A chemoenzymatic synthesis of (2R)-8-substituted-2-aminotetralins

Article abstract of DOI:10.1016/S0957-4166(02)00098-8

(2R)-2-Amino-8-methoxy-1,2,3,4-tetrahydronaphthalene, a useful precursor of the 5-hydroxytryptamine receptor agonist 8-OH-DPAT ((2R)-2-(dipropylamino)-8-hydroxytetrahydronaphthalene), has been synthesized from 1-methoxynaphthalene through a chemoenzymatic protocol. The same protocol has been subsequently applied to the synthesis of other (2R)-2-amino-1,2,3,4-tetrahydronaphthalenes.

Full text of DOI:10.1016/S0957-4166(02)00098-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 253–259
A chemoenzymatic synthesis of
(2R)-8-substituted-2-aminotetralins
Fulvia Orsini,a,* Guido Sello,a Elena Travainia and Patrizia Di Gennarob
aDipartimento di Chimica Organica e Industriale, via Venezian 21-20133, Milan, Italy
bDipartimento di Scienze dell’ Ambiente e del Territorio, Milano-Bicocca, Milan, Italy
Received 23 January 2002; accepted 22 February 2002
Abstract—(2R)-2-Amino-8-methoxy-1,2,3,4-tetrahydronaphthalene, a useful precursor of the 5-hydroxytryptamine receptor ago-
nist 8-OH-DPAT ((2R)-2-(dipropylamino)-8-hydroxytetrahydronaphthalene), has been synthesized from 1-methoxynaphthalene
through a chemoenzymatic protocol. The same protocol has been subsequently applied to the synthesis of other (2R)-2-amino-
1,2,3,4-tetrahydronaphthalenes. © 2002 Published by Elsevier Science Ltd.
1. Introduction
and for enantiopure a-dialkylated b-ketoesters (via
stereoselective alkylations of b-ketoesters).4
In previous papers we reported the bioconversion of
substituted naphthalenes to the corresponding (1R,2S)-
Herein we report a chemoenzymatic synthesis of (2R)-
2-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene 6d, a
useful precursor of (2R)-2-(dipropylamino)-8-hydroxy-
1,2-dihydroxy-1,2-dihydronaphthalenes
(cis-dihydro-
diols) using recombinant strains from Pseudomonas
fluorescens N31 (Fig. 1).
tetrahydronaphthalene (8-OH-DPAT)5 which is
a
potent and centrally active 5-hydroxytriptamine (sero-
tonin, 5-HT) receptor agonist with selectivity for 5-
HT1A receptors. Since the first report on its
pharmacological profile, 8-OH-DPAT has been fre-
quently used in the elucidation of serotonergic mecha-
nisms. Furthermore, molecules interacting with the
5-HT1A-subtype of serotonin (5-HT)-receptors are of
potential clinical interest for the treatment of depres-
sion and anxiety.
(1R,2S)-1,2-Dihydroxy-1,2-dihydronaphthalenes 1 rep-
resent a pool of enantiopure compounds which may be
used as chiral synthons and chiral auxiliaries. To this
end
(1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene
(from the bioconversion of naphthalene) has already
been converted to a series of chiral 1,2-diols, 1,2-amino
alcohols and 1,2-diamines:2 (2R,3R)-2,3-dihydroxy-
1,2,3,4-tetrahydronaphthalene3 has proven to be a use-
ful chiral auxiliary for the production of enantiopure
alcohols and acids (via stereoselective 1,4-conjugate
additions of alkyl cuprates to a,b-unsaturated esters)
2. Results and discussion
(2R)-2-Amino-8-methoxy-1,2,3,4-tetrahydronaphtha-
lene 6d was synthesized from (1R,2S)-8-methoxy-1,2-
dihydroxy-1,2-dihydronaphthalene 1d (obtained by
biotransformation of 8-methoxy naphthalene) accord-
ing to the protocol reported in the Scheme 1.
The protocol was firstly optimized on the more conve-
nient
(1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene
Figure 1.
1a, obtained with higher yields from the bioconversion
of naphthalene, and now also a commercially available
compound.6 The optimized protocol was then applied
to the preparation of 6d and (2R)-2-amino-1,2,3,4-tet-
* Corresponding author. Tel.: 02-50314111; fax: 02-50314106; e-mail:
fulvia.orsini@unimi.it
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00098-8

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F. Orsini et al. / Tetrahedron: Asymmetry 13 (2002) 253–259
Scheme 1.
For the second key step, the conversion of the hydroxy
group at the 2-position to an azido group, two
approaches have been tested: (a) a direct approach
using biphenyl phosphoryl azide in the presence of
triphenylphosphine and diethyl azodicarboxylate7
(b) an indirect two-step approach via an intermediate
tosylate/mesylate which was subsequently treated with
sodium azide.
rahydronaphthalenes 6b–c, which are also precursors of
bioactive compounds, albeit less active ones than 8-
OH-DPAT.
and
The synthetic protocol reported in Scheme 1 presents
two key steps, which required detailed investigation to
optimize the experimental conditions.
The first step, involving deoxygenation at the 1-position
(benzylic) has been investigated using several experi-
mental conditions, mainly: (a) hydrogenation over pal-
ladium on charcoal in the presence of an acid (acetic or
trifluoracetic acid) in a polar solvent, either protic (such
as methanol) or non-protic (such as ethyl acetate); (b)
hydride reduction (sodium borohydride, lithium alu-
minium hydride or sodium cyanoborohydride) in the
presence of a Lewis acid (zinc chloride, zinc iodide,
borotrifluoride or aluminium trichloride) in a polar
solvent.
The latter method has the advantage of higher yields
[79% total yields for the two steps, almost twice the
43% obtained in procedure (a)] and does not require
chromatographic separations, whereas in contrast
purification of the crude material from approach (a) is
somewhat troublesome.
