Protecting group directed cyclization: Asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor

Article abstract of DOI:10.1016/j.tet.2013.08.042

Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel-Crafts cyclization control the cis-stereochemistry of the B-ring. N-Cbz and O-benzyl protection direct first F-C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine.

Full text of DOI:10.1016/j.tet.2013.08.042

Accepted Manuscript
Protecting Group Directed Cyclization: Asymmetric Synthesis of Both cis- and
trans-Dihydrexidine from a Common Precursor
Rajesh Malhotra, Sagar Chakrabarti, Tushar K. Dey, Swarup Dutta, Krishna Babu
Alapati, Shantanu Dutta, Subho Roy, Sourav Basu, Saumen Hajra
PII:
S0040-4020(13)01316-1
10.1016/j.tet.2013.08.042
TET 24731
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 July 2013
Revised Date: 15 August 2013
Accepted Date: 16 August 2013
Please cite this article as: Malhotra R, Chakrabarti S, Dey TK, Dutta S, Alapati KB, Dutta S, Roy
S, Basu S, Hajra S, Protecting Group Directed Cyclization: Asymmetric Synthesis of Both cis- and
trans-Dihydrexidine from a Common Precursor, Tetrahedron (2013), doi: 10.1016/j.tet.2013.08.042.
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Protecting Group Directed Cyclization:
Asymmetric Synthesis of Both cis and trans-
Dihydrexidine from a Common Precursor
Leave this area blank for abstract info.
a
a,b
a,b
b
b
Rajesh Malhotra , Sagar Chakrabarti , Tushar K. Dey , Swarup Dutta , Krishna Babu Alapati, Shantanu
b
b
b,*
c,*
Dutta , Subho Roy , Sourav Basu Saumen Hajra
a
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana 125001,
b
c
India. TCG Life Sciences Ltd, Saltlake, Kolkata 700091, India. Department of Chemistry, Indian Institute of
Technology Kharagpur, Kharagpur 721302, India

ACCEPTED MANUSCRIPT
Tetrahedron
TETRAHEDRON
Pergamon
Protecting Group Directed Cyclization: Asymmetric Synthesis of
Both cis- and trans-Dihydrexidine from a Common Precursor
a
a,b
a,b
b
Rajesh Malhotra , Sagar Chakrabarti , Tushar K. Dey , Swarup Dutta , Krishna Babu
b
b
b
b,*
c,*
Alapati, Shantanu Dutta , Subho Roy , Sourav Basu Saumen Hajra
a
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana 125001,
India.
b
TCG Life Sciences Ltd, Saltlake, Kolkata 700091, India.
c
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
Abstract— Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from L-serine dictates the
cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade
cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel-Crafts
cyclization control the cis-stereochemistry of the B-ring. N-Cbz and O-benzyl protection direct first F-C cyclization yielding the trans-1-
aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine. © 2013 Elsevier Science. All
rights reserved
followed by creation of C-ring via Pictet-Spengler type
1
. Introduction
cyclization. We have demonstrated elegant asymmetric
Hexahydrobenzophenanthridines 1, fused tetracyclic
9
8
HO 10
HO
7
4
skeletons, are often found in various natural products and
1
,2
Z
A
B
11
6a
6
pharmaceuticals.
junction of the compounds plays a vital role in biological
activity. For example, trans-10,11-dihydroxy-
,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 1a,
Stereochemistry of the B/C-ring
HO
NH HO
NH
NR'
12b
1
2
C
1
5
Ar
2
5
3
known as dihydrexidine has been developed as the first
high affinity full efficacy agonist for dopamine D1
1
a: Dihydrexidine
1b: cis-Dihydrexidine
1
R1 = Cbz
R2 = CH2OBn
1
,2
R1 = Boc
R2 = CH(OCH2)2
receptor, however, cis-isomer 1b is completely inactive.
Dihydrexidine 1a is presently in clinical trial for the
potential treatment of Parkinson’s disease and the cognitive
Z
NHR1
OH
NHR'
MeO
MeO
3
Ar
deficits of schizophrenia. It also shows a high level of
2
R2
enantiospecificity in its interaction with the D1 receptor.
Thus asymmetric synthesis of both cis- and trans-isomers
of hexahydrobenzophenanthridines remains an active field
of research in organic synthesis and important to medicinal
chemistry too. There are a number of methods for
3
NHR1
Me
MeO
MeO
N
OMe
L-serine
4
-8
O
asymmetric synthesis of dihydrexidine 1a and only one
4
report
on
non-racemic
synthesis
Major
of
cis-
9
Scheme 1. Hexahydrobenzophenanthridines and their retrosynthetic
approach
hexahydrobenzophenanthridines.
comprised of construction of the aminotetralin unit 2
syntheses
—
——
*
Corresponding author.Tel.: +91 33 4000 7000; fax: +91 33 23673058; e-mail: sourav@chembiotek.com (S. Basu)
Corresponding author.Tel.:+ 91 3222 283340; fax: +91 3222 255303; e-mail: shajra@chem.iitkgp.ernet.in (S. Hajra)
*

