An efficient chemoenzymatic method to prepare optically active primary-tertiary trans-cycloalkane-1,2-diamines

Article abstract of DOI:10.1016/j.tet.2009.07.035

Optically active trans-N-Boc-cyclopentane- and cyclohexane-1,2-diamines (7) were prepared by a chemoenzymatic method from the corresponding (±)-trans-N,N-diallylcycloalkane-1,2-diamine. These mono-carbamates 7 (ee=99%) were used as the starting materials

Full text of DOI:10.1016/j.tet.2009.07.035

Tetrahedron 65 (2009) 8028–8034
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Tetrahedron
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An efficient chemoenzymatic method to prepare optically active primary–tertiary
trans-cycloalkane-1,2-diamines
a
b
a,
a,
*
*
´
´
F. Javier Quijada , Javier Gonzalez-Sabın , Francisca Rebolledo , Vicente Gotor
a
´
´
Departamento de Qu´ımica Organica e Inorganica, Universidad de Oviedo, 33071 Oviedo, Spain
b Entrechem, SL, Edificio Cient´ıfico-Tecnolo´gico, Campus de El Cristo, 33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active trans-N-Boc-cyclopentane- and cyclohexane-1,2-diamines (7) were prepared by a che-
moenzymatic method from the corresponding (ꢀ)-trans-N,N-diallylcycloalkane-1,2-diamine. These
mono-carbamates 7 (ee¼99%) were used as the starting materials in the syntheses of different vicinal
primary–tertiary diamines. Thus, by means of a simple three-step sequence involving a reductive-ami-
nation of an aromatic aldehyde with 7, N-methylation and finally, cleavage of the Boc group, several
trans-N-(arylmethyl)-N-methylcyclopentane- and cyclohexane-1,2-diamines were obtained in high
yields.
Received 26 May 2009
Accepted 16 July 2009
Available online 22 July 2009
Keywords:
Vicinal diamines
Lipase
Ó 2009 Elsevier Ltd. All rights reserved.
Aminolysis
1. Introduction
and cyclohexane-1,2-diamines have interesting applications in the
molecular recognition of carboxylic acids.8
The vicinal diamino grouping is the structural feature of many
natural products and therapeutical agents possessing a wide variety
of biological activities.1 In addition, optically active 1,2-diamines
and their derivatives have been extensively used in asymmetric
synthesis.2
The availability of the enantiopure C2-symmetric trans-cyclo-
hexane-1,2-diamine has motivated its inclusion in a vast number of
efficient catalysts and ligands.3,4 Thus, some N,N-dialkylcyclohexane-
1,2-diamines such as 1 (Fig. 1) and their thiourea derivatives 2 have
been used with prominent results in a range of nucleophile–elec-
trophile addition reactions.5–7 Moreover, we have shown that
bis(aminoamides) 3 derived from N-benzyl-N-methylcyclopentane-
The relevance of these optically active cycloalkane-1,2-diamine
derivatives has motivated to the organic chemists to continue de-
veloping new and efficient methods for their preparation. In this
regard, we have recently reported a chemoenzymatic protocol to
prepare some enantioenriched trans-N,N-dialkylcyclohexane- and
cyclopentane-1,2-diamines.9,10 The method, summarized in
Scheme 1, consists of: (1) opening of the corresponding cycloalkene
oxide with the required secondary amine, (2) stereospecific trans-
formation of the racemic trans-2-(N,N-dialkylamino)cycloalkanol
into the racemic trans-diamine and (3) enzymatic kinetic resolution
of the diamine. Although, in general, yields of either the racemic
and the optically active compounds were high, the method re-
quired the enzymatic resolution of each N,N-disubstituted diamine,
the efficacy of this resolution step strongly depending on the sub-
stituents on the nitrogen atom. Moreover, when the diamine bears
H
O
O
S
N
R2
N
R
N
NH
N
HN
N
NH
R
( )n
OH
NHR1R2
(1)
1) MsCl; 2) NH3 aq
(2)
n( )
R1
n( )
n( )
n = 1, 2
NH2
NR1R2
O
NH2
N
R1
NR1R2
Ph
Ph
R1 = alkyl,
n = 1, 2
3
( )
1
R
2 = aryl or alkyl
2
CAL-B
AcOEt
(3)
NH2
NHAc
n( )
n( )
n( )
+
Figure 1. Optically active trans-cycloalkane-1,2-diamine derivatives.
NR1R2
NR1R2
(1S,2S)
(1R,2R)
( )
* Corresponding authors. Tel./fax: þ34 985103448 (V.G.).
Scheme 1. Chemoenzymatic preparation of optically active trans-N,N-dialkylcycloalkane-
1,2-diamines.
E-mail addresses: frv@uniovi.es (F. Rebolledo), vgs@fq.uniovi.es (V. Gotor).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.035

F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
8029
a bulky substituent such as 9-antrylmethyl, the yield of the racemic
diamine was only moderate.11
Continuing with our research about new receptors based on
trans-cycloalkane-1,2-diamines and analogous to 3 (Fig. 1), we felt
the necessity of developing an alternative via to prepare optically
acetate or 1-phenylethyl acetate13 as acyl donors (Table 1, entries 2
and 3). In both reactions acetamide 5 was isolated with ee¼99%.
Nevertheless, in order to prepare higher amounts of (1R,2R)-5, the
reaction employing ethyl acetate as the acyl donor (entry 2) should
be advisable since the non-reacted ethyl acetate and the produced
ethanol are eliminated easier than 1-phenylethyl acetate and 1-
phenylethanol, which are present in the reaction mixture of
entry 3.
Transformation of (1S,2S)-6 into the required optically active
trans-N-Boc-cyclohexane-1,2-diamine [(1S,2S)-7b] was easily ac-
complished by the selective removing of the allyl groups in the
presence of a Pd(0) catalyst and N,N0-dimethylbarbituric acid
(NDMBA) as allyl group scavenger (Scheme 2).15 Thus, from this
process, the mono-Boc derivative (1S,2S)-7b was obtained with 81%
yield. Comparison of the sign of the optical rotation of this com-
pound (1S,2S)-7b (see Experimental section) with that of a com-
mercial sample16 allowed us to assign the configuration of the
compounds isolated in the enzymatic reaction, thus corroborating
that the lipase preferentially catalyzed the acylation of the (1R,2R)
enantiomer of the diamine. Similarly to the transformation of
(1S,2S)-6 into (1S,2S)-7b, the mono-Boc-carbamate (1R,2R)-7b
could be prepared if acetamide (1R,2R)-5 (ee¼99%; Table 1, entry 2)
is previously transformed into (1R,2R)-6 (acidic hydrolysis of the
amide function and subsequent tert-butoxycarbonylation of the
resulting diamine).12 It is of note the importance of this chemo-
enzymatic method because it allows easily to access to both en-
antiomers of compound 7b, which has proved synthetic interest.17
active
trans-N-(arylmethyl)-N-methylcycloalkane-1,2-diamines,
avoiding the enzymatic resolution of each diamine. For this pur-
pose, a common optically active precursor would be desirable.
Thus, we envisioned that the mono-Boc-carbamate of the corre-
sponding trans-cycloalkane-1,2-diamine would be an interesting
precursor of these primary–tertiary diamines. Herein, we wish to
report the chemoenzymatic preparation of trans-N-Boc-cyclohexane-
1,2-diamine as well as our results about the new synthetic protocol
towards primary–tertiary trans-cycloalkane-1,2-diamines.