The azide 5a was converted to the 2-amino-tetralin 6a
by hydrogenation on palladium on charcoal in ethyl
acetate (83% yield from 5a and 60.9% total yields from
1a). The absolute configuration and the enantiomeric
purity of 6a were determined by measurement of the
The best results were obtained by hydrogenation with
palladium on charcoal in the presence of acetic acid
(93% yields). Reduction with hydrides in the presence
of a Lewis acid afforded only a few percent yield of the
expected product with substantial recovery of the start-
ing diol. Under the experimental conditions used for
deoxygenation of the 2-position, the 3,4-double bond is
also reduced. However, it is not convenient to use a
single step to perform both the reduction of the double
bond and the deoxygenation of the benzylic position.
The cis-dihydrodiols 1 are in fact very sensitive to
acids, which catalyze the elimination of water to afford
the corresponding naphthols which, in turn, autocata-
lyze the elimination reaction.
1
specific rotation and by H NMR analysis of the corre-
sponding
Mosher’s
amide
[(+)-a-methoxy-a-
trifluoromethylphenylacetamide].8,9
Once optimized on (1R,2S)-1,2-dihydroxy-1,2-dihy-
dronaphthalene, the synthetic protocol was then trans-
ferred to the synthesis of 2-amino-tetralins 6b–d, with
comparable results in terms of course of the reactions,
albeit with lower yields (43 to 47% total yields from
1b–d).
As reported above for 6a, the absolute configuration
and the enantiomeric purity of (1R,2S)-1,2-dihydroxy-

F. Orsini et al. / Tetrahedron: Asymmetry 13 (2002) 253–259
255
1,2-dihydronaphthalene 6b–d were determined by mea-
silica gel flash column using a 1:1 mixture of hexane–
ethyl acetate as eluent.
1
surement of their specific rotations and by H NMR
analysis of the corresponding Mosher’ s amide.8,9
The bioconversion rates and therefore the bioproduct
amounts at a given time depend on the aromatic hydro-
carbon used: the latter, easily separable from the bio-
product, can be continuously recycled if not completed
biotransformed.
In summary, we have developed a simple and conve-
nient chemoenzymatic method to synthesize a number
of (2R)-2-aminotetralins. Added to the implicit advan-
tage of using a biotransformation step for the produc-
tion of the enantiopure precursors 1a–d, some other
advantages of this strategy are: the availability of the
starting naphthalenes used for the biotransformations;
the use of simple chemical steps to elaborate the bio-
products using common, low cost reagents and without
the need for anhydrous conditions or freshly distilled
solvents; reasonable to good total yields and high
stereoselection.
3.2. Syntheses
3.2.1. (1R,2S)-1,2-Dihydroxy-1,2,3,4-tetrahydronaphtha-
lenes 2a–d, typical procedure. (1R,2S)-1,2-Dihydroxy-8-
methoxy-1,2-dihydronaphthalene 1d (0.121 g, 0.63
mmol) in ethyl acetate (15 mL) was hydrogenated in the
presence of 10% palladium on charcoal (0.039 g) for
about 30 min. The suspension was filtered through a
Celite pad and the solvent removed under reduced
pressure to afford (1R,2S)-1,2-dihydroxy-8-methoxy-
1,2,3,4-tetrahydronaphthalene 2d (0.123 g) in quantita-
tive yield.
3. Experimental
Reagent grade tetrahydrofuran was dried at reflux over
LiAlH4 and distilled. Reagent grade dimethylfor-
mamide was distilled at reduced pressure under nitro-
3.2.1.1. (1R,2S)-1,2-Dihydroxy-8-methoxy-1,2,3,4-tet-
rahydronaphthalene 2d. Colourless crystals; mp=129–
130°C (n-hexane–ethyl acetate); [h]D=−26.9 (c=1.1
,
gen and stored over 4 A molecular sieves. Anhydrous
pyridine from Aldrich was used. Naphthalene, 1-ethyl
naphthalene, 1-methoxy naphthalene were purchased
from Aldrich and directly used. 1-Carbomethoxynaph-
thalene was synthesized from 1-naphthoic acid
(Aldrich) by treatment with methyl iodide in sodium
hydroxide–dimethyl sulfoxide solution as already
described in the literature.1 Proton and carbon nuclear
magnetic resonance (1H and 13C NMR) spectra were
recorded at 200 and 300 MHz on Brucker spectrome-
ters. MS spectra were recorded with a VG7070 E9
spectrometer. Melting points were obtained by using a
Buchi 535 apparatus. The [h]D were obtained with a
Perkin–Elmer 241 polarimeter and the elemental analy-
ses for the new compounds were determined on a
Perkin–Elmer 240 Analyser. Flash-column chro-
matographies were performed on silica gel Merck
Kieselgel 60 (230–400 mesh ASTM). Thin-layer chro-
matographies were performed on silica gel plates (60
F254, Merck): spots were detected visually by ultravio-
let irradiation (254 nm) or by spraying with
methanol:H2SO4 9:1, followed by heating at 100°C.
1
CHCl3) H NMR (CDCl3): l 1.85 (1H, m, H-3), 2.0
(1H, m, H-3%) 2.72 (1H, ddd, J=16.5, 9.0, 5.3 Hz, H-4),
2.97 (1H, dd, J=16.5, 5.3 Hz, H-4%), 3.89 (3H, s), 3.95
(1H, dd, J=9.8, 3.7 Hz, H-2), 5.0 (1H, d, J=3.7 Hz,
H-1), 6.7 (1H, d, J=7.1 Hz, H-5 or H-7), 6.8 (1H, d,
J=7.1 Hz, H-7 or H-5), 7.2 (1H, dd, J=7.1, 7.1 Hz,
H-6); 13C NMR (CDCl3): 26.3 (t), 27.6 (t), 55.4 (q),
64.9 (d), 66.9 (d), 107.7 (d), 121.2 (d), 125.2 (s), 128.6
(d), 138.1 (s), 158.3 (s); EI MS, m/z: 194 (M+), 176
(M+−H2O). Calcd for C11H14O3: C, 68.04; H, 7.22.
