Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a] isoquinolinone derivatives from l-aspartic acid

Article abstract of DOI:10.1016/j.tet.2014.06.008

This paper describes a new total synthesis for (S)-2-amino-7- methoxytetralin, (S)-7-MeO-AT, from l-aspartic acid in an overall yield of 10% over nine steps. The major loss was ascribed to a key intramolecular Friedel-Crafts cyclization step, which afforded up to 36% yield. Attempts to perform a Friedel-Crafts cyclization of an intermediate phthalimide protected amino alcohol 13 did not give the desired protected (S)-7-MeO-AT. On the other hand, two new isoindolo[1,2-a]isoquinolinone derivatives 14 and 15, were isolated in 21 and 11% yield, respectively. The yield of 15 was improved to 70%.

Full text of DOI:10.1016/j.tet.2014.06.008

Accepted Manuscript
Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a]isoquinolinone
derivatives from L-aspartic acid
Jon Erik Aaseng, Odd R. Gautun
PII:
S0040-4020(14)00854-0
10.1016/j.tet.2014.06.008
TET 25673
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 April 2014
Revised Date: 20 May 2014
Accepted Date: 2 June 2014
Please cite this article as: Aaseng JE, Gautun OR, Synthesis of (S)-2-amino-7-methoxytetralin and
isoindolo[1,2-a]isoquinolinone derivatives from L-aspartic acid, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.06.008.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of (S)-2-amino-7-methoxytetralin
Leave this area blank for abstract info.
and isoindolo[1,2-a]isoquinolinone
derivatives from
L-aspartic acid
Jon Erik Aaseng and Odd R. Gautun
Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim,
Norway
OMe
OMe
HO
H2N
OMe
O
N
N
OH
O
O
1

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a]isoquinolinone
derivatives from -aspartic acid
L
Jon Erik Aaseng and Odd R. Gautun
aDepartment of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway
ARTICLE INFO
ABSTRACT
Article history:
Received
This paper describes a new total synthesis for (S)-2-amino-7-methoxytetralin, (S)-7-MeO-AT,
from L-aspartic acid in an overall yield of 10% over nine steps. The major loss was ascribed to a
Received in revised form
Accepted
Available online
key intramolecular Friedel-Crafts cyclisation step, which afforded up to 36% yield. Attempts to
perform a Friedel-Crafts cyclization of an intermediate phthalimide protected amino alcohol 13
did not give the desired protected (S)-7-MeO-AT. On the other hand, two new isoindolo[1,2-
a]isoquinolinone derivatives 14 and 15, were isolated in 21 and 11% yield, respectively. The
yield of 15 was improved to 70%.
Keywords:
Chiral pool
L-aspartic acid
Aziridine
2014 Elsevier Ltd. All rights reserved
.
(S)-2-aminotetralins
isoindolo[1,2-a]isoquinolinone
1. Introduction
Today, several enantiopure ATs are used in the treatment of
medical conditions like Parkinson’s disease,3 glaucoma4 and
septic shock5,6 (Fig. 1).
The pharmacological activity of 2-aminotetralin (2-amino-
1,2,3,4-tetrahydronaphthalene, AT) 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
Recently, we reported the synthesis of substituted (S)-ATs via
ring-opening of aziridine 1a prepared from L-aspartic acid β-tert-
butyl ester (see Scheme 1).7 Unfortunately, this protocol was
accompanied with a disturbing elimination reaction. In order to
circumvent this side reaction we have tested an alternative chiral
C4-aziridine building block, 1b, as shown in the protocol
described in Scheme 2.
n-Pr
N
MeO
F
NH3Cl
S
OH
H
Ts
R
Rotigotine
(Parkinson's disease drug)
ST1214
(Septic shock drug)
ArMgBr
CuBr SMe2
N
N
Ts
(S)-AT
THF, -40 oC
H
N
t-BuO2C
(40 - 81% yield)
O
CH3
CO2t-Bu
1a
i-Pr
O
Ts
O
O
N
H
i-Pr
)-5,6-Diisobutyroyloxy-2-methylaminotetralin
CO2t-Bu
(
S
(4 - 27% yield)
(Glaucoma treatment)
Scheme 1.
Fig. 1. Pharmacological active 2-aminotetralins.
———
Corresponding author. Tel.: +47-73594101; fax: +47-73550877; e-mail: odd.r.gautun@ntnu.no
2

room temperature. No AT products were observed.
A
trifluoroacetyl group was therefore introduced to double protect
the amine function in 4 (see Scheme 4). Attempted Friedel-Crafts
cyclisation of 5 under the same conditions did, however, give
cleavage of the Boc-group as well as halogen exchange of the
tosyl group, resulting in chloride 6. A similar exchange has been
reported with oxophilic Lewis acids in the presence of alkyl
tosylates.14
H
X
ACCEPTED MANUSCRIPT
N
H2N
COOH
COOH
N
X
OH
OH
OTs
1b
H
N
OMe
MeO
NH2
X
(S)-7-MeO-AT
OTs
OCH3
F3C
HN
O
Scheme 2. Strategy for enantioselective synthesis of (S)-2-
b
amino-7-methoxytetralin, (S)-7-MeO-AT, from L-aspartic
Cl
acid.
OCH3
F3C
Boc
O
6
N
a
In the presented study (S)-2-amino-7-methoxytetralin, (S)-7-
MeO-AT, was chosen as the target molecule. The protocol does,
however, have the potential to offer ATs with other substituents
on the aromatic ring.
4
OTs
OCH3
F3C
Boc
O
5
c
N
I
7
2. Results and discussion
Scheme 4. (a) TFAA, Et3N, DCM, 0 ºC – rt. 99% yield. (b)
TiCl4, DCE, 80 °C, 58% yield. (c) NaI, acetone, 35 °C, 12 h.
78% yield.
2.1. Preparation and ring-opening of aziridine 1b
Natural L-aspartic acid (L-Asp) served as starting material in a
three step synthesis to N-Boc-diol 2, following literature
procedures (Scheme 3).8,9 Ring-closing of N-Boc-diol 2 to
aziridine 1b was performed according to an adopted procedure
described by Wessig and Schwartz.10 In addition to the
intermediate ditosylate 3, the reaction afforded 1b as the only
The newly formed alkyl chloride 6 could, however, serve as a
substrate for a classical Friedel Crafts alkylation reaction. The
corresponding iodide 7 was prepared for comparison (see
Scheme 4). The results of the cyclisation reactions of chloride 6
and iodide 7 are summarized in Table 1.
cyclized product.
