Enantioselective synthesis of cis-α-substituted cycloalkanols and trans-cycloalkyl amines thereof

Article abstract of DOI:10.1016/j.tet.2007.04.075

The diastereo- and enantioselective syntheses of trans-cycloalkyl amines was accomplished through a three-step sequence consisting of: (1) asymmetric transfer hydrogenation through dynamic kinetic resolution of bicyclic and monocyclic α-substituted ketones using HCO₂H/Et₃N as the hydrogen source and TsDPEN-based Ru(II) catalysts, (2) nucleophilic hydroxyl to azide substitution of the resulting cis-cycloalkanols using diphenyl phosphoryl azide under modified Mitsunobu conditions, and (3) reduction of the trans-azide intermediates with LiAlH₄ of PPh₃/H₂O to the desired targets.

Full text of DOI:10.1016/j.tet.2007.04.075

Tetrahedron 63 (2007) 6755–6763
Enantioselective synthesis of cis-a-substituted cycloalkanols
and trans-cycloalkyl amines thereof
a,
Rosario Fernandez, Abel Ros, Antonio Magriz, Hansjorg Dietrich and Jose M. Lassaletta
b
b
c
b,
*
*
ꢀ
€
ꢀ
aDepartamento de Quꢀımica Orgaꢀnica, Universidad de Sevilla, Apdo. de correos 1203, 41071-Seville, Spain
bInstituto de Investigaciones Quꢀımicas (CSIC-USe), Americo Vespuccio s/n, Isla de la Cartuja, E-41092 Seville, Spain
cBayer CropScience GmbH, Industriepark Ho€chst G386, 65926 Frankfurt am Main, Germany
Received 26 March 2007; revised 19 April 2007; accepted 23 April 2007
Available online 4 May 2007
Abstract—The diastereo- and enantioselective syntheses of trans-cycloalkyl amines was accomplished through a three-step sequence con-
sisting of: (1) asymmetric transfer hydrogenation through dynamic kinetic resolution of bicyclic and monocyclic a-substituted ketones using
HCO2H/Et3N as the hydrogen source and TsDPEN-based Ru(II) catalysts, (2) nucleophilic hydroxyl to azide substitution of the resulting cis-
cycloalkanols using diphenyl phosphoryl azide under modified Mitsunobu conditions, and (3) reduction of the trans-azide intermediates with
LiAlH4 of PPh3/H2O to the desired targets.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
allosteric modulators at the AMPA [2-amino-3-(3-hy-
droxy-5-methyl-isoxazol-4-yl)propanoic acid] receptors,9
acetylcholine esterase (AChE), and monoamine oxidase
(MAO) inhibitors with potential for treatment of Alzhe-
imer’s and Parkinson’s diseases,10 compounds with potent
hypoglycemic activity,11 etc. (Fig. 1).
Optically active amines are important building blocks for the
synthesis of a variety of biologically active molecules,
among other industrial applications. Consequently, numer-
ous methods have emerged in the past few years for their
preparation in enantiomerically pure or enriched form.1 In
spite of the considerable advances in asymmetric synthesis
and catalysis, the resolution of racemates remains as the
most important approach used by the chemical industry for
the preparation of this type of compounds. In this context,
dynamic kinetic resolution (DKR),2 not limited by the theo-
retical 50% maximum yield associated with conventional
separation techniques or classical kinetic resolutions, is es-
tablished as the most efficient technique for the resolution
of racemates wherever it is applicable. After the seminal
Inspired by the above-disclosed precedents, we have recently
reported on the transfer hydrogenation of a-substituted cy-
clic ketimines as the first DKR process involving reduction
of C]N bonds via DKR.12 In order to complement this pro-
cedure, that is limited to the synthesis of cis products, we en-
visaged that the corresponding trans-a-substituted cyclic
amines could be readily available from a-substituted ketones
OH
3
4
OH
Ar
^
work by the Noyori and Genet groups on the catalytic hy-
drogenation of b-keto esters, the hydrogenation through
DKR has found a number of applications and stimulated
the development of related reactions, including the hydroge-
nation or transfer hydrogenation5 of several types of mono-
cyclic6 and bicyclic7 cycloalkanones.
X
i
NHSO2 Pr
NHCOBn
ACAT Inhibitors
NHCOBn
Potentiators of
AMPA receptors
On the other hand, cyclic chiral amines are key structural
elements in several bioactive compounds such as inhibitors
of acyl CoA:cholesterol acyltransferase (ACAT),8 positive
R5
X
NH
NH
X
X
N
R
R4
HN
R
N
R3
O
N
R1
R2
Keywords: Asymmetric catalysis; Amines; Transfer hydrogenation;
Dynamic kinetic resolution.
* Corresponding authors. Tel.: +34 954559727; fax: +34 954624960 (R.F.);
tel.: +34 954489560; fax: +34 954460565 (J.M.L.); e-mail addresses:
ffernan@us.es; jmlassa@iiq.csic.es
Hypoglycaemic activity
AChE, MAO Inhibitors
Figure 1. Bioactive cyclic amines.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.075

6756
R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
through a three-step synthetic route consisting of: (1) asym-
metric transfer hydrogenation to cis-a-substituted cycloalk-
anols, (2) classical13 or modified14 Mitsunobu reaction with
inversion of the configuration to trans-azido intermediates,
and (3) reduction of the latter to the desired cycloalkyl
amines (Scheme 1). In this paper, we report the results col-
lected on the basis of this hypothesis and its extension to
the synthesis of cyclic cis-1,2-diols and trans-1,2-fluoro-
amines.
also with that described by Wills and co-workers for 1-aryl-
tetral-2-one derivatives,7 and can be explained if a large pro-
portion of unreactive enolic form is present in the keto/enol
equilibrium in this case.
The reactions of tetral-1-one and chroman-4-one derivatives
(ꢀ)-3,4 were accomplished using (S,S)-I as the catalysts and
5:2 HCO2H/Et3N azeotropic mixture to afford, respectively,
cis-(1S,2S)-2-methyltetral-1-ol19 (8) and cis-(3S,4S)-3-
methylchroman-4-ol (9) in high yields, good cis/trans ratios,
and excellent enantioselectivities (Table 1, entries 3 and 4).
The longer reaction times required for completion of the re-
actions and the lower diastereomeric excesses observed with
respect to indanone derivatives (ꢀ)-1,2 can be explained by
a less efficient epimerization of the less reactive (R)-3 or (R)-
4 enantiomers. This fact can be in turn tentatively attributed
to the lower acidity of the a-proton of tetralone and chroma-
none rings. Finally, it should also be mentioned that the
seven-membered 2-methyl benzosuberone (ꢀ)-5 showed
a very poor reactivity under these conditions. By increasing
the catalyst loading to 2 mol %, the corresponding alcohol
10 could be isolated in only 30% yield and with moderate
diastereo- and enantioselectivity (entry 5).
X
X
X
ATH
1) Mitsunobu
2) Reduction
n
n
n
R
R
R
R'
R'
R'
NH2
O
OH
n = 0,1; R = alkyl, F, OAc; X = CH2, O
Scheme 1. Retrosynthetic analysis for cis-cycloalkanols and trans-cyclo-
alkyl amines thereof.