ACCEPTED MANUSCRIPT
Tetrahedron
1
syntheses
of
dihydrexidine
1a
and
other
isolated in good yield (68%). H NMR spectrum of the
product showed a doublet at δ 4.02 with coupling constant
of 5.7 Hz assigned as the proton at C12b (ArCHAr′), which
seems to be designated as having cis-stereochemistry. To
further corroborate our contention, compound 9 was
hexahydrobenzophenanthridine dopamine D1 agonists
using “chiral pool” as well as catalytic asymmetric
approaches.
amino-1-phenyltetralin 2a (Ar = Ph, R′ = H) failed to give
tetracyclic unit. A two step protocol was adopted for C-ring
construction of dihydrexidine, via alkylation of N-nosyl
aminotetralin 2a (R = Ns) with MOMCl followed by
7
,8
Classical Pictet-Spengler reaction of 2-
reduced with NaBH
4
to get the free amine 10 in
quantitative yield and it was converted to the hydrochloride
salt 11. In 1H NMR spectrum, the proton at C12b (ArCHAr′)
of 11 appeared as a doublet at δ 4.31 with coupling
constant of 3.8 Hz whereas the corresponding proton of the
trans-isomer showed a doublet at 4.24 with coupling
6
a,7a
TMSOTf mediated cyclization.
This reaction was found
to be very sensitive to both reagent quality and temperature
and provided inconsistent results with 30-46% of yield. To
avoid the TMSOTf mediated reaction and to make the
synthesis more compact we thought of designing a
synthesis in which both B- and C-rings can be constructed
concurrently. Thus we report the first divergent synthesis of
dihyrexidine 1a and cis-dihydrexidine 1b from a common
intermediate 4 via sequential and cascade cyclization,
respectively (Scheme 1).
7
a
constant of 11.0 Hz. Again optical rotation of compound
11 {([α]D = -63 (c 0.15, EtOH)} did not match with the
25
2
D
5
7a
reported trans-isomer {[α]
= +123 (c 0.75, EtOH)}.
The compound 10 was also converted to the corresponding
nosyl derivative 12. It showed a doublet of C12b-H at δ 3.89
(d, J = 5.1 Hz), but the doublet of the corresponding trans-
6
a,7a
isomer
appeared at δ 4.12 (d, J = 11.6 Hz) and optical
25
rotation of compound 12 ([α]D = -78.2 (c 0.37, CHCl3)
also did not match with the reported data for the trans-
2
5
7a
25
2
. Results and Discussion
isomer {[α]
D
=+38.8 (c 0.37, CHCl
3
) and [α]
) }. In both the cases the optical rotations and
the chemical shifts as well as coupling constants of C -H
D
=+30.2 (c
6
a
1
.00, CHCl
3
Weinreb amide 4 derived from Garner’s aldehyde of L-
serine is a versatile intermediate for the divergent and
scalable synthesis of dihydrexidine 1a and other
hexahydrobenzophenanthridines has been developed in our
1
2b
1
1
in H NMR spectra differ from the trans-isomer. In H
1
3
NMR and C NMR spectra, the chemical shifts diverge
considerably too. These results unambiguously proved cis-
geometry of compounds 9-12. Earlier we have
unequivocally proved that when the aminotetralin ring was
constructed first followed by the C-ring to form
7
b
laboratory. Thus the study began with the Weinreb amide
and it was reacted with protected 2-bromobenzaldehyde 5
4
using 3.0 equivalents of n-BuLi in toluene at 0 ˚C to get
ketone 6 in 66% yield (Scheme 2). Ketone 6 was reduced
hexahydrobenzophenanthridine,
trans-geometry
was
7
with NaBH in MeOH to afford the amino alcohol 7 as a
obtained. In this case we have started with two very acid
labile groups; that might have been deprotected before the
Friedel-Crafts cyclization had occurred. Under acidic
condition the formation of isoquinoline unit (C-ring) was
faster, which in turn guided the geometry of the Friedel-
Crafts alkylation to construct the B-ring (Scheme 2). To
support the hypothesis, the cascade cyclization was
monitored by LC-MS at different intervals. Formation of
isoquinoline 8 was detected, which was also identified by
4
diastereomeric mixture (dr 84:16) in 85% yield. We have
chosen the substituent in the phenyl part in such a way that
alongside the acid catalyzed Friedel-Crafts cyclization both
the protecting groups of the phenyl moiety [-CH(OCH ) ]
as well as the amino protecting group (N-Boc) would be
cleaved at the same time and the third ring will form
concomitantly. The cyclization was carried out on the
2
2
diastereomeric mixture of 7 using PPA, MeSO H and
3
7
a
1
TFA. We were delighted to observe that all the reagents
worked well and the anticipated third ring was also formed
in one go. The imine, tetrahydrobenzophenanthridine 9 was
H NMR. In a nutshell two rings formed in the reverse
order than what we have done earlier and this led to cis-
7
stereochemistry.

ACCEPTED MANUSCRIPT
Tetrahedron
Scheme 2. Cascade cyclization of aminoalcohol 7 to cis-O-methyldihydrexidine
The above observation led us to look into the protecting
groups of the phenyl ring as well as amine more closely so
that the C-ring formation can be prevented before the
Friedel-Crafts alkylation and protecting groups should not
be too labile under acidic condition. Hence, our focus
shifted from Boc-protected Weinreb amide to Cbz-
protected compound 18 and the acid stable benzyl protected
2
-bromobenzyl alcohol. Multi-gram synthesis of Weinreb
amide 18 was done from Cbz-protected Garner’s aldehyde
7
b
1
3 (Scheme 3). The Cbz-protected Garner’s aldehyde 13
11
was prepared in five steps following literature procedure
starting from L-serine as the chiral synthon. The optical
purity of the Cbz-protected Garner’s aldehyde was verified
2
5
by comparing the optical rotation. Observed value ([α]D
=
-
67.6 (c 1.18, CHCl
3
)) matched excellently with reported
2
5
10a
22
values ([α]
1
D
= -70.1 (c 1.01, CHCl
3
)
D
and [α] = -60.2 (c
10b
3
.18, CHCl )).
The Garner’s aldehyde 13 was reacted with the ylide
generated from (3,4-dimethoxybenzyl) triphenyl
phosphonium bromide 14 to afford the alkene as a (1:1)
mixture E/Z-isomers. The byproduct Ph PO was removed
Scheme 3. Synthesis of Weinreb amide 18
3
by column purification and the product was hydrogenated
at atmospheric pressure using Pd-C catalyst poisoned with
1
1
diphenyl sulfide to prevent removal of Cbz-group to get
compound 15 in 87% yield over two steps. Acetonide
deprotection using pTSA in MeOH was facile to provide N-
protected 2-amino-4-arylbutyl alcohol 16 in 88% yield.
TEMPO mediated oxidation of 16 using PhI(OAc)2 in
aqueous acetonitrile (1:1) gave the corresponding acid 17 in
8
2% yield. The acid 17 was converted to the Weinreb
amide 18 in 76% yield (Scheme 3). All the steps leading to
the Weinreb amide from L-serine were done in multi-gram
scale with high yield.
Lithiated 19 on reaction with Weinreb amide 18 gave
ketone 20 (Scheme 4). Use of 3.0 equivalents of lithiated
reagent and maintaining the temperature gave best yield of
7
4%. The reduction using NaBH4 worked very well to

ACCEPTED MANUSCRIPT
Tetrahedron
afford 21 as a diastereomeric mixture (dr 84:16) in 90% of
yield. The Friedel-Crafts cyclization of diastereomeric
the reaction worked well in AcOH to afford the desired
aminotetralin 23 in 90% of isolated yield. To complete
synthesis, the compound 23 was heated with dry HCl in
dioxane; this afforded the corresponding chloro-compound.
Without any purification it was heated with K CO in
mixture of 21 using MeSO H that leads exclusively to the
3
aminotetralin 22 (dr >99:1) was optimized under different
conditions and gave 64% yield in the presence of 3.0
2
3
7
a
equivalents of MeSO
3
H at rt. The most unanticipated
dioxane followed by treatment with dry HCl in dioxane
achieved the synthesis of hydrochloride salt of O-methyl
dihydrexidine 24⋅HCl in 70% of yield over three steps. The
hurdle faced during the deprotection reaction. The
hydrogenation using 10% Pd-C in MeOH and in EtOAc
easily removed the Cbz protection at 1atm but the
debenzylation did not occur even at 60 psi. The most likely
reason could be poisoning of the catalyst by the free –NH2
group. Reduction was tried in MeOH using conc. HCl (3.0
equiv) at 1atm but within half an hour both the benzylic
positions reduced to give deoxygenated compound. Finally
2
5
optical rotation of the compound 24⋅HCl {[α] D = +126.5
(c 0.6, EtOH)} matched beautifully with the literature data
25
5c,7a
{[α]D = +123 (c 0.75, EtOH}.
Demethylation of the
Scheme 4. Asymmetric synthesis of dihydrexidine via sequential cyclization approach
compounds 24 and 11, as was done earlier in our
7
laboratory, accomplished the synthesis of dihydrexidine
and its cis-isomer from a common intermediate with overall
yields of 25.5% (7 steps) and 29.7% (6 steps), respectively,
4. Experimental Section
4.1. General methods
7
whereas earlier methods provided only 13.1% overall yield
over eight steps. The present route is more efficient and
scalable, in particular, for the construction of C-ring
avoiding costly and sensitive TMSOTf.
All reactions were conducted using oven-dried glassware
under an atmosphere of argon (Ar) or nitrogen (N ).
2
Commercial grade reagents were used without further
purification. Solvents were dried and distilled following
usual protocols. Column chromatography was carried out
using silica gel (100-200 and 230-400 mesh). TLC was
performed on aluminum-backed plates coated with Silica
3
. Conclusion
1
In summary we have developed the first divergent and
scalable asymmetric synthesis of dihydrexidine and its cis-
isomer from a common advanced intermediate derived
from L-serine via protection group controlled cyclization.
N-Boc and acetal protected amino alcohol 7 undergo
cascade cyclization under acidic condition leading
exclusively to cis-tetrahydrobenzophenanthridine followed
by reduction afforded the cis-dihydrexidine (with 29.7%
over yield), where formation of C-ring (isoquinoline unit)
prior to Friedel-Crafts cyclization detects the cis-
stereochemistry of the B-ring. N-Cbz and O-benzyl
protection stop the C-ring formation and exclusive F-C
cyclization yielded the trans-1-aryl-2-aminotetralin and
subsequent deprotection-cyclization to form the C-ring
afforded dihydrexidine with 25.1% overall yield in seven
gel 60 with F254 indicator. The 1 H NMR spectra were
3
recorded with a 400 MHz and C NMR spectra were
1
recorded with a 100 MHz using CDCl
3
and DMSO-d
6
. H
NMR chemical shifts are expressed in parts per million (δ)
1
3
relative to CDCl
NMR chemical shifts are expressed in parts per million (δ)
relative to the CDCl resonance (δ = 77.0) and DMSO-d (δ
3
(δ = 7.26) and DMSO-d
6
(δ =2.49);
C
3
6
= 39.7). High resolution mass spectra (HRMS) were
measured with a QTOF I (quadrupole–hexapole TOF) mass
spectrometer with an orthogonal Z-spray–electrospray
interface.
4.2. [(R)-3-(3,4-Dimethoxy-phenyl)-1-(2-[1,3]dioxolan-2-
yl-benzoyl)-propyl]-carbamic acid tert-butyl ester (6)
steps.
This
protocol
is
applicable
to
other
To a stirred solution of compound 5 (9.6 g, 41.9 mmol) in
anhydrous toluene (95 mL) n-butyl lithium (1.96 M in
hexane, 20.0 mL, 39.2 mmol) was added drop wise at 0 °C
hexahydrobenzophenanthridines too.