This observation was a contrast to the
tosylated (or mesylated) N-Boc-β-amino alcohols tendency to
form oxazolinones.11,12 We were not able to observe any
azetidine formation either, which might occur in some cases
where three- and four-membered ring formation are competitive
pathways.13
Table 1. Intramolecular Friedel-Crafts alkylation
F3C
O
F3C
HN
O
F3C
O
OMe
N
OMe
HN
R
Lewis acid
+
X
OMe
6
7
8
9
: X = Cl, R = H
: X = I, R = Boc
Entry
Substrate
Lewis
acid
Conditions,
solvent
Ratioa
8 : 9
% yield 8,b
(% ee)c
d
1
2
3
4
5
6
7
8
6
6
6
6
6
6
6
7
AlCl3
(2 equiv)
80 °C, 7 h
DCE
-
d
AlCl3
(2 equiv)
83 ºC, 20 h
DCE
-
Scheme 3.
InBr3
(2 equiv)
83 ºC, 20 h
DCE
69 : 31
83 : 17
68 : 32
complex
mixture
Ring-opening reaction of N-Boc-aziridine 1b by a copper aryl
nucleophile [from (3-methoxyphenyl)magnesium bromide and
CuBr·Me2S] provided compound 4 in a decent yield. However,
the product proved to be somewhat unstable at room temperature.
Refluxing of 4 in THF and DCM for 6 hours gave 50% and 23%
decomposition respectively. As a consequence, product 4 was
stored under an inert atmosphere at −18 °C.
AlCl3
(3 equiv)
100 ºC, 20
h, DCMe
36
(99)
InBr3
(2 equiv)
80 ºC, 20 h
DCMe
<15
(99)
d
SnCl4
(3 equiv)
BF3.Et2O
(3 equiv)
80 ºC, 20 h
DCMe
-
d
80 ºC, 20 h
DCMe
-
2.2. Intramolecular Friedel-Crafts alkylation
InBr3
(2 equiv)
80 ºC, 18 h
DCMe
71 : 29
26
(97)
Little is known about the possibilities for intramolecular
Friedel-Crafts alkylation of alkyl tosylates, or compounds
holding other sulfone based leaving groups (e.g. mesyl or
triflate). Initial efforts to ring-close tosylate 4 in the presence of
TiCl4 in DCM gave rapid cleavage of the Boc-group even at
a
The product ratio was determined by 1H NMR (400 MHz) spectroscopy of
the crude product. Isolated yield after purification.
b
c
The enantiomeric excess of the products was determined by HPLC analysis.
d
No reaction. e Reaction performed in closed pressure tube.
3

Two solvents and four Lewis acids were tested. Both, chloride
ACCEPTED MANUSCRIPT
6 and iodide 7 afforded the desired target molecule 8.
Unfortunately, neither of them provided regioselective reactions,
giving significant amounts of the 5-methoxy isomer 9 as well.
We did not succeed in finding the optimal conditions for the
reactions. The best selectivity (ratio 8 : 9 = 83 : 17) and yield (36
1
% yield based on H NMR of the product mixture) of 8 was
obtained with AlCl3 in DCM at 100 °C (closed glass pressure
tube) for 20 hours (Table 1, entry 4). The products 8 and 9 were
only partly separable by flash chromatography.
Target molecule (S)-7-MeO-AT is accessible through basic
hydrolysis of 8 in quantitative yield.15
Scheme 6. Suggested mechanism for the formation of
compounds 14 and 15.
2.3. Preparation and cyclization of phthalimide protected
amino alcohol 13
Harris et al.16 have reported preparation of ATs by ring-
closure of phthalimide protected isomer-13 (see Fig. 2).
Treatment of isomer-13 with TfOH in PhCl at 80 °C gave
quantitative yield of ATs in an ortho : para ratio of 1 : 3. Inspired
by their results, we aimed at preparing (S)-7-MeO-AT from the
13, which was assumed to be available from 4.
product, i.e. (±)-nuevamine, isolated from Berberis darwinii
Hook species.17 Several approaches to synthesize derivatives of
this class of compounds are known from literature.18-21 Some of
these compounds are considered to have potential biological
activities.22
During our work we became aware of Selvakumar and
Ramanathan’s general procedure for preparation of racemic and
fused isoindoloisoquinolinone derivatives from
a
TfOH
o
facilitated intramolecular cyclization of phenethylphthalimides in
DCM.23 Applying their method on 13 (6.8 equiv TfOH, r.t.
overnight) yielded 15 in 70% yield. In this reaction we were not
able to isolate 14.
OMe
PhthN
OMe
PhthN
p
OH
OH
isomer-13
13
(Harris et al.16
)
3. Conclusion
Fig. 2 Phthalimide protected AT precursors.
A new total synthesis for (S)-2-amino-7-methoxytetralin, (S)-
7-MeO-AT, from
L-aspartic acid has been developed. The
Synthesis of PhthN-alcohol 13 was successfully provided via
two alternative routes, according to Scheme 5.
applied protocol afforded protected (S)-7-MeO-AT in an overall
yield of 10% over nine steps. The major loss occurred in the step
involving the intramolecular Friedel-Crafts cyclisation, for which
only up to 36% yield was obtained, partially due to problems
with separation of regioisomeric products.
Attempts to perform Friedel-Crafts cyclization of the
phthalimide protected alcohol 13 did not give the desired
protected (S)-7-MeO-AT. On the other hand, this step afforded
two new isoindolo[1,2-a]isoquinolinone derivatives 14 and 15, in
21 and 11% yield, respectively. The yield of 15 of was improved
to 70%.
Scheme 5. (a) KOH, DMSO, rt, 29 h, 89% yield. (b) (i)
LiOH, MeOH/H2O, 70 ºC, 2 h. (ii) EtOH/conc HCl, rt, 5 min,
98% yield. (c) SmI2, H2O, pyrrolidine, rt, 5 min, 43% yield.
(d). Conc HCl/toluene, 65 ºC, 2 h, yield 80% (e) Phthalic
anhydride, Et3N, toluene, 100 °C, 20 h, 87% yield.
4. Experimental
4.1. General
Treatment of PhthN-alcohol 13 with TfOH according to the
procedure described by Harris et al.16 gave a product mixture
which did not appear to contain significant amounts of the
desired (S)-7-MeO-AT. We were, however, able to isolate two
main products 14 and 15, shown in Scheme 6, which were
structurally elucidated by NMR experiments (COSY, HSQC,
HMBC, NOESY). A mechanistic suggestion for the formation of
14 and 15 is given in Scheme 6.