2. Results and discussion
2.1. Chemoenzymatic preparation of optically active trans-N-
Boc-cyclohexane-1,2-diamine
Recently, we have developed an excellent method to obtain both
enantiomers of trans-cyclopentane-1,2-diamine protected as its
mono-Boc-carbamate from optically active trans-N,N-diallyl-
cyclopentane-1,2-diamine, which in turn was prepared such as
described in Scheme 1.12 The high efficacy of this method as well as
the high cost of the recently available optically active trans-N-Boc-
cyclohexane-1,2-diamine encouraged us to carry out the synthesis
of this derivative following the same strategy as for its cyclopentylic
analogue. Thus, racemic trans-N,N-diallylcyclohexane-1,2-diamine
(ꢀ)-4 (see Table 1) was obtained with very high yield (90%) from
the inexpensive cyclohexene oxide such as described in Scheme 1
[steps (1) and (2)]. Resolution of (ꢀ)-4 was accomplished by en-
zymatic acetylation catalyzed by the lipase B from Candida ant-
arctica (CAL-B). Several combinations of acylating agent and solvent
were tested and the results are collected in Table 1. In all cases the
enzyme catalyzed the acetylation of the diamine. In order to facil-
itate the separation of the produced acetamide 5 and the remaining
substrate 4, the reaction crude was treated with tert-butyl pyro-
carbonate. Thus, the remaining diamine 4 was transformed into the
Boc-carbamate and then, the resulting mixture of carbamate 6 and
acetamide 5 was easily separated by flash chromatography.
NHBoc
NH2
NHBoc
Pd(PPh3)4
NDMBA
Toluene
N
(1S,2S)-6
(1S,2S)-7b
Scheme 2. Pd-catalyzed deallylation of (1S,2S)-6.
2.2. Syntheses of (1S,2S)-N-(arylmethyl)-N-
methylcycloalkane-1,2-diamines
With both optically active mono-Boc derivatives (1S,2S)-7a,b in
hands, we attempted the preparation of the N-(arylmethyl)-
N-methylcycloalkane-1,2-diamines (Scheme 3 and Table 2). In this
regard, 1- and 2-naphthyl and 9-anthryl were chosen as aryl sub-
stituents since these units have been successfully incorporated in
the structure of many receptors of anions, amides and biologically
From the reaction using the simplest conditions, that is, ethyl
acetate as acyl donor and solvent (Table 1, entry 1), the remaining
substrate was isolated with very high ee. However, to obtain the
product with the same ee (99%), a more enantioselective reaction is
required. Consequently, we tested 1,4-dioxane as solvent and ethyl
Table 1
CAL-B catalyzed resolution of (ꢀ)-4
1) CAL-B, Solvent
28 °C, 200 rpm
2) (Boc)2O
NHAc
NH2
NHBoc
AcOR
+
+
N
N
N
( )-4
(1S,2S)-6
(1R,2R)-5
Entry
Acyl donor (AcOR)
Solvent
AcOEt
1,4-Dioxane
1,4-Dioxane
Time (h)
(1S,2S)-6
(1R,2R)-5
c
b (%)
Ec
Yielda (%)
eeS (%)
Yielda (%)
eeP (%)
1
2
3
AcOEt
71
68
96
44
99
95
70
49
92
99
99
52
49
41
125
>200
>200
AcOEtd
AcOCH(Ph)CH3
45
44
n.d.f
n.d.f
e
a
Isolated yields after flash chromatography.
Conversion degree: c¼eeS/(eeSþeeP).
b
c
Determined from eeS and eeP as in Ref. 14.
A molar ratio ester–diamine of 6:1 was used.
d
e
A molar ratio ester–diamine of 3:1 was used. Reaction was conducted to a small scale and yields of substrate and product were not determined (n.d.).

8030
F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
important species.18 Moreover, the anisotropy of these groups has
been also exploited to prepare efficient chiral solvating agents.19
Thus, diamines here prepared could be very useful for our objectives
related to the search of new compounds for the efficient and easy
determination of the enantiomeric excesses of carboxylic acids.8
were obtained in very high yields (93–99%). N-Methylation of 8–10
with methyl iodide was carried out at room temperature in pres-
ence of N,N-diisopropylethylamine. For this process, the choice of
methanol as the solvent was critical and justified by the proved
slow rate of the undesirable quaternation of the resulting tertiary
amine.20 In these conditions, the corresponding tertiary amino-
carbamates 11–13 were isolated in 79–95% yields. Finally, the Boc
group was easily removed with an 85% aqueous pyrophosphoric
solution using dichloromethane as solvent, the yields of this last
step being also very high (89–99%). It is worth noting that in this
three-step sequence a flash chromatography purification was only
required in the second step, compounds in purity states being
obtained in the first and last steps.
NHBoc
NH2
NHBoc
Ar
1) ArCHO
n( )
n( )
2) NaBH4
MeOH
N
H
(1S,2S)-7a,b
(1S,2S)-8a,b: Ar = 1-naphthyl
(1S,2S)-9a,b: Ar = 2-naphthyl
(1S,2S)-10a,b: Ar = 9-anthryl
NHBoc
Ar
NH2
3. Conclusions
MeI
Pri2NEt
MeOH
H3PO4
CH2Cl2
n( )
n( )
N
N
Ar
The chemoenzymatic preparation of optically active trans-
N-Boc-cyclohexane-1,2-diamine starting from commercially available
and inexpensive reagents has been carried out. This mono-carbamate
and its cyclopentylic analogous have been the key compounds
in the synthesis of several optically active trans-N-(arylmethyl)-
N-methylcyclopentane- and cyclohexane-1,2-diamines. The sim-
plicity and high efficacy of the method will allow its application in
the preparation of other primary–tertiary vicinal diamine derivatives.
(1S,2S)-11a,b Ar = 1-naphthyl (1S,2S)-14a,b
(1S,2S)-12a,b Ar = 2-naphthyl (1S,2S)-15a,b
(1S,2S)-13a,b
Ar = 9-anthryl (1S,2S)-16a,b
a: n = 1; b: n = 2
Scheme 3. Syntheses of (1S,2S)-N-(arylmethyl)-N-methylcycloalkane-1,2-diamines.
Table 2
4. Experimental section
4.1. General
Optically active diamines (1S,2S)-14–16 produced via Scheme 3
Entry
n
Ar
Diamine
Yielda
71
NH2
Lipase B from C. antarctica (Novozyme 435, available immobi-
lized on polyacrylamide, 7300 PLU/g) was gifted by Novo Nordisk
Co. For the enzymatic reactions, ethyl acetate of spectrophoto-
metric grade (stored with 4 Å molecular sieves), anhydrous 1,4-
dioxane and (ꢀ)-1-phenylethyl acetate were used. Melting points
were taken on samples in open capillary tubes and are uncorrected.
1H NMR and proton-decoupled 13C NMR spectra (CDCl3 solutions)
were obtained using AC-300 or DPX-300 (1H, 300.13 MHz and 13C,
75.5 MHz) and AV-400 MHz (1H, 400.13 MHz and 13C, 100.63 MHz)
1
1
1-Naphthyl
14a
14b
15a
15b
N
NH2
2
3
4
2
1
2
1-Naphthyl
2-Naphthyl
2-Naphthyl
75
80
85
N
NH2
spectrometers using the
d scale (ppm) for chemical shifts; calibra-
N
tion was made on the CDCl3 (13C; 76.95 ppm) or the residual CHCl3
(1H; 7.26 ppm) signals.
NH2
In Figure 2 we show the cyclohexylic compounds with the
numbering used in the assignation of the 1H NMR signals.
N
1
1
1
6
6
6
NHR
NHBoc
N
CH2Ar
NH2
N(Allyl)2
NH2
N
3
3
CH2Ar
3
2
2
2
R'
CH3
R = H, COCH3
R' = H or Me
N
5
1
2
9-Antryl
16a
16b
75
70
Figure 2. Cyclohexylic compounds.
