Divergent asymmetric synthesis of hexahydrobenzophenanthridine dopamine D1 agonists, A-86929, and dihydrexidine

Article abstract of DOI:10.1016/j.tetasy.2013.02.003

A divergent and scalable asymmetric synthesis of the dopamine D1 agonists, A-86929, and dihydrexidine with high diastereo- and enantioselectivity was accomplished from Weinreb amide 8 derived from inexpensive and easily available l-serine. The synthesis of A-86929 involves only one chromatographic purification.

Full text of DOI:10.1016/j.tetasy.2013.02.003

Tetrahedron: Asymmetry 24 (2013) 278–284
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Divergent asymmetric synthesis of hexahydrobenzophenanthridine
dopamine D1 agonists, A-86929, and dihydrexidine
Rajesh Malhotra a, Sagar Chakrabarti a,b, Amit Ghosh a,b, Rajib Ghosh a,b, Tushar K. Dey a,b, Swarup Dutta b,
c,
Shantanu Dutta b, Subho Roy b, Sourav Basu b, , 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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 December 2012
Accepted 5 February 2013
A divergent and scalable asymmetric synthesis of the dopamine D1 agonists, A-86929, and dihydrexidine
with high diastereo- and enantioselectivity was accomplished from Weinreb amide 8 derived from inex-
pensive and easily available
purification.
L
-serine. The synthesis of A-86929 involves only one chromatographic
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
them to the formal synthesis of dihydrexidine.9a All of the above
methods suffer from either using costly reagent/substrate, or from
scalability and stereoselectivity problems. Thus the development of
an efficient, scalable, and divergent method for the asymmetric
synthesis of dihydrexidine 1, A-86929 2a, and related compounds
using an inexpensive and easily available substrate/reagent is
highly demanding. We have developed a scalable asymmetric syn-
thesis of dihydrexidine in twelve steps from Garner’s aldehyde de-
Hexahydrobenzophenanthridine compounds, such as dihydrex-
idine 1 and (ꢀ)-(5aR,11bS)-4,5,-5a,6,7,11b-hexahydro-2-propyl-3-
thia-5-azacyclopenta[c]phenanthrene-9,10-diol], A-86929 2a and
its diacetyl prodrug derivative, ABT-431 2b (called adrogolide) have
shown tremendous promise as full dopamine D1 agonists for the
treatment of Parkinson’s and other CNS disorders.1–4 Dihydrexidine
1, introduced in late 1980s, was the first bioavailable full dopamine
D1 receptor agonist and showed approximately a 10-fold selectivity
for D1 and D5 over D2. Later, A-86929 2a was launched as a full ago-
nist at dopamine D1 receptors and was shown to be over 400 times
more selective for dopamine D1 than D2 receptors. There are
several methods for the synthesis of these two compounds in the
racemic form.2a,e,5 Since these compounds are found to exhibit a
high level of enantiospecificity in their interaction with the D1
receptor, their asymmetric synthesis is an active research area.
Ehrlich et al. developed a general chiral-pool approach from expen-
rived from
D
-serine.9b A-86929 could also be synthesized via a
-serine. Since hexahy-
similar route from the Garner aldehyde of
D
drobenzophenanthridine dopamine D1 agonists have a common
aminotetralin unit (upper part) with a variation of the aryl units
(lower part), it was more desirable and convenient to synthesize
both A-86929 and dihydrexidine and other hexahydrobenzophe-
nanthridines from a common and advanced intermediate with a
few simple chemical modifications. Herein we report an efficient
and scalable asymmetric synthesis of (+)-dihydrexidine 1 and A-
86929 2a from homoarylalanine derived from L-serine.
sive N-(trifluoroacetyl)-D
-aspartic acid anhydride.6 Tomioka et al.
described an elegant and impressive general method for the enan-
tioselective synthesis of both compounds using more than a stoichi-
ometric amount of an expensive chiral ligand.7 Hajra and Bar
reported the first concise, catalytic, and enantioselective synthesis
of dihydrexidine and A-86929 using a one-pot asymmetric aziridin-
ation and Friedel–Crafts cyclization as the key steps.8 Recently, we
developed the first catalytic enantioselective conjugate addition of
arene boronic acids to dihydro-3-nitronaphthalenes and applied
2. Results and discussion
From the literature we found that compounds 1 and 2 could be
obtained from aminotetralins 3 and 4, which in turn could be
synthesized from aminoalcohols
Friedel–Crafts cyclization. These two aminoalcohols can be obtained
from aminoaldehyde 7 (Z = H) as well as -amino Weinreb amide 8
(Z = NMeOMe). The common intermediates 7 and 8 can be easily
prepared from the Garner aldehyde 9 of -serine 10 (Scheme 1).
-serine
5 and 6, respectively, by a
a
L
To start with, Garner aldehyde 9 was synthesized from
L
⇑
Corresponding authors. Tel.: +91 33 4000 7000; fax: +91 33 2367 3058 (S.B.);
10 in five steps following a well established literature procedure.10
The enantiomeric purity of 9 was verified by comparing the
specific rotation with the literature value.10 Aldehyde 9 was
tel.:+91 32 2228 3340; fax: +91 32 2225 5303 (S.H).
E-mail addresses: sourav@chembiotek.com (S. Basu), shajra@chem.iitkgp.ernet.
in (S. Hajra).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.003

R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
279
RO
RO
accomplish this synthesis, aldehyde 7 was treated with phenyl
magnesium bromide at 0 °C and provided N-protected-amino alco-
hol 5 as a diastereomeric mixture (dr 60:40; Scheme 3). No at-
tempt was made to determine the enantiomeric purity of
aldehyde 7. The preservation of the high enantiomeric excess of
both diastereomers 5 (ee >98%) indicated no loss of ee during the
oxidation and addition reactions.11 It is noteworthy that PhLi addi-
tion to aldehyde 7 gave a messy reaction mixture under the same
reaction conditions. The TFA mediated Friedel–Crafts cyclization of
diastereomeric amino alcohol 5 under heating conditions (80 °C)
and subsequent treatment of the crude cyclized product with nosyl
chloride exclusively afforded trans-N-nosyl-2-amino-1-phenyltetr-
alin 3 (dr >99:1) while maintaining high enantioselectivity (ee
>99%).11 All of the spectroscopic data and the specific rotation of
compound 3 matched well with the literature values.7b,8a,9b The
synthesis of (+)-dihydrexidine hydrochloride was accomplished
from compound 3 as reported in the literature.9b
Similarly, a THF solution of aldehyde 7 was reacted with the
lithiated thiophene generated from 4-bromo-2-propyl thiophene
146b but this afforded an intractable mixture of compounds. When
the addition of lithiated thiophene to aldehyde 7 was carried out in
ether, it gave the desired amino alcohol 6 as a diastereomeric mix-
ture (dr 65:35) in 40% yield, but with a decrease in the ee (85% and
83%).11 Varying the reaction temperature, solvent, and concentra-
tion did not overcome these problems and provided inconsistent
results with ee values of 80–95% in low to moderate yields.