All reactions were performed under an argon or nitrogen
atmosphere. Tetrahydrofuran (THF) was distilled under nitrogen
atmosphere from Na/benzophenone. Dichloromethane was
distilled under nitrogen from calicium 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 Perkin-
Elmer 241 Polarimeter. Enantiomeric excesses were determined
by HPLC analysis, using Daicels column Chiralcel OJ (250 x 4.6
mm). 1H and 13C NMR spectra (Bruker Advance DPX
instruments 300/75 MHz and 400/100 MHz) were obtained from
Compounds 14 and 15 can be classified in the isoindolo[1,2-
a]isoquinolinone family. This family contains one known natural
4

solutions of CDCl3, and chemical shifts are in ppm and
22 −8.4 (c 1.0, CH2Cl2). 1H NMR (400 MHz): δ 7.77 (app. d, J
α
[ ]
ACCEPTED MANUSCRIPT
referenced to TMS via the lock signal of the solvent. H and 13C
8.0DHz, 2H, tolyl), 7.33 (app. d, J 8.0 Hz, 2H, tolyl), 7.19 (app. t,
J 7.8 Hz, 1H, HAr-5), 6.76 (app. dd, J 7.8, 2.6 Hz, 1H, HAr-4),
6.70 (app. d, J 7.8 Hz, 1H, HAr-6), 6.66 (app. s, 1H, HAr-2), 4.36
(d, J 8.4 Hz, 1H, NH), 4.15-4.02 (m, 2H, H-1), 3.85-3.76 (m, 1H,
H-3), 3.78 (s, 3H, CH3O), 2.85-2.76 (m, 1H, 1H, H-4), 2.69 (dd,
J 13.2, 6.8 Hz, 1H, H-4), 2.44 (s, 3H, tolyl), 1.96-1.84 (m, 1H, H-
2), 1.82-1.66 (m, 1H, H-2), 1.38 (s, 9H, t-Bu). 13C NMR (100
MHz): δ 159.7 (CAr-3), 155.1 (OC(=O)N), 144.8 (tolyl), 139.0
(CAr-1), 132.9 (tolyl), 129.9 (tolyl), 129.5 (CAr-5), 127.9 (tolyl),
121.7 (CAr-6), 115.0 (CAr-2), 112.1 (CAr-4), 79.0 (t-Bu), 67.9 (C-
1), 55.2 (CH3O), 48.8 (C-3), 41.0 (C-4), 33.2 (C-2), 28.3 (t-Bu),
21.6 (tolyl). IR (KBr): 2929 (m), 1704 (s), 1600 (m), 1490 (s),
1392 (s), 1292 (s), 1175 (s), 1097 (m) cm-1. HRMS (ESI) calcd
for C23H32NO6S (M+H)+ 450.1945, found 450.1946.
1
NMR signals were assigned by 2D correlation techniques
(COSY, HSQC, HMBC, NOESY). IR spectra were run on a
Thermo Nicolet FT-IR NEXUS instrument, and only the
strongest/structurally most important peaks are listed. Accurate
mass determination (ESI) was performed on an Agilent G1969
TOF MS instrument equipped with a dual electrospray ion
source. Samples were injected into the MS using an Agilent 1100
series HPLC and analysis was performed as a direct injection
analysis without any chromatography.
4.2. Preparation and ring-opening of aziridine 1b
4.2.1. (S)-tert-Butyl 2-(2-tosyloxy)ethyl)aziridine-
1-carboxylate (1b).
4.3. Intramolecular Friedel-Crafts alkylation
The title compound was prepared by adopting a procedure
described by Wessig and Schwartz.10 Diol 28,9 (2.42 g, 11.8
mmol) was dissolved in dry diethyl ether (180 mL) and added
tosyl chloride (6.00 g, 31.5 mmol). Pellets of KOH (3.61 g, 65
mmol) were grinded and added instantly to the mixture. After 24
h of reflux, additional KOH (1.00 g, 18 mmol) was added. The
reaction was quenched by pouring it over crushed ice (100 g).
The organic layer was washed with brine (50 mL) and dried
(MgSO4). Purification by flash chromatography (15% EtOAc in
n-pentane) provided 3.08 g of 1b as a colorless oil (76 % yield).
4.3.1. (R)-3-(tert-Butoxycarbonyl)-2,2,2-trifluoro-
acetamido-4-(3-methoxyphenyl)butyl 4-methyl-
benzenesulfonate (5).
N-Trifluoroacetylation of tosylate 4 was performed according
to a general protocol described by Moussa and Romo.26 Tosylate
4 (450 mg, 1.00 mmol) was dissolved in DCM (20 mL) and
cooled to 0 ºC, added Et3N (280 ꢀL, 2.01 mmol) followed by
TFAA (280 ꢀL, 2.01 mmol). After vigorous stirring for 2.5 h at
room temperature, the volatiles were removed under reduced
pressure. The crude mixture was dissolved in DCM (50 mL),
washed with aqueous NaHCO3 (saturated, 25 mL), aqueous citric
acid (2% wt, 20 mL) and dried (MgSO4). Removal of the solvent
yielded 5 (541 mg, 99%) as a relatively pure colorless oil. Data
Data for 1b: Rf = 0.39 (EtOAc/n-hexane, 1:2).
22 +19.3 (c 1.0,
α
[ ]D
1
CH2Cl2). H NMR (300 MHz): δ 7.80 (app d, J 8.0 Hz, 2H,
tolyl), 7.35 (app d, J 8.0 Hz, 2H, tolyl), 4.25-4.12 (m, 2H, CH2-
O), 2.47-2.37 (m, 1H, CH-N), 2.45 (s, 3H, tolyl), 2.27 (d, J 6.0
Hz, 1H, CHH-N), 1.92 (d, J 3.6 Hz, 1H, CHH-N), 1.93-1.71 (m,
2H, CH2-CH2O), 1.43 (s, 9H, t-Bu). 13C NMR (100 MHz): δ
162.1 (OC(=O)N), 144.9 (tolyl), 133.0 (tolyl), 129.9 (tolyl),
127.9 (tolyl), 81.4 (t-Bu), 68.0 (CH2-O), 34.3 (CH-N), 31.9
(CH2-CH2O), 31.4 (CH2-N), 27.9 (t-Bu), 21.6 (tolyl). IR (thin
film, NaCl): 2979 (s), 1717 (s), 1598 (m), 1367 (s), 1309 (s),
1222 (s), 1121 (m) cm-1. HRMS (ESI) calcd for C16H23NNaO5S
(M+Na)+ 364.1189, found 364.1200.
for 5: Rf = 0.37 (15% EtOAc in n-pentane).
