Biocatalytic enantioselective approach to 3-aryl-2-nitropropanols: Synthesis of enantioenriched (R)-5-methoxy-3-aminochroman, a key precursor to the antidepressant drug Robalzotan

Article abstract of DOI:10.1016/j.molcatb.2010.06.003

The results of our studies on the biocatalytic enantioselective synthesis of different 3-aryl-2-nitropropanols are presented. These compounds could be obtained in moderate to good ee both bybaker's yeast mediated reduction of (E)-2-nitro-3-arylprop-2-en-1-ol precursors and by lipase kinetic resolution of racemic 3-aryl-2-nitropropanols. The synthesis of enantioenriched (R)-5-methoxy-3-aminochroman is also achieved. This important moietyispresent in different molecules active toward the central nervous system and is also the precursor for the synthesis of Robalzotan (NAD299), a potent 5-HT_1A antagonist.

Full text of DOI:10.1016/j.molcatb.2010.06.003

Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
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Journal of Molecular Catalysis B: Enzymatic
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Biocatalytic enantioselective approach to 3-aryl-2-nitropropanols: Synthesis of
enantioenriched (R)-5-methoxy-3-aminochroman, a key precursor to the
antidepressant drug Robalzotan
Claudio Fuganti, Alessandro Sacchetti∗
Dipartimento di Chimica, Materiali ed Ingegneria Chimica “G. Natta”, Politecnico of Milan, via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The results of our studies on the biocatalytic enantioselective synthesis of different 3-aryl-2-
nitropropanols are presented. These compounds could be obtained in moderate to good ee both by baker’s
yeast mediated reduction of (E)-2-nitro-3-arylprop-2-en-1-ol precursors and by lipase kinetic resolution
of racemic 3-aryl-2-nitropropanols. The synthesis of enantioenriched (R)-5-methoxy-3-aminochroman
is also achieved. This important moiety is present in different molecules active toward the central nervous
system and is also the precursor for the synthesis of Robalzotan (NAD299), a potent 5-HT1A antagonist.
© 2010 Elsevier B.V. All rights reserved.
Received 14 October 2009
Received in revised form 27 May 2010
Accepted 10 June 2010
Available online 16 June 2010
Keywords:
3-Aryl-2-nitropropanol
3-Aminochroman
Robalzotan
Baker’s yeast
Lipase resolution
1. Introduction
ally with tartaric acid [7]. To the best of our knowledge, only two
asymmetric syntheses of 3 have been described, both starting from
The 3-aminochroman moiety 1 (Fig. 1) is a known pharma-
cophore which is present in different biologically active compounds
[1]. The most representative is Robalzotan (NAD299) 2, a potent
5-HT1A antagonist [2] which was developed for the potential treat-
ment of depression and anxiety [3]. Of particular interest is also
the 5-methoxy-3-aminochroman derivative 3, which constitutes
the core of a family of molecules active toward the central nervous
system through their ability to selectively interact with 5HT recep-
tors. For example, compound 4 was discovered as a selective 5-HT1A
ligand vs other 5-HT sites and D2 sites in rat brain membranes [4]
while (+)-S 20499 5 was developed for the treatment of anxiety and
depression [5]. More recently, in the search for novel compounds
possessing dual affinity at both the 5-HT1A receptor and the 5-HT
reuptake site, 6 was shown to possess neurochemical activity in vivo
by producing acute and rapid increases in 5-HT in the rat frontal cor-
tex [6]. 5-Methoxy-3-aminochroman 3 is also a precursor toward
the synthesis of Robalzotan [7]. In order to achieve optically pure
2, racemic 3 is resolved by means of l-tartaric acid at the begin-
ning of the synthetic sequence. Up till now, the main way to obtain
enantiomerically pure or enriched 3-aminochromans is the optical
resolution through the formation of diastereoisomeric salts, usu-
a l-serine derivative [8], and no enantioselective synthesis of these
interesting structures relying on a non-chiral pool approach has
been reported.
In the search of a new biocatalytic enantioselective synthesis
of chiral aminochroman derivatives, we thought that they could be
derived from a chiral 3-(2-hydroxyaryl)-2-nitropropanol precursor
7 through a cyclization and nitro group reduction sequence (Fig. 2).
This key intermediate 7 can be obtained by two different possible
biocatalyzed transformations. In a first approach, 7 would be the
result of a enantioselective baker’s yeast mediated reduction of a 2-
nitro-3-arylprop-2-en-1-ol precursor 8, while in a second approach
racemic nitroalcohols 7 would be resolved by means of a lipase
catalyzed acetylation of the primary hydroxy group.
It should be noted that 3-aryl-2-nitropropanols 7 can represent
useful intermediates also for the synthesis of phenylalaninols ana-
logues bearing different substituents on the aromatic ring, which
could be further converted to the corresponding aminoacids, thus
opening the way to different non-natural phenylalanine deriva-
tives. Although 3-aryl-2-nitropropanols are quite easily accessible
in few synthetic steps, only few reports [9] are known on these
molecules. More, no enantioselective synthesis of these potentially
interesting structures has been reported, at the best of our knowl-
edge.
In this paper, we describe a biocatalytic approach to the enan-
tiosynthesis of different 3-aryl-2-nitropropanols. The utility of
∗
Corresponding author. Tel.: +39 02 2399 3017; fax: +39 02 2399 3180.
E-mail address: alessandro.sacchetti@polimi.it (A. Sacchetti).
1381-1177/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcatb.2010.06.003

C. Fuganti, A. Sacchetti / Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
277
Fig. 1. Relevant molecules containing the 3-aminochroman moiety.
these compounds is then demonstrated by the synthesis of enan-
tioenriched (R)-5-metoxy-3-aminochroman 3.
2.2.2. (E)-1-Methoxy-4-(2-nitrovinyl)benzene 10b
86% yield. Spectroscopic data are in agreement with literature
[11].
2. Materials and methods
2.2.3. (E)-1-Methoxy-3-(2-nitrovinyl)benzene 10c
80% yield. mp 91 ◦C. 1H NMR (400 MHz, CDCl3) ı 7.97 (d,
J = 13.7 Hz, 1H), 7.56 (d, J = 13.7 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 7.14
(d, J = 8.0 Hz, 1H), 7.06–7.01 (m, 2H), 3.84 (s, 3H). 13C NMR (100 MHz,
CDCl3) ı 160.5, 139.4, 137.7, 131.7, 130.8, 122.1, 118.3, 114.4, 55.8.