2. Results and discussion
For the synthesis of the desired cis-cycloalkanols, initial
experiments were performed with readily available racemic
2,6-dimethylindan-1-one (ꢀ)-1 using 0.5 mol % of [Rh-
ClCp*(1R,2S)-cis-1-aminoindan-2-ol] [(R,S)-II] as the
catalyst and iPrONa/iPrOH as the hydrogen source.15 The ex-
pected 2,6-dimethylindan-1-ol 6 was isolated in a moderate
45% yield as a 1:3 cis/trans diastereomeric mixture (Scheme
2), suggesting a thermodynamically controlled formation of
the products. On the other hand, the use of Noyori/Ikariya
[RuCl(TsDPEN)(p-cymene)] catalysts (R,R)- or (S,S)-I in
5:2 HCO2H/Et3N azeotropic mixture as the solvent and hy-
drogen source (method A)16 was successfully applied to
the reduction of racemic indanones (ꢀ)-1,2 into the desired
cis-(1S,2S)-indan-1-ol derivatives17 6 and 7, obtained in ex-
cellent yields and stereoselectivities (Table 1, entries 1 and
2). No reaction was observed from a-aryl substituted inda-
nones, even using substrate/catalyst ratio (S/C)¼50 or 1.2:1
HCO2H/Et3N mixture (method B).18 This result contrasts
with the behavior of monocyclic substrates (see below) and
The behavior of 2-acetoxyindan-1-one (ꢀ)-(11) and 2-
acetoxytetral-1-one (ꢀ)-(13) as representatives of a-oxygen-
ated cyclic ketones was investigated next. In this cases, use of
(S,S)-I or (R,R)-I catalysts and 1.2:1 HCO2H/Et3N mixture as
hydrogen source and reaction medium afforded the best
results concerning reactivity and stereoselectivity, a result
in line with that previously observed for the related a-fluoro
ketones.20 The primary products from these reactions were
mixture of the expected cis-2-acetoxycycloindan-1-ols and
cis-1-acetoxycycloindan-2-ols, formed through well estab-
lished 1,2-migration of the acetyl group (Scheme 3). The cor-
responding cis vicinal diols 1221 and 1422 were obtained by
in situ deacetylation using NaOH (1 M)/MeOH (Table 1,
entries 6 and 7).
(R,R)-I (cat.)
HCO2H/Et3N
OAc
OAc
+
OH
OAc
O
OH
( )-11
X
X
n
n
(S,S)-I, S/C 200:1
HCO2H/Et3N 5:2
NaOH 1M
MeOH
R
Me
R
Me
OH
O
OH
OH
( )-1: n = 0, R = Me, X=CH2
( )-2: n = 0, R = H, X=CH2
( )-3: n = 1, R = H, X=CH2
( )-4: n = 1, R = H, X=O
( )-5: n = 2, R = H, X=CH2
6: n = 0, R = Me, X=CH2
7: n = 0, R = H, X=CH2
8: n = 1, R = H, X=CH2
9: n = 1, R = H, X=O
(1S,2R)-12
10: n = 2, R = H, X=CH2
(S,S)-I (cat.)
+
HCO2H/Et3N
OAc
OAc
OH
O
OH
OAc
Tos
N
Ru
( )-13
Ph
Ph
O
Cat.:
Rh
Cl
Cl
N
N
NaOH 1M
MeOH
H2
H2
OH
(S,S)-I
OH
(R,S)-II
(1R,2S)-14
Scheme 2. Asymmetric transfer hydrogenation of (ꢀ)-1–5 using (S,S)-I
catalyst and 5:2 HCO2H/Et3N azeotropic mixture as hydrogen source.
Scheme 3. Synthesis of diols 12 and 14.

R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
6757
Table 1. Transfer hydrogenation of cyclic a-substituted ketones and enantioselective synthesis of cis-cycloalkanols
Methoda
Catalyst
T (days)
Major product
Me
Yieldb (%)
80 (71)
cis/transc
ercis
d
Entry
Substrate
Me
Me
1
A
(S,S)-I
7
97:3 (99:1)
98:2 (99:1)
O
OH
(1S,2S)-6
( )-1
Me
Me
2
3
A
A
(S,S)-I
(S,S)-I
7
9
78
75
97:3
95:5
98.5:1.5
OH
(1S,2S)-7
O
( )-2
Me
Me
Me
Me
99:1
99:1
O
OH
(1S,2S)-8
( )-3
O
O
4
A
(S,S)-I
9
92 (80)
86/14 (95:5)
OH
(3S,4S)-9
O
( )-4
5
6
7
A
B
(S,S)-Ie
(R,R)-I
(S,S)-I
(R,R)-I
12
1
30
83:17
>99:1
97:3
79:21
99.5:0.5
96:4
Me
Me
O
( )-5
HO
(1S,2S)-10
OH
OAc
80f
80f
90
OH
O
( )-11
(1S,2R)-12
Bg
2
OH
OAc
OH
O
( )-13
(1R,2S)-14
OH
O
8
9
A
6
>99:1
>99:1
Ph
( )-15
Ph
(1R,2R)-17
OH
O
A
B
(R,R)-I
(R,R)-I
6
6
90
80
85:15
75:25
90:10
80:20
CN
CN
( )-16
(1R,2R)-18
10
(ꢀ)-16
(1R,2R)-18
a
Method A uses 5:2 HCO2H/Et3N mixture and 0.5% of catalyst; method B uses 1.2:1 HCO2H/Et3N mixture and 0.5% of catalyst.
Isolated, overall yield from starting ketone. In parenthesis: yield after fractional crystallization.
Determined by 1H NMR of the crude reaction mixture. In parenthesis: diastereomeric excess after fractional crystallization.
Determined by HPLC or GC on chiral stationary phases. In parenthesis: enantiomeric excess after fractional crystallization.
Catalyst of 2 mol % (S/C 50) was used.
b
c
d
e
f
Yields of the diols obtained by in situ deacetylation with NaOH (1 M)/MeOH.
Reaction performed with 2 mmol of ketone in 4 mL of HCO2H/Et3N mixture.
g
We next turned our attention to monocyclic substrates such
(1R,2R)-18 in moderate diastereo- and enantioselectivity
(85:15 cis/trans, 90:10 er, entry 9). Using 1.2:1 HCO2H/
Et3N mixture (method B) a poor result (entry 10) was ob-
tained for ketone (ꢀ)-16. The minor amounts (10–25%) of
trans isomers and the lower er observed for (ꢀ)-16 with re-
spect to (ꢀ)-15 can be explained as a result of the smaller
steric repulsion by the alkyl group and the proposed p-inter-
action between the h6-arene [on (R,R)-I catalyst] and the
aryl ring in (ꢀ)-15.24,25
as (ꢀ)-15,16 (Scheme 4). These are a priori more challeng-
ing systems, where the smaller steric and electronic differ-
ences at both sides of the carbonyl group constitute
additional difficulties. a-Aryl-substituted ketone (ꢀ)-15
was reduced under method A using 0.5 mol % catalyst
(R,R)-I, to give cis-(1R,2R)-2-phenylcyclohexanol23 (17)
in excellent diastereo- and enantioselectivity (Table 1, entry
8). Under the same conditions, ketone (ꢀ)-16 afforded

6758
R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
OH
X
O
X
DPPA,DBU
THF, 0 °CÆrt
(R,R)-I, S/C 200:1
HCO2H/Et3N
n
R
n
R
R'
Me
R'
Me
OH
N3
17: R=Ph
( )-15: R=Ph
( )-16: R=(CH2)2CN
6: n = 0, R' = Me, X = CH2
7: n = 0, R' = H, X = CH2
9: n = 1, R' = H, X = O
18: R=(CH2)2CN
Scheme 4. Asymmetric transfer hydrogenation of (ꢀ)-15,16 using (R,R)-I
catalyst and 5:2 or 1.2:1 HCO2H/Et3N mixture as hydrogen source.
