Stereoselective syntheses and transformations of chiral 1,3-aminoalcohols and 1,3-diols derived from nopinone

Article abstract of DOI:10.1016/j.tetasy.2014.06.017

A library of 1,3-difunctionalized pinane derivatives were synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. 1,3-Aminoalcohol 6a was prepared from (-)-nopinone 2 via stereoselective Mannich condensation and reduction of the resulting β-amino ketone 4. The key aminoalcohol 6a was transformed into primary, secondary and tertiary substituted aminoalcohols in order to study the effect of the substituent on catalytic activity. Starting from (-)-nopinone, cis- and trans-β-hydroxy esters 15 and 16 were prepared in a two-step stereoselective synthesis. Reduction of the hydroxy esters resulted in pinane-based 1,3-diols, while hydrolysis of the esters, followed by DCC-mediated amidation and subsequent reduction, led to cis- and trans-N-benzyl-1,3-aminoalcohols 8 and 23. trans-N-Benzyl-1,3-aminoalcohol 8 was also prepared by selective mono-debenzylation of 6a via a continuous-flow process in an H-Cube system. The resulting aminoalcohols and diols were applied as chiral catalysts in the reaction of diethylzinc and benzaldehyde.

Full text of DOI:10.1016/j.tetasy.2014.06.017

Tetrahedron: Asymmetry 25 (2014) 1138–1145
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective syntheses and transformations of chiral
1,3-aminoalcohols and 1,3-diols derived from nopinone
a
a
a,b,
Zsolt Szakonyi a, , Tímea Gonda , Sándor Balázs Ötvös , Ferenc Fülöp
⇑
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
b Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2014
Accepted 25 June 2014
A library of 1,3-difunctionalized pinane derivatives were synthesized and applied as chiral catalysts in the
addition of diethylzinc to benzaldehyde. 1,3-Aminoalcohol 6a was prepared from (ꢀ)-nopinone 2 via
stereoselective Mannich condensation and reduction of the resulting b-amino ketone 4. The key aminoal-
cohol 6a was transformed into primary, secondary and tertiary substituted aminoalcohols in order to study
the effect of the substituent on catalytic activity. Starting from (ꢀ)-nopinone, cis- and trans-b-hydroxy
esters 15 and 16 were prepared in a two-step stereoselective synthesis. Reduction of the hydroxy esters
resulted in pinane-based 1,3-diols, while hydrolysis of the esters, followed by DCC-mediated amidation
and subsequent reduction, led to cis- and trans-N-benzyl-1,3-aminoalcohols 8 and 23. trans-N-Benzyl-
1,3-aminoalcohol 8 was also prepared by selective mono-debenzylation of 6a via a continuous-flow process
in an H-CubeÒ system. The resulting aminoalcohols and diols were applied as chiral catalysts in the reaction
of diethylzinc and benzaldehyde.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives derived from (ꢀ)- and (+)-apopinene and myrtenic
acid.6,13,14,22–25 It emerged that monoterpene-based 1,3-aminoal-
In recent decades, natural chiral terpenes, including (+)-pule-
gone,1–3 - and b-pinene4–6 and fenchone-camphor,7–9 have pro-
cohols prepared from the aforementioned b-amino acid derivatives
are excellent building blocks for the synthesis of various 1,3-het-
erocycles, for example 2-imino-1,3-oxazines, which possess
marked anti-cancer activity.26
Herein our aim was to synthesize a library of pinane-based chiral
1,3-difunctional synthons such as 1,3-aminoalcohols, b-hydroxy
esters and 1,3-diols by starting from (ꢀ)-nopinone, prepared from
commercially available (ꢀ)-b-pinene. We also planned to develop
a selective, partial debenzylation method in a flow hydrogenation
mesoreactor (H-CubeÒ) over a supported Pd catalyst and to evaluate
the resulting synthons as catalysts in the asymmetric addition of
Et2Zn to benzaldehyde.
a
ven to be excellent sources for the synthesis of various 1,2- and
1,3-difunctional synthons, such as 1,2- and 1,3-aminoalcohols,
which have been applied as useful starting materials in the stere-
oselective synthesis of compounds of pharmacological interest.
They have also served as chiral ligands and auxiliaries in enantio-
selective transformations.10–12
The conversion of enantiomerically pure a-pinene and 3-carene
into b-amino acid derivatives such as 1,3-aminoalcohols has
recently been reported.6,13,14 These synthons have been applied
as chiral auxiliaries in the enantioselective synthesis of secondary
alcohols or pharmacons, for example, esomeprasol or chiral sulfox-
ides.15–19
2. Results and discussion
In addition to their use in enantioselective catalysis, 1,3-amino-
alcohols are good starting points for the synthesis of various
heterocyclic ring systems such as 1,3-oxazines, 1,3-thiazines or
1,4-oxazepams.11,20,21
In recent years, we have devised novel pathways to synthesize
new monoterpene-based chiral b-lactams and b-amino acid
2.1. Syntheses of pinane-based 1,3-aminoalcohols and 1,3-diols
The key 1,3-aminoalcohol 6a was synthesized from (ꢀ)-nopinone
2, prepared from commercially available (ꢀ)-b-pinene 1 by a modi-
fication of a literature method.27,28 Compound 2 was converted into
a Mannich base with the diastereomeric ratios presented in Table 1.
Condensation of 2 with dimethylamine hydrochloride led to an
inseparable diastereomeric mixture 3a,29 whereas when dibenzyl-
⇑
Corresponding authors. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail addresses: szakonyi@pharm.u-szeged.hu (Z. Szakonyi), fulop@pharm.
amine hydrochloride or (R)-N-benzyl-a-methylbenzylamine
u-szeged.hu (F. Fülöp).
http://dx.doi.org/10.1016/j.tetasy.2014.06.017
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
1139
Table 1
b-hydroxy esters and 1,3-diols starting from (ꢀ)-nopinone 2. The
synthesis of b-keto ester 14 followed the literature method.32 Sub-
sequent reduction of 14 with NaBH4 resulted in cis-b-hydroxy ester
15 in a highly stereospecific reaction (cis/trans = 95:5; Scheme 3).
Under alkaline conditions, 15 underwent fast and complete isom-
erization at the carboxylic function, resulting in the trans-counter-
part 16 in an excellent yield. The relative configuration of the
stereogenic centres at the 2- and 3-positions was determined by
Synthesis of amino ketones 3–5 via Mannich condensation
Product
R1
R2
Yield (%)
dr (a/b)
3
4
5
Me
Bn
Me
Bn
Bn
81
66
25
85:15
100:0
100:0
(R)-CH(Me)Ph
hydrochloride was applied, the reaction proceeded highly stereose-
lectively, resulting in the formation of 4a and 5a as single diastere-
oisomers, although in the case of 5a the yield was dramatically
lower (25%) (Scheme 1).
