Stereoselective synthesis and transformations of pinane-based 1,3-diaminoalcohols

Article abstract of DOI:10.1016/j.tet.2017.03.050

A library of pinane-based 1,3-diaminoalcohols and 5-aminomethyloxazolidin-2-ones was developed from commercially available (1R)-(?)-myrtenol which was transformed to N-trichloroacetyl protected allyl amine via Overmann rearrangement followed by stereoselective epoxidation with mCPBA resulting in key intermedier epoxy-amine. In order to obtain the diaminoalcohol moiety, aminolysis and azidolysis of the oxirane ring was performed. The cleavage of the oxirane ring proceeded regioselectively, affording N-trichloroacetyl protected 1,3-diaminoalcohols and oxazolidin-2-ones, which were obtained also via a thermal cyclisation. Since N deprotection of diaminoalcohols was unsuccessful under varied conditions, the protecting group was changed and Boc-protected analogues were synthesised. In this case, removal of the Boc protecting group was successful resulting in the planned diamino alcohols. An unexpected extreme δ Me_α-9 value (0.11?ppm) was measured for the dibenzylaminomethyl-substituted oxazolidine-2-one, and the stereostructure was refined by means of DFT geometry optimization. The obtained potential catalysts were applied in the test reaction of benzaldehyde and diethylzinc with low to moderate enantioselectivities (up to 74% ee).

Full text of DOI:10.1016/j.tet.2017.03.050

Accepted Manuscript
Stereoselective synthesis and transformations of pinane-based 1,3-diaminoalcohols
Tímea Gonda, Attila Balázs, Gábor Tóth, Ferenc Fülöp, Zsolt Szakonyi
PII:
S0040-4020(17)30300-9
10.1016/j.tet.2017.03.050
TET 28556
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 December 2016
Revised Date: 2 March 2017
Accepted Date: 20 March 2017
Please cite this article as: Gonda T, Balázs A, Tóth G, Fülöp F, Szakonyi Z, Stereoselective synthesis
and transformations of pinane-based 1,3-diaminoalcohols, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.03.050.
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Stereoselective synthesis and
transformations of pinane-based 1,3-
diaminoalcohols
Tímea Gonda, Attila Balázs, Gábor Tóth, Ferenc Fülöp,* Zsolt Szakonyi *

ACCEPTED MANUSCRIPT
Stereoselective synthesis and transformations of pinane-based 1,3-diaminoalcohols
Tímea Gonda,a Attila Balázs,c Gábor Tóth,d Ferenc Fülöp a,b , Zsolt Szakonyi,a*
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
bMTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eötvös u. 6, H-6720 Szeged,
Hungary
cMTA-ELTE Protein Model. Res. Group and Laboratory of Structural Chemistry and Biology H-1117 Budapest,
Pázmány Péter sétány 1/A, Hungary
dDepartment of Inorganic and Analytical Chemistry, NMR group, Budapest University of Technology and
Economics, St. Gellért tér 4, H-1111 Budapest, Hungary
Abstract
A library of pinane-based 1,3-diaminoalcohols and 5-aminomethyloxazolidin-2-ones was developed
from commercially available (1R)-(-)-myrtenol which was transformed to N-trichloroacetyl protected
allyl amine via Overmann rearrangement followed by stereoselective epoxidation with mCPBA resulting
in key intermedier epoxy-amine. In order to obtain the diaminoalcohol moiety, aminolysis and
azidolysis of the oxirane ring was performed. The cleavage of the oxirane ring proceeded
regioselectively, affording N-trichloroacetyl protected 1,3-diaminoalcohols and oxazolidin-2-ones,
which were obtained also via a thermal cyclisation. Since N deprotection of diaminoalcohols was
unsuccessful under varied conditions, the protecting group was changed and Boc-protected analogues
were synthesised. In this case, removal of the Boc protecting group was successful resulting in the
planned diamino alcohols. An unexpected extreme δ Meα-9 value (0.11 ppm) was measured for the
dibenzylaminomethyl-substituted oxazolidine-2-one, and the stereostructure was refined by means of
DFT geometry optimization. The obtained potential catalysts were applied in the test reaction of
benzaldehyde and diethylzinc with low to moderate enantioselectivities (up to 74% ee).
Keywords: diaminoalcohol, catalyst, oxazolidinone, monoterpene, stereochemistry
* Corresponding author. Tel.: +36-62-545564; Fax: +36-62-545705; fulop@pharm.u-
szeged.hu,szakonyi@pharm.u-szeged.hu

ACCEPTED MANUSCRIPT
1. Introduction
In recent years, several synthetic strategies have been developed for the preparation of enantiopure 3-
amino-1,2-diols and 1,3-aminoalcohols derived from naturally occurring monoterpenes such as (+)- and
(-)-α-pinene,1,2 (-)-β-pinene,3 (1R)-(-)-mirtenol,4-6 (+)-pulegone,7 (+)-camphor,8-10 (-)-phencone,8,9 (-)-
menthone,11,12 (+)-3-carene13 and (-)-perillaldehyde.14 These useful synthons were efficiently applied in
asymmetric catalysis and their catalytic activity has been thoroughly tested and interpreted.15
However, the field of alicyclic 1,3-diamino alcohols remained less explored although several naturally
occurring pharmacologically active compounds have been reported to bear the diaminoalcohol moiety.
(-)-Balanol,16 a fungal metabolite is an effective inhibitor of Protein Kinase C, while ophiocordin its
regioisomer shows antifungal activity.17 A variety of synthetic compounds bearing the diaminoalcohol
backbone also exert pharmacological activity as HIV-protease inhibitors,18 Chemokin receptor 2
antagonists,19 Cathepsin D with inhibitor activity20 or as antitubercular agents.21 In addition to their
pharmacological and catalytic interests, diaminoalcohols have been successfully applied in industry as
dispersing additives for coating formulations.22
We have recently reported the synthesis of pinane-based aminodiols derived from (1R)-myrtenol (1) and
their application as catalyst materials in the reaction of benzaldehyde and diethylzinc with moderate
enantioselectivity.4 In the present work, our aim was to prepare the 1,3-diaminoalcohol analogues of the
aminodiols prepared earlier and develop a new synthetic strategy for the stereoselective synthesis of the
diaminoalcohol moiety. We also planned to test the catalytic activity of the synthesized compounds to
induce the reaction of diethylzinc and benzaldehyde.
2. Results and discussion
2.1. Synthesis of 1,3-diaminoalcohols
Starting from commercially available myrtenol (1) protected allylamine 2 was synthesised by a literature
method.23-25 Epoxidation of 2 with mCPBA yielded 3 as our key intermedier used in a subsequent
stereoselective transformation (Scheme 1).
3

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OH
O
O
O
(ii)
(i)
N
CCl3
N
H
CCl3
H
1
3
2
Scheme 1. Reagents and conditions: (i) 1.5 equiv. DBU, 1.8 equiv. CCl3CN, dry CH2Cl2, 5 h then
K2CO3, dry xylene, reflux, 24 h, 92%; (ii) 7 equiv. mCPBA, NaH2PO4, CH2Cl2/H2O, 3 h, 0 °C-rt, 59%
The diaminoalcohol structure was developed by the aminolysis of the oxirane ring with various primary
and secondary amines (Scheme 2). The cleavage proceeded regioselectively on the less substituted
carbon atom of the oxirane ring in each case, resulting in N-trichloroacetyl-protected diaminoalcohols 4-
8. In a few cases, the formation of tricyclic oxazolidinone products was also observed due to a base-
catalysed cyclisation reaction. With the increase in the basicity and the amount of the applied amine, the
temperature and the reaction time, the amount of the tricyclic product also increased. With the use of
Me2NH, 13 formed exclusively, while applying R- and S-α-methylbenzylamine as nucleophiles resulted
in the formation of both products (6+11 and 7+12, respectively). As an example, ring closure reaction
could also be achieved by refluxing the N-trichloroacetyl diaminoalcohol 7 in the presence of K2CO3 to
obtain oxazolidinone 12 in a quantitative.
Scheme 2. Reagents and conditions: (i) 4 equiv. amine, 1 equiv. LiClO4, dry MeCN, 40 °C-reflux, 5-48
h, 9-82%; (ii) 5 equiv. K2CO3, EtOH, reflux, 1 h, 99%.
Table 1. Synthesis of 1,3-diaminoalcohols 4-8 and 5-aminomethyloxazolidines 9-13
Entry
Amine (equiv.)
R1
R2
Temperature Reaction
Product yield
for 4-13 (%)a
time (h)
(°C)
4