4.2. Synthesis of racemic trans-N,N-diallylcyclohexane-1,2-
diamine ( )-4
NH2
N
6
9-Anthryl
Starting from cyclohexene oxide (9.4 mmol) and diallylamine
(13.2 mmol), and following the method described in Ref. 12, (ꢀ)-4
was prepared in 90% overall yield. Bp 67 ꢁC (0.1 mmHg). 1H NMR
a
(400 MHz):
d
(ppm)¼1.11 (m, 4H), 1.62 (m, 1H), 1.74 (m, 2H), 1.98 (m,
Overall yield of the three steps.
3
1H), 2.14 (br s, 2H, NH2), 2.25 (td, 1H, J1ax,2ax¼3J2ax,3ax¼11.2 Hz,
3
The synthetic sequence consisted of three steps: (1) reductive-
amination of an aromatic aldehyde, (2) methylation of a secondary
amine and (3) deprotection of the Boc group. At first, reductive-
amination step was accomplished by treatment of the desired ar-
omatic aldehyde with the corresponding aminocarbamate 7 in
methanol, and in situ reduction of the resulting imine with NaBH4.
From these reactions, the N-substituted aminocarbamates 8–10
3J2ax,3eq¼3.5 Hz, H-2), 2.61 (td, 1H, J1ax,2ax¼3J1ax,6ax¼11.2 Hz,
3J1ax,6eq¼4.2 Hz, H-1), 2.88 (dd, 2H, j Jj¼14.2 Hz, 3J¼7.8 Hz, N–CHH–
2
CH]CH2), 3.27 (ddt, 2H, j Jj¼14.2 Hz, 3J¼4.6 Hz, 4J¼1.2 Hz, N–CHH–
2
CH]CH2), 5.06 [ddt, 2H, 3Jcis¼10.3 Hz (d), j Jj¼2.0 Hz (d), 4J¼1.2 Hz
2
3
2
(t), ]CHH], 5.14 [ddt, 2H, Jtrans¼17.2 Hz (d), j Jj¼2.0 Hz (d),
4J¼1.2 Hz (t), ]CHH], 5.79 (dddd, 2H, 3J¼17.2, 10.3, 4.6 and 7.8 Hz,
HC]); 13C NMR (75.5 MHz):
d
(ppm)¼22.7 (CH2), 24.8 (CH2), 25.5

F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
8031
20
(CH2), 34.5 (CH2), 51.1 (CH), 52.4 (CH2), 65.0 (CH), 116.0 (CH2), 137.5
(CH). MS (ESI), m/z (%)¼195 [(MþH)þ,100]. Anal. Calcd for C12H22N2:
C, 74.17; H, 11.41; N, 14.42. Found: C, 74.02; H, 11.56; N, 14.21.
[a
]
þ30.8 (c 1.0, MeOH), ee¼99%, the value given in Ref. 21 for this
23
D
compound being [
a]
þ42.99 (c 0.98, MeOH), eeꢅ99%.
D
4.5. Reductive-amination of aromatic aldehydes with (1S,2S)-
4.3. Enzymatic resolution of ( )-4 (Table 1, entry 2)
7a,b. General procedure
To a mixture of (ꢀ)-4 (2.5 mmol) and CAL-B (250 mg) under
a nitrogen atmosphere, anhydrous 1,4-dioxane (11 mL) and ethyl
acetate (15 mmol) were added. The mixture was circularly shaken
at 28 ꢁC and 200 rpm for 68 h. After, the enzyme was filtered and
washed with Methanol. Once solvents were eliminated, the re-
action crude was dissolved in methanol (10 mL) and treated with
di-tert-butyl pyrocarbonate (1.1 equiv) After 6 h of reaction at room
temperature, solvents were eliminated and the crude submitted to
flash chromatography (a gradient of hexane–ethyl acetate 10:1 to
ethyl acetate was used as eluent) to yield pure acetamide (1R,2R)-5
and carbamate (1S,2S)-6.
The aromatic aldehyde (1.39 mmol) was added under a nitrogen
atmosphere to
a solution of the corresponding (1S,2S)-7
(1.39 mmol) in anhydrous methanol (5 mL). After 5 h stirring at
room temperature, sodium borohydride (2.1 mmol) was slowly
added in portions. After 12 h, the solvent was evaporated. Except
for 8a, the resulting crude was washed with water and dried under
reduced pressure to yield pure the corresponding aminocarbamate.
In the case of 8a, the crude was dissolved in CH2Cl2 and the organic
solution washed with water. The subsequent elimination of the
solvent yielded pure 8a.
4.5.1. (1S,2S)-tert-Butyl-N-{2-[(1-naphthylmethyl)amino]cyclopentyl}-
20
4.3.1. (1R,2R)-N-[2-(Diallylamino)cyclohexyl]acetamide [(1R,2R)-
carbamate [(1S,2S)-8a]. Yield: 98%; white foam, [
a
]
þ14.5 (c 1.0,
D
20
5]. Yield: 44%; white solid, mp: 103–104 ꢁC. [
a
]
ꢂ19.8 (c 1.0,
CHCl3), ee¼99%; 1H NMR (400 MHz):
(ppm)¼1.28–1.57 [mþs, 11H.
d
D
CHCl3), ee¼99%; 1H NMR (300 MHz):
d
(ppm)¼1.06 (qd, 1H, 3Jax,ax
¼
Singlet corresponds to tBu (1.46 ppm)],1.63 (m,1H), 1.72 (m, 1H), 1.97
j Jj¼12.3 Hz, 3Jax,eq¼3.5 Hz, Hax), 1.15 (m, 2H), 1.28 (m, 1H), 1.64 (m,
(m, 2H), 2.11 (m,1H), 2.95 (q,1H, 3J¼6.4 Hz, H-2), 3.83 (br m,1H, H-1),
2
2
1H),1.73 (m,1H),1.83 (m,1H),1.95 (s, 3H, CH3), 2.47 (m, 2H, H-2 and
AB system (dA¼4.24, dB¼4.27 j JA,Bj¼13.0 Hz, N–CH2–Ar), 4.78 (br s,
Heq), 2.85 (dd, 2H, j Jj¼14.3 Hz, 3J¼7.9 Hz, 2ꢃN–CHH–CH]CH2),
1H, NH), 7.42–7.54 (m, 4H), 7.75 (d, 1H, 3J¼8.1 Hz), 7.84 (d, 1H,
2
3.25 (m, 2H, 2ꢃN–CHH–CH]CH2), 3.51 (m, 1H, H-1), 5.07–5.19 (m,
3J¼8.1 Hz), 8.15 (d, 1H, 3J¼8.1 Hz); 13C NMR (100.6 MHz):
4H, 2ꢃ]CH2), 5.72 (m, 2H, 2ꢃHC]), 6.04 (br s, 1H, NH); 13C NMR
d
(ppm)¼21.3 (CH2), 28.2 (3ꢃCH3), 30.9 (CH2), 31.2 (CH2), 49.6 (CH2),
(75.5 MHz):
d
(ppm)¼23.3 (CH2), 23.4 (CH3), 24.5 (CH2), 25.3 (CH2),
57.4 (CH), 65.9 (CH), 78.7 (C), 123.5 (CH), 125.1 (CH), 125.2 (CH), 125.7
(CH), 125.8 (CH), 127.3 (CH), 128.3 (CH), 131.5 (C), 133.6 (C), 135.8 (C),
155.5 (C]O). MS (ESI), m/z (%)¼341 [(MþH)þ, 100]. Anal. Calcd for
C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found: C, 74.24; H, 8.47; N,
8.11.
32.7 (CH2), 50.8 (CH), 52.0 (CH2), 61.7 (CH), 116.5 (CH2), 137.0 (CH),
170.1 (C]O). MS (EI), m/z (%)¼236 (Mꢄþ, 2), 195 [(MꢂCH2–
CH]CH2)þ, 100]. Anal. Calcd for C14H24N2O: C, 71.14; H, 10.23; N,
11.85. Found: C, 70.98; H, 10.37; N, 11.95.
4.3.2. (1S,2S)-tert-Butyl-N-[2-(diallylamino)cyclohexyl]-carbamate
4.5.2. (1S,2S)-tert-Butyl-N-{2-[(1-naphthylmethyl)amino]cyclohexyl}-
20
[(1S,2S)-6]. Yield: 45%; white foam. [
a
]
þ16.4 (c 1.0, CHCl3),
carbamate [(1S,2S)-8b]. Yield: 99%; white solid, mp: 150–152 ꢁC.