FTIR (CHCl3) 3108, 1636, 1577, 1511 cm−1. HRMS m/z calcd for
C9H9NO3 179.0582, found 179.0586.
2.1. General
All solvents were distilled and properly dried, when neces-
sary, prior to use. All chemicals were purchased from commercial
sources and used directly, unless indicated otherwise. All reac-
tions were monitored by thin layer chromatography (TLC) on
precoated silica gel 60 F254 (Merck); spots were visualized with
UV light or by treatment with 1% aqueous KMnO4 solution. Prod-
ucts were purified by flash chromatography on Merck silica gel
60 (230–400 mesh). 1H and 13C NMR spectra were recorded
with Bruker 400 MHz Avance (1H, 400 MHz; 13C, 100 MHz) NMR
spectrometer. Chemical shifts are reported in parts per million
downfield from SiMe4 (ı = 0.0). HRMS spectra were measured on a
Jeol SX 102 instrument equipped with its standard sources. Optical
rotations were measured with a Jasco-DIP-181 digital polarime-
ter.
2.2.4. (E)-1-Methoxy-4-(2-nitrovinyl)benzene 10d
80% yield. Spectroscopic data are in agreement with literature
[12].
2.2.5. (E)-1-Fluoro-4-(2-nitrovinyl)benzene 10e
79% yield. mp 101 ◦C. 1H NMR (400 MHz, CDCl3) ı 7.98 (d,
J = 13.7 Hz, 1H), 7.60–7.51 (m, 3H), 7.15 (t, J = 8.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3) ı 159.6 (d, J = 254.6 Hz, 1C), 132.4, 131.6, 125.9
(d, J = 9.1 Hz, 2C), 121.0 (d, J = 3.6 Hz, 1C), 111.4 (d, J = 22.1 Hz, 2C).
FTIR (CHCl3) 3013, 1636, 1600, 1507, 1341, 1245, 1269, 969 cm−1
.
2.2. General procedure for the synthesis of 10a–g
HRMS m/z calcd for C8H6FNO2 167.0383, found 167.0386.
The aldehyde (0.3 mol) was dissolved in 15 mL of acetic acid.
Nitromethane (0.6 mol) was added followed by ammonium acetate
(0.05 mol). The reaction was refluxed for 4 h, and then the mixture
was poured in 50 mL of ice. Upon cooling a precipitate was formed
which was filtered and washed with ethanol to afford pure 10a–g.
2.2.6. (E)-2-(2-nitrovinyl)Phenol 10f
68% yield. mp 133 ◦C. 1H NMR (400 MHz, CDCl3) ı 8.14 (d,
J = 13.8 Hz, 1H), 7.96 (d, J = 13.8 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.34
(t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H),
6.52–5.58 (br s, 1H). 13C NMR (100 MHz, CDCl3) ı 156.6, 138.8,
135.9, 133.6, 132.7, 121.8, 119.5, 117.0. FTIR (CHCl3) 3236, 3018,
1627, 1605, 1512, 1452, 1336, 1236, 1197 cm−1. HRMS m/z calcd
for C8H7NO3 165.0426, found 165.0422.
2.2.1. (E)-(2-nitrovinyl)Benzene 10a
82% yield. Spectroscopic data are in agreement with literature
[10].
Fig. 2. Retrosynthetic approach to the chiral 3-aminochroman moiety.

278
C. Fuganti, A. Sacchetti / Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
FTIR (CHCl3) 3596, 3242, 3032, 1528, 1351 cm−1. HRMS m/z calcd
2.2.7. (E)-3-Methoxy-2-(2-nitrovinyl)phenol 10g
65% yield. mp 79 ◦C. 1H NMR (400 MHz, d6-DMSO) ␦ 11.36–10.65
(br s, 1H), 8.42 (d, J = 13.8 Hz, 1H), 8.08 (d, J = 13.8 Hz, 1H), 7.32 (t,
J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 3.88 (s,
3H). 13C NMR (100 MHz, d6-DMSO) ␦ 160.2, 159.5. 137.2, 134.2,
130.1, 108.4, 106.2, 102.0, 55.9. FTIR (CHCl3) 3235, 3041, 1621,
1338, 1245, 1222, 1211, 1092 cm−1. HRMS m/z calcd for C9H9NO4
195.0532, found 195.0528.
for C10H11NO5 225.0637, found 225.0641.
2.4. General procedure for the synthesis of 15a–e
Compound 10b and 10d–g (0.15 mol) was dissolved in 300 mL
of CHCl3 and 100 mL of iPrOH and 70 g of SiO2 were added. Then
NaBH4 (0.23 mol) was added in portions. After 1 h 15 mL of acetic
acid were added dropwise. The reaction mixture was filtered on
celite and the solvent was removed under reduced pressure. The
residue was dissolved in EtOAc and washed with brine. The organic
layer was then dried and evaporated under reduced pressure to
afford the product without further purification.
2.3. General procedure for the synthesis of 8a–g
Compound 10a–g (0.1 mol) was dissolved in 70 mL of THF. Imi-
dazole (0.1 mol) and anthranilic acid (0.1 mol) were added. Then
50 mL of 25% aq formaldehyde were added and the solution was
stirred for 5 days. Then 50 mL of water was added followed by 50 mL
of EtOAc. The organic layer was separated and washed with 1 M aq
HCl. The organic phase was the dried over Na2SO4 and the solvent
was evaporated under vacuum. The crude was purified by silica gel
chromatography (hexane/EtOAc 7:3) to afford 8a–g.
2.4.1. 1-Methoxy-2-(2-nitroethyl)benzene 15a
88% yield. 1H NMR (400 MHz, CDCl3) ı 7.28 (td, J = 7.6, 1.7 Hz,
1H), 7.16 (dd, J = 7.5, 1.3 Hz, 1H), 6.95–6.88 (m, 2H), 4.60 (t, J = 7.3 Hz,
2H), 3.85 (s, 3H), 3.32 (t, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) ı
157.9, 131.0, 129.2, 124.4, 121.1, 110.9, 75.2, 55.7, 29.5. FTIR (CHCl3)
3311, 3254, 1519, 1455, 1362, 1324, 1236 cm−1. HRMS m/z calcd for
C9H11NO3 181.0739, found 181.0736.
