Asymmetric synthesis of a dopamine D1 agonist, dihydrexidine from d-serine

Article abstract of DOI:10.1016/j.tetasy.2011.08.014

A scalable asymmetric synthesis of trans-2-amino-6,7-dimethoxy-1- phenyltetralin 2 and its N-nosyl derivative 12 have been achieved from Garner aldehyde derived from easily available d-serine using a stereoselective PhMgBr addition, Wittig reaction and TF

Full text of DOI:10.1016/j.tetasy.2011.08.014

Tetrahedron: Asymmetry 22 (2011) 1522–1529
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of a dopamine D1 agonist, dihydrexidine from D-serine
Rajesh Malhotra a, Amit Ghosh a,b, Rajib Ghosh a,b, Sagar Chakrabarti a,b, Swarup Dutta b, Tushar K. Dey a,b
,
c,
Subho Roy b, Sourav Basu b, , Saumen Hajra
⇑
⇑
a Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana 125 001, India
b TCG Life Sciences Ltd, Saltlake, Kolkata 700 091, India
c Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A scalable asymmetric synthesis of trans-2-amino-6,7-dimethoxy-1-phenyltetralin 2 and its N-nosyl
derivative 12 have been achieved from Garner aldehyde derived from easily available -serine using a
stereoselective PhMgBr addition, Wittig reaction and TFA-mediated Friedel–Crafts cyclization as the
key steps. The synthesis of dihydrexidine is accomplished from the N-nosyl-2-amino-1-phenyltetralin 12.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 July 2011
Accepted 23 August 2011
Available online 1 October 2011
D
1. Introduction
compounds starting from costly N-(trifluoroacetyl)-D-aspartic acid
anhydride, focusing on double Friedel–Crafts reactions of two aryl
units with poor to moderate stereoselectivity.6 Tomioka et al. re-
ported a high yielding elegant and enantioselective synthesis of
dihydrexidine via a 1,4-addition of an aryllithium to dimethoxyni-
trotetralin at ꢀ90 °C.7 Use of more than a stoichiometric amount of
costly chiral ligand (2.5 equiv) and tetranitromethane, which is a
potential carcinogen, are a serious bottleneck for large scale han-
dling. Hajra et al. developed an efficient general method for the
catalytic enantioselective synthesis of 2-amino-1-aryltetralins
and then to hexahydrobenzophenanthrene via asymmetric aziri-
dination and one-pot Friedel–Crafts cyclization of the aziridine
generated in situ.8 However, scale up of the asymmetric aziridin-
ation using nitrenoid reagent (PhINNs) is another problem.
From the above reports, it is found that aminotetralin 2 is the
key precursor for the synthesis of dihydrexidine and that the
development of a scalable asymmetric route towards its synthesis,
and in turn dihydrexidine 1 is still a major challenge. We herein re-
port an efficient and scalable synthesis of 2-amino-1-phenyltetra-
lin 2 (R = H) and its N-nosyl derivative 12 (R = Ns) starting from
Garner’s aldehyde, derived from inexpensive and easily available
Dihydrexidine
1 is one of the important hexahydrobezo-
phenanthredine compounds. It has been developed and designed
as the first high affinity bioavailable full dopamine D1 agonist.1,2
This is examined for the treatment of Parkinson’s disease1,2 and
schizophrenia.3 In early clinical trials, it was administered intrave-
nously and led to intense hypotension and therefore, the develop-
ment was halted. Nevertheless, further investigation on this drug is
currently under progress in clinics to review its efficacy in improv-
ing the cognitive and working memory deficits in schizophrenia.4
Interestingly, this compound shows a high level of enantiospecific-
ity in its interaction with the D1 receptor. Hence, the development
of efficient and scalable method for the asymmetric synthesis of
dihydrexidine 1 is highly demanding.
There are few methods available in the literature for a racemic
synthesis of dihydrexidine. The first synthesis of ( )-1 was carried
out by starting from b-tetralone,1a but involved a low yielding pho-
tochemical cyclization and hence was non-viable for large scale pro-
duction. Two alternative strategies for the racemic synthesis of
dihydrexidine were reported by Nichols et al.5 The more recent
one involves intramolecular Henry cyclization of a (nitropro-
pyl)benzophenone followed by selective reduction of the resulting
tricyclic nitroalkene. This is a safe and simple method for the synthe-
sis of a nitrotetralin.5a The resolution from the mixture of isomers
was also reported with the use of (R)-O-methylmandelic acid.1d
Several attempts have been made for the asymmetric synthesis
of dihydrexidine. Ehrlich et al. have developed a general approach
for the asymmetric synthesis of hexahydrobenzophenanthridine
D-serine and the synthesis of dihydrexidine from the aminotetralin
12.
2. Results and discussion
Retrosynthetic analysis of aminotetralin 2 reveals that it can be
obtained by a Friedel–Crafts type cyclization of 1,2-aminoalcohol
3. This intermediate can in turn be prepared by the proper syn-
thetic exploitation of Garner aldehyde 4, derived from
D-serine
(Scheme 1).
⇑
Corresponding authors. Tel.: +91 33 4000 7000; fax: +91 33 23673058 (S.B.);
Garner’s aldehyde 4 was synthesized from D-serine 5 in five
tel.: +91 3222 283340; fax: +91 3222 255303 (S.H.).
E-mail addresses: sourav@chembiotek.com (S. Basu), shajra@chem.iitkgp.
ernet.in (S. Hajra).
steps by following literature procedures.9 The enantiomeric purity
of Garner’s aldehyde 4 was verified by comparing its specific rota-
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.014

R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
1523
HO
HO
MeO
NH
MeO
NHR
NHR
2
1
Dihydrexidine
MeO
MeO
NBoc
CHO
O
D-Serine
OH
PhMgBr addition
5
Garner's aldehyde
Wittig reaction
4
3
Scheme 1. Retrosynthesis of dihydrexidine 1.
tion with the literature value.9 Aldehyde 4 was reacted with phenyl
magnesium bromide that provided a mixture of diastereomers of
compound 6 with moderate selectivity (2.5:1) having the anti-iso-
mer as the major one. This step was optimized further by using
CuIꢁDMS additive10 that afforded the desired syn-isomer 6 with
excellent diastereoselectivity (dr 96:4) and in 69% yield (Scheme 2).
The free hydroxyl group of 6 was then protected as its TBDMS
ether. TBDMS was the group of choice since we have anticipated
that this group will remain stable during acidic removal of the ace-
tonide functionality. The hydroxyl functionality was protected by
reaction with TBDMSOTf and gave TBDMS-protected compound 7
in 82% yield. Refluxing a methanolic solution of compound 7 in
the presence of PPTS afforded the syn-(1R,2R)-N,O-protected-2-
amino-1-phenylpropane-1,3-diol 8 in 62% yield. Swern oxidation
of the primary alcohol 8 afforded the aldehyde and without purifi-
cation it was reacted with the ylide generated from 3,4-dime-
thoxybenzyl bromide. This reaction, under standard Wittig
conditions gave a mixture of E and Z olefinic product 9. Pd/C-cata-
lysed hydrogenation of compound 9 under atmospheric pressure
led to the formation of TBDMS-protected 1,2-hydroxyamine 10 in
almost quantitative yield. This reaction needs proper monitoring;
longer reaction time results in 10–15% of TBDMS deprotection.
For the planned Friedel–Crafts cyclization to occur, N-Boc-pro-
tected aminoalcohol 3 was prepared by desilylation of compound
10 with TBAF in THF.
Having constructed the basic framework, the intramolecular
Friedel–Crafts cyclization of 3 was carried under different reaction
conditions (Table 1). A TsCl, pyridine combination did not yield any
desired product. Other reagents such as NsCl/py, TFA and methane
sulfonic acid were found to be effective for cyclization (entries 2–
5). The NsCl/Py combination provided a moderate yield (55%) of
N-Boc-protected 2-amino-1-phenyltetralin 11. Whereas TFA and
MsOH mediated cyclization afforded 2-amino-1-phenyltetralin 2.