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diamino- oxazo-
alcohols
lidine
(4-8)
(9-13)
1
2
3
4
Dibenzylamine (4)
Dibenzylamine (4)
Benzylamine (2)
Benzylamine (4)
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
reflux
reflux
40 °C
reflux
reflux
20
48
10
10
5
20
-
-
CH2Ph
66
-
H
H
H
26
-
70
87
(1S)-α-methylbenzyl- CH(Me)Ph
9
5
6
amine (4)
(1R)-α-methylbenzyl- CH(Me)Ph
H
reflux
10
18
42
amine (4)
Benzylmethylamine
(4)
CH2Ph
Me
Me
Me
reflux
reflux
7
20
-
-
7
8
Dimethylamine (4)
10
82
a Isolated yields after purification.
Azidolysis of 3 was also performed and the regioselective formation of 14 was observed as a single
product. Catalytic reduction of the azido group with atmospheric H2 in the presence of Pd/C as catalyst
resulted in 15 (Scheme 3).
N3
NH2
O
O
O
(ii)
(i)
O
O
O
N
N
H
CCl3
N
H
H
15
3
14
Scheme 3. Reagents and conditions: (i) 2 equiv. NaN3, 0.2 equiv. NH4Cl, EtOH/H2O, 60 °C, 3.5 h, 58%;
(ii) Pd/C, 1 atm. H2, MeOH, rt, 24 h, 51%.
Reduction of the oxazolidinone ring of 10 with LiAlH4 was also performed, yielding N-benzyl-N’-
methyl-substituted derivative 16. The transformation of 16 to 17 was accomplished by catalytic
hydrogenolysis (Scheme 4).
Scheme 4. Reagents and conditions: (i) 3 equiv. LiAlH4, THF, reflux, 6 h, 54%; (ii) Pd/C, 1 atm. H2,
MeOH, 24 h, rt, 80%.
5

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Several methods are known in the literature for the cleavage of the trichloroacetyl protecting group.26-29
We found, however, that none of these worked successfully in our case. When the hydrolysis was
attempted under alkaline conditions, the formation of the oxazolidinone ring occurred, while treatment
under acidic condition (18% aq. HCl) or with NaBH4 deprotection of the amine function was not
observed. Therefore, for the preparation of unprotected 1,3-diaminoalcohols, a two-step protecting
group exchange was planned. Trichloroacetyl protecting group of 2 proved to be removable in the
presence of NaOH30 giving compound 18, which was previously reported in the literature 31
Next, Boc
.
protection of 18 was accomplished resulting in 19. Similar to previous experiments, epoxidation of 19
took place stereoselectively yielding 20. Aminolysis of the oxirane ring proceeded regioselectively as
well, serving Boc protected diaminoalcohols 21 and 22. As an exception, the use of Me2NH furnished
oxazolidinone 13 as the sole product. This is probably due to the strongly alkaline conditions of the
Me2NH solution. Deprotection of 21 and 22 was successful, affording the planned compounds 23 and 24
(Scheme 5). In order to broaden our knowledge of the role of the substitution degree of nitrogen, we also
prepared compound 25 by catalytic debenzylation of 23 in the presence of Pd/C and 1% AcOH.
O
(i)
(ii)
N
CCl3
NH2
NHBoc
H
19
18
2
(iii)
NR1R2
OH
NR1R2
OH
(v)
(iv)
O
NH2
NHBoc
NHBoc
20
23,24
21,22
(vi)
21,23: R1 = Bn, R2 = H
22,24: R1 = R2 = Bn
NMe2
NH2
OH
O
O
N
NH2
H
25
13
Scheme 5. Reagents and conditions: (i) 5 M aq. NaOH, CH2Cl2/EtOH, 24 h, 50 °C, 98%;
(ii) 1.1 equiv. Boc2O, 0.1 equiv. DMAP, 5 equiv. TEA, THF, 24 h, rt, 77%; (iii) 7 equiv. mCPBA,
NaH2PO4, CH2Cl2/H2O, 3 h, 0 °C – rt, 65%; (iv) 4 equiv. R1R2NH (21: R1 = Bn, R2 = H; 22: R1 = R2 =
6

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Bn), 1 equiv. LiClO4, dry MeCN, reflux, 12-60 h, 29-71%; (v) 10% aq. HCl, Et2O, 12 h, 76-86%; (vi)
Pd/C, 1 atm. H2, MeOH, 1% AcOH, rt, 48 h, 25%.
1
To facilitate the comparison of the fully assigned H and 13C NMR data of our key epoxide
intermediates 3 and 20 and those of product 4 formed by aminolysis, we compiled the structures and
relevant data in Figure 1.
1.42H
1.41H
7
28.3
2'
O
28.3
O
1.65
2.45
H
1.57
H
2.37
H
H
3'
H 2.82
61.9
1.87
H
1
H 2.70
2.86
62.1
1.81
H
55.6
2.89 161.6
48.7
40.6
55.1
H
49.1
40.5
35.2
28.4
H
3
NH
C
CCI3
NH
C
OC(CH3)3
5
7.34
45.6
79.2
1.44
5.04
39.7
O
44.5
4
1.30
CH3
39.7
33.8
O
1.27
CH3
26.2
H
H
2.11
26.1
H
4.19
H
6
H
2.64
4.34
H
2.53
2.04
1.04CH3
1.00CH3
22.1
22.0
3
20
7.27
H
127.6
H 7.33
128.7
129.1
H 7.27
1.37H
4.17
OH
138.3
60.6
28.3
1.97
H
2.18
H
CH2 3.70/3.57
73.8
2.79/2.64
CH2
CH2Ph
CCI3
C
N
1.55
H
51.4
40.2
35.9
62.1
NH
7.89
49.5
38.3
O
161.3
1.15
CH3
27.6
H
H
H
1.91
3.92
2.64
0.94CH3
23.8
4
Figure 1. Stereostructures and characteristic NOESY steric proximities (red arrows) of compounds 3, 20
and 4. Blue numbers refer to 1H chemical shifts and black bold numbers give the 13C δ values, whereas
cursive ones indicate atomic numbering.
Differentiation of the geminal Μeα-6 and Meβ-6 signals is straightforward considering the characteristic
Hα-4/Meα-6 NOESY cross-peaks in these compounds (2.64/1.04; 2.53/1.00 and 2.64/0.94, respectively).
7

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For all of the compounds studied in this manuscript, it was found that both in the 1H and the 13C NMR
1
spectra δ Meα-6 <δ Meβ-6. It is worth mentioning that as long as the H chemical shifts of Meβ-6
hydrogen atoms appear between 1.3-1.1 ppm, the corresponding δ Meα-6 values exhibit considerable
diamagnetic shifts in cases of oxazolidinone 9–12, and also in compound 24, with aminobenzyl or
aminodibenzyl moieties.
An unexpected extreme δ Meα-9 value (0.11 ppm) was measured for compound 9. To explain this
phenomenon we should consider the NOESY responses between the Meα-9 and the aromatic hydrogen
atoms.
1.35
H
O
3
4
25.1
2.51H
O
2.23
H
158.8
10
2.65
H
5
90.4
1
59.5
N
H 6.13
CH2Ph
1.62
47.6
H
6
2.76
N
39.0
7
H
8
48.1
1.15
CH3
26.7
35.3
H1.93 3.72
38.1
H
H
60.6
1.81
9
CH
2 3.88/3.52
7.36
H
CH
22.5
3
139.4
0.11
7.31H
H
129.5
128.3
127.1
7.23H
H
Figure 2. Left part: Schematic stereostructure and characteristic NOESY steric proximities (red arrows)
1
13
of compound 9. Blue numbers refer to H chemical shifts and black numbers give the C δ values,
whereas cursive ones indicate atomic numbering. Right part: refined structure of the lowest-energy
conformer of 9 by means of DFT geometry optimization. Calculations were carried out by using the
Gaussian 09 program package.
The characteristic 0.11/7.31 and 0.11/7.36 NOESY cross-peaks revealed the spatial proximity between
Meα-9/Ph-Hmeta and Meα-9/Ph-Hortho hydrogen atoms. It is well known that nuclei located in close
proximity above an aromatic ring show considerable diamagnetic shifts.
To get a better insight into the stereochemistry of compound 9 we have calculated by means of DFT
geometry optimization its refined stereostructure.32 As Fig. 2 displays, only one of the benzylamine
8

