Diversity-Oriented Approach Toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon

Article abstract of DOI:10.1021/acs.joc.8b01368

Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-)-maritidine, (-)-oxomaritidine, and

Full text of DOI:10.1021/acs.joc.8b01368

Subscriber access provided by UNIV OF NEW ENGLAND
Article
Diversity-oriented approach towards the syntheses of
amaryllidaceae alkaloids via a common chiral synthon
Prachi Verma, Atish Chandra, and Ganesh Pandey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01368 • Publication Date (Web): 13 Jul 2018
Downloaded from http://pubs.acs.org on July 15, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
Diversity
–
Oriented Approach Towards the Syntheses of Amaryllida-
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ceae Alkaloids via a Common Chiral Synthon
‡
‡
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Prachi Verma, Atish Chandra and Ganesh Pandey*
Molecular Synthesis and Drug Discovery Lab,
Centre of Biomedical Research, SGPGI Campus,
Raibarely Road, Lucknow- 226014, UP, India.
KEYWORDS: Amaryllidaceae alkaloids, natural product synthesis, all carbon quaternary stereocenter, conjugate addition.
ABSTRACT: Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize broad range of
Amaryllidaceae alkaloids (AA) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-
mesembrine, (-)-maritidine, (-)-oxomaritidine and (+)-mesembrane is reported.
Scaffold 1 is found as a prime structural motif in a wide variety of the AA’s and is a
novel synthon towards designing a divergent route for the synthesis of these natural
products. This is established in a few steps, starting from a chiral aza-bicyclo-
heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective
ring opening with allylmagnesium bromide, a key step that generates a crucial qua-
ternary stereocenter, fixing the stereochemistry of the rest of the molecule at an ear-
ly stage. One carbon truncation followed by intramolecular reductive amination led
to the desired core 1 in multi-gram scale.
Introduction
render an opportunity to access these natural products in ade-
quate amount enabling to explore their pharmacological prop-
erties.
The potential of alkaloids, in general, could be understood by
the fact that over one-third (35.9%) of the alkaloids which
have been examined biologically are pharmaceutically signifi-
1
cant. Many plants rich in alkaloids, are highly valued as these
are the sources of bioactive constituents that exist in trace
2
amounts and are hard to obtain for its commercial application.
Amaryllidaceae alkaloids (AA) are a class of structurally di-
verse and biologically active natural products with distinctly
important pharmacological activities exhibited by its constitu-
3
ent members such as anticancer, acetylcholinesterase (AChE)
inhibitory activity, anti-malarial, antimicrobials, antidepres-
4
sants. Hydrobromide salt of galantamine, an Amaryllidaceae
alkaloid marketed as Reminyl is a potent drug for the treatment
of mild to moderately severe dementia of the Alzheimer type,
which produces beneficial effects even after the drug treatment
5
has been withdrawn. In the past few decades, Amaryllidaceae
alkaloids have attracted remarkable attention from the synthet-
ic community, and extensive efforts have been made towards
the total and formal syntheses of these classes of fascinating
6-8
molecules. Although a large number of synthetic approaches
have been reported, a unified and divergent stereospecific
approach with viability on a gram scale synthesis still repre-
sents an attractive goal. Therefore, while planning a conceptu-
ally new synthetic route, we envisioned a common chiral
synthon that could be transformed into array of desired natural
products of the Amaryllidaceae family. The evolution of scal-
able synthetic route to chiral hydroindole core, embedded in
the structure of numerous Amaryllidaceae alkaloids, would
Figure 1 Amaryllidaceae alkaloids with the hydroindole core.
In previous literature reports, dearomatization using inter- /
intra-molecular phenolic oxidative coupling of derived phe-
nols followed by aza-Michael addition reactions, have been
9
the vastly exploited approach to build these natural products.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
The quaternary stereocenter with an aromatic substituent pre-
sent on the ring junction is the characteristic feature common
boronic acid, 3-Formylphenyl boronic acid and phenyl boronic
acid) using 5 mol% Pd(OAc) , 10 mol% (o-Tol) P, 2 equiv.
Ag CO , CH CN, at 80 °C affording aryl-substituted-7-aza-
bicyclic heptenesulfone in excellent yield (Scheme 2).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
7
b,10
to all the targeted AA with the hydroindole core.
Reports
2
3
3
on the enantioselective building of the quaternary center usual-
ly involves either enantioselective intramolecular desymmetri-
9
b,11
zation , asymmetric alkylations, enantioselective Michael
addition or metal catalyzed asymmetric cross coupling reac-
Boc
N
Boc
N
Boc
N
1
1–13
O
OTf
Ar
Ts
tions.
Some linear lengthy approaches towards the total
a
b
syntheses for mentioned AA’s (Fig. 1) are also present; they
14–15
Ts
Ts
are target-oriented
with little emphasis on the preparation
2
13
11A/B/C/D
of diverse molecular skeletons from a common intermedi-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10f,13e,16
ate.
Herein, we report an efficient unified strategy to-
O
wards the scalable, asymmetric synthesis of numerous AA
with the hydroindole core and 5,10b ethanophenanthridine
skeleton.
H
Ar=
OMe
O
O
O
Results and discussion
OMe
O
Based upon our previous experiences of building natural prod-
A
B
C
D
17
ucts utilizing the chiral ketone scaffold 2 , we sought to ex-
ploit it to design a retrosynthetic route to common divergent
intermediate 1 which is outlined in Scheme 1. We planned to
build the requisite hydroindole moiety from selective ring
opening of aryl substituted sterically congested 7-azabicyclo
heptenesulfone followed by an intramolecular amination reac-
tion. The strained bicyclic framework plays an interesting role
in controlling the stereoselectivity by allowing the nucleophile
to attack only from the exo- face while blocking the endo-
Scheme 2 Installation of desired aromatic fragment. a) NaH,
Tf O, Et O, 0 °C b) ArB(OH) , Pd(OAc) , P(o-tol) , Ag CO
CH CN, 80 °C, 66% (2 steps)
2
2
2
2
3
2
3
,
3
The crucial conjugate addition and simultaneous ring opening
by a nucleophile at trisubstituted electrophilic center on a
structurally rigid bicyclic framework was yet another major
17
21
face. This reaction serves as a boon for the synthetic design
goal to be achieved (Scheme 3). Our primary aim was to
as it fixes the stereochemistry of the crucial quaternary center
in the early stages of the synthesis. Furthermore, the stereo-
chemistry of the quaternary center serves as the handle for the
rest of the stereocenters present in the molecular framework.
Potentially general Suzuki conditions were screened and de-
veloped that facilitated the installation of different aromatic
fragment merely by changing the boronic acids so that natural
products with variable aromatic fragments at the hydroindole
ring junction could be targeted at the same time.
construct fused pyrolidine ring system with an aromatic sub-
stituent on the ring junction. Therefore, we chose vinylmagne-
sium bromide at first as a nucleophile for the conjugate addi-
tion.
Boc
N
Ts
Ar
R
Ar=
Ar
Ts
a
OMe
O
OMe
O
BocHN
Ar-A = 3,4-dimethoxy phenyl
Ar-B = 3,4-dioxomethylene phenyl
1
1A/B
12A/B
Ts
Ts
Boc
N
Boc
N
Ar
Nu
Ar
N
H
Boc
Ts
Boc
Ar
Ts
O
N
N
N
R
Ar
R
R
Ar
Ts
Ar
HN
Ar
Ts
Boc
Boc
BocHN
Ts
1A/B
12A/B
11A/B
2
14
15
16
17
Observed byproducts during the course of optimizations
Scheme 1 Retrosynthetic plan for the chiral common synthon.
Synthesis of Common Chiral Synthon (1)
Scheme 3 Preparation of 12A/B a) AllylMgBr, NHC-3 (1,3-
bis(2,4,6-trimethylphenyl)imidazolium chloride), Cu(OTf)
Et O, -7 °C, 95%. R = Allyl.
Our studies commenced from the preparation of both enantio-
mers of the chiral scaffold 2, which is available in 6 steps
starting from TMS acetylene in 100 g scale via the strategy of
2
,
2
1
8
desymmetrization developed in our laboratory. The Suzuki
Several reaction conditions in the initial phases of optimiza-
tion (Table 1), by varying catalyst, solvents at several different
temperatures, unfortunately gave decomposition products (14-
1
9
coupling of the enol triflate of the 7-aza-bicyclic heptenesul-
fone 2 was a strenuous task to be accomplished. The challeng-
es were due to i) the instability of the enol triflate ii) the tosyl
group present in the substrate acts as a poison to the palladium
1
7) or recovery of the starting material.
2
0
Later in a trial attempt with methylmagnesium bromide and
copper triflate, we observed ring opening with a series of by-
products forming simultaneously exacerbating the difficulties.
Nevertheless, this was a major clue that encouraged us to op-
timize the reaction condition and we changed nucleophile to
allyl magnesium bromide and did thorough screening of sev-
eral catalyst-solvent systems.
catalyst resulting in its low catalysis efficiency . Upon screen-
ing several bases and reaction conditions, to our surprise the
reaction proceeded magnificently with silver carbonate as a
base and acetonitrile as a solvent. The enol triflate 13 was
prepared and used immediately for further carrying out the
coupling reaction. Having optimized conditions in hand, the
reaction was carried out with several boronic acids (3,4- di-
methoxy phenyl boronic acid, 3,4-Methylenedioxy phenyl
ACS Paragon Plus Environment

Page 3 of 11
The Journal of Organic Chemistry
Total Synthesis of (-)-Crinine, (-)-Crinane and (-)-
After optimized conditions in hand using allylmagnesium
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bromide (1.5 equiv.) in the presence of copper triflate (0.3%),
NHC-3 (1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride),
0.5%) in diethyl ether at -7 °C afforded 12 A and 12 B in 95%
yield. The reaction was optimized up to the scale of 15.0
grams that enabled us to make these alkaloids on gram scale.
Amabiline from 1B
The bicyclic core 1B synthesized from (-)-2 represents a ver-
satile precursor for many of the Amaryllidaceae alkaloids in-
cluding, the structurally complex dinitrogenous pentacyclic
cage like alkaloid (-)-gracilamine which was synthesized in 6
1
7
steps from this advanced intermediate. Alkaloids (-)-crinine
(3) and (-)-amabiline (4) were synthesized from 1B via N-Boc
deprotection followed by Pictet-Spengler type cyclization us-
ing formic acid and paraformaldehyde, obtaining 19 in high
2
2
yield (95%). The detosylation of 19 with sodium amalgam
led to the formation of 20, which on allylic oxidation with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
SeO
2
gave (-)-3 in 80% yield. The dihydroxylation of the
and NMO gave (-)-4 (76%). These exceed-
same using OsO
4
ingly simple conditions effectively helped us to accomplish
the task of synthesizing these two natural products in respect-
able yields (Scheme 5).
O
O
Ts
Ts
O
O
a,b
c
N
N
Boc
1B
19
Table 1 Optimization table for the ring opening reaction.