ACCEPTED MANUSCRIPT
Tetrahedron
and stirred at that temperature for 30 minutes. Compound 4
5.0 g, 13.07 mmol) in anhydrous toluene (40 mL) was
added to the reaction mixture at 0 °C and stirred at ambient
temperature for 45 min. Reaction mixture was quenched
preheated oil bath. Reaction mixture was diluted with ethyl
(
acetate (25 mL) and successively washed with saturated
aqueous sodium bicarbonate solution (10 mL), brine (25
mL) and organic layer was dried over anhydrous sodium
sulphate, concentrated and purified by column
with saturated NH Cl (10 ml) at ice bath temperature and
4
extracted with ethyl acetate (60 mL x 3). Combined organic
layer was washed with brine (100 mL), dried over
anhydrous sodium sulphate and purified by column
chromatography (R
f 2 2
0.46 in 1:19 MeOH/CH Cl ) to get
compound 9 (0.085 g, 68%; dr >99:1) as yellow solid.
1
3
M.P. 158-160 ˚C. H NMR (CDCl ,400 MHz) : δ 8.32 (s,
chromatography (Rf 0.6, 1:1 EtOAc/hexanes) to get
1H), 7.41-7.37 (m, 1H), 7.33-7.28 (m, 2H), 7.20 (d, J =
7.4Hz ,1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.14-4.11(m, 1H),
4.02 (d, J = 5.7Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.96-
1
compound 6 (4.1 g, 66%) as colorless oil. H NMR (CDCl
3
,
4
7
00 MHz) δ : 7.68 (d, J = 7.7 Hz, 1H), 7.5- 7.46 (m, 2H),
.39-7.35 (m, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.65(d, J = 8.1
13
2.90 (m, 1H), 2.85- 2.77 (m, 1H), 2.05-2.0 (m, 2H).
C
Hz, 1H) 6.63 (s, 1H), 6.19 (s, 1H), 5.35 (d, J = 8.7 Hz, 1H),
NMR (CDCl , 100 MHz): δ 159.9, 147.9, 147.0, 138.7,
3
5
3
1
1
1
5
.07-5.02 (m, 1H), 4.04-3.93 (m, 4H), 3.83 (s, 3H), 3.8 (s,
131.1, 128.6, 128.1, 127.4, 127.3, 125.9, 113.1, 111.9, 56.0,
50.9, 55.8, 38.6, 26.9, 24.7. LC–MS (ESI): 294.0 [M+H] .
+
H), 2.66-2.57 (m, 2H), 2.14-2.08 (m, 1H), 1.76-1.72 (m,
1
3
H), 1.41 (s, 9H). C NMR (CDCl
3
, 100 MHz): δ 203.8,
νmax (KBr): 3001, 2928, 2856, 1629, 1609, 1515, 1450,
-1
55.6, 148.8, 147.3, 137.1, 136.7, 133.7, 131.1, 128.8,
27.7, 127.0, 120.3, 111.8, 111.2, 100.9, 79.6, 65.1, 65.0,
7.6, 55.8, 55.7, 33.9, 31.2, 28.3(3C). LC–MS (ESI): 472.0
1349, 1261, 1214, 1112, 1031, 1013, 963, 821, 534 cm .
25
[α]
D
- 22 (c 0.14, CH Cl ). HRMS (ESI): Calcd for
2 2
+
C H NO , 294.1494 m/z [M+H] , found 294.1489.
1
9
20
2
+
+
[
M+H] ; 489.0 [M+NH
4
] . νmax (neat): 3367 (br), 2969,
2
1
934, 1701, 1591, 1514, 1460, 1366, 1260, 1238, 1162,
4.5. (6aR,12bR)-10,11-Dimethoxy-5,6,6a,7,8,12b-hexa-
hydro-benzo-[a]-phenanthridine (10)
-
1
084, 1028, 980, 943, 865, 762, 629 cm . HRMS (ESI):
+
Calcd for C H NO Na, 494.2155 m/z [M+Na] , found
2
6
33
7
4
94.2155.
To compound 9 (0.052 g, 0.177 mmol) in ethanol (0.5 ml)
was added NaBH (4 mg, 0.10 mmol) in portions at 0 °C.
4
4
.3. {(R)-3-(3,4-Dimethoxy-phenyl)-1-[(2-[1,3]-di-
Reaction mixture was stirred at room temperature for 45
minutes. Ethanol was evaporated under reduced pressure
oxolan-2-yl-phenyl)-hydroxymethyl]-propyl}-carbamic
acid tert-butyl ester (7)
4
and quenched with NH Cl solution. Reaction mixture was
extracted with ethyl acetate (3x5 mL), washed with brine,
dried over anhydrous sodium sulphate, concentrated to get
crude compound 10 (quantitative) which was used in the
next step without any purification.
To a stirred solution of compound 6 (3.4 g, 7.22 mmol) in
anhydrous ethanol (30 mL) was added NaBH (0.343 g,
4
9
.02 mmol) in portions at 0°C. Reaction mixture was
stirred at room temperature for 2h. Excess reagent was
quenched with saturated aqueous NH Cl and extracted with
4
4.6. (6aR,12bR)-10,11-Dimethoxy-5,6,6a,7,8,12b-hexa-
ethyl acetate (50 mL x 3). Combined organic layer was
washed with brine, dried over anhydrous sodium sulphate
hydro-benzo[a]phenanthridine hydrochloride (11)
and purified by column chromatography (R 0.54 in 1:1
To a solution of compound 10 (0.052 g, 0.176 mmol) in
anhydrous ethanol (1 mL) was added ethanolic HCl (1 mL).
Reaction mixture was stirred at room temperature for 2h
and then solvent was evaporated to dryness under reduced
pressure to get a solid which was washed with ether and
f
EtOAc/hexanes) to get compound 7 (2.9 g, 85%) as
1
diastereomeric mixture (dr 84:16). H NMR (400 MHz,
CDCl
3
) δ: Major diastereomer 7.58 (d, J = 7.6 Hz, 1H),
7
.51 (d, J = 7.6 Hz, 1H), 7.36 ( t, J = 7.5 Hz, 1H), 7.27 (t, J
=
7.5 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz,
filtered to get the compound 11 (0.47 g, 82% ). M.P. >200
1
1
5
1
H), 6.67 (s, 1H), 5.28 (s, 1H), 5.01 (m, 1H), 4.18-3.88 (m,
H), 3.82 (s, 6H), 2.66 (m, 1H), 2.53 (m, 1H), 2.01 (m,
H), 1.70 (m, 1H), 1.3 (s, 9H). C NMR (100 MHz,
) δ: 155.8, 148.7, 147.9, 140.6, 134.8, 134.1, 129.3,
27.4, 127.1, 126.5, 120.1, 111.9, 111.3, 102.0, 79.2, 78.8,
2.3, 65.1, 64.9, 55.9, 55.7, 32.3, 31.8, 28.2. LC–MS (ESI):
˚C; H NMR (DMSO-d , 400 MHz) δ 10.4 (br s, 1H), 9.4
6
(br s, 1H), 7.29-7.16 (m, 4H), 6.82 (s, 1H), 6.76 (s, 1H),
1
3
4.32-4.20 (m, 3H), 3.96 (m, 1H), 3.73 (s, 3H), 3.72 (s, 3H),
1
3
CDCl
3
2.82-2.78 (m, 2H), 2.08 (m, 1H), 1.72 (m, 1H). C NMR
1
7
4
(DMSO-d , 100 MHz): δ 147.9, 146.8, 135.3, 128.4, 128.3,
6
127.6, 127.1, 126.75, 126.7, 125.3, 114.1, 112.0, 55.5, 55.3,
+
+
+
74.0 [M+H] , 491.4 [M+NH ] . ν
(KBr): 3600-3300
50.2, 40.9, 38.1, 25.8, 22.3. LC-MS (ESI): 296.0 [M+H] .
4
max
(
1
br), 3066, 2971, 2934, 1706, 1590, 1515, 1454, 1366,
ν
max (neat): 3700-3200 (br), 2920, 2767, 2677, 2577, 2420,
-
1
260, 1239, 1164, 1027, 944, 860, 763 cm .HRMS (ESI):
1740, 1610, 1518, 1455, 1436, 1406, 1251, 1106, 1022,
870, 797, 754 cm . [α]
(ESI): Calcd for C H NO 296.1651 m/z [M+H] , found
+
-1
25
D
Calcd for C26
4
H35NO
7
N 496.2311 m/z [M+Na] , found
- 63 (c 0.15, EtOH). HRMS
+
96.2311.
1
9
22
2
2
96.1647.
4
.4. (6aR,12bR)-10,11-Dimethoxy-6a,7,8,12b-tetra-
hydro-benzo[a]phenanthridine (9)
(6aR,12bR)-10,11-Dimethoxy-6-(4-nitro
sulfonyl)-5,6,6a,7,8,12b-hexahydrobenzo [a] phenanthri
benzene
To a stirred solution of compound 7 (0.20 g, 0.423 mmol;
dr 84:16) in 1, 2-dichloroethane (2 mL) was added methane
sulfonic acid (140 µl, 2.11 mmol) at ambient temperature.
Reaction mixture was heated at 50 °C overnight on a
-dine (12)
To a stirred solution of crude compound 10 (0.028 g, 0.095
mmol ) in anhydrous dichloromethane (0.5 mL) was added