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moieties in the lowest-energy conformer of 9 is neighbouring with Meα-9. The other one, in turn, is far
from Meα-9. In addition, both benzylamine groups give only one set of signals, which indicates rapid
interconversion of the corresponding two topomeric conformers. It is assumed that a C-H/aromatic π
interaction stabilizes this arrangement. To estimate the strength of this interaction, we have measured the
1H spectra in both methanole-d4 and dmso-d6 (δ Meα-9 = 0.13 and 0.06 ppm, respectively). Even at
elevated temperature (65 Co), the original conformation remained practically preserved (δ Meα-9 = 0.10
ppm), that is no change was observed either on solvation or by raising the temperature. Finally, it should
be mentioned that the DFT calculations provided additional information about the stereochemistry of the
pinane frame. Namely, the six-membered ring exists in an envelope conformation where the C-10
projects out of the plane. The Hα-C(6) and Hα-C(7) dihedral angle is 0o, whereas the dihedral angle of
120o for Hβ-C(6) and Hα-C(7) in accord with the detected Jtrans = 2 Hz and Jcis = 8.5 Hz couplings.
2.2. Application of the prepared catalysts
The prepared potential catalysts were used in the reaction of diethylzinc and benzaldehyde affording the
formation of chiral secondary alcohols. Catalysts 4-17 and 23-25 were applied in a 10% molar ratio in
reactions carried out in n-hexane at room temperature. The enantiomeric purities of 1-phenyl-1-
propanols 26 and 27 obtained were determined by GC on a Chirasil-DEX CB column, according to
literature methods.33-36 Our results are presented in Table 2.
Scheme 6. Model reaction for enantioselective catalysis
Table 2. Addition of diethylzinc to benzaldehyde, catalyzed by diaminoalcohols and oxazolidinones
Entry
Ligand
Yield (%)a
Ee (%)b
Configuration
of the major enantiomerc
1
2
3
4
85
88
79
89
4
2
0
8
S
R
-
4
5
6
7
S
9

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5
79
85
90
84
84
88
83
87
77
88
87
85
6
S
S
S
R
8
6
24
24
24
9
7
10
11
12
13
14
15
16
17
23
24
25
8
9
24
2
R
S
-
10
11
12
13
14
15
16
17
0
18
34
18
74
72
8
R
R
R
S
S
S
88
a
b
Yields obtained after silica column chromatography. Determined on the crude product by GC (Chirasil-DEX
CB column). c Determined by comparing the tR of GC analysis and the optical rotation with literature data.33,34
Low enantioselectivities was observed for N-trichloroacetyl-protected diaminoalcohols. This is
presumably due to the presence of the trichloroacetyl protecting group hindering the β-aminoalcohol
moiety in the molecule to develop a stable transition state with diethylzinc. The asymmetric induction
was similarly weak when the oxazolidinone-type catalysts were used, while the N-benzyl-N’-methyl
derivative 16 showed moderate R selectivity (entry 13). Liberation of the third coordination site by
removal of the protecting group considerably enhanced enantioselectivity to S (up to 74% ee, entry 15).
We found that increasing the steric hindrance on the nitrogen did not improve the enantioselectivity.
3. Conclusion
In conclusion, we have developed a practical method for the synthesis of monoterpene-based chiral 1,3-
diaminoalcohols and aminomethyl-substituted monoterpene-fused oxazolidin-2-ones. Compared to the
previously reported analogue pinane-based aminodiols (up to 61% ee, preferred R selectivity), the
10

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prepared diaminoalcohols showed better enantioselectivity and also a switch in the asymmetric
induction furnishing (S)-1-phenyl-1-propanol as major product.
4. Experimental section
4.1. General Methods
Commercially available compounds were used without further purification. Solvents were dried
according to standard procedures. Melting points were determined on a Kofler apparatus. Optical
rotations were measured with a Perkin-Elmer 341 polarimeter. Chromatographic separations were
carried out on Merck Kieselgel 60 (230-400 mesh ASTM). Reactions were monitored with Merck
Kieselgel 60 F254-precoated TLC plates (0.25 mm thickness). Elemental analyses were performed on a
Perkin-Elmer 2400 Elemental Analyzer. GC measurements were made on a Perkin-Elmer Autosystem
XL GC, consisting of a Flame Ionization Detector and a Turbochrom Workstation data system (Perkin-
Elmer Corporation Norwalk, USA). The column used for the direct separation of enantiomers was a
Chirasil-DEX CB column (2500 x 0.25 mm I.D.).
The 1H and 13C NMR spectroscopic data were recorded at room temperature on a Bruker Avance DRX
400 MHz spectrometer in CDCl3 or in D2O. Chemical shifts, given on the δ scale, are reported in (ppm)
units relative to TMS (in CDCl3) or DSS (in D2O) as internal standard. The NMR signals of the products
were assigned by comprehensive one- and two-dimensional NMR methods using widely accepted
strategies.37,38
Most 1H assignments were accomplished using general knowledge of chemical shift dispersion with the
1
13
aid of the H-1H coupling pattern (1H NMR spectra). Pulse programs of all experiments (1H, APT C,
1
gradient-selected HSQC, HMBC, H,1H-COSY and NOESY) were taken from the Bruker software
13
library. It should be mentioned that in the APT C spectra the signal of the quaternary CCl3 carbon
atom remained under the noise level despite of the high number of the applied scans (ns = 5000 -
38000), and the relatively long pulse repetition time (2.3 sec = D1 : 2.0 sec + aqusition time : 0.3 sec.),
respectively. The rather long relaxation time of this atom and the partial saturation resulted that the
detection of this signal failed. The presence of the CCl3 moitey was proven by HRMS and elemental
analyse.
High resolution mass spectrometric analysis was performed on a Q Exactive Plus mass spectrometer
(Thermo Scientific, Bremen, Germany) equipped with ESI ionsource. Full MS scan was collected in
positive mode in the range of 180.00-520.00 m/z using 140000 FT resolution.
11

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Compound 2 was prepared according to a literature method and was found to be identical with the
product reported therein. Compound 18 was prepared from 2 by a literature method with all of its
spectroscopic data and physical properties being similar to those reported therein.
4.2
2,2,2-Trichloro-N-{(1R,2R,3S,5R)-[6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2'-oxiran]-3-
yl}acetamide (3)
To the solution of 2 (1.00 g, 3.37 mmol) in CH2Cl2 (30 mL) the solution of NaH2PO4x2H2O (1.74 g,
1.10 mmol) in water (30 mL) was added. The mixture was cooled to 0 °C and mCPBA (1.36 g, 7.88
mmol) was added in one portion. After stirring for 1 h at 0 °C, the mixture was let to warm up to room
temperature and stirred for further 2 hours. When the reaction was complete (monitored by means of
TLC) phases were separated and the aqueous phase was extracted with CH2Cl2 (3x20 mL) and washed
with cold 5% aqueous KOH (40 mL). The organic phase was then dried over Na2SO4 and evaporated to
dryness. The crude product obtained was purified by column chromatography on silica gel (n‒
hexane/Et2O = 19/1).
Compound 3: 0.62 g (59%); white crystals; mp: 57‒60 °C; [α]2D0 = +36 (c 0.250, MeOH). IR (KBr) νmax
:
3392, 2935, 1704, 1654, 1491, 816 cm-1. 1H NMR (CDCl3), 1.04 (3H, s), 1.30 (3H, s), 1.42 (1H, d, J =
10.7 Hz), 1.65 (1H, t, J = 5.5 Hz), 1.87 (1H, dt, J = 14.5, 3.7 Hz), 2.09–2.13 (1H, m), 2.45 (1H, dt, J =
10.7, 2.3 Hz), 2.64 (1H, ddd, J = 14.5, 9.5, 2.4 Hz), 2.82 (1H, d, J = 4.5 Hz), 2.89 (1H, d, J = 4.5 Hz),
4.34 (1H, ddd, J = 9.5, 5.5, 3.7 Hz), 7.34 (1H, br s).13C NMR (CDCl3): 22.1 (Meα-6), 26.1 (Meβ-6), 28.3
(C-7), 33.8 (C-4), 38.3 (C-6), 40.6 (C-5), 45.6 (C-3), 48.7 (C-1), 55.6 (C-3’), 61.9 (C-2), 161.6 (N-
C=O), CCl3 remained under the noise level. HRMS (ESI; m/z) [M+H]+ calcd for C12H17Cll3NO2
312.0319, found 312.0317. Anal. Calcd. for C12H16Cl3NO2 (312.62): C 46.10; H 5.16; Cl 34.02; N 4.48.
Found: C 46.32; H 5.02; Cl 34.12; N 4.50.
4.3. General procedure of the aminolysis of the oxirane ring
To the solution of 3 or 20 (3.20 mmol) in dry MeCN (43 mL), LiClO4 (2.82 mmol) and the
corresponding amine (12.8 mmol for 4, 6-13 and 6.4 mmol for 5) were added. The reaction mixture was
12