X
X
n
n
BzCl
Et3N
LiAlH4 or
With the enantiomerically enriched cis-cycloalkanols in
hand, the synthesis of the target chiral trans-cycloalkyl
amines was accomplished by nucleophilic substitution of
the hydroxy group by an azido group. Modified Mitsunobu
conditions using diphenyl phosphoryl azide (DPPA) in the
presence of DBU gave rise to azides with complete inversion
of configuration at C(1),14 conditions being mild enough to
prevent b-elimination of hydrazoic acid, even in systems as
sensitive as the indane and tetraline derivatives. Finally, in
R'
Me
R'
Me
NHBz
Ph3P/H2O
NH2
19: n = 0, R' = Me, X = CH2
20: n = 0, R' = H, X = CH2
21: n = 1, R' = H, X = O
22: n = 0, R' = Me, X = CH2
23: n = 0, R' = H, X = CH2
24: n = 1, R' = H, X = O
Scheme 5. Synthesis of trans-cycloalkyl amines (1R,2S)-19–21.
€
situ reduction by LiAlH4/THF or Ph3P/H2O (Staudinger re-
3. Conclusion
action) afforded the desired trans-cycloalkyl amines 19–21
(Table 2), which were transformed into the corresponding
benzamides 22–24 for analytical purposes (Scheme 5).
Summarizing, the transfer hydrogenation of a-substituted
cyclic ketones through DKR is the key step for the synthesis
of several trans-a-substituted cycloalkyl amines. Using
Noyori/Ikariya Ru(arene)TsDPEN catalysts I in HCO2H/
Et3N mixture as the hydrogen source, good reactivities and
enantioselectivities were achieved in most cases. The ob-
served yields and the achieved levels of diastereo- and enan-
tioselectivity of the products confer synthetic utility to the
methodology.
In order to expand the scope of the of the methodology,
trans-2-fluoro cycloalkyl amines 27 and 28 were also syn-
thesized from the corresponding cis-cyclic fluorohydrins
25 and 26 (Scheme 6), that were previously obtained by
asymmetric transfer hydrogenation of the corresponding
racemic a-fluoroketones via DKR.20
Table 2. Synthesis of trans-cycloalkyl amines
Entry
Substrate
Reducing agent
LiAlH4
Product
Yielda
76
cis/transb
96:4
erc
Me
Me
NH2
1
2
3
4
98.5:1.5
98.5:1.5
97.5:2.5
98.5:1.5
OH
(1S,2S)-6
(1R,2S)-19
(1S,2S)-6
Ph3P/H2O
LiAlH4
(1R,2S)-19
74
97.5:2.5
96:4
Me
Me
80
OH
(1S,2S)-7
NH2
(1R,2S)-20
(1S,2S)-7
Ph3P/H2O
(1R,2S)-20
72
>99:1
O
O
5
6
Ph3P/H2O
Ph3P/H2O
Ph3P/H2O
Me
84
70
74
96:4
97.5:2.5
97.5:2.5
98.5:1.5
Me
F
OH
(3S,4S)-9
NH2
(3R,4R)-21
F
>99:1
>99:1
OH
NH2
(1R,2R)-27
(1S,2R)-25
F
7
F
NH2
OH
(1S,2R)-26
(1R,2R)-28
a
Isolated, overall yield from starting alcohol.
Determined by 1H NMR of the crude reaction mixture.
Of the major isomer, determined for the corresponding benzamides by HPLC on chiral stationary phases.
b
c

R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
6759
(br s, 1H), 2.33 (s, 3H), 2.52 (m, 1H), 2.61 (dd, 1H,
J¼15.6, 7.2 Hz), 2.89 (dd, 1H, J¼15.6, 7.2 Hz), 4.95 (d,
1H, J¼4.4 Hz), 7.05–7.21 (m, 3H). 13C NMR (100 MHz,
CDCl3): d 13.7, 21.3, 37.6, 39.5, 77.7, 124.7, 125.4, 129.3,
136.3, 140.3, 144.9. MS (EI): m/z 162 (M+, 83), 161 (100),
147 (67), 105 (91). HRMS m/z calcd for C11H14O:
162.1045, found: 162.1044. HPLC (Chiralcel OB, 2-propa-
nol/hexane 4:96, flow 0.35 mL/min, T¼30 ꢂC): tR¼
15.69 min (minor) and 18.09 min (major).
n
LiAlH4 or
n
DPPA,DBU
F
F
Ph3P/H2O
THF, 0 °C→rt
OH
25: n = 0
26: n = 1
N3
n
BzCl, Et3N
n
F
F
NH2
NHBz
29: n = 0
30: n = 1
4.2.2. (1S,2S)-2-Methylindan-1-ol [(1S,2S)-7]. From 2-
methylindan-1-one (ꢀ)-2 (1 g, 6.85 mmol) and following
method Awith (S,S)-I as the catalyst, after 7 days the residue
was purified by flash chromatography (1:8 EtOAc/hexane)
to afford (1S,2S)-7 (790 mg, 78%, 94% de, 97% ee) as
27: n = 0
28: n = 1
Scheme 6. Synthesis of trans-2-fluoro-1-cycloalkyl amines 27–28.
1
a white solid. Mp 49–51 ꢂC. H NMR (300 MHz, CDCl3):
4. Experimental section
d 1.13 (d, 3H, J¼6.9 Hz), 2.51 (m, 1H), 2.66 (dd, 1H,
J¼15.6, 7.2 Hz), 2.94 (dd, 1H, J¼15.6, 7.2 Hz), 4.98 (d,
1H, J¼5.4 Hz), 7.17–7.40 (m, 4H). 13C NMR (75 MHz,
CDCl3): d 13.9, 38.2, 39.5, 76.9, 125.0, 125.3, 126.9,
128.7, 143.6, 145.0. [a]2D0 +40.5 (c 0.5, CHCl3) [lit.17
(1R,2R)-7 (>98% ee): [a]2D5 ꢃ38.0 (c 0.3, CHCl3)]. MS
(EI): m/z 148 (M+, 61), 147 (88), 131 (100). HRMS m/z calcd
for C10H12O: 148.0888, found: 148.0882. HPLC (Chiralcel
OB, propan-2-ol/hexane 4:96, flow 0.5 mL/min, T¼30 ꢂC):
tR¼11.59 min (minor) and 18.88 min (major). trans Dia-
stereomers: tR¼15.51 min.
4.1. General experimental methods
Solvents were purified and dried by standard procedures.
Flash chromatography was carried out on silica gel
(0.040–0.063 or 0.015–0.040 mm). Melting points were re-
corded in a metal block and are uncorrected. 1H NMR spec-
tra were recorded at 300, 400 or 500 MHz; 13C NMR spectra
were recorded at 75, 100 or 125 MHz with the solvent peak
used as the internal reference. The diastereomeric excesses
1
(de) of the products were determined by H NMR and the
enantiomeric excess (ee) by HPLC on chiral stationary
4.2.3. (1S,2S)-2-Methyltetral-1-ol [(1S,2S)-8]. From 2-
methyltetral-1-one (ꢀ)-3 (420 mg, 2.6 mmol) and following
method Awith (S,S)-I as the catalyst, after 9 days the residue
was purified by flash chromatography (1:10 EtOAc/hexane)
to afford (1S,2S)-8 (316 mg, 75%, 90% de, 98% ee) as a
i
phases with PrOH/hexane mixture as the eluant. Catalysts
(R,R)-I and (S,S)-I,25 2-acetoxyindan-1-one (ꢀ)-11,26 and
2-acetoxytetral-1-one (ꢀ)-1326 were synthesized according
to previously described procedures.
