Asymmetric synthesis of six tetrahydroisoquinoline natural products through α-amination of an aldehyde

Article abstract of DOI:10.1016/j.tet.2021.132121

An enantioselective route towards the synthesis of C-1 substituted tetrahydroisoquinoline natural products is reported. Six different natural products are synthesized from a single aldehyde using proline-catalyzed asymmetric α-hydrazination reaction as th

Full text of DOI:10.1016/j.tet.2021.132121

Tetrahedron 88 (2021) 132121
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of six tetrahydroisoquinoline natural products
through a-amination of an aldehyde
, b, *
Anas Ansari a, Amol B. Gorde a, Ramesh Ramapanicker a
a Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India
b Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective route towards the synthesis of C-1 substituted tetrahydroisoquinoline natural
products is reported. Six different natural products are synthesized from a single aldehyde using proline-
catalyzed asymmetric a-hydrazination reaction as the key step. The highly enantioselective introduction
of an amino group is exploited to synthesize (ꢀ)-calycotomine, (ꢀ)-salsolidine, (ꢀ)-carnegine,
(þ)-homolaudanosine, (þ)-homoprotoberberine and (þ)-crispine A.
© 2021 Elsevier Ltd. All rights reserved.
Received 3 March 2021
Received in revised form
23 March 2021
Accepted 24 March 2021
Available online 27 March 2021
Keywords:
Aldehydes
Amination
Asymmetric synthesis
Natural products
Tetrahydroisoquinolines
ꢀ
1. Introduction
THIQ units. Menendez and co-authors have summarized the
research activities towards the synthesis of tetrahydroisoquinolines
The tetrahydroisoquinoline (THIQ) scaffold is an important
structural unit, found in many naturally occurring alkaloids, bio-
logically active molecules, and pharmaceuticals (Fig. 1) [1]. Among
this class of compounds, C1-substituted THIQ are the most common
and they have gained significant attention due to their high
bioactivity as SK channel ligands [2] and because they act as re-
ceptor antagonists for the treatment of insomnia [3a-d]. Various
enantioselective methods available for the synthesis of these
compounds include the transformations at C1 position like cyano
addition [4], metal catalyzed addition of terminal alkynes [5],
allylsilanes [6], asymmetric hydrogenation [7] in the presence of
chiral ligands, photoredox catalysis [8], Pictet-Spengler [9], 1,3-
dipolar cycloaddition [10] and oxidative cross-coupling [11]. Addi-
tionally, various racemic approaches using metal-catalyzed CeH
alkylation/allylation [12], metal-free coupling with different nu-
cleophiles such as allylsilanes, coumarins, nitroalkanes, Grignard
reagents [13] and through photocatalysis [14] are also available. In
the recent years, the groups of Opatz [15], and Lumb [16] have
contributed significantly to the synthesis of compounds containing
during the last two decades in two reviews [17]. We observed that
organocatalytic pathways for the asymmetric synthesis of C1-
substituted THIQs are rare. First among a few notable ones is the
chiral Pictet Spengler reaction by Hiemstra and co-workers where
moderate ee was achieved, which was further enhanced by crys-
tallizing the chiral products [18]. Itoh and co-workers reported a
method involving an asymmetric Strecker reaction using Jacobsen’s
thiourea catalyst, which resulted in high yields and enantiose-
lectivity [4a,b].
2. Results and discussion
Our group is actively involved in the use of proline-catalyzed
asymmetric amination [19] and hydroxylation of aldehydes for
the synthesis of natural products [20]. The stereochemical outcome
of the reaction is governed by proline via the enamine intermediate
(Fig. 2.). The proposed model is based on Houk’s transition state
calculation on Hajos‒Parrish‒Eder‒Sauer‒Wiechert reaction [21].
We envisaged that a divergent route for the synthesis of C1-
substituted THIQs (1e6) can be achieved from the aldehyde 7. A
retrosynthetic route is outlined in (Scheme 1).
* Corresponding author. Department of Chemistry, Indian Institute of Technology
Kanpur, Kanpur, Uttar Pradesh, 208016, India.
Our synthetic efforts started from 3,4-dimethoxyphenethyl
methanesulfonate 8, which was synthesized from commercially
E-mail address: rameshr@iitk.ac.in (R. Ramapanicker).
https://doi.org/10.1016/j.tet.2021.132121
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
Scheme 2. Synthesis of aldehyde 7.
With the desired aldehyde 7 in our hand, the synthesis of
(ꢀ)-calycotomine (1), (ꢀ)-salsolidine (2) and (ꢀ)-carnegine (3)
were carried out. The aldehyde 7 was subjected to asymmetric a-
hydrazination using dibenzyl azodicarboxylate (DBAD) in the
presence of
-proline (0 ꢁC e rt, 4 h, CH3CN). After 4 h, the crude
product was reduced using NaBH4 to get the -hydrazino alcohol 10
L
b
in 91% yield and with 95% ee (Scheme 3). The enantiomeric purity
was calculated using chiral HPLC by comparing the chromatogram
of 10 with the racemic mixture obtained from the reaction cata-
lyzed by DL-proline. The alcohol 10 was subjected to hydrogenation
with Raney-Ni (CH3OH, rt) resulting in the cleavage of the benzy-
loxycarbonyl groups and the NeN bond. The primary amine
cyclized in situ displacing the mesylate group to give (ꢀ)-calyco-
tomine (1) in 83% yield (Scheme 3).
Fig. 1. Representative tetrahydroisoquinoline containing alkaloids.
THIQs 2 and 3 were then prepared from 1. The secondary amino
group in 1 was protected as the Boc derivative (Boc2O, NaHCO3,
THF, rt) to get 11 in 93% yield. The hydroxyl group in 11 was
transformed into an unstable tosyl derivative (TsCl, pyridine,
Fig. 2. General mechanism for the proline catalyzed a-amination of aldehydes.
Scheme 1. Retrosynthetic route for THIQs 1e6 from the aldehyde 7.
available 2-(3,4-dimethoxyphenyl)ethan-1-ol using
a reported
procedure [22]. Formylation of 8 was carried out in the presence of
SnCl4 using dichloromethyl methyl ether in CH2Cl2 to get the
aldehyde 9 in 85% yield (Scheme 2). Wittig reaction of 9 with
(methoxymethyl)triphenylphosphonium bromide followed by hy-
drolysis in acidic medium gave the aldehyde 7 in 82% yield over two
steps.