OH
O
O
The exo-attack of the nucleophile to α, β-unsaturated double
bond of the rigid 7-azabicyclic system guaranteed stereoselec-
tivity and the formation of the undesired isomer was not at all
observed during the course of reaction. Time played an im-
portant role in controlling this reaction. For example, if the
reaction was allowed to stir for more than 10 minutes, it led to
the formation of many undesired products including the di
allylated one (16). Further transformations of 12 A/B to 1 A/B
involved oxidative cleavage of one carbon of the olefinic moi-
d
N
3
O
O
OH
N
HO
e
20
O
O
N
4
4 4
ety, using OsO / NaIO followed by the reductive amination
Scheme 5 Total synthesis of (-)-crinine (3) and (-)-amabiline
under acidic conditions using sodium cyanoborohydride,
which gave desired hydroindole core in 71% yields as shown
in Scheme 4. These chiral common synthons were successful-
ly exploited towards the synthesis of various AA, testifying
the robustness of our designed synthetic plan on a multigram
scale.
o
(
9
8
4) (a) TFA, CH
2
Cl
5% (2 steps); (c) Na-Hg, B(OH)
4%; (d) SeO , NaHCO , Dioxane, 102 C, 16 h, 80%; (e)
, NMO, Acetone: H O (9:1), 6 h, 76%. TFA = Trifluoro-
2
, 0 C, 6 h; (b) (HCHO)
n
, TFA, reflux,
3
, THF:MeOH (1:1), rt, 2 h
o
2
3
OsO
4
2
acetic acid, NMO = N-Methyl morpholine N-Oxide.
With 19 in hand, the synthesis of (-)-crinane (10) became ex-
tremely effortless (Scheme 6) where the advance intermediate
19 was subjected to detosylation with excess sodium amal-
gam, which removed the tosyl group and simultaneously led to
reduction of the double bond quantitatively and yielded (-)-10
(85%).
Ts
Ts
Boc
Ar
NH
Ar
Ar
Ts
a
b
O
HN
N
Boc
8A/B
Boc
1A/B
12A/B
1
Ts
Na-Hg,
THF:MeOH (1:1),
O
O
rt, 12 h
O
O
N
85%
N
Ar=
OMe
O
OMe
O
19
10
Ar-A = 3,4-dimethoxy phenyl
Ar-B = 3,4-dioxomethylene phenyl
Scheme 4 Preparation of a common chiral synthon 1A/B a)
OsO NaIO Acetone:Water (1:1) then NaCNBH
THF:AcOH (9:1), 25 °C, 71%.
Scheme 6 Total synthesis of (-)-crinane (10) a) Na-Hg,
THF:MeOH (1:1), rt, 12 h 85%.
4
,
4
,
3
,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 11
Synthesis of (+)-Mesembrine and (+)-Mesembrane
Synthesis of (-)-Maritidine and (-)-Oxomaritidine from
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
A
In an initial demonstration of the utility of 1A prepared from
the chiral ketone scaffold 2, we attempted the total synthesis
of (+)-mesembrine and (+)-mesembrane. Thus, we started the
synthesis from detosylation of “synthon” 1A followed by al-
lylic oxidation with selenium dioxide, which gave intermedi-
ate 21 (80% over two steps). We attempted to reduce the ole-
finic double bond in 21 by subjecting it to Pd-C hydrogena-
tion, which unfortunately removed the hydroxyl group. There-
fore, an alternative strategy using Raney-Nickel for hydro-
genation, resulted in clean hydrogenation product, which on
To begin with the synthesis of (-)-maritidine (6), advance in-
termediate 1A was subjected to N-Boc deprotection using TFA
followed by Pictet Spengler type cyclization resulting in the
formation of required 5,10b ethanophenanthridine skeleton 24
in excellent yields (86%). Detosylation using sodium amalgam
yielded 25, which on allylic oxidation with selenium dioxide
accomplished the synthesis of (-)-maritidine (Scheme 9). The
allylic alcohol in (-)-6 was oxidised using DMP to obtain (-)-
oxomaritidine (7) in respectable yield (98%).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
DMP oxidation furnished 22 (85% over two steps). The only
task remained to accomplish the synthesis was the introduction
of the N-methyl group in the molecular framework. The N-Boc
deprotection and N-methylation using a formalin solution and
sodium cyanoborohydride in acetonitrile, maintaining the high
dilution, gave (+)-mesembrine in 80% yield over two steps as
outlined in Scheme 7.
MeO
OMe
Ts
Ts
a, b
MeO
MeO
c
MeO
MeO
N
N
N
Boc
1
A
24
25
MeO
OMe
MeO
MeO
OMe
OH
O
OMe
MeO
MeO
e
MeO
MeO
Ts
d
N
N
a, b
c, d
6
7
OH
O
N
N
N
Scheme 9 Total synthesis of (-)-maritidine (6) and (-)-
Boc
Boc
Boc
o
oxomaritidine (7) (a) TFA, CH
TFA, reflux, 86% (2 steps); (c) Na-Hg, B(OH)
1:1), rt, 2 h 84%; (d) SeO , NaHCO , Dioxane, 102 C, 16 h,
, 0 C, 1 h, 98%. TFA = Trifluoroacetic
2
Cl
2
, 0 C, 6 h; (b) (HCHO)n,
1A
21
22
3
, THF:MeOH
MeO
OMe
o
(
8
2
3
o
2 2
0%; (e) DMP CH Cl
e, f
acid, DMP = Dess-Martin periodinane.
O
Conclusions
N
We have accomplished the enantioselective total syntheses of
seven biologically active natural products on a gram scale
through a unified strategy. Analytical data for the synthesized
natural product matched perfectly with the previous reported
data of the natural products. Our studies unambiguously en-
courage and set a platform for the synthesis of a broad range
of congeners of this class which could allow in-depth studies
towards their pharmaceutical applications.
5
Scheme 7 Total synthesis of (+)-Mesembrine (5). (a) Na-Hg,
B(OH) , THF:MeOH (1:1), rt, 2 h; (b) SeO , NaHCO , Diox-
ane, 102 C, 16 h, 80% (2 steps); (c) Raney Ni, H , EtOH 65
, 0 C, 1 h, 85% (2 steps); (e) TFA,
3
, 0 C, 8 h; (f) HCHO (35%) w/w aq. sol. NaCNBH ,
3
2
3
o
2
o
o
2 2
C 2 h. (d) DMP CH Cl
o
CH
2
Cl
2
o
25 C, 10 min., 80% (2 steps). TFA = Trifluoroacetic acid
DMP = Dess-Martin periodinane.
To complete the synthesis of (+)-mesembrane (8), 1A was
subjected to desulfonylation using excess of sodium amalgam
without boric acid which simultaneously reduced the double
EXPERIMENTAL SECTION
General Procedure. All moisture-sensitive reactions were
performed under an atmosphere of argon and glassware was
dried in an oven at 125 °C prior to use. Dry tetrahydrofuran
25
bond via Boveault Blanc type reduction to furnish 23 in 85%
yield. Similar protocol for N-methylation were followed as in
the case of mesembrine to yield 8 in excellent yields (Scheme
8).
2
(THF) and diethyl ether (Et O) were obtained by passing
commercially available pre-dried, oxygen free formulations
through activated alumina columns and dried by distillation
over sodium/benzophenone. Toluene and benzene were dis-
tilled over calcium hydride and stored over 4Å molecular
MeO
OMe
Ts
MeO
OMe
MeO
OMe
3
sieves. Pyridine and triethylamine (Et N) were distilled over
a
b, c
potassium hydroxide. Solvents used for chromatography were
distilled at respective boiling points using known procedures.
Reactions were monitored by thin layer chromatography
N
N
N
Boc
Boc
(
TLC, 0.25 mm, 60F254) and visualized by using UV light,
ethanolic solution of phosphomolybdic acid (PMA), iodine,
ninhydrin and KMnO solution. Column chromatography was
1A
23
8
Scheme 8 Total synthesis of (+)-Mesembrane (8) (a) Na-Hg,
4
o
THF:MeOH (1:1), rt, 12 h 85%; (b) TFA, CH
2
Cl
2
, 0 C, 8 h;
performed on silica gel 60-120/100-200/ 230-400 mesh. Typi-
cal syringe and cannula techniques were used to transfer air
and moisture sensitive reagents. IR spectra were recorded on a
Perkin-Elmer FT-IR Spectrometer. 1H NMR spectra were
recorded on BRUKER 400 UltraShield, BRUKER AC-600
o
(c) HCHO (35%) w/w aq. sol. NaCNBH
2 steps). TFA = Trifluoroacetic acid.
3
, 25 C, 10 min., 85%
(
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
138.2, 134.3, 129.7, 127.5, 123.0, 122.6, 119.1, 113.3, 111.5,
and BRUKER 800 ULTRASHIELD PLUS instruments using
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
deuterated chloroform as standard. Chemical shifts are report-
ed in ppm. Proton coupling constants (J) are reported as abso-
lute values in Hz and multiplicity (bs, broadened; s, singlet; d,
doublet; t, triplet; dd, doublet of doublet; dt, doublet of triplet;
td, triplet of doublet; qd, quartet of doublet; dq, doublet of
110.5, 110.4, 80.8, 64.4, 56.2, 56.1, 56.0, 28.0, 21.6. HRMS
+
+
(m/z): [M + Na] calcd for C26H31NNaSO
6
508.1764, found
508.1753.
Tert-butyl
(1R,4S)-2-phenyl-3-tosyl-7-
azabicyclo[2.2.1]hept-2-ene-7-carboxylate (11C): TLC R
=0.5 (EtOAc:Hexane = 3:7, ninhydrin). IR (film): νmax =
f
1
3
quartet; dt, doublet of triplet; p, pentet; m, multiplet).
NMR spectra were recorded on BRUKER 400 UltraShield,
BRUKER 600 UltraShield and BRUKER 800
ULTRASHIELD PLUS instruments operating at 101 MHz,
C
1
1
3
2977, 1709, 1491, 1257, cm− . H NMR (400 MHz, CDCl ) δ
7.68 (d, J = 8.4 Hz, 2H), 7.53 – 7.51 (m, 2H), 7.39 – 7.37 (m,
3H), 7.26 – 7.23 (m, 2H), 4.96 – 4.92 (m, 2H), 2.38 (s, 3H),
13
1
50 MHz and 201 MHz respectively. C NMR chemical
2.12 – 2.04 (m, 2H), 1.70 (m, 1H), 1.55 (s, 1H), 1.46 – 1.42
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
shifts are reported in ppm relative to the central line of CDCl
3
(m, 1H), 1.29 – 1.24 (m, 9H). C NMR (101 MHz, CDCl
3
) δ
(δ = 77.16). Due to presence of N-Boc protecting group some
of the spectra are showing rotameric nmr signals. Electro
spray ionization (ESI) mass spectrometry (MS) experiments
were performed on Agilent Technologies 6530Accurate-Mass
Q-TOF LC/MS. Optical rotations were measured on a Digipol
155.2, 144.5, 138.1, 130.5, 129.9, 129.8, 129.4, 128.2, 127.8,
+
80.9, 77.1, 67.7, 64.2, 28.1, 21.7. HRMS (m/z): [M + Na]
+
calcd for C24
H27NNaO
4
S 448.1553, found 448.1495.