ACCEPTED MANUSCRIPT
Tetrahedron
anhydrous triethyl amine (30 µl, 0.237 mmol) and p-
nitrobenzene sulfonyl chloride (0.022 g, 0.099 mmol) at 0
ethyl acetate in hexanes as eluent to obtain a colorless
1
3
liquid 15 (19.0 g, 95%). H NMR (CDCl , 400 MHz): δ
°
C. Reaction mixture was stirred at room temperature for
h. Water (10 mL) was added to the reaction mixture and
major rotamer 7.32 (m, 5H), 6.78-6.68 (m, 2H), 6.58 (s,
1H), 5.15-5.05 (m, 2H), 3.95 (m, 2H), 3.83 (s, 6H), 3.79
(m, 1H), 2.62-2.52 (m, 2H), 1.95 (n, 1H), 1.83 (m, 1H),
3
extracted with ethyl acetate (2x10 mL). Combined organic
layer was washed with brine, dried over anhydrous sodium
sulphate, concentrated, purified by column chromatography
1
3
3
1.69 (s, 3H0, 1.51 (s, 3H). C NMR (CDCl , 100MHz): δ
152.2, 148.8, 147.2, 136.6, 133.8, 133.6, 128.4 (2C), 127.9,
127.8, 119.9, 111.6, 111.2, 94.0, 66.9, 66.4, 56.8, 55.8,
(
(
(
8
6
R
f
~0.68 in 5% MeOH in CH
0.040 g, 84%) as yellow solid. M.P. >200 ˚C; H NMR
CDCl , 400 MHz): δ 8.3 (d, J = 8.7 Hz, 2H), 7.99 (d, J =
.7Hz, 2H), 7.19-7.13 (m, 2H), 7.06-7.04 (m, 1H), 6.93-
.91 (m, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 4.47 (d, J = 15.0
2 2
Cl ) to get pure product 12
1
+
55.7, 35.1, 32.0, 26.5, 23.1. LC-MS (ESI): 400.0(MH ),
+
3
417.0(M+NH
4
). νmax (neat): 2982, 2936, 1701, 1590, 1515,
1459, 1407, 1352, 1306, 1259, 1211, 1145, 1094, 1070,
-1
1029, 843, 763, 698 cm . HRMS (ESI): Calcd for
+
Hz,1H), 4.38 (d, J = 15.0 Hz,1H), 4.32-4.27 (m, 1H), 3.89
C H NO Na, 422.1943 m/z [M+Na] , found 422.1943.
2
3
29
5
2
5
(
d, J = 5.1 Hz,1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.88-2.77 (m,
[α]
D
3
-32.6 (c 1.02, CHCl ).
1
3
2
H), 2.08-1.99 (m, 1H), 1.86-1.81 (m, 1H). C NMR
, 100 MHz): δ 149.9, 148.2, 147.1, 144.7, 137.5,
(
CDCl
3
4.9. [(R)-3-(3,4-Dimethoxy-phenyl)-1-hydroxymethyl-
1
1
2
2
1
31.3, 128.4(2C), 128.0, 127.9, 127.7, 126.6, 126.3, 126.2,
propyl]-carbamicacid benzyl ester (16)
24.3(2C), 113.2, 111.5, 55.9, 55.8, 54.0, 45.8, 42,3, 27.0,
+
6.6. LC-MS (ESI): 481.04 [M+H] . ν
(KBr): 3105,
A solution of compound 15 (38.0 g, 95.1 mmol) and p-
toluene sulfonic acid monohydrate (1.0 g, 7.6 mmol, 0.08
equiv) in anhydrous methanol (380 mL) was stirred at room
temperature for 4h and then it was concentrated under
reduced pressure. The residue was diluted with ethyl
acetate (500 mL) and washed successively with a saturated
aqueous sodium bicarbonate solution (200 mL), water (200
mL), and brine (500 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to give the crude product, which was
max
999, 2961, 2938, 2838, 1607, 1538, 1518, 1454, 1347,
260, 1236, 1160, 1105, 1017, 972, 856, 817, 739, 684, 600
-
1
25
cm . [α]
D
3
- 78.2 (c 0.37, CHCl ). HRMS (ESI): Calcd for
+
C H N O SNa, 503.1253 m/z [M+Na] , found 503.1253.
2
5
24
2
6
4
.7. (S)-4-Formyl-2,2-dimethyl-oxazolidine-3-carboxylic
acid benzyl ester (Garner’s aldehyde 13)
This was prepared in 83% yield by following the literature
procedure.
1
0
purified by flash column chromatography(R 0.4 in 7:3
f
EtOAc/hexanes) using 1:1 ethyl acetate in hexanes as
4
.8. (R)-4-[2-(3,4-Dimethoxyphenyl)-ethyl]-2,2-di-
eluent to obtain product as off-white solid 16 (30.0 g,
1
methyl-oxazolidine-3 carboxylic acid benzyl ester (15)
88%). H NMR (CDCl
3
, 400 MHz): δ 7.32-7.27 (m, 5H),
6
.76-6.68 (m, 3H), 5.11-5.06 (m, 3H), 3.82 (s, 3H), 3.81 (s,
To a slurry of the 3,4-dimethoxybenzyl phosphonium
bromide 14 (77.5 g, 156.6 mmol, 1.25 equiv) in anhydrous
tetrahydrofuran (300 mL, 2.4 mL/mmol) at -20 °C was
added n-BuLi (2 M, 75.2 mL, 150.4 mmol, 1.2 equiv) drop
wise over 15 min. After another 20 minutes of stirring at
the same temperature, the reaction mixture was cooled to -
3H), 3.71-3.54 ( m, 3H), 2.67-2.54 (m, 2H), 1.86-1.72
1
(m,2H). H NMR (DMSO-d , 400 MHz): δ 7.37-7.3 (m,
6
5H), 7.07 (d, J = 8.4Hz, 1H, exchangeable -NH), 6.82(d, J=
8.1Hz, 1H), 6.75 (s, 1H), 6.67 (d, J = 8.1Hz, 1H), 5.06-4.99
(m, 2H), 4.62 (t, J = 5.6Hz, 1H, exchangeable -OH), 3.70
(s, 6H), 3.43-3.34 (m, 2H), 3.31-3.22 (m, 1H), 2.60-2.54
(m, 1H), 2.46-2.40 (m, 1H), 1.82-1.73 (m, 1H), 1.6-1.51
7
0 °C and a solution of the aldehyde 13 (33.0 g, 125.3
mmol, 1.0 equiv) in anhydrous tetrahydrofuran (238 mL,
.9 ml/mmol) over 15 min and stirred for another 45 min.
1
3
(m, 1H). C NMR (CDCl , 100 MHz): δ 156.7, 148.8,
3
1
147.2, 136.3, 133.9, 128.5(2C), 128.1(2C), 128.0, 120.07,
111.7, 111.3, 66.8, 65.3, 55.85, 55.75, 52.75, 33.25, 31.8.
The reaction mixture was then warmed to -15 °C over 45
min. The reaction mass was treated cautiously with
saturated aqueous ammonium chloride solution (250 mL).
It was then filtered through a celite bed and extracted with
ethyl acetate (3x500 mL). The combined organic layer was
dried over anhydrous sodium sulphate, filtered and
concentrated under reduced pressure. The crude product
was purified by flash chromatography using 30% ethyl
acetate in hexanes as eluent to provide ~1:1mixture of E/Z
isomers as pale-yellow liquid (40.0 g, 80%) which was
used as such in the next step. To 20.0 g (50.3 mmol), of the
alkene in methanol (120 mL) was added 10% Pd–C catalyst
+
+
LC-MS (ESI): 360.2 [M+H] , 377.2 [M+NH
4
] . νmax
(KBr): 3480 (br), 3308, 3062, 2947, 1688, 1666, 1590,
1547, 1518, 1456, 1341, 1253, 1146, 1065, 1029, 954, 809,
-
1
757, 740, 699 cm . HRMS (ESI): Calcd for C H NO Na,
2
0
25
5
+
25
382.1630, m/z [M+Na] , found 382.1631. [α]
D
+13.3˚ (c
0.92, CHCl3).
4.10. (R)-2-Benzyloxycarbonylamino-4-(3,4-dimethoxy-
phenyl)-butyric acid (17)
To a stirred solution of the alcohol 16 (30.0 g, 83.5 mmol,
1.0 equiv) in aqueous acetonitrile (1:1, 200 mL) were
successively added diacetoxyiodobenzene (59.1 g, 183.6
mmol, 2.2 equiv) and 2,2,6,6-tetramethyl-1-piperidinyl free
radical (TEMPO) (2.6 g, 16.7 mmol, 0.2 equiv) at 0 °C.
The reaction mixture was then stirred 17h at room
temperature. The reaction mixture was half-concentrated
under reduced pressure and then cooled by ice-bath. To it
(
2.0 g, 10% w/w) poisoned with diphenyl sulphide (0.16
mL, 1.0 mmol, 0.02 equiv) and stirred at room temperature
for 17 h under 1 atmosphere hydrogen (balloon) pressure.
The reaction mixture was then filtered through a celite bed
and washed with ethyl acetate. The filtrate was evaporated
under reduced pressure and purified by flash column
chromatography (R 0.57 in 3:7 EtOAc/hexanes) using 30%
f