Among these reagents, TFA was found to be very efficient and
showed consistent results. Later it was found that TBDMS depro-
tection was not necessary. Compound 10 on heating directly in
TFA, furnished aminotetralin 2 in 62% yield with high diastereose-
lectivity (dr >99:1) (entry 6). The overall yield of aminotetralin 2
PhMgBr (2.5 equiv)
NBoc
HO
NBoc
CuI.DMS (3.0 equiv)
THF, −78 °C
69%
O
O
D-Serine
Ph
CHO
Garner's aldehyde
5
dr 96:4
6
4
TBDMSOTf (1.1 equiv)
DIPEA (1.3 equiv)
DMAP (0.1 equiv)
NHBoc
Ph
NBoc
PPTS (0.15 equiv)
O
HO
Ph
DCM, rt
82%
MeOH, reflux, 16h
OTBDMS
TBDMSO
8
62%
7
NHBoc
Ph
10% Pd/C (10% w/w),
H2(1 atm)
MeO
1. Swern oxidation
MeOH: THF (1:1)
93%
2. ArCH2PPh3Br (2.5 equiv)
n-BuLi (2.4 equiv),
THF, −78 °C
OTBDMS
MeO
9
68% for two steps
NHBoc
Ph
NHBoc
Ph
TBAF
MeO
MeO
MeO
MeO
THF,
OH
OTBDMS
0 °C to rt, 1 h
90%
3
10
Scheme 2. Synthesis of syn-aminoalcohol 3 from Garner aldehyde, derived from D-serine.

1524
R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
Table 1
Synthesis of aminotetralin 2 and 12 by Friedel–Crafts cyclization of aminoalcohols 3 and 10
NHBoc
Ph
MeO
MeO
reagents
MeO
MeO
NHR'
solvent, T, t
OR
10: R = TBDMS
3: R = H
dr > 99:1
11: R' = Boc
2: R' = H
Entry
Aminoalcohol
Reagents
Solvent
Temp (°C)
Product
Yielda (%)
1
2
3
4
5
6
3
3
3
3
3
TsCl, Py
NsCl, Py
NsCl
MeSO3H
TFA
DCM
DCM
Py
DCM
Neat
Neat
rt to 45
rt
rt
5–10
80
80
—
11
11
2
2
2
—
25b
55
60
70
62
10
TFA
a
Isolated yield after column chromatography.
Incomplete conversion.
b
from Garner’s aldehyde 4 was found to be 13.8%. Further study re-
veals that the syn-stereochemistry of the hydroxyl functionality of
aminoalcohol 10 is not so important. Friedel–Crafts cyclization of a
diastereomeric mixture of compound 10 at the benzylic-OH also
provided the aminotetralin 2 with excellent diastereoselectivity
(dr >99:1). It is to be noted that the specific rotation of the free
aminotetralin 2 in CHCl3 was found to be inconsistent when com-
pared with the reported value.7b However, HPLC analysis of 2 on a
chiral column showed high enantioselectivity (ee 95%).
12 was transformed to dihydrexidine hydrochloride salt 1ꢁHCl in
five steps by following a known procedure (Scheme 3). Reaction
of the sodium salt of compound 12 with MOMCl provided com-
pound 13 in excellent yield.8b Then the TMSOTf mediated cycliza-
tion of N-MOM aminotetralin 13 at ꢀ50 °C gave the desired
product 14. This cyclization was found to be sensitive to reagent
quality and also temperature. The yield varies between 40% and
52%, and depends on the TMSOTf obtained from different sources.
Deprotection of the nosyl group of compound 14 with 4-methoxy-
thiophenol and K2CO3 in mixed solvent (DMSO/CH3CN = 1:49)
afforded O-methyl dihydrexidine 15 in good yield. The spectral
data and specific rotation of the synthesized compound 15, as its
Compound 2 was transformed to N-nosyl protected aminotetr-
alin 12 on treatment with nosyl chloride (4-NO2C6H4SO2Cl) and
Et3N. Now the specific rotation of the N-nosyl aminotetralin 12
{½a 2D5
ꢂ
¼ ꢀ64:2 (c 1.0, CHCl3)} is comparable with the literature data
hydrochloride salt, {½a D25
ꢂ
¼ þ110 (c 0.15, EtOH} was consistent
{Lit. ½a 2D5
ꢂ
¼ ꢀ51:25 (c 1.00, CHCl3)}.8a
with the literature data {[a]
D = +106 (c 0.75), EtOH}.1d Demethyla-
The synthesis of dihydrexidine 1 from both the aminotetralins 2
and 12 are known in the literature.5a,8a Here N-nosyl aminotetralin
tion of hexahydrobenzophenanthridine 15 using BBr3 accom-
plished the synthesis of dihydrexidine as a hydrobromide salt
dihydrexidine
1
ref. 8a
ref. 5a
MeO
MeO
MeO
MeO
MeO
NaH (1.2 equiv)
MOMCl (2.0 equiv)
NsCl, Et3N
MeO
NNs
OMe
NH2
NHNs
DCM, 0 °C
THF, 0 °C
85%
73%
2
13
12
MeO
MeO
MeO
MeO
p-MeOC6H4SH (1.2 equiv)
TMSOTf (1-5 equiv)
K2CO3 (1.2 equiv)
NH
NNs
DCM, −50 °C, 4 h
MeCN:DMSO (49:1),
rt, 3 h
46%
98%
14
15
HO
HO
HO
BBr3 (5.0 equiv)
NaHCO3
NH·HBr
HO
NH·HCl
EtOH-HCl
CH2Cl2, rt, 12 h
95%
72%
1·HBr
1·HCl
Scheme 3. Synthesis of (+)-dihydrexidine hydrochloride 1ꢁHCl from aminotetralin 12.

R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
1525
1ꢁHBr with a specific rotation of ½a D25
ꢂ
¼ þ59 (c 0.21, EtOH).11 Final-
45 min and the reaction mixture was allowed to attain room
temperature and stirred for 12 h. The reaction mass was
quenched by the slow addition of saturated aqueous ammonium
chloride solution (500 mL) at ꢀ10 to ꢀ5 °C and stirred at ambient
temperature for 1 h. It was filtered through a Celite bed and the
filtrate was extracted with ethyl acetate (3 ꢃ 750 mL). The com-
bined organic extract was washed with brine, dried over anhy-
drous sodium sulphate, filtered and concentrated under reduced
pressure to afford the crude product, which was purified by flash
chromatography using 20% ethyl acetate in hexanes as eluent to
provide the pure compound 6 (13.6 g, 69%) as a white solid. Mp
76–77 °C. 1H NMR (CDCl3, 400 MHz): d 7.4–7.26 (m, 5H, –C6H5),
5.28 (s, 1H, OH), 4.72 (d, J = 6.5 Hz, 1H, PhCHOH), 4.19 (m, 1H,
–CHN–), 3.68 (m, 1H, –CH2O–), 3.6 (m, 1H, –CH2O–), 1.59 [s,
3H, C(CH3)2], 1.53 [s, 9H, –C(CH3)3], 1.48 [s, 3H, C(CH3)2]. 13C
NMR (CDCl3, 100 MHz): d 155.8 (–OC@O), 141.8 (C of Ph), 128.4
(2CH of Ph), 128.0 (CH of Ph), 127.3 (2CH of Ph), 94.5
[C(CH3)2], 81.7 [-OC(CH3)3], 78.1 (PhCHOH), 64.7 (CH2O), 63.6 (–
CHN), 28.3 [3CH3 of –OC(CH3)3], 27.1 [CH3CCH3], 24.2 [CH3CCH3].
LC–MS (ESI) m/z: 308.2 (MH+). HPLC analysis: chiralpak AD-H,
50% n-hexane, 30% ethanol and 20% i-PrOH, 0.2 mL/min,
ly successive treatment with NaHCO3 and HCl in ethanol provided
dihydrexidine hydrochloride 1ꢁHCl. It showed >99% ee by chiral
HPLC analysis and with a specific rotation of ½a D26
¼ þ85 (c 0.25,
ꢂ
EtOH) {[Lit.1d
0.24, EtOH)]}.