1
colorless oil. H NMR (400 MHz, CDCl3): d 1.12 (d, 1H,
4.2. Transfer hydrogenation of a-substituted ketones.
General procedures
J¼6.8 Hz), 1.47 (br s, 1H), 1.53–1.94 (m, 3H), 2.74 (ddd,
1H, J¼16.8, 10.6, 6.4 Hz), 2.85 (ddd, 1H, J¼16.8, 5.2,
3.2 Hz), 4.55 (d, 1H, J¼2.8 Hz), 7.06–7.35 (m, 4H). 13C
NMR (125 MHz, CDCl3): d 17.0, 24.8, 28.9, 34.2, 71.5,
126.1, 127.9, 129.1, 129.9, 136.8, 138.7. [a]2D0 ꢃ43.7 (c 0.45,
C6H6) [lit.6d (1R,2R)-8 (97% de, 87% ee): [a]2D5 +65.5 (c
2.10, C6H6)]. MS (CI): m/z 162 (M+, 22), 161 (13), 144
(70), 119 (100). HRMS m/z calcd for C11H14O: 162.1045,
found: 162.1040. GC (Chirasil-Dex CB, Tcolumn¼120 ꢂC,
helium (90 kPa), Tinjector¼250 ꢂC, split ratio 20:1):
tR¼35.56 min (minor) and 36.46 min (major). trans Diaste-
reomers: tR¼39.08 and 40.13 min.
Method A. a-Substituted ketone (4 mmol) was added to a so-
lution of catalyst I (6.5 mg, 0.02 mmol) in 5:2 HCO2H/Et3N
(2 mL). The mixture was stirred at rt for 7–12 days, then
diluted with CH2Cl2 (20 mL) and washed with H2O
(2ꢁ15 mL). The organic layer was dried and concentrated,
and the residue was purified by flash chromatography.
Method B. a-Substituted ketone (2 mmol) was added to a
solution of catalyst I (3.3 mg, 0.01 mmol) in 1.2:1
HCO2H/Et3N (2 mL). The mixture was stirred at rt for 6–9
days and the reaction was then elaborated as in method A.
4.2.4. (3S,4S)-3-Methylchroman-4-ol [(3S,4S)-9]. From 3-
methylchroman-4-one (ꢀ)-4 (1 g, 6.2 mmol) and following
method Awith (S,S)-I as the catalyst, after 9 days the residue
was purified by flash chromatography (1:16 EtOAc/hexane)
to afford (3S,4S)-9 (935 mg, 92%, 78% de, 98% ee) as
a white solid. Crystallization from hexane afforded enriched
(3S,4S)-9 (80%, 90% de, 98% ee). Mp 66–68 ꢂC. 1H NMR
(500 MHz, CDCl3): d 1.06 (d, 3H, J¼7.0 Hz), 1.80 (br s,
1H), 2.13 (m, 1H), 3.95 (t, 1H, J¼11.0 Hz), 4.00 (dd, 1H,
J¼11.0, 3.5 Hz), 4.53 (s, 1H), 6.82–7.25 (m, 4H). 13C
NMR (125 MHz, CDCl3): d 12.0, 33.0, 66.8, 67.2, 117.1,
120.8, 124.6, 130.1, 130.5, 154.4. [a]2D0 ꢃ126.8 (c 0.69,
CHCl3). MS (EI): m/z 164 (M+, 74), 162 (8), 122 (100).
HRMS m/z calcd for C10H12O2: 164.0837, found:
164.0837. Anal. calcd for C10H12O2: C 73.15, H 7.37; found:
C 73.10, H 7.28. HPLC (Chiralcel OB, 2-propanol/hexane
Starting materials, method used for the synthesis, catalyst,
eluants, yields, and spectral and analytical data for com-
pounds 6–10, 12, 14, 17, 18, and 18(OBz) are as follows:
4.2.1. (1S,2S)-2,6-Dimethylindan-1-ol [(1S,2S)-6]. From
2,6-dimethylindan-1-one (ꢀ)-1 (6.4 g, 40 mmol) and fol-
lowing method A with (S,S)-I as the catalyst, after 7 days
the residue was purified by flash chromatography (1:12/
1:3 EtOAc/hexane) to afford (1S,2S)-6 (5.2 g, 80%, 94%
de, 96% ee) as a white solid. Crystallization from hexane af-
forded enriched (1S,2S)-6 (71%, >98% de, 98% ee). Mp
112–114 ꢂC. [a]D20 +58.3 (c 0.9, CHCl3). Anal. calcd for
1
C11H14O: C 81.44, H 8.70; found: C 81.21, H 8.57. H
NMR (400 MHz, CDCl3): d 1.12 (d, 3H, J¼6.8 Hz), 1.41

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R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
5:95, flow 0.5 mL/min, T¼30 ꢂC): tR 14.96 min (minor) and
4.2.8. (1R,2R)-2-Phenylcyclohexanol [(1R,2R)-17]. From
2-phenylcyclohexanone (ꢀ)-15 (350 mg, 2 mmol) and
following the general method A with (R,R)-I as the catalyst,
after 6 days the residue was purified by flash chromatography
(1:10 EtOAc/hexane) to afford (1R,2R)-17 (320 mg, 90%,
>98% de, >98% ee) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d 7.15–7.42 (m, 5H), 3.97–4.08 (m, 1H), 2.74 (dt,
1H, J¼12.9, 2.7 Hz), 1.30–2.15 (m, 8H). 13C NMR
(75 MHz, CDCl3): d 19.9, 24.6, 26.5, 33.3, 48.3, 70.9,
126.8, 128.1, 128.8, 144.3. [a]2D0 ꢃ106.1 (c 0.7, MeOH)
[lit.23: [a]2D5 ꢃ106.0 (c 0.2, MeOH, >98% de, >98% ee)].
Anal. calcd for C12H16O: C 81.77; H 9.15; found: C 81.42;
H 9.15. MS (EI): m/z 176 (M+, 85), 130 (84), 91 (100).
HRMS m/z calcd for C12H16O: 176.1201, found: 176.1195.
HPLC (Chiralcel OB, 2-propanol/hexane 1:99, flow 0.5 mL/
min, T¼30 ꢂC): tR¼12.7 min (minor) and 14.4 min (major).
20.95 min (major).
4.2.5. (1S,2S)-2-Methylbenzosuber-1-ol [(1S,2S)-10].
From 2-methylbenzosuberon-1-one (ꢀ)-5 (216 mg,
1.35 mmol) and following method A with (S,S)-I as the
catalyst, after 12 days purification of the residue by flash
chromatography (1:10 EtOAc/hexane) afforded (1S,2S)-10
(66 mg, 30%, 66% de, 58% ee) as a colorless oil. 1H NMR
(500 MHz, CDCl3): d 0.81 (d, 3H, J¼6.5 Hz), 1.61–2.04
(m, 5H), 2.64 (m, 2H), 2.95 (m, 1H), 4.86 (s, 1H), 7.06–
7.33 (m, 4H). 13C NMR (125 MHz, CDCl3): d 16.6, 24.8,
34.5, 35.6, 37.7, 78.3, 125.9, 126.0, 127.2, 129.6, 141.2,
142.0. [a]2D0 ꢃ115.0 (c 0.8, CHCl3). MS (EI): m/z 176 (M+,
80), 122 (40), 105 (100). HRMS m/z calcd for C12H16O:
176.1201, found: 176.1210. HPLC (Chiralcel OJ, 2-propa-
nol/hexane 3:97, flow 0.5 mL/min, T¼30 ꢂC): tR¼9.24 min
(minor) and 11.67 min (major). trans Diastereomers:
tR¼10.24 and 18.72 min.