Found: C, 68.23; H, 6.71%.
3.2.1.2.
(1R,2S)-Dihydroxy-1,2,3,4-tetrahydronaph-
thalene 2a. (Quantitative yield) colorless crystals; mp=
140–142°C (n-hexane–ethyl acetate); [h]D=−43.0 (c=
3.28 mg/mL, MeOH) (lit.:10 [h]D=−38.0 (c=8.7
1
mg/mL, CHCl3); H NMR (CDCl3): l 1.86 (1H, dddd,
J=13.5, 6.0, 6.0 3.6 Hz, H-3), 1.99 (1H, dddd, J=13.5,
9.7, 9.0, 6.0 Hz, H-3%), 2.73 (1H, ddd, J=17.1, 9.0, 6.0
Hz, H-4), 2.93 (1H, ddd, J=17.1, 6.0, 6.0 Hz, H-4%),
3.93 (1H, ddd, J=9.7, 3.6, 3.6 Hz, H-2), 4.62 (1H, d,
J=3.6 Hz, H-1), 6.99 (1H, d, J=4.7 Hz, H-5 or H-7),
7.19 (2H, dd, J=4.7, 4.7 Hz), 7.38 (1H, d, J=4.7 Hz);
13C-NMR (CDCl3), 26.11 (t), 26.80 (t), 69.45 (d), 69.90
(d), 126.25 (d), 127.95 (d), 129.45 (d), 129.78 (d), 136.14
(s), 136.38 (s); MS (EI), m/z: 164 (M+), 146 (M+−H2O).
3.1. Biotransformations
3.1.1. Typical procedure.1 E. coli JM109 transformed
with the recombinant plasmid (pVL1778)1 was grown
(initial OD equal to 0.1) at 37°C in a 3000 mL flask
containing 600 mL of M9 medium with glucose 0.2%
(wt/vol), thiamine 1 mg/mL, ampicillin 100 mg/mL, and
the inducer salicylic acid 1 mM. When the culture
reached the A540 of 1.0, the cells were collected, washed
twice and resuspended in the same medium, supplied
with 1 g/L of the aromatic hydrocarbon and put on a
rotatory shaker; the reaction was followed at different
incubation times (1–24 h) at 30°C. The cells were then
removed by centrifugation for 10 min. The solution was
extracted with ethyl acetate (3×300 mL), the organic
phases were collected, dried (Na2SO4), and evaporated
under vacuum. If needed, the product was purified on a
3.2.1.3. (1R,2S)-1,2-Dihydroxy-8-ethyl-1,2,3,4-tetra-
hydronaphthalene 2b. (Quantitative yield) colorless crys-
tals mp=164°C (n-hexane–ethyl acetate); [h]D=−44.35
1
(c=0.354 mg/mL, CHCl3); H NMR (CDCl3): l 1.27
(3H, t, J=7.8 Hz, CH2ꢀCH3), 1.86 (1H, dddd, J=12.0,
11.2, 6.0, 3.0 Hz, H-3), 1.95 (1H, dddd, J=12.0, 12.0,
7.6, 4.2 Hz, H-3%), 2.7–2.95 (2H, m, H-4, H-4%), 2.9 (2H,
q, J=7.8 Hz, CH2ꢀCH3), 3.83 (1H, ddd, J=11.2, 4.2,
4.2 Hz, H-2), 4.85 (d, 1H, J=4.2 Hz, H-1), 6.67 (1H,
dd, J=7.8, 7.8 Hz, H-6), 7.1 (1H, d, J=7.8 Hz, H-5 or

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F. Orsini et al. / Tetrahedron: Asymmetry 13 (2002) 253–259
H-7), 7.2 (1H, d, J=7.8 Hz, H-7 or H-5); 13C NMR
(CDCl3):15.65 (q), 24.51 (t), 25.36 (t), 28.89 (t), 66.37
(d), 70.49 (d), 126.48 (2C, d), 128.39 (d), 134.0 (s),
136.24 (s), 144.88 (s); EI MS, m/z: 192 (M+), 174
(M+−H2O), 159 (M+−H2OꢀCH3). Calcd for C12H16O2:
C, 75; H, 8.3. Found: C, 74.5; H, 7.98%.
126.6 (d), 129.3 (d), 130.2 (d), 135.1 (s), 136.4 (s); EI
MS, m/z: 148 (M+), 130 (M+−H2O). Calcd for
C10H12O: C, 81.08; H, 8.11. Found: C, 80.98; H, 8.09%.
3.2.2.3.
(2S)-8-Ethyl-2-hydroxy-1,2,3,4-tetrahydro-
naphthalene 3b. (98%), Colorless oil; [h]D=−46.3 (c=
1
5.38, CHCl3); H NMR (CDCl3): l 1.29 (3H, t, J=7.4
3.2.1.4. (1R,2S)-1,2-Dihydroxy-8-carbomethoxy-1,2,
3,4-tetrahydronaphthalene 2c. (Quantitative yield) color-
less crystals, mp=150°C (n-hexane–ethyl acetate);
[h]D=−169 (c=2.68 mg/mL, CHCl3) 1H NMR
(CDCl3): l 1.78–2.21 (2H, m, H-3, H-3%), 2.68-3.02 (2H,
m, H-4, H-4%), 3.78 (1H, ddd, J=13.7, 4.8, 4.8 Hz,
H-2), 3.85 (3H, s), 4.96 (1H, d, J=4.8 Hz, H-1),
7.15–7.39 (2H, m, H-5, H-7), 7.68 (1H, dd, J=7.1, 7.1
Hz, H-6); 13C NMR (CDCl3): 25.42 (t), 28.95 (t), 52.51
(q), 66.09 (d), 69.44 (d), 127.48 (d), 128.63 (d), 130.75
(s), 133.43 (d), 137.32 (s), 138.14 (s), 169.16 (s). MS,
(EI) m/z: 204 (M+−H2O). Calcd for C12H14O4: C, 64.86;
H, 6.3. Found: C, 64.55; H, 6.15%
Hz, CH2ꢀCH3), 1.84 (1H, dddd, J=15.0, 15.0, 10.0, 7.0
Hz, H-3), 2.12 (1H, m, H-3%), 2.55-3.08 (3 H, m, H-1,
H-4, H-4%), 2.66 (2H, q, J=7.4 Hz, CH2ꢀCH3), 3.16
(1H, dd, J=16.4, J=5.0 Hz, H-1%), 4.20 (1H, m, H-2),
6.99–7.22 (3H, m, aromatic hydrogens); 13C NMR
(CDCl3): 14.16 (q), 25.55 (d), 27.71 (t), 31.27 (t), 35.12
(t), 67.64 (d), 125.40 (d), 125.74 (d), 126.24 (d), 132.15
(s), 135.56 (s), 142.43 (s); EI MS, m/z: 176 (M+), 158
(M+−H2O), 143 (M+− H2OꢀMe). Calcd for C12H16O: C,
81.82; H, 9.15. Found: C, 80.54; H, 8.92%.