ACCEPTED MANUSCRIPT
kept at reflux temperature for 8‒48 h, and after completion (monitored by means of TLC) the solvent
was evaporated. The crude product was then dissolved in water (20 mL) and extracted with CH2Cl2
(3x30 mL). The combined organic phase was washed with brine (30 mL), dried (Na2SO4) and
evaporated to dryness.
4.3.1.
2,2,2-Trichloro-N-[(1R,2S,3S,5R)-2-dibenzylaminomethyl-2-hydroxy-6,6-
dimethylbicyclo[3.1.1]hept-3-yl]acetamide (4)
The compound was prepared according to the general procedure 4.3., applying dibenzylamine (6.4
mmol) and 48 h reflux. The crude product was purified by column chromatography on silica gel (n‒
hexane/EtOAc/AcOH = 90/10/1).
Compound 4: 0.33 g (20%); white crystals; mp: 168‒171 °C; [α]2D0 = +10 (c 0.250, MeOH). IR (KBr)
1
νmax: 3377, 2933, 1716, 1485, 1039, 824, 753, 703 cm-1. H NMR (CDCl3): 0.94 (3H, s), 1.15 (3H, s),
1.37 (1H, d, J = 10.4 Hz), 1.55 (1H, ddd, J = 13.9, 6.2, 2.4 Hz), 1.89–1.93 (1H, m), 1.97 (1H, t, J = 6.0
Hz), 2.18 (1H, dtd, J = 10.4, 6.0, 2.4 Hz), 2.64 (1H, ddt, J = 13.9, 10.0, 2.5 Hz), 2.64 (1H, d, J = 13.9
Hz), 2.79 (1H, d, J = 13.9 Hz), 3.57 (2H, d, J = 13.3 Hz), 3.70 (2H, d, J = 13.3 Hz), 3.92 (1H, dt, J =
13
10.0, 6.2 Hz), 4.17 (1H, s), 7.25–7.29 (6H, m), 7.33 (4H, t, J = 7.0 Hz), 7.89 (1H, d, J = 6.2 Hz). C
NMR (CDCl3): 23.8 (Meα-6), 27.6 (Meβ-6), 28.3 (C-7), 35.9 (C-4), 38.3 (C-6), 40.2 (C-5), 49.5 (C-3),
51.4 (C-1), 60.6 (PhCH2), 62.1 (NCH2-2), 73.8 (C-2), 127.6 (Ph-Cpara), 128.7 (Ph-Cmeta), 129.1 (Ph-
Cortho), 138.3 (Ph-Cipso), 161.3 (N-C=O), CCl3 remained under the noise level. HRMS (ESI; m/z)
[M+H]+ calcd for C26H32Cll3N2O2 509.1524, found 509.1515. Anal. Calcd. for C26H31Cl3N2O2 (509.90):
C 61.24; H 6.13; Cl 20.86; N 5.49. Found: C 61.37; H 6.02; Cl 20.90; N 5.55.
13

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4.3.2.
2,2,2-Trichloro-N-[(1R,2S,3S,5R)-2-benzylaminomethyl-2-hydroxy-6,6-
dimethylbicyclo[3.1.1]hept-3-yl]acetamide (5)
The compound was prepared according to the general procedure 4.3., applying benzylamine (6.4 mmol)
and 40 °C heating. After 48 h (when the reaction was still not complete, but formation of 10 was first
indicated) the reaction was worked up according to the general procedure. The crude product was
purified by column chromatography on silica gel (n‒hexane/EtOAc = 4/1).
Compound 5: 0.34 g (26%); colourless oil (59 % of starting material was regained); [α]2D0 = +7 (c 0.250,
1
MeOH). IR (KBr) νmax: 3377, 2924, 1713, 1496, 1454, 823, 701 cm-1. H NMR (CDCl3): 0.97 (3H, s),
1.27 (3H, s), 1.50 (1H, d, J = 10.5 Hz), 1.59‒1.66 (1H, m), 1.94‒2.00 (1H, m), 2.12 (1H, t, J = 5.9 Hz),
2.24‒2.31 (1H, m), 2.57‒2.66 (1H, m), 2.74 (2H, dd, J = 12.4, 24.5 Hz), 3.82 (2H, dd, J = 13.8, 15.2
13
Hz), 4.06-4.14 (1H, m), 7.27‒7.34 (5H, m), 7.83 (1H, d, J = 7.3 Hz). C NMR (CDCl3): 23.8, 27.8,
28.3, 35.7, 38.6, 40.3, 48.7, 50.7, 53.7, 56.6, 73.8, 92.9, 127.7, 128.4, 128.7, 138.5, 161.6. HRMS (ESI;
m/z) [M+H]+ calcd for C19H26Cl3N2O2 419.1054, found 419.1059.Anal. Calcd. for C19H25Cl3N2O2
(419.77): C 54.36; H 6.00; Cl 25.34; N 6.67. Found: C 54.21; H 6.07; Cl 25.50; N 6.70.
4.3.3.
2,2,2-Trichloro-N-{(1R,2S,3S,5R)-2-hydroxy-6,6-dimethyl-2-[(1S-
phenylethylamino)methyl]bicyclo[3.1.1]hept-3-yl}acetamide (6) and (1R,2S,3S,8R)-9,9-dimethyl-2-
[(1S)-(1-phenylethylamino)methyl]-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one (11)
14

ACCEPTED MANUSCRIPT
It was prepared according to the general procedure 4.3., applying (1S)-phenylethylamine and 5 h reflux.
The crude product (mixture of 6 and 11) was purified by column chromatography on silica gel with
gradient elution (from n‒hexane/EtOAc = 4/1 to n‒hexane/EtOAc = 1/1).
Compound 6: 0.12 g (9%); white crystals; mp: 74‒76 °C; [α]2D0 = +41 (c 0.250, MeOH). IR (KBr) νmax
:
1
3382, 2914, 1714, 1688, 1525, 823, 703. H NMR (CDCl3): 0.94 (3H, s), 1.27 (3H, s), 1.35 (3H, d, J =
6.6 Hz), 1.48 (1H, d, J = 10.4 Hz), 1.54‒1.62 (1H, m), 1.91‒2.05 (2H, m), 2.23‒2.31 (1H, m), 2.41 (1H,
d, J = 12.4 Hz), 2.59 (1H, d, J = 12.4 Hz), 2.54‒2.63 (1H, m), 3.73 (1H, q, J = 6.5, 13.0 Hz), 3.95‒4.05
(1H, m), 7.19‒7.33 (5H, m), 7.70 (1H, d, J = 6.8 Hz).13C NMR:23.7, 23.9, 27.9, 28.4, 35.6, 38.6, 40.3,
48.6, 50.9, 54.9, 58.4, 73.6, 126.6, 127.5, 128.7, 142.5, 161.5, CCl3 remained under the noise level.
HRMS (ESI; m/z) [M+H]+ calcd for C20H28Cl3N2O2 433.1211, found 433.1216. Anal. Calcd. for
C20H27Cl3N2O2 (433.80): C 55.37; H 6.27; Cl 24.52; N 6.46. Found: C 55.21; H 6.22; Cl 24.55; N 6.70.
Compound 11: 0.88 g (87%); white crystals; mp: 143‒146 °C; [α]2D0 = +20 (c 0.250, MeOH). IR (KBr)
νmax: 3328, 2925, 1760, 703 cm-1. 1H NMR (CDCl3): 0.42 (3H, s), 1.19 (3H, s), 1.34 (3H, d, J = 6.5 Hz),
1.37 (1H, d, J = 11.2 Hz), 1.66‒1.73 (1H, m), 1.87‒1.93 (1H, m), 2.07‒2.16 (2H, m), 2.22‒2.30 (1H, m),
2.50 (1H, d, J = 13.2 Hz), 2.71 (1H, d, J = 13.2 Hz), 3.74 (1H, q, J = 6.5, 13.0 Hz), 3.96‒4.01 (1H, m),
13
5.41 (1H, br s), 7.19‒7.24 (1H, m), 7.27‒7.34 (4H, m). C NMR (CDCl3): 22.8, 24.4, 24.9, 26.7, 34.9,
38.2, 39.3, 47.7, 47.9, 54.1, 58.3, 89.6, 126.9, 127.0, 128.3, 145.3, 159.0. HRMS (ESI; m/z) [M+H]+
calcd for C19H27N2O2 315.2067, found 315.2073. Anal. Calcd. for C19H26N2O2 (314.42): C 72.58; H
8.33; N 8.91. Found: C 72.87; H 8.23; N 8.70.
4.3.4
2,2,2-Trichloro-N-[(1R,2S,3S,5R)-2-hydroxy-6,6-dimethyl-2-((1R)-
phenylethylaminomethyl)bicyclo[3.1.1]hept-3-yl]acetamide (7) and (1R,2S,3S,8R)-9,9-Dimethyl-2-
[(1R)-(1-phenylethylamino)methyl]-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one (12)
Method A: The compound was prepared according to the general procedure 4.3., applying (1R)-
phenylethylamine and 8 h reflux. The crude product (mixture of 7 and 12) was purified by coloumn
15