½
a 2D5
ꢂ
¼ þ83 (c 0.25, EtOH); Lit.7b
½
a 2D5
ꢂ
¼ þ85:5 (c
3. Conclusion
In conclusion, we have accomplished an asymmetric synthesis
of 2-amino-1-phenyltetralin 2 and its N-nosyl derivative 12. The
highly efficient diastereoselective synthesis (dr >99:1) was
achieved starting from commercially available D-serine. The pro-
cess is also scalable. The synthesis of dihydrexidine as a hydrobro-
mide salt 1ꢁHBr and also as a hydrochloride salt 1ꢁHCl has been
completed with high enantiomeric purity (ee >99%) from the N-no-
syl-2-amino-1-phenyltetralin 12 in five steps.
4. Experimental
All reactions were conducted using oven-dried glassware un-
der an atmosphere of argon (Ar). Commercial grade reagents
were used without further purification. Solvents were dried
and distilled following the usual protocols. Column chromatogra-
phy was carried out using silica gel (100–200 mesh). TLC was
performed on aluminium-backed plates coated with Silica Gel
60 with F254 indicator. The 1H NMR spectra were recorded with
a 400 MHz and 13C NMR spectra were recorded with a 100 MHz
using CDCl3, DMSO-d6 and CD3OD. 1H NMR chemical shifts are
expressed in parts per million (d) relative to CDCl3 (d = 7.26),
DMSO-d6 (d = 2.49) and CD3OD (d = 3.31); 13C NMR chemical
shifts are expressed in parts per million (d) relative to the CDCl3
(d = 77.0), DMSO-d6 (d = 39.7) and CD3OD (d = 49.0). High resolu-
tion mass spectra (HRMS) were obtained under positive electron
spray ionization (m/z values are given). HPLC analyses were car-
ried out by Chiralpak AD-H, Chiralcel OD-RH and Chiralcel OJ-RH
210 nm, tR (major) 18.57, tR (minor) 20.41, ee 97.8%. ½a D25
¼
ꢂ
ꢀ19:0 (c 1.0, CHCl3).
4.3. (R)-4-[(R)-(tert-Butyldimethylsilanyloxy)phenylmethyl]-2,
2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 7
To
a stirred solution of the alcohol 6 (24.0 g, 78 mmol,
1.0 equiv) in anhydrous dichloromethane (240 mL) was added
2,4-dimethylaminopyridine (0.952 g, 7.8 mmol, 0.1 equiv) and
diisopropylethylamine (16.3 mL, 93.6 mmol, 1.2 equiv) followed
by TBDMS-triflate (17.9 mL, 78 mmol, 1.0 equiv) dropwise over
25 min at room temperature. The reaction mixture was stirred
for 1 h at ambient temperature and then diluted with dichloro-
methane (500 mL). The reaction mass was successively washed
with water (150 mL), a saturated solution of aqueous sodium
bicarbonate (2 ꢃ 150 mL) and the organic layer was dried over
anhydrous sodium sulphate, filtered and concentrated under re-
duced pressure. The crude product was purified by flash chroma-
tography using 10% ethyl acetate in hexanes as an eluent to
afford the pure product 7 (27.0 g, 82%) as a colourless liquid.
1H NMR (CDCl3, 400 MHz) (two rotamers): d 7.26 (m, 5H, –
C6H5), 5.24 (d, J = 5.7 Hz, 0.5 H, PhCHO–), 5.11 (d, J = 4.7 Hz, 0.5
H, PhCHO–), 4.28 (dd, J = 9.7 Hz, J = 17.9 1H, –CH2O–), 4.17 (m,
0.5 H, –CHN–), 4.04 (m, 0.5 H, –CHN–), 3.88 (quasi t, J = 8.2 Hz,
1H, –CH2O–), 1.57 [s, 4.5H, –OC(CH3)3], 1.50 [s, 4.5H, –OC(CH3)3],
1.33 [s, 1.5H, C(CH3)2], 1.31 [s, 1.5H, C(CH3)2], 0.88 [s, 9H, –
SiC(CH3)3], 0.76 [s, 1.5 H, C(CH3)2], 0.71 [s, 1.5 H, C(CH3)2],
0.065 [s, 1.5 H, –Si(CH3)2], 0.038 [s, 1.5 H, –Si(CH3)2], ꢀ0.084 [s,
1.5 H, –Si(CH3)2], ꢀ0.10 [s, 1.5 H, –Si(CH3)2]. 1H NMR at 80 °C
columns (0.46 cm ꢃ 25 cm) 5
l.
4.1. (R)-4-Formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid
tert-butyl ester 4 (Garner’s aldehyde)
This was prepared in 73.5% yield as a colourless liquid by
following literature procedure.9 1H NMR (CDCl3, 400 MHz) (two
rotamers): d 9.55 (s. 0.5H, –CHO), 9.50 (s, 0.5H, –CHO), 4.28 (m,
0.5H, –NCH–), 4.15 (m, 0.5H, –NCH–), 4.07–4.01 (m, 2H, –CH2O–),
1.59 [s, 3H, –C(CH3)2–], 1.5 [s, 3H, –C(CH3)2–], 1.46 [s, 4.5H, –
OC(CH3)3], 1.38 [s, 4.5H, –O(CH3)3]. 13C NMR (CDCl3, 100 MHz): d
(rotamers) 199.3/199.2 (–CHO), 152.5/151.2 (–OC@O), 95.0/94.2
[C(CH3)2], 81.2/80.9 [-OC(CH3)3], 64.69/64.63 (–CH2O), 63.8/63.3
(–NCH–), 28.1 [3C, –OC(CH3)3], 26.6/25.6 [C(CH3)2], 24.6/23.7
[C(CH3)2]. ½a 2D5
ꢂ
¼ þ93:5 (c 1.00, CHCl3); Lit.9a
½
a 2D0
ꢂ
¼ þ95:0 (c
(DMSO-d6, 400 MHz):
d 7.32–7.24 (m, 5H, –C6H5), 5.15 (d,
1.34, CHCl3); Lit.9b
½
a 2D0
ꢂ
¼ þ83:8 (c 1.00, CHCl3).