Tert-butyl (1R,4S)-2-(6-formylbenzo[d][1,3]dioxol-5-yl)-3-
tosyl-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate (11D),
TLC R =0.5 (EtOAc:Hexane = 1:1, ninhydrin). IR (film):
νmax = 2977, 1709, 1491, 1257, cm− . H NMR (400 MHz,
CDCl ) δ 9.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H),
7
81 M6U Automatic Polarimeter. HPLC were performed on
f
1
1
Agilent Technologies 1260 Infinity.
Preparation of tert-butyl (1R,4S)-2-(benzo[d][1,3]dioxol-5-
yl)-3-tosyl-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate
3
7.26 – 7.24 (m, 2H), 6.66 (s, 1H), 6.08 (d, J = 1.6 Hz, 2H),
(11B) To a suspension of sodium hydride (0.164 g, 4.1 mmol)
4.98 (s, 1H), 4.74 (s, 1H), 2.38 (s, 3H), 2.19 – 2.05 (m, 2H),
13
in diethylether (20 mL), taken in a two neck jacketed flask
equipped with argon inlet and circulatory chiller at -10 ºC, was
added a solution of 2 (1.0 g, 2.74 mmol) in 10 mL diethylether
and stirred for 1.5 hour. Temperature was raised to -3 ºC and
triflic anhydride (0.69 mL, 4.1 mmol) was added. The solution
was stirred for 1 hour, quenched with water (10 mL), extracted
with ethyl acetate (3X10 mL), dried over sodium sulfate, con-
centrated under vacuum to obtain crude enol triflate as a semi
solid residue.
1.75 – 1.69 (m, 1H), 1.52 – 1.46 (m, 1H), 1.27 (s, 9H).
NMR (101 MHz, CDCl
C
3
) δ 188.4, 152.2, 149.3, 145.1, 137.2,
130.0, 129.4, 128.0, 111.3, 106.9, 102.6, 81.5, 68.9, 63.4,
+
53.5, 27.9, 21.7. HRMS (m/z): [M + Na] calcd for
+
C
26
H27NNaO
7
S 520.1400, found 520.1455.
Preparation
of
tert-butyl
((1R,2S)-2-allyl-2-
(benzo[d][1,3]dioxol-5-yl)-3-tosylcyclohex-3-en-1-
yl)carbamate (12B) Copper triflate (0.035 g, 0.095 mmol)
and
1,3-bis(2,4,6-trimethylphenyl)imidazolium
chloride
The solution of enol triflate in acetonitrile (15 mL) was added
(0.435 g, 0.127 mmol) were taken in a dried two neck jacketed
flask equipped with argon balloon and magnetic stir bar. It
was evacuated under high vacuum for 15 minutes and flushed
with argon, diluted with 10 mL diethyl ether. The suspension
was cooled to -7 ºC and allylmagnesium bromide (0.8 M, 7.99
mL) was added. After 10 minutes, solution of 11B (1.5 g, 3.19
mmol) in 3 mL dichloromethane was added and stirred for
additional 10 minutes. The reaction mixture was quenched
with aqueous solution of ammonium chloride (10 mL), ex-
tracted with ethyl acetate (3 X10 mL), dried over sodium sul-
fate, concentrated under vacuum and purified by chromatog-
raphy on silica gel (30% EtOAc/Hexane) to obtain 12B (1.54
3
,4-methylenedioxyphenyl boronic acid (0.448 g, 2.7 mmol),
Pd(OAc) (0.03 g, 0.135 mmol), tri-o-tolyl phosphine (0.082
2
g, 0.27 mmol) and silver carbonate (0.798 g, 2.9 mmol) and
the reaction mixture was stirred at 80 ºC for 3 h. The progress
of reaction was monitored by TLC. After completion, it was
concentrated under vacuum and purified by chromatography
on silica gel (15% EtOAc/Hexane) to obtain 11B (0.85 g,
6
f
6%) as a semisolid. TLC R =0.6 (EtOAc:Hexane = 1:3, nin-
1
1
hydrin). IR (film): νmax = 2922, 1706, 1486, 1153, cm− . H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.25 (d, J
=
8.0 Hz, 2H), 7.08 (m, 2H), 6.82 (d, J = 8.8, Hz, 1H), 5.99 (s,
2
1
1
H), 4. 92 (m, 2H), 2.39 (s, 3H), 2.08 (m, 2H), 1.67 (m, 1H),
g, 95%) in solid form (mp 160.4–162.00 °C). TLC R
f
=0.4
13
.40 (m, 1H), 1.28 (s, 9H). C NMR (101 MHz, CDCl
3
) δ
(EtOAc:Hexane = 1:3, ninhydrin). IR (film): νmax = 2920,
1
1
55.2, 149.2, 147.5, 144.4, 138.1, 129.8, 127.7, 124.4, 123.9,
3
1698, 1488, 1040 cm− . H NMR (400 MHz, CDCl ) δ 7.42
110.0, 108.2, 101.6, 80.9, 67.6, 64.3, 28.0, 21.6. HRMS (m/z):
(bs, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H),
6.64 (d, J = 7.2 Hz, 1H), 6.46 (bs, 2H), 5.98 – 5.96 (m, 1H),
5.76 (d, J = 22.4 Hz, 2H), 5.19 (d, J = 17.2 Hz, 1H), 5.10 (d, J
= 10.4 Hz, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.11 – 4.07 (m, 1H),
3.24 – 3.05 (m, 2H), 2.50 (bs, 2H), 2.35 (s, 3H), 1.95 (m, 1H),
+
+
[M + Na] calcd for C25
H27NNaO
6
S
492.1451, found
492.1455. [α]D²² = +147.2° (c = 2.5, MeOH). Note: 11A, 11C
and 11D were also prepared by using exactly the same proce-
dure by using 3,4-dimethoxy phenyl boronic acid, phenyl bo-
ronic acid and 3-formylphenylboronic acid, respectively (da-
ta’s attached).
1
3
1.71 (bs, 1H), 1.21 (d, J = 53.2 Hz, 9H). C NMR (101 MHz,
CDCl ) δ 155.0, 147.3, 146.5, 146.2, 143.6, 143.5, 139.3,
36.4, 135.0, 129.5, 127.6, 122.1, 118.2, 109.5, 107.4, 101.2,
79.7, 57.2, 49.5, 38.5, 28.5, 25.3, 21.9. HRMS (m/z): [M +
3
1
Tert-butyl
azabicyclo[2.2.1]hept-2-ene-7-carboxylate (11A): TLC
=0.5 (EtOAc:Hexane = 3:7, ninhydrin). IR (film): νmax =
(1R,4S)-2-(3,4-dimethoxyphenyl)-3-tosyl-7-
+
+
6
Na] calcd for C28H33NNaO S 534.1921, found 534.1924.
R
f
[α]D²² = -5.6° (c = 5, MeOH). Note: 12A was also prepared by
using exactly the same procedure starting with 11A.
−1
1
3
2942, 1650, 1506, 1151 cm . H NMR (400 MHz, CDCl ) δ
7.70 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 2.0 Hz, 1H), 7.25 (dd, J =
6.7, 4.0 Hz, 3H), 6.86 (d, J = 8.4 Hz, 1H), 4.98 (bs, 1H), 4.93
Tert-butyl ((1S,2R)-1-allyl-3',4'-dimethoxy-6-tosyl-1,2,3,4-
(
–
bs, 1H), 3.91 (s, 6H), 2.38 (s, 3H), 2.09 – 2.07 (m, 2H), 1.71
tetrahydro-[1,1'-biphenyl]-2-yl)carbamate (12A) TLC R
=0.5 (EtOAc:Hexane = 2:3, ninhydrin). IR (film): νmax =
f
1
3
1.67 (m, 1H), 1.27 (m, 1H), 1.22 (s, 9H). C NMR (101
) δ 155.1, 150.7, 149.1, 148.4, 148.3, 144.4,
−1 1
MHz, CDCl
3
3
2934, 1706, 1518, 1257 cm . H NMR (400 MHz, CDCl ) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
.38 (s, 1H), 7.18 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H),
Page 6 of 11
7
110.3, 79.5, 77.1, 66.8, 60.5, 55.8, 55.2, 51.7, 50.7, 44.8, 44.5,
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6.79 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.48 (s, 1H), 6.02 (m,
1H), 5.18 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10.0 Hz, 1H), 4.63
(d, J = 10.0 Hz, 1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.57 (s, 3H),
33.1, 32.4, 28.5, 24.3, 21.4. HRMS (m/z): [M + Na] calcd for
+
C
28
H35NNaO
6
S 536.2077, found 536.2068.
3
3
.30 (m, 1H), 3.08 (m, 1H), 2.54 (d, J = 2.8 Hz, 2H), 2.35 (s,
Preparation of (5S,11bS)-1-tosyl-4,4a-dihydro-3H,6H-
5,11b-ethano[1,3]dioxolo[4,5-j]phenanthridine (19): A solu-
tion of 1B (3 g, 6.03 mmol) in 100 mL dichloromethane was
taken in a round bottom flask equipped with magnetic stir bar
under argon atmosphere. The reaction mixture was cooled to 0
°C and trifluoroacetic acid (0.461 mL, 6.03 mmol) was added
slowly. The solution was stirred for 6 hours. After the comple-
tion, the reaction mixture was quenched with saturated solu-
1
3
H), 2.06 – 1.89 (m, 1H), 1.76 (m, 1H), 1.23 (s, 9H). C NMR
) δ 154.9, 147.9, 147.0, 146.4, 143.2, 142.8,
(101 MHz, CDCl
3
1
5
38.8, 133.8, 132.1, 129.1, 127.2, 121.4, 118.3, 111.7, 109.9,
5.8, 55.2, 49.1, 38.8, 29.7, 28.2, 24.9, 24.7, 21.5. HRMS
+
+
(m/z): [M + Na] calcd for C29
H37NNaSO
6
550.2234, found
5
50.2235.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Preparation
of
tert-butyl
(3aS,7aR)-3a-
3
tion of NaHCO (50 mL) and allowed to stir for another 1 hour
(benzo[d][1,3]dioxol-5-yl)-4-tosyl-2,3,3a,6,7,7a-hexahydro-
until the bubbling ceased. The organic layer was extracted
with dichloromethane (3X50 mL), dried over sodium sulfate
and concentrated under vacuum to obtain N-Boc deprotected
material as a white solid residue.
1
H-indole-1-carboxylate (1B) To a solution of 12B (1.25 g,
2
.44 mmol) in dioxane-water (9:3, 12 mL) was added 2,6-
lutidine (0.567 mL, 4.8 mmol), OsO
g, 0.048 mmol), and NaIO (2.1 gm, 9.75 mmol). The reaction
mixture was stirred at 25 °C and progress was monitored by
TLC. After the reaction was completed, water (10 mL) and
4
(2.5% in t-butanol, 0.495
4
The crude N-Boc deprotected material was dissolved in tri-
fluoroacetic acid (50 mL) under argon atmosphere and para-
formaldehyde (0.27 g, 9.0 mmol) was added. The reaction
mixture was heated at 85 °C on an oil bath for 12 hours. The
progress of the reaction was monitored by TLC. After comple-
tion, the reaction mixture was neutralized by adding saturated
solution of NaHCO very slowly until the bubbling ceased.
