yield (3 steps)); mp 130–132 ºC; H NMR (500
MHz, CDCl ) δ 6.75 (d, J = 0.9 Hz, 2H), 4.82 (t, J = 2.9 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 4.05
3
(d, J = 14.9 Hz, 1H), 3.85 (s, 3H), 3.53 (ddd, J = 16.8, 8.3, 7.9 Hz, 2H), 3.04 (dd, J = 17.6, 3.3 Hz,
1
2
1
H), 2.70 (dd, J = 17.6, 2.7 Hz, 1H), 2.59 (s, 3H), 2.38 (d, J = 2.8 Hz, 1H), 2.37 – 2.28 (m, 2H),
1
3
.07 – 2.00 (m, 1H), 1.99 – 1.80 (m, 2H); C NMR (100 MHz, CDCl ) δ 207.4, 147.3, 145.4,
3
31.1, 124.2, 120.5, 112.0, 88.1, 57.8, 56.0, 52.9, 47.0, 39.9, 38.2, 35.2, 33.5, 28.9; HRMS (ESI)
+
calcd for C H NO [M+H] : 288.1660; found: 288.1598.
1
7
22
3
(4aS,8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-
cd]azepin-6-one (or) Narwedine (15):
To a solution of compound 14 (1.0 g, 3.48 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added
o
to LDA (2.5M, 1.35 mL, 17.4 mmol, 5.0 equiv) with stirring at -78 C under an argon atmosphere.
After 0.5 h, a solution of diphenyl disulfide (3.7 g, 17.4 mmol) in THF (15 mL) was added at -78
o
o
C, and then the reaction mixture was stirred at 0 C for 2 h. The reaction was quenched with H O
2
(
10 mL), and the mixture was extracted with CH Cl (3 x 20 mL). The combined organic layers
2
2
were washed with brine, dried over Na SO and concentrated under reduced pressure. To the
2
4
resultant crude (mixture of α- and β-phenylsulfide) in CH Cl (15 mL) was added (±)-camphor-
2
2
1
0-sulfonic acid (550 mg, 2.25 mmol), and the mixture was stirred at room temperature for 10 min
1
2

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under an argon atmosphere. A solution of m-CPBA (65%, 590 mg, 2.25 mmol) in CH Cl (15 mL)
2
2
o
o
was added at -78 C, and the mixture was stirred at -40 C for 0.5 h. The reaction was quenched
with saturated aqueous Na S O solution (10 mL). The reaction mixture was poured to saturated
2
2
3
aqueous NaHCO solution (10 mL) and brine (10 mL), and extracted with CH Cl (3 x 20 mL).
3
2
2
The organic layers were washed with brine, dried over Na SO and concentrated under reduced
2
4
pressure. The mixture of the crude residue and NaHCO (500 mg) in toluene (50 mL) was stirred
3
o
at 110 C for 2 h under an argon atmosphere. Saturated aqueous NaHCO solution (10 mL) and
3
H O (50 mL) were added, and the mixture was extracted with CH Cl (3 x 30 mL). The organic
2
2
2
layers were dried over Na SO and concentrated under reduced pressure. The crude residue was
2
4
purified by column chromatography on silica gel (CHCl /CH OH, 9:1) to afford compound 15 as
3
3
1
a pale yellow solid (447 mg, 45% yield); mp 184–186 ºC; H NMR (400 MHz, CDCl ) δ 6.94 (dd,
3
J = 10.4, 1.8 Hz, 1H), 6.68 (q, J = 8.2 Hz, 2H), 6.04 (d, J = 10.4 Hz, 1H), 4.73 (dt, J = 4.2, 2.3 Hz,
1
3
3
1
H), 4.14 (d, J = 15.3 Hz, 1H), 3.84 (s, 3H), 3.78 (d, J = 15.4 Hz, 1H), 3.29 (t, J = 13.1 Hz, 1H),
.15 (dd, J = 17.8, 2.3 Hz, 2H), 2.75 (dd, J = 17.8, 3.8 Hz, 1H), 2.46 (s, 3H), 2.27 (td, J = 13.6,
1
3
.2 Hz, 1H), 1.88 (d, J = 13.1 Hz, 1H); C NMR (100 MHz, CDCl ) δ 194.3, 146.9, 144.1, 130.4,
3
28.5, 127.1, 122.1, 111.9, 87.9, 60.3, 56.0, 53.9, 48.8, 42.0, 37.2, 32.9; HRMS (ESI) calcd for
+
C H NO [M+H] : 286.1443; found: 286.1437.