J = 4.4 Hz, 1H, PhCHO–), 4.14–4.07 (m, 2H, –HCHO– and –CHN–
), 3.89 (dd, J = 9.3, 6.9 Hz, 1H, –HCHO–), 1.51 [s, 9H, –OC(CH3)3],
1.29 [s, 3H, C(CH3)2], 0.87 [s, 9H, –SiC(CH3)3], 0.75 [s, 3H,
C(CH3)2], 0.05 [s, 3H, –Si(CH3)2], 0.07 [s, 3H, –Si(CH3)2]. 13C
NMR (CDCl3, 100 MHz) (two rotamers): d 152.7 (0.5C, –OC@O),
152.1 (0.5C, –OC@O), 140.9 (0.5C of Ph), 140.4 (0.5C of Ph),
127.6 (CH of Ph), 127.5 (CH of Ph), 127.3 (CH of Ph), 127.2 (CH
of Ph), 94.7/94.1 [C(CH3)2], 79.9 [-OC(CH3)3], 72.1/71.6 (PhCHO–
), 62.6/62.5 (CH2O), 62.1/61.9 (–CHN), 28.7/28.4 [-OC(CH3)3],
25.7 [SiC(CH3)3], 25.2/24.5 [CH3CCH3], 24.4/23.0 [CH3CCH3], 18.0
[SiC(CH3)3], ꢀ4.7/ꢀ4.8/ꢀ4.9 [Si(CH3)2]. LC–MS (ESI) m/z: 422.0
(MH+). HPLC analysis: (chiralcel OD-RH, 10 mM ammonium
bicarbonate/acetonitrile (35:65), 1.0 mL/min, 215 nm, tR (major)
4.2. (R)-4-[(R)-Hydroxyphenylmethyl]-2,2-dimethyloxazolidine
-3-carboxylic acid tert-butyl ester 6
To a slurry of copper(I) iodide (36.6 g, 192.3 mmol, 3.0 equiv)
in anhydrous tetrahydrofuran (383 ml) maintained at ꢀ78 °C was
added dimethylsulphide (76.2 ml) under a nitrogen atmosphere
and stirred for 5 min. A solution of phenyl magnesium bromide
in THF (1.0 M; 160 mL, 160.2 mmol, 2.5 equiv) was slowly added
at the same temperature over 20 min. The temperature was al-
lowed to rise to ꢀ35 to ꢀ40 °C and stirred for 30 min. It was then
re-cooled to ꢀ78 °C and a solution of Garner’s aldehyde 4 (14.7 g,
64.1 mmol, 1.0 equiv) in anhydrous THF (114 mL) was added over
9.48; tR (minor) 10.74 min); 93.8% ee. ½a D25
¼ þ62:2 (c 1.01,
ꢂ

1526
R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
CHCl3). HRMS (ESI): calcd for C23H39NO4SiNa, 444.2546, m/z
using 20% ethyl acetate in hexanes as eluent to provide a colourless
liquid of pure compound 9 as a mixture of E/Z isomers (17.8 g,
67.6%). 1H NMR (CDCl3, 400 MHz) (major trans-isomer): {Ar = 3,4-
MeOC6H3) d 7.3–7.2 (m, 5H, C6H5), 6.88 (s, 1H, 3,4-MeOC6H3) 6.87
(d, J = 8.3 Hz, 1H, , 3,4-MeOC6H3), 6.80 (d, J = 8.3 Hz, 1H, 3,4-
MeOC6H3), 6.44 (d, J = 16.0 Hz, 1H, ArCH@), 6.08 (dd, J = 16.0,
6.1 Hz, 1H, ACH@CH–), 4.90–4.78 (br s, 1H, NH), 4.82 (s, 1H,
PhCHO), 4.43 (br s, 1H, CHN), 3.87 [s, 6H, Ar(OCH3)2], 1.32 [s, 9H,
–C(CH3)3], 0.89 [s, 9H, –SiC(CH3)3], ꢀ0.01 [s, 3H, SiC(CH3)2], ꢀ0.13
[s, 3H, SiC(CH3)2]. 13C NMR (CDCl3,100 MHz) (major trans-isomer):
d 155.2 (–OC@O), 148.8 (MeOC of Ar), 148.5 ((MeOC of Ar), 141.4 (C,
Ph), 130.4 (C, Ar), 130.0 (ACH@), 127.9 (CH, Ph), 127.8 (=CH), 127.3
(CH, Ph), 126.4 (CH, Ph), 119.3 (CH, Ar), 111.0 (CH, Ar), 108.7 (CH,
Ar), 79.2 [OC(CH3)3], 76.7 (PhCHO), 55.9 (CHN), 55.8 (OCH3), 55.6
(OCH3), 28.2 [3CH3 of –OC(CH3)3], 25.7 [3CH3 of –SiC(CH3)3], 18.1
[-SiC(CH3)3], ꢀ5.0 [-SiC(CH3)2], ꢀ5.1 [-SiC(CH3)2]. LC–MS (ESI) m/
z: 514.2 (MH+). HPLC analysis: (chiralpak AD-H, n-hexane contain-
ing 0.1% diethyl amine/i-PrOH (98:2), 0.8 mL/min, 260 nm, tR (ma-
jor) 11.48 and 4.79 min, tR (minor) 13.99 and 6.41 min), 96.9% ee.
HRMS (ESI): calcd for C29H43NO5SiNa, 536.2808 m/z [M+Na]+, found
536.2808.
[M+Na]+; found 444.2546.
4.4. [(1R,2R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-hydroxymeth
yl-2-phenyl-ethyl]-carbamic acid tert-butyl ester 8
To a solution of the dimethyloxazolidine derivative 7 (7.0 g,
16.6 mmol, 1.0 equiv) in methanol (133 mL, 8 mL/mmol) was
added PPTS (0.625 g, 2.5 mmol, 0.15 equiv) and the mass was stir-
red at 80 °C for 16 h. The reaction mixture was then concentrated
under vacuum and diluted with ethyl acetate (300 mL). The ethyl
acetate layer was washed with water (50 mL), brine, dried over so-
dium sulphate, filtered and concentrated under vacuum. The crude
product was purified by flash chromatography using 25% ethyl ace-
tate in hexanes as eluent to provide the pure compound 8 (3.9 g,
62%) as a colourless liquid. 1H NMR (CDCl3, 400 MHz): d 7.32–
7.25 (m, 5H, –C6H5), 4.89 (d, J = 3.3 Hz, 1H, PhCHO–), 3.73 (m, 1H,
–NCH–), 3.69–3.60 (m, 2H, –CH2O–), 2.37 (br s, 1H, OH), 1.35 [s,
9H, –OC(CH3)3], 0.89 [s, 9H, –SiC(CH3)3], 0.05 [s, 3H, –SiC(CH3)2],
ꢀ0.17 [s, 3H, –SiC(CH3)2]. 13C NMR (CDCl3, 100 MHz); d 156.1 (–
OC@O), 141.5 (C of Ph), 128.1(2CH of Ph), 127.5 (CH of Ph) 126.3
(2CH of Ph), 79.5 [-OC(CH3)3], 73.6 (PhCHO), 63.0 (–CH2O), 58.4
(CHN), 28.2 [3CH3 of –OC(CH3)3], 25.78 [3CH3 of –SiC(CH3)3], 18.1
[-SiC(CH3)3], ꢀ4.6 [-SiC(CH3)2], ꢀ5.2 [-SiC(CH3)2]. LC–MS (ESI) m/
z: 382.4 (MH+). HPLC analysis: (chiralpak-AD-H, n-hexane contain-
ing 0.05% TFA/i-PrOH (98:2), 1.0 mL/min, 210 nm, tR (major)
4.6. [(R)-1-[(R)-(tert-Butyldimethylsilanyloxy)-phenylmethyl]-
3-(3,4-dimethoxyphenyl)-propyl]-carbamic acid tert-butyl ester
10
5.96 min, tR (minor) 6.82 min) 93.7% ee. ½a D25
ꢂ
¼ ꢀ31:3 (c 1.0,
To a solution of the alkene 9 (7.0 g, 15.2 mmol, 1.0 equiv) in a
mixture of methanol and THF (1:1, 150 mL) was added 10% Pd–C cat-
alyst (0.7 g, 10% w/w) and stirred at rt for 1.5 h under hydrogen
(1 atm.; 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 using 20% ethyl acetate in hexanes to give
the pure product 10 (6.5 g, 93%) as a colourless liquid. 1H NMR
(CDCl3, 400 MHz): (Ar = 3,4-MeOC6H3) d 7.27–7.2 (m, 5H, C6H5),
6.78 (d, J = 8.0 Hz, 1H, 3,4-MeOC6H3), 6.70 (d, J = 8.0 Hz, 1H, 3,4-
MeOC6H3), 6.69 (s, 1H, 3,4-MeOC6H3), 4.72 (br s, 1H, NH), 4.54 (d,
J = 9.6 Hz, 1H, PhCHO–), 3.84 [s, 6H, Ar(OCH3)2], 3.74 (m, 1H, –
CHN), 2.66 (m, 1H, ArCH2), 2.57 (m, 1H, ArCH2), 1.88 (m, 1H, –CH2–
), 1.58 (m, 1H, –CH2–), 1.36 [s, 9H, –C(CH3)3], 0.88 [s, 9H, –SiC(CH3)3],
0.02 [s, 3H, –Si(CH3)2], ꢀ0.16 [s, 3H, –Si(CH3)2]. 13C NMR (CDCl3,
100 MHz): d 155.4 (–OC@O), 148.7 (MeOC of Ar), 147.0 (MeOC of
Ar), 141.7 (C, Ph), 134.5 (C, Ar), 127.8 (2CH, Ph), 127.1 (CH, Ph),
126.4 (2CH, Ph), 120.1 (CH, Ar), 111.8 (CH, Ar), 111.2 (CH, Ar), 78.8
[OC(CH3)3], 75.7 (PhCHO–), 56.2 (CHN), 55.9 (OCH3), 55.8 (OCH3),
33.7 (CH2), 32.1(CH2), 28.3 [3CH3 of –OC(CH3)3], 25.8 [3CH3 of –
SiC(CH3)3], 18.1 [-SiC(CH3)3], ꢀ4.6 [-SiC(CH3)2], ꢀ5.1 [–SiC(CH3)2].