O
O
i
The reduction of aminoketone 4a with LAH under mild condi-
tions resulted exclusively in the formation of trans-1,3-aminoalco-
hol 6a. The relative configuration of the stereogenic centres at the
2- and 3-positions was determined by NOESY measurement.
Debenzylation of 6a led to the key primary aminoalcohol 7.
Starting from 7, secondary and tertiary aminoalcohols 8–12 were
then synthesized (Scheme 2). Reductive alkylation of 7 with benz-
aldehyde, salicylaldehyde or acetone furnished N-monosubstituted
derivatives 8–10. Ring closure of 9, followed by LAH reduction, led
to N-benzyl-N-methyl derivative 11. Similar ring closure of 20-
hydroxybenzyl-substituted compound 9 with formaldehyde took
place regioselectively, resulting in N-substituted 1,3-benzoxazine
12 as the only product. In order incorporate the secondary alcohol
functional group, 6a was subjected to O-alkylation with benzyl
bromide and NaH, giving 13 in acceptable yield.
COOMe
14
2
ii
OH
OH
iii
COOMe
COOMe
16
15
iv
iv
OH
OH
OH
OH
Since alicyclic and bicyclic b-hydroxy esters and 1,3-diols might
serve as chiral catalysts or could be used as starting materials for
the synthesis of more complex 1,3-heterocycles,30,31 we decided
on the preparation and transformation of some pinane-based
18
17
Scheme 3. Reagents and conditions: (i) CO(OMe)2, NaH, 68%; (ii) NaBH4, MeOH,
0 °C, 92% (15:16 = 95:5); (iii) NaOMe, MeOH, rt, 3 h, 90%; (iv) LAH, THF, rt, 1 h,
60–78%.
O
O
O
i
ii
+
NR1R2
NR1R2
1
2
3-5a
3-5b
1
: R = R2 = Me;
: R1 = R2 = Bn;
4a,b
iii
3a,b
5a,b: R1 = Bn, R2 = (R)-CH(Me)Ph;
OH
OH
+
NBn2
NBn2
6a
6b
Scheme 1. Reagents and conditions: (i) 2 equiv NaIO4, cat. TBAB, cat. RuCl3, EtOAc/H2O, rt, 24 h, 85%; (ii) 1.18 equiv (CH2O)n, 1.08 equiv of amine hydrochloride, dry EtOH,
reflux, 1.5 h, 25–66%; (iii) R1 = R2 = Bn, 4 equiv LAH, THF, rt, 1.5 h, 85%.
OH
OH
OH
ii or iii
i
NHR1
NBn2
NH2
6a
7
8-10
v
vi
iv
OH
O
OH
OBn
NBn2
N
NR1R2
13
12
8: R1 = Bn; 9: R1 = 2'-HOC6H4CH2; 10: R1 = i-Pr; 11: R1 = Bn, R2 = Me
11
Scheme 2. Reagents and conditions: (i) 10% Pd/C, MeOH, 1 atm H2, rt, 12 h, 79%; (ii) 1 equiv PhCHO (8) or 20-HOC6H4CHO (9), dry EtOH, rt, 2 h, then 3 equiv NaBH4, dry EtOH,
rt, 1 h, 47–95%; (iii) dry acetone, rt, 2 h, then 3 equiv NaBH4, dry EtOH, rt, 1 h, 53%; (iv) R1 = Bn, CH2O/H2O, rt, 1 h, then 3 equiv LAH, THF, reflux, 3 h, 65%, (v) R1 = 20-
HOC6H4CH2, CH2O/H2O, rt, 1 h, 62%; (vi) BnBr, NaH, THF, reflux, 15 h, 88%.

1140
Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
NOESY measurements. Reduction of the cis- and trans-hydroxy
esters gave the corresponding pinane-based 1,3-diols 17 and 18.
Starting from 15 and 16, an alternative synthesis of N-benzyl-
the rapid screening of the reaction conditions, with an excellent
level of control over the most important parameters that deter-
mine the product selectivity.37,38 The H-CubeÒ system was oper-
ated in ‘Full H2’ mode to deliver the total amount of H2 produced
to the reaction zone. Aliquots of the reaction mixture containing
1 mg mLꢀ1 solution of 6a in MeOH/AcOH = 99:1 were pumped con-
tinuously through the system, and the most important reaction
parameters were systematically fine-tuned to obtain high conver-
sion and selective secondary amine formation.
substituted 1,3-aminoalcohol
8 and its cis-analogue 23 was
devised (Scheme 4). Alkaline hydrolysis of 16 with LiOH resulted
in the formation of trans-b-hydroxy acid 20. In view of the rapid
isomerization under alkaline conditions, the cis-analogue 19 was
prepared in an acidic medium. Compounds 19 and 20 were
successfully converted into amides 21 and 22 with benzylamine
in the presence of DCC. Upon reduction of the amides with LAH,
cis- and trans-1,3-aminoalcohols 23 and 8 were obtained.
Since Pd/C is commonly used when debenzylations are
performed in batch reactors, this was our initial choice of catalyst
(10% Pd/C).39 When a flow rate of 1 mL minꢀ1 was maintained at
80 °C, quantitative conversion was achieved, but no secondary
amine was obtained, with 7 being formed selectively (Table 2, entry
1). When the temperature was lowered to 50 °C, the desired second-
ary amine became detectable in the reaction mixture (entry 2); at
room temperature it was formed in a satisfactory ratio of 81%, while
the conversion remained quantitative (entry 3). The adjustment of
the flow rate is related to fine-tuning of the residence time on the
catalyst bed. We therefore attempted to improve the selectivity of
the N-debenzylation as a function of the flow rate. It was found that
at a flow rate of 1.5 mL minꢀ1, the proportion of 8 formed increased
slightly (85%), but at the expense of conversion (92%, entry 4). It was
demonstrated that the longer the residence time, the higher the for-
mation of the primary amine 7, since 8 was obtained in a proportion
of only 73% at a flow rate of 0.5 mL minꢀ1 (entry 5). In spite of the
above results, we were not totally satisfied, since the Pd/C catalyst
deactivated rapidly: a conversion of only 39% was achieved after
2 h of continuous use under the conditions shown in Table 2, entry
3. This was probably due to irreversible adsorption of the substrate
or the product(s) onto the catalyst carrier. We therefore changed the
catalyst to 5% Pd/BaSO4, with which the formation of the target sec-
ondary amine 8 was exclusive at room temperature with a flow rate
of 1 mL minꢀ1, with a high conversion of 91% being achieved (entry
6). Indeed, Pd/BaSO4 also proved to be a better choice in terms of
reusability, as a conversion of 59% was detected after 2 h of
continuous use (Scheme 5).