4.2.9. 3-[(1R,2R)-2-Hydroxycyclohexyl]propanenitrile
[(1R,2R)-18]. From 3-(2-oxocyclohexyl)propanenitrile
(ꢀ)-16 (906 mg, 6.0 mmol) and following method A with
(R,R)-I as the catalyst, after 6 days the residue was purified
by flash chromatography (1:9 EtOAc/hexane) to afford
(1R,2R)-18 (850 mg, 90%, 70% de, 80% ee) as a colorless
4.2.6. (1S,2R)-Indane-1,2-diol [(1S,2R)-12]. From 2-acet-
oxyindan-1-one (ꢀ)-11 (380 mg, 2 mmol) and following
method B with (R,R)-I as the catalyst, after 1 day the reaction
was elaborated as described. The residue was dissolved in
MeOH (6 mL), treated with NaOH 1 M (4 mL), stirred for
15 min, neutralized with HCl (1 N), diluted with H2O, and
extracted with CH2Cl2 (3ꢁ15 mL). Flash chromatography
(2:3 EtOAc/hexane) afforded (1S,2R)-12 (240 mg, 80%,
1
oil. H NMR (300 MHz, CDCl3): d 3.82–3.90 (m, 1H),
2.26–2.50 (m, 2H), 1.15–1.85 (m, 11H). 13C NMR
(75 MHz, CDCl3): d 15.1, 20.5, 25.0, 26.4, 27.7, 33.2,
40.2, 68.5, 120.4. [a]D20 +20.4 (c 1.0, CHCl3). MS (CI): m/z
154 (M++1, 20), 153 (M+, 11), 136 (100). HRMS m/z calcd
for C9H16NO: 154.1233, found: 154.1232.
1
>98% de, 99% ee) as a white solid. Mp 100–102 ꢂC. H
NMR (500 MHz, CDCl3): d 2.45 (d, 1H, J¼5.5 Hz), 2.54
(d, 1H, J¼7.0 Hz), 2.94 (dd, 1H, J¼16.5, 3.5 Hz), 3.11 (dd,
1H, J¼16.5, 6.0 Hz), 4.48 (m, 1H), 4.99 (t, 1H, J¼5.5 Hz),
7.22–7.42 (m, 4H). 13C NMR (125 MHz, CDCl3): d 38.7,
73.5, 76.0, 125.1, 125.4, 127.2, 128.9, 140.2, 142.0. [a]D20
ꢃ46.5 (c 0.8, CHCl3) [lit.21: [a]D25 ꢃ48.0 (CHCl3)]. MS
(EI): m/z 150 (M+, 17), 133 (92), 104 (100). HRMS m/z calcd
for C9H10O2: 150.0681, found: 150.0671. Anal. calcd for
C9H10O2: C 71.98, H 6.71; found: C 71.94, H 6.69. HPLC
(Chiralcel OK, 2-propanol/hexane 10:90, flow 0.8 mL/min,
T¼30 ꢂC): tR 10.81 min (minor) and 12.90 min (major).
4.2.9.1. O-Benzoyl derivative (1R,2R)-18(OBz). To a
solution of (1R,2R)-18 (153 mg, 1.0 mmol) in dry CH2Cl2
was added benzoyl chloride (1.2 equiv) and Et3N
(1.2 equiv). After for 8 h, the mixture was concentrated
and the residue was purified by flash chromatography (1:9
EtOAc/hexane) to afford (1R,2R)-18(OBz) (200 mg, 78%,
1
70% de, 80% ee) as a colorless oil. H NMR (300 MHz,
CDCl3): d 8.03 (d, 2H, J¼7.6 Hz), 7.56 (t, 1H, J¼7.6 Hz),
7.44 (t, 2H, J¼7.6 Hz), 5.23–5.33 (m, 1H), 4.99 (td, 1H,
J¼8.2, 4.3 Hz), 3.49–3.67 (m, 2H), 3.40 (td, 1H, J¼8.2,
4.3 Hz), 1.97–2.14 (m, 2H), 2.25–2.45 (m, 2H), 1.15–1.85
(m, 11H). 13C NMR (75 MHz, CDCl3): d 15.0, 21.0, 25.3,
27.4, 28.2, 30.5, 39.6, 71.5, 119.9, 128.8, 129.8, 130.7,
133.4, 166.2. [a]2D0 +21.5 (c 0.5, CHCl3). MS (EI): m/z 258
(M++1, 4), 123 (71), 105 (100), 77 (11). HRMS calcd for
C16H20NO2: 258.1494, found: 258.1493. HPLC (Chiralpak
AD, 2-propanol/hexane 5:95, flow 0.5 mL/min, T¼30 ꢂC):
tR¼7.1 min (major) and 7.9 min (minor).
4.2.7. (1R,2S)-Tetral-1,2-diol [(1R,2S)-14]. From 2-acetoxy-
tetral-1-one (ꢀ)-13 (408 mg, 2 mmol) and following mod-
ified method B (2 mmol haloketone/4 mL 1.2:1 HCO2H/
Et3N mixture) with (S,S)-I as the catalyst, after 2 days the re-
action was elaborated as described. The residue was dissolved
in MeOH (6 mL), treated with NaOH 1 M (4 mL), stirred for
15 min, neutralized with HCl (1 N), diluted with H2O, and ex-
tracted with CH2Cl2 (3ꢁ15 mL). Flash chromatography (1:1
EtOAc/hexane) afforded (1R,2S)-14 (260 mg, 80%, 94% de,
4.3. General method for the synthesis of amines (19–21
and 27–28) and benzamides (22–24 and 29–30)
1
92% ee) as a white solid: H NMR (400 MHz, CDCl3):
d 1.88 (m, 1H), 2.00 (m, 1H), 2.57 (d, 2H, J¼
5.2 Hz), 2.76 (ddd, 1H, J¼17.2, 9.6, 6.4 Hz), 2.94 (dt, 1H,
J¼17.2, 5.6 Hz), 3.97 (m, 1H), 4.66 (t, 1H, J¼5.2 Hz),
7.08–7.40 (m, 4H). 13C NMR (75 MHz, CDCl3): d 26.4,
27.2, 69.8, 70.2, 126.7, 128.4, 128.9, 130.2, 136.5, 136.6.
[a]2D0 ꢃ23.8 (c 0.96, CHCl3) [lit.22: [a]2D5 ꢃ38.0 (c 0.9,
CHCl3, >98% ee)]. MS (EI): m/z 164 (M+, 18), 147 (76),
118 (100). HRMS calcd for C10H12O2: 164.0837, found:
164.0832. Anal. calcd for C10H12O2: C 73.15, H 7.37; found:
C 73.03, H 7.10. HPLC (Chiralcel OK, 2-propanol/hexane
5:95, flow 1.5 mL/min, T¼30 ꢂC): tR 11.0 min (major) and
13.90 min (minor).
Method A. Diphenyl phosphoryl azide (1.2 equiv) was added
to a solution of the alcohol in dry toluene ([alcohol]¼0.7–
1.2 M) under argon. The reaction mixture was cooled at
0 ꢂC, stirred for 10 min, and DBU (1.2 equiv) was added
slowly over 20 min. The mixture was stirred 2 h at 0 ꢂC,
then for 20 h at rt, and the solvent was removed in vacuo.
The residue was dissolved in a 1:1 EtOAc/hexane mixture,
filtered through a short silica pad, concentrated, dissolved
in dry THF ([azide]z0.5 M) and added dropwise to a sus-
pension of LiAlH4 (1.5 equiv) in dry THF. The reaction mix-
ture was stirred for 1 h at rt and heated to reflux for 2 h. After

R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
6761
cooling, the excess LiAlH4 was destroyed by slow addition
of 10:1 THF/H2O, filtered through Celite and concentrated
to dryness. Purification by flash chromatography afforded
the corresponding amine.
(100). HRMS m/z calcd for C10H13N: 147.1048, found:
147.1060.