ACCEPTED MANUSCRIPT
Tetrahedron
was added sodium hydroxide solution (4.0 M, 100 mL).
4.12. [(R)-1-(2-Benzyloxymethyl-benzoyl)-3-(3,4-di meth
The aqueous part was washed with diethyl ether (2x100
mL). It was then acidified to pH 4 by the drop wise
addition of hydrochloric acid solution (4 M) at 5-10 °C.
The compound was extracted with ethyl acetate (3x500
mL), combined organic layers was successively washed
with water (150 mL), brine (250 mL), dried over anhydrous
sodium sulfate and solvents removed under reduced
pressure. The crude was purified by column
-oxyphenyl)-propyl]-carbamic acid benzyl ester (20)
To a solution of the aryl bromide 19 (6.38 g, 23 mmol, 3.0
equiv) in anhydrous THF (60 mL) was added n-butyl
lithium (2.3 M in hexanes; 9.4 mL, 21.6 mmol) dropwise at
-78 °C under nitrogen atmosphere and stirred for 15 min. A
pre-cooled (-78 °C) solution of Weinreb amide 18 (3.0 g,
7.2 mmol, 1.0 equiv) in anhydrous THF (60 mL) was then
added to it. The reaction mass was stirred at -78°C for 30
min and then brought to -20 °C in another 30 minutes. It
chromatography (R
f 2 2
0.46 in 1:9 MeOH/CH Cl ) using 5%
methanol in dichloromethane to give 17 (25.5 g, 82%) as a
1
light brown sticky-solid. H NMR (DMSO-d
6
, 400 MHz):
was carefully quenched with
a
saturated aqueous
δ12.6 ( br s, 1H, exchangeable, -CO H), 7.6 (br s, 1H,
exchangeable -NH), 7.37-7.29 (m, 5H), 6.83(d, J = 8.1 Hz,
ammonium chloride solution (60 mL) and allowed to come
to room temperature. It was extracted with ethyl acetate
(2x150 mL). The combined organic layer was washed with
water, brine, dried over anhydrous sodium sulfate and
filtered. Solvents removed under vacuum and the crude
2
1
3
1
1
1
3
H), 6.76 (s, 1H), 6.67 (d, J = 7.8 Hz,1H), 5.04 (s, 2H),
.89-3.84 (m, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 2.59-2.53 (m,
13
H), 1.94-1.82 (m, 2H). C NMR (DMSO-d , 100 MHz): δ
6
73.9, 156.1, 148.5, 146.9, 137.0, 133.4, 128.2(2C), 127.7,
27.6(2C), 120.0, 112.2, 111.8, 65.3, 55.4, 55.2, 53.2, 32.8,
product was purified by flash column chromatography (R
f
0.56 7:13 EtOAc/hexanes) using 40% ethyl acetate in
-
1.1. LC-MS (ESI): 372.2[M-H] . νmax (neat): 3700-3200
hexanes to afford the ketone 20 (2.95 g, 74%) as a colorless
1
(
br), 2922, 2852, 1718, 1515, 1458, 1418, 1342, 1260,
sticky mass. H NMR (CDCl , 400MHz): δ 7.6(d, J = 7.6
3
-
1
25
D
1
+
C
237, 1150, 1051, 1026, 807, 763, 738, 697 cm . [α]
16.9 (c 1.14, MeOH). HRMS (ESI): Calcd for
Hz, 1H), 7.57(d, J = 7.6 Hz, 1H), 7.5 (t, J = 7.5 Hz, 1H),
7.36-7.16 (m, 10H), 6.74(d, J = 8.1 Hz, 1H), 6.61 (d, J =
8.1 Hz, 1H), 6.59 (s, 1H), 5.70 (d, J = 7.3 Hz, 1H), 5.24-
+
20
H23NO
6
Na, 396.1423 m/z [M+Na] , found 396.1423 .
5
.19 (m, 1H), 5.16-5.09 (m, 2H), 4.78 (s, 2H), 4.57 (s, 2H),
4
.11. [(R)-3-(3,4-Dimethoxy-phenyl)-1-(methoxymethyl-
3.83 (s, 3H), 3.78 (s, 3H), 2.58 (quasi t, J = 7.7 Hz, 2H),
1
3
carbamoyl)-propyl]-carbamic acid benzyl ester (18)
2.13-2.04 (m, 1H), 1.76-1.67 (m, 1H). C NMR (CDCl3,
00 MHz): δ 202.1, 156.1, 148.7, 147.3, 139.5, 137.9,
1
To a solution of the acid 17 (25.0 g, 66.9 mmol) in
anhydrous dichloromethane (240 mL) at -15 °C was added
N-methylmorpholine (16.2 mL, 147.3 mmol, 2.2 equiv).
Isobutylchloroformate (10.5 mL, 80.3 mmol, 1.2 equiv)
was added in dropwise fashion under vigorous stirring at -
136.3, 134.3, 133.2, 132.0, 128.5, 128.4(4C), 128.3(2C),
128.0, 127.9, 127.6(2C), 127.5, 127.3, 120.3, 111.7, 111.1,
72.9, 70.1, 66.8, 56.8, 55.8, 55.6, 34.4, 31.1. LC-MS (ESI):
+
+
554.4(MH ), 571.4(M+NH
4
).νmax(neat): 3354 (br), 3031,
2933, 2857, 1716, 1695, 1514, 1454, 1353,1260, 1236,
-
1
1
5
°C. After 15 min, N,O-dimethylhydroxylamine
1151, 1072, 1029, 742, 699 cm . HRMS (ESI): Calcd for
+
hydrochloride (10.4 g, 107.1 mmol, 1.6 equiv) was added.
The mixture was then stirred at -15 °C for an additional 1h
and then allowed to warm to room temperature and stirred
for 1h. The reaction mixture was poured into ice cold water
C H NO Na, 576.2362 m/z [M+Na] , found 576.2362.
3
4
35
6
2
5
[α]
D
3
-5.9˚ (c 1.02, CHCl ).
4.13. [(R)-1-[(2-Benzyloxymethyl-phenyl)-hydroxy-
methyl]-3-(3,4-dimethoxy-phenyl)-propyl]-carbamic
acid benzyl ester (21)
(
280 ml) and extracted with dichloromethane (2x500 mL).
The combined organic layer was washed with water, brine,
and dried over anhydrous sodium sulfate. Solvent was
removed under vacuum and the crude product was purified
by flash column chromatography(Rf 0.5 in 13:7
EtOAc/hexanes) using 40% ethyl acetate in hexanes to
To a solution of the ketone 20 (2.85 g, 5.1 mmol, 1.0 equiv)
in absolute ethanol (28 mL) was added sodium borohydride
(0.192 g, 5.1 mmol, 1.0 equiv) portion-wise at 0 °C under
nitrogen and allowed to stir at ambient temperature for 2 h.
The reaction mass was quenched with a chilled saturated
aqueous ammonium chloride solution (35 mL). The
volatiles were evaporated under reduced pressure followed
by extraction into ethyl acetate (2x100 mL); combined
organic layer washed with water, brine, dried over
anhydrous sodium sulfate and concentrated under reduced
pressure to afford the crude alcohol which was purified by
1
obtain 18 (21.3 g, 76%) as a colorless sticky mass. H
NMR (CDCl
3
, 400 MHz): δ 7.34-7.31 (m, 5H), 6.78-6.71
(
5
m, 3H), 5.47 (d, J = 8.8 Hz,1H), 5.13(d, J = 12.3 Hz),1H),
.06 (d, J = 12.3 Hz, 1H), 4.74 (m, 1H), 3.84 (s, 3H), 3.83
(
(
1
1
5
s, 3H), 3.62 (s, 3H), 3.16 (s, 3H), 2.70-2.55 (m, 2H), 2.02
13
m, 1H), 1.86-1.82 (m, 1H). C NMR (CDCl
3
, 100MHz): δ
72.6, 156.1, 148.7, 147.2, 136.3, 133.5, 128.4 (2C), 128.0,
27.9 (2C), 120.3, 111.9, 111.2, 66.8, 61.4, 55.9, 55.8,
+
0.5, 34.5, 32.0, 31.1. LC-MS (ESI): 417.4 [M+H] , 434.4
flash
column
chromatography(Rf
0.5
in
7:13
]
+
[
M+NH
4
. νmax (KBr): 3277, 2932, 2845, 1715, 1648,
EtOAc/hexanes) using 40% ethyl acetate in hexanes to
1
1
517, 1459, 1260, 1239, 1153, 1057, 1027, 989, 748, 629
obtain 21 (2.6 g, 91%) as a colorless oil . H NMR (CDCl ,
3
-
1
cm .HRMS (ESI): Calcd for C22
H
28
N
2
O
6
Na, 439.1845 m/z
400 MHz): δ 7.53 (d, J = 7.8 Hz, 1H), 7.38-7.26 (m, 8H),
7.25-7.18 (m, 5H), 6.72 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 7.8
Hz, 1H), 6.59 (s, 1H), 5.19 (d, J = 9.2 Hz, 1H), 5.01 (tAB, J
+
25
[
M+Na] , found 439.1845. [α] D +51.4 (c 1.01, CH OH).
3
=
13.2 Hz, 2H), 4.63 (d, J = 11.0 Hz, 1H), 4.55 (qAB J =
1
2
1.4 Hz, 2H), 3.93 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H),
.70-2.58 (m, 2H), 2.46 (m, 1H), 1.99 (m, 1H), 1.71 (m,