23 +40.2 (c 1.0,
α
[ ]
CH2Cl2). H NMR (400 MHz): δ 7.76 (app. d,DJ 8.4 Hz, 2H,
tolyl), 7.33 (app. d, J 8.4 Hz, 2H, tolyl), 7.16 (app. t, J 7.9 Hz,
1H, HAr-5), 6.75 (app. dd, J 7.9, 2.2 Hz, 1H, HAr-4), 6.68 (app. d,
J 7.9 Hz, 1H, HAr-6), 6.64 (app. s, 1H, HAr-2), 4.75-4.60 (m, 1H,
H-3), 4.15-3.90 (m, 2H, H-1), 3.76 (s, 3H, CH3O), 3.14 (dd, J
13.6, 10.4 Hz, 1H, H-4), 2.85 (dd, J 13.6, 6.0 Hz, 1H, H-4), 2.43
(s, 3H, tolyl), 2.40-2.29 (m, 1H, H-2), 2.11-2.00 (m, 1H, H-2),
1
1.39 (s, 9H, t-Bu). 13C NMR (100 MHz): δ 160.5 (q, JC,F 39.2
2
Hz, NC(O)CF3), 159.7 (CAr-3), 150.8 (Boc), 144.9 (tolyl), 138.2
(CAr-1), 132.7 (tolyl), 129.9 (tolyl), 129.6 (CAr-5), 128.0 (tolyl),
121.5 (CAr-6), 115.3 (q, JC,F 287.3, CF3), 114.5 (CAr-2), 112.8
1
4.2.2. (R)-3-(tert-Butoxycarbonylamino)-4-(3-
methoxyphenyl)butyl 4-methylbenzenesulfonate (4).
(CAr-4), 86.2 (Boc), 67.1 (C-1), 57.5 (C-3), 55.1 (CH3O), 38.7
(C-4), 30.9 (C-2), 27.3 (Boc), 21.6 (tolyl). IR (thin film, NaCl):
2985 (m), 1758 (m), 1713 (m), 1600 (m), 1456 (m), 1398 (m),
1261 (m), 1144 (s), 1098 (m) cm-1. HRMS (ESI) calcd for
C25H30F3NO7S (M+NH4)+ 563.2033, found 563.2036.
The title compound was made by adopting a procedure
described by Burgaud and co-workers.24 A solution of 3-
bromoanisole (1.50 ml, 11.8 mmol) in anhydrous THF (8.5 mL)
was added slowly to magnesium turnings (280 mg, 11.5 mmol)
over a period of approximate 10 min. Once the addition was
complete, the reaction was continued with vigorous stirring for
30 min, then titrated utilizing salicylaldehyde as a titration
indicator,25 and used immediately in the following reaction. A
solution of Boc-aziridine 1b (535 mg, 1.57 mmol) and
CuBr·Me2S (48 mg, 0.233 mmol, 15 mol %) in dry THF (25 mL)
was cooled to −40 °C under argon atmosphere. To the solution, a
standardized amount the Grignard solution (3.14 mmol, 2 equiv)
was added over a period of 5 min. The reaction mixture was
stirred for 2 h and allowed to warm to −10 °C. The reaction
mixture was quenched by aqueous NH4Cl (saturated, 30 mL),
warmed up to room temperature and extracted with diethyl ether
(4 × 50 mL). The combined organic layer was washed with brine
and dried (MgSO4). Purification performed by flash
chromatography (15% EtOAc in n-pentane), yielded 4 (564 mg,
80%) as a white crystalline material. Data for 4: Mp 74 - 77 °C
(decomp. gas evolves), Rf = 0.33 (15% EtOAc in n-pentane).
4.3.2. (R)-N-(4-Chloro-1-(3-methoxyphenyl)butan-
2-yl)-2,2,2-trifluoroacetamide (6).
Double protected amine 5 (66 mg, 0.12 mmol) was dissolved
in dry 1,2-dichloroethane (3.0 mL). Dropwise to this solution,
TiCl4 (40 ꢀL, 0.365 mmol) was added, and the mixture was
heated to 80 °C for 2.5 h. After cooling the mixture to room
temperature, a phosphate buffer (pH 7, 10 mL, 1 M) was added.
The mixture was diluted with DCM (20 mL) and the layers
separated. The aqueous layer was extracted with additional DCM
(2 × 10 mL). The combined organic layer was dried (MgSO4),
filtrated and concentrated under reduced pressure. The residue
was purified by flash chromatography (15% EtOAc in n-pentane)
affording 6 (23 mg, 58%) as white solid. The white solid material
could also be recrystallized (n-hexane/EtOAc) to fine crystalline
needles. Data for 6: Mp 103 - 104 °C, Rf = 0.51 (15% EtOAc in
5

1
n-pentane). 23 −24.6 (c 1.0, CH2Cl2). H NMR (400 MHz): δ
α
[ ]
accordance to data reported by Cecchi et al.28
Enantiomeric excess was determined by chiral HPLC
analysis (Chiralcel OJ, i-PrOH/n-hexane (1:9), 1.0
ml/min, 230 nm, tR 25.4 min (S) and 53.8 min (R)).
Compound 9 was purified by flash chromatography (10%
EtOAc in n-pentane) up to 70% purity. Data for 9: Rf =
ACCEPTED MANUSCRIPT
7.24 (app. t, JD7.9 Hz, 1H, HAr-5), 6.81 (app. dd, J 7.9, 2.4 Hz,
1H, HAr-4), 6.74 (app. d, J 7.9 Hz, 1H, HAr-6), 6.70 (app. s, 1H,
HAr-2), 6.31 (d, J 7.6 Hz, 1H, NH), 4.44-4.30 (m, 1H, H-2), 3.79
(s, 3H, CH3O), 3.56 (t, J 6.6 Hz, 2H, H-4), 2.97-2.83 (m, 2H, H-
1), 2.17-1.95 (m, 2H, H-3). 13C NMR (100 MHz): δ 160.0 (CAr-
2
3), 156.9 (app. d, JC,F 35.7 Hz, C=O), 137.6 (CAr-1), 129.9 (CAr-
5), 121.6 (CAr-6), 115.7 (q, JC,F 289.3 Hz, CF3), 114.9 (CAr-2),
1
1
0.42 (10% EtOAc in n-pentane). H NMR (400 MHz): δ
7.13 (app. t, J 8.0 Hz, 1H, H-7), 6.71 (app. d, J 8.0 Hz,
1H, H-6), 6.70 (app. d, J 8.0 Hz, 1H, H-8), 6.24 (br, 1H,
NH), 4.40-4.27 (m, 1H, H-2), 3.83 (s, 3H, CH3O), 3.17
(dd, J 16.2, 5.0 Hz, 1H, H-1), 2.97-2.67 (m, 3H, H-1 and
112.6 (CAr-4), 55.2 (OCH3), 49.7 (C-2), 41.1 (C-4), 39.9 (C-1),
36.0 (C-3). IR (KBr): 3312 (m), 1704 (s), 1558 (m), 1487 (m),
1439 (m), 1262 (m), 1156 (s), 1056 (m), 699 (m) cm-1. HRMS
(ESI) calcd for C13H15ClF3NO2 (M+NH4)+ 327.1082, found
327.1078.