3.2.2.4. (2S)-8-Carbomethoxy-2-hydroxy-1,2,3,4-tetra-
hydronaphthalene 3c. (70%), Colorless oil, [h]D=−3.2
(c=5.67 mg/mL, CHCl3); 1H NMR (CDCl3): l 1.73
(1H, m, H-3), 2.03 (1H, m, H-3%), 2.73–3.19 (2H, m,
H-4, H-4%), 3.04 (1H, dd, J=16.0, 6.4 Hz, H-1), 3.44
(1H, dd, J=16.0, 4.8 Hz, H-1%), 3.86 (3H, s), 4.15 (1H,
m, H-2), 7.11–7.17 (2H, m), 7.70 (1H, d, J=8.0 Hz);
13C NMR (CDCl3): 27.19 (t), 30.20 (t), 36.73 (t), 51.81
(q), 66.68 (d), 125.39 (d), 128.24 (d), 130.50 (s), 132.55
(d), 135.60 (s), 136.97 (s), 168.40 (s); EI MS, m/z: 206
(M+), 188 (M+−H2O). Calcd for C12H14O3: C, 69.90; H,
6.80. Found: C, 69.56; H, 6.90%.
3.2.2.
(2S)-2-Hydroxy-1,2,3,4-tetrahydronaphthalenes
3a–d, typical procedure. (1R,2S)-1,2-Dihydroxy-8-
methoxy-1,2,3,4-tetrahydronaphthalene 2d (0.114 g,
0.59 mmol) dissolved in ethyl acetate (15 mL) was
hydrogenated over palladium on charcoal in the pres-
ence of acetic acid (two drops). The suspension was
filtered on a Celite pad and the solvent removed under
reduced pressure. The crude material (0.1 g) was chro-
matographed on silica gel (n-hexane:ethyl acetate 8:2)
to give of (2S)-2-hydroxy-8-methoxy-1,2,3,4-tetra-
hydronaphthalene 3d (0.075 g, 0.42 mmol, 71%) and
8-methoxy-2-oxo-1,3,4-trihydronaphthalene (0.012 g,
0.07 mmol, 12%).
3.2.3. (2S)-2-p-Toluenesulphonyloxy-1,2,3,4-tetrahydro-
naphthalenes 4a–d, typical procedure. To a solution of
alcohol 3d (0.065 g, 0.36 mmol) in dry pyridine (0.7
mL) at 0°C was added p-toluensulphonyl chloride
(0.102 g, 0.43 mmol). The reaction was monitored by
thin layer chromatography (silica gel, eluting with n-
hexane:ethyl acetate 7:3), then poured into ice water
and extracted with ethyl acetate (3×7 mL). The com-
bined organic extracts were washed with 0.3N HCl to
acid pH, then with a saturated NaCl solution to neutral
pH. The organic phase was dried (Na2SO4) and the
solvent removed under reduced pressure. The crude
material (0.116 g) was chromatographed (silica gel,
eluting with n-hexane:ethyl acetate 9:1) and afforded
tosylate 4d (0.089 g, 0.27 mmol, 75%) and unreacted
alcohol 3d (0.006 g, 0.034 mmol, 10%).
3.2.2.1.
(2S)-2-Hydroxy-8-methoxy-1,2,3,4-tetra-
hydronaphthalene 3d. Colorless crystals, mp=104°C (n-
hexane–ethyl acetate); [h]D=−50.5 (c=8.7 mg/mL,
1
CHCl3); H NMR (CDCl3): l 1.78 (1H, dddd, J=12.5,
7.8, 7.5, 5.0 Hz, H-3), 2.0 (1H, dddd, J=12.5, 8.8, 5.3,
2.8 Hz, H-3%), 2.55 (1H, dd, J%=17.5, 7.5 Hz, H-1), 2.8
(1H, ddd, J=16.3, 8.8, 7.5 Hz, H-4), 2.94 (1H, ddd,
J=16.3, 5.3, 5.0 Hz, H-4%), 3.07 (1H, dd, J=17.5, 5.0
Hz, H-1%), 3.8 (3H, s), 4.13 (1H, dddd, J=7.8, 7.5, 5.0,
2.8 Hz, H-2), 6.65 (1H, d, J=7.6 Hz, H-5 or H-7), 6.72
(1H, d, J=7.6 Hz, H-7 or H-5), 7.1 (1H, dd, J=7.6, 7.6
Hz, H-6); 13C NMR (CDCl3): 27.1 (t), 30.9.(t), 32.4 (t),
55.3 (q), 67.1 (d), 107.1, (d), 120.8 (d), 123.3 (s), 126.3
(d), 137.1 (s), 157.5 (s); EI MS, m/z: 178 (M+), 163
(M+−Me), 160 (M+−H2O), 147 (M+−OMe), 145 (M+−
H2OꢀMe), 129 (M+−H2OꢀOMe). Calcd for C11H14O2:
C, 74.16; H, 7.86. Found: C, 71.73; H, 7.17%.