3
The organic layer was extracted with dichloromethane (3X50
mL), concentrated under vacuum and purified by chromatog-
CH
2
Cl
2
(30 mL) were added to it. The organic layer was sepa-
Cl (3X15
rated, and the water layer was extracted by CH
2
2
mL). The combined organic layer was washed with brine (15
mL) and dried over sodium sulfate. The solvent was removed
under vacuum to obtain a crude residue which was dissolved
in 20 mL AcOH:THF (1:9) and sodium cyanoborohydride
(0.283 g, 4.5 mmol) was added. The reaction mixture was
stirred at room temperature for 12 hours, neutralized with satu-
rated sodium bicarbonate solution (7 mL), washed with brine
solution (10 mL) and extracted with ethyl acetate (3X10 mL).
Solvent was evaporated under vacuum and crude residue was
purified by chromatography on silica gel (25%
EtOAc/Hexane) to obtain 1B (0.865 g, 71%) as white amor-
raphy on silica gel (5% MeOH/CH
2
Cl
2
) to obtain 19 (2.33 g,
95%) as a solid (mp 155.5-156.2 °C).
1
TLC R
f
= 0.5 (MeOH:CH
2
Cl
2
= 1:9, ninhydrin). H NMR (400
MHz, CDCl
3
) δ 7.79 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.34 (d,
J = 8.0 Hz, 2H), 6.69 (d, J = 6.8 Hz, 1H), 6.51 (s, 1H), 5.93 (d,
J = 6.4 Hz, 2H), 4.86 (d, J = 16 Hz, 1H), 4.25 (d, J = 16.4 Hz,
1H) 3.97 (m, 1H), 3.78 (d, J = 12.4 Hz, 1H), 3.42 (m, 1H),
phous solid (mp 239.8–241.2 °C). TLC
R
f
=0.5
(EtOAc:Hexane = 2:3, ninhydrin). IR (film): νmax = 2920,
−1 1
3
2
.16 – 3.09 (m, 1H), 2.51 – 2.47 (m, 1H), 2.44 (s, 3H), 2.33 –
1681, 1643, 1400 cm . H NMR (400 MHz, CDCl
1H), 7.17 – 7.12 (m, 2H), 6.98 (d, J = 6.9 Hz, 2H), 6.62 (d, J =
3
) δ 7.38 (s,
1
3
.19 (m, 3H), 1.40 – 1.31 (m, 1H) ppm. C NMR (101 MHz,
) δ 147.4, 147.1, 145.0, 143.8, 139.5, 135.4, 130.3,
27.6, 118.8, 107.9, 106.6, 101.7, 70.6, 59.0, 51.9, 50.1, 39.9,
9.7, 24.3, 21.6, 21.1 ppm. IR (film): νmax = 2924, 1596,
CDCl
3
6
1
7
2
=
.0 Hz, 1H), 6.45 (t, J = 8.0 Hz, 1H), 6.25 (d, J = 24.0 Hz,
H), 5.82 – 5.73 (m, 2H), 3.93 (d, J = 7.6 Hz, 1H), 3.79 (d, J =
.6 Hz, 1H), 3.47 – 3.35 (m, 2H), 3.16 – 3.05 (m, 1H), 2.53 –
.42 (m, 3H), 2.31 (s, 3H), 2.20 (d, J = 9.6 Hz, 1H), 2.03 (d, J
9.2 Hz, 1H), 1.64 (m, 1H), 1.33 (d, J = 10.4 Hz, 9H).
) δ 154.4, 147.7, 147.3, 146.9, 143.0,
42.3, 139.1, 133.9, 129.2, 127.4, 121.3, 121.1, 109.1, 108.7,
07.9, 107.8, 101.3, 79.8, 67.3, 52.1, 51.2, 45.0, 44.7, 33.5,
1
2
1
C
=
-1
+
383, 1240, 1077 cm . HRMS (m/z): [M + H] calcd for
+
1
3
23
H24NO
4
S 410.1421, found 410.1411. [α]D²² = -217.75° (c
C
0.4, EtOH).
NMR (101 MHz, CDCl
1
1
3
Preparation
of
(5S,11bS)-4,4a-dihydro-3H,6H-5,11b-
+
ethano[1,3]dioxolo[4,5-j]phenanthridine (20): To a stirring
solution of boric acid (1.50 g, 24.4 mmol) in anhydrous meth-
anol (50 mL) was added a solution of 19 (2.0 g, 4.88 mmol) in
32.8, 28.7, 24.9, 24.6, 24.4, 21.8. HRMS (m/z): [M + Na]
calcd for C27H31NNaO S 520.1764, found 520.1771. [α]D²² =
6
-188.9° (c = 1.25, MeOH). Note: 1A was also prepared by
using exactly the same procedure starting with 12A (data at-
tached).
+
5
0 mL THF. The reaction mixture was stirred at room temper-
ature and sodium amalgam (3.50 g, 7%) was added four times
portion wise in 10 min interval while stirring at ambient tem-
perature. The reaction mixture was allowed to stir for addi-
tional 2 hours. The progress of the reaction was monitored by
TLC and after the completion of the reaction, water (30 mL)
was added dropwise, extracted with dichloromethane (3X50
mL). The combined organic layer was washed with brine (5
mL) and dried over sodium sulfate. Solvent was evaporated to
give colorless sticky liquid which was purified by chromatog-
Tert-butyl(3aS,7aR)-3a-(3,4-dimethoxyphenyl)-4-tosyl-
2
,3,3a, 6,7,7a-hexahydro-1H-indole-1-carboxylate (1A):
TLC R =0.5 (EtOAc:Hexane = 1:1, ninhydrin). IR (film):
f
−1
1
νmax = 2921, 1597, 1516, 1386, 1143 cm . H NMR (400
MHz, CDCl3) δ 7.38 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.05
(d, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 2H), 6.70 (d, J = 8.4
Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 27.6 Hz, 1H),
raphy on silica gel (5% MeOH/CH
4%) as a sticky material. TLC R =0.4 (MeOH:CH
ninhydrin). IR (film): νmax = 3021, 2916, 1383, 1115 cm . H
NMR (400 MHz, CDCl ) δ 6.82 (s, 1H), 6.48 (s, 1H), 6.32 (d,
J = 10.0 Hz, 1H), 5.88 (dd, J = 6.2 Hz, 1.2 Hz, 2H), 5.80 –
2
Cl
2
) to obtain 20 (1.04 g,
3
5
2
9
1
.99 (dd, J = 10.6, 4.0 Hz, 1H), 3.80 (s, 3H), 3.63 – 3.38 (m,
H), 3.23 – 3.12 (m, 1H), 2.55 – 2.44 (m, 3H), 2.30 (s, 3H),
.22 – 2.01 (m, 1H), 1.74 – 1.65 (m, 1H), 1.33 (d, J = 13.7 Hz,
H). C NMR (101 MHz, CDCl
47.1, 142.9, 141.9, 138.9, 131.9, 128.8, 127.1, 120.1, 111.0,
8
f
2
Cl = 1:9,
2
−
1 1
1
3
) δ 154.1, 148.1, 147.4,
3
3
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
5
.77 (m, 1H), 4.45 (d, J = 16.8 Hz, 1H), 3.82 (d, J = 16.8 Hz,
wise, extracted with dichloromethane (3X50 mL). The com-
bined organic layer was washed with brine (5 mL) and dried
over sodium sulfate. Solvent was evaporated to give colorless
sticky liquid which was purified by chromatography on silica
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1H), 3.52 – 3.45 (m, 1H), 3.18 (dd, J = 12.8 Hz, 3.6 Hz, 1H),
2.95 – 2.88 (m, 1H), 2.25 – 2.14 (m, 3H), 2.09 – 2.02 (m, 1H),
1
3
1.90 (m, 1H), 1.68 – 1.57 (m, 1H) ppm. C NMR (101 MHz,
CDCl ) δ 146.8, 146.2, 139.1, 127.9, 127.5, 125.1, 107.3,
03.5, 101.2, 67.6, 62.1, 52.8, 45.0, 44.7, 30.1, 25.0, 24.2
3
gel (5% MeOH/CH
85%) as a solid foam. TLC R
ninhydrin). IR (film): νmax = 2361, 2343, 1736, 1486, 1378,
2
Cl
2
) to obtain (-)-Crinane (10) (1.06 g,
1
f
=0.4 (MeOH:CH Cl = 1:9,
2
2
+
+
2
ppm. HRMS (m/z): [M + H] calcd for C16H18NO 256.1332,
found 256.1326. [α]D = -65.3° (c = 0.5 in EtOH).
2
4
−1 1
1259 cm . H NMR (400 MHz, CDCl
3
) δ 6.70 (s, 1H), 6.45 (s,
1
H), 5.88 (s, 2H), 4.44 (d, J = 16.8 Hz, 1H), 3.84 (d, J = 16.8
Preparation of (-)-Crinine (3): To a solution of 20 (1.0 g,
.91 mmol) in dioxane (50 mL) was added 0.3 g sodium bi-
carbonate and SeO (0.65 g, 5.86 mmol) and resulting suspen-
Hz, 1H), 3.48 – 3.44 (m, 1H), 2.96 – 2.87 (m, 2H), 2.34 – 2.26
(m, 2H), 1.90 (d, J = 10.0 Hz, 1H), 1.78 – 1.76 (m, 3H), 1.62
(m, 1H), 1.54 – 1.44 (m, 1H), 1.32 (m, 1H), 1.31 – 1.16 (m,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
3
sion was immersed in an oil bath set at 102 °C and stirred for
16 h under argon atmosphere. The progress of reaction was
monitored by TLC. After completion, the reaction was cooled
to room temperature and filtered through a celite pad. The
filtrate was concentrated and the residue was purified by
1H). C NMR (101 MHz, CDCl ) δ 146.8, 146.1, 141.4, 124.3,
3
106.5, 103.5, 101.0, 67.7, 61.4, 51.9, 43.2, 37.3, 29.9, 28.9,
+
+
27.0, 24.2, 21.7. HRMS (m/z): [M + H] calcd for C H NO
16 20
2
2
4
258.1489, found 258.1426. [α]D = -9.3° (c = 0.75 in CHCl3).
chromatography on silica gel (20% MeOH/CH
(0.847 g, 80%) as a pale yellow solid (mp 207.5 – 208.2 °C).
TLC R =0.3 (MeOH:CH Cl = 1:4, ninhydrin). IR (film):
νmax = 3350, 2926, 1397, 1160 cm . H NMR (400 MHz,
CDCl ) δ 6.84 (s, 1H), 6.59 (d, J = 10.0 Hz, 1H), 6.49 (s, 1H),
.05 – 5.95 (m, 1H), 5.90 (dd, J = 6, 1.2 Hz, 2H), 4.41 (d, J =
2
Cl
2
) affording
Preparation of tert-butyl (3aR)-3a-(3,4-dimethoxyphenyl)-
6-hydroxy-2,3,3a,6,7,7a-hexahydro-1H-indole-1-
3
f
2
2
carboxylate (21): To a stirring solution of boric acid (0.60 g,
9.7 mmol) in anhydrous methanol (15 mL) was added a solu-
tion of 1A (1.0 g, 1.94 mmol) in 15 mL THF. The reaction
mixture was stirred at room temperature and sodium amalgam
(0.8 g, 7%) was added four times portion wise in 10 min inter-
val while stirring at ambient temperature. The reaction mixture
was allowed to stir for additional 2 hours. The progress of
reaction was monitored by TLC and after the completion of
the reaction, water (6 mL) was added drop wise, extracted
with ethyl acetate (3X50 mL). The combined organic layer
was washed with brine (5 mL) and dried over sodium sulfate.
