Synthesis of substituted (S)-2-aminotetralins via ring-opening of aziridines prepared from l-aspartic acid β-tert-butyl ester

Article abstract of DOI:10.1016/j.tet.2010.09.025

This paper describes the total synthesis of the hydrochloride salts of (2S)-2-amino-7-methoxytetralin (21-HCl) and (2S)-2-amino-6-fluoro-7- methoxytetralin (ST1214), from a common enantiomerically pure aziridine 4b, which was available from l-aspartic acid β-tert-butyl ester. The synthesis of 21-HCl and ST1214 proceeded in nine steps and 5 and 6% overall yields, respectively. Key steps are the regioselective ring-opening of 4b with ArMgBr/CuBr·SMe₂ and the intramolecular Friedel-Crafts cyclisation providing α-tetralone. Substituted naphthalenes were formed as side products in the latter reaction.

Full text of DOI:10.1016/j.tet.2010.09.025

Tetrahedron 66 (2010) 8982e8991
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Synthesis of substituted (S)-2-aminotetralins via ring-opening of aziridines
prepared from
L
-aspartic acid b-tert-butyl ester
*
Jon Erik Aaseng, Odd R. Gautun
Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2010
Received in revised form 15 August 2010
Accepted 6 September 2010
Available online 21 September 2010
This paper describes the total synthesis of the hydrochloride salts of (2S)-2-amino-7-methoxytetralin
(21-HCl) and (2S)-2-amino-6-fluoro-7-methoxytetralin (ST1214), from a common enantiomerically pure
aziridine 4b, which was available from L-aspartic acid b-tert-butyl ester. The synthesis of 21-HCl and
ST1214 proceeded in nine steps and 5 and 6% overall yields, respectively. Key steps are the regioselective
ring-opening of 4b with ArMgBr/CuBr$SMe2 and the intramolecular FriedeleCrafts cyclisation providing
a
-tetralone. Substituted naphthalenes were formed as side products in the latter reaction.
Keywords:
Chiral pool
Ó 2010 Elsevier Ltd. All rights reserved.
L-Aspartic acid
Aziridine
FriedeleCrafts cyclisation
(S)-2-Aminotetralins
1. Introduction
The pharmacological activity of 2-aminotetralin (2-amino-
1,2,3,4-tetrahydronaphthalene) was first described by Bamberger
and Filehne in 1889.1 Since then a large number of articles and
patents, mostly describing studies of the physiological properties of
this class of compounds, have appeared.2 Today, several enantio-
pure 2-aminotetralins (AT) are used in the treatment of medical
conditions like Parkinson’s disease,3 glaucoma,4 and septic shock5,6
(Fig. 1).
The availability of substituted AT building blocks in high enan-
tiomeric purity for the synthesis and biological testing has been
limited to less general methods and/or to non-cost efficient
methods. AT in enantiomeric pure forms have been obtained by
optical resolution of starting materials to enantiopure pre-
cursors,7e9 and from optical resolution of racemic AT.10,11 Various
chemo enzymatic protocols have also been successfully utilized in
the synthesis of enantiopure AT.12e14 Starting from substituted
2-tetralones, stereoselective catalytic hydrogenation of prochiral
enamides and ene carbamates have been performed with chiral
catalysts, typically complexes of ruthenium15e17 or rhodium.18e20
Fig. 1. Pharmacological active 2-aminotetralins.
Herein, we report a new chiral pool synthesis of substituted AT
starting from -aspartic acid -tert-butyl ester (1, see Scheme 1).
Naturally occurring
a
L
-amino acids like
L L-phe-
-aspartic acid,21,22
L
b
nylalanine,23 and
-tyrosine23 have been used in multi-step
The strategy applies regioselective ring-opening of the corre-
sponding, and activated aziridino tert-butyl ester 4 with various
substituted aryl nucleophiles to compounds 5e8. This provides
a potentially basis for the preparation of a variety of substituted and
enantiopure AT with (S)-configuration. A FriedeleCrafts cyclisation,
reductive deoxygenation of the ring carbonyl group, and finally
reactions to construct optically pure AT.
* Corresponding author. Tel.: þ47 73594101; fax: þ47 73594256; e-mail address:
odd.gautun@chem.ntnu.no (O.R. Gautun).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.025

J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
8983
analogues of 1 were either purchased (2a, X¼Cbz) or synthesized
(2b, X¼Ts) via a modified protocol described by Barlos et al.
(Scheme 2).27 The Cbz amino alcohol 3a was obtained from a so-
dium borohydride reduction of 2a, via an in situ formed mixed
anhydride intermediate, in 89% yield.28 To our surprise, a similar
attempt to reduce the Ts protected amino acid 2b to 3b did not
work at all. Thus, other well-known methods for reduction of
amino acids were tested: (i) the combined sodium borohydride/
iodine reducing system described by McKennon et al. failed to
provide 3b,29 (ii) reduction with borane (6 equiv) afforded 3b in
modest 25% yield (best result),30 and (iii) conversion of 2b to an
N-acylbenzotriazole,31 which was further treated with sodium
borohydride, resulted in ca. 20% yield of 3b.32 The low yield ob-
served in the latter method was primarily due to difficulties in the
N-acylbenzotriazole preparation, and not the reduction itself. An
alternative attempt to achieve alcohol 3b in acceptable yield was
made by a de- and reprotection sequence starting from alcohol 3a
(see step c, Scheme 2). Catalytic hydrogenolysis over Pd/C and
subsequent N-tosylation gave 3b in 84% overall yield.
Aziridines 4a and 4b were prepared from respective amino
alcohols in a Mitsunobu-type reaction by adopting a procedure
described by Lapinsky and Bergmeier, in 71 and 90% yields,
respectively (see Scheme 2).33
An alternative Mitsunobu reagent system to the classical diethyl
azodicarboxylate (DEAD)dtriphenylphosphine (Ph3P) reagents
is 1,10-(azodicarbonyl)piperidine (ADDP)dtributylphosphine (n-
Bu3P).34 The latter system has been reported to provide higher
yields in the Mitsunobu reaction for compounds with pKa>11. Test
reactions with 3a (predicted pKa¼11.33ꢀ0.46)35 resulted, however,
in lower yields of 4a (up to 28%), and the ADDP/n-Bu3P system was
not evaluated any further.
Scheme 1. General protocol for asymmetric synthesis of substituted (S)-2-amino-
tetralins starting from L-aspartic acid -tert-butyl ester.
b
removal of the N-protecting group complete the synthesis of
substituted AT.
Four target molecules 21e23 and ST1214 (see Fig. 2), differing in
the aromatic substituent pattern, were chosen to test the general
synthetic route shown in Scheme 1. Two steps in the synthesis appear
to be central: (i) the regioselective ring-opening of the enantiopure
aziridine 4 with substituted aryl nucleophile, and (ii) the intra-
molecular FriedeleCrafts cyclisation to form a
a-tetralone. Two
N-protected aziridines 4a24 and 4b (see Scheme 2) were chosen to be
tested in the former step. The N-benzyloxycarbonyl (Cbz) and N-p-
toluenesulfonyl (Ts) are, in general, complimentary protecting groups
for amines,25a,b but also activate (electron-withdrawing groups) the
aziridine for ring-opening reactions.26 The bulky tert-butyl ester
group in 4a,b was selected to protect the carbonyl moiety against
nucleophilic attack.25c The target molecules have an electron-rich
aromatic ring in common, which should be beneficial for a successful
intramolecular FriedeleCrafts cyclisation to form a-tetralone.
In the ‘normal’ Mitsunobu reaction, the hydrazine side product
(formed in stoichiometric amount) might be a troublesome waste in
the purification step.36 Recently, an organocatalytic Mitsunobu-type
reaction, using catalytic amounts of DEAD was reported by But and
Toy.37 In their protocol, stoichiometric amounts of iodosobenzene
diacetate, PhI(OAc)2, as an oxidant converts the hydrazine side
product back to the DEAD. By utilizing this system, only a catalytic
amount of DEAD (0.1 equiv) is required, and easily removable iodo-
benzene and acetic acid are formed together with triphenylphos-
phine oxide as by-products. Unfortunately, in our hands, applying the
organocatalytic system with amino alcohol 3b provided only stoi-
chiometric amounts of 4b with respect to DEAD, i.e., up to 10% yield.
Fig. 2. Target molecules.
2.2. Nucleophilic ring-opening of aziridines 4a and 4b
Recently, Song et al. reported the reactivity of the Cbz protected
aziridine 4a with various N-, O- and S-nucleophiles in pseudopep-
tide synthesis.24 Excellent regioselectivity was observed for N- and
S-nucleophiles with attack entirely at the less substituted aziridine
carbon. For O-nucleophiles, in combination with an activating
Lewis acid (BF3$OEt2), the regioselectivity in the ring-opening
reaction was poor and varied from 1:1 to 3:1. The report did not
mention results with carbon nucleophiles.
The regioselective ring-opening of 4a and 4b with aryl cuprates
were performed in accordance to an adopted literature procedure,
described by Burgaud et al.38 The cuprate was prepared from an
arylmagnesium bromide (ArMgBr) and a catalytic amount of
CuBr$SMe2 at ꢁ40 ꢂC. Initial experiments revealed that stoichio-
metric control of the Grignard reagent was crucial for the outcome
of the reaction. Therefore, freshly prepared ArMgBr solutions were
always standardized by titration utilizing salicylaldehyde phenyl-
hydrazone as an indicator.39 The results from reacting aziridine
4a and 4b with ArMgBr/CuBr$SMe2 (ArMgBr prepared from
four bromobenzenes: 3-bromoanisole, 2-fluoro-5-bromoanisole,
2-bromoanisole, and 4-bromoveratrole) are presented in Scheme 3.
Scheme 2. (a) (i) Me3SiCl, (ii) Et3N, TsCl, 2b (84% yield); (b) (i) i-BuOCOCl, NMM, DME,
ꢁ15 ꢂC, (ii) NaBH4, 3a (89% yield), 3b (0% yield); (c) (i) H2, 10% Pd/C, abs EtOH, rt, (ii)
TsCl, DMAP, Et3N, DCM, rt, 3b (84% yield); (d) DEAD, Ph3P, THF, 0 ꢂC, 4a (71% yield), 4b
(90% yield).
2. Results and discussion
2.1. Preparation of activated aziridino tert-butyl esters 4a and
4b from
L-aspartic acid b-tert-butyl ester (1)
Aziridines 4a24 and 4b were prepared from respective
L-apartic
acid derivatives as described in Scheme 2. The N-protected

8984
J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
In all cases the ring-opening reaction gave only one regioisomer,
formed by attack at the less substituted aziridine carbon, as
observed by 1H NMR spectroscopic analysis of the crude product. In
general, 2 equiv of the respective Grignard reagent was required to
reach acceptable yields. Attempts with 1.0e1.5 equiv of the nucleo-
phile resulted in low yields, and in some cases failed to provide any
product at all. In gram scale experiments, we found it convenient to
add 3 equiv of the reagent due to a significantly lower conversion.