The lithiated arene might be more basic than the corresponding
Grignard reagent; the former might act as a base for the partial
epimerization of aldehyde 5 during the addition reaction. We at-
tempted to prepare the Grignard reagent from 4-bromo-2-propyl-
thiophene using Mg and also i-PrMgX, but this was unsuccessful.
We therefore looked for a scalable, easy to handle route, where in-
stead of aldehyde 7, Weinreb amide 8 was used as the advanced
intermediate. The TEMPO catalyzed direct oxidation of alcohol 13
to an acid using NaOCl/NaClO2 and PhI(OAc)2 as secondary oxi-
dants was studied.12 The latter was found to be more efficient for
obtaining acid 15, which was converted into the corresponding
Weinreb amide 8 in good yield (Scheme 4). There was complete
preservation of the enantiomeric purity during the oxidation and
amidation steps, with both acid 15 (ee >98%) and Weinreb amide
8 (ee >98%) showing excellent enantiomeric excess.11
HO
HO
NH
NH
S
n-Pr
R = H; A-86929
2a:
1: Dihydrexidine
2b: R = Ac; Adrogolide
MeO
MeO
MeO
NHR'
MeO
NHR'
3
4
S
n-Pr
MeO
MeO
MeO
MeO
OH
OH
NHR'
NHR'
5
6
S
n-Pr
NHR
MeO
Z
O
MeO
7:
8:
Z = H
Z = NMeOMe
BocN
OHC
L-serine
O
10
The synthesis of amide 8 was scaled up to 20 g. This proved to
be quite stable and could be easily used as a common precursor
of the synthesis of many hexahydrobenzophenanthridine com-
pounds. Thus the addition of the lithiated thiophene, generated
from 4-bromo-2-propyl thiophene 14,6b to amide 8 was facile
and afforded ketone 16 in high yield (81%) without any loss of ste-
reochemical integrity (Scheme 5).11 Ketone 16 was reduced with
NaBH4 and provided the corresponding aminoalcohol 6 as a diaste-
reomeric mixture (dr 75:25) with conservation of the high ee.11
Unlike the ArLi addition to aldehyde 7 (Scheme 3), it afforded the
opposite diastereoselectivity. Compound 6 was subjected to TFA
mediated Friedel–Crafts cyclization and underwent smooth cycli-
zation at 50 °C within half an hour to afford 2-amino-1-aryl tetralin
4. The crude cyclized product 4 was directly used for a Pictet–Spen-
gler cyclization. For this purpose, an aqueous ethanolic solution of
compound 4 and formalin was heated with concd HCl for 3 h. Dilu-
tion of the ice-cold reaction mixture with ether gave the hydro-
chloride salt of O-methyl A-86929 17ꢁHCl as a white solid in 53%
yield (over two steps) with excellent diastereo- (dr >99:1) and
enantioselectivity (ee >99%).11 The optical rotation of 17ꢁHCl
9
Scheme 1. Retrosynthetic analysis of hexahydrobenzophenanthridine compounds.
reacted with the ylide generated from (3,4-dimethoxybenzyl)tri-
phenylphosphonium bromide 11 which resulted in the alkene as
an E/Z-mixture (Scheme 2). After removal of the Ph3PO by-product,
it was used directly for the reduction using Pd-C catalyst under an
atmospheric pressure of hydrogen (H2-baloon) and provided the
protected amino alcohol 12. Acetonide deprotection of 12 using
PTSA afforded N-protected 2-amino-4-arylbutyl alcohol 13 in high
yield. There was no loss of ee over the course of these reactions as
the enantiomeric excess of compounds 12 and 13 was found to be
very high (ee >98%).11 Oxidation of alcohol 13 was thought to give
aldehyde 7, which could then be used as an advanced intermediate.
However, this was not successful with (COCl)2/DMSO (Swern oxi-
dation), IBX, PDC, or PCC and gave either a poor yield and/or a mix-
ture of uncharacterized compounds. Oxidation with PyꢁSO3
complex and DMSO was found to be very efficient and afforded
aldehyde 7 in 65% yield.
{½a 2D5
ꢂ
¼ ꢀ243 (c 0.55, MeOH)} was comparable with the lit.7c value
Reaction of aldehyde 7 with a variety of metaloarenes (ArM) fol-
lowed by Friedel–Crafts cyclization and simple chemical modifica-
tion can afford a large number of hexahydrobenzo–phenanthridine
compounds including dihydrexidine and A-86929. In order to
{½a 2D5
ꢂ
¼ ꢀ257 (c 0.55, MeOH), ½a D25
¼ ꢀ263 (c 3.31, MeOH)} and
ꢂ
chiral HPLC analysis showed >99% ee.11 Finally the demethylation
of compound 17 by BBr3 at ꢀ78 °C accomplished the synthesis of
A-86929 as its hydrobromide salt 2aꢁHBr in 85% yield. The specific

280
R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
BocN
11,
1. ArCH2PPh3Br
n-Bu-Li
BocN
OHC
MeO
MeO
O
ref. 10
O
THF, -20 °C to -78 °C
L-serine
2. 10% Pd-C, H2 (1 atm),
MeOH, rt 1 h
9
10
12
79% over two steps
ee: >98%
NHBoc
OH
NHBoc
O
MeO
MeO
MeO
H
Py.SO3, i-Pr2NEt
PTSA
MeOH, rt, 3 h
88%
CH2Cl2, -15 °C
65%
MeO
13
ee: >98%
7
Scheme 2. Synthesis of (R)-N-Boc-2-amino-4-arylbutyraldehyde 7 from L-serine.