LC–MS (ESI) m/z: 515.8 (MH+); 533.0 (M+NH4þ). HPLC analysis: (chi-
ralcel OJ-RH, acetonitrile/10 mM ammonium acetate (1:1), 1.0 mL/
min, 202 nm, tR (major) 20.19, tR (minor) 17.84 min), 96.4%ee.
CHCl3). HRMS (ESI): cald for C20H35NOSiNa, 404.2233 m/z
[M+Na]+; found 404.2233.
4.5. [(R)-1-[(R)-(tert-Butyldimethylsilanyloxy)-phenylmethyl]-
3-(3,4-dimethoxyphenyl)-allyl]-carbamic acid tert-butyl ester 9
To a solution of oxalylchloride (2.9 mL, 33.4 mmol, 1.3 equiv) in
anhydrous dichloromethane (34 mL) at ꢀ60 °C was added dimeth-
ylsulfoxide (4.7 mL, 66.8 mmol, 2.6 equiv) dropwise over 15 min
and stirred for 30 min. A solution of the alcohol 8 (9.8 g, 25.7 mmol,
1.0 equiv) in anhydrous DCM (26 mL) was added dropwise over
15 min and stirred at ꢀ60 °C for 1 h. Diisopropylethylamine
(13.4 mL, 77.1 mmol, 3.0 equiv) was added dropwise at the same
temperature. After 20 min, the reaction mixture was brought to
0–5 °C and, 1 M aqueous hydrochloric acid solution was added until
the pH reached 3–4. It was finally extracted with DCM (3 ꢃ 150 mL)
and the combined organic parts were washed with 1 M aqueous
hydrochloric acid solution (50 mL), water (25 mL), aqueous 5% so-
dium carbonate solution (3 ꢃ 25 mL) and then with brine. The or-
ganic layer was dried over sodium sulphate, filtered and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography using 20% ethyl acetate in hexanes to
provide the aldehyde which was used immediately in the subse-
quent step.
To a slurry of the 3,4-dimethoxybenzyl phosphonium salt
(44.6 g, 90.4 mmol, 2.4 equiv) in anhydrous tetrahydrofuran
(110 mL, 3 mL/mmol) at ꢀ15 °C was added n-BuLi (1.8 M;
49.2 mL, 88.6 mmol, 2.3 equiv) dropwise over 15 min. After
15 min of stirring at the same temperature, the reaction mixture
was cooled to ꢀ60 °C followed by the slow addition of a solution
of the aldehyde (14.3 g, 37.6 mmol, 1.0 equiv) in anhydrous tetra-
hydrofuran (180 mL, 2 mL/mmol) over 45 min. The reaction mix-
ture was then warmed to ꢀ15 °C and stirred for 1 h. The reaction
mass was allowed to warm to ꢀ5 °C and a saturated aqueous
ammonium chloride solution (250 ml) was added cautiously. It
was then filtered through a Celite bed and extracted with ethyl ace-
tate (3 ꢃ 500 mL). The combined organic layer was dried over anhy-
drous sodium sulphate, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
½
a 2D5
ꢂ
¼ ꢀ5:7 (c 0.85, CHCl3). HRMS (ESI): calcd for C29H45NO5SiNa,
538.2964 m/z [M+Na]+, found 538.2964.
4.7. [(R)-3-(3,4-Dimethoxyphenyl)-1-(R)-hydroxyphenylmethyl)
-propyl]-carbamic acid tert-butyl ester 3
To a solution of the TBDMS protected alcohol 10 (14.0 g,
27.1 mmol, 1.0 equiv) in anhydrous THF (135 mL) at 0–5 °C was
added TBAF in THF (1 M; 81.5 mL, 81.5 mmol, 3.0 equiv) dropwise
over 15 min. The reaction mixture was then allowed to warm to
ambient temperature and stirred for 1 h. It was then concentrated
under reduced pressure and purified by flash chromatography
using 30% ethyl acetate in hexanes top provide the pure compound
3 (9.8 g, 90%) as a white solid. Mp 104–105 °C.
1H NMR (CDCl3, 400 MHz): (Ar = 3,4-MeOC6H3) d 7.33–7.25 (m,
5H. C6H5), 6.76 (d, J = 8.0 Hz, 1H, 3,4-MeOC6H3), 6.66 ((d, J = 8.0 Hz,

R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
1527
1H, 3,4-MeOC6H3), 6.64 (s, 1H, 3,4-MeOC6H3), 4.67 (d, J = 4.3 Hz,
1H, PhCHOH), 4.66 (s, 1H, NH), 3.83 (s, 6H, 3,4-Ar(OCH3)2), 3.73
(m, 1H, NCH), 2.92 (br s, 1H, OH), 2.66 (m, 1H, ArCH2), 2.55 (m,
1H, ArCH2), 1.85 (m, 1H, ArCH2CH2), 1.71 (m, 1H, ArCH2CH2),
1.38 [s, 9H, –C(CH3)3]. 13C NMR (CDCl3, 100 MHz): d 156.4
(–OC@O), 148.7 (MeOC, Ar), 147.0 (MeOC, Ar), 141.6 (C, Ph),
134.1 (C, Ar), 128.1 (2CH, Ph), 127.5 (CH, Ph), 126.2 (2CH, Ph),
120.1 (CH, Ar), 111.6 (CH, Ar), 111.1 (CH, Ar), 79.4 [OC(CH3)3],
76.1 (PhCHO–), 56.1 (CHN), 55.8 (OCH3), 55.6 (OCH3), 33.4 (CH2),
31.9 (CH2), 28.2 [3CH3 of –OC(CH3)3]. LC–MS (ESI): 402.2 (MH+);
419.2 (M+NH4þ). HPLC analysis: (chiralpak AD-H, n-hexane/i-PrOH
(8:2), 1.0 mL/min, 220 nm, tR (major) 13,99, tR (minor) 8.85 min):
128.8 (2CH), 128.5 (2CH), 127.8 (2CH), 127.5 [C, (MeO)2C6H2],
127.3 [C, (MeO)2C6H2], 126.9 (CH, C6H5), 124.1 (2CH), 112.8 [CH,
(MeO)2C6H2], 110.7 [CH, (MeO)2C6H2], 57.1 (CH, ArCHPh or CHN),
55.8 (OCH3), 55.7 (OCH3), 51.5 (CH, CHN or ArCHPh), 27.6 (CH2),
26.1 (CH2). LC–MS (ESI) m/z: 467.2 (MH+). HPLC analysis: (chir-
alpak AD-H, n-hexane/i-PrOH (9:1), 1.0 mL/min, 220 nm, tR (major)
25.47, tR (minor) 33.41 min), 98.4% ee. ½a D25
¼ ꢀ64:2 (c 1.0, CHCl3);
ꢂ
Lit.8a
½
a 2D5
ꢂ
¼ ꢀ51:25 (c 1.00, CHCl3).
4.10. (1S,2R)-N-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-na
phthalen-2-yl)-N-methoxymethyl-4-nitro-benzenesulfonamide
13
92.6% ee. ½a 2D5
¼ ꢀ5:5 (c 1.04, CHCl3). HRMS (ESI): calcd for
ꢂ
C23H31NO5Na, 424.2100 m/z [M+Na]+, found 424.2100.