Solvent was evaporated to give colorless sticky liquid.
−1
1
3
6
16.8 Hz, 1H), 4.37 – 4.33 (m, 1H), 3.79 (d, J = 16.8 Hz, 1H),
3.38 (m, 2H), 2.92 – 2.89 (m, 1H), 2.21 – 2.14 (m, 1H), 2.02 –
1
.98 (m, 1H), 1.98 – 1.91 (m, 1H), 1.83 – 1.68 (m, 2H) ppm.
1
3
C NMR (101 MHz, CDCl
3
) δ 146.8, 146.4, 137.3, 131.1,
1
4
2
28.0, 124.2, 107.2, 103.2, 101.1, 63.5, 63.1, 61.2, 52.9, 44.7,
+
+
3.3, 31.8. HRMS (m/z): [M + H] calcd for C16H18NO
3
2
4
3
72.1281, found 272.1279. [α]D = -27.7° (c = 0.25, CHCl ).
Preparation of (-)-Amabiline (4): To a solution of 20 (1.0 g,
.91 mmol) in acetone-water (9:1, 100 mL) was added N-
methyl morpholine N-oxide (0.567 mL, 4.8 mmol), OsO
3
To a crude solution (1.0 g, 2.78 mmol) in dioxane (10 mL)
was added 0.03 g sodium bicarbonate and SeO (0.462 g, 4.17
2
4
(2.5% in t-butanol, 0.495 g, 0.048 mmol). The reaction mix-
ture was stirred at 25 °C and progress was monitored by TLC.
After the reaction was completed, Na S O (20 mL) was added
2 2 3
to it and was allowed to stir for another 1 hour. The whole
reaction mixture was evaporated under high vacuum to re-
move the solvent. The organic layer was extracted by CH
mmol) and resulting suspension was immersed in an oil bath
set at 102 °C and stirred for 16 hours under argon atmosphere.
The progress of reaction was monitored by TLC. After com-
pletion, the reaction was cooled to room temperature and fil-
tered through a celite pad. The filtrate was concentrated and
the residue was purified by chromatography on silica gel (30%
EtOAc/Hexane) affording 21 (0.835 g, 80 %) as a yellow sem-
2 2
Cl
(3X50 mL). The combined organic layer was dried over sodi-
um sulfate. The solvent was removed under vacuum to obtain
a crude residue which was purified by chromatography on
basic alumina (5% MeOH/CH
(0.86 g, 76 %) as white solid (mp 239.8–241.2 °C). TLC R
=0.3 (MeOH:CH Cl
3368, 2919, 1599, 1481 cm . H NMR (600 MHz, CDCl
isolid. TLC R
(film): νmax = 2973, 2836, 1688, 1453, 1127 cm . H NMR
(400 MHz, CDCl ) δ 6.97 – 6.91 (m, 2H), 6.83 (m, 1H), 6.02
f
=0.5 (EtOAc:Hexane = 1:1, ninhydrin). IR
−1
1
2
Cl
2
) to obtain (-)-amabiline (4)
3
f
(d, J = 10.0 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 4.30 (bs, 1H),
3.89 (s, 3H), 3.86 (s, 3H), 3.80 – 3.63 (m, 1H), 3.21 – 3.18
(m, 1H), 2.54 – 2.51 (m, 1H), 2.40 – 2.35 (m, 1H), 1.84 – 1.77
2
2
= 1:3, ninhydrin). IR (film): νmax =
−1
1
3
) δ
1
3
6
1
.80 (s, 1H), 6.48 (s, 1H), 5.90 (m, 2H), 4.59 (d, J = 2.5 Hz,
H), 4.32 (d, J = 16.8 Hz, 1H), 4.11 – 4.06 (m, 1H), 3.70 (d, J
16.2 Hz, 1H), 3.31 – 3.23 (m, 2H), 2.79 – 2.75 (m, 1H), 2.07
(m, 3H), 1.63 – 1.54 (m, 1H), 1.46 (s, 9H). C NMR (101
MHz, CDCl ) δ 154.7, 148.9, 148.0, 135.5, 133.0, 132.6,
3
=
–
119.4, 110.9, 110.3, 79.9, 63.6, 62.4, 62.1, 56.0, 50.9, 46.0,
+
1.96 (m, 2H), 1.87 – 1.79 (m, 3H), 1.36 (d, J = 7.8 Hz, 1H).
45.8, 36.1, 31.9, 31.0, 28.6. HRMS (m/z): [M + Na] calcd for
1
3
+
C NMR (151 MHz, CDCl
3
) δ 146.9, 146.3, 136.9, 107.0,
C
21
H29NNaO
5
398.1938, found 398.1943. [α]D²² = +138.9°
1
2
03.8, 101.0, 69.6, 68.9, 63.3, 61.6, 50.8, 49.9, 37.6, 26.8,
(c = 1.25, MeOH).
+
+
4
5.4. HRMS (m/z): [M + H] calcd for C16H20NO 290.1387,
24
found 290.1385. [α]D = -34.7° (c = 0.5, EtOH).
Preparation of tert-butyl (3aR)-3a-(3,4-dimethoxyphenyl)-
6-oxooctahydro-1H-indole-1-carboxylate (22) : To a solu-
tion of 21 (1.5 g, 4.0 mmol) in ethanol (30 mL) was added
Raney Nickel (catalytic amount) and resulting suspension was
immersed in an oil bath set at 75 °C and stirred for 2 hours
under hydrogen atmosphere. The progress of the reaction was
monitored by TLC. After completion, the reaction was cooled
to room temperature and filtered through a celite pad. The
filtrate was concentrated under high vacuum.
Preparation of (-)-Crinane (10): To a stirring solution of 19
2.0 g, 4.88 mmol) in THF:MeOH (1:1, 50 mL), sodium amal-
(
gam (3.50 g, 7%) was added four times portion wise in 10 min
interval while stirring at the ambient temperature. The reaction
mixture was allowed to stir for additional 12 hours. The pro-
gress of the reaction was monitored by TLC and after the
completion of the reaction, water (30 mL) was added drop-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
f
=0.6
The residue was dissolved in dry CH
2
Cl
2
(20 mL) and was
tain 23 (0.6 g, 85%) as a semi solidsolid. TLC R
(EtOAc:Hexane = 1:9, ninhydrin). IR (film): νmax = 2923,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cooled to 0 °C, added DMP (1.69 g, 4.0 mmol), the reaction
was allowed to stir for 1 h. The progress of the reaction was
monitored by TLC, neutralized with saturated sodium bicar-
bonate solution (20 mL), washed with brine solution (10 mL)
and extracted with ethyl acetate (3X20 mL). Solvent was
evaporated under vacuum and crude residue was purified by
chromatography on silica gel (20% EtOAc/Hexane) to obtain
−1
1
3
2853, 1396 cm . H NMR (400 MHz, CDCl ) δ 6.85– 6.78
(m, 3H), 4.22–4.02 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.34 –
3.29 (m, 1H), 3.06 – 2.95 (m, 1H), 2.33 (m, 1H), 2.07 (m,
2H), 1.88 (bs, 1H), 1.75 – 1.51 (m, 4H), 1.52 – 1.34 (m, 10H),
1.25 (t, J = 11.2 Hz, 1H). C NMR (101 MHz, CDCl ) δ
3
154.4, 148.7, 147.1, 140.6, 117.9, 111.0, 109.3, 79.0, 59.7,
58.8, 55.9, 47.7, 47.1, 43.6, 43.1, 35.6, 33.8, 32.3, 29.2, 28.7,
1
3
2
2 (1.27 g, 85 %) as a white sticky liquid. TLC R
f
=0.5
+
+
(
1
6
EtOAc:Hexane = 3:7, ninhydrin). IR (film): νmax = 2923,
28.6, 23.5. HRMS (m/z): [M + Na] calcd for C21
H
31NO
4
Na
−1
1
20
688, 1461, 1396, 1255 cm . H NMR (400 MHz, CDCl
3
δ
384.2145, found 384.2126. [α]D = +262.3° (c = 0.25,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.82 (m, 3H), 4.89– 4.46 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H),
MeOH).
3.44– 3.38 (m, 3H), 2.92 (dd, J = 15.6, 6.0 Hz, 1H), 2.69 (m,
1H), 2.43 – 2.04 (m, 6H), 1.46 (s, 9H). 13C NMR (101 MHz,
Preparation of (+)-Mesembrane (8): To a solution of 23 (1.0
g, 2.76 mmol) in CH Cl (15 mL), trifluoroacetic acid (0.20
2 2
mL, 2.76 mmol) was added at 0 °C and stirred for 8 hours. The
reaction mixture was quenched with saturated sodium bicar-
bonate solution (10 mL) and extracted with dichloromethane
CDCl
3
) δ 210.6, 149.1, 147.9, 137.7, 118.0, 111.2, 109.5, 80.1,
6
0.3, 56.1, 56.0, 44.5 36.7, 33.3, 28.6. HRMS (m/z): [M +
+
+
Na] calcd for C21
H29NNaO
5
398.1938, found 398.1937.
2
4
[
α]D = +98.6° (c = 0.5, MeOH).
(3X15 mL). The organic layer was dried over sodium sulfate
Preparation of (+)-Mesembrine (5): To a solution of 22 (1.0
g, 2.66 mmol) in CH Cl (15 mL), trifluoroacetic acid (0.20
and concentrated under vacuum. The crude residue was dis-
solved in chloroform and passed through a small pad of basic
alumina and concentrated under reduced pressure.
2
2
mL, 2.66 mmol) was added at 0 °C and stirred for 8 hours. The
reaction mixture was quenched with saturated sodium bicar-
bonate solution (10 mL) and extracted with dichloromethane
(3X15 mL). The organic layer was dried over sodium sulfate
and concentrated under vacuum. The crude residue was dis-
solved in chloroform and passed through a small pad of basic
alumina and concentrated under reduced pressure.
It was then dissolved in acetonitrile (10 mL) and formalde-
hyde (0.025 mL of a 35% w/w aqueous solution) and
NaCNBH (0.173 g, 2.76 mmol) was added. The resulting
3
mixture was stirred at room temperature for 10 minutes and
was quenched with saturated sodium bicarbonate solution (10
2 2
mL). The reaction mixture was extracted with CH Cl (3X10
mL) and dried over sodium sulfate, purified by column chro-
matography on basic alumina (2-4% MeOH/DCM) to afford
pure (+)-mesembrane (8) (0.646 g, 85 %) as a pale yellow oil.
It was then dissolved in acetonitrile (10 mL) followed by addi-
tion of formaldehyde (.025 mL of a 35% w/w aqueous solu-
tion) and NaCNBH (0.167 g, 2.66 mmol). The resulting mix-
3
ture was stirred at room temperature for 10 minutes and was
quenched with saturated sodium bicarbonate solution (10 mL).