NHBoc
NHBoc
MeO
MeO
PhMgBr
MeO
MeO
Ph
THF, 0 °C
MeO
MeO
H
1. TFA, 80 °C
OH
2. NsCl,
Et3N, CH2Cl2
NHNs
O
5
7
dr: 60: 40
3
ee: 98.5% and 98%
Br
dr > 99:1
ee: >99%
n-Pr
S
ref. 9b
40%
14
,
n-BuLi
Et2O, -78 °C
BocHN
HO
HO
NH·HCl
S
HO
HO
MeO
MeO
OH
NH
1·HCl
6
dr: 65:35
2a
S
ee: 85% and 83%
Scheme 3. Formal asymmetric synthesis of dihydrexidine and A-86929 from aldehyde 7.
NHBoc
OH
NHBoc
OH
PhI(OAc)2 (2.2 equiv)
TEMPO (20 mol %)
MeO
MeO
MeO
MeO
CH3CN/H2O (1:1)
rt, 14 h
O
67%
13
15
ee: >98%
i-BuOCOCl (1.0 equiv)
NMP (2.0 equiv)
NHBoc
Me
MeO
MeO
N
Me(MeO)NH.HCl (1.03 equiv)
OMe
CH2Cl2, -15 °C to rt
68%
O
8
ee: >98%
Scheme 4. Synthesis of Weinreb amide 8.

R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
281
(+)-Dihydrexidine
MeO
MeO
ref. 9b
MeO
PhMgBr
THF, 0 °C
NaBH4
1. TFA, 80 °C
NHBoc
MeO
8
NHBoc
3
EtOH
O
77%
HO
2. NsCl, Et3N
52%
0 °C to rt
18
90%
dr: >99:1
ee: >99%
Br
5
dr: 70:30
n-Pr
81%
S
14, n-BuLi
ee: 98.5% and 98%
Et2O/THF, -78 °C
MeO
MeO
MeO
MeO
MeO
TFA, 50 °C
30 min
NaBH4
MeO
NH2
NHBoc
NHBoc
O
EtOH,
HO
0 °C to rt
16
S
95%
6
4
S
S
dr: 75:25
ee: 98.5% and 98%
ee: 99%
(HCHO)n
conc. HCl
EtOH, heat
53%
over two steps
HO
HO
MeO
MeO
BBr3
NH.HBr
NH.HCl
CH2Cl2
-78 °C
85%
S
S
17·HCl
2a·HBr
dr: >99:1
ee: >99%
Scheme 5. Divergent asymmetric synthesis of dihydrexidine and A-86929 from Weinreb amide 6.
rotation of compound 2aꢁHBr {½a D23
ꢂ
¼ ꢀ176:2 (c 1.0, MeOH)}
¼ ꢀ171 (c 0.76, MeOH)}.
compounds from an advanced chiral precursor, derived from
L
-ser-
matched well with the lit.7c,8b data {½a D25
ꢂ
ine. The synthesis of dopamine D1 agonists, dihydrexidine, and A-
86929, started from Weinreb amide 8, a common intermediate
with high diastereo- and enantioselectivity. This method can be
scaled up to a few grams and needs minimum column purification.
The synthesis of A-86929 from Weinreb amide 8 uses only one col-
umn chromatographic purification. Variation in the Wittig reaction
and in the addition of metaloarene to the Weinreb amide could
provide a variety of hexahydrobenzophenanthridine compounds.
It should be noted that the synthesis of A-86929 from Weinreb
amide 8 was achieved using only one column chromatographic
purification.
Weinreb amide 8 can be exploited as a common precursor for
the synthesis of other hexahydrobenzophenanthridines. As a re-
sult, it was further utilized for the synthesis of dihydrexidine. Thus
treatment of a THF solution of amide 8 with PhMgBr at 0 °C and
subsequent reduction of the product aminoketone 18 with NaBH4
provided aminoalcohol 5 as a diastereomeric mixture in good yield
(Scheme 5). It should be noted that the major diastereomer was
opposite to the isomer obtained from the addition of PhMgBr to
aldehyde 7 (Scheme 3). The TFA mediated Friedel–Crafts cycliza-
tion of aminoalcohol 5 followed by reaction with nosyl chloride
4. Experimental
4.1. General
All reactions were conducted using oven-dried glassware under
an argon atmosphere (Ar) or nitrogen (N2). Commercial grade re-
agents 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 per-
formed on aluminum-backed plates coated with Silica gel 60 with
exclusively afforded trans-N-nosyl-2-amino-1-phenyltetralin
3
(dr >99:1) in 52% yield with high enantiopurity.11 Dihydrexidine
was synthesized from aminotetralin 3 using our earlier protocol.9b
3. Conclusion
F
254 indicator. The 1H NMR spectra were recorded at 400 MHz and
In conclusion, we have described a divergent asymmetric proto-
col for the synthesis of hexahydrobenzophenanthridine
13C NMR spectra were recorded at 100 MHz using CDCl3 and
DMSO-d6. 1H NMR chemical shifts are expressed in parts per

282
R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
million (d) relative to CDCl3 (d = 7.26) and DMSO-d6 (d = 2.49); 13C
NMR chemical shifts are expressed in parts per million (d) relative
to the CDCl3 resonance (d = 77.0), DMSO-d6 (d = 39.7), and MeOH-
d4 (d = 49.0). High resolution mass spectra (HRMS) were obtained
under positive electron spray ionization (m/z values are given).
Chiral HPLC analyses were carried out comparing with the corre-
sponding racemic compound by Chiralpak AD-H column
(4.6 ꢃ 250 mm), Chiralpak-IC column (4.6 ꢃ 250 mm), and Lux
Amylose-2 column (4.6 ꢃ 250 mm). Specific rotation values were
measured on a polarimeter.
(4.6 ꢃ 250 mm) 5
l, n-hexane/i-PrOH 90:10, 1.0 mL/min, 210 nm,
tr (major) 11.00, tr (minor) 12.41; ee >98%. ½a D25
¼ þ9:3 (c 0.77,
ꢂ
CHCl3). HRMS (ESI): Calcd for C17H27NO5Na, 348.1787 m/z
[M+Na]+, found 348.1787.
4.1.3. (R)-tert-Butyl (4-(3,4-dimethoxyphenyl)-1-oxobutan-2-
yl)carbamate 7
To a stirred solution of compound 13 (1.0 g, 3.07 mmol) in
anhydrous dichloromethane (9.0 mL) was added anhydrous diiso-
propylethylamine (1.6 mL, 9.2 mmol) at ꢀ15 °C under a nitrogen
atmosphere.