3.2.3.1. (2S)-8-Methoxy-2-toluenesulphonyloxy-1,2,3,
4-tetrahydronaphthalene 4d. Colorless oil; [h]D=−33.5
1
(c=11.9 mg/mL, CHCl3); H NMR (CDCl3): l 1.95–
2.05 (2H, m, H-3, H-3%), 2.5 (3H, s), 2.79 (1H, ddd,
J=17.0, 6.0, 6.0 Hz, H-4), 2.81 (1H, dd, J=17.0, 5.5
Hz, H-1%), 2.95 (1H, ddd, J=17.0, 6.0, 6.0 Hz, H-4%),
2.96 (1H, dd, J=17.0, 5.5 Hz, H-1%), 3.76 (3H, s), 4.85
(1H, dddd, J=5.5, 5.5, 5.4, 5.4 Hz, H-2), 6.62 (1H, d,
J=7.9 Hz, H-5 or H-7), 6.68 (1H, d, J=7.9 Hz, H-7 or
H-5), 7.1 (1H, dd, J=7.9 J=7.9 Hz, H-6), 7.35 (2H, d,
J=7.9 Hz, H-3% or H-5%), 7.82 (2H, d, J=7.9 Hz, H-2%
or H-6%); 13C NMR (CDCl3): 21.6 (q), 25.96 (t), 28.2 (t),
29.4 (t), 55.1 (q), 78.5 (d), 107.1 (d), 120.6 (d), 121.4 (s),
126.6 (d), 127.6 (2C, d), 129.7 (2C, d), 134.5 (s), 136.1
(s), 144.4 (s), 157.2 (s); EI MS, m/z: 332 (M+),
3.2.2.2. (2S)-2-Hydroxy-1,2,3,4-tetrahydronaphthalene
3a. (93%), Colorless oil; [h]D=−61.9 (c=10.7 mg/mL,
1
MeOH); H NMR (CDCl3): l 1.80 (1H, dddd, J=12.0,
6.0, 6.0, 1.5 Hz, H-3), 2.05 (1H, dddd, J=12.0, 6.0, 7.5,
7.5 Hz, H-3%), 2.78 (1H, dd, J%=16.5, 7.5 Hz, H-1), 2.82
(1H, ddd, J%=16.5, 7.5, 6.0 Hz, H-4), 2.97 (1H, ddd,
J=16.5, 6.0, 6.0 Hz, H-4%), 3.10 (1H, dd, J=16.5, 4.5
Hz, H-1%), 4.15 (1H, dddd, J=7.5, 7.5, 4.5, 1.5 Hz,
H-2), 7.1–7.25 (4H, m, aromatic hydrogens); 13C NMR
(CDCl3): 27.8 (t), 32.1 (t), 38.9 (t), 67.7 (d), 124.6 (d),

F. Orsini et al. / Tetrahedron: Asymmetry 13 (2002) 253–259
257
160 (M+−PTSH). Calcd for C18H20O4S: C, 65.06; H,
with n-hexane:ethyl acetate 7:3). After 1 h at 110°C, the
solution was cooled, diluted with water (4 mL) and
extracted with n-pentane (3×5 mL). The combined
organic extracts were dried (Na2SO4) and the solvent
removed under reduced pressure to afford azide 5d
(0.040 g, 0.2 mmol, 91%).
6.02. Found: C, 65.35; H, 6.1%.
3.2.3.2. (2S)-2-p-Toluenesulphonyloxy-1,2,3,4-tetra-
hydronaphthalene 4a. (83%): Colorless crystals; mp=
86°C (n-hexane–ethyl acetate); [h]D=−42.9 (c=16.4
1
mg/mL, CHCl3); H NMR (CDCl3): l 1.95-2.05 (2H,
m, H-3, H-3%), 2.47 (3H, s), 2.68–3.14 (3H, H-1, H-4,
H-4%), 3.20 (1H, dd, J=17.0, 5.0 Hz, H-1%), 4.94 (1H,
dddd, J=12.9, 6.4, 7.1, 7.1 Hz, H-2), 6.95–7.20 (4H,
aromatic hydrogens), 7.35 (2H, d, J=7.9 Hz, H-2%%,
H-6%% or H-3%%, H-5%%), 7.83 (2H, d, J=7.9 Hz, H-3%%,
H-5%% or H-6%%, H-2%%); 13C NMR (CDCl3): 21.6 (q), 26.15
(t), 28.66 (t), 35.23 (t), 78.33 (d), 126.10 (d), 126.34 (d),
127.66 (2C, d), 128.55 (d), 129.17 (d), 129.85 (2C, d),
132.46 (s), 134.59 (s), 134.94 (s), 144.59 (s); EI MS,
m/z: 172 (PTSH+), 130 (M+−PTSH). Calcd for
C17H18O3S: C, 67.50; H, 6.00. Found: C, 67.09; H,
5.86%.
(b) From alcohols 3a–d, typical procedure. (1R,2S)-1,2-
Dihydroxy-1,2,3,4-tetrahydronaphthalene 3a (0.145 g,
0.98 mmol) was added at 0°C to a solution of
triphenylphosphine (0.257 g, 0.98 mmol) and diethyla-
zodicarboxylate (0.171 g, 0.98 mmol) in dry tetra-
hydrofuran (3 mL). After stirring the mixture for 10
min. diphenylphosphoryl azide (0.270 g, 0.98 mmol)
was added dropwise. The reaction was monitored by
thin-layer chromatography (silica gel, eluting with n-
hexane:ethyl acetate 1:1). After stirring the mixture for
43 h, the solvent was removed under reduced pressure.