Scheme 3. Synthesis of (ꢀ)-Calycotomine (1), (ꢀ)-Salsolidine (2), (ꢀ)-Carnegine (3).
2

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
CH2Cl2, 0 ꢁC - rt), which was immediately reduced with LiAlH4 to 12
(88% over two steps). Removal of the N-Boc group in 12 with tri-
fluoroacetic acid (50%, CH2Cl2, 0 ꢁC) gave (ꢀ)-salsolidine (2) in 92%
yield (Scheme 3). Reduction of the N-Boc group in 12 using LiAlH4
(THF, reflux) gave (ꢀ)-carnegine (3) in 89% yield (Scheme 3).
Our next target was (þ)-homolaudanosine (4). A limited num-
ber of syntheses are available in the literature. Szarek and co-
workers achieved its synthesis by functionalization of tartaric
acid [23], and few reports are using nucleophilic addition on imines
at C1 position in the presence of metal catalysts [5b,6b,24]. We
started the synthesis from the alcohol 11 by oxidizing it into the
aldehyde 13 (92%, IBX, DMSO, rt, Scheme 4). Aldehyde 13 was
immediately subjected to
a
Wittig reaction with (3,4-
dimethoxybenzyl)triphenylphosphonium bromide (t-BuOK, THF,
0 ꢁC - rt) leading to the olefin 14 as a mixture of isomers (93% yield).
Hydrogenation of the double bond in 14 (H2, Pd/C, EtOAc, rt) fol-
lowed by the reduction of the N-Boc group (LiAlH4, THF, reflux)
provided (þ)-homolaudanosine (4) (85% over two steps, Scheme 4).
The optical rotation of our synthetic sample of 4 {[
a
]
25 þ 5.1 (c 0.2,
D
CH2Cl2)} was in close agreement with that reported in the literature
{[a
]
25 þ 3.0 (c 1.3, CHCl3)} [5b].
D
With the optimized technique in our hand, we attempted the
synthesis of the more complex molecule, (þ)-homoprotoberberine
(5). The racemic homoprotoberberine framework has been con-
structed with metal-mediated [25] and with metal free synthetic
pathways [26]. Three chiral syntheses have been reported so far.
Other than the synthesis by Szarek and co-workers using tartaric
acid [23], nucleophilic addition on isoquinoline ring by Ohsawa and
co-workers [27] and copper catalyzed CeC coupling of terminal
alkynes by Liu and co-workers [5d] are the methods available. We
began our synthesis of 5 by carrying out Cbz protection of 1 (benzyl
chloroformate, NaHCO3, 0 ꢁC - rt) to get the tertiary benzyl carba-
mate 15 in 90% yield (Scheme 5).
The hydroxyl group in 15 was oxidized to an aldehyde function
to get 16 (92%, IBX, DMSO, rt). The aldehyde 16 was subjected to a
Wittig reaction with (3,4,5-trimethoxybenzyl)triphenylphospho-
nium bromide (t-BuOK, THF, 0 ꢁC - rt) to get the olefin 17 as a
mixture of isomers (94%). Hydrogenation of 17 followed by Pictet-
Spengler reaction of the resulting amine (HCHO, HCl, EtOH,
Scheme 5. Synthesis of (þ)-Homoprotoberberine (5).
chemists and several interesting syntheses are available. Methods
such as lithiation [28], CeH allylation [13d] at C-1 position and
Lewis acid catalyzed lactamization [12c] have been employed. A
number of enantioselective synthesis of (þ)-crispine A (6) are re-
ported. Several strategies have been used such as functionalization
of the C-1 position through nucleophilic addition using chiral
auxiliaries [4b,5c,6b], through asymmetric Pictet-Spengler re-
actions [15,29,30], with the help of chiral metal complexes [31] and
a few metal-free synthesis are also available [4c]. In contrast to the
previously reported methods, our strategy offers an alternative
synthetic route for (þ)-crispine A (6) in four steps from the alde-
hyde 7 (Scheme 6). In order to produce the opposite stereochem-
reflux) yielded (þ)-homoprotoberberine (5) in 85% yield (Scheme
25
istry to that of compounds (1e5) at the C1 position,
used as the catalyst for the asymmetric -functionalization. Alde-
hyde 7 was treated with dibenzyl azodicarboxylate in the presence
of -proline and after the complete disappearance of the yellow
D-proline was
5). The optical rotation of our sample of 5 {[
a
]
‒ 101 (c 0.6,
D
25
a
CH2Cl2)} was consistent with that reported in literature {[
98.5 (c 0.12, CH3OH)} [5d].
a]
‒
D
D
Crispine A has remained as an attractive choice for synthetic
color, Wittig reaction was carried out on the aldehyde function by
adding (carbethoxymethylene)triphenylphosphorane (Ph3P]
Scheme 4. Synthesis of (þ)-Homolaudanosine (4).
Scheme 6. Synthesis of (þ)-Crispine A (6).
3

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
CHCO2Et) to get the unsaturated ester 18 in 89% yield and 93% ee
(Scheme 6).
d
¼ 190.9, 153.5,148.3, 133.2,127.1, 115.0, 114.5, 70.0, 56.3, 56.2, 37.4,
32.4 ppm; FTIR (thin film): 3011, 2935, 2852, 1711, 1678, 1600, 1570,
1516, 1465 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ Na]þ calcd. for
The reduction of the g-hydrazino a,b-unsaturated ester 18 was
performed using Raney-Ni, which resulted in a mixture of products
as observed on TLC. To our delight, when the mixture was treated
with K2CO3 (CH3OH, reflux), a tricyclic lactam 19 could be isolated
as the major product in 79% yield. The lactam 19 was reduced using
LiAlH4 (THF, reflux) to get 6 in 88% yield (Scheme 6). The measured
C12H16NaO6S 311.0565, found 311.0565.