OH
OH
i or ii
COOMe
COOH
19,20
15,16
iii
OH
OH
iv
H
N
H
N
Ph
Ph
O
8,23
21,22
Scheme 4. Reagents and conditions: (i) 15, 10% HCl/H2O, Et2O, rt, 48 h, 65%; (ii) 16,
10% LiOH/H2O, Et2O, rt, 6 h, 85%; (iii) DCC, BnNH2, DCM, 0 °C to rt, 1 h, 27–45%; (iv)
LAH, THF, reflux, 2 h, 57–74%.
2.2. Selective synthesis of 8 in a flow hydrogenation
mesoreactor (H-CubeÒ)
Heterogeneous catalytic hydrogenations can gain significant
benefit from continuous-flow (CF) processing, due to the greatly
enhanced heat and mass transfer, and improved mixing proper-
ties.33–35 Thus, the synthesis of 8 was attempted in a dedicated
flow hydrogenation mesoreactor (H-CubeÒ), and an effective meth-
odology was developed for selective partial N-debenzylation over a
supported Pd catalyst. The H2 gas was produced by the electrolytic
decomposition of deionized water; the pyrophoric hydrogenation
catalyst was encompassed in a stainless steel cartridge.36 These
features allow for improved operational safety and simplicity com-
pared with the traditional batch process. The flow setup allowed
2.3. Application of pinane-based 1,3-aminoalcohols and diols as
chiral ligands in the enantioselective addition of diethylzinc to
benzaldehyde
The application of the prepared 1,3-aminoalcohols 6a–13 and
23, 1,3-diols 17 and 18 and amides 21 and 22 as catalysts in the
Table 2
Selective synthesis of 8 in a flow hydrogenation mesoreactor
Entry
Catalyst
T (°C)
Flow ratea (mL minꢀ1
)
Conversionb (%)
Selectivityb (%)
8
7
1
2
3
4
5
6
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
5% Pd/BaSO4
80
50
rt
rt
rt
1
1
1
1.5
0.5
1
Quantitative
Quantitative
Quantitative
92
Quantitative
91
0
23
81
85
73
100
77
19
15
27
0
rt
100
a
ccompd 8 = 1 mg mLꢀ1 in MeOH/AcOH = 99:1.
b
Determined by 1H NMR spectroscopic analysis of the crude material.
OH
OH
OH
Ph
H-Cube®
H
N
+
'Full H2' mode
Ph
NH2
N
Ph
7
8
6a
Scheme 5.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
1141
ethylation of benzaldehyde resulted in the formation of 1-phenyl-
1-propanol enantiomers 25 and 26 (Scheme 6).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker Avance DRX
400 spectrometer (400 MHz, d = 0 (TMS)), in the solvents indicated.
Chemical shifts are expressed in ppm (d) relative to TMS as an
internal reference. J values are given in Hz. 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 Work-
station data system (Perkin-Elmer Corporation Norwalk, USA). The
column used for the direct separation of enantiomers was a Chira-
sil-DEX CB column (2500 ꢁ 0.25 mm I.D.). Optical rotations were
obtained with a Perkin-Elmer 341 polarimeter. Melting points
were determined on a Kofler apparatus and are uncorrected. Chro-
matographic separations were carried out on Merck Kieselgel 60
(230–400 mesh ASTM). Reactions were monitored with Merck Kie-
selgel 60 F254-precoated TLC plates (0.25 mm thickness). All the
chemicals and solvents were used as supplied.
O
OH
OH
H
Et2Zn/n-hexane or toluene
+
rt or 0 °C, 10 mol% catalyst
6a-13, 17, 18, 21-23, Ar atm.
74-93%
24
25: (R)
26: (S)
Scheme 6. Catalysed addition of diethylzinc to benzaldehyde.
The enantiomeric purity of the secondary alcohol obtained was
determined by GC on a Chirasil-DEX CB column, according to a
literature method.40,41 Catalysts were applied in a 10% molar ratio
and the reactions were carried out in n-hexane or toluene at room
temperature or 0 °C. The results are presented in Table 3.
In the addition of Et2Zn in n-hexane solution to benzaldehyde,
low enantioselectivities were achieved in each case. The stereose-
lectivity was not improved either by changing the solvent to
toluene or by applying a lower temperature. The asymmetric
induction was similarly weak when diols 17 and 18 or amides 21
and 22 were used. The formation of the (S)-enantiomer 26 was pre-
dominant in most cases.
CF experiments were performed with the H-CubeÒ (Thales Nano)
flow system combined with a built-in electrolytic cell. Compounds 3
and 14 were prepared according to literature methods, and were
identical with the products reported therein.29,32 The configurations
of the new stereogenic centres in 6a, 8, 16 and 18 were determined
in NOESY experiments, based on the observation of NOE effects
between H-C(2) and H-C-7 and also between H-C(3) and Me-C(6).
Similarly, NOE effects were observed between H-C(2) and H-C(7)
and also between H-C(3) and H-C(7) in the cases of 15, 17 and 23.
We presume that the low catalytic activity observed was due to
the high steric hindrance of the endo-hydroxy group at the 2-posi-
tion, caused by the dimethylmethylene bridge of the pinane ring
system.
3. Conclusions
4.1.1. Modified method for the preparation of nopinone 2
To a solution of (ꢀ)-b-pinene 1 (10.20 g, 74.9 mmol) in H2O
(200 mL) and EtOAc (200 mL), RuCl3 (0.2 g, 0.96 mmol), NaIO4
(34.5 g, 0.16 mol) and TBAB (0.6 g, 1.9 mmol) were added. The mix-
ture was stirred for 24 h at room temperature. The organic and
aqueous phases were separated and the aqueous phase was
extracted with EtOAc (2 ꢁ 150 mL) The combined organic layer
was dried (Na2SO4), filtered and evaporated. The crude product
obtained was purified by vacuum distillation (8.80 g, 85%). All of
the physical and chemical properties of 2 were identical with those
reported in the literature.42
In conclusion, we have developed a library of new chiral
pinane-based 1,3-aminoalcohols, 1,3-diols and b-hydroxy amides
(7–13, 17, 18, and 21–23). A selective, partial debenzylation
method was achieved in a flow hydrogenation mesoreactor over
a supported Pd catalyst. From a catalytic aspect, our results
revealed that (probably because of the appreciable steric influence
of the bicyclic ring system) a stable transition state could not be
formed in the reactions of the applied catalysts and Et2Zn, and their
catalytic activity was therefore lower compared with other mono-
terpene-based 1,3-difunctional catalysts.