D
20
ee¼95%; 1H NMR (300 MHz):
d
(ppm)¼0.93–1.27 (m, 4H), 1.43 (s,
[
d
a
]
þ31.4 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
D
9H, tBu), 1.60–1.91 (m, 3H), 2.37 (m, 2H), 2.84 (dd, 2H, j Jj¼14.0 Hz,
3J¼7.9 Hz, 2ꢃN–CHH–CH]CH2), 3.25 (m, 3H, H-1 and 2ꢃN–CHH–
CH]CH2), 5.00–5.24 (m, 5H, 2ꢃ]CH2 and NH), 5.72 (m, 2H,
(ppm)¼1.05–1.50 [mþs, 13H. Singlet corresponds to But
2
2
(1.40 ppm)],1.62–1.83 (m, 3H), 2.10 (br d,1H, j Jj¼11.0 Hz), 2.21 (br d,
1H, j Jj¼11.0 Hz), 2.34 (br t, 1H, J1ax,2ax¼3J2ax,3ax¼9.8 Hz, H-2), 3.35
2
3
2ꢃHC]); 13C NMR (75.5 MHz):
d
(ppm)¼20.5 (CH2), 24.6 (CH2),
(br m, 1H, H-1), 4.11 (d, 1H, j Jj¼12.9 Hz, N–CHH–Ar), 4.35 (d, 1H,
2
2
25.4 (CH2), 28.4 (3ꢃCH3), 33.4 (CH2), 51.7 (CH), 52.3 (CH2), 62.0
(CH), 78.7 (C), 116.4 (CH2), 137.3 (CH), 156.3 (C]O). MS (ESI), m/z
(%)¼295 [(MþH)þ, 100]. Anal. Calcd for C17H30N2O2: C, 69.35; H,
10.27; N, 9.51. Found: C, 69.12; H, 10.43; N, 9.30.
j Jj¼12.9 Hz, N–CHH–Ar), 4.53 (br s,1H, NH), 7.48 (m, 4H), 7.75 (d,1H,
3J¼8.1 Hz), 7.84 (d, 1H, 3J¼7.6 Hz), 8.14 (d, 1H, 3J¼8.1 Hz); 13C NMR
(75.5 MHz):
d
(ppm)¼24.5 (CH2), 24.6 (CH2), 28.2 (3ꢃCH3), 31.4 (CH2),
32.6 (CH2),,48.14 (CH2), 54.0 (CH), 60.74 (CH), 78.8 (C), 123.6 (CH),
125.1 (CH), 125.3 (CH), 125.8 (CH), 126.0 (CH), 127.5 (CH), 128.4 (CH),
131.6 (C), 133.6 (C), 136.1 (C), 155.8 (C]O). MS (ESI), m/z (%)¼355
[(MþH)þ, 100], 377 [(MþNa)þ, 54]. Anal. Calcd for C22H30N2O2: C,
74.54; H, 8.53; N, 7.90. Found: C, 74.31; H, 8.57; N, 7.66.
4.3.3. Determination of enantiomeric excesses of 5 and 6. Chiral
HPLC was used. Conditions: Chiralpak AS column (25 cmꢃ4.6 mm
i.d.), hexane–isopropyl alcohol (H/iPA) mixtures, T¼40 ꢁC. For
(ꢀ)-5: H/iPA 90:10; 0.8 mL/min; tR¼9.6 (R,R) and 13.9 (S,S) min;
RS¼2.8. For (ꢀ)-6: H/iPA 98:2; 0.3 mL/min; tR¼11.2 (R,R) and 12.2
(S,S) min; RS¼1.0.
4.5.3. (1S,2S)-tert-Butyl-N-{2-[(2-naphthylmethyl)amino]cyclopentyl}-
20
carbamate [(1S,2S)-9a]. Yield: 96%; white solid, mp: 112–114 ꢁC. [
a]
D
þ1.9 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
(ppm)¼1.23–1.50
d
4.4. (1S,2S)-tert-Butyl-N-(2-aminocyclohexyl)carbamate
(1S,2S)-7b
[mþs, 11H. Singlet corresponds to tBu (1.46 ppm)], 1.54–1.82 (m, 2H),
1.95 (mþbr s, 2H), 2.12 (m,1H), 2.85 (q,1H, 3J¼6.7 Hz, H-2), 3.78 (br m,
2
1H, H-1), 3.92 (d, 1H, j Jj¼12.0 Hz, N–CHH–Ar), 4.03 (d, 1H,
2
It was obtained from (1S,2S)-6 following the method described
in Ref. 12. Yield: 81% (purified by flash chromatography using
successively ethyl acetate and ethyl acetate–methanol 10:1 as el-
uents); cream solid, mp: 118–119 ꢁC. Spectral data are in good
agreement with those previously published.21
j Jj¼12.0 Hz, N–CHH–Ar), 4.51 (br s,1H, NH), 7.42–7.51 (m, 3H), 7.75 (s,
1H), 7.81 (m, 3H); 13C NMR (75.5 MHz):
d
(ppm)¼21.5 (CH2), 28.3
(3ꢃCH3), 31.1 (CH2), 31.5 (CH2), 52.0 (CH2), 57.6 (CH), 64.9 (CH), 79.1
(C), 125.3 (CH), 125.8 (CH), 126.3 (CH), 126.4 (CH), 127.4 (CH), 127.5
(CH), 127.8 (CH), 132.4 (C), 133.2 (C), 137.8 (C), 155.7 (C]O). MS (ESI),
m/z (%)¼341 [(MþH)þ, 100], 681 [(2MþH)þ, 18]. Anal. Calcd for
C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found: C, 73.92; H, 8.54; N, 8.01.
In order to establish the configuration of the compounds iso-
lated in the enzymatic reaction, the sign of the optical rotation of
20
(1S,2S)-7b ([
a]
þ25.8 (c 1.0, CHCl3), ee¼99%) was compared to
D
that reported in the Aldrich catalogue (see Ref. 16), good correlation
being observed between both values. However, when the optical
rotation was measured in methanol, the value obtained for our
compound differed of that reported in Ref. 21. Thus, for (1S,2S)-7b
4.5.4. (1S,2S)-tert-Butyl-N-{2-[(2-naphthylmethyl)amino]cyclohexyl}-
carbamate [(1S,2S)-9b]. Yield: 98%; white solid, mp: 229–231 ꢁC.
20
[
d
a
]
þ80.4 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
D
(ppm)¼1.10–1.40 (m, 4H), 1.47 (s, 9H), 1.69 (m, 2H), 1.84 (br s, 1H,

8032
F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
3
NH), 2.02–2.20 (m, 2H), 2.29 (td, 1H, J1ax,2ax¼3J2ax,3ax¼10.1 Hz,
(C), 133.7 (C), 134.8 (C), 155.5 (C]O). MS (ESI), m/z (%)¼355
[(MþH)þ, 100], 731 [(2MþNa)þ, 18]. Anal. Calcd for C22H30N2O2: C,
74.54; H, 8.53; N, 7.90. Found: C, 74.68; N, 8.69; N, 7.75.