2.3.1. (E)-2-Nitro-3-phenylprop-2-en-1-ol 8a
71% yield. Spectroscopic data are in agreement with literature
[13].
2.4.2. 1-Methoxy-4-(2-nitroethyl)benzene 15b
81% yield. Spectroscopic data are in agreement with literature
[14].
2.3.2. (E)-3-(2-methoxyphenyl)-2-Nitroprop-2-en-1-ol 8b
73% yield. mp 72 ◦C. 1H NMR (400 MHz, CDCl3) ı 8.35 (s, 1H),
7.50 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H),
6.90 (d, J = 7.8 Hz, 1H), 4.60 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.09 (t,
J = 6.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) ı 158.7, 149.5, 133.9,
133.0, 131.0, 121.3, 120.9, 111.2, 57.0, 56.0. FTIR (CHCl3) 3595, 3032,
1520, 1362, 1325, 1253, 1199 cm−1. HRMS m/z calcd for C10H11NO4
209.0688, found 209.0693.
2.4.3. 1-Fluoro-4-(2-nitroethyl)benzene 15c
93% yield. 1H NMR (400 MHz, CDCl3) ı 7.15 (dd, J = 8.6, 5.3 Hz,
2H), 6.97 (t, J = 8.6 Hz, 2H), 4.56 (d, J = 7.5 Hz, 2H), 3.24 (t, J = 7.5 Hz,
2H). 13C NMR (100 MHz, CDCl3) ı 161.7 (d, J = 246.3 Hz, 1C), 131.3
(d, J = 2.9 Hz, 1C), 129.8 (d, J = 8.3 Hz, 2C), 115.3 (d, J = 21.4 Hz, 2C),
75.8, 32.1. FTIR (CHCl3) 3319, 3032, 1523, 1369, 1244, 1123 cm−1
.
HRMS m/z calcd for C8H8FNO2 169.0539, found 169.0544.
2.3.3. (E)-3-(3-methoxyphenyl)-2-Nitroprop-2-en-1-ol 8c
68% yield. mp 69 ◦C. 1H NMR (400 MHz, CDCl3) ı 8.16 (s, 1H),
7.38 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H),
7.02 (dd, J = 7.7, 2.0 Hz, 1H), 4.70 (s, 2H), 3.84 (s, 3H), 2.66 (br s,
1H). 13C NMR (100 MHz, CDCl3) ı 160.3, 150.0, 137.9, 132.8, 130.4,
122.7, 117.1, 115.4, 57.0, 55.6. FTIR (CHCl3) 3491, 3028, 1552, 1377,
1356, 1211 cm−1. HRMS m/z calcd for C10H11NO4 209.0688, found
209.0691.
2.4.4. 2-(2-nitroethyl)Phenol 15d
83% yield. Spectroscopical data are in agreement with literature
[15].
2.4.5. 3-Methoxy-2-(2-nitroethyl)phenol 15e
89% yield. 1H NMR (400 MHz, CDCl3) ı 7.53–7.05 (br s, 1H), 6.98
(t, J = 7.8 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 4.47
(t, J = 7.2 Hz, 2H), 3.73 (s, 3H), 3.32 (t, J = 7.2 Hz, 2H). FTIR (CHCl3)
3574, 3211, 1517, 1448, 1319, 1274 cm−1 13C NMR (100 MHz,
.
2.3.4. (E)-3-(4-methoxyphenyl)-2-Nitroprop-2-en-1-ol 8d
73% yield. Spectroscopic data are in agreement with literature
[13].
CDCl3) ı 158.5, 155.3, 127.9, 110.0, 108.1, 97.5, 73.5, 55.2, 21.3.
HRMS m/z calcd for C9H11NO4 197.0688, found 197.0684.
2.5. General procedure for the baker’s yeast reduction of 8a–g
and of 13
2.3.5. (E)-3-(4-fluorophenyl)-2-Nitroprop-2-en-1-ol 8e
65% yield. Spectroscopic data are in agreement with literature
[13].
To a mechanically stirred mixture of commercial baker’s yeast
(200 g) in tap water (0.8 L) at 35 ◦C was added a solution of glucose
(50 g) in water (100 mL). After 1 h was added in one portion the
substrate 8a–g (10 mmol) adsorbed on the resin XAD 1180 (20 g).
The vigorous stirring was continued for 24 h. Then, the mixture was
filtered on a sintered glass funnel (porosity 0, >165 ␮m) and the
resin was washed with acetone (50 mL) and EtOAc (4× 100 mL). The
combined organic phase was dried over Na2SO4 and concentrated
under reduced pressure to give an oil that was submitted to column
chromatography purification using n-hexane/EtOAc (8:2) as eluant
to give 12a–e.
2.3.6. (E)-2-(3-hydroxy-2-nitroprop-1-enyl)Phenol 8f
52% yield. mp 122 ◦C. 1H NMR (400 MHz, CDCl3) ı 10.45–9.81
(br s, 1H), 8.26 (s, 1H), 7.59 (dd, J = 7.7, 1.4 Hz, 1H), 7.35 (td, J = 7.7,
1.4 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.92 (t, J = 7.7 Hz, 1H), 5.82–5.31
(br s, 1H), 4.52 (s, 2H). 13C NMR (100 MHz, d6-DMSO) ı 157.0, 149.4,
132.4, 131.7, 130.1, 119.2, 118.4, 115.6, 54.8. FTIR (CHCl3) 3593,
3254, 3030, 1519, 1455, 1362, 1324, 1236 cm−1. HRMS m/z calcd
for C9H9NO4 195.0532, found 195.0527.
2.3.7. (E)-2-(3-hydroxy-2-nitroprop-1-enyl)-3-Methoxyphenol
8g
2.6. General procedure for the synthesis of 12b and 12d–g
52%yield. mp103 ◦C. 1HNMR(400 MHz, CDCl3) ı 9.56–9.02(br s,
1H), 8.51 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.71–6.63 (m, 2H), 4.77 (s,
2H), 3.79 (s, 3H), 2.85–2.73 (br s, 1H). 13C NMR (100 MHz, CDCl3)
ı 159.0, 158.6, 147.8, 133.7, 131.3, 109.9, 105.9, 103.3, 56.3, 55.8.