The crude material (1.043 g) was purified by column
chromatography (silica gel, eluting with n-hexane:ethyl
acetate 8/2, 1/1) to afford azide 5a (0.073 g, 0.42 mmol,
43%), accompanied by an unidentified compound
(0.021 g).
3.2.3.3.
(2S)-8-Ethyl-2-toluenesulphonyloxy-1,2,3,4-
tetrahydronaphthalene 4b. (76%) colorless syrup; [h]D=
1
−43.2 (c=8.19 mg/mL, CHCl3); H NMR (CDCl3): l
1.16 (3H, t, J=7.5 Hz, CH3ꢀCH2), 1.97–2.10 (2H, H-3,
H-3%), 2.48 (3H, s), 2.49 (2H, q, J=7.5 Hz, CH3-CH2),
2.72–3.07 (4H, H–1, H-1%, H-4, H-4%), 5.00 (1H, m,
H-2), 6.92–7.10 (3H, aromatic hydrogens), 7.38 (2H, d,
J=8.0 Hz, H-2%%, H-6%% or H-3%%, H-5%%), 7.86 (2H, d,
J=8.0 Hz, H-3%%, H-5%% or H-6%%, H-2%%); 13C NMR
(CDCl3): 13.95 (q), 21.45 (q), 25.37 (t), 26.63 (t), 28.25
(t), 32.02 (t), 78.86 (d), 125.62 (d), 126.14 (2C, d),
127.54 (2C, d), 129.69 (2C, d), 130.26 (s), 134.41 (s),
134.73 (s), 142.20 (s), 144.50 (s); EI MS, m/z: 158
(M+−PTSH). Calcd for C19H22O3S: C, 69.1; H, 6.70.
Found: C, 69.23; H, 6.83%.
3.2.4.1. (2R)-2-Azido-8-methoxy-1,2,3,4-tetrahydro-
naphthalene 5d. (Procedure a): colorless oil; [h]D=
1
+34.8 (c=5.4 mg/mL, CHCl3); H NMR (CDCl3): l
1.86 (1H, dddd, J=13.0, 9.0, 6.0, 6.0 Hz, H-3), 2.09
(1H, dddd, J=13.0, 6.0, 6.0, 3.0 Hz, H-3%), 2.66 (1H,
dd, J=17.0, 8.0 Hz, H-1), 2.83 (1H, ddd, J=17.0, 9.0,
6.0 Hz, H-4), 2.96 (1H, ddd, J=17.0, 6.0, 6.0 Hz, H-4%),
3.09 (1H, dd, J=17.0, 6.0 Hz, H-1%), 3.80 (3H, s), 3.85
(1H, dddd, J=8.0, 6.0, 6.0, 3.0 Hz, H-2), 6.6 (1H, d,
J=7.8 Hz, H-5 or H-7), 6.7 (1H, d, J=7.8 Hz, H-7 or
H-5), 7.15 (1H, dd, J=7.8, 7.8 Hz, H-6); 13C NMR
(CDCl3): 27.2 (t), 27.7 (t), 28.7 (t), 55.5 (d), 57.2 (q),
107.2 (d), 120.8 (d), 122.4 (s), 126.6 (d), 136.5 (s), 157.4
(s); EI MS, m/z: 203 (M+), 175 (M+−N2), 161 (M+−N3),
160 (M+−CH3ꢀN2).
3.2.3.4. (2S)-8-Carbomethoxy-2-toluenesulphonyloxy-
1,2,3,4-tetrahydronaphthalene 4c. (90%), Colorless
1
syrup; [h]D=−4.4 (c=14.4 mg/mL, CHCl3); H NMR
(CDCl3): l 1.99 (1H, m, H-3), 2.08 (1H, m, H-3%), 2.42
(3H, s), 2.78 (1H, ddd, J=17.1, 6.4, 6.4 Hz, H-4), 3.02
(1H, ddd, J=17.1, 6.4, 6.4 Hz, H-4%), 3.21 (1H, dd,
J=17.1, 6.4 Hz, H-1), 3.31 (1H, dd, J=17.1, 4.8 Hz,
H-1%), 3.80 (3H, s), 4.97 (1H, m, H-2), 7.14 (1H, dd,
J=7.9, 7.9 Hz, H-6), 7.18 (1H, d, J=7.9 Hz, H-5 or
H-7), 7.30 (2H, d, J=7.9 Hz, H-2%%, H-6%% or H-3%%,
H-5%%), 7.69 (1H, d, J=7.9 Hz, H-7 or H-5), 7.77 (2H, d,
J=7.9 Hz, H-3%%, H-5%% or H-6%%, H-2%%); 13C NMR
(CDCl3): 21.54 (q), 26.10 (t), 27.61 (t), 33.64 (t), 51.76
(q), 78.04 (d), 125.81 (d), 127.61 (2C, d), 128.71 (d),
129.75 (2C, d), 130.09 (s), 132.72 (d), 133.91 (s), 134.65
(s), 136.27 (s), 144.48 (s), 167.64 (s). EI MS, m/z: 360
(M+), 329 (M+−OCH3), 188 (M+−PTSH), 156 (M+−
PTSHꢀH3OH). Calcd for C19H20O5S: C, 63.33; H, 5.56.
Found: C, 63.81; H, 5.83%.
3.2.4.2.
(2R)-2-Azido-1,2,3,4-tetrahydronaphthalene
5a. (97%) (Procedure a): colorless oil; [h]D=+59.3 (c=6
1
mg/mL, CHCl3); H NMR (CDCl3): l 1.9 (1H dddd,
J=17.0, 5.0, 5.0, 1.7 Hz, H-3), 2.10 (1H, dddd, J=17.0,
7.5, 5.5, 5.5 Hz, H-3%), 2.82 (1H, dd, J=16.5, 8.6 Hz,
H-1), 2.85 (1H, ddd, J=16.5, 5.5, 5.0 Hz, H-4), 2.88
(1H, ddd, J=16.5, 5.5, 5.0 Hz, H-4%), 3.08 (1H, dd,
J=16.5, 5.0 Hz, H-1%), 3.88 (1H, dddd, J=8.6, 7.5, 5.0,
1.7 Hz, H-2), 7.05-7.15 (4H, aromatic hydrogens); 13C
NMR (CDCl3): 27.04 (t), 28.08 (t), 29.68 (t), 57.07 (d),
126.05 (d), 126.32 (d), 128.70 (d), 129.23 (d), 133.67 (s),
135.17 (s); MS (FAB), m/z: 185 (M++CaꢀN2).