ACCEPTED MANUSCRIPT
Tetrahedron
1
3
1
1
(
1
5
5
2
8
H). C NMR (CDCl , 100 MHz): δ 158.2, 148.6, 146.9,
1H), 4.20 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H), 3.53 (s, 3H),
3.17 (t, J = 11.0 Hz, 1H), 3.08-3.01 (m, 1H), 2.88 (m, 1H),
3
40.7, 137.5, 136.6, 134.47, 134.43, 130.0, 128.5, 128.37
2C), 128.35 (2C), 127.9 (2C), 127.8, 127.7 (2C), 127.6,
27.4, 126.8, 120.0, 111.6, 111.1, 72.9, 72.5, 70.4, 66.3,
5.7, 55.6, 31.6, 31.5, 29.6. LC-MS (ESI): 556.2 [M+H] ,
1
3
2.09-2.0 (m, 1H), 1.95 (m,1H), 1.91 (m, 1H). C NMR
(CDCl , 100 MHz): δ 147.6, 147.5, 142.9, 140.5, 130.4,
3
+
130.1, 129.3, 128.8, 128.0, 126.9, 112.8, 110.8, 63.1, 55.83,
+
+
73.2 [M+NH
4
] . νmax (neat): 3600-3300 (br), 3031, 2962,
55.8, 54.8, 48.1, 30.6, 28.2. LC-MS (ESI): 314.2 [M+H] .
856, 1710, 1590, 1515, 1455, 1334, 1237, 1143, 1028,
08, 759, 741, 699 cm . HRMS (ESI): Calcd for
νmax (neat): 3700-3200 (br), 3064, 2932, 1609, 1561, 1514,
-
1
-1
1450, 1405, 1255, 1219, 1117, 1014, 870, 755 cm .
+
C H NO Na, 578.2519 m/z [M+Na] , found 578.2518.
HRMS (ESI): Calcd for C H NO , 314.1756 m/z [M+H]
3
4
37
6
19 24
3
+
25
,
found 314.1751. [α]
D
-40.3 (c 0.69, EtOH)
4
.14. [(1S,2R)-1-(2-Benzyloxymethyl-phenyl)-6,7-di-
methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamic
acid benzyl ester (22)
4.16. (6aR,12bS)-10,11-Dimethoxy-5,6,6a,7,8,12b-
hexahydro-benzo[a]phenanthridine hydrochloride (24)
To a solution of the alcohol 21 (0.6 g, 1.07 mmol, 1.0
equiv; dr 84:16) in dichloromethane (12 mL) at 5-10 °C
was added methanesulphonic acid (0.21 mL, 3.2 mmol, 3.0
equiv) and the mixture was allowed to stir at room
temperature for 17 h. It was cooled to 5-10 °C; aqueous
saturated sodium bicarbonate (20 mL) was added to it
followed by extraction with dichloromethane (3x 50 mL).
The combined organic part was washed with brine, shaken
with anhydrous sodium sulphate, filtered and evaporated
under reduced pressure. It was purified by flash column
A solution of amino alcohol 23 (0.085 g, 0.27 mmol, 1.0
equiv) in 1,4-dioxane (3.6 mL) and 12 N aqueous HCl (3.2
mL) was heated under reflux for 2h. The reaction mixture
was concentrated under reduced pressure to afford the
intermediate chloride. It was immediately dissolved in
anhydrous t-BuOH (6.5 mL); anhydrous potassium
carbonate (1.49 g, 10.8 mmol, 40.0 equiv) was added and
the mixture was heated under reflux for 1h. The mixture
was cooled to room temperature, poured into water and
extracted with chloroform (3x10 mL). The organic layer
was washed with brine, dried over anhydrous sodium
sulfate, concentrated under reduced pressure and purified
by flash column chromatography (10% MeOH in EtOAc,
chromatography(R 0.4 in 7:13 EtOAc/hexanes) using 30%
f
ethyl acetate in hexanes to obtain 22 (0.37 g, 64%; dr
1
>
99:1) as a colorless oil. H NMR (CDCl , 400 MHz): δ
3
7
6
.35-7.19 (m, 13H), 6.98 (d, J = 6.8 Hz, 1H), 6.62 (s, 1H),
.03 (s, 1H), 5.9 (d, J = 6.4 Hz, 1H), 4.99 (d, J = 12.4
f
R ~0.4) to give the desired amine (0.60 g, 75%) which was
converted to its hydrochloride salt by stirring with 4 mL of
2N HCl in dioxane for 30 min. It was then evaporated and
the solid obtained was recrystallised from methanol/diethyl
Hz,1H), 4.91 (d, J = 12.4 Hz,1H), 4.76 (d, J = 10.8 Hz,1H),
4
1
2
.67-4.58 (m, 3H), 4.27 (d, J = 8.4 Hz, 1H), 3.99-3.93 (m,
H), 3.85 (s, 3H), 3.50 (s, 3H), 3.07-3.02 (m, 1H), 2.87-
ether to get pure compound 24 (0.063 g, 70%) as a light
1
3
1
.79 (m, 1H), 2.36 (m, 1H), 1.74-1.65 (m, 1H). C NMR
, 100 MHz): δ 155.9, 147.6, 147.3, 143.6, 137.5,
brown solid. H NMR (DMSO-d , 400 MHz): δ 9.82 (br s,
6
(
CDCl
3
1H), 9.61 (br s, 1H), 7.45-7.33 (m, 4H), 6.87 (s, 2H), 4.38
(m, 2H), 4.24 (d, J = 11.0 Hz, 1H), 3.76 (s, 3H), 3.73 (s,
3H), 2.98 (m,1H), 2.83(m, 2H), 2.20 (m, 1H), 1.95 (m, 1H).
1
1
7
36.9, 136.0, 130.1, 130.0, 129.4, 129.1, 128.4(4C), 128.3,
28.1(2C), 127.8, 127.7, 127.6(2C), 126.5, 113.0, 110.9,
2.6, 71.0, 65.9, 55.8 (2C), 54.1, 45.7, 28.1, 27.2. LC-MS
1
3
C NMR (DMSO-d , 400MHz): δ 147.5, 146.5, 137.3,
6
+
+
(
ESI): 538.4 [M+H] , 555.4 [M+NH
4
] . νmax (neat): 3339,
129.4, 127.7, 127.5, 126.7, 125.0, 124.7, 112.5, 112.0, 56.5,
3
1
030, 2934, 2855, 1715, 1609, 1513, 1453, 1404, 1357,
55.5, 55.4, 43.3, 40.1, 26.9, 25.1. LC-MS (ESI): 296.2
-
1
+
25
5b,c
25
253, 1229, 1115, 1045, 752, 699 cm . HRMS (ESI):
[M+H] . [α]
D
= +126.5 (c 0.6, EtOH); {Lit
D
[α] =
+
2a
25
Calcd for C H NO Na, 560.2413 m/z [M+Na] , found
5
+123.0 (c 0.3, EtOH); Lit [α] +106.0 (c 0.75, EtOH)}.
3
4
35
5
D
25
60.2413. [α]
D
3
-51.6 (c 1.0, CHCl ).
4
.15. [2-((1S,2R)-2-Amino-6,7-dimethoxy-1,2,3,4-
Acknowledgements
tetrahydro-naphthalen-1-yl)-phenyl]-methanol (23)
We thank DBT (BIPP), New Delhi (sanction no.:
102/IFD/SAN/1191/2009-2010) for providing financial
support.
To a solution of protected amine 22 (0.4 g, 1.27 mmol) in
acetic acid (2.5 mL) was added 10% Pd-C (0.040 g, 10%
w/w) and stirred under 1atm (H2 balloon) for 7h. The
reaction mixture was filtered over a celite bed using 150
mL of ethyl acetate and the volatiles were concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate (100ml) and washed with aqueous saturated sodium
bicarbonate (30 mL). The organic part was separated and
washed with brine, dried over anhydrous sodium sulphate
and evaporated under vacuum. It was purified by flash
column chromatography (R 0.4 in 1:9 MeOH/CH Cl )
Supplementary data
1
13
H NMR-, C NMR spectra and LC-mass spectra for
compounds 6, 7, 9, 11, 12, 15, 16, 17, 18, 20, 21, 22, 23
and 24. This material is available free of charge via the
Internet at http://dx.doi.org/.
f
2
2
using 10% methanol in DCM to obtain yellow oil 23 (0.210
1
g, 90%). H NMR (CDCl , 400 MHz): δ 7.38-7.3 6 (m,
3
1
6
H), 7.23-7.19 (m, 2H), 6.97-6.95 (m, 1H), 6.60 (s, 1H),
.03 (s, 1H), 4.97 (d, J =11.4 Hz,1H), 4.47 (d, J = 11.4 Hz,