Table 3
Addition of diethylzinc to benzaldehyde, catalysed by various types of 1,3-aminoalcohols, 1,3-diols and b-hydroxy amides
Entry
Catalyst (10 mol %)
Solvent
T
Yielda (%)
eeb (%)
Config. of major productc
1
2
3
4
5
6
7
8
6a
6a
6a
6a
7
n-Hexane
n-Hexane
Toluene
rt
0 °C
rt
0 °C
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
84
82
85
80
78
87
82
86
81
83
86
86
88
80
81
80
74
16
8
3
(S)
(S)
(R)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
Toluene
4
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
Toluene
14
13
9
6
2
8
9
10
11
12
13
17
18
21
22
22
23
9
10
11
12
13
14
15
16
17
6
8
13
14
18
26
16
4
n-Hexane
a
b
C
Yields after silica column chromatography.
Determined on the crude product by GC (Chirasil-DEX CB column).
Determined by comparing the GC analysis tR and the specific rotation with the literature data.40,41

1142
Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
4.1.2. General procedure for the preparation of amino ketones
4a and 5a
NMR measurement). 7: 0.90 g (93%); pale-orange crystals;
20 = +39 (c 0.250, MeOH); 1H NMR (CDCl3) d (ppm): 0.65 (1H,
[a]
D
To a solution of (+)-nopinone 2 (2.76 g, 20.0 mmol) in dry EtOH
(8.0 mL), paraformaldehyde (0.71 g, 23.6 mmol) and then diben-
zylamine hydrochloride or (R)-N-benzyl-1-phenylethylamine
hydrochloride (21.5 mmol) were added and the mixture was
refluxed for 1.5 h. The solvent was evaporated off and the residue
was dissolved in CH2Cl2 (200 mL). The solution was washed with
5% aqueous KOH (150 mL) and the aqueous phase was extracted
with CH2Cl2 (2 ꢁ 100 mL). The combined organic layer was dried
(Na2SO4), filtered and evaporated. The crude product was purified
by column chromatography on silica gel (n-hexane/EtOAc = 9:1).
d, J = 10.1 Hz), 1.10 (3H, s), 1.24 (3H, s), 1.28 (1H, ddd, J = 2.1, 5.6,
12.3 Hz), 1.92–2.31 (5H, m), 2.68 (1H, dd, J = 6,5, 12.3 Hz), 2.80
(1H, dd, J = 6.5, 12.3 Hz), 3.82–3.88 (1H, m); 13C NMR (CDCl3) d
(ppm): 22.7, 28.0, 30.1, 31.3, 38.2, 41.8, 42.6, 48.8, 51.1, 78.9. Anal.
Calcd for C10H19NO (169.26): C, 70.96; H, 11.31; N, 8.28. Found:
C, 70.84; H, 11.26; N, 8.30.
4.1.5. (1R,2S,3R,5R)-3-Benzylaminomethyl-6,6-dimethylbicyclo
[3.1.1]heptan-2-ol 8
Method A: To a solution of 7 (1.95 g, 11.5 mmol) in dry EtOH
(200 mL), benzaldehyde (1.23 g, 11.6 mmol) was added in one por-
tion, and the solution was stirred at room temperature for 1 h and
then evaporated to dryness. The residual product was dissolved in
dry EtOH (200 mL) and stirred for a further 1 h. Next, NaBH4
(1.30 g, 34.4 mmol) was added in small portions to the mixture
under ice cooling. After stirring for 1 h, the mixture was evaporated
to dryness, and the residue was dissolved in H2O and extracted
with CHCl3 (3 ꢁ 150 mL). The combined organic layer was dried
(Na2SO4), filtered and evaporated to dryness. The crude product
obtained was purified by column chromatography on silica gel
(toluene/EtOH = 4:1)
4.1.2.1. (1R,3R,5R)-3-Dibenzylaminomethyl-6,6-dimethylbicyc-
lo [3.1.1]heptan-2-one 4a. Compound 4a: 4.98 g (66%); white crystals;
mp: 145–147 °C; [a]D
20 = +118 (c 0.177, MeOH); 1H NMR (CDCl3) d
(ppm): 0.82 (3H, s), 0.99 (1H, d, J = 10.9 Hz), 1.27 (3H, s), 1.97–2.01
(2H, m), 1.84–1.91 (1H, m), 2.10–2.16 (1H, m), 2.30–2.38 (1H, m),
2.47 (1H, t, J = 5.3 Hz), 2.59 (1H, dd, J = 11.4, 22.2 Hz), 2.61–2.69 (1H,
m), 2.84 (1H, dd, J = 4.1, 10.9 Hz), 3.34 (2H, d, J = 13.4 Hz), 3.83 (2H, d,
J = 13.3 Hz), 7.19–7.38 (10H, m); 13C NMR (CDCl3) d (ppm): 22.4, 25.9,
26.2, 27.1, 40.4, 43.0, 58.7, 58.8, 60.0, 127.4, 128.6, 129.4, 139.9,
215.8. Anal. Calcd for C24H29NO (347.49): C, 82.95; H, 8.41; N, 4.03.
Found: C, 82.75; H, 8.47; N, 4.12.
Method B: To a slurry of LiAlH4 (88 mg, 2.32 mmol) in freshly
distilled THF (10 mL), 21 (200 mg, 0.73 mmol) in freshly distilled
THF (15 mL) was added dropwise at room temperature. The mix-
ture was then refluxed for 2 h (the reduction was monitored by
means of TLC), and the mixture was decomposed with H2O
(0.2 g) in THF (3 mL) under ice cooling. The inorganic material
was filtered off, washed with THF, dried (Na2SO4), filtered and
evaporated to dryness. The residue was dissolved in Et2O and
extracted with 5% aqueous HCl solution (4 ꢁ 10 mL). The aqueous
layer was basified with 10% KOH solution and extracted with
CH2Cl2 (4 ꢁ 20 mL). The organic layer was dried (Na2SO4), filtered
and evaporated to dryness. 10: Method A: 1.41 g (47%), Method
4.1.2.2. (1R,3R,5R)-3-{[N-Benzyl-N-((R)-1-phenylethyl)amino]me-
thyl}-6,6-dimethylbicyclo[3.1.1]heptan-2-one 5a. Compound 5a:
1.05 g (29%); a colourless oil; [a]
20 = +89 (c 0.18, MeOH); 1H NMR
D
(CDCl3) d (ppm): 0.77 (3H, s), 1.14 (1H, d, J = 10.7 Hz), 1.28 (3H, s),
1.43 (3H, d, J = 7.0 Hz), 1.85–1.93 (1H, m), 1.99–2.07 (1H, m), 2.14–
2.20 (1H, m), 2.36–2.53 (3H, m), 2.66 (1H, t, J = 12.4 Hz), 2.81 (1H,
dd, J = 5.3, 12.5 Hz), 3.40 (1H, d, J = 14.2 Hz), 3.75 (2H, d,
J = 14.2 Hz), 3.85–3.93 (1H, m), 7.19–7.38 (10H, m). Anal. Calcd for
C25H31NO (361.52): C, 83.06; H, 8.64; N, 3.87. Found: C, 83.17;
H, 8.47; N, 3.99.