To a well stirred solution of 12 (5.3 g, 11.3 mmol, 1.0 equiv) in
anhydrous THF (110 mL) at 0–5 °C was added sodium hydride
(50% dispersion in mineral oil; 0.81 g, 16.9 mmol, 1.5 equiv) and
the reaction mixture was stirred for 1 h min at 0–5 °C under a nitro-
gen atmosphere. Methoxymethylenechloride (MOMCl) (2.7 g,
33.9 mmol, 3.0 equiv) was added slowly to the reaction mixture
and stirred for 0.5 h at the same temperature and then allowed to
attain room temperature and stirred. After 2 h, the reaction was
quenched by the addition of an aqueous solution of saturated
ammonium chloride (50 mL). It was then extracted with ethyl ace-
tate (3 ꢃ 150 mL) and the combined organic part was dried over
anhydrous sodium sulphate and evaporated under vacuum. The
crude product was purified by flash chromatography using 30%
ethyl acetate in hexanes to provide the pure compound 13 (4.9 g,
85%) as a yellow solid. Mp 60–61 °C (Lit.8b Mp 56–57 °C). 1H NMR
(CDCl3, 400 MHz): d 8.02 (d, J = 9.2 Hz, 2H, 4-NO2C6H4SO2–), 7.61
(d, J = 9.2 Hz, 2H, 4-NO2C6H4SO2–), 7.08–7.05 (m, 1H, C6H5), 6.99
(t, J = 7.2 Hz, 2H, C6H5), 6.88 (m, 2H, C6H5), 6.54 [s, 1H, (MeO)2C6H2],
5.97 [s, 1H, (MeO)2C6H2], 5.03 (d, J = 10.9 Hz, 1H, MeOCH2N), 4.68
(d, J = 10.9 Hz, 1H, MeOCH2N), 4.21 (d, J = 10.3 Hz, 1H, PhCHAr),
4.09 (m, 1H, CHN), 3.82 (s, 3H, ArOCH3), 3.47 (s, 3H, ArOCH3), 3.34
(s, 3H, –CH2OCH3), 3.02–2.98 (m, 1H, ArCH2), 2.84–2.78 (m, 1H,
ArCH2), 2.19–2.1 (m, 2H, CH2). 13C NMR (CDCl3): d 149.3 (C, 4-
NO2C6H4SO2), 147.4 [MeOC, (MeO)2C6H2], 147.2 [MeOC,
(MeO)2C6H2], 146.2 (C, 4-NO2C6H4SO2), 143.6 (C, C6H5), 130.2 [C,
(MeO)2C6H2] , 129.2 (2CH), 128.2 (2CH), 128.1 (2CH), 127.6 [C,
(MeO)2C6H2], 126.6 (CH), 123.7 (2CH), 112.8 [CH, (MeO)2C6H2],
110.4 [CH, (MeO)2C6H2], 76.9 (MeOCH2N), 62.8 (CH, ArCHPh or
CHN), 55.7 (–OCH3), 55.6 [2(–OCH3)], 48.6 (CH, CHN or ArCHPh),
30.1 (CH2), 29.4 (CH2). HPLC analysis: (chiralpak AD-H, n-hexane/
i-PrOH (9:1), 1.0 mL/min, 210 nm, tR (major) 23.71, tR (minor)
4.8. (1S,2R)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-naphth
alen-2-ylamine 2
The protected amino alcohol 10 (3.1 g, 6.0 mmol) was heated
with freshly distilled trifluoroaceticacid (15 mL) at 80 °C for 5 h
and concentrated under reduced pressure. It was diluted with
methanol (15 mL) and solid sodium bicarbonate powder was
added under stirring until the effervescence ceased. It was concen-
trated and purified by filter column chromatography using 10%
methanol in dichloromethane to provide aminotetralin 2 as a yel-
low sticky solid which was used immediately for the subsequent
step. 1H NMR (CDCl3, 400 MHz): d 7.31–7.13 (m, 5H, C6H5), 6.59
[s, 1H, 3,4-(MeO)2C6H3], 6.15 [s, 1H, 3,4-(MeO)2C6H3], 3.83 [s, 3H,
Ar(OCH3)2], 3.69 (d, J = 8.1 Hz, 1H, PhCHAr), 3.55 [s, 3H, Ar(OCH3)2],
3.16 (m, 1H, CHN), 2.99–2.91 (m, 1H, ArCH2), 2.86–2.81 (m, 1H,
ArCH2), 2.02 (br m, 3H, 1H of CH2 and NH2), 1.72 (m, 1H, CH2).
13C NMR (CDCl3, 100 MHz): d 147.3 (MeOC, Ar), 147.1 (MeOC,
Ar), 144.2 (C, Ph), 130.0 (C, Ar), 129.3 (2CH, Ph), 128.4 (2CH, Ph),
128.3 (C, Ar), 126.6 (CH, Ph), 112.9 (CH, Ar), 110.8 (CH, Ar), 55.7
(2CH3O), 55.0 (CH, ArCHPh or CHN), 54.4 (CH, CHN or ArCHPh),
30.2 (CH2), 27.5 (CH2). HPLC Analysis: (Chiralpak AD-H, n-hexane
containing 0.1% Et2NH/i-PrOH (8:2), 1.0 mL/min, 288 nm, tR (ma-
jor) 6.33 min, tR (minor) 7.27 min), 94.6% ee. LC–MS (ESI) m/z:
284.2 (MH+).
4.9. (1S,2R)-N-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydronaph
thalen-2-yl)-4-nitro-benzenesulfonamide 12
To a solution of aminotetralin 2 (1.05 g, 3.7 mmol, 1.0 equiv) in
anhydrous DCM (20 mL) was added p-nitrobenzenesulphonyl chlo-
ride (0.862 g, 3.89 mmol, 1.05 equiv) and triethylamine (1.28 mL,
9.25 mmol, 2.5 equiv) at 0–5 °C. The reaction mass was allowed
to attain room temperature and stirred for 3 h, concentrated under
reduced pressure, diluted with water (20 mL) and extracted with
dichloromethane (3 ꢃ 40 mL). The combined organic layer was
washed with water, brine, dried over anhydrous sodium sulphate
and evaporated under vacuum. The crude product was purified
by flash chromatography using 30% ethyl acetate in hexanes. The
yellow solid obtained was dissolved in methanol and kept at 0 °C
for 12 h. It was filtered and the filtrate evaporated to obtain the
enantiomerically pure N-nosylaminotetralin 12 (1.25 g, 44%) as a
yellow solid. Mp 64–65 °C (Lit.8a Mp 63–64 °C). 1H NMR (CDCl3,
400 MHz): d 8.15 (d, J = 8.4 Hz, 2H, 4-NO2C6H4SO2–), 7.73 (d,
J = 8.4 Hz, 2H, 4-NO2C6H4SO2–), 7.15–7.09 (m, 3H, C6H5), 6.83 (d,
J = 7.2 Hz, 2H, C6H5), 6.59 [s, 1H, (MeO)2C6H2], 6.07 [s, 1H,
(MeO)2C6H2], 4.75 (d, J = 7.6 Hz, 1H, NH), 3.84 (s, 3H, OCH3), 3.81
(d, J = 7.1 Hz, 1H, ArCHPh), 3.61 (m, 1H, CHN), 3.55 (s, 3H, OCH3),
2.95–2.87 (m, 1H, ArCH2), 2.84–2.75 (m, 1H, ArCH2), 2.26–2.21
(m, 1H, CH2), 1.77–1.70 (m, 1H, CH2). 13C NMR (CDCl3, 100 MHz):
d 149.6 (C, 4-NO2C6H4SO2), 147.9 [MeOC, (MeO)2C6H2], 147.5
[MeOC, (MeO)2C6H2], 146.0 (C, 4-NO2C6H4SO2), 142.8 (C, C6H5),
26.17 min); 99.7% ee.
½
a 2D5
ꢂ
¼ ꢀ52:2 (c 0.99, CHCl3); {Lit.8b
½
a 2D8
ꢂ
¼ ꢀ36:0 (c 1.00, CHCl3)}. HRMS (ESI): calcd for C26H28N2O7SNa,
535.1515 m/z [M+Na]+, found 535.1515.