4.3. 4,5-dimethoxy-2-(2-oxoethyl)phenethylmethanesulfonate (7)
optical rotation for (þ)-crispine A (6) {[
a
]
25 þ 90.4 (c 0.36, CH2Cl2)}
D
Potassium t-butoxide (0.59 g, 5.27 mmol) was added to a stirred
solution of methoxymethyltriphenylphosphonium bromide (2.13 g,
6.25 mmol) in dry THF (15 mL) at 0 ꢁC under nitrogen atmosphere
and the stirring was continued at this temperature for 20 min, after
which the aldehyde 9 (0.95 g, 3.29 mmol) in dry THF (12 mL) was
added to the reaction mixture dropwise and further stirring was
continued at room temperature for 2 h. After the complete disap-
pearance of starting material on TLC, the reaction mixture was
quenched with saturated NH4Cl solution (10 mL). The product was
extracted with EtOAc (3 ꢂ 15 mL), and dried over anhydrous
Na2SO4. The solvents were removed under reduced pressure, and
the crude product was purified through column chromatography
(85:15 petroleum ether/EtOAc) to get enol ether as a colorless oil
(0.93 g, 90%). The enol ether was dissolved in THF (15 mL) and 2 N
HCl (5 mL) was added dropwise to the reaction mixture and stirred
for 6 h. The product was extracted with EtOAc (3 ꢂ 15 mL), and
dried over anhydrous Na2SO4. The solvents were removed under
reduced pressure and the crude product was purified through
column chromatography (75:25 petroleum ether/EtOAc) to get an
aldehyde 7 as a colorless oil (0.81 g, 82%); 1H NMR (CDCl3,
25
matched with that reported in literature {[
a
]
þ 90 (c 1.0,
D
CHCl3)}.29
Thus, the syntheses of six THIQs (1e6) were achieved from a
single aldehyde 7 using proline-catalyzed asymmetric a-amination
as the key step.
3. Conclusions
We have demonstrated an application of proline-catalyzed a-
amination reaction of aldehydes for the synthesis of C1-substituted
tetrahydroisoquinolines. This organocatalytic pathway has led to
the synthesis of all the six target molecules with high enantiose-
lectivity. Syntheses of six different natural products from a com-
mon aldehyde exemplify the synthetic utility of this methodology
where all the reactions performed are simple and high yielding. The
current method is complimentary to existing methods, which rely
on a late cyclization reaction through aromatic electrophilic sub-
stitution reactions such as Pictet-Spengler or Bischler-Napieralski
reactions. However, the current method requires a suitable alde-
hyde as the starting material, the preparation of which need not be
always trivial with high selectivity as in the case reported here.
400 MHz)
d
9.72 (t, J ¼ 1.9 Hz, 1H), 6.74 (s, 1H), 6.64 (s, 1H), 4.30 (t,
J ¼ 7.1 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.70 (d, J ¼ 1.9 Hz, 2H), 2.96
(t, J ¼ 7.1 Hz, 2H), 2.90 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
4. Experimental section
d
¼ 199.0, 148.7, 148.4, 127.5, 122.7, 114.0, 113.4, 69.7, 56.1, 56.0, 47.9,
37.4, 32.5 ppm; FTIR (thin film): 2938, 2836, 2728, 1720, 1609, 1519,
1466 cmꢀ1. HRMS (ESI-TOF) m/z [M þ Na]þ calcd. for C13H18NaO6S
325.0722, found 325.0726.
4.1. General information
All of the chemicals were purchased from commercial sources.
The 1H NMR spectra of compounds containing the hydrazino group
were complex at r.t. due to the presence of rotamers. They were
therefore recorded at 80 ꢁC in DMSO‑d6. Column chromatography
was done with silica gel (particle size 60e120 and 100e200 mesh)
purchased from Merck. The enantiomeric ratios were determined
by chiral HPLC analysis using Daicel chiralpak IC and Phenomenex
Cellulose-1 columns with a mixture of hexane and isopropanol as
an eluent at 25 ꢁC. Optical rotation was measured using a 5.0 mL cell
4.4. Dibenzyl (R)-1-(1-(4,5-dimethoxy-2-(2-((methylsulfonyl)oxy)
ethyl)phenyl)-2-hydroxyethyl)hydrazine-1,2-dicarboxylate (10)
To a stirred solution of the aldehyde 7 (1.00 g, 3.31 mmol) in
CH3CN (20 mL) were added dibenzylazodicarboxylate (DBAD),
(1.08 g, 3.64 mmol) and L
-proline (0.04 g, 0.33 mmol) at 0 ꢁC under
with a 10 dm path length and is reported as [
solvent).
a
]
D
25(c in g per 100 mL
nitrogen atmosphere and the mixture was stirred for 2 h. The
stirring was continued at room temperature until the solution
turned colorless from yellow. The reaction mixture was again
cooled to 0 ꢁC, NaBH4 (0.18 g, 4.96 mmol) and ethanol (5 mL) were
added to the reaction mixture. The stirring was continued for
additional 15 min and the reaction was quenched with saturated
NH4Cl solution (5 mL). The product was extracted with ethyl ace-
tate (3 ꢂ 30 mL), dried over anhydrous Na2SO4. The solvents were
removed under reduced pressure, and the product was purified
4.2. 2-formyl-4,5-dimethoxyphenethyl methanesulfonate (9)
To a stirred solution of 8 (1.10 g, 4.23 mmol) at ꢀ20 ꢁC in dry
CH2Cl2 (20 mL) was added dichloromethyl methyl ether (0.57 mL,
6.34 mmol) and stirred for 30 min SnCl4 (1 M solution in CH2Cl2,
7.19 mL, 7.19 mmol) was added dropwise over a period of 30 min at
the same temperature. The reaction mixture was warmed to r.t. and
stirred for an additional 12 h. The reaction was monitored through
TLC, and after the complete disappearance of starting material on
TLC, the reaction mixture was quenched with a saturated solution
of NaHCO3 (10 mL) and the product was extracted with CH2Cl2
(3 ꢂ 25 mL), and dried over Na2SO4. The solvents were removed
under reduced pressure and the crude product was purified
through column chromatography (75:25 petroleum ether/EtOAc)
to get 9 as an oil which solidified on cooling, m.p. 74e76 ꢁC (1.03 g,
through column chromatography (40:60 petroleum ether/EtOAc)
25
to get an alcohol 10 as a syrup (1.81 g, 91%); [
a
]
¼ þ1.5 (c 0.26,
D
CH2Cl2); 1H NMR (400 MHz, DMSO‑d6, 80 ꢁC)
d
¼ 9.26 (s, 1H), 7.28
(s, 10H), 6.87 (s, 1H), 6.81 (s, 1H), 5.37 (s, 1H), 5.08 (s, 4H), 4.54 (s,
1H), 4.33 (s, 2H), 3.91e3.82 (m, 1H), 3.72 (s, 4H), 3.63 (s, 4H), 3.01 (s,
3H) ppm; 13C NMR (100 MHz, DMSO‑d6, rotamers)
d
¼ 158.4, 156.3,
148.5, 147.9, 147.5, 136.9, 136.8, 136.7, 114.3, 114.1, 112.2, 111.8, 70.9,
67.5, 67.0, 66.2, 61.2, 56.1, 56.0, 55.9, 55.8, 37.0, 31.8 ppm; FTIR (thin
film): 3453, 3302, 2931, 2854, 1712, 1519, 1455 cmꢀ1. HRMS (ESI-
TOF) m/z: [M þ NH4]þ calcd. for C29H38N3O10S 620.2278, found
620.2279; HPLC (Diacel IC column, hexane: IPA ¼ 80:20, flow rate:
85%); 1H NMR (400 MHz, CDCl3)
d
¼ 10.03 (s, 1H), 7.29 (s, 1H), 6.78
(s, 1H), 4.41 (t, J ¼ 6.7 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.41 (t,
J ¼ 6.7 Hz, 2H), 2.92 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
1 mL/min,
l
¼ 282 nm), tR major ¼ 68.0, tR minor ¼ 79.3, 95% ee.