B: 0.14 g (74%); white crystals; mp: 76–78 °C; [a]
20 = +40 (c
D
4.1.3. (1R,2S,3R,5R)-3-Dibenzylaminomethyl-6,6-dimethylbicy-
clo[3.1.1]heptan-2-ol 6a
0.24, MeOH); 1H NMR (CDCl3) d (ppm): 0.63 (1H, d, J = 10.1 Hz),
1.11 (3H, s), 1.24 (3H, s), 1.22–1.32 (1H, m), 1.90–1.96 (1H, m),
2.05–2.19 (4H, m), 2.24–2.32 (1H, m), 2.76 (1H, dd, J = 5.1,
11.2 Hz), 2.54 (1H, dd, J = 9.8, 11.2 Hz), 3.83 (2H, dd, J = 7.2,
13.0 Hz), 3.85–3.89 (1H, m), 7.22–7.34 (5H, m); 13C NMR (CDCl3)
d (ppm): 22.7, 28.2, 30.9, 31.5, 38.3, 40.4, 42.0, 48.8, 54.6, 58.8,
To a slurry of LiAlH4 (2.5 g, 65.9 mmol) in THF (150 mL), com-
pound 4a (5.0 g, 14.4 mmol) in THF (150 mL) was added dropwise
at room temperature. After stirring for 1.5 h (the reduction was
monitored by means of TLC), the mixture was decomposed with
H2O (12.5 g) in THF (100 mL) under ice cooling. The inorganic
material was filtered off and washed with THF. Drying (Na2SO4)
and evaporation gave the crude product, which was purified by
column chromatography on silica gel (n-hexane/EtOAc = 4:1). 6a:
80.3, 127.4, 128.5, 128.8, 140.7. Anal. Calcd for
C17H25NO
(259.39): C, 78.72; H, 9.71; N, 5.40. Found: C, 78.91; H, 9.65;
N, 5.30.
4.25 g (85%); white crystals; mp: 52–54 °C; [
a
]
D
20 = +39 (c 0.250,
4.1.6. (1R,2S,3R,5R)-3-(2-Hydroxybenzylaminomethyl)-6,6-di-
methylbicyclo[3.1.1]heptan-2-ol 9
To a solution of 7 (0.20 g, 1.18 mmol) in dry EtOH (20 mL), salicyl-
aldehyde (126 lL, 1.18 mmol) was added. The mixture was stirred
MeOH); 1H NMR (CDCl3) d (ppm): 0.35 (1H, d, J = 10.2 Hz), 1.07
(3H, s), 1.20 (3H, s), 1.15–1.23 (1H, m), 1.84–1.91 (1H, m), 1.96–
2.09 (2H, m), 2.12–2.20 (1H, m), 2.23–2.34 (1H, m), 2.38 (1H, dd,
J = 5.6, 12.1 Hz), 2.48 (1H, dd, J = 10.3, 12.2 Hz), 3.41 (1H, d,
J = 13.2 Hz), 3.60 (1H, dd, J = 2.7, 4.9 Hz), 3.82 (1H, d, J = 13.2 Hz),
7.21–7.37 (10H, m); 13C NMR (CDCl3) d (ppm): 22.8, 28.2, 30.8,
31.3, 37.5, 38.3, 42.1, 48.4, 59.4, 63.5, 79.9, 127.5, 128.7, 129.5,
for 1 h at room temperature and then evaporated to dryness. The
residue was dissolved in dry EtOH (20 mL), the solution was stirred
for 30 min, and NaBH4 (0.13 g, 3.44 mmol) was then added cau-
tiously in small portions. The mixture was stirred for 12 h at room
temperature. The solvent was then removed and the residue
obtained was dissolved in H2O and extracted with CH2Cl2. The
organic layer was dried (Na2SO4), filtered and evaporated to dryness.
The crude product was purified by column chromatography on silica
139.5. Anal. Calcd for
C24H31NO (349.51): C, 82.47; H, 8.94;
N, 4.01. Found: C, 82.25; H, 8.90; N, 4.09.
4.1.4. (1R,2S,3R,5R)-3-Aminomethyl-6,6-dimethylbicyclo[3.1.1]
heptan-2-ol 7
gel (toluene/EtOH = 4:1). 9: 0.31 g (95%); a yellow oil; [a]
20 = +66 (c
D
To a suspension of palladium-on-carbon (10% Pd, 0.3 g) in
MeOH (100 mL), compound 6a (2.00 g, 5.7 mmol) was added and
the mixture was stirred under an H2 atmosphere at room temper-
ature and normal pressure. When the reaction was completed (as
monitored by TLC, 12 h), the mixture was filtered through a Celite
pad and the solution was evaporated to dryness, resulting in the
formation of primary aminoalcohol 7 in high purity (based on
0.250, MeOH); 1H NMR (CDCl3) d (ppm): 0.65 (1H, d, J = 10.4 Hz),
0.86 (1H, d, J = 6.6 Hz), 1.09 (3H, s), 1.24 (3H, s), 1.34 (1H, dd,
J = 2.5, 7.5 Hz), 1.92–1.99 (1H, m), 2.03–2.09 (1H. m), 2.16–2.32
(3H, m), 2.74 (2H, d, J = 7.1 Hz), 3.87 (1H. t, J = 3.3 Hz), 4.04 (2H,
dd, J = 13.9, 17.1 Hz), 6.78 (1H, dt, J = 1.2, 7.3 Hz), 6.86 (1H, d,
J = 8.10), 7.01 (1H, d, J = 7.5 Hz), 7.17 (1H, dt, J = 7.6, 1.6 Hz). 13C
NMR (CDCl3) d (ppm): 22.6, 27.8, 29.9, 31.6, 38.0, 38.8, 41.6, 49.2,

Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
1143
53.0, 57.9, 78.9, 116.8, 119.4, 122.6, 128.8, 129.2, 158.4. Anal. Calcd
for C17H25NO2 (275.39): C, 74.14; H, 9.15; N, 5.09. Found: C, 73.87; H,
9.23; N, 5.17.