Compound 15a–e (0.10 mmol) was dissolved in 80 mL of
methanol. The pH was adjusted to 8 with 0.1 M aq NaOH and
formaldehyde (0.15 mmol, 37% aq solution) was added. After 45ꢀ

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279
the solution is acidified with 1 M aq HCl and extracted with EtOAc.
The organic phase was dried over Na2SO4 and concentrated under
reduced pressure to give an oil that was purified by column chro-
matography with n-hexane/EtOAc (8:2) as eluant to give 12b and
12d–g.
2.6.6. 2-(3-hydroxy-2-nitropropyl)Phenol 12f
(Rf = 0.11 n-hexane/EtOAc 8:2); mp 97 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.34–7.21 (br s, 1H), 7.16 (td, J = 7.6, 1.8 Hz, 1H), 7.11 (dd,
J = 7.6, 1.6 Hz, 1H), 6.88 (td, J = 7.6, 1.6 Hz, 1H), 6.81 (dd, J = 7.6, 1.8 Hz,
1H), 4.89–4.81 (m, 1H), 4.07 (dd, J = 12.9, 3.0 Hz, 1H), 3.90 (dd,
J = 12.9, 6.0 Hz, 1H), 3.36–3.22 (m, 2H), 2.51–2.23 (br s, 1H). 13C NMR
(100 MHz, CDCl3) ı 154.3, 131.1, 129.3, 121.6, 120.7, 115.8, 88.9,
63.0, 31.1. FTIR (CHCl3) 3308, 3022, 1550, 1237, 1198 cm−1. HRMS
m/z calcd for C9H11NO4 197.0688, found 197.0693. Chiral HPLC con-
ditions: Chiralcel OD column; eluant 9:1 n-hexane/i-PrOH; flow
rate, 1 mL/min; ꢀ = 210 nm; tR = (S) 21.10 min (R) 27.30 min.
2.6.1. 2-Nitro-3-phenylpropan-1-ol 12a
(Rf = 0.21 n-hexane/EtOAc 8:2); mp 71 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.29–7.08 (m, 5H), 4.75–4.68 (m, 1H), 3.96–3.85 (m,
2H), 3.23 (dd, J = 14.0, 7.2 Hz, 1H), 3.07 (dd, J = 14.0, 7.4 Hz, 1H),
2.15–2.02 (br s, 1H). 13C NMR (100 MHz, CDCl3) ı 129.5, 123.7 (2C),
123.6 (2C), 122.3, 84.5, 57.0, 30.5. FTIR (CHCl3) 3398, 3031, 1561,
1297, 1193 cm−1. HRMS m/z calcd for C9H11NO3 181.0739, found
181.0742. Chiral HPLC conditions: Chiralcel OD column; eluant
98:2 n-hexane/i-PrOH; flow rate, 0.7 mL/min; ꢀ = 210 nm; tR = (R)
80.25 min, (S) 94.31 min.
2.6.7. 2-(3-hydroxy-2-nitropropyl)-3-Methoxyphenol 12g
(Rf = 0.10 n-hexane/EtOAc 8:2); mp 93 ◦C. 1H NMR (400 MHz,
CDCl3) ı 8.05–7.41 (br s, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.40 (d, J = 8.0 Hz,
1H), 6.35 (d, J = 8.0 Hz, 1H), 4.74–4.66 (m, 1H), 3.87 (dd, J = 12.7,
2.9 Hz, 1H), 3.80 (dd, J = 12.7, 6.4 Hz, 1H), 3.68 (s, 3H), 3.27–3.15
(m, 2H), 2.92–2.76 (br s, 1H). 13C NMR (100 MHz, CDCl3) ı 159.0,
155.9, 128.8, 110.2, 108.8, 102.9, 87.2, 62.5, 55.7, 23.6. FTIR (CHCl3)
3454, 3036, 1549, 1366, 1292, 1093 cm−1. HRMS m/z calcd for
2.6.2. 3-(2-methoxyphenyl)-2-Nitropropan-1-ol 12b
(Rf = 0.25 n-hexane/EtOAc 8:2); mp 87 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.21 (td, J = 7.8, 1.8 Hz, 1H), 7.05 (dd, J = 7.5, 1.8 Hz, 1H),
6.87–6.80 (m, 2H), 4.91–4.84 (m, 1H), 3.94 (dd, J = 12.4, 7.4 Hz,
1H), 3.86 (dd, J = 12.4, 3.4 Hz, 1H), 3.78 (s, 3H), 3.21–3.08 (m, 2H),
3.08–2.90 (br s, 1H). 13C NMR (100 MHz, CDCl3) ı 157.8, 131.3,
129.3, 123.7, 121.1, 110.8, 88.9, 63.2, 55.6, 31.4. FTIR (CHCl3) 3404,
3033, 1553, 1246, 1203 cm−1. HRMS m/z calcd for C10H13NO4
211.0845, found 211.0844. Chiral HPLC conditions: Chiralcel OD
column; eluant 98:2–95:5 n-hexane/i-PrOH; flow rate, 0.7 mL/min;
ꢀ = 210 nm; tR = (S) 50.98 min, (R) 53.53 min.
C10H13NO5 227.0794, found 227.0789. Chiral HPLC conditions:
Chiralcel OD column; eluant 95:5 n-hexane/i-PrOH; flow rate,
0.7 mL/min; ꢀ = 210 nm; tR = (S) 54.71 min (R) 59.98 min.
2.6.8. 3-Nitrochroman 14
Spectroscopical data are in agreement with literature [4]. Chiral
HPLC conditions: Chiralcel OD column; eluant 98:2 n-hexane/i-
PrOH; flow rate, 0.7 mL/min; ꢀ = 210 nm; tR = (major) 36.91 min,
(minor) 39.06 min.