ACCEPTED MANUSCRIPT
chromatography on silica gel with gradient elution (from n‒hexane/EtOAc = 4/1 to n‒hexane/EtOAc =
1/1).
Method B: To the solution of 7 (50 mg, 0.12 mmol) in EtOH (4 mL) K2CO3 (80 mg, 0.6 mmol) was
added and the mixture was kept at reflux temperature for 1 h then evaporated to dryness. After the
addition of water (10 mL) the aqueous phase was extracted with Et2O (3x10 mL). The organic phase
was dried (Na2SO4) and evaporated and the crystalline product was washed with n‒hexane.
Compound 7: 0.25 g (18%); white crystals; mp: 96‒99 °C; [α]2D0 = –14 (c 0.250, MeOH). IR (KBr) νmax
:
1
3317, 2926, 1707, 1491, 819 cm-1. H NMR (CDCl3): 0.87 (3H, s), 1.21 (3H, s), 1.43 (3H, d, J = 6.5
Hz), 1.46 (1H, d, J = 10.6 Hz), 1.58‒1.65 (1H, m), 1.92‒1.97 (1H, m), 2.00‒2.07 (1H, m), 2.20‒2.29
(1H, m), 2.50 (1H, d, J = 12.4 Hz), 2.56‒2.64 (1H, m), 2.69 (1H, d, J = 12.4 Hz), 3.77‒3.85 (1H, m),
4.07‒4.15 (1H, m), 7.26‒7.37 (5H, m), 7.83 (1H, d, J = 7.2 Hz).13C NMR (CDCl3): 23.2, 23.6, 27.7,
28.1, 35.8, 38.5, 40.3, 48.7, 50.6, 55.4, 58.6, 73.8, 126.7, 127.7, 128.8, 143.5, 161.5, CCl3 remained
under the noise level. HRMS (ESI; m/z) [M+H]+ calcd for C20H28Cl3N2O2 433.1211, found 433.1219.
Anal. Calcd. for C20H27Cll3N2O2 (433.80): C 55.37; H 6.27; Cl 24.52; N 6.46. Found: C 55.45; H 6.20;
Cl 24.59; N 6.51.
Compound 12: method A: 0.42 g (42%); method B: 33 mg (92%); white crystals; mp: 182‒184 °C; [α]
1
20
D
= -45 (c 0.250, MeOH). H NMR (CDCl3): 0.52 (3H, s), 1.24 (3H, s), 1.31-1.35 (4H, m), 1.70–1.76
(1H, m), 1.89–1.95 (1H, m), 2.15–2.25 (1H, m), 2.26–2.33 (1H, m), 2.51 (1H, t, J = 5.5 Hz), 2.56 (1H,
d, J = 12.9 Hz), 2.76 (1H, d, J = 12.9 Hz), 3.70–3.81 (2H, m), 6.17 (1H, br s), 7.19–7.25 (1H, m), 7.27–
13
7.34 (4H, m). C NMR (CDCl3):22.9, 24.5, 25.1, 26.7, 35.3, 38.2, 39.2, 46.1, 49.2, 54.4, 58.4, 89.6,
126.8, 127.0, 128.4, 145.4, 158.8. HRMS (ESI; m/z) [M+H]+ calcd for C19H27N2O2 315.2067, found
315.2068. Anal. Calcd. for C19H26N2O2 (314.42): C 72.58; H 8.33; N 8.91. Found: C 72.41; H 8.32; N
8.97.
16

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4.3.5.
2,2,2-Trichloro-N-[2-((1R,2S,3S,5R)-N’-benzyl-N’-methylaminomethyl)-2-hydroxy-6,6-
dimethylbicyclo[3.1.1]hept-3-yl]acetamide (8)
The compound was prepared according to the general procedure 4.3., applying N-methylbenzylamine
and 7 h reflux. The crude product was purified by column chromatography on silica gel (n‒
hexane/EtOAc = 4/1).
Compound 8: 0.28 g (20%); colourless oil; [α]2D0 = +1 (c 0.250, MeOH). IR (KBr) νmax: 3383, 2925,
1709, 1496, 823, 750, 700 cm-1. 1H NMR (CDCl3): 0.98 (3H, s), 1.23 (3H, s), 1.44 (1H, d, J = 10.5 Hz),
1.57‒1.65 (1H, m), 1.91‒1.98 (1H, m), 2.00‒2.07 (1H, m), 2.20‒2.28 (1H, m), 2.33 (3H, s), 2.52‒2.72
(3H, m), 3.54‒3.67 (2H, m), 3.95‒4.03 (1H, m), 7.23‒7.36 (5H, m) 8.04 (1H, br s). 13C NMR (CDCl3):
23.8, 27.7, 28.3, 35.8, 38.3, 40.2, 45.0, 49.7, 52.2, 64.0, 73.5, 127.7, 128.7, 129.1, 137.6, 161.8, CCl3
remained under the noise level. HRMS (ESI; m/z) [M+H]+ calcd for C20H28Cl3N2O2 433.1211, found
433.1218. Anal. Calcd. for C20H27Cl3N2O2 (433.80): C 55.37; H 6.27; Cl 24.52; N 6.46. Found: C 55.26;
H 6.32; Cl 24.55; N 6.70.
4.3.6. (1R,2S,3S,8R)-2-Benzylaminomethyl-9,9-dimethyl-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one
(10)
It was prepared according to the general procedure 4.3., applying benzylamine and 12 h reflux. The
crude product was purified by column chromatography on silica gel (toluene/EtOH = 9/1).
Compound 10: 0.67 g (70%); white crystals; mp: 141‒150 °C; [α]2D0 = –20 (c 0.250, MeOH). IR (KBr)
νmax: 2941, 1720, 1369, 1314, 1147 cm-1. 1H NMR (CDCl3): 0.67 (3H, s), 1.25 (3H, s), 1.37 (1H, d, J =
10.7 Hz), 1.75 (1H, dt, J = 2.5, 13.7 Hz), 1.92‒1.98 (1H, m), 2.17‒2.34 (3H, m), 2.78 (2H, s), 3.88 (2H,
s), 4.00‒4.08 (1H, m), 6.06 (1H, br s), 7.21‒7.36 (5H, m).13C NMR (CDCl3): 23.2, 25.0, 26.8, 35.1,
38.3, 39.3, 47.2, 48.5, 53.7, 55.4, 89.4, 127.1, 128.3, 128.4, 139.6, 158.7. HRMS (ESI; m/z) [M+H]+
calcd for C18H25N2O2 301.1911, found 301.1904. Anal. Calcd. for C18H24N2O2 (300.40): C 71.97; H
8.05; N 9.33. Found: C 72.11; H 8.09; N 9.11.
17

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4.3.7. (1R,2S,3S,8R)-2-Dimethylaminomethyl-9,9-dimethyl-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-
one (13)
The compound was prepared according to the general procedure 4.3., applying Me2NH and 10 h reflux.
The crude product was purified by column chromatography on silica gel (toluene/EtOH = 9/1).
Compound 13: 0.63 g (82%); white crystals; mp: 150‒153 °C; [α]2D0 = –12 (c 0.250, MeOH). IR (KBr)
νmax: 3267, 2947, 2362, 1747, 1705, 1290, 997 cm-1. 1H NMR (CDCl3): 0.84 (3H, s), 1.30 (3H, s), 1.40
(1H, d, J = 10.8 Hz), 1.72‒1.79 (1H, m), 1.94‒2.00 (1H, m), 2.21‒2.35 (3H, m), 2.33 (6H, s), 2.53 (2H,
q, J = 14.4, 33.4 Hz), 3.94‒4.00 (1H, m), 5.59 (1H, br s). 13C NMR (CDCl3): 23.3, 25.0, 26.8, 36.3, 38.3,
39.2, 47.1, 47.8, 48.5, 66.1, 89.8, 158.8. HRMS (ESI; m/z) [M+H]+ calcd for C13H23N2O2 239.1754,
found 239.1753.Anal. Calcd. for C13H22N2O2 (238.33): C 65.51; H 9.30; N 11.75. Found: C 65.78; H
9.12; N 11.70.
4.4. (1R,2S,3S,8R)-2-Dibenzylaminomethyl-9,9-dimethyl-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one
(9)
To the solution of 3 (2.00 g, 6.40 mmol) in dry MeCN (40 mL) LiClO4 (0.74 g, 6.95 mmol) and
dibenzylamine (4.92 mL, 25.60 mmol) were added. The reaction mixture was kept at reflux temperature
for 48 h and then evaporated. The crude product was then dissolved in water (80 mL) and extracted with
CH2Cl2 (3x100 mL). The combined organic phase was washed with brine (60 mL), dried (Na2SO4) and
evaporated to dryness. The crude product was purified by column chromatography on silica gel (n‒
hexane/EtOAc/AcOH = 66/33/1).
18