4

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
4.5. (R)-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)
methanol (1)
28.6, 21.9 ppm; FTIR (thin film): 2972, 2929, 2855, 1691, 1612, 1518,
1465, 1454 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd. for
C
17H26NO4 308.1862, found 308.1866.
To a solution of 10 (1.10 g, 1.82 mmol) in CH3OH (20 mL), was
added Raney-Ni (0.90 g, prewashed with absolute ethanol) fol-
lowed by 0.10 mL of acetic acid, and the mixture was stirred for 16 h
at r.t. under a hydrogen atmosphere. The reaction mixture was then
filtered through a celite pad, and the solution was concentrated
under reduced pressure. The crude product was purified by column
4.8. (S)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (2)
To a stirred solution of 12 (0.25 g, 0.81 mmol) in dry CH2Cl2
(5 mL) was added trifluoroacetic acid (0.5 mL) at 0 ꢁC. The reaction
was monitored on TLC and after the complete disappearance of
starting material, the solvents were removed under reduced pres-
sure and the crude mixture was dissolved in EtOAc (4 mL) and
NaHCO3 (0.20 g, 2.43 mmol) was added. The mixture was stirred for
10 min to neutralize any residual acids present. The solids were
filtered off, and the solution was concentrated and purified by
chromatography (92:08 CH2Cl2/CH3OH) to get 1 as a white solid,
25
m.p. 139 ꢁC (0.33 g, 83%); [
a
]
D
¼ ꢀ31.4 (c 0.40, CH2Cl2); 1H NMR
(400 MHz, CDCl3)
d
¼ 6.58 (s, 1H), 6.57 (s, 1H), 3.96 (dd, J ¼ 9.2,
4.3 Hz, 1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.74 (dd, J ¼ 10.6, 3.9 Hz, 1H),
3.64e3.58 (m, 1H), 3.08e3.01 (m, 3H), 2.75e2.59 (m, 3H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
¼ 147.9, 147.6, 127.4, 126.6, 112.0, 109.2,
column chromatography (93:07 CH2Cl2/CH3OH) to get 2 as an
64.0, 56.1, 55.96, 38.8, 28.9 ppm; FTIR (thin film): 3300 cmꢀ1. HRMS
(ESI-TOF) m/z: [M þ H]þ calcd. for C12H18NO3224.1287, found
224.1294.
25
oil(0.33 g, 92%); [
CDCl3)
a]
¼ ꢀ45.4 (c 0.60, CH2Cl2); 1H NMR (400 MHz,
D
d
¼ 6.61 (s, 1H), 6.55 (s, 1H), 4.04 (dd, J ¼ 13.4, 6.8 Hz, 1H),
3.84 (s, 3H), 3.83 (s, 3H), 3.24 (m, 1H), 2.99 (m, 1H), 2.84e2.73 (m,
1H), 2.64 (m, 1H), 2.03 (s, 1H), 1.43 (d, J ¼ 6.7 Hz, 3H) ppm; 13C NMR
4.6. Tert-butyl (R)-1-(hydroxymethyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (11)
(100 MHz, CDCl3)
d
¼ 147.4, 147.3, 132.3, 126.8, 111.8, 109.1, 56.0,
55.9, 51.2, 41.8, 29.5, 22.8 ppm; FTIR (thin film): 2926, 2854, 1512,
1463 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þcalcd. for C12H18NO2
208.1338, found 208.1338.
To a stirred solution of 1 (0.56 g, 2.51 mmol) in THF (15 mL) were
added NaHCO3 (0.52 g, 6.27 mmol) and (Boc)2O (1.15 mL,
5.02 mmol) and the reaction mixture was stirred for 8 h. After the
complete disappearance of starting material the reaction mixture
was filtered, concentrated and purified by column chromatography
4.9. (S)-6,7-dimethoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline
(3)
(60:40 petroleum ether/EtOAc) to get 11 as a colorless oil (0.75 g,
25
To a stirred solution of LiAlH4 (0.12 g, 3.25 mmol) in dry THF
(4 mL) was added 12 (0.25 g, 0.81 mmol) dissolved in dry THF
(5 mL) at 0 ꢁC under nitrogen atmosphere. The reaction mixture
was stirred for 30 min at same temperature and further it was
refluxed for 8 h. After the complete disappearance of starting ma-
terial on TLC, the reaction was quenched carefully with 2 N KOH
solution (2 mL) and filtered through a celite pad. The solvents were
removed under reduced pressure and the crude product obtained
93%); [
a
]
¼ þ53.0 (c 0.46, CH2Cl2); 1H NMR (400 MHz, CDCl3)
D
d
¼ 6.66 (s, 1H), 6.60 (s, 1H), 5.12 (d, J ¼ 56.2 Hz, 1H), 3.82 (t,
J ¼ 10.1 Hz, 9H), 3.31 (d, J ¼ 62.0 Hz, 1H), 2.79 (bs, 1H), 2.66 (d,
J ¼ 15.1 Hz, 1H), 1.47 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 157.0, 148.1, 147.6, 127.2, 125.3, 111.4, 110.2, 80.5, 67.5, 56.5, 56.1,
55.9, 39.7, 28.5, 28.2 ppm; FTIR (thin film): 3451, 2929, 1688, 1611,
1519, 1464, 1454 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd. for
C
17H26NO5 324.1811, found 324.1817.