4.3.2.1. N-Benzoyl derivative (1R,2S)-23. From
(1R,2S)-20 (16 mg, 0.1 mmol), the general procedure af-
forded (1R,2S)-23 (21 mg, 82%, 95% de, 97% ee) as a light
yellow solid. Mp 174–176 ꢂC. 1H NMR (300 MHz, CDCl3):
d 1.32 (d, 3H, J¼6.6 Hz), 2.35 (m, 1H), 2.60 (dd, 1H,
J¼15.6, 9.0 Hz), 3.12 (dd, 1H, J¼15.6, 7.8 Hz), 5.34 (t,
1H, J¼8.4 Hz), 6.28 (d, 1H, J¼8.4 Hz), 7.16–7.77 (m,
9H). 13C NMR (75 MHz, CDCl3): d 18.1, 38.5, 44.5, 61.3,
119.5, 123.0, 123.9, 124.7, 126.8, 126.9, 127.9, 128.6,
131.5, 134.5, 142.7, 143.3, 167.5. [a]2D0 +50.9 (c 0.6,
CHCl3). MS (EI): m/z 251 (M+, 25), 130 (100), 122 (30),
105 (55). HRMS m/z calcd for C17H27NO: 251.1310, found:
251.1305. HPLC (Chiralpak AD, 2-propanol/hexane 4:96,
flow 1.0 mL/min, T¼30 ꢂC): tR¼21.47 min.
Method B. The synthesis of the azide is as described for
method A. The crude azide was dissolved in dry THF ([azi-
de]z0.1 M), and Ph3P (1.2 equiv) and H2O (2 equiv) were
added. After refluxing overnight, the reaction mixture was
diluted with H2O and extracted with CH2Cl2. Purification
by flash chromatography afforded the corresponding amine.
For analytical purposes, the obtained amines were trans-
formed into the corresponding benzamides by conventional
benzoylation using benzoyl chloride (1.2 equiv) and Et3N
(1.2 equiv) in dry CH2Cl2.
Starting materials, method used for the synthesis, catalyst,
eluants, yields, and spectral and analytical data for com-
pounds 19–24 and 27–30 are as follows:
4.3.3. (3R,4R)-3-Methyl-4-aminochromane [(3R,4R)-21].
From (3S,4S)-9 (164 mg, 1 mmol) and following method
B, flash chromatography (20:1 CH2Cl2/MeOH) afforded
(3R,4R)-21 (110 mg, 84%, 92% de, 95% ee)27 as a light
4.3.1. (1R,2S)-2,6-Dimethyl-1-aminoindane [(1R,2S)-19].
From (1S,2S)-6 (324 mg, 2 mmol) and following method
B, the residue was purified by flash chromatography (20:1
CH2Cl2/MeOH) to afford (1R,2S)-19 (232 mg, 72%, >98%
1
yellow oil. H NMR (500 MHz, CDCl3): d 1.03 (d, 3H,
J¼6.5 Hz), 1.79–1.87 (m, 1H), 3.57 (d, 1H, J¼6.5 Hz),
3.86 (dd, 1H, J¼11.0, 7.0 Hz), 4.21 (dd, 1H, J¼11.0,
3.0 Hz), 6.78 (d, 1H, J¼8.0 Hz), 6.89 (t, 1H, J¼8.0 Hz),
7.13 (t, 1H, J¼8.0 Hz), 7.35 (d, 1H, J¼8.0 Hz). 13C NMR
(125 MHz, CDCl3): d 14.9, 36.0, 52.3, 68.5, 116.6, 120.6,
126.0, 128.3, 129.0, 154.1. [a]2D0 ꢃ3.0 (c 0.6, CHCl3). MS
(CI): m/z 162 (M+ꢃ1, 5), 147 (56). HRMS calcd for
C10H14NO: 164.1075, found: 164.1077. HPLC (Chiralpak
AD, 2-propanol/hexane 4:96, flow 1.0 mL/min, T¼30 ꢂC):
tR¼21.47 min.
1
de, 97% ee)27 as a light yellow solid. Mp 89–91 ꢂC. H
NMR (500 MHz, CDCl3): d 1.24 (d, 3H, J¼6.5 Hz), 1.72
(br s, 2H), 1.98 (m, 1H), 2.34 (s, 3H), 2.42 (dd, 1H,
J¼15.5 Hz, 9.5 Hz), 2.98 (dd, 1H, J¼15.5 Hz, 7.5 Hz),
3.74 (d, 1H, J¼8.5 Hz), 6.99 (d, 1H, J¼7.5 Hz), 7.05 (d,
1H, J¼7.5 Hz), 7.12 (s, 1H). 13C NMR (125 MHz, CDCl3):
d 17.7, 21.4, 38.2, 47.2, 64.1, 123.9, 124.2, 127.9, 136.1,
139.1, 147.4. [a]2D0 +3.5 (c 0.9, CHCl3). MS (CI): m/z 161
(M+, 17), 160 (51), 145 (100), 144 (72). HRMS m/z calcd
for C11H14N: 160.1126, found: 160.1134.
4.3.3.1. N-Benzoyl derivative (3R,4R)-24. From
(3R,4R)-21 (29 mg, 0.18 mmol), the general procedure af-
forded (3R,4R)-24 (40 mg, 83%, 92% de, 95% ee) as a white
solid. Mp 224–226 ꢂC. 1H NMR (400 MHz, CDCl3): d 1.10
(d, 3H, J¼7.2 Hz), 2.16–2.26 (m, 1H), 3.98 (dd, 1H,
J¼11.2, 7.2 Hz), 4.19 (dd, 1H, J¼11.2, 3.2 Hz), 5.06 (t, 1H,
J¼7.2 Hz), 6.26 (d, 1H, J¼8.0 Hz), 6.84 (d, 1H, J¼8.0 Hz),
6.90 (t, 1H, J¼7.2 Hz), 7.18 (t, 1H, J¼8.0 Hz), 7.22 (t, 1H,
J¼7.2 Hz), 7.43 (t, 2H, J¼7.6 Hz), 7.51 (t, 1H, J¼7.6 Hz),
7.78 (d, 2H, J¼7.6 Hz). 13C NMR (100 MHz, CDCl3):
d 14.5, 33.8, 50.5, 69.0, 116.9, 121.1, 121.7, 127.0, 128.7,
129.2, 129.5, 131.8, 134.2, 154.8, 167.2. [a]2D0 ꢃ3.0 (c 0.6,
CHCl3). MS (CI): m/z 267 (M+, 13), 147 (100), 122 (45).
HRMS m/z calcd for C17H18NO2: 268.1338, found:
268.1328. HPLC (Chiralpak AD, 2-propanol/hexane 4:96,
flow 1.0 mL/min, T¼30 ꢂC): tR¼21.47 min.
4.3.1.1. N-Benzoyl derivative (1R,2S)-22. From
(1R,2S)-19 (18 mg, 0.11 mmol), the general procedure af-
forded (1R,2S)-22 (25 mg, 86%, >98% de, 97% ee) as light
yellow solid. Mp 157–159 ꢂC. 1H NMR (300 MHz, CDCl3):
d 1.30 (d, 3H, J¼6.6 Hz), 2.25–2.40 (m, 4H), 2.55 (dd, 1H,
J¼15.6 Hz, 9.0 Hz), 3.07 (dd, 1H, J¼15.6 Hz, 7.8 Hz),
5.30 (t, 1H, J¼8.7 Hz), 6.25 (d, 1H, J¼8.7 Hz), 7.02–7.83
(m, 8H). 13C NMR (75 MHz, CDCl3): d 18.5, 21.5, 38.4,
45.0, 61.6, 124.8, 127.2, 128.9, 129.0, 131.9, 134.8, 136.9,
139.9, 143.7, 167.8. [a]2D0 +37.5 (c 0.5, CHCl3). MS (EI):
m/z 266 (M++1, 28), 265 (20), 144 (100), 105 (53). HRMS
m/z calcd for C18H20NO: 266.1545, found: 266.1550. HPLC
(Chiralpak AD, 2-propanol/hexane 4:96, flow 1.0 mL/min,
T¼30 ꢂC): tR¼11.15 min (minor) and 14.88 min (major).
cis Diastereomers tR¼22.64 min.