Compounds 5a and 5b were isolated in 60 and 81% yields, re-
spectively, and represent the most successful ring-opening re-
actions of aziridines 4a,b (see Scheme 3). For compounds 6a,b and
7a,b the yields were typically 40e50%. Reactions with the highly
electron-rich veratrole nucleophile, prepared from 4-bromovera-
trole, proved to be challenging and afforded 8a in only 6% yield,
whereas 8b was not detected at all.
8b
OMe
OMe
Cu(OTf)2
DCM, rt
H
N
4b
+
Ts
O
10
O
(37% yield)
Scheme 5. Lewis acid catalyzed lactonization of aziridine 4b.
2.3. Intramolecular FriedeleCrafts cyclisation
The attempted intramolecular FriedeleCrafts cyclisation of tert-
butyl ester 5b, adopting a recent literature procedure utilizing
1.1 equiv of dimethylchlorosilane (Me2HSiCl) and 10 mol % of in-
dium tribromide (InBr3) as reagents at 80 ꢂC,45 failed to give the
R1
R1
i) Mg, THF
ii) 4a or 4b (1 equiv)
CuBr.SMe2 (15 mol %)
THF, 40 oC
H
N
R2
R3
R2
R3
desired a-tetralone 14b. Me2HSiCl is reported to react with tert-
Br
X
butyl ester on the expense of its silane proton, forming a chlorosilyl
ester, RCO2Si(Cl)Me2. The latter compound mimics an acid chloride
and, in combination with InBr3, a FriedeleCrafts acylation was
expected. Decreasing the reaction temperature to 50 ꢂC was also
unsuccessful and resulted in a gradual decomposition of 5b. These
negative results forced us to look for other mild procedures for
FriedeleCrafts acylation, preferably described to work at ambient,
or lower, reaction temperatures.
Finally, we ended up with literature methods using carboxylic
acid as substrate. A selective cleavage of tert-butyl esters 5a,b, 6a,b,
and 7a,b to respective carboxylic acids was performed in accor-
dance to a procedure described by Mehta et al.,46 where tri-
ethylsilane is used as a carbocation scavenger in the presence of
trifluoroacetic acid (TFA) in DCM (see Scheme 6). Except for the
preparation of 12a, the yields varied in the range of 52e89%.
t-BuO2C
(2-3 equiv)
5 8
-
H
N
H
N
OMe
OMe
F
X
X
t-BuO2C
6a
t-BuO2C
5a
: X = Cbz, 60% yield
: X = Ts, 81% yield
: X = Cbz, 45% yield
5b
6b: X = Ts, 49% yield
OMe
H
N
H
N
OMe
OMe
X
X
t-BuO2C
7a
t-BuO2C
8a
: X = Cbz, 6% yield
: X = Cbz, 51% yield
7b: X = Ts, 40% yield
R1
8b
: X = Ts, 0% yield
H
N
R2
R3
Scheme 3. Nucleophilic ring-opening of aziridines 4a,b with various aryl cuprates.
X
TFA, Et3SiH
5 7
-
In all reactions with the N-Cbz aziridine 4a, various amounts of
benzyl alcohol (up to 23%) were observed in the crude reaction
mixture. This occurrence can probably be explained by the fact that
the Cbz group is not fully compatible with Grignard reagents. We
did also observe various amounts of biaryls (Wurtz coupling
products), which are known side products in this type of reactions,
especially for electron-rich arenes.40
In the ring-opening reactions of 4b, various amounts of N-Ts
alkene 9 were isolated as side product (4e27% yield, see Scheme 4).
A suggested mechanism for the base promoted reaction is shown in
Scheme 4. However, a mechanism involving aziridinyl anions fol-
lowed by a 1,2-H shift, as recently reviewed by Florio and Luisi,
cannot be excluded.41
DCM, 90 min, rt
HO2C
11-13
H
N
H
N
OMe
F
OMe
X
X
HO2C
HO2C
11a: X = Cbz, 78% yield
11b: X = Ts, 89% yield
12a: X = Cbz, 12% yield
12b: X = Ts, 84% yield
OMe
H
N
Ts
N
X
Ts
N
ArMgBr
THF, 40 oC
HO2C
H
O
t-Bu
H
13a
: X = Cbz, 68% yield
CO2t-Bu
ArMgBr
13b
: X = Ts, 52% yield
O
4b
9
Scheme 6. Transforming tert-butyl esters to carboxylic acids.
Scheme 4. Base promoted ring-opening of Ts-aziridine 4b.
The low isolated yield obtained for 12a (12%) was primarily due
to difficulties with purification of the compound, and not the re-
action itself.
The intramolecular FriedeleCrafts cyclisation of 11a,b, 12b, and
13a,b was evaluated by using two reported methods: method A
(reagents: PCl5/SnCl4),21 and method B {reagents: trifluoroacetic
anhydride (TFAA)dtrifluoroacetic acid (TFA)}.47 The reagents given
Because of the unsuccessful attempts to synthesize dimethoxy
analogues 8a and 8b, another approach was also tested. Aziridine
4b was reacted with veratrole under the addition of an azaphilic
42
Lewis acid {Cu(OTf)2 or BF3$OEt243}. From the reaction mixtures
containing several unidentified products, only lactone 1044 was
isolated and characterized (Scheme 5).

J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
8985
for method A are well known from the literature to perform a range
of FriedeleCrafts acylation reactions with related substrates,21,48e50
and were chosen after an initial screening of alternative chlori-
nating reagents (oxalyl chloride, thionyl chloride) and Lewis acids
(AlCl3, BF3$OEt2, TMSOTf). A summary of the more promising re-
sults from the work with carboxylic acids 11a,b and 12b are pre-
sented in Table 1. The results clearly demonstrate that we did not
succeed in finding optimal conditions for the reaction. The best
results were obtained by applying method A at 0 ꢂC providing
The FriedeleCrafts cyclisations of 11b applying method B resul-
ted in decreased product regioselectivity {78:22 (pathway ratio I:II),
entries 5 and 6} compared to method A (95:5, entry 3). The constant
pathway I:II ratio (78:22), accompanied with decreased yield of 14b
(from 23 to 9% yield) and increased formation of 16 with prolonged
reaction time (from 30 min to 16 h, entries 5 and 6, respectively),
supports our mechanistic proposal given in Scheme 7.
The intramolecular cyclisation of 12b, either by method A or B,
appears to be regiospecific, i.e., only follow pathway I, forming
a
-tetralones 14a (Table 1, entry 2),14b (entry 4) and 15b (entry 8) in
mixtures of a-tetralone 15b and naphthalene 17 (entries 7, 8, and
28, 40, and 41% isolated yields, respectively. At room temperature,
cyclisation of 11b (entry 3) resulted in significant amounts of
p-TsNH2, and naphthalenes 1651 and 18.52 We rationalise that
formation of the side products to go through two competitive
9). Aromatization of 15b to 17 is expected to follow the same
mechanism as described in Scheme 7.
Attempted FriedeleCrafts cyclisation reactions of carboxylic
acids 13a and 13b, either by using method A or B, provided only
(regioselective) reaction pathways
(11b/14b0/18) as shown in Scheme 7. Aromatization of the two
regioisomeric
-tetralones 14b and 14b0 is expected to proceed
through a keto-enol equilibrium, and from elimination of the re-
spective enol tautomer. Since 14b0 or its enol tautomer was never
detected in the reaction mixtures, we assume that the enol form of
14b0 is the major tautomer in pathway II, which is stabilized
through a hydrogen bond and lined up for a rapid elimination to
form naphthalene 18 (see Scheme 7).
I
(11b/14b/16) and II
traces of a-tetralone.
a
2.4. Reductive deoxygenation and deprotection of
N-protected -tetralone to substituted AT
a
Reductive removal of the ring carbonyl group in
a-tetralones
14b and 15b were performed by a catalytic hydrogenolysis (Pd/C) at
medium pressure (5 atm H2) by adopting a literature procedure
(see Scheme 8).22 The enantiomeric excess of 19 was determined to
Table 1
Intramolecular FriedeleCrafts cyclisation
H
H
MeO
R
N
N
OMe
R
MeO
R
X
X
Method A or B
+
+
HO2C
O
OMe OH
OH
16: R = H
17: R = F
11a: X = Cbz, R = H
14a: X = Cbz, R = H
14b: X = Ts, R = H
15b: X = Ts, R = F
18
11b: X = Ts, R = H
12b: X = Ts, R = F
Method A: i) PCl5, DCM, ii) SnCl4
Pathway I
Pathway II
Method B: TFAA, TFA, DCM
Entry
Substrate
Method
Conditions
Pathway I:II ratioa
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
11a
11a
11b
11b
11b
11b
12b
12b
12b
A
A
A
A
B
B
A
A
B
0ꢂ (30 min)/rt (3 h)
97:3
97:3
95:5
14a
14a
14b
14b
14b
14b
15b
15b
15b
25
28
27c
40
23
9
0
0
ꢂC (4 h)
ꢂC (1 h)/rt (3 h)
0 ꢂC (6 h)
rt (30 min)
rt (16 h)
91:9
78:22
78:22
100:0
100:0
100:0
0
ꢂC (1 h)/rt (3 h)
39d
41
29
0 ꢂC (4 h)
ꢂC (4 h)
0
a
The pathway ratio (regioselectivity ratio) was determined by 1H NMR (400 MHz) spectroscopic analysis of the crude product. For substrate 11b: pathway I is the sum of
compounds 14bþ16, and pathway II is compound 18.
b
Isolated yield.
c
Isolated side products: 16 (30% yield) and 18 (3% yield).
Isolated side product: 17 (30% yield).
d
H
H
H
N
H
N
MeO
MeO
Ts
Ts
Ts
Ts
I
16
+
O
O
OH
H
14b
11b
TsNH2
H
H
N
H
N
+
18
II
O
O
O
H3C
H3C
H
14b'
stabilizedenol
Scheme 7. Side products formed in the FriedeleCrafts cyclisation of 11b via pathway
I and II.
Scheme 8. Reductive removal of carbonyl group and deprotection of N-tosyl group.

8986
J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
be 99% by chiral HPLC analysis (Chiralpack AD). The instantaneous
deprotection of tosylamides 19 and 20 to 21-HCl and ST1214, re-
spectively, were performed by a one-step SmI2 protocol recently
developed by Ankner and Hilmersson (see Scheme 8).53
The N-Cbz tetralone 14a was simultaneously deoxygenated and
deprotected by catalytic hydrogenolysis (Scheme 9). Treatment of
the liberated amine with hydrochloric acid yielded target molecule
21-HCl (70% yield, two steps). Tosylation of 21-HCl provided
a sample of tosylate 19 for the purpose of chiral HPLC analysis. High
enantiopurity was also found here (99% ee), indicating no problems
with racemization.
chromatography. The elemental analyses were performed at the
€
Mikroanalytisches labor Beller, Gottingen, Germany.