TLC R
f 2 2
=0.3 (MeOH:CH Cl = 1:4, ninhydrin). IR (film):
−1 1
νmax = 2923, 2853, 1396 cm . H NMR (400 MHz, CDCl
3
δ
The reaction mixture was extracted with CH
2
Cl
2
(3X10 mL)
6.93 – 6.89 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H),
3.87 (s, 3H), 3.25 (m, 1H), 2.58 (m, 1H), 2.33 (s, 3H), 2.32–
2.31 (m, 1H) 1.95 – 1.79 (m, 5H), 1.55 (m, 3H), 1.37 (m, 1H),
and dried over sodium sulfate, purified by column chromatog-
raphy on basic alumina (2-4% MeOH/DCM) to afford pure
1
3
(
=
2
+)-mesembrine (0.614 g, 80 %) as a colourless oil. TLC R
0.5 (MeOH:CH Cl = 3:7, ninhydrin). IR (film): νmax =
923, 2853, 1688, 1517, 1396 cm . H NMR (600 MHz,
CDCl δ 6.95 (dd, J = 8.4, 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz,
H), 6.86 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.15 –
f
3
1.16 (m, 1H). C NMR (101 MHz, CDCl ) δ 148.7, 146.9,
2
2
140.4, 119.0, 110.8, 110.7, 68.8, 56.0, 55.9, 54.5, 47.6, 41.1,
−1
1
+
40.7, 36.1, 23.8, 23.0, 20.5. HRMS (m/z): [M + H] calcd for
+
20
3
17 2
C H26NO 276.1958, found 276.1946. [α]D = +15.9° (c =
1
3
2
0.25, MeOH).
.11 (m, 1H), 2.96 (t, J = 3.6 Hz, 1H), 2.60 – 2.56 (m, 2H),
.46 – 2.41 (m, 1H), 2.37 – 2.29 (m, 4H), 2.28 – 2.16 (m, 3H),
Preparation
of
(5S,10bS)-8,9-dimethoxy-1-tosyl-4,4a-
1
3
2.17 – 2.03 (m, 2H). C NMR (101 MHz, CDCl
3
) δ 211.6,
dihydro-3H,6H-5,10b-ethanophenanthridine (24). A solu-
tion of 1A (2 g, 3.90 mmol) in 100 mL dichloromethane was
taken in a round bottom flask equipped with magnetic stir bar
under argon atmosphere. The reaction mixture was cooled to 0
°C and trifluoroacetic acid (0.30 mL, 3.90 mmol) was added
slowly. The solution was stirred for 6 hours. After the comple-
tion, the reaction mixture was quenched with saturated solu-
149.1, 147.6, 140.4, 118.0, 111.1, 110.1, 77.1, 70.5, 56.0,
+
55.0, 47.6, 40.7, 40.2, 39.0, 36.4, 35.4. HRMS (m/z): [M + H]
+
24
calcd for C17
H24NO
3
290.1751, found 290.1740. [α]D
=
+
63.8° (c = 0.25, MeOH).
Preparation
of
tert-butyl
(3aR)-3a-(3,4-
dimethoxyphenyl)octahydro-1H-indole-1-carboxylate (23):
To a stirring solution of 1A (1.0 g, 1.94 mmol) in (1:1)
THF:MeOH (20 mL), sodium amalgam (0.8 g, 7%) was added
four times portion wise in 10 min interval while stirring at the
ambient temperature. The reaction mixture was allowed to stir
for additional 12 hours. The progress of reaction was moni-
tored by TLC and after the completion of the reaction, water
3
tion of NaHCO (50 mL) which was allowed to stir for another
1 hour until the bubbling ceased. The organic layer was ex-
tracted with dichloro methane (3X50 mL), dried over sodium
sulfate and concentrated under vacuum to obtain N-Boc depro-
tected material as a white solid residue.
The N-Boc deprotected material was dissolved in trifluoroace-
tic acid (50 mL) under argon atmosphere and paraformalde-
hyde (0.175 g, 5.85 mmol) was added. The reaction mixture
was heated at 85 °C on an oil bath for 12 hours. The progress
of the reaction was monitored by TLC. After completion, the
reaction mixture was neutralized by adding saturated solution
(
(
6 mL) was added drop wise, extracted with ethyl acetate
3X50 mL). The combined organic layer was washed with
brine (5 mL) and dried over sodium sulfate. Solvent was
evaporated to give colorless sticky liquid which was purified
by chromatography on silica gel (10% EtOAc/Hexane) to ob-
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
of NaHCO
layer was extracted with dichloromethane (3X50 mL), it was
concentrated under vacuum and purified by chromatography
on silica gel (5% MeOH/CH Cl ) to obtain 24 (1.427 g, 86 %)
as a solid (mp 211.3- 211.8 °C). TLC R = 0.5 (MeOH:CH Cl
1:9, ninhydrin). IR (film): νmax = 2919, 1596, 1384, 1311,
3
very slowly until the bubbling ceased. The organic
MHz, CDCl
3
) δ 147.6, 147.4, 137.2, 132.4, 127.6, 125.3,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
110.0, 105.9, 67.2, 64.3, 63.1, 62.2, 56.2, 56.0, 53.7, 44.3,
44.1, 32.9. HRMS (m/z): [M + H] calcd for C17H22NO
3
288.1594, found 288.1586. [α]D = -27.7° (c = 0.25, CHCl ).
3
+
+
2
4
2
2
f
2
2
=
Preparation of (-)-Oxomaritidine (7): To a solution of 6 (1.0
g, 3.48 mmol) in dry CH Cl (20 mL) cooled to 0 °C, was
-
1 1
1
2
1
263 cm . H NMR (400 MHz, CDCl
H), 7.62 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.60 (t, J = 4.4 Hz,
H), 6.49 (s, 1H), 4.45 (d, J = 17.2 Hz, 1H), 3.93 (s, 3H), 3.88
3
) δ 7.82 (d, J = 8.4 Hz,
2
2
added DMP (1.47 g, 3.48 mmol) and the reaction was allowed
to stir for 1 hour. The progress of the reaction was monitored
by TLC, neutralized with sat. sodium bicarbonate solution (5
mL), washed with brine solution (5 mL) and extracted with
ethyl acetate (3X20 mL). Solvent was evaporated under vacu-
um and crude residue was purified by chromatography on
(d, J = 17.6 Hz, 1H), 3.81 (s, 3H), 3.33 – 3.28 (m, 2H), 3.09 –
2
.99 (m, 1H), 2.89 – 2.82 (m, 1H), 2.44 (s, 3H), 2.25 – 2.18
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
(m, 3H), 1.73 – 1.69 (m, 1H), 1.31 – 1.24 (m, 1H). C NMR
(101 MHz, CDCl ) δ 150.1, 147.4, 146.5, 144.1, 143.0, 140.7,
3
137.8, 129.9, 127.7, 124.5, 110.2, 109.3, 71.6, 62.3, 56.2,
silica gel (10% MeOH/CH
white solid (mp 145.5
(MeOH:CH Cl = 1:9, ninhydrin). IR (film): νmax = 2928,
1675, 1607, 1513, 1461, 1314 cm . H NMR (400 MHz,
CDCl ) δ 7.71 (d, J = 10.4 Hz, 1H), 6.91 (s, 1H), 6.58 (s, 1H),
2
Cl
2
) to obtain 7 (0.971 g, 98%) as a
+
56.0, 54.0, 50.1, 43.7, 25.7, 24.2, 21.6. HRMS (m/z): [M + H]
–
146.7 °C). TLC =0.6
R
f
+
calcd for C24
H28NO
4
S 426.1734, found 426.1720. [α]D²² = -
2
2
−1
1
1
7.75° (c = 0.4, EtOH).
3
Preparation of (5S,10bS)-8,9-dimethoxy-4,4a-dihydro-
H,6H-5,10b-ethanophenanthridine (25): To a stirring solu-
tion of boric acid (1.44 g, 23.45 mmol) in anhydrous methanol
50 mL) was added a solution of 24 (2.0 g, 4.69 mmol) in 50
6.10 (d, J = 10.0 Hz, 1H), 4.42 (d, J = 17.6 Hz, 1H), 3.91 (s,
3H), 3.84 (s, 3H), 3.81 (d, J = 16.8 Hz, 1H), 3.68 (dd, J =
13.2, 5.6 Hz, 1H), 3.61 – 3.52 (m, 1H), 3.08 – 2.97 (m, 1H),
2.71 (dd, J = 16.8, 5.6 Hz, 1H), 2.49 (dd, J = 16.8, 13.0 Hz,
3
(
1
3
mL THF. The reaction mixture was stirred at room tempera-
ture and sodium amalgam (3.25 g, 7%) was added four times
portion wise in 10 min interval while stirring at the ambient
temperature. The reaction mixture was allowed to stir for addi-
tional 2 hours. The progress of reaction was monitored by
TLC and after the completion of the reaction; water (30 mL)
was added drop wise, extracted with dichloromethane (3X50
mL). The combined organic layer was washed with brine (5
mL) and dried over sodium sulfate. Solvent was evaporated
which gave colorless sticky liquid and purified by chromatog-
1H), 2.40 (m, 1H), 2.22 – 2.15 (m, 1H). C NMR (101 MHz,
CDCl ) δ 198.2, 149.6, 148.2, 147.8, 135.0, 129.0, 125.4,
110.3, 105.7, 69.2, 61.7, 56.4, 56.1, 54.3, 45.0, 44.5, 40.3.
3
+
+
3
HRMS (m/z): [M + H] calcd for C17H20NO 286.1438, found
286.1425. [α]D = -47.7° (c = 0.25, MeOH).
2
4
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the
ACS Publication website.
raphy on silica gel (5% MeOH/CH
4%) as a semisolid. TLC R =0.4 (MeOH:CH
hydrin). IR (film): νmax = 2934, 2850, 1607, 1462, 1263 cm .
2
Cl
2
) to obtain 25 (1.069 g,
1H and 13C spectra of all new compounds.
8
f
2
Cl = 1:9, nin-
2
−1
1
H NMR (400 MHz, CDCl
3
)δ 6.84 (s, 1H), 6.52 (s, 1H), 6.45
AUTHOR INFORMATION
Corresponding Author
(dd, J = 10.0, 1.6 Hz, 1H), 5.81 – 5.77 (m, 1H), 4.44 (d, J =
1
1
1
6.8 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.37 (d, J = 16.8 Hz,
H), 3.41 – 3.35 (m, 1H), 3.14 – 3.10 (dd, J = 13.0, 4.0 Hz,
H), 2.91 – 2.84 (m, 1H), 2.21 – 2.16 (m, 3H), 2.06 – 1.99
Ganesh Pandey*
Email: gp.pandey@cbmr.res.in
(
(
m, 1H), 1.79 – 1.76 (m, 1H), 1.66 – 1.55 (m, 1H). 13C NMR
101 MHz, CDCl
3
) δ 147.1, 147.0, 138.1, 128.0, 126.7, 124.9,
ORCID
1
2
09.6, 105.7, 67.1, 61.9, 55.8, 55.7, 52.5, 45.1, 43.7, 24.8,
Ganesh Pandey: 0000-0001-7203-294X
+
+
2
4.3. HRMS (m/z): [M + H] calcd for C17H22NO 272.1645,
2
4
found 272.1632. [α]D = -65.3° (c = 0.5 in EtOH).
Author Contributions
‡PV and AC contributed equally.