1
7
20
3
(±)-Galanthamine (1):
To a solution of the enone (narwedine) 15 (500 mg, 1.75 mmol, 1.0 equiv) in anhydrous THF (10
mL) was added LS-Selectride (1.0 M in THF, 2.11 mL, 2.10 mmol, 1.25 equiv) at -78 °C, the
resulting mixture was stirred at -78 °C to room temperature for 2 h, concentrated to give a solid,
and which was purified by silica gel flash column chromatography (CHCl /CH OH, 9:1) to obtain
3
3
1
13
compound 1 as a colorless solid (480 mg, 96% yield); mp 124–126 ºC; (The H and C NMR
1
spectra were in good agreement with literature); H NMR (400 MHz, CDCl ) δ 6.67 (d, J = 8.2
3
Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.07 (dd, J = 10.3, 1.1 Hz, 1H), 6.00 (ddd, J = 10.2, 4.9, 1.0 Hz,
1
1
2
1
H), 4.61 (s, 1H), 4.19 – 4.06 (m, 2H), 3.84 (s, 3H), 3.68 (d, J = 14.6 Hz, 1H), 3.33 – 3.21 (m,
H), 3.05 (d, J = 14.4 Hz, 1H), 2.69 (ddt, J = 15.7, 3.1, 1.4 Hz, 1H), 2.40 (s, 3H), 2.13 – 1.99 (m,
1
3
H), 1.71 (br s, 1H), 1.58 (ddd, J = 13.7, 3.9, 1.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ 145.8,
3
44.0, 133.0, 129.2, 127.5, 126.8, 122.0, 111.1, 88.7, 62.0, 60.6, 55.9, 53.8, 48.2, 42.1, 33.8, 29.9;
+
HRMS (ESI) calcd for C H NO [M+H] : 288.1600; found: 288.1591.
1
7
22
3
1
3

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DOI: 10.1039/C8OB03123A
Acknowledgement
TV thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, for a senior
research fellowship. SC thanks DST for J. C. Bose fellowship (SB/S2/JCB-002/2015) for financial
support. Authors thank DST (VI-D&P/513/2014-15/TDT) and National Mol Bank facility at
CSIR-IICT for sample storage.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: srivaric@iict.res.in
ORCID
Srivari Chandrasekhar: 0000-0003-3695-4343
Prathama S. Mainkar: 0000-0002-2696-3759
CSIR-IICT Manuscript Communication Number: IICT/Pubs./2018/317
References:
(
(
(
(
(
1) M. E. Maier, Org. Biomol. Chem., 2015, 13, 5302-5343.
2) D. J. Newman and G. M. Cragg, J. Nat. Prod., 2016, 79, 629-661.
3) S. G. Papageorgiou and K. G. Yiannopoulou, Ther Adv Neurol Disord., 2013, 6, 19-33.
4) (a) U. Rinner, C. Dank and T. Hudlicky, Targets in Heterocyclic Systems 2016, 20, 283-315.
b). J. Marco-Contelles, M. do Carmo Carreiras, C. Rodríguez, M. Villarroya and A. G. García,
Chem. Rev. 2006, 106, 116-133.
5) For total synthesis of (-)-galanthamine, see: (a) B. M. Trost, W. Tang and F. D. Toste, J. Am.
(
Chem. Soc. 2005, 127, 14785-14803. (b) V. Satcharoen, N. J. McLean, S. C. Kemp, P. C. Nicholas
and R. Brown, Org. Lett. 2007, 9, 1867-1869. (c) J.-Q. Chen, J.-H. Xie, D.-H. Bao, S. Liu and
Q.-L. Zhou, Org. Lett. 2012, 14, 2714-2717. (d) Y. Zang and I. Ojima, J. Org. Chem. 2013, 78,
4
013-4018. (e) J. Choi, H. Kim, S. Park and J. Tae, Synlett 2013, 24, 379-382. (f) M. Node, S.