4.2. Preparation of activated aziridino tert-butyl esters 4a and
4b from L-aspartic acid b-tert-butyl ester (1)
Commercially available (S)-2-Amino-4-tert-butoxy-4-oxobuta-
noic acid (1) and (S)-(Benzyloxycarbonylamino)-4-tert-butoxy-4-
oxobutanoic acid (2a) were purchased from Aldrich and used
without any further purification.
4.2.1. (S)-4-tert-Butoxy-2-(4-methylphenyl-sulfinimido)-4-oxo-
butanoic acid (2b). The title compound 2b was prepared according
to a modified literature procedure.27 In the original paper amino
acids were tritylated to give N-trityl amino acids. Here, the amino
function in 1 was protected with a tosyl group. To a stirred solution
of 1 (1.00 g, 5.29 mmol) in anhydrous DCM (12 mL) was added
Scheme 9. Reductive deoxygenation and N-deprotection.
chlorotrimethylsilane (670 mL, 5.28 mmol) at room temperature.
The reaction mixture was heated under a gentle reflux for 2 h, and
then allowed to attain room temperature. Triethyl amine (1.50 mL,
10.8 mmol) and a solution of p-toluenesulfonyl chloride (1.01 g,
5.30 mmol) in anhydrous DCM (5 mL) were added, and the re-
sultant mixture stirred for 2 h at room temperature. The reaction
was quenched by addition of MeOH (0.8 mL) and concentrated
under reduced pressure. The residue was dissolved in 5% aqueous
K2CO3 (50 mL) to ensure pH>9. After washing with diethyl ether
(100 mL), the aqueous layer was acidified with 10% aqueous citric
acid (80 mL, pH 2e3) and then extracted with EtOAc (3ꢃ100 mL).
The combined EtOAc layer was dried (MgSO4) and concentrated
under reduced pressure. The residue was recrystallized from EtOAc/
n-hexane (1:1) to afford pure 2b (1.44 g, 84% yield) as white crys-
3. Conclusion
It has been demonstrated that chiral aziridines, obtained from
L-aspartic acid b-tert-butyl ester, can be applied as chiral building
blocks in the synthesis of various substituted (2S)-2-amino-
tetralins in highly enantiopure form in line with the general
synthetic route presented in Scheme 1. The total synthesis of two
of four selected target molecules, differing in the aromatic sub-
stituent pattern was accomplished in nine steps and 5e6% overall
yields. The key steps are the regioselective ring-opening of azir-
idines 4a,b with ArMgBr/CuBr$SMe2 and the intramolecular
FriedeleCrafts cyclisation providing
a-tetralone. Both steps
showed some limitations due to formation of side products. The
ring-opening reaction worked for three of four anisoles ArMgBr/
CuBr$SMe2, yielding only one regioisomer by attack at the less
substituted aziridine carbon atom and isolated in 40e81% yields.
Optimal conditions for the FriedeleCrafts cyclisation were not
found, since significant amounts of substituted naphthalenes (up
tals. Data for 2b: mp 127e130 ꢂC. [
(400 MHz):
a
]
23 þ47.6 (c 1.0, CH2Cl2). 1H NMR
D
d
7.74 (app. d, 2H, J 8.0 Hz, tolyl), 7.29 (app. d, 2H, J
8.0 Hz, tolyl), 5.70 (d, 1H, J 8.0 Hz, NH), 4.17e4.10 (m, 1H, H-2), 2.89
(dd, 1H, J 17.0, 4.2 Hz, H-3), 2.73 (dd, 1H, J 17.0, 5.0 Hz, H-3), 2.42 (s,
3H, PhCH3), 1.44 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 175.9 (C-1),
169.7 (C-4), 143.9 (tolyl), 136.7 (tolyl), 129.8 (tolyl), 127.2 (tolyl),
82.6 (t-Bu), 52.0 (C-2), 38.7 (C-3), 28.0 (t-Bu), 21.5 (PhCH3). IR (KBr):
3333 (br), 2983 (s), 1760 (s), 1716 (s), 1600 (w), 1371 (s), 1162
(s) cmꢁ1. HRMS (ESI) calcd for C15H20NO6S (MꢁH)ꢁ 342.1017, found
342.1010.
to 33% yield) were formed, presumably from the desired
lones (obtained in ca. 40% yield).
a-tetra-
4. Experimental
4.1. General
4.2.2. (S)-tert-Butyl 3-(benzyloxycarbonylamino)-4-hydroxybutanoate
(3a). Reduction of 2a to 3a was performed according to a general
procedure described by Rodriguez et al.28 To a cold (ꢁ15 ꢂC) solu-
tion of 2a (5.00 g, 15.5 mmol) in anhydrous DME (125 mL), were
successively added N-methyl morpholine (NMM) (1.75 mL,
15.9 mmol) and isobutyl chloroformate (2.10 mL, 16.1 mmol). After
5 min, the mixture was filtrated, and the precipitate washed with
additional DME (2ꢃ20 mL). The filtrate and the washings were
combined and cooled to ꢁ15 ꢂC. A solution of sodium borohydride
(1.80 g, 47.6 mmol) in water (13 mL) was added in one portion,
producing a strong evolution of gas, which ceased rapidly. After
5 min, water (125 mL) was added to the mixture, and the stirring
All reactions were performed under an argon or nitrogen
atmosphere. Tetrahydrofuran (THF) was distilled under nitrogen
atmosphere from Na/benzophenone. Dichloromethane was dis-
tilled under nitrogen from calcium hydride. Melting points were
determined on a Buchi 535 apparatus and are uncorrected. TLC was
performed on Merck silica gel 60 F254 plates, using UV light at
312 nm and a 5% alcoholic molybdophosphoric acid for detection.
Silica gel for flash chromatography was purchased from Merck.
Optical rotations were measured with a PerkineElmer 241 Polar-
imeter. Enantiomeric excesses were determined by HPLC analysis,
using Daicels column Chiralpak AD (250ꢃ4.6 mm). 1H and 13C NMR
spectra (Bruker Advance DPX instruments 300/75 MHz and 400/
100 MHz) were obtained from solutions of CDCl3, and chemical
shifts are in parts per million and referenced to TMS via the lock
signal of the solvent. 1H and 13C NMR signals were assigned by 2D
correlation techniques (COSY, HSQC, HMBC). IR spectra were run on
a Thermo Nicolet FT-IR NEXUS instrument, and only the strongest/
structurally most important peaks are listed. Accurate mass de-
termination (ESI) was performed on an Agilent G1969 TOF MS in-
strument equipped with a dual electrospray ion source. Samples
were injected into MS using an Agilent 1100 series HPLC and
analysis was performed as a direct injection analysis without any
continued for
1 h. The mixture was extracted with EtOAc
(4ꢃ125 mL) and dried (MgSO4). The concentrated crude was puri-
fied by flash chromatography [50% EtOAc in petroleum ether (bp
60e80 ꢂC)] to afford 3a (4.25 g, 89% yield) as a colorless oil. Spec-
troscopic data of 3a was comparable with reported data.54 Rf
23
23
(EtOAc/n-hexane, 1:2)¼0.13. [
a
]
ꢁ9.8 (c 1.1, EtOH), {lit. [
a
]
ꢁ8.7
D
D
(c 1.1, EtOH)}.54 1H NMR (400 MHz):
d
7.39e7.27 (m, 5H, Ph), 5.60
(d, 1H, J 7.6 Hz, NH), 5.09 (s, 2H, PhCH2), 4.08e3.99 (m, 1H, H-3),
3.67 (d, 2H, J 4.8 Hz, H-4), 2.95 (br, 1H, OH), 2.61e2.48 (m, 2H, H-2),
1.42 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 171.0 (C-1), 156.2 (OC(]O)
N), 136.3 (Ph), 128.4 (Ph), 128.1 (Ph), 128.0 (Ph), 81.3 (t-Bu), 66.8
(PhCH2), 64.3 (C-4), 50.0 (C-3), 37.2 (C-2), 27.9 (t-Bu). IR (KBr): 3342

J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
8987
(br), 2978 (m), 1727 (s), 1533 (m), 1368 (s), 1255 (s), 1158 (s), 1061
(NeCH), 32.7 (NeCH2), 28.0 (t-Bu), 21.6 (PhCH3). IR (KBr): 2973 (m),
(s) cmꢁ1. MS (ESI) 332.2 (MþNa)þ.
1717 (m), 1598 (m) 1156 (m) cmꢁ1
. HRMS (ESI) calcd for
C15H21NNaO4S (MþNa)þ 334.1084, found 334.1093.
4.2.3. (S)-tert-Butyl4-hydroxy-3-(4-methylphenyl-sulfonamido)bu-
tanoate (3b). The Cbz group in 3a was removed under neutral
conditions (10% Pd/C, 1 atm H2, abs EtOH) by following an adopted
literature procedure given by Park et al.55 The released amino group
was tosylated in accordance to the general procedure described by
Gandon et al.56 N-Cbz alcohol 3a (4.50 g, 14.6 mmol) was dissolved
with stirring in abs EtOH (80 mL). Pd/C (10%, 100 mg) was added,
the flask was evacuated and then an atmosphere of hydrogen was
secured. The mixture was stirred under balloon pressure of hy-
drogen for 22 h (reaction complete according to TLC). The mixture
was filtered through Celite, the filter cake was washed with abs
EtOH, and the combined filtrate and washings were evaporated to
dryness. The residue was re-dissolved in anhydrous DCM (40 mL)
and added DMAP (170 mg, 1.39 mmol) and triethyl amine (4.00 mL,
28.9 mmol). The resultant stirred mixture was cooled to 0 ꢂC, and
a solution of p-toluensulfonyl chloride (2.80 g, 14.7 mmol) in
anhydrous DCM (15 mL) was slowly added over a period of 50 min.
The reaction mixture was allowed to warm to room temperature,
and then stirred for further 12 h. Water (100 mL) and additional
DCM (100 mL) were added. The layers were separated and the
aqueous phase extracted with DCM (2ꢃ50 mL). The combined or-
ganic layer was dried (Na2SO4), concentrated under reduced pres-
sure, and residue purified by flash chromatography {50% EtOAc in
pet. ether (bp 60e80 ꢂC)} to afford 3b (4.05 g, 84% yield) as a viscous
4.3. Nucleophilic ring-opening of aziridines 4a and 4b
Aziridines 4a and 4b were ring opened with various ArMgBr/
CuBr$SMe2 through an adopted literature procedure.38 The con-
centration of generated aryl Grignard reagents in THF was de-
termined in accordance to the literature, utilizing salicylaldehyde
phenylhydrazone as a titration indicator.39 The concentration of
ArMgBr was typically kept in the range of 1.0e1.1 M.
4.3.1. (R)-tert-Butyl3-(benzyloxycarbonylamino)-4-(3-methoxy-
phenyl)butanoate (5a). A solution of 3-bromoanisole (1.50 mL,
11.8 mmol) in anhydrous THF (8.5 mL) was added slowly to mag-
nesium turnings (280 mg, 11.5 mmol) over a period of approximate
10 min. Once the addition was completed, the reaction was con-
tinued with vigorous stirring for 30 min, then titrated39 and used
immediately in the following reaction.