4.11. (6aR,12bS)-10,11-Dimethoxy-6-(4-nitro-benzenesulfonyl)-
5,6,6a,7,8,12a-hexahydrobenzo[a]-phenanthridine 14
To a well stirred solution of 13 (0.3 g, 0.585 mmol, 1.0 equiv) in
dichloromethane (12 mL) at ꢀ50 °C was added TMS-triflate
(0.27 mL, 1.46 mmol, 2.5 equiv) dropwise over 5 min. The reaction
mixture was then slowly allowed to come to ꢀ10 °C over 4 h and
an aqueous solution of saturated sodium bicarbonate (10 mL) was
added. The reaction mass was extracted with DCM (3 ꢃ 40 mL)
and the combined organic part was dried over anhydrous sodium
sulphate, filtered and evaporated under reduced pressure. The
crude product was purified by flash chromatography using 70%
dicloromethane in hexanes (0.13 g, 46%) as a yellow solid. Mp 89–
90 °C [Lit.8b Mp 88–89 °C].
1H NMR (CDCl3, 400 MHz): d 8.02 (d, J = 8.5 Hz, 2H, 4-NO2C6H4-
SO2–), 7.7 (d, J = 8.5 Hz, 2H, 4-NO2C6H4SO2–), 7.27 (m, 1H, C6H4),
7.1 (t, J = 7.5 Hz, 1H, C6H4), 6.91 (t, J = 7.5 Hz, 1H, C6H4), 6.85 [s,
1H, (MeO)2C6H2], 6.76 (d, J = 7.4 Hz, 1H, C6H4), 6.69 [s, 1H,

1528
R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
(MeO)2C6H2], 4.68 (d, J = 16.0 Hz, 1H, PhCH2N), 4.53 (d, J = 16.0 Hz,
1H, PhCH2N), 4.12 (d, J = 11.6 Hz, 1Hß ArCHPh), 3.89 (s, 3H, Ar-
OCH3), 3.78 (s, 3H, ArOCH3), 3.17 (quasi t, J = 11.5 Hz, 1H, CHN),
3.02 (t, J = 14.0 Hz, 1H, CH2), 2.89–2.8 (m, 2H, CH2), 2.09–2.0 (m,
1H, CH2). 13C NMR (CDCl3,100 MHz): d 149.6 (C), 147.9 (C) 146.8
(C), 143.9 (C), 138.5 (C), 135.0 (C), 129.6 (C), 128.6 (2CH, 4-
NO2C6H4SO2–), 127.7 (CH, C6H4), 126.1 (CH, C6H4), 125.7 (CH,
C6H4), 123.9 (C), 123.76 (CH, C6H4) , 123.70 (2CH, 4-NO2C6H4SO2–
), 112.4 [CH, (MeO)2C6H2], 111.9 [CH, (MeO)2C6H2], 61.5 (CH,
ArCHPh or CHN), 56.0 (–OCH3), 55.8 (–OCH3), 47.6 (PhCH2N),
43.8 (CH, CHN or ArCHPh), 31.2 (CH2), 29.4 (CH2). LC–MS (ESI) m/
z: 481.2 (MH+). HPLC analysis: (chiralpak AD-H, 80% n-hexane con-
taining 0.1% diethyl amine/EtOH (8:2), 1.0 mL/min, 234 nm, tR (ma-
2.35–2.25 (m, 1H, CH2), 2.0–1.94 (m, 1H, CH2). 13C NMR (CD3OD,
100 MHz): d 144.6 [HOC, (HO)2C6H2], 143.7 [HOC, (HO)2C6H2],
136.5 (C), 129.9 (C), 128.6 (C), 128.4 (CH, C6H4), 127.9 (CH, C6H4),
127.5 (CH, C6H4), 127.1 (CH, C6H4), 125.0 (C), 115.8 [CH, (HO)2C6H2],
114.5 [CH, (HO)2C6H2], 58.3 (CH, ArCHPh or CHN), 45.2 (CH2), 41.3
(CH, CHN or ArCHPh), 26.8 (CH2), 26.0 (CH2). ½a D25
¼ þ59 (c 0.21,
ꢂ
EtOH).
4.14. (6aR,1bS)-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenz
o[a]phenan-thridine hydrochloride 1ꢁHCl (dihydrexidine hydro
chloride)
The residue was dissolved in water (2 mL), and the pH was ad-
justed to 9–10 with aqueous NaHCO3 under an N2 atmosphere. It
was extracted with CHCl3 (3 ꢃ 10 mL), and the combined organic
layers were dried over sodium sulphate and concentrated to give
a crude solid. This was purified by flash column chromatography
using 15% MeOH in ethyl acetate. A solution of the powder in EtOH
(1 mL) and EtOH–HCl (3 mL) was stirred at rt for 0.5 h and then con-
centrated to obtain a light yellow powder (0.029 g, 70.7%). Mp
>120 °C (dec) [Lit.7b Mp >122 °C (dec)]. 1H NMR (CD3OD,
200 MHz): d 7.49–7.34 (m, 4H, C6H4), 6.76 [s, 1H, (MeO)2C6H2],
6.62 [s, 1H, (MeO)2C6H2], 4.40 (s, 2H, PhCH2N), 4.16 (d, J = 11.0 Hz,
1H, ArCHPh), 3.03 (dt, J = 11.2, 6.0 Hz, 1H, CHN), 2.95–2.86 (m,
1H, ArCH2), 2.84–2.65 (m, 1H, ArCH2), 2.35–2.25 (m, 1H, CH2),
2.0–1.94 (m, 1H, CH2). 1H NMR (DMSO-d6, 400 MHz): d 9.86 (s,
1H, NH/OH), 9.58 (s, 1H, NH/OH), 8.87 (s, 1H, OH/NH), 8.85 (s, 1H,
OH/NH), 7.45–7.30 (m, 4H, C6H4), 6.71 [s, 1H, (MeO)2C6H2], 6.62
[s, 1H, (MeO)2C6H2], 4.36 (s, 2H, PhCH2N), 4.14 (d, J = 11.0 Hz, 1H,
ArCHPh), 2.93 (m. 1H, CHN), 2.79–2.68 (m, 2H, ArCH2), 2.17 (m,
1H, CH2), 1.92 (m, 1H, CH2). 13C NMR (DMSO-d6, 100 MHz): d
143.9 [HOC, (HO)2C6H2], 143.0 [HOC, (HO)2C6H2], 136.0 (C), 130.3
(C), 127.7 (CH, C6H4), 127.6 (C), 127.4 (CH, C6H4), 126.7(CH, C6H4),
126.3 (CH, C6H4), 115.8 [CH, (HO)2C6H2], 114.3[CH, (HO)2C6H2],
56.5 (CH, ArCHPh or CHN), 43.9 (CH2), 40.2 (CH, CHN or ArCHPh),
26.1 (CH2), 25.1 (CH2). LC–MS (ESI) m/z: 268.2 (MH+). HPLC analy-
jor) 15.37, tR (minor) 19.19 min); ee >99%. ½a D25
¼ þ38:8 (c 0.37,
ꢂ
CHCl3) [Lit.8a
C
½
a 2D8
ꢂ
¼ þ30:2 (c 1.00, CHCl3)]. HRMS (ESI): calcd for
25H24N2O6Sna, 503.1252 m/z [M+Na]+, found 503.1253.
4.12. (6aR,12bS)-10,11-Dimethoxy-5,6,6a,7,8,12b-hexahydroben
zo[a]phenanthridine 15
To a well stirred solution of 14 (1.0 g, 2.08 mmol, 1.0 equiv) in
20 mL of CH3CN/DMSO (49:1) at rt, were added 4-methoxythiophe-
nol (0.58 g, 4.16 mmol, 2.0 equiv) and K2CO3 (0.86 g, 6.24 mmol,
3.0 equiv). The reaction mixture was then allowed to stir for 3 h.