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Compound 9: 1.65 g (66%); solid foam; mp: 66‒70 °C; [α]2D0 = +10 (c 0.250, MeOH). IR (KBr) νmax
:
3257, 3926, 2359, 1743, 1016, 748, 701 cm-1. 1H NMR (CDCl3): 0.11 (3H, s,), 1.15 (3H, s), 1.35 (1H, d,
J = 10.7 Hz), 1.62 (1H, dt, J = 14.6, 2.0 Hz), 1.80–1.82 (1H, m), 1.93 (1H, ddd, J = 13.5, 8.5, 2.0 Hz),
2.23 (1H, d, J = 5.3 Hz), 2.22–2.26 (1H, m), 2.65 (1H, d, J = 14.6 Hz), 2.76 (1H, d, J = 14.6 Hz), 3.52
(1H, d, J = 13.3 Hz), 3.72 (1H, dd, J = 8.5, 2.0 Hz), 3.88 (1H, d, J = 13.3 Hz), 6.13 (1H, br s), 7.23 (2H,
t, J = 7.3 Hz), 7.31 (4H, t, J = 7.3 Hz), 7.36 (4H, d, J = 7.3 Hz).13C NMR (CDCl3): 22.5 (Meα-9), 25.1
(C-10), 26.7 (Meβ-9), 35.3 (C-7), 38.1 (C-9), 39.0 (C-8), 47.6 (C-1), 48.1 (C-6), 59.5 (NCH2-2), 60.6
(PhCH2), 90.4 (C-2), 127.1 (Ph-Cpara), 128.3 (Ph-Cmeta), 129.5 (Ph-Cortho), 139.4 (Ph-Cipso), 158.8 (C-4).
HRMS (ESI; m/z) [M+H]+ calcd for C25H31N2O2 391.2380, found 391.2385. Anal. Calcd. for
C25H30N2O2 (390.52): C 76.89; H 7.74; N 7.17. Found: C 76.59; H 7.80; N 7.21.
4.5. (1R,2S,3S,8R)-2-Azidomethyl-9,9-dimethyl-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one (14)
To the solution of 3 (1.00 g, 3.20 mmol) in EtOH (12 mL), water (1.44 mL), NH4Cl (34 mg, 0.64 mmol)
and NaN3 (0.42 mg, 6.46 mmol) were added. The reaction mixture was heated to 60 °C for 3.5 h, then
water was added (40 mL) and the mixture was extracted with CH2Cl2 (3x40 mL). The combined organic
phase was washed with saturated NaHCO3 solution, than dried over Na2SO4 and evaporated to dryness.
The crude product obtained was purified by column chromatography on silica gel (n‒hexane/EtOAc =
1/1).
Compound 14: 0.44 g (58%); white crystals; mp: 145‒148 °C; [α]2D0 = –61 (c 0.250, MeOH). IR (KBr)
νmax: 3262, 2931, 2103, 1796, 1723, 1295, 979 cm-1. 1H NMR (CDCl3): 0.84 (3H, s), 1.31 (3H, s), 1.43
(1H, d, J = 11.2 Hz), 1.80 (1H, dt, J = 2.6, 14.0 Hz), 1.98‒2.04 (1H, m), 2.20‒2.32 (2H, m), 2.33‒2.42
(1H, m), 3.45 (2H, dd, J = 13.5, 14.6 Hz), 3.88‒3.94 (1H, m), 6.55 (1H, br s). 13C NMR (CDCl3): 23.5,
25.5, 26.6, 35.0, 38.2, 39.1, 46.9, 48.0, 57.8, 88.1, 158.2. HRMS (ESI; m/z) [M+H]+ calcd for
C11H17N4O2 237.1346, found 237.1347. Anal. Calcd. for C11H16N4O2 (236.27): C 55.92; H 6.83; N
23.71. Found: C 55.88; H 6.79; N 23.56.
19

ACCEPTED MANUSCRIPT
4.6. (1R,2S,3S,8R)-2-Aminomethyl-9,9-dimethyl-3-oxa-5-azatricyclo[6.1.1.02,6]decan-4-one (15)
To a suspension of Pd/C (5%, 0.20 g) in MeOH (20 mL) a solution of 14 (0.46 g, 1.95 mmol) in MeOH
(10 mL) was added. The mixture was stirred at room temperature and atmospheric pressure under H2
atmosphere for 24 h. When the reaction was complete, indicated by TLC, the mixture was filtered
through a Celite pad and the solvent was removed. The crude product was purified by column
chromatography on silica gel (toluene/EtOH = 4/1).
Compound 15: 0.21 g (51%); white crystals; mp: 164‒167 °C; [α]2D0 = –20 (c 0.250, MeOH). IR (KBr)
νmax: 3399, 2941, 1756, 1707, 1290, 1010, 995 cm-1. 1H NMR (CDCl3): 0.85 (3H, s), 1.30 (3H, s), 1.40
(1H, d, J = 11.1 Hz), 1.46 (2H, br s), 1.75‒1.82 (1H, m), 1.96‒2.02 (1H, m), 2.20‒2.39 (3H, m), 2.90
13
(2H, s), 3.92 (1H, d, J = 8.6 Hz), 5.90 (1H, br s). C NMR (CDCl3): 23.5, 25.3, 26.8, 35.3, 38.3, 39.3,
46.8, 48.2, 49.4, 89.7, 158.9. HRMS (ESI; m/z) [M+H]+ calcd for C11H19N2O2 211.1441, found
211.1439. Anal. Calcd. for C11H18N2O2 (210.27): C 62.83; H 8.63; N 13.32. Found: C 62.97; H 8.59; N
13.25.
4.7.
(1R,2S,3S,5R)-2-Benzylaminomethyl-6,6-dimethyl-3-methylaminobicyclo[3.1.1]heptan-2-ol
(16)
To the stirred suspension of LiAlH4 (0.33 g, 8.7 mmol) in dry THF (16 mL) the solution of 10 (0.87 g,
2.9 mmol) in dry THF (4 mL) was added dropwise under ice cooling. The reaction mixture was kept at
reflux temperature for 6 h, then the mixture of water (0.66 mL) and THF (4 mL) was added dropwise
with cooling. After 30 min stirring, the inorganic material was filtered off and washed with THF. The
filtrate was dried and evaporated. The crude product was purified as a hydrochloric salt. Liberation of
the base for analysis gave yellow oil.
20

ACCEPTED MANUSCRIPT
Compound 16: 0.45 g (54%); yellow oil; [α]2D0 = +12 (c 0.250, MeOH). IR (KBr) νmax: 3320, 2919,
1
1452, 735, 698 cm-1. H NMR (CDCl3): 0.83 (3H, s), 1.23 (3H, s), 1.25‒1.30 (2H, m), 1.36‒1.44 (1H,
m), 1.85‒1.91 (1H, m), 2.11‒2.21 (2H, m), 2.48 (3H, s), 2.59 (2H, s), 2.76‒2.85 (1H, m), 3.81 (2H, s),
7.19‒7.25 (1H, m), 7.28‒7.34 (4H, m) 13C NMR (CDCl3): 23.8, 27.7, 27.9, 34.8, 36.0, 38.3, 40.6, 50.5,
54.1, 57.3, 59.5, 74.3, 126.8, 128.1, 128.2, 140.8. HRMS (ESI; m/z) [M+H]+ calcd for C18H29NO2
289.2274, found 289.2278. Anal. Calcd. for C18H28N2O (288.43): C 74.96; H 9.78; N 9.71. Found: C
74.65; H 9.88; N 10.01.
NH2
OH
N
H
17
4.8. (1R,2S,3S,5R)-2-Aminomethyl-6,6-dimethyl-3-methylaminobicyclo[3.1.1]heptane-2-ol (17)
To a suspension of Pd/C (5%, 0.20 g) in MeOH (10 mL), a solution of 16 (0.37 g, 1.28 mmol) in MeOH
(20 mL) was added. The mixture was stirred at room temperature and atmospheric pressure under a H2
atmosphere for 24 h. Then the reaction mixture was filtered through a Celite pad and the solvent was
removed. The crude product was purified as a hydrochloric salt recrystallizing from EtOH/Et2O mixture.
The liberation of the base gave white crystals.
Compound 17: 0.20 g (80%); mp: 97‒100 °C; [α]2D0 = +10 (c 0.250, MeOH). IR (KBr) νmax: 3378, 2920,
1616, 1498, 1023 cm-1. 1H NMR (CDCl3): 0.95 (3H, s), 1.26 (3H, s), 1.22–1.44 (2H, m), 1.51–1.59 (1H,
13
m), 1.90–1.98 (1H, m), 2.09–2.26 (2H, m), 2.54 (3H, s), 2.72 (2H, s), 2.83–2.92 (1H, m). C NMR
(CDCl3): 24.0, 27.7, 27.8, 34.7, 35.3, 38.4, 40.6, 49.2, 52.1, 57.5. HRMS (ESI; m/z) [M+H]+ calcd for
C11H23N2O 199.1805, found 199.1802. Anal. Calcd. for C11H22N2O (198.31): C 66.62; H 11.18; N
14.13. Found: C 66.74; H 11.02; N 14.10.
4.9. (1R,3S,5R)-6,6-Dimethyl-2-methylenebicyclo[3.1.1]hept-3-ylamine (18)
21