A solution of pyridine–sulfur trioxide complex
4.1.1. (R)-tert-Butyl 4-(3,4-dimethoxyphenethyl)-2,2-dimethyl-
oxazolidine-3-carboxylate 12
(PyꢁSO3; 1.46 g, 9.23 mmol) in anhydrous DMSO (9 mL) was added
to the above solution in one portion. The reaction mixture was stir-
red at the same temperature for 30 min and then slowly poured
into ice cold brine (200 mL), and extracted with dichloromethane
(3 ꢃ 50 mL). The combined organic extract was washed with a
10% aqueous citric acid solution (50 mL), brine (50 mL), dried over
anhydrous sodium sulfate, filtered, concentrated, and purified by
column chromatography to afford compound 7 (0.65 g, 65%). 1H
To a suspension of (3,4-dimethoxybenzyl)triphenylphospho-
nium bromide (25.5 g, 51.78 mmol) in anhydrous THF (100 mL)
was added n-butyllithium (2.35 M, 26.8 mL, 45.5 mmol) at
ꢀ20 °C under an argon atmosphere. The reaction mixture was stir-
red at ꢀ20 °C for 20 min and cooled to ꢀ78 °C. A solution of Garner
aldehyde 7 (9.5 g, 41.43 mmol) in anhydrous THF (80 mL) was
added dropwise to the reaction mixture. The resulting mass was
stirred at ꢀ78 °C for 45 min and then slowly raised to ꢀ10 °C.
The reaction was quenched with a saturated aqueous ammonium
chloride solution (250 mL) and extracted with ethyl acetate
(3 ꢃ 200 mL). The combined organic layers were washed with
water (200 mL), saturated brine (250 mL), and dried over anhy-
drous sodium sulfate. The solvent was removed under vacuum
and most of the triphenylphosphine oxide was removed by precip-
itation on stirring with 50% ether in hexanes. Column chromatog-
raphy of the crude product over silica gel gave an E/Z mixture of
the olefin (13.2 g) as a colorless sticky oil. The oily compound
was dissolved in methanol (100 mL) and thoroughly degassed
using nitrogen. The 10% Pd-C catalyst (0.25 g, 1.8 mmol) was then
added and hydrogenated using a hydrogen-balloon at rt for 1 h.
The reaction mass was filtered over a Celite bed and washed with
methanol (50 mL). The solvent was removed under vacuum and
the crude product was purified by column chromatography to af-
ford pure compound 12 (11.9 g, 79% over two steps) as a colorless
sticky oil. 1H NMR (CDCl3, 400 MHz): d 6.78–6.55 (m, 3H), 3.91 (m,
1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.75 (m, 1H), 2.53 (m, 2H), 2.11–1.90
(m. 2H), 1.57 (s, 3H), 1.52 (s, 3H), 1.52 (s, 3H), 1.45 (s, 9H). 13C NMR
(CDCl3, 100 MHz): d 152.0, 148.9, 147.2, 134.1, 120.0, 111.7, 111.4,
93.1, 79.3, 66.8, 66.8, 57.4, 55.9, 55.8, 35.5, 32.3, 28.3, 27.5, 24.4.
LC–MS (ESI): 365.8 [M+H]+, 387.8 [M+Na]+. HPLC analysis: CHIRAL-
NMR (CDCl3, 400 MHz):
d 9.54 (s, 1H), 6.79–6.78 (m, 1H),
6.72–6.70 (m, 2H), 5.05 (br s, 1H), 4.24 (br s, 1H), 3.86 (s, 3H),
3.85(s, 3H), 2.65 (t, J = 7.8 Hz, 2H), 2.20–2.18 (m, 1H), 1.89–1.82
(m, 1H), 1.45 (s, 9H). 13C NMR (CDCl3, 100 MHz): d 199.6, 155.5,
148.9, 147.5, 133.1, 120.3, 120.1, 111.7, 111.4, 80.1, 59.4, 55.8,
55.8, 31.0, 30.9, 28.2.
4.1.4. (R)-2-((tert-Butoxycarbonyl)amino)-4-(3,4-dimethoxy-
phenyl)butanoic acid 15
To a stirred solution of compound13 (2.4 g, 7.3 mmol) in aqueous
acetonitrile (1:1, 17 mL) were successively added diacetoxyiodo-
benzene (5.2 g, 16.1 mmol) and 2,2,6,6-tetramethyl-1-piperidinyl
free radical (TEMPO; 0.23 g, 1.5 mmol) at rt. The reaction mixture
was then stirred overnight at ambient temperature. After removal
of the solvent under reduced pressure, the reaction mass was diluted
with sodium hydroxide solution (4 M, 9 mL) and washed with
diethyl ether (2 ꢃ 50 mL). The aqueous layer was acidified to pH
ꢄ4 by the dropwise addition of hydrochloric acid solution (4 M) at
an ice bath temperature. The compound was extracted into ethyl
acetate (2 ꢃ 50 mL), and the combined organic layers washed with
water (50 mL), brine (100 mL), dried over anhydrous sodium sulfate.
Thesolvent was removed in order to obtainthe crude product, which
was purified by column chromatography over silica gel to give acid
15 (1.7 g, 67%). 1H NMR (DMSO-d6, 400 MHz): d 12.41 (s, 1H; CO2H),
7.18 (d, J = 8.0 Hz, 1H; NH), 6.84 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.68
(d, J = 8.2 Hz, 1H), 3.84–3.81 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.28–
CEL OD-H (4.6 ꢃ 250 mm) 5
90:10:0.1, 1.0 mL/min, 280 nm, tr (major) 5.54, tr (minor) 5.21; ee
>98%.