was purified by column chromatography (95:05 CH2Cl2/CH3OH) to
25
get 3 as an oil (0.16 g, 89%); [
a
]
¼ ꢀ27.5 (c 0.20, CH2Cl2); 1H NMR
D
4.7. Tert-butyl (S)-6,7-dimethoxy-1-methyl-3,4-
dihydroisoquinoline-2(1H)-carboxylate (12)
(400 MHz, CDCl3)
d
¼ 6.56 (s, 1H), 6.55 (s, 1H), 3.83 (s, 6H), 3.62 (dd,
J ¼ 13.3, 6.7 Hz, 1H), 3.12e3.03 (m, 1H), 2.79 (dd, J ¼ 11.0, 5.3 Hz,
2H), 2.75e2.65 (m,1H), 2.50 (s, 3H), 1.40 (d, J ¼ 6.6 Hz, 3H) ppm; 13
C
To
a stirred solution of 11 (0.74 g, 2.29 mmol) in dry
NMR (100 MHz, CDCl3)
d
¼ 147.5, 147.4, 130.8, 125.4, 111.2, 109.9,
CH2Cl2(20 mL) at 0 ꢁC were added pyridine (0.46 mL, 5.72 mmol)
and p-toluenesulfonyl chloride (0.87 g, 4.58 mmol) and the stirring
was continued for 3 h. The reaction was monitored through TLC and
after the complete disappearance of alcohol on it, the reaction
mixture was quenched with saturated citric acid solution (5 mL)
and the product was extracted with CH2Cl2 (3 ꢂ 15 mL), dried over
anhydrous Na2SO4. The solvents were removed under reduced
pressure, and the product was purified through column chroma-
tography (70:30 petroleum ether/EtOAc) to get the unstable tosy-
lated product (1.04 g, 96%). To a stirred solution of LiAlH4 (0.16 g,
4.38 mmol) in dry THF (5 mL) at 0 ꢁC was added the tosylated
product obtained as above (1.04 g, 2.18 mmol) and the reaction
mixture was stirred for 2 h at room temperature. After the complete
disappearance of starting material on TLC, the reaction mixture was
quenched carefully with saturated NH4Cl solution (5 mL) and
filtered on celite pad. The solvents were removed under reduced
pressure, and the product was purified by column chromatography
58.7, 56.0, 55.2, 48.5, 42.5, 27.0, 19.8 ppm; FTIR (thin film): 2924,
2852, 1514, 1463 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd. for
C
13H20NO2 222.1494, found 222.1497.
4.10. Tert-butyl (R)-1-formyl-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (13)
To a stirred solution of an alcohol 11 (0.47 g,1.47 mmol) in DMSO
(10 mL) was added IBX (0.61 g, 2.20 mmol) and the reaction
mixture was stirred for 3 h. After the complete disappearance of
starting material on TLC, saturated NaHCO3 solution (10 mL) was
added and the product was extracted with EtOAc (3 ꢂ 15 mL), dried
over anhydrous Na2SO4. The solvents were removed under reduced
pressure and the product was purified by column chromatography
(80:20 petroleum ether/EtOAc) to get 13 as an oil (0.43 g, 92%);
25
[
a
]
D
¼ þ9.0 (c 0.44, CH2Cl2); 1H NMR (400 MHz, CDCl3)
¼ 9.41 (d,
d
(80:20 petroleum ether/EtOAc) to get the desired product 12 as a
J ¼ 28.6 Hz, 1H), 6.80 (d, J ¼ 9.7 Hz, 1H), 6.64 (s, 1H), 5.30, 5.10 (s,
1H), 3.85 (d, J ¼ 5.2 Hz, 6H), 3.79e3.60 (m, 2H), 2.78 (bs, 2H),1.47 (d,
colorless oil (0.61 g, 88%); [
(400 MHz, CDCl3)
a
]
D
¼ þ49.5 (c 0.40, CH2Cl2); 1H NMR
25
d
¼ 6.56 (d, J ¼ 9.3 Hz, 2H), 5.08 (d, J ¼ 53.4 Hz,
J ¼ 11.5 Hz, 9H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 197.0, 196.9,
1H), 4.08 (d, J ¼ 66.4 Hz, 1H), 3.82 (m, 6H), 3.15 (d, J ¼ 29.6 Hz, 1H),
154.8, 148.8, 148.1, 128.2, 127.8, 119.1, 111.5, 110.6, 110.3, 81.4, 80.9,
64.6, 63.9, 56.1, 56.0, 41.0, 39.9, 28.7, 28.3 ppm; FTIR (thin film):
2926, 2851, 1735, 1694, 1610, 1519, 1464 cmꢀ1. HRMS (ESI-TOF) m/z:
[M þ H]þ calcd. for C17H24NO5 322.1654, found 322.1656.