Copper bromide/dimethylsulfide complex (CuBr$SMe2) (60 mg,
0.29 mmol) was added to a solution of Cbz-aziridine 4a (575 mg,
1.97 mmol) in anhydrous THF (24 mL) under argon atmosphere. The
solution was cooled to ꢁ40 ꢂC and added the standardized solution
of (3-mehoxyphenyl)magnesium bromide in THF (1.0 M, 3.94 mL,
3.94 mmol) over a period of 5 min. The reaction was stirred for 1.5 h
and allowed to warm to ꢁ10 to 0 ꢂC. The reaction mixture was
quenched with aqueous NH4Cl (saturated, 30 mL), warmed up to
room temperature and extracted with diethyl ether (4ꢃ50 mL). The
combined organic layer was washed with brine (50 mL), dried
(MgSO4), and concentrated under reduced pressure. The crude
product was analyzed by 1H NMR spectroscopy to determine the
regioisomeric ratio and, thereafter purified by flash chromatogra-
oil that solidified after a few days. Data for 3b: mp 58e60 ꢂC. Rf
23
(EtOAc/pet. ether, 1:1)¼0.35. [
a
]
D
þ21.5 (c 1.0, CH2Cl2). 1H NMR
(400 MHz):
d
7.78 (app. d, 2H, J 8.3 Hz, tolyl), 7.31 (app. d, 2H, J
8.3 Hz, tolyl), 5.59 (d, 1H, J 6.4 Hz, NH), 3.64e3.53 (m, 3H, H-3, and
H-4), 2.44 (dd, 1H, J 16.0, 4.0 Hz, H-2), 2.43 (s, 3H, PhCH3), 2.37 (dd,
1H, J 16.2, 5.8 Hz, H-2), 2.32 (t,1H, J 6.0 Hz, OH),1.40 (s, 9H, t-Bu). 13C
NMR (100 MHz):
d
170.9 (C-1), 143.6 (tolyl), 137.5 (tolyl), 129.8
phy (10% EtOAc in n-hexane), to yield 5a (470 mg, 60% yield) as
23
(tolyl),127.1 (tolyl), 81.9 (t-Bu), 64.1 (C-4), 52.1 (C-3), 37.2 (C-2), 28.0
(t-Bu), 21.5 (PhCH3). IR (KBr): 3580 (m), 3477 (m), 3296 (m), 3244
(s), 2984 (m), 1706 (s), 1365 (s) 1151 (s) cmꢁ1. HRMS (ESI) calcd for
C15H24NO5S (Mþ1)þ 330.1370, found 330.1374.
a colorless oil. Data for 5a: Rf (15% EtOAc in n-pentane)¼0.31. [
a]
D
þ13.4 (c 1.0, CH2Cl2). 1H NMR (400 MHz):
d 7.40e7.30 (m, 5H, Ph),
7.19 (t, 1H, J 7.8 Hz, HAr-5), 6.80e6.74 (m, 2H, HAr-4, and HAr-6), 6.73
(br s, 1H, HAr-2), 5.36 (d, 1H, J 7.2 Hz, NH), 5.08 (s, 2H, PhCH2),
4.30e4.10 (m, 1H, H-3), 3.77 (s, 3H, OCH3), 2.93 (dd, 1H, J 13.2,
5.6 Hz, H-4), 2.80 (dd, 1H, J 13.2, 8.0 Hz, H-4), 2.43 (dd, 1H, J 15.6,
5.6 Hz, H-2), 2.35 (dd, 1H, J 15.8, 5.8 Hz, H-2), 1.45 (s, 9H, t-Bu). 13C
Aziridines 4a and 4b were synthesized from their respective
amino alcohols 3a,b via an adoptet Mitsunobu reaction described
by Lapinsky and Bergmeier.33
NMR (100 MHz):
d 170.9 (C-1), 159.7 (CAr-3), 155.6 (OC(]O)N),
4.2.4. (S)-Benzyl 2-(2-tert-butoxy-2-oxoethyl)-aziridine-1-carboxyl-
ate (4a). Triphenylphosphine (800 mg, 3.05 mmol) was added to a
stirred solution of N-Cbz alcohol 3a (0.955 mg, 2.90 mmol) in an-
hydrous THF (24 mL). The mixture was cooled to 0 ꢂC and diethyl
139.2 (CAr-1), 136.6 (Ph), 129.5 (CAr-5), 128.5 (Ph), 128.0 (2C, Ph),
121.7 (CAr-6), 114.8 (CAr-2), 112.2 (CAr-4), 81.2 (t-Bu), 66.5 (PhCH2),
55.1 (OCH3), 49.4 (C-3), 40.3 (C-4), 38.5 (C-2), 28.1 (t-Bu). IR (thin
film, NaCl): 3339 (br), 2977 (m), 1724 (s), 1491 (s), 1261 (s), 1153 (s),
1045 (s) cmꢁ1. HRMS (ESI) calcd for C23H29NNaO5 (MþNa)þ
422.1938, found 422.1942.
azodicarboxylate (DEAD) (470 mL, 3.02 mmol) added dropwise over
a period of 5 min. The reaction mixture was stirred for 5 h at 0 ꢂC.
The mixture was concentrated and the residue purified by flash
chromatography (10% EtOAc in n-hexane) to provide pure aziridine
4.3.2. (R)-tert-Butyl 4-(3-methoxyphenyl)-3-(4-methylphenylsulfon-
amido)butanoate (5b). The title compound was prepared from 4b
and (3-methoxyphenyl)magnesium bromide/CuBr$SMe2 in accor-
dance with the procedure described for preparation of 5a. The
crude product was purified by flash chromatography (20% EtOAc in
4a (600 mg, 71% yield) as a colorless oil. Data for 4a: Rf (10% EtOAc
23
in n-hexane)¼0.15. [
a]
þ19.5 (c 0.76, MeOH), {lit. [
a
]
D
þ23.7 (c
D
0.76, MeOH)}.24
4.2.5. (S)-tert-Butyl 2-(1-tosylaziridin-2-yl)acetate (4b). Ts-azir-
idine 4b was synthesized in accordance to the procedure described
for preparation of aziridine 4a. The crude product was purified by
flash chromatography (20% EtOAc in n-hexane) to afford 4b
(84e90% yield) as colorless crystals. Data for 4b: Rf (20% EtOAc in
n-hexane) to afford 5b (68e81% yield) as colorless oil. Data for 5b:
þ19.2 (c 1.0, CH2Cl2). 1H
23
Rf (20% EtOAc in n-hexane)¼0.24. [
a
]
D
NMR (300 MHz):
d
7.61 (app. d, 2H, J 8.3 Hz, tolyl), 7.21 (app. d, 2H, J
8.4 Hz, tolyl), 7.13 (t, 1H, J 7.9 Hz, HAr-5), 6.73 (dd, 1H, J 8.0, 2.2 Hz,
HAr-4), 6.60 (d, 1H, J 7.6 Hz, HAr-6), 6.51 (app. s, 1H, HAr-2), 5.22 (d,
1H, J 8.2 Hz, NH), 3.73 (s, 3H, OCH3), 3.75e3.61 (m, 1H, H-3), 2.78
(dd,1H, J 13.5, 7.3 Hz, H-4), 2.71 (dd,1H, J 13.6, 6.7 Hz, H-4), 2.41 (dd,
1H, J 16.4, 4.6 Hz, H-2), 2.40 (s, 3H, PhCH3), 2.33 (dd, 1H, J 16.5,
n-hexane)¼0.27. Mp 56e57 ꢂC. [
a
]
D
23 þ10.6 (c 1.0, CH2Cl2). 1H NMR
(400 MHz):
d 7.84 (app. d, 2H, J 8.3 Hz, tolyl), 7.33 (app. d, 2H, J
8.3 Hz, tolyl), 3.14e3.02 (m, 1H, NeCH), 2.69 (d, 1H, J 7.0 Hz, NCH2),
2.44 (s, 3H, PhCH3), 2.44 (dd,1H, J 16.4, 6.4 Hz, C(]O)CH2), 2.36 (dd,
1H, J 16.4, 6.3 Hz, C(]O)CH2), 2.13 (d, 1H, J 4.5 Hz, NCH2), 1.39 (s, 9H,
6.0 Hz, H-2), 1.44 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 170.7 (C-1),
159.7 (CAr-3), 143.2 (tolyl), 138.5 (CAr-1), 137.5 (tolyl), 129.6 (tolyl),
129.5 (CAr-5), 127.0 (tolyl), 121.6 (CAr-6), 114.6 (CAr-2), 112.4 (CAr-4),
81.5 (t-Bu), 55.1 (OCH3), 52.0 (C-3), 40.6 (C-4), 38.9 (C-2), 28.1
t-Bu). 13C NMR (100 MHz):
d
169.0 (C]O), 144.5 (tolyl), 134.9 (tolyl),
129.7 (tolyl), 128.1 (tolyl), 81.5 (t-Bu), 37.8 (C(]O)CH2), 36.1

8988
J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
(t-Bu), 21.5 (PhCH3). IR (thin film, NaCl): 3288 (br), 2977 (s), 1731
(s), 1601 (m) 1163 (m), 1093 (m) cmꢁ1. HRMS (ESI) calcd for
C22H29NNaO5S (MþNa)þ 442.1659, found 442.1661.
1246 (s), 1151 (s) cmꢁ1. HRMS (ESI) calcd for C23H30NO5 (Mþ1)þ
400.2118, found 400.2111.
4.3.6. (R)-tert-Butyl 4-(2-methoxyphenyl)-3-(4-methylphenylsulfon-
amido)butanoate (7b). The title compound was prepared from 4b
and (2-methoxyphenyl)magnesium bromide/CuBr$SMe2 in accor-
dance with the procedure described for preparation of 5a. Purifi-
cation of the crude mixture by flash chromatography (10% EtOAc in
n-pentane) provided 7b (30e40% yield) in a mixture with start
4.3.3. (R)-tert-Butyl 3-(benzyloxycarbonylamino)-4-(4-fluoro-3-me-
thoxyphenyl)butanoate (6a). The title compound was prepared
from 4a and (4-fluoro-3-methoxyphenyl)magnesium bromide/
CuBr$SMe2 in accordance to the procedure described for prepara-
tion of 5a. Purification of the crude mixture by flash chromatog-
raphy (10% EtOAc in n-pentane), provided 6a (45% yield) as a white
material 4b. Data for 7b: 1H NMR (400 MHz):
8.4 Hz, tolyl), 7.16e7.14 (m, 1H, HAr-4), 7.12 (app. d, 2H, J 8.4 Hz,
tolyl), 6.90 (dd,1H, J 7.4,1.8 Hz, HAr-6), 6.77 (dd,1H, J 7.4, 0.9 Hz, HAr-
d 7.51 (app. d, 2H, J
crystalline material. Data for 6a: Rf (10% EtOAc in n-pentane)¼0.10.