¼ ꢀ37:7 (c 0.51, CHCl3). HRMS (ESI): Calcd for
20H31NO5Na, 388.2100 m/z [M+Na]+, found 388.2100.
l, n-hexane/i-PrOH/diethyl amine:
½
a 2D5
ꢂ
3.26 (m, 1H), 2.57–2.54 (m, 1H), 1.91–1.79 (m, 2H), 1.40 (s, 9H). 13
C
NMR (DMSO-d6, 100 MHz): d 174.2, 155.6, 148.5, 146.9, 133.5,
120.0, 112.3, 111.8, 77.9, 55.4, 55.2, 52.7, 32.8, 31.1, 28.1(3C). LC–
MS (ESI): 340 [M+H]+, 357.2 [M+NH4]+. HPLC analysis: CHIR-
C
4.1.2. (R)-tert-Butyl (4-(3,4-dimethoxyphenyl)-1-hydroxybutan-
2-yl)carbamate 13
ALPAK-IC (4.6 ꢃ 250 mm)
5
l
,
n-hexane/EtOH/diethylamine:
A solution of compound 12 (7.45 g, 20.4 mmol) and PTSA
(0.250 g, 1.8 mmol) in methanol (105 mL) was stirred at room tem-
perature for 3 h and the solvents then removed under vacuum. The
residue was diluted with ethyl acetate (250 mL) and washed suc-
cessively with a saturated aqueous sodium bicarbonate solution
(200 mL), water (200 mL), and brine (200 mL). The organic layer
was dried over anhydrous sodium sulfate and removed under vac-
uum to give the crude product, which was purified by column
chromatography over silica gel to provide compound 13 (5.8 g,
88%) as a white solid. Mp 70–72 °C; 1H NMR (CDCl3, 400 MHz): d
6.79–6.77 (m, 1H), 6.72–6.70 (m, 2H), 4.63 (br s, 1H), 3.86 (s,
3H), 3.84 (s, 3H), 3.66 (m, 2H), 3.57–3.55 (m, 1H), 2.66–2.60 (m,
2H), 2.2 (br s,1H), 1.82–1.73 (m, 2H), 1.45 (s, 9H). 13C NMR (CDCl3,
100 MHz): d 156.4, 148.7, 147.1, 134.1, 120.0, 111.6, 111.2, 79.5,
65.6, 55.8, 55.7, 52.2, 33.4, 31.8, 28.3(3C). LC–MS (ESI): 326.4
[M+H]+, 348.6 [M+Na]+. HPLC analysis: CHIRALPAK AD-H
70:30:0.1, 1.0 mL/min, 280 nm, tr (major) 7.97, tr (minor) 10.40, ee
>98%. ½a 2D5
¼ þ4:1 (c 0.51, MeOH). HRMS (ESI): Calcd for C17H25NO6-
ꢂ
Na, 362.1580 m/z [M+Na]+, found 362.1580.
4.1.5. (R)-tert-Butyl (4-(3,4-dimethoxyphenyl)-1-(methoxy-
(methyl)amino)-1-oxobutan-2-yl)carbamate 8
To the solution of compound 15 (3.3 g, 9.7 mmol) in anhydrous
dichloromethane (35 mL) was added N-methylmorpholine
(2.1 mL, 19.5 mmol). The reaction mixture was cooled to ꢀ15 °C
and isobutylchloroformate (1.26 mL, 9.7 mmol) was added and stir-
red. After 15 min, N,O-dimethylhydroxylamine hydrochloride
(0.98 g, 10.02 mmol) was added at this temperature (ꢀ15 °C). The
mixture was then stirred at ꢀ15 °C for an additional 1 h and then al-
lowed to warm to rt and stirred for 1 h. The reaction mixture was
poured into ice cold water (40 mL) and extracted with dichloro-
methane (2 ꢃ 50 mL). The combined organic layer was washed with

R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
283
water, brine, and dried over anhydrous sodium sulfate. The solvent
was removed under vacuum and the crude product was purified
by column chromatography over silica gel to provide the title com-
pound 8 (2.5 g, 68%) as a colorless sticky mass. 1H NMR (CDCl3,
400 MHz): d 6.79–6.73 (m, 3H), 5.19 (m,1H), 4.68 (br s, 1H), 3.86
(s, 3H), 3.84 (s, 3H), 3.62 (s, 3H), 3.16 (s, 3H), 2.68–2.65 (m, 1H),
2.62–2.57 (m, 1H), 1.99–1.97 (m, 1H), 1.82–1.78 (m, 1H), 1.44 (s,
9H). 13C NMR (CDCl3, 100 MHz): d 173.1, 155.5, 148.7, 147.2,
133.7, 120.3, 111.9, 111.2, 79.5, 61.4, 55.9, 55.8, 49.9, 34.6, 31.2,
28.3 (3C). LC–MS (ESI): 383.2 [M+H]+. HPLC analysis: CHIRALPAK-
9.65, ee 98%. HRMS (ESI): Calcd for C24H35NO5SNa, 472.2134 m/z
[M+Na]+, found 472.2134.c
4.1.8. (5aR,11bS)-9,10-Dimethoxy-2-propyl-4,5,5a,6,7,11b-hexa-
hydrobenzo[f]thieno[2,3-c]quinoline hydrochloride 17ꢁHCl
A solution of compound 6 (0.30 g, 0.67 mmol) in anhydrous tri-
fluoroacetic acid (1.5 mL) was heated at 50 °C on a pre-heated oil
bath for 30 min. The residue was neutralized with a saturated
aqueous sodium bicarbonate solution under ice-cold conditions.
The product was extracted into ethyl acetate (3 ꢃ 30 mL). The com-
bined organic layer was washed with water, brine, dried over
anhydrous sodium sulfate, and the solvents were removed under
vacuum to afford aminotetralin 4 (0.23 g, 100%) which was used
immediately in the next step without any purification.
IA (4.6 ꢃ 250 mm) 5
l, 100% EtOH, 0.5 mL/min, 210 nm, tr (major)
10.12, tr (minor) 8.05, ee >98%. ½a D25
¼ þ11 (c 0.51, MeOH). HRMS
ꢂ
(ESI): Calcd for C19H30N2O6Na, 405.2002 m/z [M+Na]+, found
405.2002.
To the solution of crude compound 4 (0.23 g, 0.67 mmol) in
absolute ethanol (5.0 mL) was added 37% formalin (0.52 mL). The
reaction mixture was stirred at rt for 15 min. after which concd
HCl (0.19 mL) was added and then heated at 50 °C for 30 min.