2.82 (bs, 1H), 2.60 (d, J ¼ 15.7 Hz, 1H), 1.47 (s, 9H), 1.40 (d, J ¼ 6.7 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 154.5, 147.6, 131.0, 130.4,
126.3, 125.9, 111.4, 109.8, 79.6, 56.1, 55.9, 50.2, 49.5, 38.0, 36.6, 28.6,
5

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
4.11. Tert-butyl (S)-1-(3,4-dimethoxystyryl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (14)
ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 157.2, 155.8, 148.2, 147.7, 136.5,
128.6, 128.2, 128.0, 124.9, 111.7, 111.4, 110.1, 109.9, 67.6, 67.1, 56.9,
56.1, 55.9, 39.5, 28.2 ppm; FTIR (thin film): 3440, 2925, 2854, 1689,
1611, 1518, 1433 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd. for
Potassium t-butoxide (0.30 g, 2.74 mmol) was added to a stirring
solution of (3,4-dimethoxybenzyl)triphenylphosphonium bromide
(1.80 g, 3.66 mmol) in dry THF (15 mL) at 0 ꢁC under nitrogen at-
mosphere and the stirring was continued at this temperature for
20 min. The aldehyde 13 (0.59 g, 1.83 mmol) in dry THF (12 mL) was
added dropwise to the reaction mixture at the same temperature
and the stirring was continued for next 2 h. After the complete
disappearance of starting material on TLC, the reaction mixture was
quenched with saturated NH4Cl solution (10 mL). The product was
extracted with EtOAc (3 ꢂ 15 mL), and dried over anhydrous
Na2SO4. The solvents were removed under reduced pressure and
the crude product was purified through column chromatography
C
20H24NO5 358.1654, found 358.1658.
4.14. Benzyl (R)-1-formyl-6,7-dimethoxy-3,4-dihydroisoquinoline-
2(1H)-carboxylate (16)
Same procedure was used as 11 was converted to 13; column
chromatography (80:20 petroleum ether/EtOAc) to get 16 as a clear
25
oil (0.48 g, 92%); [
a
]
¼ ꢀ8.2 (c 0.61, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3)
d
¼ 9.49 (d, J ¼ 17.7 Hz, 1H), 7.43e7.28 (m, 5H), 6.80 (d,
J ¼ 22.8 Hz, 1H), 6.64 (s, 1H), 5.41, 5.29 (s, 1H), 5.19 (d, J ¼ 14.1 Hz,
2H), 3.91 (m, 1H), 3.86 (d, J ¼ 10.4 Hz, 6H), 3.72e3.57 (m, 1H), 2.78
(80:20 petroleum ether/EtOAc) to get the olefin 14 as a syrup
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 196.5, 156.2, 155.5,
(0.77 g, 93%); [
CDCl3)
a
]
D
¼ þ13.3 (c 0.80, CH2Cl2); 1H NMR (500 MHz,
148.9, 148.1, 136.3, 128.6, 128.2, 127.6, 119.4, 118.8, 111.5, 110.5, 110.2,
67.8, 64.3, 56.1, 56.0, 40.9, 28.4 ppm; FTIR (thin film): 2925, 2853,
1698, 1610, 1519, 1464 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd.
for C20H22NO5 356.1498, found 356.1498.
25
d
¼ 6.90e6.85 (m, 2H), 6.79 (d, J ¼ 8.0 Hz, 1H), 6.64 (d,
J ¼ 2.4 Hz, 2H), 6.33 (d, J ¼ 14.9 Hz, 1H), 6.19 (s, 1H), 5.65 (d,
J ¼ 87.8 Hz, 1H), 4.16 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 3.82 (s, 3H),
3.22 (s, 1H), 2.88 (t, J ¼ 13.0 Hz, 1H), 2.65 (d, J ¼ 15.8 Hz, 1H), 1.49 (s,
9H) ppm; 13C NMR (125 MHz, CDCl3)
d
¼ 154.7, 149.1, 148.9, 148.0,
4.15. Benzyl (S)-6,7-dimethoxy-1-(3,4,5-trimethoxystyryl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate (17)
147.5, 131.3, 129.8, 127.4, 127.1, 127.0, 119.8, 111.4, 111.1, 110.9, 108.9,
79.9, 56.1, 56.0, 55.9, 55.9, 38.3, 28.6, 28.4 ppm; FTIR (thin film):
2932, 2835, 1689, 1603, 1583, 1515, 1463 cmꢀ1. HRMS (ESI-TOF) m/z:
[M þ H]þ calcd. for C26H34NO6 456.2386, found 456.2381.
Potassium t-butoxide (0.17 g, 1.51 mmol) was added to a stirring
solution of triphenyl(3,4,5-trimethoxybenzyl)phosphonium bro-
mide (1.054 g, 2.02 mmol) in dry THF (10 mL) at 0 ꢁC under nitrogen
atmosphere and the stirring was continued at this temperature for
20 min. The aldehyde 16 (0.36 g, 1.01 mmol) in dry THF (8 mL) was
added dropwise to the reaction mixture at the same temperature
and the stirring was continued for next 2 h. After the complete
disappearance of starting material on TLC, the reaction mixture was
quenched with saturated NH4Cl solution (10 mL). The product was
extracted with EtOAc (3 ꢂ 15 mL), and dried over anhydrous
Na2SO4. The solvents were removed under reduced pressure and
the crude product was purified through column chromatography
4.12. (S)-1-(3,4-dimethoxyphenethyl)-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (4)
To a stirred solution of 14 (0.32 g, 0.70 mmol) in EtOAc (5 mL)
was added Pd/C (0.02 g) and the reaction mixture was stirred for 2 h
at r.t. under hydrogen atmosphere. The reaction mixture was
filtered on a celite pad and the solvents were removed under
reduced pressure. The crude product obtained was transferred to a
stirring solution of LiAlH4 (0.10 g, 2.80 mmol) in dry THF (5 mL) at
0 ꢁC under nitrogen atmosphere. The reaction mixture was stirred
for 30 min at same temperature and further it was refluxed for 8 h.
After the complete disappearance of starting material on TLC, the
reaction was quenched carefully with 2 N KOH solution (2 mL) and
filtered through a celite pad. The solvents were removed under
reduced pressure and the crude product obtained was purified by
(80:20 petroleum ether/EtOAc)to get the olefin 17 as a syrup
25
(0.77 g, 93%); [
CDCl3)
a]
¼ ꢀ15.7 (c 0.46, CH2Cl2); 1H NMR (400 MHz,
D
d
¼ 7.34 (m, 5H), 6.63 (d, J ¼ 7.7 Hz, 2H), 6.52 (s, 2H), 6.27 (s,
2H), 5.75 (d, J ¼ 49.2 Hz, 1H), 5.23 (s, 1H), 5.15 (d, J ¼ 12.3 Hz, 1H),
4.18 (d, J ¼ 33.8 Hz, 1H), 3.87 (s, 4H), 3.83 (s, 6H), 3.82 (s, 5H), 3.31
(bs, 1H), 2.91 (bs, 1H), 2.68 (d, J ¼ 15.9 Hz, 1H) ppm; 13C NMR
column chromatography (95:05 CH2Cl2/CH3OH) to get 4 as an oil
(100 MHz, CDCl3)
d
¼ 155.3, 153.3, 148.1, 147.6, 137.9, 136.7, 132.2,
25
(0.22 g, 85%); [
a
]
¼ þ5.1 (c 0.20, CH2Cl2); 1H NMR (400 MHz,
128.6, 128.1, 126.7, 126.6, 126.4, 111.4, 110.8, 103.6, 67.4, 61.0, 56.1,
55.9, 38.5, 28.3 ppm; FTIR (thin film): 2997, 2926, 2853, 1697, 1610,
1582, 1509, 1463, 1454 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd.
for C30H34NO7 520.2335, found 520.2338.