3J2ax,3eq¼3.9 Hz, H-2), 3.37 (br m, 1H, H-1), 3.86 (d, 1H, j Jj¼13.4 Hz,
2
2
N–CHH–Ar), 4.07 (d, 1H, j Jj¼13.4 Hz, N–CHH–Ar), 4.50 (br s, 1H,
NH), 7.46 (m, 3H), 7.76 (s, 1H), 7.80 (m, 3H); 13C NMR (75.5 MHz):
d
(ppm)¼24.6 (CH2), 24.8 (CH2), 28.3 (3ꢃCH3), 31.6 (CH2), 32.8 (CH2),
4.6.2. (1S,2S)-tert-Butyl-N-{2-[(methyl)(1-naphthylmethyl)amino]-
20
50.4 (CH2), 54.2 (CH), 60.4(CH), 79.1 (C), 125.4 (CH), 125.8 (CH), 126.2
(CH), 126.5 (CH), 127.53 (CH), 127.56 (CH), 127.9 (CH), 132.5 (C), 133.3
(C),138.3 (C),156.0 (C]O). MS (ESI), m/z (%)¼355 [(MþH)þ,100], 377
[(MþNa)þ, 40]. Anal. Calcd for C22H30N2O2: C, 74.54; H, 8.53; N, 7.90.
Found: C, 74.37; H, 8.36; N, 8.07.
cyclohexyl}carbamate [(1S,2S2S)-11b]. Yield: 85%; white foam. [a]
D
þ15.5 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
(ppm)¼0.94 [qd,
d
2
3
1H, 3Jax,ax¼j Jj¼12.8 Hz (q), Jax,eq¼3.6 Hz (d), Hax], 1.03–1.50 [mþs,
12H. Singlet corresponds to iBu (1.41 ppm)], 1.64 (br d, 1H,
2
2
j Jj¼10.7 Hz), 1.81 (m, 1H), 1.99 (br d,1H, j Jj¼11.2 Hz), 2.22 (s, 3H, N–
CH3), 2.29 (td, 1H, J1ax,2ax¼3J2ax,3ax¼11.3 Hz, J2ax,3eq¼3.2 Hz, H-2),
3
3
2
2
4.5.5. (1S,2S)-tert-Butyl-N-{2-[(9-anthrylmethyl)amino]cyclopentyl}-
carbamate [(1S,2S)-10a]. Yield: 93%; yellow solid, mp: 145–146 ꢁC.
2.39 (brd,1H, j Jj¼12.3 Hz), 3.31 (m,1H, H-1), 3.94(d,1H, j Jj¼12.9 Hz,
2
N–CHH–Ar), 4.11 (d, 1H, j Jj¼12.9 Hz, N–CHH–Ar), 5.01 (br s,1H, NH),
20
[a
]
þ16.4 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
d
(ppm)¼
7.35–7.60 (m, 4H), 7.78 (m, 1H), 7.86 (d, 1H, 3J¼7.9 Hz), 8.23 (d, 1H,
D
t
1.23–1.55 [mþs, 11H. Singlet corresponds to Bu (1.37 ppm)], 1.63–
1.95 (m, 3H), 2.14 (m, 2H), 3.13 (q,1H, 3J¼6.3 Hz, H-2), 3.90 (br m,1H,
H-1), 4.54 (br s, 1H, NH), 4.78 (s, 2H, N–CH2–Ar), 7.40–7.60 (m, 4H),
8.00 (d, 2H, 3J¼8.3 Hz), 8.32–8.48 (m, 3H); 13C NMR (75.5 MHz):
3J¼7.9 Hz); 13C NMR (75.5 MHz):
(ppm)¼22.0 (CH2), 24.5 (CH2), 25.3
d
(CH2), 28.3 (3ꢃCH3), 33.1 (CH2), 35.8 (CH3), 51.6 (CH), 56.6 (CH2), 64.1
(CH), 78.5(C),124.3 (CH),125.0 (CH),125.6 (CH),125.9(CH),127.1 (CH),
127.9 (CH), 128.5 (CH), 132.3 (C), 133.8 (C), 134.8 (C), 156.1 (C]O). MS
(ESI), m/z (%)¼369 [(MþH)þ, 100], 391 [(MþNa)þ, 70]. Anal. Calcd for
C23H32N2O2: C, 74.96; H, 8.75; N, 7.60. Found: C, 75.19; H, 8.58; N, 7.35.
d
(ppm)¼21.6 (CH2), 28.3 (3ꢃCH3), 31.3 (CH2), 31.7 (CH2), 44.2 (CH2),
57.6 (CH), 66.5 (CH), 79.1 (C),124.1 (CH),124.8 (CH),125.9 (CH),127.0
(CH), 128.9 (CH), 130.1 (C), 131.4 (C), 155.7 (C]O). MS (ESI), m/z
(%)¼391 [(MþH)þ,100]. Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74;
N, 7.17. Found: C, 76.73; H, 7.95, N, 7.02.
4.6.3. (1S,2S)-tert-Butyl-N-{2-[(methyl)(2-naphthylmethyl)amino]-
20
cyclopentyl}carbamate [(1S,2S)-12a]. Yield: 86%; white foam. [a]
D
þ8.6 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
(ppm)¼1.30–1.90
d
4.5.6. (1S,2S)-tert-Butyl-N-{2-[(9-anthrylmethyl)amino]cyclohexyl}-
carbamate [(1S,2S)-10b]. Yield: 98%; yellow solid, mp: 176–177 ꢁC.
[mþs, 14H. Singlet corresponds to tBu (1.51 ppm)], 2.13 (m, 1H), 2.27
(s, 3H), 2.77 (br q, 1H, 3J¼6.9 Hz, H-2), 3.69 (d, 1H, j Jj¼13.2 Hz, N–
2
þ36.2 (c 1.0, CHCl3), ee¼99%; 1H NMR (400 MHz):
CHH–Ar), 3.78 (d, 1H, j Jj¼13.2 Hz, N–CHH–Ar), 3.99 (br m, 1H, H-1),
20
2
[
a
]
D
d
(ppm)¼1.15 (m, 1H), 1.27–1.42 [mþs, 11H. Singlet corresponds to
4.70 (br s, 1H, NH), 7.46 (m, 3H), 7.75 (s, 1H), 7.83 (m, 3H); 13C NMR
tBu (1.36 ppm)], 1.49 (m, 1H), 1.60–1.75 (m, 2H, Heq and NH), 1.82
(75.5 MHz):
d
(ppm)¼21.0 (CH2), 24.1 (CH2), 28.3 (3ꢃCH3), 31.9 (CH2),
2
2
(br d, 1H, j Jj¼11.7 Hz, Heq), 2.15 (br d, 1H, j Jj¼11.7 Hz, Heq), 2.35
38.0 (CH3), 52.6 (CH), 59.0 (CH2), 70.3 (CH), 78.9 (C),125.3 (CH),125.7
(CH),127.0 (2CH),127.5 (2CH),127.7 (CH),132.5 (C),133.1 (C),137.1 (C),
155.4 (C]O). MS (ESI), m/z (%)¼355 [(MþH)þ, 100], 709 [(2MþH)þ,
23]. Anal. Calcd for C22H30N2O2: C, 74.54; H, 8.53; N, 7.90. Found: C,
74.71; H, 8.72; N, 7.96.
(br d, 1H, j Jj¼12.7 Hz, Heq), 2.55 (td, 1H, 3J2ax,1ax¼3J2ax,3ax¼10.5 Hz,
2
3J2ax,3ec¼3.9 Hz, H-2), 3.38 (m, 1H, H-1), 4.58 (br s, 1H, NH), 4.62 (d,
2
2
1H, j Jj¼12.0 Hz, N–CHH–Ar), 4.80 (d, 1H, j Jj¼12.0 Hz, N–CHH–Ar),
7.42–7.58 (m, 4H), 7.99 (d, 2H, 3J¼8.8 Hz), 8.32 (d, 2H, 3J¼8.8 Hz),
8.39 (s, 1H); 13C NMR (75.5 MHz):
d
(ppm)¼24.7 (2ꢃCH2), 28.2
(3ꢃCH3), 31.6 (CH2), 32.7 (CH2), 42.1 (CH2), 53.7 (CH), 61.0 (CH),
79.0 (C), 124.0 (CH), 124.8 (CH), 126.0 (CH), 127.0 (CH), 129.0 (CH),
130.1 (C), 131.4 (C), 155.8 (C]O). MS (ESI), m/z (%)¼405 [(MþH)þ,
100]. Anal. Calcd for C26H32N2O2: C, 77.19; H, 7.97; N, 6.92. Found: C,
77.38; H, 8.16; N, 6.75.