3.2.4.3.
(2R)-2-Azido-8-ethyl-1,2,3,4-tetrahydro-
naphthalene 5b. (76%) (Procedure a): colorless thick
oil; [h]D=+34.1 (c=20 mg/mL, CHCl3); 1H NMR
(CDCl3): l 1.27 (3H, t, J=7.5 Hz, CH3CH2), 1.88
(1H, dddd, J=15.5, 9.9, 9.9, 5.8 Hz, H-3), 2.17 (1H,
H-3%) 2.64 (2H, q, J=7.5 Hz, CH3CH2), 2.74 (1H, dd,
J=17.1, 8.6 Hz, H-1), 2.84–3.06 (2H, H-4, H-4%),
3.12 (1H, dd J=17.1, 6.2 Hz, H-1%), 3.91 (1H, m, H-2),
7.01 (1H, d, J=7.1 Hz, H-5 or H-7), 7.08 (1H, d,
J=7.1 Hz, H-7 or H-5), 7.16 (1H, dd, J=7.1, 7.1 Hz,
3.2.4. (2R)-2-Azido-1,2,3,4-tetrahydronaphthalenes 5a–d.
(a) From tosylates 4a–d, typical procedure. To a solution
of tosylate 4d (0.073 g, 0.22 mmol) in dimethylfor-
mamide (0.7 mL) was added sodium azide (Fluka) (0.23
g, 0.35 mmol). The reaction flask was immersed into a
pre-heated (110°C) oil bath. The reaction was moni-
tored by thin-layer chromatography (silica gel, eluting

258
F. Orsini et al. / Tetrahedron: Asymmetry 13 (2002) 253–259
H-6); 13C NMR (CDCl3): 14.30 (q), 25.68 (t), 27.84
(2C, t), 31.63 (t), 57.71 (d), 125.81 (d), 126.23 (d),
124.54 (d), 131.30 (s), 135.23 (s), 142.50 (s); EI MS,
m/z: 201 (M+), 158 (M+−N2ꢀMe), 144 (M+−N3–Me).
112°C (ethyl acetate–di-isopropyl ether); [h]D=+73.0
(c=8.05 mg/mL, CHCl3); 1H NMR (CDCl3): l 1.19
(3H, t, J=8.0 Hz, CH3CH2), 1.58 (1H, dddd, J=13.0,
10.0, 4.0, 4.0 Hz, H-3), 1.99 (1H, dddd, J=13.0, 8.0,
8.0, 2.5 Hz, H-3%), 2.4 (1H, dd, J=16.0, 5.0 Hz, H-1),
2.59 (2H, q, J=8.0 Hz, CH3CH2), 2.89 (2H, m, H-4,
H-4%), 3.04 (1H, dd, J=16.0, 5.0 Hz, H-1%), 3.19 (1H,
dddd, J=10.0, 8.0, 5.0, 2.5 Hz, H-2), 6.95 (1H, d,
J=7.5 Hz, H-5 or H-7), 7.02 (1H, d, J=7.5 Hz, H-7 or
H-5), 7.08 (1H, dd, J=7.5, 7.5 Hz, H-6); 13C NMR
(CDCl3): 14.28 (q), 25.65 (t), 28.88 (t), 32.52 (t), 35.93
(t), 47.84 (d), 125.46 (d), 125.75 (d), 126.59 (d), 132.98
(s), 135.81 (s), 142.4 (s); EI MS, m/z: 175 (M+), 158
(M+−NH3) 143 (M+−NH3ꢀMe). Calcd for C12H17N: C,
82.29; H, 9.7. Found: C, 82.09; H, 9.6%.
3.2.4.4. (2R)-2-Azido-8-carbomethoxy-1,2,3,4-tetra-
hydronaphthalene 5c. (90%) (Procedure a): colorless
thick oil; [h]D=+8.8 (c=26.1 mg/mL, CHCl3); 1H
NMR (CDCl3): l 1.7 (1H, m, H-3), 2.06 (1H, m, H-3%),
3.2–3.75 (4H, H-1, H-1% H-4, H-4%), 3.45 (1H, dd,
J=18.0, 5.0 Hz, H-1%), 3.9 (3H, s), 7.15 (1H, d, J=6.5
Hz, H-5 or H-7), 7.20 (1H, d, J=6.5 Hz, H-7 or H-5),
7.78 (1H, dd, J=6.5, 6.5 Hz, H-6); 13C NMR (CDCl3):
27.04 (t), 27.22 (t), 33.04 (t), 51.81 (d), 56.96 (q), 125.69
(d), 128.58 (d), 132.74 (d), 130.10 (s), 134.83 (s), 136.41
(s), 167.81 (s); EI MS, m/z: 203 (M+−N2), 200 (M+−
OMe), 188 (M+−N2ꢀMe).
3.2.5.4. (2R)-2-Amino-8-carbomethoxy-1,2,3,4-tetra-
hydronaphthalene 6c. (80%); Colorless crystals, mp=
3.2.5. (2R)-2-Amino-1,2,3,4-tetrahydronaphthalenes 6a–
d, typical procedure. A suspension of 5d (0.038 g, 0.19
mmol) and 10% palladium (0.013 g) on charcoal in
ethyl acetate (3 mL) were stirred under a hydrogen
atmosphere. The reaction was monitored by thin-layer
chromatography (silica gel, eluting with chloro-
form:methanol:iso-propylamine 9:0.5:0.5). After 2 h,
the suspension was filtered on a Celite pad. The solvent
was removed under reduced pressure and gave amine
6d (0.030 g, 0.17 mmol, 89%).