ACCEPTED MANUSCRIPT
Tetrahedron
References
4. (a) Ehrlich, P. P.; Michaelides, M. R.; McLaughlin, M. M.;
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4
79; Corrigendum: Hajra, S.; Bar, S. Tetrahedron: Asymm.
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1
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3
1
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1
1. Sajiki, H; Mori, A.; Miyakawa, Y; Oshahi, E.; Haga, T.;
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ACCEPTED MANUSCRIPT
Supporting Information
Protecting Group Directed Cyclization: Asymmetric Synthesis
of Both cis-and trans-Dihydrexidine from a Common
Precursor
a
a,b
a,b
a,b
Rajesh Malhotra , Sagar Chakrabarti , Amit Ghosh , Rajib Ghosh , Tushar K.
a,b
b
b
b
b
Dey , Swarup Dutta , Krishna Babu Alapati, Shantanu Dutta , Subho Roy ,
b,*
c,*
Sourav Basu Saumen Hajra
a
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar,
Haryana 125001, India.
b
TCG Life Sciences Ltd, Saltlake, Kolkata 700091, India.
c
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
Content
NMR, LC-MS spectra and HPLC chromatogram of compound 6
NMR, LC-MS spectra and HPLC chromatogram of compound 7
…… S-3
……. S-8
NMR and LC-MS spectra of compound 9
NMR and LC-MS spectra of compound 11
NMR and LC-MS spectra of compound 12
NMR and LC-MS spectra of compound 15
NMR and LC-MS spectra of compound 16
NMR and LC-MS spectra of compound 17
NMR and LC-MS spectra of compound 18
NMR and LC-MS spectra of compound 20
NMR and LC-MS spectra of compound 21
NMR and LC-MS spectra of compound 22
……………………………. S-14
……………………………. S-19
……………………………. S-23
……………………………. S-27
……………………………. S-32
……………………………. S-37
……………………………. S-42
……………………………. S-46
……………………………. S-51
……………………………. S-56
*
Corresponding author.Tel.: +91 33 4000 7000; fax: +91 33 23673058; e-mail: sourav@chembiotek.com (S. Basu)
Corresponding author.Tel.:+ 91 3222 283340; fax: +91 3222 255303; e-mail: shajra@chem.iitkgp.ernet.in (S. Hajra)
*
S-1