23
Mp 46e48 ꢂC. [
d
a]
þ14.3 (c 0.3, CH2Cl2). 1H NMR (400 MHz):
D
7.39e7.28 (m, 5H, Ph), 6.96 (dd,1H, J 11.2, 8.0 Hz, HAr-5), 6.78 (app.
5), 6.73 (dd, 1H, J 8.2, 1.0 Hz, HAr-3), 5.50 (d, 1H, J 7.2 Hz, NH), 3.75 (s,
3H, OCH3), 3.77e3.67 (m, 1H, H-3), 2.80 (dd, 1H, J 13.6, 8.0 Hz, H-4),
2.71 (dd, 1H, J 13.6, 6.4 Hz, H-4), 2.54 (dd, 1H, J 16.4, 4.0 Hz, H-2),
2.41 (dd, 1H, J 16.4, 7.2 Hz, H-2), 2.37 (s, 3H, PhCH3), 1.46 (s, 9H, t-
d, 1H, J 7.2 Hz, HAr-2), 6.71e6.63 (m, 1H, HAr-6), 5.37 (d, 1H, J 8.4 Hz,
NH), 5.08 (d, 1H, J 12.4 Hz, PhCH2), 5.06 (d, 1H, J 12.4 Hz, PhCH2),
4.22e4.08 (m, 1H, H-3), 3.83 (s, 3H, OCH3), 2.90 (dd, 1H, J 13.2,
6.4 Hz, H-4), 2.79 (dd, 1H, J 13.2, 7.6 Hz, H-4), 2.44 (dd, 1H, J 15.8,
Bu). 13C NMR (100 MHz):
d 170.8 (C-1), 157.2 (CAr-2), 142.7 (tolyl),
5.4 Hz, H-2), 2.35 (dd, 1H, J 15.8, 5.8 Hz, H-2), 1.45 (s, 9H, t-Bu). 13C
137.3 (tolyl), 131.3 (CAr-6), 129.4 (tolyl), 127.2 (CAr-4), 126.9 (tolyl),
125.0 (CAr-1), 120.8 (CAr-5), 110.4 (CAr-3), 81.1 (t-Bu), 55.2 (OCH3),
51.5 (C-3), 40.2 (C-2), 34.8 (C-4), 28.1 (t-Bu), 21.5 (PhCH3). HRMS
(ESI) calcd for C22H29NNaO5S (MþNa)þ 442.1659, found 442.1662.
1
NMR (100 MHz):
d
170.9 (C-1), 155.6 (OC(]O)N), 151.4 (d, JCF
2
244.3 Hz, CAr-4), 147.5 (d, JCF 10.9 Hz, CAr-3), 136.5 (Ph), 134.0 (d,
3
4JCF 3.9 Hz, CAr-1), 128.5 (Ph), 128.1 (Ph), 128.0 (Ph), 121.5 (d, JCF
6.6 Hz, CAr-6), 115.9 (d, 2JCF 18.2 Hz, CAr-5), 114.3 (CAr-2), 81.3 (t-Bu),
66.6 (PhCH2), 56.2 (OCH3), 49.5 (C-3), 39.9 (C-4), 38.5 (C-2), 28.1 (t-
Bu). IR (thin film, NaCl): 3325 (br), 2977 (w), 1724 (s), 1610 (w), 1518
(s), 1152 (s), 1120 (s) cmꢁ1. HRMS (ESI) calcd for C23H28FNNaO5
(MþNa)þ 440.1844, found 440.1847.
4.3.7. (R)-tert-Butyl 3-(benzyloxycarbonylamino)-4-(3,4-dimethoxy-
phenyl)butanoate (8a). The title compound was prepared from 4a
and (3,4-dimethoxyphenyl)magnesium bromid/CuBr$SMe2 in
accordance with the procedure described for preparation of 5a. The
crude product was purified flash chromatography (two columns:
first with 20% EtOAc in n-hexane, and then 2% abs EtOH in DCM) to
4.3.4. (R)-tert-Butyl 4-(4-fluoro-3-methoxyphenyl)-3-(4-methylph-
enylsulfonamido)butanoate (6b). The title compound was prepared
from 4b and (4-fluoro-3-methoxyphenyl)magnesium bromide/
CuBr$SMe2 in accordance with the procedure described for prep-
aration of 5a. Purification of the crude mixture by flash chroma-
afford 8a (ca. 6% yield) as colorless crystalline material. Data for 8a:
23
Rf (2% abs EtOH in DCM)¼0.20. Mp 75e77 ꢂC. [
a
]
þ9.6 (c 0.5,
D
CH2Cl2). 1H NMR (400 MHz):
d 7.38e7.28 (m, 5H, Ph), 6.79 (d, 1H, J
8.4 Hz, HAr-5), 6.75e6.65 (m, 2H, HAr-2 and HAr-6), 5.36 (d, 1H, J
8.4 Hz, NH), 5.09 (s, 2H, PhCH2), 4.22e4.10 (m, 1H, H-3), 3.86 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 2.90 (dd, 1H, J 13.4, 6.2 Hz, H-4), 2.77 (dd,
1H, J 13.6, 8.0 Hz, H-4), 2.44 (dd,1H, J 15.8, 5.4 Hz, H-2), 2.36 (dd,1H, J
tography (15% EtOAc in n-pentane), afforded 6b (49% yield) as
23
a colorless oil. Data for 6b: Rf (20% EtOAc in n-hexane)¼0.25. [
a]
D
þ34.4 (c 1.0, CH2Cl2). 1H NMR (400 MHz):
d 7.54 (app. d, 2H, J
8.0 Hz, tolyl), 7.18 (app. d, 2H, J 8.0 Hz, tolyl), 6.86 (dd, 1H, J 11.2,
8.0 Hz, HAr-5), 6.57e6.48 (m, 2H, HAr-2, and HAr-6), 5.27 (d, 1H, J
8.4 Hz, NH), 3.76 (s, 3H, OCH3), 3.71e3.60 (m, 1H, H-3), 2.78 (dd,
1H, J 13.8, 6.4 Hz, H-4), 2.66 (dd, 1H, J 13.8, 7.8 Hz, H-4), 2.50e2.30
(m, 2H, H-2), 2.41 (s, 3H, PhCH3), 1.44 (s, 9H, t-Bu). 13C NMR
16.0, 5.6 Hz, H-2),1.46 (s, 9H, t-Bu).13C NMR (100 MHz):
d
171.0 (C-1),
155.6 (OC(]O)N), 148.9 (CAr-3), 147.8 (CAr-4), 136.6 (Ph), 130.2 (CAr
-
1),128.5 (Ph),128.1 (Ph), 128.0 (Ph), 121.4 (CAr-6), 112.4 (CAr-2), 111.2
(CAr-5), 81.2 (t-Bu), 66.6 (PhCH2), 55.9 (OCH3), 55.8 (OCH3), 49.6 (C-
3), 39.8 (C-4), 38.5 (C-2), 28.1 (t-Bu). IR (KBr): 3373 (m), 2978 (m),
1717 (s),1694 (s), 1589 (w), 1524 (s), 1252 (m),1150 (m) cmꢁ1. HRMS
(ESI) calcd for C24H31NNaO6 (MþNa)þ 452.2044, found 452.2050.
(100 MHz):
d
170.7 (C-1), 151.4 (d, 1JCF 244.8 Hz, CAr-4), 147.5 (d, 2JCF
4
10.8 Hz, CAr-3), 143.3 (tolyl), 137.3 (tolyl), 133.4 (d, JCF 3.9 Hz,
CAr-1), 129.5 (tolyl), 126.9 (tolyl), 121.3 (d, JCF 6.6 Hz, CAr-6), 115.8
(d, JCF 18.2 Hz, CAr-5), 114.0 (CAr-2), 81.6 (t-Bu), 55.9 (OCH3), 52.3
3
2
4.3.8. (E)-tert-Butyl 4-(4-methylphenylsulfon-amido)but-2-enoate (9).
The title compound was isolated in various amounts (4e27% yield)
from the ring-opening reactions of aziridine 4b with ArMgBr/
CuBr$Me2S. Data for 9: colorless crystalline material. Mp 63e65 ꢂC.
(C-3), 40.2 (C-4), 40.0 (C-2), 28.1 (t-Bu), 21.4 (PhCH3). IR (thin film,
NaCl): 3290 (br), 2978 (m), 1728 (s), 1611 (m) 1519 (s), 1151
(m) cmꢁ1. HRMS (ESI) calcd for C22H32FN2O5S (MþNH4)þ 455.2010,
found 455.2012.
1H NMR (400 MHz):
d 7.75 (app. d, 2H, J 8.3 Hz, tolyl), 7.31 (d, 2H, J
8.4 Hz, tolyl), 6.63 (dt, 1H, J 15.7, 5.3 Hz, H-3), 5.84 (dt, 1H, J 15.7,
1.7 Hz, H-2), 5.20 (br s, 1H, NH), 3.74e3.68 (m, 2H, H-4), 2.42 (s, 3H,
4.3.5. (R)-tert-Butyl 3-(benzyloxycarbonylamino)-4-(2-methoxyph-
enyl)butanoate (7a). The title compound was prepared from 4a and
(2-methoxyphenyl)magnesium bromide/CuBr$SMe2 in accordance
with the procedure described for preparation of 5a. Purification of
the crude mixture by flash chromatography (10% EtOAc in n-pen-
tane), afforded 7a (51% yield) as a white crystalline material. Data
PhCH3), 1.44 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 165.0 (C-1), 143.7
(tolyl), 140.9 (C-3),136.8 (tolyl), 129.8 (tolyl),127.1 (tolyl), 124.8 (C-2),
80.8 (t-Bu), 43.8 (C-4), 28.0 (t-Bu), 21.5 (PhCH3). IR (KBr): 3265 (m),
2978 (m), 1712 (s), 1651 (m) 1598 (m), 1451 (m), 1321 (s), 1159
(m) cmꢁ1. HRMS (ESI) calcd for C15H25N2O4S (MþNH4)þ 329.1530,
found 329.1532.
for 7a: Rf (25% EtOAc in n-hexane)¼0.19. Mp 42e43 ꢂC. [
a
]
23 þ16.0
D
(c 1.0, CH2Cl2). 1H NMR (400 MHz):
d 7.37e7.25 (m, 5H, Ph), 7.20
(app. t, 1H, J 8 Hz, HAr-4), 7.11 (app. d, 1H, J 7 Hz, HAr-6), 6.87 (app. t,
1H, J 7 Hz, HAr-5), 6.83 (app. d, 1H, J 8 Hz, HAr-3), 5.45 (d,1H, J 8.2 Hz,
NH), 5.03 (s, 2H, PhCH2), 4.30e4.18 (m, 1H, H-3), 3.80 (s, 3H, OCH3),
3.00e2.80 (m, 2H, H-4), 2.43 (d, 2H, J 5.7 Hz, H-2), 1.45 (s, 9H, t-Bu).