Preparation of (-)-Maritidine (6): To a solution of 25 (1.0 g,
.68 mmol) in dioxane (50 mL) was added 0.3 g sodium bi-
carbonate and SeO (0.612 g, 5.52 mmol) and resulting sus-
3
ACKNOWLEDGMENT
2
We are grateful to Department of Science and Technology for
funding J. C. Bose fellowship, DST-INSPIRE and INSPIRE Fac-
ulty to GP, PV and AC respectively.
pension was immersed in an oil bath set at 102 °C and stirred
for 16 h under argon atmosphere. The progress of reaction was
monitored by TLC. After completion, the reaction was cooled
to room temperature and filtered through a celite pad. The
filtrate was concentrated and the residue was purified by
REFERENCES
chromatography on silica gel (20% MeOH/CH
6 (0.844 g, 80%) as a white solid (mp 230.6 –231.1 °C). TLC
=0.6 (MeOH:CH Cl = 1:9, Ninhydrin). IR (film): νmax =
2922, 1589, 1384, 1238, cm . H NMR (400 MHz, CDCl
2 2
Cl ) affording
(
1) Cordell, G. A.; Quinn-Beattie M. L.; Farnsworth, N. R. The Po-
tential of Alkaloids in Drug Discovery. Phyther. Res., 2001, 15, 183–
05.
2) Takos, A. M.; Rook, F. Towards a Molecular Understanding of
R
f
2
2
2
−1 1
3
) δ
.85 (s, 1H), 6.67 (d, J = 10.0 Hz, 1H), 6.52 (s, 1H), 5.99 –
.95 (m, 1H), 4.43 (d, J = 16.8 Hz, 1H), 4.39 – 4.31 (m, 1H),
.87 (s, 3H), 3.81 (s, 3H), 3.78 (d, J = 16.8 Hz, 1H), 3.48 –
(
6
5
3
3
the Biosynthesis of Amaryllidaceae Alkaloids in Support of Their
Expanding Medical Use. Int. J. Mol. Sci., 2013, 14, 11713–11741.
(3) a) Jin, Z. Amaryllidaceae and Sceletium Alkaloids. Nat. Prod.
Rep., 2007, 24, 886–905 b) Jin, Z. Amaryllidaceae and Sceletium
Alkaloids. Nat. Prod. Rep., 2011, 28, 1126–1142; c) Jin, Z.; Arai, H.;
Yamamoto, N.; Takahashi, K.; Gericke, N.; Viljoen, A. M.; Mann, I.;
.33 (m, 2H), 2.94 – 2.87 (m, 1H), 2.19 (m, 1H), 2.03 – 1.95
m, 1H), 1.94 – 1.91 (m, 1H), 1.77 (m, 2H). 1 C NMR (101
3
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
Oppolzer, W.; Spivey, A. C.; Evidente, A.; Kornienko, A.; Kiss, R.;
Synthesis of (-)-Mesembrine. Chem. Sci., 2011, 2, 1519; c) Du, K.;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Kinzy, T. G.; Mathieu, V. Amaryllidaceae and Sceletium Alkaloids.
Nat. Prod. Rep., 2013, 30, 849–868; d) Bastida, J.; Berkov, S.; Torras,
L.; Pigni, N. B.; De Andradre, J. P.; Martínez, V.; Codina C.; Vi-
ladomat F.; Chemical and Biological Aspects of Amaryllidaceae Al-
kaloids, 2011, vol. 661.
(4) a) Refaat, J.; Kamel, M. S.; Ramadan, M. A.; Ali, A. A. Cri-
num; An Endless Source of Bioactive Principles: A Review. Part III;
Crinum Alkaloids: Belladine-, Galanthamine-, Lycorine-, Tazettine-
type Alkaloids and Other Minor types. Int. J. Pharm. Sci. Res., 2012,
Yang, H.; Guo, P.; Feng, L.; Xu, G.; Zhou, Q.; Chung, L. W.; Tang,
W. Efficient Syntheses of (-)-Crinine and (-)-Aspidospermidine, and
the Formal Synthesis of (-)-Minfiensine by Enantioselective Intramo-
lecular Dearomative Cyclization. Chem. Sci., 2017, 8, 6247–6256.
(10) a) Song, Z. L.; Wang, B. M.; Tu, Y. Q.; Fan, C. A.; Zhang, S.
Y. A General Efficient Strategy for cis-3a-Aryloctahydroindole Alka-
2
loids via Stereocontrolled ZnBr -Catalyzed Rearrangement of 2,3-
Aziridino Alcohols. Org. Lett., 2003, 5, 2319–2321; b) Gan, P.;
Smith, M. W.; Braffman, N. R.; Snyder, S. A. Pyrone Diels–Alder
Routes to Indolines and Hydroindolines: Syntheses of Gracilamine,
3
, 3630–3638; b) Refaat, J.; Kamel, M. S.; Ramadan, M. A.; Ali, A.
7
A. Crinum; An Endless Source of Bioactive Principles: A Review.
Part V. Biological Profile. Int. J. Pharm. Sci. Res., 2013, 4, 1239–
Mesembrine, and Δ ‐Mesembrenone. Angew. Chem. Int. Ed., 2016,
55, 3625–3630; c) Guerard, K. C.; Sabot, C.; Racicot, L.; Canesi, S.
Oxidative Friedel−Crafts Reaction and its Application to the Total
Syntheses of Amaryllidaceae Alkaloids. J. Org. Chem., 2009, 74,
2039–2045; d) Raghavan, S.; Ravi, A. Synthesis of Crinane Utilizing
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
252; c) Ghosal, S.; Saini, K. S.; Razdan, S. Crinum Alkaloids: Their
Chemistry and Biology. Phytochemistry, 1985, 24, 2141–2156; d)
López, S.; Bastida, J.; Viladomat, F.; Codina, C. Acetylcholinesterase
Inhibitory Activity of some Amaryllidaceae Alkaloids and Narcissus
Extracts. Life Sci., 2002, 71, 2521–2529; e) Henry, S.; Kidner, R.;
Reisenauer, M. R.; Magedov, I. V.; Kiss, R.; Mathieu, V.; Lefranc,
F.; Dasari, R.; Evidente, A.; Yu, X.; Ma, X.; Pertsemlidis, A.; Cencic,
R.; Pelletier, J.; Cavazos, D. A.; Brenner, A. J.; Aksenov, A. V.;
Rogelj, S.; Kornienko A.; Frolova, L. V. 5,10b-Ethanophenanthridine
Amaryllidaceae Alkaloids Inspire the Discovery of Novel Bicyclic
ring Systems with Activity against Drug Resistant Cancer Cells. Eur.
J. Med. Chem., 2016, 120, 313–328; f) Likhitwitayawuid, K.; Anger-
hofer, C. K.; Chai, H.; Pezzuto, J. M.; Cordell, G. A. Cytotoxic and
Antimalarial Alkaloids from the Bulbs of Crinum amabile. J. Nat.
Prod., 1993, 56, 1331–1338.
an Allylic Sulfoxide for the Construction of
a Hydroindole
ring via Vinylogous C–N Bond Formation. Org. Biomol. Chem.,
2016, 14, 10222–10229; e) Overman, L. E.; Sugai, S. Total Synthesis
of (-)-Crinine. Use of Tandem Cationic Aza‐Cope Rearrange-
ment/Mannich Cyclizations for the Synthesis of Enantiomerically
Pure Amaryllidaceae Alkaloids. Helv. Chim. Acta, 1985, 68, 745–
749; f) Pearson, W. H.; Lovering, F. E. Assembly of 3a-
Arylperhydroindoles by the Intramolecular Cycloaddition of 2-
Azaallyl Anions with Alkenes. Total Syntheses of (±)-Crinine, (±)-6-
Epicrinine, (-)-Amabiline, and (-)-Augustamine. J. Org. Chem., 1998,
63, 3607–3617.
(11) Bao, X.; Wang, Q.; Zhu, J. Palladium‐Catalyzed Enantioselec-
tive Desymmetrizing Aza‐Wacker Reaction: Development and Appli-
cation to the Total Synthesis of (-)‐Mesembrane and (+)‐Crinane.
Angew. Chem. Int. Ed., 2018, 57, 1995 –1999.
(5) a) Berkov, S.; Codina, C.; Bastida, J. The Genus Galanthus: A
Source of Bioactive Compounds. Phytochem. - A Glob. Perspect. role
Nutr. Heal., 2012, 235–254; b) Marco-Contelles, J.; Carreiras, C.;
Rodriguez, C.; Villarroya, M.; Garcia, A. G. Synthesis and Pharma-
cology of Galantamine. Chem. Rev., 2006, 106, 116–133.
(12) a) Denmark, S. E.; Marcin, L. R. Asymmetric Construction of
a Quaternary Carbon Center by Tandem [4 + 2]/[3 + 2] Cycloaddition
of a Nitroalkene. The Total Synthesis of (-)-Mesembrine. J. Org.
Chem., 1997, 62, 1675–1686; b) Taber, D. F.; Neubert, T. D. Enanti-
oselective Construction of Cyclic Quaternary Centers:ꢀ (-)-
Mesembrine. J. Org. Chem., 2001, 66, 143–147; c) Taber, D. F.; He,
Y. Opening of Aryl-Substituted Epoxides To Form Quaternary Stere-
ogenic Centers:ꢀ Synthesis of (-)-Mesembrine. J. Org. Chem., 2005,
70, 7711–7714; d) Arns, S.; Lebrun, M.-E.; Grise, C. M.; Denissova,
I.; Barriault, L. Diastereoselective Construction of Quaternary Car-
bons Directed via Macrocyclic Ring Conformation:ꢀ Formal Synthesis
of (-)-Mesembrine. J. Org. Chem., 2007, 72, 9314–9322; e) Kano, T.;
Hayashi, Y.; Maruoka, K. Construction of a Chiral Quaternary Car-
bon Center by Catalytic Asymmetric Alkylation of 2-
Arylcyclohexanones under Phase-Transfer Conditions. J. Am. Chem.
Soc., 2013, 135, 7134–7137; f) Paul, T.; Malachowski, W. P.; Lee, J.
The Enantioselective Birch−Cope Sequence for the Synthesis of Car-
bocyclic Quaternary Stereocenters. Application to the Synthesis of
(+)-Mesembrine. Org. Lett., 2006, 8, 4007–4010; g) Ozaki, T.; Koba-
yashi, Y. Synthesis of (-)-Mesembrine Using the Quaternary Carbon-
Constructing Allylic Substitution. Org. Chem. Front., 2015, 2, 328–
335.