2.7. General procedure for the lipase mediated resolution of 12b
and 12d–g
2.6.3. 3-(3-methoxyphenyl)-2-Nitropropan-1-ol 12c
(Rf = 0.25 n-hexane/EtOAc 8:2); mp 81 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.23 (t, J = 8.0 Hz, 1H), 6.81 (dd, J = 8.2, 2.1 Hz, 1H), 6.77
(d, J = 7.8 Hz, 1H), 6.73 (s, 1H), 4.83–4.75 (m, 1H), 4.04–3.91 (m,
2H), 3.79 (s, 3H), 3.28 (dd, J = 13.9, 7.2 Hz, 1H), 3.11 (dd, J = 13.9,
7.5 Hz, 1H), 2.35–2.27 (br s, 1H). 13C NMR (100 MHz, CDCl3) ı 160.2,
136.7, 130.3, 121.5, 115.1, 113.1, 90.0, 62.8, 55.5, 36.2. FTIR (CHCl3)
3411, 3033, 1547, 1257, 1212 cm−1. HRMS m/z calcd for C10H13NO4
211.0845, found 211.0841. Chiral HPLC conditions: chiralcel OD col-
umn; eluant 9:1 n-hexane/i-PrOH; flow rate, 1 mL/min; ꢀ = 210 nm;
tR = (major) 16.50 min, (minor) 18.25 min.
1 g of the substrate was dissolved in 10 mL of MTBE and 10 mL of
vinyl acetate, then 1 g of the enzyme was added. The mixture was
stirred for 1–12 h and then filtered. The solvent was evaporated
under reduced pressure and the residue was purified by silica gel
chromatography (hexane/EtOAc 7:3).
2.7.1. 3-(2-methoxyphenyl)-2-Nitropropyl acetate 16b.
(Rf = 0.23, hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) ı 7.22
(td, J = 7.8, 1.8 Hz, 1H), 7.03 (dd, J = 7.5, 1.8 Hz, 1H), 6.87–6.81 (m,
2H), 5.08–5.00 (m, 1H), 4.45–4.34 (m, 2H), 3.79 (s, 3H), 3.18 (dd,
J = 13.8, 7.8 Hz, 1H), 3.10 (dd, J = 13.8, 6.8 Hz, 1H), 1.98 (s, 3H).
13C NMR (100 MHz, CDCl3) ı 170.3, 157.8, 131.2, 129.6, 123.0,
121.1, 110.9, 85.7, 63.9, 55.6, 32.0, 20.7. FTIR (CHCl3) 3024, 1746,
1557, 1238 cm−1. HRMS m/z calcd for C12H15NO5 253.0950, found
253.0947. Chiral HPLC conditions: Chiralcel OD column; eluant
98:2 n-hexane/i-PrOH; flow rate, 0.7 mL/min; ꢀ = 210 nm; tR = (S)
20.84 min, (R) 16.86 min.
2.6.4. 3-(4-methoxyphenyl)-2-Nitropropan-1-ol 12d
(Rf = 0.20 n-hexane/EtOAc 8:2); mp 80 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.07 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.79–4.70
(m, 1H), 3.96 (dd, J = 12.4, 8.2 Hz, 1H), 3.87 (dd, J = 12.4, 3.0 Hz, 1H),
3.75 (s, 3H), 3.35–2.19 (br s, 1H), 3.15 (dd, J = 14.1, 8.2 Hz, 1H), 3.01
(dd, J = 14.1, 6.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) ı 159.1, 130.3
(2C), 127.2, 114.6 (2C), 91.0, 62.9, 55.6, 35.4. HRMS m/z calcd for
C10H13NO4 211.0845, found 211.0849. FTIR (CHCl3) 3436, 3034,
1550, 1255 cm−1. Chiral HPLC conditions: chiralcel OD column; elu-
ant 9:1 n-hexane/i-PrOH; flow rate, 1 mL/min; ꢀ = 210 nm; tR = (R)
14.65 min, (S) 29.61 min.
2.7.2. 3-(4-methoxyphenyl)-2-Nitropropyl acetate 16d
(Rf = 0.20, hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) ı
7.05 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.92–4.83 (m, 1H),
4.42–4.35 (m, 2H), 3.73 (s, 3H), 3.18 (dd, J = 14.3, 8.1 Hz, 1H), 3.01
(dd, J = 14.3, 6.3 Hz, 1H), 2.00 (s, 3H). 13C NMR (100 MHz, CDCl3)
ı 170.0, 158.9, 129.7 (2C), 125.8, 114.2 (2C), 86.9, 63.0, 55.0, 35.2,
20.1. FTIR (CHCl3) 3038, 1749, 1554, 1266, 1324 cm−1. HRMS m/z
calcd for C12H15NO5 253.0950, found 253.0944. Chiral HPLC con-
ditions: Chiralcel OD column; eluant 95:5 n-hexane/i-PrOH; flow
rate, 0.7 mL/min; ꢀ = 210 nm; tR = (R) 22.82 min, (S) 26.33 min.
2.6.5. 3-(4-fluorophenyl)-2-Nitropropan-1-ol 12e
(Rf = 0.28 n-hexane/EtOAc 8:2); mp 69 ◦C. 1H NMR (400 MHz,
CDCl3) ı 7.14 (dd, J = 8.5, 5.1 Hz, 2H), 6.99 (t, J = 8.6 Hz, 2H), 4.79–4.71
(m, 1H), 4.01–3.89 (m, 2H), 3.22 (dd, J = 14.4, 7.8 Hz, 1H), 3.09
(dd, J = 14.4, 6.7 Hz, 1H), 2.80–2.71 (br s, 1H). 13C NMR (100 MHz,
CDCl3) ı 162.1 (d, J = 250.3 Hz, 1C), 130.8–129.9 (3C), 115.6 (d,
J = 21.8 Hz, 2C), 89.9, 62.3, 34.9. FTIR (CHCl3) 3553, 3043, 1517, 1325,
1266, 1106 cm−1. HRMS m/z calcd for C9H10FNO3 199.0645, found
199.0641. Chiral HPLC conditions: Chiralcel OD column; eluant 95:5
n-hexane/i-PrOH; flow rate, 0.7 mL/min; ꢀ = 210 nm; tR = (major)
31.07 min, (minor) 34.30 min.
2.7.3. 3-(4-fluorophenyl)-2-Nitropropyl acetate 16e
(Rf = 0.20, hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) ı 7.13
(dd, J = 8.7, 5.3 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 4.95–4.86 (m, 1H),
4.48–4.37 (m, 2H), 3.23 (dd, J = 14.5, 8.5 Hz, 1H), 3.07 (dd, J = 14.4,

280
C. Fuganti, A. Sacchetti / Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
6.4 Hz, 1H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3) ı 170.0, 162.1 (d,
J = 250.1 Hz, 1C), 130.3 (d, J = 7.6 Hz, 2C), 129.8, 115.7 (d, J = 20.3 Hz,
2C), 86.8, 63.0, 35.2, 20.2. FTIR (CHCl3) 3042, 1748, 1560, 1511,
1249, 1366, 1047 cm−1. HRMS m/z calcd for C11H12FNO4 241.0750,
found 241.0755. Chiral HPLC conditions: Chiralcel OD column;
eluant 95:5 n-hexane/i-PrOH; flow rate, 0.7 mL/min; ꢀ = 210 nm;
tR = (minor) 20.57 min, (major) 22.51 min.