4.6.4. (1S,2S)-tert-Butyl-N-{2-[(methyl)(2-naphthylmethyl)amino]cyclo-
20
hexyl}carbamate [(1S,2S)-12b]. Yield: 95%; white foam. [
a
]
þ20.2
D
(c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
d
(ppm)¼1.12–1.42 (m,
2
4Hax), 1.50 (s, 9H), 1.68 (br d, 1H, j Jj¼13.9 Hz, Heq), 1.84 (br d, 1H,
2
2
j Jj¼11.7 Hz, Heq),1.99 (br d,1H, j Jj¼12.6 Hz, Heq), 2.32 (s, 3H, N–CH3),
2
2.41 (m, 2H), 3.39 (m, 1H, H-1), 3.50 (d, 1H, j Jj¼13.3 Hz, N–CHH–Ar),
2
4.6. General procedure for the N-methylation of (1S,2S)-8–10
3.88 (d, 1H, j Jj¼13.3 Hz, N–CHH–Ar), 5.30 (br s, 1H, NH), 7.46 (m, 3H),
7.71 (s,1H), 7.82 (m, 3H); 13C NMR (75.5 MHz):
d
(ppm)¼22.7 (CH2), 24.6
To a solution of the corresponding aminocarbamate 8–10
(1.24 mmol) in anhydrous methanol (8 mL), methyl iodide
(1.49 mmol) was added. After 12 h stirring at room temperature,
N,N-diisopropylethylamine (1.24 mmol) and methyl iodide (two
successive additions of 0.62 mmol) were added under nitrogen
atmosphere and the mixture was stirred for another 20 h. Then, the
solution was evaporated to dryness, the crude was dissolved in
CH2Cl2 (15 ml) and washed with aqueous 3 N NaOH (2ꢃ15 ml) and
brine (10 ml). The organic layer was dried with Na2SO4, and evap-
orated under reduced pressure. The resulting crude was purified by
flash chromatography (mixtures of hexane–ethyl acetate).
(CH2), 25.4 (CH2), 28.5 (3ꢃCH3), 33.4 (CH2), 37.1 (CH3), 51.8 (CH), 56.8
(CH2), 65.9 (CH), 78.8 (C), 125.4. (CH), 125.8 (CH), 127.0 (2CH), 127.5
(2CH), 127.8 (CH), 132.7 (C), 133.3 (C), 137.4 (C), 156.1 (C]O). MS (ESI),
m/z (%)¼369 [(MþH)þ, 100], 759 [(2MþNa)þ, 18]. Anal. Calcd for
C23H32N2O2: C, 74.96; H, 8.75; N, 7.60. Found: C, 75.15; H, 8.49; N, 7.65.
4.6.5. (1S,2S)-tert-Butyl-N-{2-[(9-anthrylmethyl)-(methyl)amino]cyclo-
pentyl}carbamate [(1S,2S)-13a]. Yield: 82%; yellow solid, mp: 157–
20
158 ꢁC. [
d
a]
D
þ25.3 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
(ppm)¼1.20–1.50 [mþs, 10H. Singlet corresponds to tBu (1.45 ppm)],
1.53–1.90 (m, 4H), 2.18–2.30 [mþs, 4H. Singlet corresponds to N–CH3
(2.26)], 2.83 (m, 1H, H-2), 3.93 (m, 1H, H-1), 4.42–4.67 [m, 3H, AB
2
4.6.1. (1S,2S)-tert-Butyl-N-{2-[(methyl)(1-naphthylmethyl)amino]-
system corresponding to N–CH2–Ar (j Jj¼13.0 Hz) overlapped with
20
cyclopentyl}carbamate [(1S,2S)-11a]. Yield: 81%; white foam. [
a
]
NH], 7.40–7.57 (m, 4H), 8.01 (d, 2H, 3J¼8.2 Hz), 8.41 (s,1H), 8.49 (d, 2H,
D
þ10.2 (c 1.0, CHCl3), ee¼99%; 1H NMR (400 MHz):
d
(ppm)¼1.32–
3J¼9.0 Hz); 13C NMR (75.5 MHz):
(ppm)¼20.6 (CH2), 22.6 (CH2), 28.6
d
1.75 [mþs,14H. Singlet corresponds to tBu (1.46 ppm)], 2.16 (m,1H),
(3ꢃCH3), 31.3 (CH2), 36.6 (CH3), 51.0 (CH2), 52.4 (CH), 69.9 (CH), 78.9
(C), 124.75 (CH), 124.79 (CH), 125.6 (CH), 127.3 (CH), 128.9 (CH), 130.3
(C), 131.2 (C), 131.3 (C), 155.7 (C]O). MS (ESI), m/z (%)¼405 [(MþH)þ,
100]. Anal. Calcd for C26H32N2O2: C, 77.19; H, 7.97; N, 6.92. Found: C,
76.95; H, 8.19; N, 6.75.
2.25 (s, 3H, N–CH3), 2.81 (m, 1H, H-2), 3.95 (m, 1H, H-1), 3.95 (d, 1H,
2
2
j Jj¼13.1 Hz, N–CHH–Ar), 4.11 (d, 1H, j Jj¼13.1 Hz, N–CHH–Ar), 4.58
(br s, 1H, NH), 7.47 (m, 4H), 7.77 (d, 1H, 3J¼7.8 Hz), 7.85 (d, 1H,
3J¼7.8 Hz), 8.31 (d, 1H, 3J¼7.8 Hz); 13C NMR (100.6 MHz):
d
(ppm)¼20.6 (CH2), 22.6 (CH2), 28.3 (3ꢃCH3), 31.4 (CH2), 37.3
(CH3), 52.3 (CH), 57.7 (CH2), 70.0 (CH), 78.7 (C), 124.4 (CH), 125.0
(CH), 125.4 (CH), 125.6 (CH), 127.1 (CH), 127.7 (CH), 128.2 (CH), 132.2
4.6.6. (1S,2S)-tert-Butyl-N-{2-[(9-anthrylmethyl)(methyl)amino]cyclo-
20
hexyl}carbamate [(1S,2S)-13b]. Yield: 79%; yellow foam. [
a
]
þ54.3
D

F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
8033
(c 1.0, CHCl3), ee¼99%; 1H NMR (400 MHz):
d
(ppm)¼0.76 [qd, 1H,
(CH),126.7 (CH),127.2 (2CH),127.4 (CH),132.3 (C),133.0 (C),137.1 (C).
MS(EI), m/z (%)¼254 (Mꢄþ,12), 210 (17),170(59),141 (100). HRMS (EI)
calcd for C17H22N2 (Mꢄþ): 254.1783; found: 254.1783.
2
3Jax,ax¼j Jj¼13.2 Hz (q), 3Jax,eq¼3.7 Hz (d), Hax], 1.05–1.60 [mþs, 13H.