4.4. Deprotection of tert-butyl ester
Deprotection of the tert-butyl ester group in 5a,b, 6a,b, and 7a,b
to 11a,b, 12a,b, and 13a,b, respectively, was performed according to
an adopted procedure described by Mehta et al.46
13C NMR (100 MHz):
d 171.0 (C-1), 157.6 (CAr-2), 155.7 (OC(]O)N),
136.8 (Ph), 131.3 (CAr-6), 128.4 (Ph), 128.0 (Ph), 127.9 (2C, Ph, and
CAr-5), 126.2 (CAr-1), 120.6 (CAr-4), 110.4 (CAr-3), 80.8 (t-Bu), 66.3
(PhCH2), 55.2 (OCH3), 49.0 (C-3), 39.4 (C-2), 34.6 (C-4), 28.1 (t-Bu).
IR (KBr): 3342 (br), 2977 (m), 1723 (s), 1602 (m), 1587 (m), 1495 (s),
4.4.1. (R)-3-(Benzyloxycarbonylamino)-4-(3-methoxyphenyl)buta-
noic acid (11a). A solution of N-Cbz tert-butyl ester 5a (470 mg,
1.18 mmol) in anhydrous DCM (3.2 mL) was added triethylsilane

J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
8989
(500
m
L, 3.10 mmol), and then trifluoroacetic acid (1.6 mL) drop-
(d, 1H, J 8.4 Hz, NH), 3.76 (s, 3H, OCH3), 3.75e3.64 (m, 1H, H-3), 2.83
(dd, 1H, J 13.8, 6.4 Hz, H-4), 2.72 (dd, 1H, J 13.8, 8.1 Hz, H-4),
2.72e2.58 (m, 2H, H-2), 2.41 (s, 3H, PhCH3). 13C NMR (100 MHz):
wise. The reaction was stirred vigorously for 90 min at room tem-
perature. Evaporation under reduced pressure afforded a white
solid material, which was recrystallized from petroleum ether/
d
175.9 (C-1), 151.5 (d, 1JCF 245.0 Hz, CAr-4), 147.5 (d, 2JCF 10.8 Hz, CAr
-
4
EtOAc (5:3), to afford pure 11a (316 mg, 78%). Data for 11a: mp
3), 143.6 (tolyl), 136.9 (tolyl), 133.1 (d, JCF 3.9 Hz, CAr-1), 129.5
(tolyl), 126.8 (tolyl), 121.3 (d, 3JCF 6.8 Hz, CAr-6), 115.9 (d, 2JCF 18.3 Hz,
CAr-5), 114.0 (d, 3JCF 2.1 Hz, CAr-2), 55.9 (OCH3), 51.9 (C-3), 40.2 (C-4),
38.5 (C-2), 21.5 (PhCH3). IR (KBr): 3300 (br), 2924 (m), 1729 (s), 1613
(m) 1521 (s), 1160 (m) cmꢁ1. HRMS (ESI) calcd for C18H19FNO5S
(MꢁH)ꢁ 380.0973, found 380.0981.
23
88e92 ꢂC. [
a
]
þ20.0 (c 1.0, CH2Cl2). 1H NMR (400 MHz):
D
d
7.38e7.28 (m, 5H, Ph), 7.20 (t, 1H, J 7.8 Hz, HAr-5), 6.80e6.70 (m,
3H, HAr-2, HAr-4, and HAr-6), 5.31 (d, 1H, J 8.4 Hz, NH), 5.09 (d, 1H, J
12.4 Hz, PhCH2), 5.07 (d, 1H, J 12.3 Hz, PhCH2), 4.35e4.10 (m, 1H, H-
3), 3.76 (s, 3H, OCH3), 2.95 (dd,1H, J 12.4, 5.7 Hz, H-4), 2.80 (dd,1H, J
13.4, 7.8 Hz, H-4), 2.64e2.48 (m, 2H, H-2). 13C NMR (100 MHz):
d
176.6 (C-1), 159.7 (CAr-3), 155.7 (OC(]O)N), 138.8 (CAr-1), 136.3
4.4.5. (R)-3-(Benzyloxycarbonylamino)-4-(2-methoxyphenyl)buta-
noic acid (13a). The title compound was prepared from 7a in ac-
cordance with the procedure described for preparation of 11a. The
crude product was recrystallized from EtOAc/petroleum ether (4:6)
to afford 13a (68% yield) as a colorless crystalline material. Data for
(Ph), 129.6 (CAr-5), 128.5 (Ph), 128.1 (Ph), 128.0 (Ph), 121.7 (CAr-6),
114.8 (CAr-2), 112.3 (CAr-4), 66.8 (PhCH2), 55.5 (OCH3), 49.0 (C-3),
40.1 (C-4), 37.2 (C-2). IR (KBr): 3341 (s), 2960 (br), 1700 (s), 1535
(m), 1261 (m), 1053 (m) cmꢁ1. HRMS (ESI) calcd for C19H21NNaO5
(MþNa)þ 366.1312, found 366.1318.
13a: mp 87e90 ꢂC. [
a]
23 þ20.9 (c 1.0, CH2Cl2). 1H NMR (400 MHz):
D
d
7.39e7.25 (m, 5H, Ph), 7.21 (app. t, 1H, J 8 Hz, HAr-4), 7.12 (app. d,
4.4.2. (R)-4-(3-Methoxyphenyl)-3-(4-methylphenyl-sulfonamido)
butanoic acid (11b). The title compound was prepared from 5b in
accordance with the procedure described for preparation of 11a.
The crude product was purified by flash chromatography (EtOAc in
1H, J 7 Hz, HAr-6), 6.88 (app. t, 1H, J 7 Hz, HAr-5), 6.84 (app. d, 1H, J
8 Hz, HAr-3), 5.52 (d, 1H, J 8.2 Hz, NH), 5.05 (s, 2H, PhCH2), 4.32e4.17
(m, 1H, H-3), 3.78 (s, 3H, OCH3), 2.95 (d, 2H, J 6.8 Hz, H-4),
2.70e2.40 (m, 2H, H-2). 13C NMR (100 MHz):
d 177.0 (C-1), 157.5
n-pentane, gradient: 20e40%). This afforded 11b in 89% yield as
(CAr-2), 155.8 (OC(]O)N), 136.6 (Ph), 131.4 (CAr-6), 128.5 (Ph), 128.2
(CAr-4), 128.0 (2C, Ph), 125.8 (CAr-1), 120.7 (CAr-5), 110.7 (CAr-3), 66.6
(PhCH2), 55.2 (OCH3), 48.7 (C-3), 37.7 (C-2), 34.3 (C-4). IR (KBr):
3329 (s), 2936 (br), 1693 (s), 1537 (s), 1245 (s), 1113 (m) cmꢁ1. HRMS
(ESI) calcd for C19H21NNaO5 (MþNa)þ 366.1312, found 366.1312.
23
a colorless crystalline material. Data for 11b: mp 79e81 ꢂC. [
a]
D
þ36.1 (c 1.0, CH2Cl2). 1H NMR (300 MHz):
d 7.60 (app. d, 2H, J 8.3 Hz,
tolyl), 7.21 (app. d, 2H, J 8.3 Hz, tolyl), 7.13 (app. t, 1H, J 8 Hz, HAr-5),
6.73 (app. d, 1H, J 8 Hz, HAr-4), 6.61 (d, 1H, J 7.6 Hz, HAr-6), 6.51 (m,
1H, HAr-2), 5.51 (d, 1H, J 8.4 Hz, NH), 3.73 (s, 3H, OCH3), 3.80e3.66
(m, 1H, H-3), 2.85 (dd, 1H, J 13.7, 7.4 Hz, H-4), 2.74 (dd, 1H, J 13.7,
7.0 Hz, H-4), 2.58 (d, 2H, J 5.3 Hz, H-2), 2.40 (s, 3H, PhCH3). 13C NMR
4.4.6. (R)-4-(2-Methoxyphenyl)-3-(4-methylphenyl-sulfonamido)
butanoic acid (13b). The title compound was prepared from 7b in
accordance with the procedure described for preparation of 11a.
The product was attempted purified by flash chromatography
(EtOAc/petroleum ether, 1:1). However, we were not able to sepa-
rate 13b from Ts-lactone 10. The yield of 13b was estimated to 52%
(100 MHz):
d 176.2 (C-1), 159.8 (CAr-3), 143.4 (tolyl), 138.2 (CAr-1),
137.0 (tolyl), 129.7 (tolyl), 129.7 (CAr-5), 127.0 (tolyl), 121.6 (CAr-6),
114.6 (CAr-2), 112.5 (CAr-4), 55.1 (OCH3), 51.6 (C-3), 40.5 (C-4), 37.9
(C-2), 21.5 (PhCH3). IR (KBr): 3203 (br), 1699 (s), 1598 (m), 1493 (m),
1337 (m), 1158 (m), 1090 (m) cmꢁ1
.
HRMS (ESI) calcd for
from 1H NMR analysis. Data for 13b: 1H NMR (400 MHz):
d 7.53
C18H20NO5S (MꢁH)ꢁ 362.1068, found 362.1066.
(app. d, 2H, J 8.4 Hz, tolyl), 7.22e7.14 (m, 1H, HAr-4), 7.14 (app. d, 2H,
J 8.4 Hz, tolyl), 6.93 (dd, 1H, J 7.4, 1.8 Hz, HAr-6), 6.83e6.77 (m, 1H,
HAr-5), 6.73 (dd, 1H, J 8.4, 0.8 Hz, HAr-3), 5.65 (d, 1H, J 7.6 Hz, NH),
3.74 (s, 3H, OCH3), 3.82e3.70 (m, 1H, H-3), 2.83 (dd, 1H, J 13.6,
7.8 Hz, H-4), 2.77 (dd, 1H, J 13.6, 6.8 Hz, H-4), 2.65 (dd, 1H, J 16.6,
4.4.3. (R)-3-(Benzyloxycarbonylamino)-4-(4-fluoro-3-methoxy-
phenyl)butanoic acid (12a). The title compound was prepared from
6a in accordance with the procedure described for preparation of
11a. The crude product was purified by flash chromatography
(EtOAc in n-pentane, gradient: 20e100%). This afforded 12a in 12%
yield as a colorless crystalline material. Data for 12a: mp 96e98 ꢂC.
6.2 Hz, H-2), 2.59 (dd,1H, J 16.6, 6.6 Hz, H-2), 2.38 (s, 3H, PhCH3). 13
C
NMR (100 MHz):
d 176.4 (C-1), 157.1 (CAr-2), 143.1 (tolyl), 136.9
(tolyl), 131.3 (CAr-6), 129.5 (tolyl), 128.3 (CAr-4), 126.9 (tolyl), 125.2
(CAr-1), 120.9 (CAr-5), 110.4 (CAr-3), 55.2 (OCH3), 51.2 (C-3), 38.9 (C-
2), 34.8 (C-4), 21.5 (PhCH3).