H-4), 2.16-2.04 (m, 1H, H-3), 1.94-1.80 (m, 1H, H-3). 13
NMR (100 MHz): δ 157.3 (C-5), 156.7 (app. d, JC,F 36.7
C
2
Hz, C=O), 134.1 (C-8a), 126.8 (C-7), 123.9 (C-4a), 121.5
(C-8), 115.8 (app. d, JC,F 288.6 Hz, CF3), 107.7 (C-6),
55.3 (CH3O), 45.9 (C-2), 35.0 (C-1), 27.5 (C-3), 20.7 (C-
4). HRMS (ESI) calcd for C13H15F3NO2 (M+H)+
274.1049, found 274.1053.
1
4.3.3. (R)-tert-Butyl 4-iodo-1-(3-methoxyphenyl)-
butan-2-yl(2,2,2-trifluoroacetyl)carbamate (7)
The title compound was synthesized by adopting a procedure
described by Saplay et al.27 Tosylate 5 (136 mg, 0.249 mmol)
was dissolved in acetone (2.0 mL) and added NaI (70 mg, 0.467
mmol). After vigorous stirring at 35 °C for 12 h, the solvent was
removed under reduced pressure. The crude mixture was
dissolved in water (10 mL) and DCM (15 mL), separated and
additionally extracted with DCM (2 × 10 mL). After drying
(MgSO4), the solvent was removed, and the residue purified by
flash chromatography (10% EtOAc in n-pentane). Pure iodide 7
(b)
Table 1, entry 8: Iodide 7 (42 mg, 0.084 mmol) was
dissolved in DCM (6 mL) and added InBr3 (55 mg, 0.155
mmol). The mixture was heated to 80 °C in a pressure
glass tube for 18 h. The mixture was cooled to room
temperature and added an aqueous phosphate buffer (pH
7, 10 mL, 1 M) and DCM (10 ml). The layers were
separated and the aqueous phase extracted with additional
DCM (3 × 10 mL). The combined organic layer was dried
(MgSO4) and concentrated under reduced pressure. 1H
NMR analysis of the residue showed a product ratio 8 : 9
= 71 : 29. The crude product was purified by flash
chromatography (10% EtOAc in n-pentane). Impure 8
(6.4 mg, 26% yield, 93% pure, 97% ee) was isolated as
colorless crystals.
was achieved in 78% yield as slightly yellow oil. Data for 7: Rf =
1
0.65 (10% EtOAc in n-pentane).
23 +1.95 (c 1.05, CH2Cl2). H
α
[ ]D
NMR (300 MHz): δ 7.19 (app. t, J 7.9 Hz, 1H, HAr-5), 6.80-6.72
(m, 2H, HAr-4 and HAr-6), 6.70 (app. s, 1H, HAr-2), 4.75-4.61 (m,
1H, H-2), 3.78 (s, 3H, CH3O), 3.21-3.01 (m, 3H, H-4 and H-1),
2.91 (dd, J 13.7, 6.2 Hz, 1H, H-1), 2.62-2.47 (m, 1H, H-3), 2.27-
2.13 (m, 1H, H-3), 1.42 (s, 9H, t-Bu). 13C NMR (100 MHz): δ
2
160.2 (app. d, JC,F 44.9 Hz, C(=O)CF3), 159.8 (CAr-3), 151.0
(OC(=O)N), 138.3 (CAr-1), 129.6 (CAr-5), 121.5 (CAr-6), 115.4 (q,
1JC,F 288.3 Hz, CF3), 114.5 (CAr-2), 112.7 (CAr-4), 86.2 (CMe3),
61.3 (C-2), 55.1 (CH3O), 38.3 (C-1), 35.7 (C-3), 27.4 ((CH3)3C),
0.4 (C-4). IR (thin film, NaCl): 2984 (w), 1759 (m), 1713 (s),
1602 (m), 1586 (m), 1490 (m), 1456 (m), 1372 (m), 1260 (s),
1170 (s), 1043 (w), 836 (m) cm-1. HRMS (ESI) calcd for
C18H23F3INO4 (M+NH4)+ 519.0962, found 519.0963.
4.4. Preparation and cyclization of phthalimide protected amino
alcohol 13
4.4.1. (R)-4-(3-Methoxybenzyl)-1,3-oxazinan-2-one
(10).
Tosylate 4 (0.502 g, 1.12 mmol) was dissolved in DMSO (24
mL) and added KOH (0.302 g, 5.38 mmol). The mixture was
stirred at room temperature for 29 h. An aqueous phosphate
buffer solution was added (pH 7, 12 mL) to quench excess KOH,
and then poured into a mixture of H2O (150 mL), brine (150 mL)
and EtOAc (200 mL). The layers were separated and the aqueous
layer extracted with additional EtOAc (3 × 150 mL). The
combined organic layer was dried (MgSO4), concentrated under
reduced pressure, and the residue purified by flash
chromatography (EtOAc) affording 10 (0.220 g, 89%) as white
4.3.4. (S)-2-Trifluoroacetylamino-7-methoxy-
1,2,3,4-terahydronaphthalene (8) and (S)-2-
trifluoroacetylamino-5-methoxy-1,2,3,4-
terahydronaphthalene (9).
The intramolecular Friedel-Crafts alkylation of chloride 6
(experiment a, Table 1, entry 4) and iodide 7 (experiment b,
Table 1, entry 8) afforded partly inseparable mixtures of 8 and 9.
solid. Data for 10: Mp 80 - 84 °C, Rf = 0.22 (EtOAc).