MeOH); 1H NMR (CDCl3) d (ppm): 0.66 (1H, d, J = 10.2), 1.12 (3H,
s), 1.19–1.27 (4H, m), 1.91–1.96 (1H, m), 2.06–2.15 (2H, m),
2.23–2.33 (2H, m), 2.61 (1H, t, J = 12.2 Hz), 2.91 (1H, dd, J = 5.9,
12.2 Hz), 3.96 (1H, br s), 4.06 (2H, br s), 4.81–5.04 (2H, m), 6.78
(1H, d, J = 8.1 Hz), 6.87 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 7.5 Hz),
7.11 (1H, t, J = 7.7 Hz). 13C NMR (CDCl3) d (ppm): 22.7, 28.0, 30.5,
31.2, 38.0, 38.3, 42.0, 48.5, 50.8, 61.3, 79.9, 83.6, 116.8, 120.4,
120.9, 128.0, 128.1, 154.5. Anal. Calcd for C18H25NO2 (287.40): C,
75.22; H, 8.77; N, 4.87. Found: C, 74.91; H, 8.89; N, 5.00.
4.1.7. (1R,2S,3R,5R)-3-Isopropylaminomethyl-6,6-dimethylbicy-
clo[3.1.1]heptan-2-ol 10
A solution of 7 (0.3 g, 1.77 mmol) in dry acetone (25 mL) was
stirred for 1 h at room temperature and then evaporated to dry-
ness. The residue was dissolved in dry EtOH (25 mL), and NaBH4
(0.20 g, 5.29 mmol) was added cautiously in small portions. The
mixture was stirred for 12 h at room temperature. The solvent
was then removed and the residue was dissolved in H2O and
extracted with CH2Cl2. The organic layer was dried (Na2SO4), fil-
tered and evaporated to dryness. The crude product was purified
by column chromatography on silica gel (CHCl3/MeOH = 1:2). 10:
4.1.10. N,N-Dibenzyl-1-((1R,2S,3R,5R)-2-benzyloxy-6,6-dimethyl
bicyclo[3.1.1]heptan-3-yl)methanamine 13
A solution of 6a (0.48 g, 1.37 mmol) in freshly distilled THF
(12 mL) was added to a suspension of NaH (60% in mineral oil,
350 mg, 8.8 mmol) in freshly distilled THF (3 mL) under an Ar
0.20 g (53%); yellow crystals; mp 54–57 °C;
[
a]
20 = +104 (c
atmosphere. A solution of benzyl bromide (176 lL, 1.48 mmol)
D
0.250, MeOH); 1H NMR (CDCl3) d (ppm): 0.65 (1H, d, J = 10.2 Hz),
1.08 (6H, d, J = 6.3 Hz), 1.11 (3H, s), 1.24 (3H, s) 1.25–1.31 (1H,
m), 1.91–2.19 (5H, m), 2.26–2.33 (1H, m), 2.50 (1H, t,
J = 10.7 Hz), 2.77 (1H, dd, J = 5.1, 11.1 Hz), 2.79–2.86 (1H, m),
3.85 (1H, dd, J = 2.7, 4.9 Hz). 13C NMR (CDCl3) d (ppm): 22.6, 23.3,
23.5, 28.2, 31.1, 31.6, 38.2, 40.7, 42.0, 48.6, 49.4, 56.7, 80.4. Anal.
Calcd for C13H25NO (211.34): C, 73.66 H; 11.92 N; 6.63. Found: C,
73.89 H; 11.69 N; 6.48.
was then added. The mixture was stirred for 15 h at reflux temper-
ature, after which H2O (3 mL) was added dropwise. The THF was
evaporated off and the mixture was diluted with H2O (10 mL)
and extracted with EtOAc (3 ꢁ 30 mL). The organic layer was dried
(Na2SO4), filtered and evaporated to dryness. The crude product
obtained was purified by column chromatography on silica gel
(n-hexane/EtOAc = 19:1). Isolated compound 13: 0.53 g (88%); a
colourless oil; [a]
20 = +171 (c 0.255, MeOH); 1H NMR (CDCl3) d
D
(ppm): 0.40 (1H, dd, J = 10.0 Hz), 1.06 (3H, s), 1.17 (3H, s), 1.40–
1.50 (1H, m), 1.85–1.91 (1H, m), 2.06–2.20 (2H, m), 2.22–2.51
(4H, m), 3.42 (1H, t, J = 3.6 Hz), 3.56 (4H, dd, J = 13.5, 52.5 Hz),
4.50 (2H, dd, J = 11.8, 52.7 Hz), 7.16–7.37 (15 H, m).13C NMR
(CDCl3) d (ppm): 22.7, 27.7, 28.3, 31.5, 34.9, 38.1, 42.0, 43.9, 58.6,
63.9, 70.6, 85.6, 127.1, 127.4, 127.7, 128.4, 128.5, 129.5, 139.9.
Anal. Calcd for C30H34NO (424.60): C, 84.86; H, 8.07; N, 3.30.
Found: C, 85.02; H, 8.00; N, 3.22.
4.1.8. (1R,2S,3R,5R)-3-(N-Benzyl-N-methylaminomethyl)-6,6-di
methylbicyclo[3.1.1]heptan-2-ol 11
To a solution of compound 8 (2.27 g, 8.8 mmol) in Et2O (20 mL),
33% aqueous CH2O solution (60 mL) was added, and the mixture
was stirred for 1 h at room temperature. The layers were separated
and the aqueous layer was extracted with Et2O (2 ꢁ 100 mL). The
combined organic layer was dried (Na2SO4), filtered and evaporated.
The crude product obtained was flashed on a thin silica gel column
(n-hexane/EtOAc = 4:1), evaporated to dryness and then used with-
out further purification. To a slurry of LiAlH4 (1.14 g, 30.0 mmol) in
THF (80 mL), the crude product (5.00 g, 6.6 mmol) in THF (70 mL)
was added dropwise at room temperature. After refluxing for 8 h
(the reduction was monitored by means of TLC), the mixture was
cooled and the LiAlH4 was decomposed with H2O (2.5 g) in THF
(50 mL) under ice cooling. The inorganic material was filtered off
and washed with THF. Drying (Na2SO4) and evaporation gave the
crude product, which was purified as the hydrochloride salt. 11:
4.1.11. Stereoselective reduction of oxoester 14
A solution of compound 14 (6.00 g, 30.6 mmol) in MeOH
(400 mL) was cooled to 0 °C, and NaBH4 (3.48 g, 92.0 mmol) was
added in small portions. The mixture was stirred for 1 h at 0 °C
(the reaction was monitored by means of TLC), after which 5%
aqueous HCl was then added (40 mL) and the MeOH was evapo-
rated off at room temperature. Next, cold H2O was added and the
mixture was extracted with CH2Cl2 (2 ꢁ 200 mL). The combined
organic layer was dried (Na2SO4), filtered and evaporated. The
crude product obtained was purified by column chromatography
on silica gel to give compounds 15 and 16 (n-hexane/EtOAc = 4:1).