2.7.4. 3-(2-hydroxyphenyl)-2-Nitropropyl acetate 16f
(Rf = 0.18, hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) ı
8.11–7.64 (br s, 1H), 7.11 (td, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 8.1 Hz,
1H), 6.82–6.77 (m, 2H), 5.19–5.11 (m, 1H), 4.51–4.40 (m, 2H), 3.23
(dd, J = 13.9, 7.6 Hz, 1H), 3.17 (dd, J = 13.9, 7.1 Hz, 1H), 2.02 (s, 3H).
13C NMR (100 MHz, CDCl3) ı 170.4, 154.3, 130.7, 128.7, 120.6,
120.2, 115.1, 84.9, 63.4, 31.3, 20.1. FTIR (CHCl3) 3291, 3037, 1746,
1557, 1240, 1197 cm−1. HRMS m/z calcd for C11H13NO5 239.0794,
found 239.0791. Chiral HPLC conditions: Chiralcel OD column; elu-
ant 98:2 n-hexane/i-PrOH; flow rate, 1 mL/min; ꢀ = 210 nm; tR = (R)
66.03 min, (S) 71.84 min.
Scheme 1. Reagents and conditions: (i) MeNO2, AcOH, AcONH4 (65–86%); (ii) CH2O,
Imidazole, Anthranilic acid (52–73%).
3. Results and discussion
3.1. Studies on baker’s yeast mediated reduction of
(E)-ˇ-aryl-˛-nitroalkene precursors 8
We first studied the baker’s yeast mediated reduction of a series
of ˇ-aryl-˛-nitroalkene derivatives 8. The biocatalytic reduction of
activated double bonds, in particular of ˛,ˇ unsaturated aldehy-
des and ketones, is a well known topic in organic chemistry [16]
and the utility of baker’s yeast for this transformation has been
demonstrated [17]. The reduction of substituted ˛-nitroalkenes by
baker’s yeast has also been studied [18]. The enantioselectivity was
found to be a function of the position of the substituent on the
double bond: while ˇ,ˇ-disubstituted ˛-nitroalkenes gave the cor-
responding saturated product with excellent ee, the presence of
substituents at the ˛-position of the double bond gave scarce enan-
tioselectivity. Investigation [19] of the mechanism of this reaction
showed that a reversible non-stereoselective protonation occurs at
the ˛-carbon, followed by a stereoselective addition of hydride at
the ˇ-position. Recently, isolated enzymes have been exploited for
the reduction of activated double bonds [20] and it was reported
that ˛-substituted-˛-nitroalkenes can be reduced with good ee
by means of cloned reductases [21] or by microbial extracts from
Clostridium sporogenes [22]. The biocatalytic reduction of 2-nitro-3-
phenylprop-2-en-1-ols 8 has never been reported until now. Thus,
we decided to investigate the baker’s yeast reduction of compounds
8a–g, which were prepared according to Scheme 1.
2.7.5. 3-(2-hydroxy-6-methoxyphenyl)-2-Nitropropyl acetate
16g
(Rf = 0.25, hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) ı 7.05
(t, J = 8.3 Hz, 1H), 6.73–6.63 (br s, 1H), 6.46–6.40 (m, 2H), 5.06–4.98
(m, 1H), 4.54 (dd, J = 12.2, 8.9 Hz, 1H), 4.33 (dd, J = 12.2, 3.1 Hz,
1H), 3.79 (s, 3H), 3.33 (dd, J = 13.3, 6.6 Hz, 1H), 3.25 (dd, J = 13.3,
8.1 Hz, 1H), 2.00 (s, 3H). 13C NMR (100 MHz, CDCl3) ı 170.6, 158.7,
155.3, 128.7, 109.3, 108.2, 102.7, 84.7, 63.7, 55.3, 24.2, 20.4. FTIR
(CHCl3) 3434, 2962, 1755, 1464, 1380, 1159 cm−1. HRMS m/z calcd
for C12H15NO6 269.0899 found 269.0897. Chiral HPLC conditions:
Chiralcel OD column; eluant 98:2 n-hexane/i-PrOH; flow rate,
0.7 mL/min; ꢀ = 210 nm; tR = (R) 89.84 min, (S) 100.02 min.
2.8. 2-(2-amino-3-hydroxypropyl)-3-Methoxyphenol 19
(Rf = 0.10, hexane/EtOAc 7:3); Compound 12g (2.5 g, 11.0 mmol),
was dissolved in 50 mL of ethanol and 500 mg of wet Ni-Raney were
added. The mixture was stirred under hydrogen atmosphere for
48 h and then filtered over celite to remove the catalyst. The solvent
was evaporated under reduced pressure to afford 19 (1.93 g, 89%
yield) without further purification. mp 122 ◦C. 1H NMR (400 MHz,
CDCl3) ı 6.99 (t, J = 8.1 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.34 (d,
J = 8.2 Hz, 1H), 5.05–4.31 (br s, 4H), 3.75 (s, 3H), 3.56–3.45 (br m,
2H), 3.38–3.28 (br m, 1H), 3.11 (dd, J = 13.4, 11.2 Hz, 1H), 2.88 (dd,
J = 13.4, 3.0 Hz, 1H). FTIR (CHCl3) 3410, 3381, 3318, 1576, 1480,
1323, 1059 cm−1. HRMS m/z calcd for C10H15NO3 197.1052, found
197.1059.
Reaction of commercially available aromatic aldehydes 9a–f
with nitromethane in the presence of acetic acid and ammonium
acetate [23], gave the (E)-ˇ-aryl-˛-nitroalkenes 10 in good yields.
The non-commercially available aldehyde 9g was prepared start-
ing from 11 [24] as reported in Scheme 2. A Morita–Baylis–Hillman
reaction of 10a–g with formaldehyde using imidazole as base and
anthranilic acid as additive [25] allowed to obtain the desired 8a–g
in good yields.