4.3.4. (1R,2R)-2-Fluoro-1-aminoindane [(1R,2R)-27].
From (1S,2R)-2-fluoroindan-1-ol [(1S,2R)-25]20 (152 mg,
1 mmol) and following method B, flash chromatography
(40:1/20:1 CH2Cl2/MeOH) afforded (1R,2R)-27 (106 mg,
70%, >98% de, 95% ee)27 as a brown oil. 1H NMR
(500 MHz, CDCl3): d 1.65 (br s, 2H), 3.04 (m, 1H), 3.32
(m, 1H), 4.43 (dd, 1H, JH,F¼18.5 Hz, J¼5.5 Hz), 4.95
(ddd, 1H, JH,F¼53.5 Hz, J¼11.5, 5.5 Hz), 7.20 (d, 1H,
J¼5.5 Hz), 7.23–7.27 (m, 2H), 7.33 (d, 1H, J¼5.5 Hz).
13C NMR (125 MHz, CDCl3): d 36.6 (d, JC,F¼22 Hz),
62.0 (d, JC,F¼23 Hz), 101.7 (d, JC,F¼184 Hz), 124.0,
125.0, 127.5, 128.3, 138.1, 142.7. 19F NMR (377 MHz,
4.3.2. (1R,2S)-2-Methyl-1-aminoindane [(1R,2S)-20].
From (1S,2S)-7 (294 mg, 2 mmol) and following method
B, purification by flash chromatography (20:1 CH2Cl2/
MeOH) afforded (1R,2S)-20 (216 mg, 74%, 95% de, 97%
1
ee)27 as a light yellow oil. H NMR (300 MHz, CDCl3):
d 1.27 (d, 3H, J¼6.6 Hz), 1.60 (br s, 2H), 1.97 (m, 1H),
2.48 (dd, 1H, J¼15.6, 9.3 Hz), 3.02 (dd, 1H, J¼15.6,
7.8 Hz), 3.78 (d, 1H, J¼8.1 Hz), 7.13–7.30 (m, 4H). 13C
NMR (75 MHz, CDCl3): d 17.9, 38.8, 47.3, 64.4, 123.5,
124.7, 126.7, 127.4, 142.4, 147.6. [a]2D0 +17.5 (c 0.5,
CHCl3). MS (CI): m/z 147 (M+, 25), 146 (45), 130

6762
R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
CDCl3): d ꢃ107.5. [a]D20 +3.5 (c 0.9, CHCl3). MS (CI): m/z
152 (M++1, 21), 151 (M+, 35), 132 (100). HRMS m/z calcd
for C9H9NF: 150.0719, found: 150.0718.
Junta de Andalucıa (grant 2005/FQM-658) for financial sup-
port. Bayer CropScience is gratefully acknowledged for pre-
doctoral fellowships to A.R. and A.M. and for the donation
of chemicals.
ꢀ
4.3.4.1. N-Benzoyl derivative (1R,2R)-29. From
(1R,2R)-27 (15 mg, 0.10 mmol), the general procedure af-
forded (1R,2R)-29 (19 mg, 86%, >98% de, 95% ee) as a light
yellow solid. Mp 157–159 ꢂC. 1H NMR (500 MHz, CDCl3):
d 3.17 (m, 1H), 3.40 (m, 1H), 5.30 (ddt, 1H, JH,F¼51.5 Hz,
J¼6.0, 3.5 Hz), 5.67 (ddd, 1H, JH,F¼18.0 Hz, J¼7.5,
3.5 Hz), 6.27 (br s, 1H), 7.27 (d, 2H, J¼7.0 Hz), 7.30 (d,
1H, J¼6.5 Hz), 7.34 (d, 1H, J¼7.5 Hz), 7.41 (t, 2H,
J¼7.5 Hz), 7.49 (t, 1H, J¼7.5 Hz), 7.76 (d, 2H, J¼7.5 Hz).
13C NMR (125 MHz, CDCl3): d 37.4 (d, JC,F¼23 Hz), 60.6
(d, JC,F¼28 Hz), 98.2 (d, JC,F¼186 Hz), 124.9, 125.3,
127.1, 127.8, 128.6, 129.1, 131.8, 133.9, 139.3, 139.8,
167.5. 19F NMR (377 MHz, CDCl3): d ꢃ103.4. [a]2D0 +37.5
(c 0.5, CHCl3). MS (EI): m/z 257 (M++2, 11), 256 (M++1,
64), 235 (75), 105 (100). HRMS m/z calcd for C16H15NOF:
256.1138, found: 256.1133. HPLC (Chiralpak AD, 2-propa-
nol/hexane 10:90, flow 1.0 mL/min, T¼30 ꢂC): tR¼
15.22 min (minor) and 18.42 min (major).
References and notes
1. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069; (b)
Brunel, J. M. Recent Res. Dev. Org. Chem. 2003, 7, 155; (c)
Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195.
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Jpn. 1995, 68, 36; (b) Ratovelomanana-Vidal, V.; Genet, J.-P.
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A. B. E.; Backwall, J.-E. Chem. Soc. Rev. 2001, 30, 321; (d)
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3. Noyori, R.; Ikeda, T.; Ohkuma, M.; Widhalm, M.; Kitamura,
H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.;
Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134.
^
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4. (a) Genet, J. P.; Mallart, S.; Juge, S. French Patent, 8911159,
^
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1989; (b) Genet, J. P.; Pinel, C.; Mallart, S.; Juge, S.;
Thorimbert, S.; Laffite, J. A. Tetrahedron: Asymmetry 1991,
2, 555.
4.3.5. (1R,2R)-2-Fluoro-1-aminotetraline [(1R,2R)-28].
From (1S,2R)-2-fluorotetral-1-ol [(1S,2R)-26]20 (166 mg,
1 mmol) and following method B, flash chromatography
(40:1/20:1 CH2Cl2/MeOH) afforded (1R,2R)-28 (122 mg,
74%, >98% de, 97% ee)27 as a brown oil. 1H NMR
(500 MHz, CDCl3): d 1.89 (br s, 2H), 2.04 (m, 1H), 2.23 (m,
1H), 2.87 (m, 1H), 2.95 (m, 1H), 4.04 (dd, 1H, JH,F¼14.0 Hz,
J¼6.0 Hz), 4.57 (dm, 1H, JH,F¼50.0 Hz), 7.08 (d, 1H,
J¼7.5 Hz), 7.17 (t, 1H, J¼7.5 Hz), 7.22 (t, 1H, J¼7.5 Hz),
7.54 (d, 1H, J¼7.5 Hz). 13C NMR (125 MHz, CDCl3):
d 26.4, 26.6 (d, JC,F¼29 Hz), 54.7 (d, JC,F¼22 Hz), 94.0 (d,
JC,F¼172 Hz), 126.6, 127.2, 127.7, 128.3, 138.2. 19F NMR
(377 MHz, CDCl3): d ꢃ110.8. [a]2D0 +3.5 (c 0.9, CHCl3).
HRMS m/z calcd for C10H13NF: 166.1032, found: 166.1030.
5. Reviews: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997,
30, 97; (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry
1999, 10, 2045; (c) Clapham, S. E.; Hadzovic, A.; Morris,
R. H. Coord. Chem. Rev. 2004, 248, 2201; (d) Gladiali, S.;
Alberico, E. Chem. Soc. Rev. 2006, 35, 226.
6. (a) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori,
R. J. Org. Chem. 1996, 61, 4872; (b) Matsumoto, T.; Murayama,
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(c) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem.
Soc. 2000, 122, 6510; (d) Ohkuma, T.; Hattori, T.; Ooka, H.;
Inoue, T.; Noyori, R. Org. Lett. 2004, 6, 2681; (e) Ohkuma,
T.; Li, J.; Noyori, R. Synlett 2004, 1383.