D
CDCl3)
d
¼ 6.73 (dd, J ¼ 24.6, 7.4 Hz, 3H), 6.54 (d, J ¼ 13.6 Hz, 2H),
3.83 (s, 10H), 3.81 (s, 2H), 3.41 (s, 1H), 3.15 (d, J ¼ 7.5 Hz, 1H), 2.71
(m, 4H), 2.49 (d, J ¼ 22.3 Hz, 4H), 2.03 (s, 2H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 148.8, 147.3, 147.0, 135.5, 129.8, 126.7, 120.2,
111.9, 111.3, 111.3, 110.1, 62.7, 56.0, 56.0, 55.8, 48.0, 42.7, 37.1, 31.3,
25.3 ppm; FTIR (thin film): 2925, 28523, 1514, 1463 cmꢀ1. HRMS
(ESI-TOF) m/z: [M þ H]þ calcd. for C20H30NO4 372.2175, found
372.2171.
4.16. (S)-2,3,9,10,11-pentamethoxy-5,6,8,13,14,14a hexahydrobenzo
[5,6]azepino[2,1-a]isoquinoline (5)
To a stirred solution of 17 (0.25 g, 0.48 mmol) in EtOAc (5 mL)
was added Pd/C (0.02 g) and the reaction mixture was stirred for 5 h
at r.t. under hydrogen atmosphere. After the complete disappear-
ance of starting material on TLC, the reaction mixture was filtered
on a celite pad and the solvents were removed under reduced
pressure. The crude product was dissolved in EtOH (7 mL) followed
by addition of HCHO (37% w/w, 4.00 mL) and HCl (12 mol/L,
1.00 mL) under nitrogen atmosphere and the reaction mixture was
refluxed in the dark for 12 h. After the complete disappearance of
starting material on TLC, the solvents were evaporated and satu-
rated NaHCO3 solution (10 mL) was added to the residue and the
product was extracted with CH2Cl2 (3 ꢂ 10 mL). The solvents were
removed under reduced pressure and the crude product was pu-
rified through column chromatography (98:02 CH2Cl2/CH3OH) to
4.13. Benzyl (R)-1-(hydroxymethyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (15)
To a stirred solution of 1 (0.35 g, 1.56 mmol) in THF (5 mL) at 0 ꢁC
were added NaHCO3 (0.26 g, 3.12 mmol) and benzyl chloroformate
(50% solution in toluene 0.66 mL, 2.34 mmol) and the reaction
mixture was stirred for 4 h and then filtered, concentrated and
purified by column chromatography (60:40 petroleum ether/
25
EtOAc) to get 15 as a colorless oil (0.49 g, 90%); [
a
]
D
¼ þ69.6 (c 0.26,
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
¼ 7.44e7.26 (m, 5H), 6.67 (s,
1H), 6.60 (s, 1H), 5.19 (t, J ¼ 19.1 Hz, 3H), 4.00 (d, J ¼ 13.8 Hz, 1H),
3.83 (s, 6H), 3.80 (s, 1H), 3.41 (d, J ¼ 57.1 Hz, 1H), 2.92e2.50 (m, 3H)
6

A. Ansari, A.B. Gorde and R. Ramapanicker
Tetrahedron 88 (2021) 132121
25
get 5 as a clear oil (0.16 g, 83%); [
a
]
D
¼ ꢀ101.0 (c 0.60, CH2Cl2); 1H
4.19. (R)-8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]
isoquinoline (6)
NMR (400 MHz, CDCl3)
d
¼ 6.54 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H),
4.52 (d, J ¼ 14.9 Hz, 1H), 4.13 (dd, J ¼ 9.3, 4.4 Hz, 1H), 3.94 (d,
J ¼ 14.9 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (d, J ¼ 1.5 Hz, 6H),
3.80 (s, 3H), 3.13 (t, J ¼ 13.7 Hz, 1H), 2.99e2.89 (m, 1H), 2.79e2.67
(m, 2H), 2.62 (dd, J ¼ 19.8, 8.7 Hz, 2H), 1.90 (dd, J ¼ 13.9, 8.0 Hz, 2H)
To a stirred solution of LiAlH4 (0.09 g, 2.26 mmol) in dry THF
(3 mL) was added 19 (0.14 g, 0.56 mmol) dissolved in dry THF (4 mL)
at 0 ꢁC under nitrogen atmosphere. The reaction mixture was
stirred for 30 min at same temperature and further it was refluxed
for 8 h. After the complete disappearance of starting material on
TLC, the reaction was quenched carefully with 2 N KOH solution
(2 mL) and filtered through a celite pad. The solvents were removed
under reduced pressure and the crude product obtained was pu-
rified by column chromatography (87:13 CH2Cl2/CH3OH) to get 6 as
ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 152.3, 151.8, 147.5, 147.0, 140.2,
138.8, 132.0, 126.1, 123.8, 111.4, 109.9, 108.1, 65.3, 61.4, 60.8, 56.0,
56.0, 55.8, 50.8, 42.7, 35.4, 31.5, 29.0 ppm; FTIR (thin film): 2925,
2853, 1597, 1518, 1493, 1462 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ
calcd. for C23H30NO5 400.2124, found 400.2128.