102–104°C
(ethyl
acetate–di-isopropyl
ether);
[h]D=+119.25 (c=5.2 mg/mL, CHCl3); 1H NMR
(CDCl3) l: 1.60 (1H, m, H-3), 2.00 (1H, m, H-3%), 2.77
(1H, dd, J=17.0, 9.0 Hz, H-1), 2.90–2.95 (2H, m, H-4,
H-4%), 3.15 (1H, m, H-2), 3.40 (1H, dd, J=17.0, 5.0Hz,
H-1%), 3.85 (3H, s), 7.15 (1H, dd, J=7.9 Hz, H-6), 7.25
(1H, d, J=7.9 Hz, H-5 or H-7), 7.68 (1H, d, J=7.9 Hz,
H-7 or H-5). 13C NMR (CDCl3) 28.80 (t); 31.54 (t);
37.86 (t); 47.20 (d); 51.76 (q); 125.27 (d); 128.06 (d);
130.25 (s); 132.58 (d); 136.49 (s); 137.08 (s); 168.26 (s).
EI MS, m/z: 205 (M+), 188 (M+−NH3); 174 (M+−
OMe), 156 (M+−NH3–MeOH). Calcd for C12H15NO2:
C, 70.24; H, 7.32. Found: C, 70.51; H, 7.12%
3.2.5.1. (2R)-2-Amino-8-methoxy-1,2,3,4-tetrahydro-
naphthalene 6d. Colorless crystals; mp=103–104°C
(ethyl acetate–di-iso-propyl ether); [h]D=+79.7 (c=5.8
1
mg/mL, CHCl3); H NMR (CDCl3): l 1.55 (1H, dddd,
J=12.3, 8.5, 5.5, 1.5 Hz, H-3), 1.95 (1H, dddd, J=12.3,
4.3, 4.3, 1.5 Hz, H-3%), 2.26 (1H, dd, J=16.7, 8.9 Hz,
H-1), 2.8-2.85 (2H, H-4, H-4%), 3.05 (1H, dd, J=16.7,
5.1 Hz, H-1%), 3.10 (1H, dddd, J=8.9, 8.5, 5.1, 1.5 Hz,
H-2), 3.8 (3H, s), 6.65 (1H, d, J=7.5 Hz, H-5 or H-7),
6.70 (1H, d, J=7.5 Hz, H-7 or H-5), 7.1 (1H, dd,
J=7.5, 7.5 Hz, H-6); 13C NMR (CDCl3): 28.9 (t), 32.2
(t), 33.2 (t), 47.2 (d), 55.2 (q), 107.0 (d), 120.9 (d), 124.2
(s), 125.6 (d), 137.2 (s), 157.4 (s); EI MS, m/z: 177
(M+), 160 (M+−NH3), 145 (M+−NH3ꢀCH3). Calcd for
C11H15NO: C, 74.58; H, 8.47. Found: C, 74.20; H,
8.20%.
Acknowledgements
Genencor International (1700 Lexington Avenue,
Rochester, New York 14606, USA) is gratefully
acknowledged for a generous supply of cis-(1R,2S)-
dihydroxy-1,2-dihydronaphthalene. National Research
Council (CNR), Italy and Ministero della Ricerca Sci-
entifica e Tecnologica (MURST) are acknowledged for
financial support. Dr. Marinella Ferrari is acknowl-
edged for computer aided bibliographic research.
3.2.5.2. (2R)-2-Amino-1,2,3,4-tetrahydronaphthalene
6a. (83%); Colorless crystals; mp=97–99°C (ethyl ace-
tate–di-iso-propyl ether) [h]D=+85.4 (c=5.0 mg/mL,
References
1
CHCl3); H NMR (CDCl3): l 1.63 (1H, dddd, J=14.0,
1. (a) Di Gennaro, P.; Galli, E.; Albini, G.; Pelizzoni, F.;
Sello, G.; Bestetti, G. Res. Microbiol. 1997, 148, 355–364;
(b) A mutant of Pseudomonas fluorescens N3, blocked at
the dihydrodiol dehydrogenase level, can be also used to
produce the bioconversion products: Di Gennaro, P.;
Sello, G.; Bianchi, D.; D’ Amico, P. J. Biol. Chem. 1997,
28, 30254–30260.
2. Orsini, F.; Sello, G.; Bestetti, G. Tetrahedron: Asymmetry
2001, 12, 2961–2969.
3. Orsini, F.; Pelizzoni, F. Tetrahedron: Asymmetry 1996, 7,
1033–1040.
10.0, 9.5, 6.7 Hz, H-3), 1.99 (1H, m, H-3%), 2.58 (1H,
ddd, J=17.0, 9.5 Hz, H-1), 2.85 (1H, m, H-4), 2.91
(1H, m, H-4%), 3.02 (1H, ddd, J=17.0, 4.0 Hz, H-1%),
3.21 (1H, dddd, J=9.5, 9.5, 4.0, 3.0 Hz, H-2), 7.02–7.20
(4H, aromatic hydrogens); 13C NMR (CDCl3): 28.06
(t), 38.82 (t), 39.37 (t), 47.08 (d), 2×125.77 (d), 128.67
(d), 129.31 (d), 135.26 (s), 135.85 (s); EI MS, m/z: 147
(M+), 130 (M+−NH3). Calcd for C10H13N: C, 81.63; H,
8.84. Found: C, 81.93; H, 8.70%.
3.2.5.3.
(2R)-2-Amino-8-ethyl-1,2,3,4-tetrahydro-
4. Orsini, F.; Rinaldi, S. Tetrahedron: Asymmetry 1997, 7,
1039–1048.
naphthalene 6b. (83%); Colorless crystals, mp=111–

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1
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