The reaction mixture was cooled to rt, diluted with diethyl ether
(10 mL) and stirred for 45 min. The suspended solution was filtered
and the solid product was washed with diethyl ether (5 mL) to pro-
vide diastereo- and enatiomerically pure O-methyl A-86929 as a
hydrochloride salt 17ꢁHCl (0.135 g, 53%) as a white solid. Mp
270–272 °C; 1H NMR (CDCl3, 400 MHz): d 10.70 (br s, 1H), 10.20
(br s, 1H), 6.98 (s, 1H), 6.84 (s, 1H), 6.68 (s, 1H), 4.54 (d,
J = 15.7 Hz, 1H), 4.34 (d, J = 15.7 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H),
3.86 (s, 3H), 3.82 (s, 3H), 3.15 (m, 1H), 2.99 (m, 1H), 2.90–2.77
(m, 1H), 2.78 (t, J = 7.2 Hz, 2H), 2.61 (m, 1H), 2.37 (m, 1H), 1.70
(m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 1H NMR (DMSO-d6, 400 MHz): d
9.82 (br s, 2H), 7.12 (s, 1H), 6.94 (s, 1H), 6.87 (s, 1H), 4.43 (d,
J = 15.6 Hz, 1H), 4.35 (d, J = 15.6 Hz, 1H), 4.06 (d, J = 10.6 Hz, 1H),
3.74 (s, 3H), 3.69 (s, 3H), 3.17 (m, 1H), 2.90 (m, 2H), 2.83 (t,
J = 7.0 Hz, 2H), 2.28 (m, 1H), 1.90 (m, 1H), 1.64 (m, 2H), 0.93 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d 147.9, 147.2, 145.4,
134.5, 129.0, 127.6, 125.0, 123.7, 111.8, 109.9, 57.6, 56.0, 55.9,
42.7, 39.7, 32.1, 26.8, 24.9, 24.7, 13.5. LC–MS (ESI): 344.2 [M+H]+.
4.1.6. (R)-tert-Butyl (4-(3,4-dimethoxyphenyl)-1-oxo-1-(5-prop-
ylthiophen-3-yl)butan-2-yl)carbamate 16
To a solution of compound 14 (1.9 g, 9.3 mmol) in anhydrous
diethyl ether (16 mL) was added dropwise n-butyl lithium
(2.03 M in hexanes; 3.9 mL, 7.9 mmol) at ꢀ78 °C under nitrogen
and stirred for 40 min. A pre-cooled (ꢀ78 °C) solution of Weinreb
amide 8 (1.03 g, 2.7 mmol) in anhydrous THF (6.0 mL) was then
added dropwise. The reaction mass was stirred at ꢀ78 °C for 1 h
and then carefully quenched with a saturated aqueous ammonium
chloride solution (20 mL), after which it was allowed to return to rt
and diluted with ethyl acetate (100 mL). The layers were separated,
and the organic layer was washed with water, brine, and dried over
anhydrous sodium sulfate. The solvent was removed under vacuum
and the crude product was purified by column chromatography
over silica gel to afford ketone 16 (1.04 g, 81%) as a colorless sticky
mass. 1H NMR (CDCl3, 400 MHz): d 7.74 (s, 1H), 7.06 (s, 1H), 6.78 (d,
J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 5.38 (d, J = 8.7 Hz,
1H), 5.04 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.72 (t, J = 7.3 Hz, 2H),
2.64 (t, J = 7.3 Hz, 2H), 2.15–2.11 (m, 1H), 1.88–1.82 (m, 1H),
1.68–1.61 (m, 2H), 1.44 (s, 9H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): d 193.3, 155.5, 148.9, 147.4, 147.0, 139.1,
133.5, 131.5, 123.6, 120.4, 112.0, 111.3, 79.7, 55.9, 55.8, 55.2,
35.7, 31.8, 31.1, 28.3 (3C), 24.5, 13.5. LC–MS (ESI): 448.2 [M+H]+,
465.2 [M+NH4]+. HPLC analysis: CHIRALPAK-IA (4.6 ꢃ 250 mm)
HPLC analysis: Lux amylose-2 (4.6 ꢃ 250 mm) 5
l, hexane/EtOH/
diethyl amine 80:20:0.1, 1.0 mL/min, 285 nm, tr (major) 7.26, tr
(minor) 16.4, ee >99%.
½
a 2D5
ꢂ
¼ ꢀ243:3 (c 0.55, MeOH) {lit.7c
5l, 100% EtOH, 0.5 mL/min, 210 nm, tr (major) 10.37, tr (minor)
½ ꢂ
a 2D5
¼ ꢀ257 (c 0.55, MeOH)}.
9.38, ee >98%. ½a D25
¼ ꢀ28:5 (c 0.39, CH2Cl2). HRMS (ESI): Calcd for
ꢂ
C
24H33NO5SNa, 470.1977 m/z [M+Na]+, found 470.1977.
4.1.9. (5aR,11bS)-2-Propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thi-
eno[2,3-c]quinoline-9,10-diol hydrobromide 2aꢁHBr (A-86929ꢁHBr)
To compound 17ꢁHCl (0.084 g, 0.24 mmol) in dry DCM (1.6 ml)
was added BBr3 (0.9 ml, 1.0 M solution in CH2Cl2) at ꢀ78 °C. The
reaction mixture was stirred at ꢀ78 °C for 1 h and then placed in
an ice bath and stirred for 2 h. The reaction mixture was further
cooled to ꢀ78 °C and quenched with 1.0 mL of MeOH. The cooling
bath was removed and the mixture was stirred for 2 h at rt, after
which it was concentrated under reduced pressure and the sticky
mass was triturated with ether to give a pure product as a light
brown solid. (0.07 g, 85%). 1H NMR (DMSO-d6, 400 MHz): d 9.44
(br s, 1H), 9.25 (br s, 1H), 8.76 (s, 1H), 8.75 (s, 1H), 6.99 (s, 1H),
6.79 (s, 1H), 6.59 (s, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.40 (m, 1H),
3.92 (d, J = 10.2 Hz, 1H), 3.16 (m, 1H), 2.81 (t, J = 7.6, 2H), 2.88–
2.66 (m, 2H), 2.18 (m, 1H), 1.81 (m, 1H), 1.66 (m, 2H), 0.96 (t,
J = 7.3 Hz, 3H). 1H NMR (d4-MeOH, 400 MHz): d 6.99 (s, 1H), 6.87
(s, 1H), 6.65 (s, 1H), 4.45 (AA0 t, J = 17.2 Hz, 2H), 4.00 (d,
J = 10.9 Hz, 1H), 3.19 (m, 1H), 2.99–2.86 (m, 1H), 2.84 (t,
J = 7.5 Hz, 2H), 2.80 (m, 1H), 2.37–2.28 (m, 1H), 1.97–1.88 (m,
1H), 1.71 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). 1H NMR (MeOH-d4,
100 MHz): d 147.1, 145.3, 144.6, 134.6, 129.1, 128.7, 126.7, 125.7,
116.5, 113.5, 58.7, 44.3, 40.7, 33.0, 26.5, 26.2, 26.0, 13.8. LC–MS
4.1.7. tert-Butyl [(1R,2R)- and (1S,2R)-4-(3,4-dimethoxyphenyl)-
1-hydroxy-1-(5-propylthiophen-3-yl)butan-2-yl]carbamate 6
To a solution of compound 16 (0.720 g, 1.6 mmol) in absolute
ethanol (17 mL) was added sodium borohydride (0.077 g,
2.0 mmol) in portions at 0 °C under nitrogen and then allowed to
stir at ambient temperature for 1 h. The reaction mass was
quenched with a saturated aqueous ammonium chloride solution
(10 mL). The product was extracted into ethyl acetate
(2 ꢃ 50 mL), and the combined organic layer washed with water,
brine, dried over anhydrous sodium sulfate and the solvent re-
moved under vacuum to afford alcohol 6 (0.65 g, 90%) as a diaste-
reomeric mixture (dr 75:25). The crude product 6 was used as such
in the next step without any purification. Mp 76–80 °C; 1H NMR
(CDCl3, 400 MHz): d (major isomer) 6.9 (s, 1H), 6.75 (d, J = 8.0 Hz,
1H), 6.67 (m, 2H), 6.63 (s, 1H), 4.81 [s, 1H; ArCHOH; minor isomer
4.59 (d, J = 8.0 Hz)], 4.66 (br s, 1H), 3.83 (s, 6H), 3.84 (m, 1H), 2.80–
2.40 (m, 4H), 1.75–1.51 (m, 4H), 1.45 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H).