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Compound 2 (0.60 g, 2.02 mmol) was dissolved in the mixture of EtOH (2.15 mL) and CH2Cl2 (1.10
mL) then 5 M aqueous NaOH was added (1.36 mL) to the solution. The mixture was stirred at 50 °C for
4 hours, then water (5 mL) was added and the aqueous phase was extracted with CH2Cl2 (3x10 mL). The
organic phase was dried over Na2SO4 and the solvent was evaporated. The crude product obtained was
purified as a hydrochloric salt and the base was liberated for analysis. Isolated compound: 0.30 g (98%).
The product was referenced to the authentic compound reported in the literature.39Anal. Calcd. for
C10H17N (151.25): C 79.41; H 11.33; N 9.26. Found: C 79.55; H 11.21; N 9.30.
4.10. tert-Butyl (1R,3S,5R)-(6,6-dimethyl-2-methylenebicyclo[3.1.1]hept-3-yl)carbamate (19)
To 18 (0.30 g, 1.98 mmol) in THF (5 mL) Boc2O (0.47 g, 2.15 mmol), TEA (0.81 mL, 11.02 mmol) and
DMAP (23 mg, 0.19 mmol) were added. The reaction mixture was stirred for 24 h, then the solvent was
removed in vacuo. The crude product obtained was purified by column chromatography on silica gel (n-
hexane/EtOAc = 19/1).
Compound 19: 0.38 g (77%); white crystals; mp 59‒62 °C; [α]2D0 = +7 (c 0.250, MeOH). IR (KBr) νmax
:
3328, 2931, 2359, 1700, 1675, 1527, 1365, 1251, 1172, 889 cm-1. 1H NMR (CDCl3): 0.75 (3H, s), 1.17
(1H, d, J = 10.2 Hz), 1.26 (3H, s), 1.46 (9H, s), 1.76 (1H, dt, J = 2.8, 14.7 Hz), 1.98‒2.04 (1H, m), 2.39‒
2.54 (3H, m), 4.48 (1H, br s), 4.66 (1H, br s), 4.81 (1H, s), 5.01 (1H, s). 13C NMR (CDCl3): 22.0, 25.9,
28.4, 29.9, 35.2, 39.9, 40.6, 45.8, 51.5, 79.2, 111.2, 153.8. HRMS (ESI; m/z) [M+Na]+ calcd for
C15H25NO2Na 274.1778, found 274.1777. Anal. Calcd. for C15H25NO2 (251.36): C 71.67; H 10.02; N
5.57. Found: C 71.51; H 10.22; N 5.63.
4.11.
tert-Butyl[((1R,2R,3S,5R)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2'-oxiran)-3-
yl]carbamate (20)
22

ACCEPTED MANUSCRIPT
To the solution of 19 (1.35 g, 5.37 mmol) in CH2Cl2 (50 mL) the solution of NaH2PO4 x2H2O (2.80 g,
1.77 mmol) in water (50 mL) was added. The mixture was cooled to 0 °C then mCPBA (1.97 g, 11.42
mmol) was added in one portion and the mixture was stirred for 1 h at 0 °C and 1 h at room temperature.
When the reaction was complete (monitored by means of TLC) phases were separated and the aqueous
phase was extracted with CH2Cl2 (3x50 mL). The combined organic phase was washed with ice-cold 5%
aqueous KOH (100 mL), was dried (Na2SO4) and evaporated to dryness. The crude product was purified
by column chromatography on silica gel (n-hexane/EtOAc = 19/1).
Compound 20: 0.94 g (65%); white crystals; mp: 75‒78 °C; [α]2D0 = +9 (c 0.250, MeOH). IR (KBr) νmax
:
3327, 2980, 1685, 1533, 1363, 1176 cm-1. 1H NMR (CDCl3): 1.00 (3H, s), 1.27 (3H, s), 1.41 (1H, d, J =
10.6 Hz), 1.44 (9H, s), 1.57 (1H, t, J = 5.5 Hz), 1.81 (1H, dt, J = 14.4, 3.7 Hz), 2.02–2.06 (1H, m), 2.37
(1H, dtd, J = 10.6, 5.5, 2.4 Hz), 2.53 (1H. ddt, J = 14.4, 9.5, 2.4 Hz), 2.70 (1H, d, J = 4.9 Hz), 2.86 (1H,
d, J = 4.9 Hz), 4.19 (1H, br s), 5.04 (1H, br s).13C NMR (CDCl3): 22.0 (Meα-6), 26.2 (Meβ-6), 28.3 (C-
7), 35.2 (C-4), 39.7 (C-6), 40.5 (C-5), 44.5 (C-3), 49.1 (C-1), 55.1 (C-3’), 62.1 (C-2), 28.4 and 79.2
(Me3-C-O), N-C=O remained under the noise level. HRMS (ESI; m/z) [M+Na]+ calcd for C15H25NO3Na
290.1727, found 290.1723. Anal. Calcd. for C15H25NO3 (267.64): C 67.38; H 9.42; N 5.24. Found: C
67.31; H 9.45; N 5.30.
4.12. tert-Butyl (1R,2S,3S,5R)-(2-benzylaminomethyl-2-hydroxy-6,6-dimethyl-bicyclo[3.1.1]hept-3-
yl)carbamate (21)
The compound was prepared according to the general procedure 4.3., applying 20 (3.20 mmol),
benzylamine and 12 h reflux. The crude product was purified by column chromatography on silica gel
(toluene/EtOH = 9/1).
Compound 21: 0.85 g (71%); colourless oil; [α]2D0 = –9 (c 0.250, MeOH). IR (KBr) νmax: 3437, 2925,
1701, 1497, 1168, 698 cm-1. 1H NMR (CDCl3): 0.97 (3H, s), 1.23 (3H, s), 1.25‒1.29 (1H, m), 1.47‒1.58
(1H, m), 1.87‒1.98 (2H, m), 2.17‒2.24 (1H, m), 2.45‒2.57 (1H, m), 2.52 (1H, d, J = 11.7 Hz), 2.88 (1H,
d, J = 12.5 Hz), 3.74 (1H, d, J = 13.2 Hz), 3.81 (1H, d, J = 13.2 Hz), 3.98‒4.08 (1H, m), 5.27 (1H, d, J =
8.8 Hz), 7.21‒7.34 (5H, m). 13C NMR (CDCl3): 23.8, 27.8, 28.3, 28.4, 37.1, 38.4, 40.4, 48.1, 52.0, 54.0,
23