23 +51.5
(a)
Table 1, entry 4: Chloride 6 (22 mg, 0.071 mmol) was
dissolved in DCM (5 mL) and added AlCl3 (30 mg, 0.225
mmol). The mixture was heated to 100 °C in a glass
pressure tube for 20 h. The mixture was cooled to room
temperature and then added an aqueous phosphate buffer
(pH 7, 10 mL, 1 M) and DCM (10 mL). The layers were
separated and the aqueous phase extracted with additional
DCM (3 × 10 mL). The combined organic layer was dried
(MgSO4) and concentrated under reduced pressure. 1H
NMR analysis of the residue showed a product ratio 8 : 9
= 83 : 17. The crude product was purified by flash
chromatography (10% EtOAc in n-pentane). Impure 8
(7.8 mg, 36% yield, 90% pure, >99% ee) was isolated as
colorless crystals. The spectroscopic data of 8 was in
α
[ ]D
1
(c 1.02, CH2Cl2). H NMR (400 MHz): δ 7.26 (app. t, J 7.9 Hz,
1H, HAr-5), 6.82 (app. dd, J 7.9, 2.5 Hz, 1H, HAr-4), 6.77 (app. d,
J 7.6 Hz, 1H, HAr-6), 6.72 (app. s, 1H, HAr-2), 5.06 (br, 1H, NH),
4.36 (dt, J 11.2, 4.2 Hz, 1H, H-6), 4.22 (td, J 10.9, 2.8 Hz, 1H, H-
6), 3.81 (s, 3H, CH3O), 3.76-3.67 (m, 1H, H-4), 2.89 (dd, J 12.5,
6.9 Hz, 1H, CHHPh), 2.66 (dd, J 13.4, 8.7 Hz, 1H, CHHPh),
2.09-1.98 (m, 1H, H-5), 1.86-1.74 (m, 1H, H-5). 13C NMR (100
MHz): δ 160.1 (CAr-3), 153.7 (C-2), 137.5 (CAr-1), 130.1 (CAr-5),
121.4 (CAr-6), 115.1 (CAr-2), 112.4 (CAr-4), 65.5 (C-6), 55.2
(CH3O), 52.1 (C-4), 42.9 (CH2Ph), 27.5 (C-5). IR (KBr): 3253
(m), 2939 (m), 1699 (s), 1602 (m), 1584 (m), 1489 (m), 1434
(m), 1293 (m), 1154 (m), 1092 (m), 1043 (m), 781 (m), 736 (m)
cm-1. HRMS (ESI) calcd for C12H16NO3 (M+H)+ 222.1125, found
222.1130.
6

et al.31 N-Boc-alcohol 11 (32 mg, 0.11 mmol) was
dissolved in toluene (5 ml) and conc HCl (1 mL), and
heated to 65 ºC for 2 hours. Evaporation of the solid under
reduced pressure gave 20 mg of 12 (80% yield).
4.4.2. (R)-tert-Butyl 4-hydroxy-1-(3-methoxy-
phenyl)butan-2-ylcarbamate (11).
ACCEPTED MANUSCRIPT
The title compound was synthesized by adopting a procedure
described by Ankner and Hilmersson.29 Tosylate 4 (211 mg, 0.47
mmol) was instantaneous deprotected by the addition of a
solution of SmI2 (28 mL, 0.1 M, 2.8 mmol) in THF, water (150
mg, 8.33 mmol) and pyrrolidine (0.46 mL, 5.51 mmol), under
vigorous stirring. After 10 min, the reaction mixture was diluted
with diethyl ether (30 mL) and treated with an aqueous solution
of potassium sodium tartrate and potassium carbonate (25 mL,
10% w/v each). The layers were separated, and the aqueous
phase was extracted with additional diethyl ether (3 × 30 mL).
The combined organic layer was washed with brine (20 mL) and
dried (MgSO4). Purification by flash chromatography (25 to 40%
EtOAc in n-pentane) afforded 11 (59 mg, 43%) as a colorless
viscous oil. Data for 11: Rf = 0.24 (40% EtOAc in n-pentane).
4.4.4. (R)-2-(4-Hydroxy-1-(3-methoxyphenyl)-
butan-2-yl)isoindoline-1,3-dione (13).
Phth protection of the amine group in 12 was performed
according to a procedure described by Liu et al.32 HCl-salt 12
(178 mg, 0.767 mmol) and phthalic anhydride (116 mg, 0.783
mmol) was dissolved in toluene (10 mL), and added
triethylamine (214 ꢀL, 1.53 mmol). The mixture was refluxed for
2 h, and then stirred at 100 °C for 18 h. The reaction mixture was
allowed to cool to room temperature and added DCM (30 mL).
The resulting mixture was successively washed with aqueous
citric acid (10% wt, 10 mL), water (10 mL), and aqueous
NaHCO3 (saturated, 10 mL). The organic layer was dried
(MgSO4) and concentrated in vacou. Purification of the crude by
flash chromatography (EtOAc/n-pentane, 1:1) yielded 13 (217
23 ‒13.1 (c 1.1, CH2Cl2). 1H NMR (400 MHz): δ 7.21 (app. t,
α
[ ]D
J 7.9 Hz, 1H, HAr-5), 6.78 (app. d, J 7.9 Hz, 1H, HAr-4), 6.77
(app. d, J 7.9 Hz, 1H, HAr-6), 6.73 (app. s, 1H, HAr-2), 4.49 (d, J
8.9 Hz, 1H, NH), 4.10 (m, 1H, H-2), 3.70-3.55 (m, 2H, H-4),
3.80 (s, 3H, CH3O), 3.20 (br, 1H, OH), 2.79 (d, J 6.7 Hz, 2H, H-
1), 1.95-1.75 (m, 1H, H-3), 1.70-1.55 (m, 1H, H-3), 1.42 (s, 9H,
t-Bu). 13C NMR (100 MHz): δ 159.8, 157.0, 139.4, 129.6, 121.8,
115.1, 112.1, 80.0, 59.0, 55.3, 48.0, 41.7, 38.1, 28.4. IR (neat):
3366 (m), 2937 (w), 1686 (s), 1521 (s), 1488 (m), 1452 (m), 1365
(m), 1262 (s), 1156 (s), 1044 (s), 1029 (s) cm-1. HRMS (ESI)
calcd for C16H26NO4 (M+H)+ 296.1856, found 296.1856.
mg, 87% yield) as a colorless oil. Data for 13: Rf = 0.28
1
(EtOAc/n-pentane, 1:1).
23 +136.9 (c 1.0, CH2Cl2). H NMR
α
[ ]
(400 MHz): δ 7.80-7.71 (m, D2H, Phth), 7.71-7.60 (m, 2H, Phth),
7.10 (app. t, J 7.9 Hz, 1H, HAr-5), 6.77 (app. d, J 7.9 Hz, 1H, HAr-
6), 6.72 (app. s, 1H, HAr-2), 6.66 (app. dd, J 7.9, 2.4 Hz, 1H, HAr-
4), 4.81-4.66 (m, 1H, H-2), 3.72-3.63 (m, 1H, H-4), 3.69 (s, 3H,
CH3O), 3.62-3.50 (m, 1H, H-4), 3.40 (dd, J 13.8, 10.0 Hz, 1H, H-
1), 3.12 (dd, J 13.8, 6.3 Hz, 1H, H-1), 2.44-2.28 (m, 1H, H-3),
2.12-1.96 (m, 1H, H-3). 13C NMR (100 MHz): δ 168.8 (Phth),
159.6 (CAr-3), 139.6 (CAr-1), 133.9 (Phth), 131.6 (Phth), 129.4
(CAr-5), 123.2 (Phth), 121.2 (CAr-6), 114.1 (CAr-2), 112.4 (CAr-4),
59.6 (C-4), 55.1 (CH3O), 50.0 (C-2), 38.4 (C-1), 34.7 (C-3). IR
(thin film, NaCl): 3460 (m), 2934 (m), 1770 (m), 1699 (s), 1602
(m), 1394 (m), 1263 (m), 1086 (m), 872 (m), 782 (m), 721 (s)
cm-1. HRMS (ESI) calcd for C19H20NO4 (M+H)+ 326.1387, found
326.1383.