13C NMR (CDCl3, 100 MHz): d 193.3, 155.5, 148.9, 147.4, 147, 139.1,
133.5, 131.5, 123.6, 120.4, 112.0, 111.3, 79.7, 55.9, 55.8, 55.2, 35.7,
31.8, 31.1, 28.3, 24.5, 13.5. LC–MS (ESI): 450.0 [M+H]+. HPLC anal-
ysis: CHIRALPAK-IA (4.6 ꢃ 250 mm)
5l, hexane/IPA: 90:10,
1.0 mL/min, 230 nm, major diastereomer tr (major) 12.75, tr (min-
(ESI): 316.2 [M+H]+.
¼ ꢀ171 (c 0.76, MeOH)}.
½
a 2D5
ꢂ
¼ ꢀ176:2 (c 1.0, MeOH) {lit.7c
½ ꢂ
a 2D5
or) 11.21, ee 98.5%; minor diastereomer tr (major) 20.84, tr (minor)

284
R. Malhotra et al. / Tetrahedron: Asymmetry 24 (2013) 278–284
4.1.10. (R)-tert-Butyl (4-(3,4-dimethoxyphenyl)-1-oxo-1-phen-
ylbutan-2-yl)carbamate 18
over sodium sulfate, and the solvent was evaporated. Column chro-
matographic purification followed by crystallization from MeOH at
ꢀ5 °C afforded exclusively trans-N-nosyl-2-amino-1-phenyltetra-
lin 3 (0.095 g, 52%) as a yellow solid with excellent enantioselectiv-
ity (ee >99%). 1H NMR (CDCl3, 400 MHz): d 8.15 (d, J = 8.8 Hz, 2H),
7.73 (d, J = 8.8 Hz, 2H), 7.15–7.09 (m, 3H), 6.83 (d, J = 6.64 Hz, 2H),
6.59 (s, 1H), 6.07 (s, 1H), 4.74 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 3.81
(d, J = 7.2 Hz, 1H), 3.63 (m, 1H), 3.56 (s, 3H), 2.96–2.87 (m, 1H),
2.83- 2.76 (m, 1H), 2.25–2.21 (m, 1H), 1.78–1.73 (m, 1H). 13C
NMR (CDCl3, 100 MHz): 149.6, 148.0, 147.5, 146.0, 142.9, 128.8,
128.5, 127.9, 127.6, 127.4, 127.0, 124.1, 112.8, 110.8, 57.1, 55.8,
55.7, 51.5, 27.7, 26.1. LC–MS (ESI) m/z: 467.2 [M+H]+. Chiral HPLC
To a solution of Weinreb amide 8 (0.30 g, 0.78 mmol, 1.0 equiv) in
anhydrous THF (2.4 mL) at 0–5 °C was added phenylmagnesium
bromide (1 M in THF; 1.6 ml, 2.1 equiv, 1.6 mmol) over 10 min.
The mixture was then allowed to return to ambient temperature
over 90 min and then brought to 0–5 °C followed by the careful addi-
tion of aqueous ammonium chloride solution. It was then extracted
by ethyl acetate (3 ꢃ 50 mL). The combined organic extract was
washed once with brine and evaporated under reduced pressure.
The crude mass was purified by flash chromatography using ethyl
acetate in hexane to afford ketone 18 (0.21 g, 67%) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3): d 7.79 (d, J = 7.6 Hz, 2H), 7.50 (m,
1H), 7.37 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.67–6.64 (m, 2H), 5.54
(d, J = 7.8 Hz, 1H), 5.29 (m,1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.66–2.59
(m, 2H), 2.13–2.1 (m, 1H), 1.83–1.78 (m, 1H), 1.42 (s, 9H). 13C NMR
(100 MHz, CDCl3): d 199.0, 155.4, 148.7, 147.2, 134.4, 133.4, 133.2,
128.5(2C), 128.3(2C), 120.3, 111.8, 111.2, 79.5, 55.7, 55.6, 54.2,
analysis: CHIRALPAK AD-H (4.6 ꢃ 250 mm) 5
l, n-hexane/i-PrOH
90:10, 1.0 mL/min. 220 nm, tr (major) 25.2, tr (minor) 33.1 ee
>99%. ½a 2D5
ꢂ
¼ ꢀ64:4 (c 0.96, CHCl3) {lit.9b
½
a 2D5
ꢂ
¼ ꢀ64:2 (c 1.00,
CHCl3); lit.8a
½
a 2D5
ꢂ
¼ ꢀ51:2 (c 1.00, CHCl3)}.