The solvent was concentrated under reduced pressure and the
crude reaction mass was subjected to flash column purification
using 0–10% MeOH in DCM as an eluent to obtain 15 (0.6 g, 98%)
as a pale yellow sold. The solid was converted into its hydrochloride
salt using an ethanolic solution of HCl, which was triturated with
ethyl acetate to obtain the greenish-white solid 15ꢁHCl (0.65 g,
94%). Mp >200 °C [Lit.7b Mp >236 (dec)]. 1H NMR (DMSO-d6,
400 MHz): d 10.27 (br s, 1H, NH), 10.05 (br s, 1H, NH), 7.42–7.31
(m, 4H, C6H4), 6.88 [s, 1H, (MeO)2C6H2], 6.85 [s, 1H, (MeO)2C6H2],
4.37 (s, 2H, PhCH2N), 4.28 (d, J = 10.9 Hz, 1H, ArCHPh), 3.76 (s, 3H,
ArOCH3), 3.7 (s, 3H, ArOCH3), 2.94 (m, 1H, CHN), 2.90–2.72 (m,
2H, ArCH2), 2.24–2.19 (m, 1H, CH2), 2.05–1.95 (m, 1H, CH2). 13C
NMR (DMSO-d6, 100 MHz): d 147.5 [MeOC, (MeO)2C6H2], 146.5
[MeOC, (MeO)2C6H2], 137.3 (C), 130.4(C), 129.4 (C), 127.7 (CH,
C6H4) 127.5 (CH, C6H4), 126.7 (CH, C6H4), 125.0 (CH, C6H4), 124.7
(C), 112.5 [CH, (MeO)2C6H2], 111.9 [CH, (MeO)2C6H2], 56.5 (CH,
ArCHPh or CHN), 55.5 (–OCH3), 55.4 (–OCH3), 43.3 (CH2N), 40.5
(CH, CHN or ArCHPh), 26.9 (CH2), 25.1 (CH2). LC–MS (ESI) m/z:
296.2 (MH+). HPLC analysis: (chiralcel OD-H, n-hexane containing
0.1% diethyl amine/EtOH (9:1), 1.0 mL/min, 234 nm, tR (major)
sis: (chiralpak AD-H (4.6 ꢃ 250 mm) 5
l, n-hexane containing 0.1%
diethylamine)/EtOH, 1.0 mL/min, 288 nm, tR (major) 7.06); ee
>99.9%. ½a 2D6
ꢂ
¼ þ85 (c 0.25, EtOH); {Lit.1d
½
a 2D5
ꢂ
¼ þ83 (c 0.25, EtOH);
Lit.7b
½
a 2D5
ꢂ
¼ þ85:5 (c 0.24, EtOH)}.
Acknowledgements
We thank DBT (BIPP), New Delhi (sanction no.: 102/IFD/SAN/
1191/2009–2010) for providing financial support.
8.84, tR (minor) 9.95 min; ee >99%. ½a D25
ꢂ
¼ þ110:0 (c 0.15, EtOH)
{Lit.7b
½
a 2D5
ꢂ
¼ þ123:0 (c 0.3, EtOH); Lit.1d
½ ꢂ
a 2D5
¼ þ106:0 (c 0.75,
References
EtOH)}.
1. (a) Brewster, W. K.; Nichols, D. E.; Riggs, R. M.; Mottola, D. M.; Lovenberg, T. W.;
Lewis, M. H.; Mailman, R. B. J. Med. Chem. 1990, 33, 1756–1764; (b) Taylor, J. R.;
Lawrence, M. S.; Redmont, D. E.; Elsworth, J. D.; Roth, R. H.; Nochols, D. E.;
Mailman, R. B. Eur. J. Pharmacol. 1991, 199, 389–391; (c) Seiler, M. P.;
Hagenbach, A.; Wüthrich, H.-J.; Marksteun, R. J. Med. Chem. 1991, 34, 303–
307; (d) Knoerzer, T. A.; Nichols, D. E.; Brewster, W. K.; Watts, V. J.; Mottola, D.;
Mailman, R. B. J. Med. Chem. 1994, 37, 2453–2460; (e) Michaelides, M. R.; Hong,
Y., Jr.; DiDomenico, S.; Asin, K. E.; Britton, D. R.; Lin, C. W.; Williams, M.;
Shiosaki, K. J. Med. Chem. 1995, 38, 3445–3447.
4.13. (6aR,1bS)-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenz
o[a]phenan-thridine hydrobromide 1ꢁHBr (dihydrexidine hydro
bromide)
To a solution of compound 15 (0.04 g, 0.135 mmol, 1.0 equiv) in
DCM (6 mL) was added BBr3 solution in DCM (1.0 M; 0.67 mL,
0.675 mmol, 5.0 equiv) over 10 min at 0 °C, and the mixture was
stirred at rt. After 12 h, the mixture was quenched with MeOH
(6.0 mL), stirred for 0.5 h, and then concentrated under reduced
pressure to obtain a brown solid. This was triturated with ether
to obtain dihydrexidine hydrobromide 1ꢁHBr (0.047 g) as a light
brown solid in quantitative yield. 1H NMR (CD3OD, 400 MHz): d
7.52 (d, J = 8.0 Hz, 1H, C6H4), 7.44–7.36 (m, 3H, C6H4), 6.80 [s, 1H,
(MeO)2C6H2], 6.67 [s, 1H, (MeO)2C6H2], 4.45 (s, 2H, PhCH2N), 4.21
(d, J = 11.2 Hz, 1H, ArCHPh), 3.06–3.02 (dt, J = 11.2, 6.0 Hz, 1H,
CHN), 2.95–2.86 (m, 1H, ArCH2), 2.84–2.65 (m, 1H, ArCH2),
2. Huang, X.; Lawler, C. P.; Lewis, M. M.; Nichols, D. E.; Mailman, R. B. Int. Rev.
Neurobiol. 2001, 48, 65–139.
3. (a) George, M. S.; Molnar, C. E.; Grenesko, E. L.; Anderson, B.; Mu, Q.; Johnson,
K.; Nahas, Z.; Knable, M.; Fernandes, P.; Juncos, J.; Huang, X.; Nichols, D. E.;
Mailman, R. B. Schizophr. Res. 2007, 93, 42–50; (b) Goldman-Rakic, P. S.;
Castner, S. A.; Svensson, T. H.; Siever, L. J.; Williams, G. V. Psychopharmacology
(Berl.) 2004, 3–16; (c) Mu, Q.; Johnson, K.; Morgan, P. S.; Grenesko, E. L.;
Molnar, C. E.; Anderson, B.; Nahas, Z.; Kozel, F. A.; Kose, S.; Knable, M.;
Fernandes, P.; Nichols, D. E.; Mailman, R. B.; George, M. S. Schizophr. Res. 2007,
94, 332–341; (d) Nichols, D. E.; Lewis, M. M. Med. Chem. Res. 2004, 13, 105–126.
4. Zhang, J.; Xiong, B.; Zhen, X.; Zhang, A. Med. Res. Rev. 2009, 29, 272–294.
5. (a) Negash, K.; Nichols, D. E. Tetrahedron Lett. 1996, 37, 6971–6972; (b) Cueva, J.
P.; Nichols, D. E. Synthesis 2009, 715–720.

R. Malhotra et al. / Tetrahedron: Asymmetry 22 (2011) 1522–1529
1529
6. Ehrlich, P. P.; Michaelides, M. R.; McLaughlin, M. M.; Hsaio, C. US 5659037,
1997.
7. (a) Asano, Y.; Yamashita, M.; Nagai, K.; Kuriyama, M.; Yamada, K. I.; Tomioka, K.
Tetrahedron Lett. 2001, 42, 8493–8495; (b) Yamashita, M.; Yamada, K. I.;
Tomioka, K. Tetrahedron 2004, 60, 4237–4242.
9. (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361–2364; (b) Williams, L.;
Zhang, Z.; Shao, F.; Carroll, P. J.; Joullie, M. M. Tetrahedron 1996, 52, 11673–
11694.
10. (a) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223; (b) Husain, A.;
Ganem, B. Tetrahedron Lett. 2002, 43, 8621–8623.
8. (a) Hajra, S.; Bar, S. Tetrahedron: Asymmetry 2011, 22, 775–779; (c) Hajra, S.;
Bar, S. Chem. Commun. 2011, 47, 3981–3982.
11. The specific rotation of dihydrexidine as hydrobromide salt 1ꢁHBr has not been
previously reported.