(13) a) Nishimata, T.; Sato, Y.; Mori, M. Palladium-Catalyzed
Asymmetric Allylic Substitution of 2-Arylcyclohexenol Derivatives:ꢀ
Asymmetric Total Syntheses of (+)-Crinamine, (-)-Haemanthidine,
and (+)-Pretazettine. J. Org. Chem., 2004, 69, 1837–1843; b) Petit, L.;
Banwell, M. G.; Willis, A. C. The Total Synthesis of the Crinine
Alkaloid Hamayne via a Pd[0]-Catalyzed Intramolecular Alder-Ene
Reaction. Org. Lett., 2011, 13, 5800–5803; c) Mori, M.; Kuroda, S.;
Zhang, C.-S.; Sato, Y. Total Syntheses of (-)-Mesembrane and (-)-
Mesembrine via Palladium-Catalyzed Enantioselective Allylic Substi-
tution and Zirconium-Promoted Cyclization. J. Org. Chem., 1997, 62,
3263–3270; d) Zhang, Q.-Q.; Xie, J.-H.; Yang, X.-H.; Xie, J.-B.;
Zhou, Q.-L. Iridium-Catalyzed Asymmetric Hydrogenation of α-
Substituted α,β-Unsaturated Acyclic Ketones: Enantioselective Total
Synthesis of (-)-Mesembrine. Org. Lett., 2012, 14, 6158–6161; e)
Zuo, X.-D.; Guo, S.-M.; Yang, R.; Xie, J.-H.; Zhou, Q.-L. Bioinspired
Enantioselective Synthesis of Crinine-type Alkaloids via Iridium-
Catalyzed Asymmetric Hydrogenation of Enones. Chem. Sci., 2017,
8, 6202–6206; f) Wang, L.-N.; Cui, Q.; Yu, Z.-X. A Concise Total
(6) a) Das, M. K.; De, S.; Bisai, A. Concise Total Syntheses of (±)-
Mesembrane and (±)-Crinane. Org. Biomol. Chem., 2015, 13, 3585–
3
588; b) Stevens, R. V.; Lesko, P. M.; Lapalme, R. General Methods
of Alkaloid Synthesis. XI. Total Synthesis of the Sceletium Alkaloid
A-4 and an Improved Synthesis of (±)-Mesembrine. J. Org. Chem.,
1975, 40, 3495–3498; c) Stevens, R. V.; Wentland, M. P. Thermal
Rearrangement of Cyclopropylimines. IV. Total Synthesis of dl-
Mesembrine. J. Am. Chem. Soc., 1968, 90, 5580–5583; d) Wunberg,
J. B. P. A.; Speckamp, W. N. Total Syntheses of dl-Mesembrine, dl-
Dihydromaritidine and dl-epi-Dihydromaritidine via Regioselective
+
NaBH
4
/H Reduction of Imides. Tetrahedron, 1978, 34, 2579–2586;
e) Keck, G. E.; Webb, R. R. Alkaloid Synthesis via Intramolecular
Ene reaction. 2. Application to dl-Mesembrine and dl-
Dihydromaritidine. J. Org. Chem., 1982, 47, 1302-1309.
(
7) a) Martin, S. F.; Campbell, C. L. Total Syntheses of (±)-Crinine
and (±)-Buphanisine. J. Org. Chem., 1988, 53, 3184–3190; b) Pear-
son, W. H.; Lovering, F. E. Application of the 2-Azaallyl anion Cy-
cloaddition Method to Syntheses of (±)-Crinine and (±)-6-Epicrinine.
Tetrahedron Lett., 1994, 35, 9173–9176; c) Muxfeldt, H.; Schneider,
R. S.; Mooberry, J. B. A Total Synthesis of (±)-Crinine. J. Am. Chem.
Soc., 1966, 88, 3670–3671; d) Yang, L.; Wang, X.; Pan, Z.; Zhou, M.;
Chen, W.; Yang, X. Synthetic Studies Towards Crinine-Type Amaryl-
lidaceae Alkaloids: Synthesis of (±)-Oxocrinine and Formal Synthesis
of (±)-Crinine. Synlett., 2011, 2, 207–210; e) Whitlock, Jr., H. W.;
Smith, G. L. Total Synthesis of dl-Crinine. J. Am. Chem. Soc., 1967,
8
9, 3600–3603.
8) a) Bru, C.; Thal, C.; Guillou, C. Concise Total Synthesis of (±)-
(
Maritidine. Org. Lett., 2003, 5, 1845–1846; b) Pandey, G.; Gupta, N.
R.; Pimpalpalle, M. Stereoselective One-Step Construction of Vicinal
Quaternary and
Tertiary Stereocenters
of
the
5,10b-
Ethanophenanthridine Skeleton: Total Synthesis of (±)-Maritidine.
Org. Lett., 2009, 11, 2547–2550; c) Roe, C.; Stephenson, G. R. Elec-
trophilic C12 Building Blocks for Alkaloids:ꢀ Formal Total Synthesis
of (±)-Maritidine. Org. Lett. 2008, 10, 189–192.
(
9) a) Bru, C.; Guillou, C. Total Syntheses of Crinine and Related
Alkaloids. Tetrahedron, 2006, 62, 9043–9048; b) Gu, Q.; You, S.-L.
Desymmetrization of Cyclohexadienones via Cinchonine Derived
Thiourea-catalyzed Enantioselective Aza-Michael Reaction and Total
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
Synthesis of (-)-Mesembrine. J. Org. Chem., 2016, 81, 10165–10171;
Reactions of Organoboron Derivatives with Organic Electrophiles,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
g) Zhao, Y.; Zhou, Y.; Liang, L.; Yang, X.; Du, F.; Li, L.; Zhang, H.
Palladium-Catalyzed Sequential Arylation and Allylic Alkylation of
Highly Functionalized Ketones: A Concise Synthesis of Mesembrine.
Org. Lett., 2009, 11, 555–558.
1995–1998. J. Organomet. Chem., 1999, 576, 147–168.
(20) a) Hoyos, L. J.; Primet, M.; Praliaud, H. Sulfur Poisoning and
Regeneration
Dehydrogenation of Cyclohexane on Pd/Al
Al Catalysts. J. Chem. Soc. Faraday Trans., 1992, 88, 113–119; b)
An, L. D.; Deng, Y. Q. Mechanism of Sulfur Poisoning of Supported
of
Palladium-based
Catalysts.
Part
1.—
2
–
O
2 3
and Pd/SiO
(
14) a) Wang, L.-N.; Cui, Q.; Yu, Z.-X. A Concise Total Synthesis
2 3
O
of (-)-Mesembrine. J. Org. Chem., 2016, 81, 10165–10171; b) Geog-
hegan, K.; Evans, P. Double Reduction of Cyclic Aromatic Sulfona-
mides: Synthesis of (+)-Mesembrine and (+)-Mesembranol. J. Org.
Chem., 2013, 78, 3410–3415; c) Spittler, M.; Lutsenko, K.; Czekelius,
C. Total Synthesis of (+)-Mesembrine Applying Asymmetric Gold
Catalysis. J. Org. Chem., 2016, 81, 6100−6105.
Pd(Pt)/Al
219–234.
2 3 2 2
O Catalysts for H -O Reaction. Appl. Catal., 1990, 66,
(21) a) Tissot, M.; Hernández, A. P.; Müller, D.; Mauduit, M.;
Alexakis, A. Highly Enantioselective and Regioselective Copper-
Catalyzed 1,4 Addition of Grignard Reagents to Cyclic Enynones.
Org. Lett., 2011, 13, 1524–1527; b) Llamas, T.; Arrayás, R. G.; Car-
retero, J. C. Catalytic Asymmetric Conjugate Reduction of β,β‐
Disubstituted α,β‐Unsaturated Sulfones. Angew. Chem.Int. Ed., 2007,
46, 3329; c) Llamas, T.; Arrayás, R. G.; Carretero, J. C.; Angew.
Chem. Int. Ed., 2007, 119, 3393.
(22) Pictet, A.; Spengler, T. Über die Bildung von Isochinolin‐
derivaten durch Einwirkung von Methylal auf Phenyl‐äthylamin,
Phenyl‐alanin und Tyrosin. Eur. J. Inorg. Chem., 1911, 44, 2030–
2036.
(23) a) Riley, H.L.; Morley, J.F.; Friend, N. A. C. Selenium diox-
ide, a New Oxidising Agent. Part I. Its Reaction with Aldehydes and
Ketones. J. Chem. Soc. 1932, 1875–1883; b) Młochowski, J.;
Młochowska, H. W-. Developments in Synthetic Application of Sele-
nium(IV) Oxide and Organoselenium Compounds as Oxygen Donors
and Oxygen-Transfer Agents. Molecules, 2015, 20, 10205–10243.
(24) Dess, D. B.; Martin, J. C. Readily Accessible 12-I-5 Oxidant
for the Conversion of Primary and Secondary Alcohols to Aldehydes
and Ketones. J. Org. Chem., 1983, 48, 4155–4156.
(25) a) Bouveault, L.; Blanc, G. Hydrogenation of the Ether of the
Acids Furthermore Possessing the Ether-oxide or Acetal Functions.
Bull. Soc. Chim. Fr., 1904, 31, 1210–1213; b) Bouveault, L.; Blanc,
G. Transforming Saturated Monobasic Acids into the Corresponding
Primary Alcohols. Bull. Soc. Chim. Fr., 1904, 31, 666–672; (c) Bou-
veault, L.; Blanc, G. Preparation of Primary Alcohols by Means of the
Corresponding Acids. Compt. Rend., 1903, 136, 1676–1678.
(
15) a) Gao, Y.; Wang, D.; Wang, Y. Asymmetric Syntheses of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Amaryllidaceae Alkaloids (-)-Crinane and (+)-4a-
Dehydroxycrinamabine. Org. Lett., 2017, 19, 3516−3519; b) Findlay,
A. D.; Banwell, M. G. A Chemoenzymatic Total Synthesis of (+)-
Amabiline. Org. Lett., 2009, 11, 3160–3162.
(16) Wei, M.-X.; Wang, C.-T.; Du, J.-Y.; Qu, H.; Yin, P.-R.; Bao,
X.; Ma, X.-Y.; Zhao, X.-H.; Zhang, G.-B.; Fan, C.-A. Enantioselec-
tive Synthesis of Amaryllidaceae Alkaloids (+)‐Vittatine, (+)‐epi‐
Vittatine, and (+)‐Buphanisine. Chem. Asian J., 2013, 8, 1966–1971.
(
17) Chandra, A.; Verma, P.; Nigel, A.; Pandey, G. Asymmetric
Total Synthesis of (-)‐Gracilamine Using a Bioinspired Approach.
Eur. J. Org. Chem., 2017, 6788–6792.
(
18) a) Pandey, G.; Rajender, S. A Temperature‐Guided Diastere-
oselectivity Switch During the Desymmetrization of meso‐7‐
Azabicyclo[2.2.1]heptadiene: New Strategy towards the Synthesis of
Aminocyclitols. Chem. Eur. J., 2011, 17, 6304; b) Pandey, G.; Tiwari,
S. K.; Singh, R. S.; Mali, R. S. A Short and Efficient Synthesis of
Enantiopure (+)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one Utilizing an
Asymmetric Desymmetrization Protocol: Formal Total Synthesis of (-
)
-Epibatidine. Tetrahedron Lett., 2001, 42, 3947–3949; c) Pandey, G.;
Tiwari, K. N.; Puranik, V. G. Use of Enantiomerically Pure 7-
Azabicyclo[2.2.1]heptan-2-ol as a Chiral Template for the Synthesis
of Aminocyclitols. Org. Lett., 2008, 10, 3611–3614.
(
19) a) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-
Coupling Reactions of Organoboron Compounds. Chem. Rev., 1995,
5, 2457–2483; b) Suzuki, A. Recent Advances in the Cross-coupling
9
ACS Paragon Plus Environment