1.57 g (65%); white crystals; mp: 146–150 °C;
[a]
20 = +23 (c
D
0.250, MeOH); 1H NMR (CDCl3) d (ppm), two rotamers in a 1:1 ratio
were observed: 0.56 (1H, d, J = 10.0 Hz), 0.59 (1H, d, J = 10.0 Hz), 1.04
(3H, s), 1.05 (3H, s), 1.19 (3H, s), 1.28–1.36 (1H, m), 1.85–2.01 (2H,
m), 2.13–2.26 (2H, m), 2.50–2.54 (1H, m), 2.70 (3H, s), 2.76 (3H, s),
2.93–3.21 (2H, m), 3.72–3.81 (1H, m), 4.10 (1H, br s), 4.23–4.56
(2H, m), 7.40–7.70 (5H, m); 13C NMR (CDCl3) d (ppm): 23.2, 28.3,
28.4, 29.8, 30.0, 32.0, 32.8, 34.7, 34.9, 37.9, 41.5, 41.6, 48.7, 48.8,
52.0, 59.3, 59.8, 63.5, 63.7, 76.2, 76.4, 129.5, 129.8, 130.4, 130.7,
132.3, 132.4, 138.0. Anal. Calcd for C18H27ClNO (309.87): C, 69.77;
H, 9.11; N, 4.40. Found: C, 69.89; H, 9.35; N, 4.25.
4.1.11.1. (1R,2S,3R,5R)-Methyl 2-hydroxy-6,6-dimethylbicyclo
[3.1.1]heptane-3-carboxylate 15. Compound 15: 5.15 g (85%); a
yellow oil; [
a
]
20 = ꢀ10 (c 0.240, MeOH); 1H NMR (CDCl3) d
D
(ppm): 1.00 (3H, s), 1.15 (3H, s), 1.17 (1H, d, J = 10.1 Hz), 1.75–
1.90 (2H, m), 2.00–2.13 (2H, m), 2,32 (1H, dd, J = 9.0, 12.3 Hz),
3.25 (1H, dd, J = 9.0, 17.8 Hz), 3.59 (3H, s), 4.39–4.45 (1H, m),
4.84 (1H, d, J = 5.0 Hz); 13C NMR (CDCl3) d (ppm): 23.5, 26.5,
26.9, 28.5, 38.9, 40.3, 48.0, 51.8, 71.9, 174.1. Anal. Calcd for
C11H18O3 (198.26): C, 66.64; H, 9.15. Found: C, 66.76; H, 9.12.
4.1.9. (1R,2S,3R,5R)-3-[(2H-Benz[e][1,3]oxazin-3(4H)-yl)methyl]
-6,6-dimethylbicyclo[3.1.1]heptan-2-ol 12
To a solution of 9 (0.20 g, 0.73 mmol) in Et2O (5 mL), 33% aque-
ous CH2O solution (6 mL) was added and the mixture was stirred
for 1 h at room temperature. The mixture then was basified with
10% cold aqueous KOH (pH = 10). The aqueous layer was extracted
with Et2O (2 ꢁ 20 mL). The combined organic layer was washed
with saturated NaCl solution (3 ꢁ 30 mL), then dried (Na2SO4), fil-
tered and evaporated to dryness. The crude product obtained was
purified by column chromatography on silica gel (n-hexane/
4.1.11.2. (1R,2S,3S,5R)-Methyl 2-hydroxy-6,6-dimethylbicyclo
[3.1.1]heptane-3-carboxylate 16. Compound 16: 0.18 g (3%);
white crystals; mp: 29–30 °C; [a]
20 = +50 (c 0.250, MeOH); 1H
D
NMR (CDCl3) d (ppm): 0.78 (1H, d, J = 10.1 Hz), 1.01 (3H, s), 1.19
(3H, s), 1.75–1.83 (1H, m), 1.85–1.92 (1H, m), 1.94–1.99 (1H, m),
2.15–2.28 (2H, m), 2.76–2.85 (1H, m), 3.64 (3H, s), 4.16–4.22
(1H, m), 4.93 (1H, d, J = 4.1 Hz). 13C NMR (CDCl3) d (ppm): 23.0,
28.2, 28.8, 30.1, 37.5, 41.9, 44.7, 48.2, 52.5, 74.3, 177.8. Anal. Calcd
for C11H18O3 (198.26): C, 66.64; H, 9.15. Found: C, 66.78; H 9.01.
EtOAc = 4:1). 12: 0.13 g (62%); a yellow oil; [a]
20 = +58 (c 0.260,
D

1144
Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
4.1.12. Isomerization of 15 to 16
ture was stirred for 1 h at room temperature (the reaction was
monitored by means of TLC). The solution was acidified (pH = 2)
with 10% aqueous HCl, and then extracted with CH2Cl2. The organic
layer was dried (Na2SO4), filtered and evaporated to dryness. 20:
Compound 15 (0.54 g, 2.7 mmol) was dissolved in dry MeOH
(10 mL) and the solution was added to a solution of Na (0.013 g,
0.57 mmol) in dry MeOH (10 mL). The mixture was stirred at room
temperature for 3 h (the reaction was monitored be means of TLC).
The solution was evaporated down to 10 mL, and Et2O (80 mL)
was then added. The mixture was extracted with ice-cold H2O
(2 ꢁ 50 mL). The organic layer was dried (Na2SO4), filtered and evap-
orated. The crude product obtained was purified by column chroma-
tography on silica gel (n-hexane/EtOAc = 4:1). 16: 0.46 g (85%).
0.39 g (85%); white crystals; mp: 93–96 °C; [a]
20 = +57 (c 0.250,
D
MeOH); 1H NMR (CDCl3) d (ppm): 0.84 (1H, d, J = 10.3 Hz), 1.10
(3H, s), 1.26 (3H, s), 1.98–2.18 (3H, m), 2.25–2.37 (2H, m), 3.05
(1H, m), 4.42 (1H, dd, J = 3.0, 4.9 Hz). 13C NMR (CDCl3) d (ppm):
22.6, 27.8, 28.9, 29.5, 37.6, 41.0, 44.9, 47.9, 75.9, 182.1. Anal. Calcd
for C10H16O3 (184.23): C, 65.19; H, 8.75. Found: C, 65.03; H, 8.91.