an oil which solidified on cooling, m.p. 81 ꢁC (0.11 g, 88%);
25
4.17. Dibenzyl (R,E)-1-(1-(4,5-dimethoxy-2-(2-((methylsulfonyl)
oxy)ethyl)phenyl)-4-ethoxy-4-oxobut-2-en-1-yl)hydrazine-1,2-
dicarboxylate (18)
[
a
]
D
¼ þ90.4 (c 0.36, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
¼ 6.58
(s, 1H), 6.54 (s, 1H), 3.82 (s, 6H), 3.53 (t, J ¼ 7.3 Hz, 1H), 3.14 (d,
J ¼ 11.3 Hz, 1H), 3.08e2.92 (m, 2H), 2.68 (m, 3H), 2.38e2.26 (m, 1H),
1.98e1.82 (m, 2H), 1.72 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
To a stirred solution of an aldehyde 7 (0.40 g, 1.32 mmol) in
d
¼ 147.5, 147.4, 130.4, 126.0, 111.3, 108.9, 62.7, 56.0, 55.9, 53.1, 48.1,
CH3CN (12 mL) at 0 ꢁC were added dibenzyl azodicarboxylate
30.7, 27.7, 22.3 ppm; FTIR (thin film): 2925, 2854, 2791, 1737, 1611,
1512, 1464 cmꢀ1. HRMS (ESI-TOF) m/z: [M þ H]þ calcd. for
(DBAD), (0.43 g, 1.45 mmol) and D-proline (0.02 g, 0.13 mmol). The
reaction mixture was stirred for 2 h at 0 ꢁC and then at room
temperature for next 2 h. The reaction mixture was again cooled to
C14H20NO2 234.1494, found 234.1490.
0
ꢁC and the Wittig salt Ph3P]CHCO2Et (1.14 g, 3.30 mmol) in
Declaration of competing interest
CH2Cl2 (7 mL) was added and stirred for additional 3 h at room
temperature. The solvents were removed under reduced pressure
and the product was isolated by column chromatography (60:40
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.
petroleum ether/EtOAc) to get 18 as
a syrup (0.78g, 89%);
25
[
a
]
¼ þ16.8 (c 0.26, CH2Cl2); 1H NMR (400 MHz, DMSO‑d6, 80 ꢁC)
D
d
¼ 9.55 (s, 1H), 7.26 (s, 10H), 7.10e6.99 (m, 1H), 6.83 (s, 2H), 6.06 (s,
Acknowledgments
1H), 5.89 (s, 1H), 5.04 (d, J ¼ 42.8 Hz, 4H), 4.31 (d, J ¼ 30.9 Hz, 2H),
4.16e4.01 (m, 2H), 3.72 (d, J ¼ 17.2 Hz, 3H), 3.63 (s, 3H), 3.03 (s, 1H),
3.02e2.88 (m, 4H), 1.22e1.09 (m, 3H) ppm; 13C NMR (100 MHz,
We thank the Science and Engineering Research Board,
Department of Science and Technology India for funding this
project through EMR/2017/000414. We thank Prof. Manas K. Ghorai
for the chiral HPLC facility that was essential for the completion of
this work. A.A. thanks the Council of Scientific and Industrial
Research (India), New Delhi for a Senior Research Fellowship.
DMSO‑d6, rotamers)
d
¼ 165.9, 165.7, 157.3, 156.3, 155.5, 155.2, 149.1,
148.8, 148.4, 148.3, 147.5, 146.1, 146.0, 144.9, 136.9, 136.8, 136.7,
136.6, 129.6, 129.3, 128.9, 128.8, 128.4, 128.1, 127.8, 127.6, 123.6,
122.2, 114.2, 113.9, 111.6, 71.0, 70.8, 70.5, 67.7, 66.8, 66.1, 60.6, 56.3,
56.2, 56.1, 56.0, 55.9, 37.0, 37.0, 31.7, 31.4, 14.6 ppm; FTIR (thin film):
3311, 3063, 2958, 2935, 1713, 1519 cmꢀ1. HRMS (ESI-TOF) m/z:
[M þ NH4]þ calcd. for C33H42N3O11S 688.2540, found 688.2540;
HPLC (Cellulose-1 column, hexane: IPA ¼ 90:10, flow rate: 1 mL/
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132121.
min,
l
¼ 254 nm), tR major ¼ 59.1, tR minor ¼ 70.6, 93% ee.
References
4.18. (R)-8,9-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]
isoquinolin-3(2H)-one (19)
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was added Raney Ni (0.80 g, prewashed with absolute ethanol)
followed by 0.05 mL of acetic acid, and the mixture was stirred for
16 h at room temperature under a hydrogen atmosphere. The re-
action mixture was then filtered through a celite pad, and the so-
lution was concentrated under reduced pressure. The crude
product was dissolved in CH3OH (10 mL) and K2CO3 (0.24 g,
1.78 mmol) was added and the reaction mixture was refluxed for
10 h. The reaction mixture was filtered through celite pad and the
solvents were removed under reduced pressure and purified by
ꢀ
[2] A. Graulich, J. Scuvee-Moreau, L. Alleva, C. Lamy, O. Waroux, V. Seutin, J.-
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F. Liegeois, J. Med. Chem. 49 (2006) 7208e7214.
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6721e6739.
column chromatography (92:08 CH2Cl2/CH3OH) to get 19 as an oil
25
(0.17 g, 79%); [
a
]
¼ þ171.9 (c 0.32, CH2Cl2); 1H NMR (400 MHz,
D
[5] a) Z. Li, C.-J. Li, Org. Lett. 6 (2004) 4997e4999;
b) A.M. Taylor, S.L. Schreiber, Org. Lett. 8 (2006) 143e146;
c) W. Lin, S. Ma, Org. Chem. Front. 1 (2014) 338e346;
d) S.T. Sun, C.K. Li, P.E. Floreancig, H.X. Lou, L. Liu, Org. Lett. 17 (2015)
1684e1687;
CDCl3)
d
¼ 6.59 (s, 1H), 6.55 (s, 1H), 4.70 (t, J ¼ 7.8 Hz, 1H), 4.28 (m,
1H), 3.84 (s, 3H), 3.84 (s, 3H), 2.99 (m, 1H), 2.93e2.80 (m, 1H),
2.69e2.40 (m, 4H), 1.88e1.76 (m, 1H) ppm; 13C NMR (100 MHz,
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56.0, 37.1, 31.8, 28.1, 27.8 ppm; FTIR (thin film): 2927, 2853, 1680,
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8