Kodama, Y. Hamashima, T. Katoh, K. Nishide and T. Kajimoto, Chem. Pharm. Bull. 2006, 54,
1
1
662-1679. (g) P. Magnus, N. Sane, B. P. Fauber and V. Lynch, J. Am. Chem. Soc. 2009, 131,
6045-16047. (h) P. Chen, X. Bao, L.-F. Zhang, M. Ding, X.-J. Han, J. Li, G.-B. Zhang, Y.-Q. Tu
and C.-A. Fan, Angew. Chem., Int. Ed. 2011, 50, 8161-8166. (i) L. Li, Q. Yang, Y. Wang and Y.
1
4

Page 15 of 15
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB03123A
Jia, Angew. Chem., Int. Ed. 2015, 54, 6255-6259. (j) T. Kato, H. Tanimoto, H. Yamada and N.
Chida, Heterocycles 2010, 82, 563-579; For total synthesis of (±)-galanthamine, see: (k) X.-D. Hu,
Y.-Q. Tu, E. Zhang, S. Gao, S. Wang, A. Wang, C.-A. Fan and M. Wang, Org. Lett. 2006, 8,
1
823-1825. (l) T. Ishikawa, K. Kudo, K. Kuroyabu, S. Uchida, T. Kudoh and S. Saito, J. Org.
Chem. 2008, 73, 7498-7508. (m) J. H. Chang, H.-U. Kang, I.-H. Jung and C.-G. Cho, Org. Lett.
010, 12, 2016-2018. (n) Y. Feng and Z.-X. Yu, J. Org. Chem. 2015, 80, 1952-1956. (o) N.
2
Yamamoto, T. Okada, Y. Harada, N. Kutsumura, S. Imaide, T. Saitoh, H. Fujii and H. Nagase,
Tetrahedron 2017, 73, 5751-5758. (p) J. Nugent, E. Matousova and M. G. Banwell, Eur. J. Org.
Chem. 2015, 3771-3778. (q) M. A. A. Endoma-Arias and T. Hudlicky, Chem. Eur. J. 2016, 22,
1
4540-14543.
6) (a) S. Chandrasekhar, D. Basu, M. Sailu and S. Kotamraju, Tetrahedron Lett. 2009, 50, 4882-
884. (b) S. Kallepu, M. Kavitha, R. Yeeravalli, K. Manupati, S. Jadav, A. Das, P. S. Mainkar
and S. Chandrasekhar, ACS Omega, 2018, 3, 63-75.
7) For aryne insertion reactions, see: (a) P. Gouthami, R. Chegondi and S. Chandrasekhar, Org.
(
4
(
Lett. 2016, 18, 2044-2046. (b) R. Kranthikumar, R. Chegondi and S. Chandrasekhar, J. Org.
Chem. 2016, 81, 2451-2459. (c) P. M. Tadross, C. D. Gilmore, P. B. Bugga, S. C. Virgil and B.
M. Stoltz, Org. Lett. 2010, 12, 1224-1227. (d) P. M. Tadross, S. C. Virgil and B. M. Stoltz, Org.
Lett. 2010, 12, 1612-1614. (e) U. K. Tambar, D. C. Ebner and B. M. Stoltz, J. Am. Chem. Soc.
2006, 128, 11752-11753. (f) K. M. Allan and B. M. Stoltz, J. Am. Chem. Soc. 2008, 130, 17270-
17271. For recent reviews, see: (g) P. M. Tadross and B. M. Stoltz, Chem. Rev. 2012, 112, 3550-
3577. (h) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev. 2012, 41, 3140-3152.
(
8) V. Schulze, H. Lerchen, D. Bierer, A. M. Wengner, G. Siemeister, P. Lienau, U. Krenz, D.
Kosemund, D. Stöckigt, M. Brüning, U. Lücking and I. Terebesi, WO patent 2014198647, 2014.
9) W. C. Shieh and J. A. Carlson, J. Org. Chem. 1994, 59, 5463-5465.
(
1
5