4.4.3. (R)-3-Amino-4-(3-methoxyphenyl)butan-1-ol
hydrochloride (12).
(a)
Hydrochloride 12 was synthesized from the cyclic
carbamate 10 by adopting a procedure described by Curtis
et al.30 Cyclic carbamate 10 (197 mg, 0.89 mmol) was
dissolved in MeOH/H2O (8 mL, 1:1) and added LiOH
(178 mg, 7.43 mmol). The mixture was under vigorous
stirring heated at 70 °C for 2 h. The solvent was removed
under reduced pressure and the residue dissolved in
diethyl ether (30 mL) and water (15 mL). The layers were
separated and the aqueous phase extracted with DCM (4 ×
20 mL). The combined organic layer was concentrated
under reduced pressure. The residue was redissolved in
abs ethanol (10 mL) and added conc hydrochloric acid
(0.5 mL). The resultant mixture was stirred for 5 min at
room temperature, and then the solvent removed under
reduced pressure. Attempts with diethyl ether trituration
did not yield the expected solid product. However,
hydrochloride 12 (202 mg, 98%) was isolated as a pale
4.4.5. Preparation of diol 14 and ether 15.
Cyclization of phthalimide 13 was performed by adopting a
procedure described by Harris et al.16 Phthalimide 13 (22.8 mg,
0.070 mmol) was dissolved in anhydrous chlorobenzene (1 mL)
and added triflic acid (12.5 ꢀL, 0.141 mmol). The reaction
mixture was heated to 80 °C for 4 h. Quenching of the room
tempered mixture was done by the addition of a phosphate buffer
solution (pH 7, 10 mL, 1 M). Extraction with DCM (3 × 15 mL),
drying over MgSO4 and removal of the solvent under reduced
pressure, resulted in a yellow crude mixture. Isolation of the two
main products 14 (4.8 mg, 21% yield) and 15 (2.3 mg, 11%
yield), both colorless oils, was performed by column
chromatography (2 colums: EtOAc, then 5% MeOH in DCM).
yellow oil and used without further purification. Data for
1
12:
23 +16.7 (c 0.9, abs EtOH). H NMR (400 MHz,
α
[ ]D
OMe
3
OMe
D2O): δ 7.37 (t, J 7.8 Hz, 1H, HAr-5), 7.00-6,93 (m, 2H,
HAr-4, HAr-6), 6.92 (app. s, 1H, HAr-2), 3.84 (s, 3H,
CH3O), 3.80-3.59 (m, 3H, H-1 and H-3), 3.06 (dd, J 14.1,
6.6 Hz, 1H, H-4), 2.91 (dd, J 14.1, 8.0 Hz, 1H, H-4), 1.98-
1.83 (m, 2H, H-2). 13C NMR (100 MHz, D2O): δ 159.9
(CAr-3), 138.1 (CAr-1), 131.0 (CAr-5), 122.9 (CAr-6), 115.7
(CAr-2), 113.6 (CAr-4), 59.0 (C-1), 56.0 (CH3O), 52.2 (C-
3), 39.0 (C-4), 34.3 (C-2). IR (KBr): 2885 (br), 1602 (m),
1489 (m), 1264 (m), 1156 (m), 1046 (s), 875 (w), 781 (s),
744 (m), 698 (s) cm-1. HRMS (ESI) calcd for C11H18NO2
(M‒Cl)+ 196.1332, found 196.1335.
3
2
2
4
4
1
1
4a
4a
12c
12b
HO
12c
12b
12
9
12
9
5
6
12a
8a
5
6
11
10
11
10
12a
N
8
O N
13
8a
8
13
14
14
O
O
OH
15
14
Fig. 4. Numbering of 14 and 15 with respect to 1H and 13
C
NMR interpretation.
(b)
Compound 12 was alternatively synthesized from N-Boc-
alcohol 11 by adopting a procedure described by Prashad
7

Data for 14: Rf = 0.31 (5% MeOH in DCM).
α
20 -0.5 (c 0.6,
[ ]
3
Mueller, W. WO 9949852. PCT Int. Appl. 1999. Chem. Abstr. 1999,
ACCEPTED MANUSCRIPT
D
1
CH2Cl2). H NMR (400 MHz): δ 7.88 (app. d, J 7.7 Hz, 1H, H-
12), 7.61-7.55 (m, 1H, H-11), 7.54 (d, J 8.7 Hz, 1H, H-1), 7.40-
7.31 (m, 2H, H-9 and H-10), 6.74 (dd, J 8.7, 2.6 Hz, 1H, H-2),
6.64 (d, J 2.6 Hz, 1H, H-4), 5.27 (s, 1H, 12b-OH), 4.69-4.60 (m,
1H, H-6), 3.87-3.64 (m, 2H, H-14), 3.77 (s, 3H, CH3O), 3.05 (dd,
J 15.8, 6.5 Hz, 1H, H-5), 2.88 (dd, J 15.8, 5.2 Hz, 1H, H-5),
2.29-2.11 (m, 1H, H-13), 1.94-1.78 (m, 1H, H-13). 13C NMR
(100 MHz): δ 168.4 (C=O), 159.5 (C-3), 147.8 (12a), 135.3 (4a),
132.3 (C-11), 130.4 (8a), 129.2 (C-10), 128.5 (12c), 127.7 (C-1),
123.2 (C-9), 123.0 (C-12), 113.9 (C-4), 112.5 (C-2), 87.1 (C-
12b), 68.9 (C-14), 55.3 (CH3O), 46.5 (C-6), 34.7 (C-5), 34.3 (C-
13). Configuration (6R, 12bS) was determined by NOESY
analysis. IR (KBr): 3403 (m), 1682 (s), 1610 (m), 1467 (m), 1389
(m), 1256 (m), 1111 (m), 1035 cm-1. HRMS (ESI) calcd for
C19H20NO4 (M+H)+ 326.1387, found 326.1395.
131:276964.
4
5
6
Bongrani, S.; Razzetti, R. ; Chiesi, P. WO 2001008667. PCT Int.
Appl. 2001. Chem. Abstr. 2001, 134:125975.
Moretti, G. P. ; Foresta, P. WO 9833762. PCT Int. Appl. 1998.
Chem. Abstr. 1998, 129:161424.
Ruggiero, V.; Piovesan, P.; Fabrizi, C.; Lauro, G. M.; Campo, S.;
Albertoni, C.; Nucera, E.; Carminati, P.; Ghirardi, O. Shock 2004, 21,
77-85.