[
a
]
23 þ18.2 (c 0.5, CH2Cl2), 1H NMR (300 MHz):
d 7.40e7.19 (m, 5H,
D
Ph), 6.97 (dd, 1H, J 11.2, 8.2 Hz, HAr-5), 6.78 (d, 1H, J 7.8 Hz, HAr-2),
6.73e6.63 (m, 1H, HAr-6), 5.27 (d, 1H, J 8.3 Hz, NH), 5.09 (d, 1H, J
12.3 Hz, PhCH2), 5.06 (d, 1H, J 12.3 Hz, PhCH2), 4.30e4.13 (m, 1H, H-
3), 3.83 (s, 3H, OCH3), 2.94e2.86 (m, 1H, H-4), 2.83 (dd, 1H, J 13.6,
4.5. Intramolecular FriedeleCrafts cyclisation
7.7 Hz, H-4), 2.68e2.50 (m, 2H, H-2). 13C NMR (100 MHz):
d
177.4
The intramolecular FriedeleCrafts cyclisations of 11a,b and 12b
and attempted cyclisations of 13a,b, were conducted by following
two reported methods: method A (reagents: PCl5/SnCl4),21 and
method B {reagents: trifluoroacetic anhydride (TFAA)dtrifluoro-
acetic acid (TFA)}.47 The synthesis of 14a from 11a is shown as
a general example for method A, and preparation of 14b from 11b is
shown as a general example for method B.
(C-1), 156.5 (OC(]O)N), 151.6 (d, 1JCF 245.0 Hz, CAr-4), 147.6 (d, 2JCF
4
11.3 Hz, CAr-3), 135.6 (Ph), 133.2 (d, JCF 3.9 Hz, CAr-1), 128.7 (Ph),
3
2
128.5 (Ph), 128.1 (Ph), 121.5 (d, JCF 5.6 Hz, CAr-6), 116.1 (d, JCF
18.0 Hz, CAr-5), 114.3 (br, CAr-2), 67.6 (Cbz), 56.2 (OCH3), 49.2 (C-3),
39.9 (C-4), 37.5 (C-2). IR (KBr): 3332 (m), 2933 (br),1698 (s),1539 (s)
1518 (s), 1453 (m), 1420 (m), 1276 (s), 1217 (m), 1152 (m), 1055
(m) cmꢁ1
.
4.5.1. Method A:21 (R)-benzyl 7-methoxy-4-oxo-1,2,3,4-tetrahydro-
naphthalene-2-ylcarbamante (14a). N-Cbz-acid 11a (300 mg,
0.870 mmol) was dissolved in anhydrous DCM (12 mL), cooled to
4.4.4. (R)-4-(4-Fluoro-3-methoxyphenyl)-3-(4-methylphenylsul-
fonamido)butanoic acid (12b). The title compound was prepared
from 6b in accordance with the procedure described for prepara-
tion of 11a. The crude product was purified by flash chromatogra-
phy (EtOAc in n-pentane, gradient: 20e40%). This provided 12b in
0
ꢂC and added PCl5 (200 mg, 0.960 mmol) in one portion. After
vigorous stirring for 1 h, SnCl4 (120 mL, 1.03 mmol, 1.2 equiv) was
added, and the reaction mixture stirred for an additional 5 h at 0 ꢂC.
The reaction was quenched by addition of aqueous saturated
NaHCO3 (50 mL), warmed to room temperature, and extracted with
DCM (5ꢃ50 mL). The combined organic layer was dried (MgSO4)
and concentrated. The crude product was analyzed by 1H NMR
84% yield as a colorless crystalline material. Data for 12b: mp
23
90e95 ꢂC. [
a
]
þ58.5 (c 1.0, CH2Cl2). 1H NMR (400 MHz):
d 7.52
D
(app. d, 2H, J 8.1 Hz, tolyl), 7.18 (app. d, 2H, J 8.1 Hz, tolyl), 6.86 (dd,
1H, J 11.0, 8.6 Hz, HAr-5), 6.53 (d, 2H, J 9.6 Hz, HAr-2, and HAr-6), 5.49

8990
J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
spectroscopy to determine the regioisomeric ratio and, thereafter,
purified by flash chromatography (EtOAc/n-hexane, 2:1) to afford
8.4 Hz, H-5), 6.71 (app. d, 1H, J 8 Hz, H-2), 5.13 (br s, 1H, OH), 4.00 (s,
3H, OCH3). 13C NMR (100 MHz): 152.0 (d, 1JCF 248.5 Hz, C-7), 151.0
d
14a (80 mg, 28% yield) as colorless crystals. Data for 14a: Rf (EtOAc/
(d, 4JCF 12.5 Hz, C-1), 148.3 (d, 2JCF 13.9 Hz, C-6), 132.5 (d, 4JCF 1.5 Hz,
C-4a), 125.8 (d, 6JCF 2.4 Hz, C-3), 119.4 (d, 5JCF 1.8 Hz, C-4), 119.0 (d,
3JCF 8.2 Hz, C-8a), 108.0 (d, 3JCF 2.1 Hz, C-5), 107.5 (C-2), 107.0 (d, 2JCF
19.7 Hz, C-8), 56.0 (OCH3). IR (KBr): 3297 (br), 1642 (m) 1525 (s),
1492 (m), 1430 (m),1296 (s), 1189 (m),1164 (s),1148 (s) cmꢁ1. HRMS
(ESI) calcd for C11H10FO2 (MþH)þ 193.0659, found 193.0659.
23
n-hexane, 1:2)¼0.15. Mp 115e117 ꢂC. [
a
]
þ3.1 (c 1.0, CH2Cl2). 1H
D
NMR (300 MHz): d 8.01 (d, 1H, J 8.8 Hz, H-5), 7.38e7.28 (m, 5H, Ph),
6.86 (dd,1H, J 8.8, 2.4 Hz, H-6), 6.72 (d,1H, J 2.4 Hz, H-8), 5.09 (s, 2H,
PhCH2), 4.88e4.64 (m, 1H, NH), 4.43e4.27 (m, 1H, H-2), 3.86 (s, 3H,
OCH3), 3.29 (d, 1H, J 15.2 Hz, H-1), 3.02e2.84 (m, 2H, H-1, and H-3),
2.66 (dd, 1H, J 16.6, 8.2 Hz, H-3). 13C NMR (100 MHz):
d 194.4 (C-4),
164.2 (C-7), 155.5 (OC(]O)N), 143.0 (C-8a), 136.2 (Ph), 129.7 (C-5),
128.6 (2C, Ph), 128.1 (Ph), 125.7 (C-4a), 113.8 (C-6), 113.4 (C-8), 66.9
(PhCH2), 55.5 (OCH3), 47.3 (C-2), 44.6 (C-3), 36.3 (C-1). IR (KBr):
3392 (m), 1690 (s), 1668 (s), 1598 (s), 1542 (m), 1441 (w), 1249 (m),
1105 (m) cmꢁ1. HRMS (ESI) calcd for C19H20NO4 (MþH)þ 326.1387,
found 326.1380.
4.6. Reductive deoxygenation and deprotecting of N-
protected a-tetralone to substituted AT
4.6.1. (S)-N-(7-Methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)-4-
methylbenzenesulfonamide (19). Reductive removal of the ring
carbonyl group in 14b was performed in accordance with an
adopted literature procedure.22
A solution of 14b (94 mg,
4.5.2. Method B:47 (R)-N-(7-methoxy-4-oxo-1,2,3,4-tetrahydro-naph-
thalene-2-yl)-4-methyl-benzenesulfonamide (14b). To an ice-cooled
stirred solution of Cbz-acid 11b (110 mg, 0.30 mmol) in anhydrous
0.27 mmol) in AcOH (30 mL) was hydrogenated at 5 atm and room
temperature for 38 h using 10% Pd/C (50 mg) as catalyst. After an
initial filtration through Celite and concentration under reduced
pressure, the crude product was purified by flash chromatography
(20% EtOAc in n-pentane) to afford 19 (51 mg, 57% yield) as colorless
crystalline needles. Data for 19: Rf (20% EtOAc in n-hexane)¼0.14.
DCM (2.0 mL) was added dropwise TFAA (70
mL, 1.5 equiv). The
mixture was then added TFA (2.0 mL) and vigorously stirred for
30 min. The reaction was quenched by the addition of aqueous
saturated NaHCO3 (40 mL) and DCM (40 mL). The layers were sep-
arated and the aqueous phase extracted with additional DCM
(2ꢃ40 mL). The combined organic layer was dried (MgSO4) and the
solvent removed under reduced pressure. The crude product was
analyzed by 1H NMR spectroscopy to determine the regioisomeric
ratio. Recrystallization from MeOH provided 24.4 mg of 14b (23%
yield) as a white solid. Data for 14b: Rf (EtOAc/n-hexane, 1:2)¼0.16.
Mp 126e128 ꢂC. [
a]
23 ꢁ80.7 (c 1.0, CH2Cl2). HPLC (Chiralpak AD, i-
D
PrOH/n-hexane (1/9), 1.0 mL/min, 230 nm): 99% ee, tR 28.7 (S) and
30.3 (R) min. 1H NMR (400 MHz):
d 7.77 (app. d, 2H, J 8.3 Hz, tolyl),
7.31 (app. d, 2H, J 8.3 Hz, tolyl), 6.96 (d, 1H, J 8.4 Hz, H-5), 6.69 (dd,
1H, J 8.4, 2.8 Hz, H-6), 6.47 (d, 1H, J 2.8 Hz, H-8), 4.44 (br d, 1H, J
8.1 Hz, NH), 3.74 (s, 3H, OCH3), 3.71e3.57 (m, 1H, H-2), 2.92 (dd, 1H,
J 16.2, 5.0 Hz, H-1), 2.79e2.68 (m, 2H, H-4), 2.57 (dd, 1H, J 16.2,
7.5 Hz, H-1), 2.44 (s, 3H, PhCH3), 1.98e1.84 (m, 1H, H-3), 1.79e1.63
Mp 164e166 ꢂC. [
a]
D
23 ꢁ59.0 (c 1.0, DMF). 1H NMR (400 MHz):
d 7.95
(d,1H, J 8.7 Hz, H-5), 7.73 (app. d, 2H, J 8.0 Hz, tolyl), 7.31 (app. d, 2H, J
8.0 Hz, tolyl), 6.84 (dd, 1H, J 8.7, 2.4 Hz, H-6), 6.63 (d, 1H, J 2.3 Hz, H-
8), 4.78 (d, 1H, J 7.9 Hz, NH), 3.99e3.88 (m, 1H, H-2), 3.85 (s, 3H,
OCH3), 3.20 (dd,1H, J 16.2, 3.6 Hz, H-1), 2.94 (dd,1H, J 16.0, 8.2 Hz, H-
1), 2.69 (dd, 1H, J 16.9, 3.8 Hz, H-3), 2.48 (dd, 1H, J 16.8, 8.9 Hz, H-3),
(m, 1H, H-3). 13C NMR (100 MHz):
d 157.7 (C-7), 143.4 (tolyl), 138.0
(C-8a), 134.4 (tolyl), 129.7 (tolyl), 129.7 (C-5), 127.0 (tolyl), 127.0 (C-
4a), 113.8 (C-8), 112.8 (C-6), 55.2 (OCH3), 49.4 (C-2), 36.7 (C-1), 29.7
(C-3), 25.9 (C-4), 21.5 (PhCH3). IR (KBr): 3318 (s), 3052 (w), 3009
(w), 2938 (m), 2836 (m), 1609 (s), 1505 (s), 1456 (m), 1422 (m), 1322
(s), 1161 (s), 1251 (s), 1062 (m), 811 (m) cmꢁ1. Anal. Calcd for
C18H21NO3S: C, 65.23; H, 6.39; N, 4.23; S, 9.67. Found: C, 64.83; H,
6.35; N, 4.18; S, 9.78.