2.9. tert-Butyl 1-hydroxy-3-(2-hydroxy-6-
methoxyphenyl)propan-2-ylcarbamate
20.
Compounds 8a–g were then submitted to reduction by baker’s
yeast. For practical work-up, the starting materials were adsorbed
on non-polar resins (XAD 1180) [26] and then added to a water
suspension of baker’s yeast in the presence of glucose. After 24 h
the mixture was filtered and the resin was washed with EtOAc
to recover the reaction product. The conversion was estimated by
GC/MS and 1H NMR analysis on the crude and the ee of the reduced
Compound 19 (1.8 g, 9.1 mmol), was dissolved in 40 mL of dry
acetonitrile and Boc anhydride (2.38 g, 10.9 mmol), was added. The
mixture was stirred for 24 h then the solvent was evaporated under
reduced pressure. The residue was purified by silica gel chromatog-
raphy (hexane/EtOAc 8:2, Rf = 0.18) to afford 20 (2.1 g, 78% yield)
whose spectroscopic data were in agreement with literature [8a].
2.9.1. 5-Methoxy-3-aminochroman 3
Compound 20 was converted in to compound 3 by a two-step
sequence according to a previously reported procedure [8a] (46%
yield after two steps). Spectroscopic data were in agreement with
literature.
Scheme 2. Reagents and conditions: (i) Me2SO4, K2CO3 (86%); (ii) DIBAL-H, THF,
−78 ◦C (68%).

C. Fuganti, A. Sacchetti / Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
281
Table 1
Baker’s yeast mediated reduction of 8a–g.
Scheme 4. Reagents and conditions: (i) NaBH4, SiO2, CHCl3/i-PrOH (81–93%); (ii)
CH2O, NaOH, MeOH (48–71%).
Compound
Conversiona
eeb (config.)
the rate of racemization of the nitroalkane product under the same
conditions as the baker’s yeast reduction was evaluated. Results
confirmed that racemization is a very slow process, thus supporting
the observation that the low stereoselectivity were not a result of
non-enzymatic racemization of the product, because the reduction
with yeast was completed within some hours (24 h in our case).
12a
12b
12c
12d
12e
12f
98%
76%
93%
96%
96%
7%
20% (R)
4% (R)
24% (nd)
42% (R)
26% (nd)
0%
12g
5%
0%
a
Conversions are calculated from GC/MS and 1H NMR analysis on the crude.
3.2. Studies on lipase mediated kinetic resolution of racemic
primary 2-nitroalcohols
b
ee are determined by chiral HPLC on
a chiralcell OD column using hex-
ane/isopropanol as eluant. See Section 2 for details.
Since compounds 8f and 8g could not be reduced with baker’s
yeast, we decided to achieve the desired optically active 12g by
means of a lipase catalyzed kinetic resolution of the corresponding
primary 2-nitro alcohol. To the best of our knowledge this strategy
has never been reported before in the literature. Substrates were
prepared according to the synthetic sequence reported in Scheme 4.
The reduction of 10b and 10d–g with NaBH4 at 0 ◦C in THF/MeOH
gave the products with poor yields. Running the reaction in CHCl3/i-
PrOH at room temperature in the presence of SiO2, [31] afforded the
wanted 2-aryl nitroethane compounds 15a–e in good yields. The
nitroaldol reaction of 15a–e with formaldehyde in MeOH with cat-
alytic amount of NaOH, gave the racemic 3-aryl-2-nitropropanols
12b and 12d–g with satisfactory yields.
A preliminary screening for the best performing lipase was per-
formed on racemic 12b (see Table 2). The substrate was reacted in
a vinylacetate/MTBE 1:1 solution with Pig Pancreatic Lipase, lipase
from Candida rugosa, and Amano PS lipase. Reactions with both the
PPL and C. rugosa proceed very quickly with good conversion (25ꢀ
and 45% conv. for PPL; 20ꢀ and 55% conv. for C. Rugosa). This rapid
acetylation led to low ee. Better results were obtained with lipase
from Amano PS. In this case a slower reaction occurred and after
1 h the acetylated product 16b was obtained with 19% of conver-
sion and 73% of ee. The unchanged 12b was obtained in 81% yield
and 17% ee. Notably an inversion of configuration of the acetylated
product was observed for C. rugosa.
The absolute configuration of 16b (as obtained from Amano PS
catalyzed resolution) was estabilished by converting the residual
enantioenriched 12b (ee 17% by chiral HPLC) into the known sul-
fonamide 17 by a reduction of the nitro group with Zn and conc.
HCl followed by reaction with benzensulfonyl chloride, according
to Scheme 5. The optical rotatory power of 17 ([␣]D25 = +11.1, c 1.0,
acetone) compared with the literature [32] value for enantiomer-
ically pure 17 ([␣]D25 = +66.5, c 1.0, acetone) allowed to confirm
a R configuration for the major enantiomer of unreacted 12b and
a S configuration for the major enantiomer of the acetylated prod-
uct 16b. The ee calculated from the measured optical rotator power
(19.5% ee) is in agreement with that derived by chiral HPLC analysis
(17% ee).
products were measured by chiral HPLC. Results are reported in
Table 1.
Most of the products were obtained with high conversions. The
enantioselectivity was modest and it was influenced by the substi-
tution pattern of the aromatic ring. The best result was obtained
with compound 12d, bearing a p-methoxy substituent on the aro-
matic ring (42% ee). Moving the methoxy group to the meta and
ortho position of the phenyl ring produced a lowering of the ee (24%
ee for 12c and 4% ee for 12b respectively). This finding is in con-
trast with the observation that for the bioreduction of arylenones,
the best result was obtained with the methoxy substituent in the
meta position [27]. The presence of the phenol function in com-
pounds 12f and 12g inhibited the activity of baker’s yeast and the
desired reduced product 12g, precursor to the synthesis of 3, was
obtained with no enantioselection, in 5% conversion together with
unreacted starting material.
The absolute configuration of the newly formed stereocenter
was established for both 12a and 12d by reduction of the nitro
group with Zn and 30% aq H2SO4 to give the corresponding known
aminoalcohols. The optical rotatory power of the obtained prod-
ucts ([␣]D25 = +5.1, c 1.0, EtOH for aminoalcohol from 12a [28] and
[␣]D25 = +5.5, c 1.8, MeOH for aminoalcohol from 12d [29]) com-
pared with the literature value for their enantiomerically pure
forms allowed to assign the R configuration for both 12a and 12d.