Singlet corresponds to But (1.37 ppm)], 1.81 (br d, 1H, j Jj¼11.0 Hz,
2
Heq), 2.12–2.25 (m, 2H), 2.28 (s, 3H, N-CH3), 2.35 (br d, 1H,
2
j Jj¼13.2 Hz, Heq), 3.24 (tt, 1H, 3J1ax,2ax¼3J1ax,6ax¼10.5 Hz,
4.7.4. (1S,2S)-N-Methyl-N-(2-naphthylmethyl)cyclohexane-1,2-di-
2
20
3J1ax,6eq¼3J1ax,NH¼3.9 Hz, H-1), 4.52 (d, 1H, j Jj¼13.0 Hz, N-CHH–Ar),
amine [(1S,2S)-15b]. Yield: 91%; white solid, mp: 91–93 ꢁC. [
a]
D
2
4.62 (d, 1H, j Jj¼13.0 Hz, N–CHH–Ar), 4.87 (br s, 1H, NH), 7.43–7.56
þ26.2 (c 1.0, CHCl3), ee¼99%; 1H NMR (400 MHz):
(ppm)¼1.08 (m,
d
3
(m, 4H), 8.01 (d, 2H, J¼8.6 Hz), 8.41 (m, 3H); 13C NMR (75.5 MHz):
1H), 1.19 (m, 3H), 1.65 (m, 1H), 1.72–2.03 [mþs, 5H. Singlet corre-
d
(ppm)¼23.0 (CH2), 24.4 (CH2), 25.2 (CH2), 28.3 (3ꢃCH3), 32.8 (CH2),
sponds to NH2 (1.92)], 2.16 (s, 3H, N–CH3), 2.21 (m, 1H, H-2), 2.68
3
3
35.0 (CH3), 49.7 (CH2), 51.4 (CH), 63.1 (CH), 78.2 (C), 124.3 (CH), 124.7
(CH), 125.7 (CH), 127.4 (CH), 129.0 (CH), 130.1 (C), 131.0 (C), 131.3 (C),
156.0 (C]O). MS (ESI), m/z (%)¼419 [(MþH)þ, 100]. Anal. Calcd for
C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C, 77.26; H, 8.42; N,
6.51.
(td, 1H, J1ax,2ax¼3J1ax,6ax¼10.2 Hz, J1ax,6eq¼4.2 Hz, H-1), 3.58 (d,
2
2
1H, j Jj¼13.2 Hz, N–CHH–Ar), 3.80 (d, 1H, j Jj¼13.2 Hz, N–CHH–Ar),
7.43 (m, 2H), 7.49 (dd, 1H, J¼1.5 and 8.6 Hz), 7.70 (s, 1H), 7.79 (m,
3H); 13C NMR (100 MHz):
d
(ppm)¼21.7 (CH2), 24.8 (CH2), 25.5
(CH2), 34.8 (CH2), 36.1 (CH3), 51.1 (CH), 58.0 (CH2), 69.2 (CH), 125.1
(CH), 125.6 (CH), 126.6 (CH), 126.8 (CH), 127.3 (2CH), 127.6 (CH),
132.4 (C), 133.1 (C), 137.6 (C). MS (ESI), m/z (%)¼269 [(MþH)þ, 100].
Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N,10.44. Found: C, 80.32;
H, 9.26; N, 10.18.
4.7. General procedure for the removal of the Boc group of
(1S,2S)-11–13
To a solution of the corresponding aminocarbamate 11–13
(1.07 mmol) in CH2Cl2 (3 mL), an aqueous solution of H3PO4 (85%,
2 mL) was added. After 4 h stirring, water (3 mL) was added to the
mixture and the acid aqueous layer washed with CH2Cl2 (2ꢃ10 mL).
Then, the aqueous layer was basified with NaOH pellets and
extracted with CH2Cl2 (3ꢃ15 mL). The combined basic organic
layers were washed with brine (10 ml), dried with Na2SO4 and
evaporated under reduced pressure to yield the corresponding di-
amine 14–16 in state of purity.
4.7.5. (1S,2S)-N-(9-Anthrylmethyl)-N-methylcyclopentane-1,2-di-
amine [(1S,2S)-16a]. Yield: 99%. Spectral data are in good agree-
ment with those previously published.11
4.7.6. (1S,2S)-N-(9-Anthrylmethyl)-N-methylcyclohexane-1,2-di-
amine [(1S,2S)-16b].
3'
2'
4'
4'a
9'a
9'
1'
10'
1
5
6
4.7.1. (1S,2S)-N-Methyl-N-(1-naphthylmethyl)cyclopentane-1,2-di-
NH2
CH2
10'a
20
N
5'
amine [(1S,2S)-14a]. Yield: 89%; yellow oil. [
a
]
D
þ90.3 (c 1.0,
3
4
8'a
2
CHCl3), ee¼99%; 1H NMR (300 MHz):
d
(ppm)¼1.27 (m, 1H), 1.51 (br
CH3
6'
8'
7'
s, 2H, NH2), 1.62–1.79 (m, 4H), 1.91 (m, 1H), 2.20 (s, 3H, N–CH3), 2.68
(q, 1H, 3J¼8.1 Hz, H-2), 3.17 (q, 1H, 3J¼8.1 Hz, H-1), AB system
2
20
Yield: 90%; yellow foam. [
NMR (400 MHz):
a
]
D
þ29.9 (c 1.0, CHCl3), ee¼99%; 1
H
(
dA¼3.96, dB¼4.02, j JA,Bj¼13.1 Hz, N–CH2–Ar), 7.35–7.58 (m, 4H),
7.76 (d, 1H, 3J¼7.7 Hz), 7.84 (dd, 1H, J¼1.7 and 7.7 Hz), 8.32 (d, 1H,
d
(ppm)¼1.01 [m, 1H, H-6ax], 1.22 (m, 2H, H-4ax
3J¼8.0 Hz); 13C NMR (75.5 MHz):
d
(ppm)¼20.4 (CH2), 21.3 (CH2),
and H-5ax), 1.41 (m, 1H, H-3ax), 1.65 (m, 1H, H-5eq), 1.87 (m, 1H, H-
4eq), 1.90 (m, 1H, H-6eq), 2.03–2.20 [6H, m (H-3eq)þbr s (NH2)þs
(N–CH3). Singlets are centred to 2.09 and 2.16, respectively], 2.31
32.6 (CH2), 36.8 (CH3), 53.7 (CH), 58.3 (CH2), 73.3 (CH), 124.3 (CH),
124.8 (CH),125.2 (CH),125.3 (CH),126.8 (CH),127.5 (CH),128.1 (CH),
132.1 (C), 133.6 (C), 135.0 (C). MS (EI), m/z (%)¼254 (Mꢄþ, 16), 210
(28), 170 (57), 141 (100). HRMS (EI) calcd for C17H22N2 (Mꢄþ):
254.1783; found: 254.1786.
3
3
3
(ddd, 1H, J2ax,3ax¼11.6 Hz, J2ax,1ax¼10.2 Hz, J2ax,3eq¼3.2 Hz, H-2),
2.65 (td, J1ax,2ax¼3J1ax,6ax¼10.2 Hz, J1ax,6eq¼4.0 Hz, H-1), 4.50 (d,
3
3
2
2
1H, j Jj¼12.0 Hz, N–CHH–Ar), 4.64 (d, 1H, j Jj¼12.0 Hz, N–CHH–Ar),
7.44 [m, 2H, H-30(H-60)], 7.51 [m, 2H, H-20(H-70)], 7.99 [d, 2H,
3
J4 ,3 ¼8.2 Hz, H-40(H-50)], 8.40 (s, 1H, H-100), 8.42 [d, 2H,
4.7.2. (1S,2S)-N-Methyl-N-(1-naphthylmethyl)cyclohexane-1,2-di-
0
0
20
amine [(1S,2S)-14b]. Yield: 89%; white solid, mp: 74–76 ꢁC. [
a]
J1 ,2 ¼8.8 Hz, H-1 (H-8 )]; 13C NMR (100 MHz):
d
(ppm)¼22.3 (C-3),
3
0
0
0
0
D
þ55.5 (c 1.0, CHCl3), ee¼99%; 1H NMR (300 MHz):
d
(ppm)¼1.08–
25.0 (C-5), 25.6 (C-4), 34.3 (CH3), 34.6 (C-6), 50.7 (CH2), 51.1 (C-1),
67.8 (C-2), 124.7 [C-10(C-80) and C-30(C-60)], 125.5 [C-20(C-70)], 127.3
(C-100), 129.0 [C-40(C-50)], 130.9 (C-90), 131.2 [C-90a(C-80a)], 131.3 [C-
40a(C-100a)]. MS (EI), m/z (%)¼318 (Mꢄþ, 71), 220 (100), 191 (92), 127
(70). HRMS (EI) calcd for C22H26N2 (Mꢄþ): 318.2096; found:
318.2098.