References
35.2, 30.8, 28.1(3C). ½a D25
¼ ꢀ24:7 (c 2.95, CHCl3). LC–MS (ESI):
ꢂ
400.0 [M+H]+, 417 [M+NH4]+. HRMS (ESI): Calcd for C23H29NO5Na,
1. (a) Peter, S.; Ruben, I.; Bjorn, K. CNS Drug Rev. 2004, 10, 230–242; (b) Giardina,
W. J.; Williams, M. CNS Drug Rev. 2001, 7, 305–316; (c) Huang, X.; Lawler, C. P.;
Lewis, M. M.; Nichols, D. E.; Mailman, R. B. Int. Rev. Neurobiol. 2001, 48, 65–139.
2. (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.
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, 174, 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, 105–114;
(e) Zhang, J.; Xiong, B.; Zhen, X.; Zhang, A. Med. Res. Rev. 2009, 29, 272–294.
4. (a) Rascol, O.; Blin, O.; Thalamas, C.; Descombes, S.; Soubrouillard, C.; Azulay,
P.; Fabre, N.; Viallet, F.; Lafnitzegger, K.; Wright, S.; Carter, J. H.; Nutt, J. G. Ann.
Neurol. 1999, 45, 736–741; (e) Haney, M.; Collins, E. D.; Ward, A. S.; Foltin, R.
W.; Fischman, M. W. Psychopharmacology 1999, 143, 102–110; (f) Gorelick, D.
A.; Gardner, E. L.; Xi, Z. X. Drugs 2004, 64, 1547–1573; (g) Michaelides, M. R.;
Hong, Y.; DiDomenico, S., Jr.; Asin, K. E.; Britton, D. R.; Lin, C. W.; Williams, M.;
Shiosaki, K. J. Med. Chem. 1995, 38, 3445; (h) Shiosaki, K.; Jenner, P.; Asin, K. E.;
Britton, D.; Lin, C. W.; Michaelides, M. R.; Smith, L.; Bianchi, B.; DiDomenico, S.
J.; Hodges, L.; Hong, Y.; Mahan, L.; Mikusa, J.; Miller, T.; Nikkel, A.; Stashko, M.;
Witte, D.; Williams, M. J. Pharmacol. Exp. Ther. 1996, 276, 150–160.
5. (a) Negash, K.; Nichols, D. E. Tetrahedron Lett. 1996, 37, 6971–6972; (b) Cueva, J.
P.; Nichols, D. E. Synthesis 2009, 715–720.
422.1943 m/z [M+Na]+, found 422.1943.
4.1.11. tert-Butyl [(1R,2R)- and (1S,2R)-4-(3,4-dimethoxyphenyl)
-1-hydroxy-1-phenylbutan-2-yl]carbamate 59b
To a solution of ketone 18 (0.20 g, 0.5 mmol) in absolute ethanol
(5 mL) was added sodium borohydride (0.024 g, 1.8 mmol) in por-
tions at 0 °C under nitrogen and then allowed to stir at ambient tem-
perature for 1 h. The reaction mass was quenched with a saturated
aqueous ammonium chloride solution (5 mL). The product was ex-
tracted into ethyl acetate (2 ꢃ 30 mL), and the combined organic
layer washed with water, brine, dried over anhydrous sodium sul-
fate, and the solvent was removed under vacuum to afford alcohol
5 (0.18 g, 91%) as a diastereomeric mixture (dr 70:30). The crude
product 5 was used in the next step without any purification. 1H
NMR (CDCl3, 400 MHz): major isomer: d 7.33–7.25 (m, 5H C6H5),
6.76 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 4.67 (d,
J = 4.3 Hz, 1H, PhCHOH) [minor isomer 4.74 (d, J = 8.1 Hz)], 4.66 (s,
1H, NH), 3.83 (s, 6H), 3.73 (m, 1H), 2.23 (br s, 1H), 2.66 (m, 1H),
2.55 (m, 1H), 1.85 (m, 1H), 1.71 (m, 1H), 1.38 (s, 9H). 13C NMR (CDCl3,
100 MHz): d 156.4, 148.7, 147.0, 141.6, 134.1, 128.1, 127.5, 126.2,
120.1, 111.6, 111.1, 79.4, 76.1, 56.1, 55.8, 55.6, 33.4, 31.9, 28.2. HPLC
analysis: CHIRALPAK-IA (4.6 ꢃ 250 mm)
5l, n-hexane/i-PrOH:
80:20, 1.0 mL/min, 220 nm, major diastereomer tr (major) 7.37, tr
(minor) 6.86, ee 98.5%; minor diastereomer tr (major) 11.21, tr (min-
or) 8.49, ee 98%. LC–MS (ESI): 402.0 [M+H]+.
6. (a) Ehrlich, P. P.; Michaelides, M. R.; McLaughlin, M. M.; Hsaio, C. U.S. Patent
5,659,037, 1997.; (b) Ehrlich, P. P.; Ralston, J. W.; Michaelides, M. R. J. Org.
Chem. 1997, 62, 2782–2785.
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; (c) Yamashita, M.; Yamada, K. I.;
Tomioka, K. J. Am. Chem. Soc. 2004, 126, 1954–1955.
4.1.12. N-((1R,2R)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-
naphthalen-2-yl)-4-nitrobenzenesulfonamide 3
Compound 5 (0.156 g, 0.389 mmol) was heated with trifluoro-
acetic acid (1.5 mL) at 80 °C on a preheated oil bath for 5 h, concen-
trated under reduced pressure, and neutralized with a saturated
aqueous solution of sodium bicarbonate. The product was ex-
tracted into ethyl acetate (3 ꢃ 20 mL). The combined organic layer
was washed with brine, dried over anhydrous sodium sulfate, and
evaporated to dryness. The residue was dissolved in anhydrous
dichloromethane (8 mL) and cooled to 0 °C under nitrogen. Anhy-
drous triethylamine (0.16 ml, 1.16 mmol) and nosyl chloride
(0.13 g, 0.58 mmol) were then added at 0 °C. The reaction mixture
was then stirred at rt for 2 h, quenched with a saturated aqueous
sodium bicarbonate solution (5 mL) and extracted with CH2Cl2
(3 ꢃ 10 mL). Combined organic layer was washed with brine, dried
8. (a) Hajra, S.; Bar, S. Tetrahedron: Asymmetry 2011, 22, 775–779; (b) Hajra, S.;
Bar, S. Chem. Commun. 2011, 47, 3981–3982.
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R.; Asijaa, S.; Roy, S.; Dutta, S.; Basu, S. Adv. Synth. Catal. 2012, 354, 2433–2437;
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11. Enantiomeric excess (ee) was determined by chiral HPLC compared with the
corresponding racemic compound.
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A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62,
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