The absolute configuration of 12b was determined according to
Scheme 5 (vide infra). We also performed the baker’s yeast medi-
ated reduction of 13 [30] (Scheme 3), and the 3-nitrochroman
derivative 14 was obtained in 86% of conversion and 21% ee
([␣]D25 = +19.2, c 1.3, CHCl3, absolute configuration not deter-
mined). In earlier reports [18a], the low stereoselectivity of the
baker’s yeast mediated reduction of disubstituted nitroolefines was
attributed to racemization of the products because of acidity of the
proton in ˛ position of the nitro moiety. In a recent work [18b],
The R configuration of the untransformed product 12b is the cor-
rect one for the obtainment of the (R)-5-metoxy-3-aminochroman
precursor of Robalzotan. For this reason in order to improve the
ee of (R)-12b, we repeated the Amano PS lipase mediated resolu-
Scheme 3. Baker’s yeast mediated reduction of 13.

282
C. Fuganti, A. Sacchetti / Journal of Molecular Catalysis B: Enzymatic 66 (2010) 276–284
Table 2
Lipase mediated resolution of racemic 12b.
Lipase
Time
Conversiona
ee 16bb
E
Configuration
PPL
25ꢀ
20ꢀ
1 h
4 h
45%
55%
19%
33%
16%
17%
73%
67%
1.6
1.5
7.6
6.9
S
R
S
S
C. rugosa
Amano PS
Amano PS
a
Conversions are estimated from 1H NMR analysis on the crude.
ee are determined by chiral HPLC on a chiralcell OD column using hexane/isopropanol as eluant. See Section 2 for details.
b
Scheme 5. Reagents and conditions: (i) Zn, HCl conc., EtOH (92%); (ii) PhSO2Cl, TEA, DCM (87%).
tion of racemic 12b and, under the same conditions, after 4 h the
acetylated product was isolated after chromatographic separation
in 33% yield and 67% ee, while residual nitroalcohol was achieved
in 67% yield and 33% ee. This latter enantioenriched product was
then resolved again to afford (R)-12b with 97% ee and with an over-
all 21% yield, after two resolution steps. Following these promising
results we studied the substrate scope for this novel lipase medi-
ate resolution of 3-aryl-2-nitropropanols. Results are reported in
Table 3.
Scheme 6. Synthetic strategy to obtain (R)-3.
Again a relation between the substitution pattern of the aro-
matic ring and the ee is evident. For 12d and 12e, both bearing a
substituent in the para position, the resolution is less efficient if
compared with 12b and 12f. The presence of two substituents in
the ortho position is also detrimental, and the desired compound
12g was obtained in 24% yield and 53% ee. It is worth to notice that
for 12f and 12g the acetylation occurred with high chemoselec-
tivity; in fact only the primary alcoholic function was acetylated,
while the phenol moiety remained unchanged. The absolute con-
figuration of compound 12f was established by transformation into
12b (Me2SO4, K2CO3) while for 12g was determined to be R by
converting it in o the target (R)-3 (vide infra).
3.3. Synthesis of enantioenriched
(R)-5-methoxy-3-aminochroman
In order to obtain enantioenriched (R)-3, we investigated the
intramolecular cyclization reaction of enantioenriched (R)-12g,
obtained from Amano PS mediated resolution, to give intermediate
18 which, after reduction of the nitro group, would afford (R)-3. We
tested different reaction conditions to make the cyclic arylether 18
by activating the alcoxy function toward an intramolecular nucle-
ophilic displacement by the phenol function (Scheme 6).
This transformation proved to be a non-trivial issue. We first
tried to tosylate the primary alcohol function, but treatment of
Table 3
Lipase mediated resolution of racemic 12d–g.
Substrate
Time
Conversiona
ee 16d–g (config.)b
ee 12d–g (config.)b
E
12d
12e
12f
12g
12g
6 h
6 h
6 h
6 h
12 h
43%
37%
46%
37.5%
76%
36% (S)
23% (nd)
51% (S)
31% (S)
17% (S)
28% (R)
14% (nd)
43% (R)
19% (R)
53% (R)
2.7
1.8
4.6
2.2
2.2
a
Conversions are estimated from 1H NMR analysis on the crude.
ee are determined by chiral HPLC on a chiralcell OD column using hexane/isopropanol as eluant. See Section 2 for details.
b

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283
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Scheme 7. Reagents and conditions: (i) H2, Ni-Raney, EtOH (86%); (ii) Boc2O, ace-
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quantitatively afforded the tosylation of the phenol oxygen, leav-
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alcohol function into a bromide (PBr3 or NBS/PPh3) or into an iodide
derivative (I2/PPh3/Imidazole) we could only obtain an inseparable
mixture of products deriving from the degradation of the starting
material. Also cyclization under Mitsunobu conditions (DIAD, PPh3)
failed to achieve the desired nitrochroman 18. We ascribed these
events to the presence of the nitro group; for example, it is well
known that ꢁ-nitroalcohols, under Mitsunobu conditions react at
the nitro function, giving cyclic alkylnitronates [33]. For these rea-
sons, we decided to first reduce the nitro function to the amino
group by hydrogenation in the presence of Ni-Raney in ethanol to
afford 19 (Scheme 7).
The crude product 19 was then protected at the amino group
with Boc. Treating 19 with Boc anhydride in DCM in the pres-
ence of TEA gave poor yields due to the competing formation of
the oxazolidinone derivative involving the ˇ-aminoalcohol moi-
ety [34]. Better results were obtained by reacting 19 with Boc
anhydride in acetonitrile without catalyst to afford 20 whose spec-
troscopical data are in agreement with literature [8a]. The measure
of the optical rotatory power of 20 ([␣]D25 = +5.7, c 1.0, CHCl3,
[␣]D25 = +11.2, c 1.0, CHCl3 from lit.) allowed to confirm the R con-
figuration and a calculated 51% ee is in agreement with ee measured
by chiral HPLC. 20 could be finally converted to the (R)-5-metoxy-
3-aminochroman 3 following a previously reported procedure [8a]
through a Mitsunobu–Boc deprotection sequence.
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Acknowledgement
We are grateful for the generous financial support from the E.U.
INTENANT project.

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