1.33 (m, 4H),1.61–1.75 [mþs, 3H. Singlet corresponds to NH2 (1.72)],
1.85 (m, 1H), 1.95 (m, 2H), 2.16 (s, 3H, N–CH3), 2.29 (td, 1H,
3J1ax,2ax¼3J2ax,3ax¼10.3 Hz, J2ax,3eq¼3.5 Hz, H-2), 2.67 (td, 1H,
3
3J1ax,2ax¼3J1ax,6ax¼10.3 Hz, 3J1ax,6eq¼4.1 Hz, H-1), 4.03 (s, 2H, N–CH2–
Ar), 7.33–7.62 (m, 4H), 7.77 (dd, 1H, J¼2.9 and 6.6 Hz), 7.83 (d, 1H,
3J¼7.9 Hz), 8.26 (d, 1H, 3J¼7.5 Hz); 13C NMR (100 MHz):
d
(ppm)¼21.6 (CH2), 25.1 (CH2), 25.7 (CH2), 35.1 (CH2), 35.3 (CH3),
Acknowledgements
51.4 (CH), 57.4 (CH2), 68.8 (CH), 124.6 (CH), 125.0 (CH), 125.5 (CH),
125.6 (CH), 127.0 (CH), 127.8 (CH), 128.4 (CH), 132.4 (C), 133.8 (C),
135.4 (C). MS (EI), m/z (%)¼268 (Mꢄþ, 8), 210 (12),170 (69),141 (100).
HRMS (EI) calcd for C18H24N2 (Mꢄþ): 268.1939; found: 268.1938.
Financial support from the Spanish MICINN (CTQ2007-61126) is
gratefully acknowledged. F.J.Q. thanks the Spanish MICINN for
a predoctoral fellowship.
4.7.3. (1S,2S)-N-Methyl-N-(2-naphthylmethyl)cyclopentane-1,2-di-
References and notes
20
amine [(1S,2S)-15a]. Yield: 97%; white foam. [
a
]
þ61.0 (c 1.0,
D
CHCl3), ee¼99%; 1H NMR (400 MHz):
(ppm)¼1.27 (m, 1H), 1.58 (s,
d
1. Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101–114.
2. (a) Fache, F.; Schultz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100,
2159–2231; (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580–2627.
3. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161–3196.
4. For some applications of C2-symmetric derivatives of trans-cyclohexane-1,
2-diamine, see: (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129,
14548–14549; (b) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129,
11583–11592.
2H, NH2), 1.62 (m, 3H), 1.74 (m, 1H), 1.93 (m, 1H), 2.22 (s, 3H, N-CH3),
2.64 (q, 1H, 3J¼7.8 Hz, H-2), 3.18 (q, 1H, 3J¼7.8 Hz), 3.65 (d, 1H,
2
2
j Jj¼13.2 Hz, N–CHH–Ar), 3.76 (d, 1H, j Jj¼13.2 Hz, N–CHH–Ar), 7.45
(m, 2H), 7.52 (dd,1H, J¼1.5 and 8.6 Hz), 7.79 (s, 1H), 7.81 (m, 3H); 13C
NMR (100 MHz):
d
(ppm)¼20.6 (CH2), 22.6 (CH2), 33.1 (CH2), 37.7
(CH3), 53.9 (CH), 59.2 (CH2), 73.3 (CH), 125.0 (CH), 125.4 (CH), 126.6

8034
F.J. Quijada et al. / Tetrahedron 65 (2009) 8028–8034
5. For some examples using 1 as catalyst for asymmetric aldol reactions, see: (a)
Luo, S.; Xu, H.; Zhang, L.; Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653–656; (b) Luo,
S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074–3075.
6. For some examples using compounds 2 (R2¼aryl) in the enantioselective Mi-
chael addition to activate olefins, see: (a) Zu, L. S.; Xie, H. X.; Li, H.; Wang, H.;
Jiang, W.; Wang, W. Adv. Synth. Catal. 2007, 349, 1882–1886; (b) Li, H.; Zu, L. S.;
Wang, J.; Wang, W. Tetrahedron Lett. 2006, 47, 3145–3148; (c) Hoashi, Y.; Okino,
T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032–4035; (d) Okino, T.; Hoashi,
Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125.
7. For the use of 2 (R2¼alkyl) in the cyanosilylation of ketones, see: (a) Zuend, S. J.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872–15883; (b) Fuerst, D. E.; Ja-
cobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964–8965.
13. Gonza´lez-Sabı´n, J.; Gotor, V.; Rebolledo, F. Tetrahedron: Asymmetry 2004, 15,
481–488.
14. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. Am. Chem. Soc. 1982, 104, 7294–
7299.
15. Garro-Helion, F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993, 58, 6109–6113.
16. Aldrich catalogue (2009–2010): (1S,2S)-trans-N-Boc-1,2-cyclohexanediamine
20
[
a
]
þ26.2 (c 1.0, CHCl3), eeꢅ99%.
D
17. For some recent applications, see: (a) Hanessian, S.; Vinci, V.; Fettis, K.; Maris,
T.; Viet, M. T. P. J. Org. Chem. 2008, 73, 1181–1191; (b) Cherney, R. J.; Mo, R.;
Meyer, D. T.; Nelson, D. J.; Lo, Y. C.; Yang, G.; Scherle, P. A.; Mandlekar, S.;
Wasserman, Z. R.; Jezak, H.; Solomon, K. A.; Tebben, A. J.; Carter, P. H.; Decicco,
C. P. J. Med. Chem. 2008, 51, 721–724.
8. (a) Pen˜a, C.; Gonza´lez-Sabı´n, J.; Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron:
18. (a) Gunnlaugsson, T.; Davis, A. P.; O’Brien, J. E.; Glynn, M. Org. Lett. 2002, 4,
2449–2452; (b) Galindo, F.; Becerril, J.; Burguete, M. I.; Luis, S. V.; Vigara, L.
Tetrahedron Lett. 2004, 45, 1659–1662; (c) Neelakandan, P. P.; Hariharan, M.;
Ramaiah, D. J. Am. Chem. Soc. 2006, 128, 1134–1135.
19. Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy; John
Wiley and Sons: Hoboken, NJ, 2007.
20. Lassau, C.; Jungers, J.-C. Bull. Soc. Chim. France 1968, 2678–2685.
21. Wu, C.; Kobayashi, H.; Sun, B.; Yoo, T. M.; Paik, C. H.; Gansow, O. A.; Carrasquillo,
J. A. Bioorg. Med. Chem. 1997, 5, 1925–1934.
´
´
Asymmetry 2007, 18, 1981–1985; (b) Pen˜a, C.; Gonzalez-Sabın, J.; Alfonso, I.;
Rebolledo, F.; Gotor, V. Tetrahedron 2008, 64, 7709–7717.
´
´
9. Gonzalez-Sabın, J.; Rebolledo, F.; Gotor, V. Chem.dEur. J 2004, 10, 5788–5794.
10. Gonza´lez-Sabı´n, J.; Rebolledo, F.; Gotor, V. J. Org. Chem. 2007, 72, 1309–1314.
11. Quijada, F. J.; Gonza´lez-Sabı´n, J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry
2008, 19, 2589–2593.
12. Pen˜a, C.; Gonza´lez-Sabı´n, J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry
2008, 19, 751–755.