7
8
Aaseng, J. E.; Gautun, O. R. Tetrahedron 2010, 66, 8982-8991.
Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66,
206-215.
9
Burgess, K. US 6472533. U.S. 2002. Chem. Abstr. 2002,
137:311035.
10 Wessig, P.; Schwarz, J. Synlett 1997, 893-894.
11 Ma, D.; Xie, W.; Zou, B.; Lei, Q.; Pei, D. Tetrahedron Lett. 2004,
45, 8103-8105.
Data for 15: Rf = 0.48 (5% MeOH in DCM).
α
23 +40.8 (c
[ ]D
1
0.13, CH2Cl2). H NMR (400 MHz): δ 8.02 (app. d, J 7.4 Hz,
1H, H-12), 7.87 (app. d, J 7.4 Hz, 1H, H-9), 7.69 (d, J 8.5 Hz,
1H, H-1), 7.65 (app. t, J 7.4 Hz, 1H, H-11), 7.55 (app. t, J 7.4 Hz,
1H, H-10), 6.81 (dd, J 8.5, 2.7 Hz, 1H, H-2), 6.72 (d, J 2.7 Hz,
1H, H-4), 4.99 (app. t, J 5.4 Hz, 1H, H-6), 3.85-3.79 (m, 2H, H-
14), 3.80 (s, 3H, CH3O), 3.51 (dd, J 17.2, 6.8 Hz, 1H, H-5), 2.95
(d, J 17.2 Hz, 1H, H-5), 2.32-2.17 (m, 1H, H-13), 1.69 (app. d, J
12.0 Hz, 1H, H-13). 13C NMR (100 MHz): δ 166.9 (C=O), 159.6
(C-3), 144.9 (12a), 138.7 (4a), 131.6 (C-11), 130.4 (8a), 129.8
(C-10), 128.0 (C-1), 124.6 (12c), 124.1 (C-9), 123.3 (C-12),
112.8 (C-4), 112.8 (C-2), 85.3 (C-12b), 59.2 (C-14), 55.3
(CH3O), 41.6 (C-6), 34.4 (C-5), 31.1 (C-13). Configuration (6R,
12bS) was determined by NOESY analysis. IR (KBr): 3442 (w),
2919 (m), 1781 (s), 1607 (m), 1429 (m), 1244 (m), 1036 (m) cm-
1. HRMS (ESI) calcd for C19H18NO3 (M+H)+ 308.1281, found
308.1292.
12 Van den Broek, L. A. G. M.; Lazaro, E.; Zylicz, Z.; Fennis, P. J.;
Missler, F. A. N.; Lelieveld, P.; Garzotto, M.; Wagener, D. J. T.;
Ballesta, J. P. G.; Ottenheijm, H. C. J. J. Med. Chem. 1989, 32, 2002-
2015.
13 Fernandez-Megia, E.; Montaos, M. A.; Sardina, F. J. J. Org. Chem.
2000, 65, 6780-6783.
14 Vizgert, R. V.; Polyakova, E. V.; Chervinskii, A. Y. Zh. Obshch.
Khim. 1984, 54, 905-909.
15 Aaseng, J. E.; Melnes, S.; Reian, G.; Gautun, O. R. Tetrahedron
2010, 66, 9790-9797.
16 Harris, M. C. J.; Jackson, M.; Lennon, I. C.; Ramsden, J. A.; Samuel,
H. Tetrahedron Lett. 2000, 41, 3187-3191.
17 Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron
Lett. 1984, 25, 599-602.
18 Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E. J.
Org. Chem. 1997, 62, 2080-2092.
4.4.6. Preparation of ether 15 adopting Selvakumar
and Ramanathan’s general procedure.2 3
19 Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. Eur. J. Org.
Chem. 2005, 3437-3442.
Phthalimide 13 (0.164 g, 0.50 mmol) was dissolved with
stirring in dry dichloromethan (15 mL) and added triflic acid (0.3
mL, 3.39 mmol) via syringe at room temperature. The resulting
wine red solution was stirred overnight and quenched with water
(10 mL) followed by sodium bicarbonate (1.5 g). The organic
layer was separated and the aqueous layer extracted with
dichloromethane (3 × 15 mL). The combined organic extract was
washed with brine (10 mL), dried (MgSO4), filtered and the
solvent removed under vacuum. The residue was purified by
flash chromatography (EtOAc/n-hexane, 1:1) to yield 15 (0.108
g, 70% yield) as a viscous colorless oil. The spectroscopic data
20 Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004, 45, 1253-
1256.
21 Walker, G. N.; Kempton, R. J. J. Org. Chem. 1971, 36, 1413-1416.
22 Mertens, A.; Zilch, H.; Koenig, B.; Schaefer, W.; Poll, T.; Kampe,
W.; Seidel, H.; Leser, U.; Leinert, H. J. Med. Chem. 1993, 36, 2526-
2535.
23 Selvakumar, J.; Ramanathan, C. J. Org. Biomol. Chem. 2011, 9,
7643-7646.
was in accordance with the data reported above.
1.02, CH2Cl2).
α
20 +73.9 (c
[ ]D
24 Burgaud, B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035-13050.
25 Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755-3756.
26 Moussa, Z.; Romo, D. Synlett 2006, 3294-3298.
27 Saplay, K. M.; Sahni, R.; Damodaran, N. P.; Dev, S. Tetrahedron
1980, 36, 1455-1461.
Acknowledgements
We thank Dr. Trygve Andreassen for his valuable help in the
NMR interpretation of compounds 14 and 15, and Dr. Susana
Villa González for performing the mass spectrometric
measurements.
28 Cecchi, R.; Croci, T.; Boigegrain, R.; Boveri, S.; Baroni, M.;
Boccardi, G.; Guimbard, J. P.; Guzzi, U. Eur. J. Med. Chem. 1994,
29, 259-267.
29 Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503-506.
30 Curtis, K. L.; Evinson, E. L.; Handa, S.; Singh, K. Org. Biomol.
Chem. 2007, 5, 3544-3553.
References and notes
1
2
Bamberger, E.; Filehne, W. Ber. 1889, 22, 777-778.
31 Prashad, M.; Har, D.; Hu, B.; Kim, H. Y.; Girgis, M. J.; Chaudhary,
A.; Repic, O.; Blacklock, T. J.; Marterer, W. Org. Process Res. Dev.
2004, 8, 330-340.
SciFinder®. 2014. Search for "2-aminotetralin" resulted in more
than 700 hits,
physicological
(20.02.2014).
a
great part of them concerning studies of
properties of 2-aminotetralin derivatives
32 Liu, H.; Pattabiraman, V. R.; Vederas, J. C. Org. Lett. 2007, 9, 4211-
4214.
8