7. Alcock, N. J.; Mann, I.; Peach, P.; Wills, M. Tetrahedron:
Asymmetry 2002, 13, 2485.
8. Vaccaro, W.; Amore, C.; Berger, J.; Burrier, R.; Clader, J.;
Davis, H.; Domalski, M.; Fevig, T.; Salisbury, B.; Sher, R.
J. Med. Chem. 1996, 39, 1704.
4.3.5.1. N-Benzoyl derivative (1R,2R)-30. From
(1R,2R)-28 (14 mg, 0.08 mmol), the general procedure af-
forded (1R,2R)-30 (18 mg, 84%, >98% de, 97% ee) as white
solid. Mp 157–159 ꢂC. 1H NMR (500 MHz, CDCl3): d 2.13
(m, 1H), 2.21 (m, 1H), 2.85 (dt, 1H, J¼17.0, 6.0 Hz), 3.03
(dt, 1H, J¼17.0, 8.0 Hz), 5.00 (ddd, 1H, JH,F¼53.5 Hz,
J¼7.0, 2.5 Hz), 5.45 (m, 1H), 6.28 (d, 1H, J¼7.0 Hz), 7.14
(d, 1H, J¼7.0 Hz), 7.21 (m, 2H), 7.30 (d, 1H, J¼7.0 Hz),
7.41 (t, 2H, J¼7.5 Hz), 7.49 (t, 1H, J¼7.5 Hz), 7.76 (d, 2H,
J¼7.5 Hz). 13C NMR (100 MHz, CDCl3): d 24.9 (d,
JC,F¼8 Hz), 25.6 (d, JC,F¼20 Hz), 51.8 (d, JC,F¼27 Hz),
89.5 (d, JC,F¼176 Hz), 126.8, 126.9, 127.8, 128.5, 128.6,
129.1, 131.7, 133.4, 133.9, 136.0, 167.0. 19F NMR
(377 MHz, CDCl3): d ꢃ108.5. [a]2D0 +37.5 (c 0.5, CHCl3).
MS (CI): m/z 270 (M++1, 82), 250 (100), 249 (61), 105
(81). HRMS m/z calcd for C17H17NOF: 270.1294, found:
270.1294. HPLC (Chiralpak AD, 2-propanol/hexane 10:90,
flow 1.0 mL/min, T¼30 ꢂC): tR¼15.29 min (minor) and
21.61 min (major).
9. Shepherd, T. A.; Aikins, J. A.; Bleakman, D.; Cantrell, B. E.;
Rearick, J. P.; Simon, R. L.; Smith, E. C. R.; Stephenson,
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K.; Deverill, M.; Kamboj, R. K. J. Med. Chem. 2002, 45, 2101.
10. (a) Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner,
D.; Goldenberg, W.; Miskolczi, I.; Molnar, S.; Rantal, F.;
Tamas, T.; Toth, G.; Zagyva, A.; Zekany, A.; Lavian, G.;
Gross, A.; Friedman, R.; Razin, M.; Huang, W.; Krais, B.;
Chorev, M.; Youdim, M. B.; Weinstock, M. J. Med. Chem.
2002, 45, 5260; (b) Glezer, S.; Finberg, J. P. M. Eur. J.
Pharmacol. 2003, 472, 173; (c) Am, O. B.; Amit, T.;
Youdim, M. B. H. Neurosci. Lett. 2004, 355, 169; (d)
Bonneh-Barkay, D.; Ziv, N.; Finberg, J. P. M.
Neuropharmacology 2005, 48, 406; (e) Abu-Raya, S.;
Blaugrund, E.; Trembovler, V.; Lazarovici, P. Drug Dev. Res.
2000, 50, 285.
11. (a) Hartmann, S.; Ullrich, S.; Hupfer, C.; Frahm, A. W. Eur. J.
Med. Chem. 2000, 35, 377; (b) Grisar, J. M.; Claxton, G. P.;
Carr, A. A.; Wiech, N. L. J. Med. Chem. 1973, 16, 679.
ꢀ
Acknowledgements
12. Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Fernandez, R.;
Lassaletta, J. M. Adv. Synth. Catal. 2005, 347, 591.
13. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 23, 1977.
ꢀ
We thank the Spanish ‘Ministerio de Ciencia y Tecnologıa’
(grants CTQ2004-00290 and CTQ2004-00241) and the

R. Fernaꢀndez et al. / Tetrahedron 63 (2007) 6755–6763
6763
14. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886.
15. (a) Ohkuma, T.; Noyori, R. Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 1, Chapter 6.1; Reviews, see:
Ref. 5a,b and (b) Palmer, M. J.; Wills, M. Tetrahedron:
Asymmetry 1999, 10, 2045.
21. The absolute configuration of (1S,2R)-12 was assigned by
comparison of its optical rotation with literature data
[(1S,2R)-12 had [a]D20 ꢃ46.5 (c 0.8, CHCl3); lit. [a]2D5 ꢃ48.0
(CHCl3): Boyd, D. R.; Sharma, N. D.; Bowers, N. I.;
Goodrich, P. A.; Groocock, M. R.; Blacker, A. J.; Clarke,
D. A.; Howard, T.; Dalton, H. Tetrahedron: Asymmetry 1996,
6, 1559].
16. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521.
22. The absolute configuration of (1R,2S)-14 was assigned by com-
parison of its optical rotation with literature data [(1R,2S)-14
had [a]2D0 ꢃ23.8 (c 0.96, CHCl3); lit.21 [a]2D5 ꢃ38.0 (c 0.9,
CHCl3, >98% ee)].
23. The absolute configuration of (1R,2R)-17 was assigned by
comparison of its optical rotation with literature data
[(1R,2R)-17 had [a]2D0 ꢃ106.1 (c 0.7, MeOH); lit. (1S,2S)-17
(de >98%, ee 96%) [a]2D0 +106.0 (c 0.2, MeOH): Nishiyama,
H.; Park, S.-B.; Itoh, K. Tetrahedron: Asymmetry 1992, 3,
1029].
17. The absolute configuration of (1S,2S)-7 was assigned by com-
parison of its optical rotation with literature data [(1S,2S)-7 had
[a]2D0 +40.5 (c 0.5, CHCl3) [lit. (1R,2R)-7 (>98% ee): [a]2D5
ꢃ38.0 (c 0.3, CHCl3)]: Bowers, N. I.; Boyd, D. R.; Sharma,
N. D.; Goodrich, P. A.; Groocock, M. R.; Blacker, A. J.;
Goode, P.; Dalton, H. J. Chem. Soc., Perkin Trans. 1 1999,
1453. The absolute configuration of (1S,2S)-6 was assigned
by analogy.
18. For a very recent study of the effect of pH in asymmetric trans-
fer hydrogenation of ketones in aqueous media, see: Wu, X.;
Li, X.; King, F.; Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407.
19. The absolute configuration of (1S,2S)-8 was assigned by com-
parison of its optical rotation with literature data [(1S,2S)-8 had
[a]2D0 ꢃ43.7 (c 0.5, C6H6); lit.6d (1R,2R)-8 (97% de, 87% ee):
[a]2D0 +65.5 (c 2.1, C6H6)].
24. (a) Nishio, M.; Hirota, M. Tetrahedron 1989, 45, 7201; (b)
Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.;
Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron 2006,
62, 1864.
25. Haack, K.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 285.
26. Sengupta, S.; Mondal, S. Tetrahedron Lett. 1999, 40, 3469.
27. De and ee determinations were performed for the correspond-
ing benzamide derivatives.
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ꢀ
20. Ros, A.; Magriz, A.; Dietrich, H.; Fernandez, R.; Alvarez, E.;
Lassaletta, J. M. Org. Lett. 2006, 8, 127.