ACCEPTED MANUSCRIPT
58.6, 74.0, 79.4, 127.4, 128.3, 128.5, 138.6, 156.2. HRMS (ESI; m/z) [M+H]+ calcd for C22H35N2O3
375.2642, found 375.2639. Anal. Calcd. for C22H34N2O3 (374.52): C 70.55; H 9.15; N 7.48. Found: C
70.39; H 9.02; N 7.70.
4.13. tert-Butyl (1R,2S,3S,5R)-(2-dibenzylaminomethyl-2-hydroxy-6,6-dimethyl-bicyclo[3.1.1]hept-
3-yl)carbamate (22)
It was prepared according to the general procedure 4.3., applying 20 (3.20 mmol) dibenzylamine and 60
h reflux. The crude product was purified by column chromatography on silica gel (toluene/EtOH = 9/1).
Compound 22: 0.43 g (29%); colourless oil; [α]2D0 = –7 (c 0.250, MeOH). IR (KBr) νmax: 2937, 1724,
1454, 1365, 1149, 746, 698 cm-1. 1H NMR (CDCl3): 0.91 (3H, s), 1.11 (3H, s), 1.24‒1.29 (1H, m), 1.37
(9H, s), 1.47‒1.56 (1H, m), 1.61 (1H, s), 1.85 (2H, d, J = 6.1 Hz), 2.10‒2.15 (1H, m), 2.51 (1H, t, J =
10.8 Hz), 2.71 (2H, m), 3.61 (2H, d, J =13.4 Hz), 3.67 (2H, d, J = 13.4 Hz), 3.78 (1H, m), 4.04 (1H, br
s), 5.41 (1H, d, J = 6.9 Hz), 7.22‒7.36 (10H, m).13C NMR (CDCl3):23.6, 27.9, 28.4, 28.7, 29.7, 37.2,
40.4, 48.7, 52.3, 60.4, 62.6, 78.7, 127.4, 128.5, 129.2, 129.4, 129.6, 131.9, 132.8, 138.7, 151.3. HRMS
(ESI; m/z) [M+H]+ calcd for C29H41N2O3 465.3112, found 465.3098. Anal. Calcd. for C29H40N2O3
(464.64): C 74.96; H 8.68; N 6.03. Found: C 74.81; H 8.72; N 6.11.
4.14. General procedure for Boc deprotection
To the solution of 21 or 22 (0.22 mmol) in Et2O (5mL) 10% aqueous HCl solution was added (5 mL).
The mixture was stirred vigorously at room temperature overnight then the phases were separated and
the aqueous phase was evaporated to dryness.
24

ACCEPTED MANUSCRIPT
4.11.1.
(1R,2S,3S,5R)-3-Amino-2-benzylaminomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane-2-ol
hydrochloride (23)
The compound was prepared according to the General procedure 4.14 starting form 21.
Compound 23: 66 mg (86%); white crystals; mp: 151‒153 °C; [α]2D0 = +8 (c 0.250, MeOH). IR (KBr)
νmax: 3367, 2925, 1591, 1501, 1457, 699 cm-1. 1H NMR (D2O): 0.83 (3H, s), 1.32 (3H, s), 1.39 (1H, d, J
= 11.3 Hz), 1.81‒1.90 (1H, m), 2.10‒2.16 (1H, m), 2.38 (1H, t, J = 5.9 Hz), 2.45‒2.54 (1H, m), 2.55‒
2.63 (1H, m), 3.18 (1H, d, J = 13.1 Hz), 3.34 (1H, d, J = 13.1 Hz), 3.71 (1H, dd, J = 5.6, 10.3 Hz), 4.35
13
(1H, d, J = 13.4 Hz), 4.48 (1H, d, J = 13.4 Hz), 7.61 (5H, s). CNMR (D2O): 22.8, 26.5, 27.2, 32.6,
38.6, 39.9, 48.2, 48.5, 51.9, 53.4, 72.9, 129.9, 130.5, 130.7, 135.7. HRMS (ESI; m/z) [M+H]+ calcd for
C17H27N2O 275.2118, found 275.2117. Anal. Calcd. for C17H28Cl2N2O (347.32): C 58.79; H 8.13; Cl
20.42; N 8.07. Found: C 58.97; H 8.00; Cl 20.35; N 8.05.
4.14.2.
(1R,2S,3S,5R)-3-Amino-2-dibenzylaminomethyl-6,6-dimethyl-bicyclo[3.1.1]heptan-2-ol
hydrochloride (24)
It was prepared according to the general procedure 4.14 starting from 22.
Compound 24: 60 mg (76%); white crystals; mp: 247‒250 °C; [α]2D0 = –8 (c 0.250, MeOH). IR (KBr)
νmax: 3373, 2929, 1602, 1501, 1458, 755, 703 cm-1. 1H NMR (D2O): 0.47 (3H, s), 1.02 (3H, s), 1.36 (1H,
d, J = 11.3 Hz), 1.75‒1.84 (1H, m), 1.98‒2.05 (1H, m), 2.08 (1H, t, J = 5.8 Hz), 2.34‒2.52 (2H, m),
3.39‒3.48 (2H, m), 3.62 (1H, d, J = 14.4 Hz), 4.23‒5.13 (4H, m), 7.52‒7.79 (10 H, m).13C NMR (D2O):
22.3, 26.4, 26.9, 27.1, 32.5, 38.3, 39.8, 48.9, 49.6, 58.7, 73.6, 129.5, 130.0, 131.2, 132.2. HRMS (ESI;
m/z) [M+H]+ calcd for C24H33N2O 365.2587, found 365.2581. Anal. Calcd. for C24H34Cl2N2O (437.45):
C 65.90; H 7.83; Cl 16.21; N 6.40. Found: C 65.88; H 7.81; Cl 16.10; N 6.65.
25

ACCEPTED MANUSCRIPT
4.15. (1R,2S,3S,5R)-3-Amino-2-aminomethyl-6,6-dimethylbicyclo[3.1.1]heptan-2-ol hydrochloride
(25)
To a suspension of Pd/C (5%, 80 mg) in MeOH (10 mL), a solution of liberated base of 23 (0.15 g, 0.55
mmol) in MeOH (5 mL) and AcOH (150 µl)were added. The mixture was stirred at room temperature
and atmospheric pressure under H2 atmosphere for 48 h. Then the reaction mixture was filtered through
a Celite pad and the solvent was removed and the resulted product was purified as hydrochloride salt
recrystallizing from EtOH/Et2O mixture. The base was liberated for further investigations.
Compound 25: 35 mg (25%); yellow crystals, mp: 155-157 °C; [α]2D0 = –3 (c 0.250, MeOH). IR (KBr)
1
νmax: 3373, 2923, 1604, 1504, 1023 cm-1. H NMR (D2O): 1.08 (3H, s), 1.41 (3H, s), 1.45 (1H, d, J =
11.2 Hz), 1.88‒1.95 (1H, m), 2.15‒2.21 (1H, m), 2.42 (1H, t, J = 5.9 Hz), 2.50‒2.58 (1H, m), 2.61‒2.71
(1H, m), 3.26 (1H, d, J = 13.4 Hz), 3.31 (1H, d, J = 13.4 Hz), 3.81 (1H, dd, J = 5.6, 10.2 Hz). 13C NMR
(D2O): 23.0, 27.3, 32.7, 40.1, 46.6, 48.0, 48.2, 56.6, 72.8. HRMS (ESI; m/z) [M+H]+ calcd for
C10H21N2O 185.1648, found 185.1649. Anal. Calcd. for C10H22Cl2N2O (257.20): C 46.70; H 8.62; Cl
27.57; N 10.89. Found: C 46.52; H 8.81; Cl 27.35; N 10.90.
4.15. General procedure for the reaction of aldehydes with diethylzinc in the presence of chiral
catalyst
To the respective catalyst (0.1 mmol), 1 M Et2Zn in n-hexane solution (3 mL, 3 mmol) was added under
an argon atmosphere at room temperature. The reaction was stirred for 25 min at room temperature, and
benzaldehyde (1 mmol) was then added to the solution, with subsequent stirring at room temperature for
a further 20 h. The reaction was quenched with saturated NH4Cl solution (15 mL) and the mixture was
extracted with EtOAc (2x20 mL). The combined organic phase was washed with H2O (10 mL), dried
(Na2SO4) and evaporated under vacuum. The crude secondary alcohols obtained were purified by flash
column chromatography (n-hexane/EtOAc = 4/1). The ee and absolute configuration of the resulting
material were determined by chiral GC, using a chiral stationary phase (Chirasil-Dex CB column) at
90 °C.33,34
Summary
A pinane-based 1,3-diaminoalcohol library has been developed starting from commercially available
(1R)-myrtenol. Stereoselective synthesis of the key intermedier epoxide was followed by regioselective
cleavage of the oxirane ring on the less substituted carbon in all cases. Under certain conditions the
formation of pinane-fused oxazolidinones was observed. As removal of trichloroacetyl protecting group
26

ACCEPTED MANUSCRIPT
was unsuccessful, a protecting group exchange was performed and the obtained N-Boc diaminoalcohols
were easily deprotected resulting in diaminoalcohols with combined primary, secondary or tertiary
amino functions. The obtained potential catalysts were applied in the reaction of benzaldehyde and
diethylzinc providing from low to moderate (S)-selectivities.
Acnowledgements
The authors are grateful for financial support from the Hungarian Research Foundation (OTKA K-
112442 and K-115731) and GINOP-2.3.2 -15-2016-00012. We also would like to thank Ákos
Vendrinszky for his participation in the experimental work.
Supplementary data
Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/...
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