ACCEPTED MANUSCRIPT
NMR and LC-MS spectra of compound 23
……………………………. S-60
……………………………. S-64
NMR and LC-MS spectra of compound 24
S-2

ACCEPTED MANUSCRIPT
[(R)-3-(3,4-Dimethoxy-phenyl)-1-(2-[1,3]dioxolan-2-yl-benzoyl)-propyl]-
carbamic acid tert-butyl ester 6:
1
H NMR spectrum (400MHz, CDCl ) of compound 6.
3
S-3

ACCEPTED MANUSCRIPT
13
C NMR spectrum (100MHz, CDCl ) of compound 6
3
S-4

ACCEPTED MANUSCRIPT
APT spectrum (100MHz, CDCl ) of compound 6.
3
S-5

ACCEPTED MANUSCRIPT
LCMS spectrum of compound 6.
S-6

ACCEPTED MANUSCRIPT
IR spectrum (neat) of compound 6
S-7

ACCEPTED MANUSCRIPT
{(R)-3-(3,4-Dimethoxy-phenyl)-1-[(2-[1,3]dioxolan-2-yl-phenyl)-hydroxy-methyl]-
propyl}-carbamic acid tert-butyl ester 7:
1
H NMR spectrum (400MHz, CDCl ) of compound 7
3
S-8

ACCEPTED MANUSCRIPT
1
3
C NMR spectrum (100MHz, CDCl ) of compound 7
3
S-9

ACCEPTED MANUSCRIPT
APT spectrum (100MHz, CDCl ) of compound 7
3
S-10

ACCEPTED MANUSCRIPT
LCMS spectrum of compound 7
S-11

ACCEPTED MANUSCRIPT
S-12

ACCEPTED MANUSCRIPT
HPLC spectrum [(Zorbax-SB C8column (250x4.6mm)5µ; Mobile phase: ACN
containing 10mM NH OAc in H O; Diluent :MeOH)] of compound 7
4
2
IR spectrum (KBr) of compound 7.
S-13

ACCEPTED MANUSCRIPT
(6aR,12bR)-10,11-Dimethoxy-6a,7,8,12b-tetrahydro-benzo[a]phenanthridine 9:
1
H NMR spectrum (400MHz, CDCl ) of compound 9
3
S-14

ACCEPTED MANUSCRIPT
1
3
C NMR spectrum (100MHz, CDCl ) of compound 9
3
S-15

ACCEPTED MANUSCRIPT
APT spectrum (100MHz, CDCl ) of compound 9
3
S-16

ACCEPTED MANUSCRIPT
LCMS spectrum of compound 9.
S-17

ACCEPTED MANUSCRIPT
IR spectrum (KBr) of compound 9
S-18

ACCEPTED MANUSCRIPT
(6aR, 12bR)-10, 11-Dimethoxy-5, 6, 6a, 7, 8,12b-hexahydro-benzo [a]
phenanthridine hydrochloride 11:
1
H NMR spectrum (d -DMSO, 400MHz) spectrum of compound 11
6
S-19