2.44 (s, 3H, PhCH3). 13C NMR (100 MHz):
d 193.5 (C-4), 164.3 (C-7),
143.9 (tolyl), 142.5 (C-8a), 137.5 (tolyl), 129.9 (tolyl), 129.7 (C-5),127.0
(tolyl), 125.7 (C-4a), 114.0 (C-6), 113.4 (C-8), 55.6 (OCH3), 49.6 (C-2),
45.1 (C-3), 37.3 (C-1), 21.6 (PhCH3). IR (KBr): 3243 (m), 2962 (w),
1668 (s),1600 (s),1461 (m),1160 (s),1089 (m) cmꢁ1. HRMS (ESI) calcd
for C18H19NNaO4S (MþNa)þ 368.0927, found 368.0925.
4.6.2. (S)-N-(6-Fluoro-7-methoxy-1,2,3,4-tetra-hydronaphthalene-
2-yl)-4-methylbenzene-sulfonamide (20). The title compound was
prepared from 15b (45 mg, 0.12 mmol) in accordance to the pro-
cedure described for preparation of 19. The crude product was
purified by flash chromatography (25% EtOAc in n-pentane) to af-
ford 20 (33 mg, 76% yield) as colorless crystalline needles. Data for
4.5.3. (R)-N-(6-Fluoro-7-methoxy-4-oxo-1,2,3,4-tetrahydronaph-
thalene-2-yl)-4-methylbenzene-sulfonamide (15b). The title com-
pound was prepared from 12b. The crude product was purified by
flash chromatography (EtOAc/n-hexane, 1:2). Data for 15b: white
crystalline material. Mp 173e175 ꢂC (decomp.). Rf (EtOAc/n-hexane,
20: Rf (25% EtOAc in n-hexane)¼0.28. Mp 139e142 ꢂC. [
a
]
23 ꢁ79.6 (c
D
0.5, CH2Cl2). 1H NMR (400 MHz):
d 7.77 (app. d, 2H, J 8.4 Hz, tolyl),
1:2)¼0.14. [
a
]
23 ꢁ53.8 (c 0.5, DMF). 1H NMR (400 MHz, DMSO-d6):
7.31 (d, 2H, J 8.4 Hz, tolyl), 6.75 (d, 1H, J 12.0 Hz, H-5), 6.51 (d, 1H, J
8.4 Hz, H-8), 4.59 (d, 1H, J 7.6 Hz, NH), 3.81 (s, 3H, OCH3), 3.75e3.67
(m, 1H, H-2), 2.91 (dd, 1H, J 16.2, 5.0 Hz, H-1), 2.78e2.62 (m, 2H, C-
4), 2.58 (dd, 1H, J 16.2, 7.6 Hz, H-1), 2.44 (s, 3H, PhCH3), 1.93e1.83
D
d
8.03 (s, 1H, NH), 7.71 (app. d, 2H, J 8.0 Hz, tolyl), 7.50 (d, 1H, J
11.6 Hz, H-5), 7.39 (app. d, 2H, J 8.0 Hz, tolyl), 7.08 (d, 1H, J 8.4 Hz, H-
8), 3.90 (s, 3H, OCH3), 3.70e3.58 (m, 1H, H-2), 3.06 (dd, 1H, J 16.0,
4.0 Hz, H-1), 2.90 (dd, 1H, J 16.0, 8.8 Hz, H-1), 2.58e2.46 (m, 2H, H-
(m, 1H, H-3), 1.75e1.63 (m, 1H, H-3). 13C NMR (100 MHz):
d
151.0 (d,
3), 2.39 (s, 3H, PhCH3). 13C NMR (100 MHz):
d
193.3 (C-4), 151.8 (d,
1JCF 244.9 Hz, C-6), 145.8 (d, JCF 11.1 Hz, C-7), 143.5 (tolyl), 138.0
(tolyl), 129.8 (tolyl), 128.9 (d, 4JCF 3.4 Hz, C-8a), 127.4 (d, 3JCF 6.0 Hz,
C-4a), 127.0 (tolyl), 115.7 (d, 2JCF 17.8 Hz, C-5), 113.9 (d, 3JCF 2.0 Hz, C-
8), 56.3 (OCH3), 49.2 (C-2), 36.2 (C-1), 29.2 (C-3), 26.0 (d, 4JCF 1.3 Hz,
C-4), 21.6 (PhCH3). IR (KBr): 3314 (m), 2943 (w), 1520 (s), 1425 (m),
1323 (s), 1292 (m), 1159 (s), 1108 (m), 1030 (w) cmꢁ1. HRMS (ESI)
calcd for C18H20FNNaO3S (MþNa)þ 372.1040, found 372.1036.
2
2JCF 11.2 Hz, C-7), 150.5 (d, 1JCF 245.2 Hz, C-6), 142.7 (tolyl), 139.3.5
4
(d, JCF 3.0 Hz, C-8a), 138.2 (tolyl), 129.7 (tolyl), 126.4 (tolyl), 124.9
(d, 3JCF 4.8 Hz, C-4a), 113.6 (d, 3JCF 8.4 Hz, C-8), 112.3 (d, 2JCF 17.8 Hz,
C-5), 56.4 (OCH3), 49.0 (C-2), 44.0 (C-3), 35.5 (C-1), 21.0 (PhCH3). IR
(KBr): 3242 (m), 2959 (w), 2360 (w), 1670 (s), 1613 (s), 1515 (m),
1450 (m), 1316 (s), 1159 (s), 1086 (m) cmꢁ1. HRMS (ESI) calcd for
C18H22FN2O4S (MþNH4)þ 381.1279, found 381.1277.
4.6.3. (S)-2-Amino-7-methoxy-1,2,3,4-tetrahydro-naphthalene hydro-
4.5.4. 7-Fluoro-6-methoxynaphthalen-1-ol (17). Compound 17 was
isolated as a side product in the FriedeleCrafts cyclisation of 12b
(Table 1, entry 7). Data for 17 (colorless oil): Rf (n-hexane/EtOAc,
d 7.81 (d, 1H, J 12.5 Hz, H-8), 7.32
(app. d, 1H, J 8 Hz, H-4), 7.24 (app. t, 1H, J 8 Hz, H-3), 7.18 (d, 1H, J
chloride (21-HCl). The title compound was prepared from N-Cbz
a-tetralone 14a (80 mg, 0.25 mmol) in accordance to the procedure
described for preparation of 19, and by treating the crude product
with a concd hydrochloric solution (2 mL). Concentration of the
latter solution under reduced pressure provided the crude hydrogen
2:1)¼0.56. 1H NMR (400 MHz):

J.E. Aaseng, O.R. Gautun / Tetrahedron 66 (2010) 8982e8991
8991
9. Yanagi, T.; Kikuchi, K.; Takeuchi, H.; Ishikawa, T.; Nishimura, T.; Kamijo, T.;
Yamamoto, I. Chem. Pharm. Bull. 2001, 49, 340e344.
chloride salt 21-HCl, which was further recrystallized from abs EtOH
to afford pure 21-HCl (37 mg, 70% yield) as a white solid. Data for 21-
10. Amari, G.; Del Canale, M.; Razzetti, R.; Monici Preti, P.A.; Rondelli, I. WO
2001085668. PCT Int. Appl., 2001. Chem. Abstr. 2001, 135, 357780.
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Int. Appl., 1982. Chem. Abstr. 1982, 99, 5381.
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HCl: [
a
]
23 ꢁ64.9 (c 0.5, MeOH), {lit. [
a]
D
20 ꢁ66.1 (c 0.5, MeOH)}.57 The
D
enantiomeric excess was determined to be 99% by chiral HPLC
analysis, after a derivatization of 21-HCl to tosylate 19. The procedure
for the latter reaction is shown below.
To an ice-cooled solution of 21-HCl (21 mg, 0.098 mmol) in
anhydrous pyridine (2 mL) was added p-TsCl (29 mg, 0.152 mmol),
and the resultant mixture was stirred for 2.5 h at 0 ꢂC. The mixture
was allowed to warm to room temperature, and then concentrated
under reduced pressure. The residue was purified by flash chro-
matography (EtOAc/n-hexane, 1:2) to provide pure 19 (8 mg, 25%
yield) as a colorless crystalline material. Spectroscopic data was
consistent with data presented earlier for the compound (see
chapter 4.6.1). HPLC (Chiralpak AD, i-PrOH/n-hexane (1/9), 1.0 mL/
min, 230 nm): 99% ee, tR 28.7 (S), and 30.3 (R) min.
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4.6.4. (S)-2-Amino-7-methoxy-1,2,3,4-tetrahydro-naphthalene hydro-
chloride (21-HCl). Instantaneous cleavage of the tosyl protecting
group in 19 was performed in accordance with an adopted literature
procedure.53 To a solution of SmI2 (8.0 mL, 0.1 M, 0.81 mmol,
10.7 equiv) in THF was added N-tosylamide 19 (25 mg, 0.076 mmol,
1 equiv) followed by water (40 mL, 30 equiv) and pyrrolidine (130 mL,
20 equiv) under a nitrogen atmosphere. The reaction was completed
after few seconds. The resulting mixture was diluted with diethyl
ether (6 mL) and treated with an aqueous solution of potassium
sodium tartrate and potassium carbonate (10 mL, 10% w/v each). The
aqueous phase was extracted with diethyl ether (3ꢃ10 mL). The
combined organic layer was dried (Na2SO4) and concentrated under
reduced pressure. The crude amine was re-dissolved in 96% EtOH
(3 mL) and concd hydrochloric solution (1 mL), before evaporation of
the solvent. Discoloration of crude 21-HCl was done by treatment
with active carbon in 96% EtOH (5 mL) at 40 ꢂC for 15 min. Finally, the
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23
orless solid (7.2 mg, 45% yield). Data for 21-HCl: [
a
]
ꢁ64.6 (c 0.5,
D
MeOH), {lit. [
a
]
20 ꢁ66.1 (c 0.5, MeOH)}.57
D
4.6.5. (S)-2-Amino-6-fluoro-7-methoxy-1,2,3,4-tetrahydronaph-
thalene hydrochloride (ST1214). Cleavage of tosyl group in 20, and
then HCl precipitation of the liberated amine to form ST1214 (65%
yield), was performed in accordance to the procedure described for
preparation of 21-HCl (chapter 4.6.4). Data for ST1214: [
a]
23 ꢁ50.9
D
(c 1.0, H2O), {lit. [
a
]Dꢁ52.5 (c 1.0, H2O)}.58
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Supplementary data
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Supplementary data associated with this article can be found in
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