4.1.13. (1R,2S,3S,5R)-3-Hydroxymethyl-6,6-dimethylbicyclo
[3.1.1]heptan-2-ol 17
4.1.17. (1R,2S,3S,5R)-N-Benzyl-2-hydroxy-6,6-dimethylbicyclo
[3.1.1]heptane-3-carboxamide 21
To a slurry ofLiAlH4 (0.34 g, 9.0 mmol) in THF (30 mL), compound
15 (0.89 g, 4.5 mmol) in THF (20 mL) was added dropwise at room
temperature. After stirring for 1 h (the reduction was monitored
by means of TLC), the mixture was decomposed with H2O (1.0 g)
in THF (20 mL) under ice cooling. The inorganic material was filtered
off and washed withTHF. Drying (Na2SO4) and evaporation led to the
crude product, which was purified by column chromatography on
silica gel (n-hexane/EtOAc = 9:1). Isolated compound 17:
A solution of 20 (1.19 g, 6.46 mmol) in dry CH2Cl2 (50 mL) was
cooled to 0 °C, and DCC was added (1.33 g, 6.46 mmol). The mixture
was stirred for 1 h at 0 °C, after which benzylamine (0.8 mL,
7.3 mmol) was added. When the reaction was complete (monitored
by means of TLC, 1 h), the mixture was washed with saturated
NaHCO3 solution (2 ꢁ 30 mL). The organic layer was dried (Na2SO4),
filtered and evaporated to dryness. The crude product obtained was
purified by column chromatography on silica gel (n-hexane/
EtOAc = 1:1). 21: 0.80 g (45%); white crystals; 103–106 °C;
0.60 g (78%); white crystals; mp: 30–31 °C; [a]
20 = +27 (c 0.235,
D
MeOH); 1H NMR (CDCl3) d (ppm): 0.96 (3H, s), 1.15 (3H, s), 1.18
(1H, d, J = 9.1 Hz), 1.48 (1H, dd, J = 9.2, 12.5 Hz), 1.79–1.90 (2H, m),
2.00–2.10 (2H, m), 2.20–2.32 (1H, m), 3.42 (1H, dt, J = 6.2, 10.3 Hz),
3.64–3.71 (1H, m), 4.19–4.29 (3H, m). 13C NMR (CDCl3) d (ppm):
23.6, 26.0, 28.6, 29.4, 35.6, 38.9, 41.2, 48.1, 63.6, 72.5. Anal. Calcd
for C10H18O2 (170.25): C, 70.55; H, 10.66. Found: C, 70.75; H, 10.51.
[a]
20 = +47 (c 0.265, MeOH); 1H NMR (CDCl3) d (ppm): 0.95 (1H,
D
d, J = 10.3 Hz), 1.09 (3H, s), 1.26 (3H, s), 1.99–2.08 (2H, m), 2.08–
2.17 (1H, m), 2.18–2.25 (1H, m), 2.27–2.34 (1H, m), 2.77–2.85
(1H, m), 4.26 (1H, dd, J = 2.8, 5.1 Hz), 4.42–4.54 (2H, m), 6.23 (1H,
br s), 7.27–7.37 (5H, m). 13C NMR (CDCl3) d (ppm): 22.6, 25.6,
25.9, 27.9, 28.2, 29.7, 37.7, 41.1, 44.1, 45.8, 48.7, 77.3, 127.8,
128.0, 129.0, 138.9, 176.1. Anal. Calcd for C17H23NO2 (273.37): C,
74.69; H, 8.48; N, 5.12. Found: C, 74.33; H, 8.57; N, 5.21.
4.1.14. (1R,2S,3R,5R)-3-Hydroxymethyl-6,6-dimethylbicyclo
[3.1.1]heptan-2-ol 18
To a slurry of LiAlH4 (0.85 g, 22.4 mmol) in THF (60 mL), com-
pound 16 (2.23 g, 11.3 mmol) in THF (25 mL) was added dropwise
at room temperature. After stirring for 1 h (the reduction was mon-
itored by means of TLC), the mixture was decomposed with H2O
(2.4 g) in THF (25 mL) under ice cooling. The inorganic material
was filtered off and washed with THF. Drying (Na2SO4) and evapo-
ration led to the crude product, which was purified by column
chromatography on silica gel (n-hexane/EtOAc = 9:1). 18: 1.14 g
4.1.18. (1R,2S,3R,5R)-N-Benzyl-2-hydroxy-6,6-dimethylbicyclo
[3.1.1]heptane-3-carboxamide 22
A solution of 19 (0.25 g, 1,36 mmol) in dry CH2Cl2 (15 mL) was
cooled to 0 °C, and DCC was added (0.28 g, 1.36 mmol). The mix-
ture was stirred for 1 h at 0 °C, after which benzylamine (163 lL,
1.48 mmol) was added. When the reaction was complete (moni-
tored by means of TLC, 1 h), the mixture was washed with
saturated NaHCO3 solution (2 ꢁ 30 mL). The organic layer was
dried (Na2SO4), filtered and evaporated to dryness. The crude prod-
uct obtained was purified by column chromatography on silica gel
(n-hexane/EtOAc = 2:1). 22: 95 mg (27%); white crystals; 97–
(60%); white crystals; mp: 32–35 °C; [a]
20 = +47 (c 0.250, MeOH);
D
1H NMR (CDCl3) d (ppm): 0.69 (1H, d, J = 9.9 Hz), 1.02 (3H, s), 1.17
(3H, s), 1.48 (1H, dd, J = 2.8, 8.5 Hz), 1.81–2.02 (4H, m), 2.07–2.15
(1H, m), 3.29 (1H, dt, J = 6.2, 9.9 Hz), 3.45 (1H, dt, J = 4.6, 9.8 Hz),
3.61–3.67 (1H, m), 4.45–4.53 (3H, m); 13C NMR (CDCl3) d (ppm):
23.1, 28.4, 29.1, 30.3, 38.1, 41.8, 41.9, 48.6, 67.5, 74.9. Anal. Calcd
for C10H18O2 (170.25): C, 70.55; H, 10.66. Found: C, 70.23; H, 10.86.
100 °C; [
a
]
D
20 = ꢀ10 (c 0.250, MeOH); 1H NMR (CDCl3) d (ppm):
1.16 (3H, s), 1.19 (1H, d, J = 10.4 Hz), 1.23 (3H, s), 1.98–2.04 (1H,
m), 2.05–2.14 (1H, m), 2.18–2.31 (3H, m), 3.09 (1H, dd, J = 9.3,
17.6 Hz), 4.51 (2H, d, J = 4.8 Hz), 4.56 (1H, dd, J = 4.8, 7.9 Hz), 6.12
(1H, br s), 7.27–7.34 (5H, m). 13C NMR (CDCl3) d (ppm): 22.5,
25.9, 27.9, 28.8, 38.8, 40.0, 40.7, 43.9, 47.0, 73.0, 127.9, 128.1,
129.1, 138.4, 174.9. Anal. Calcd for C17H23NO2 (273.37): C, 74.69;
H, 8.48; N, 5.12. Found: C, 74.81; H, 8.39; N, 5.14.
4.1.15. (1R,2S,3R,5R)-2-Hydroxy-6,6-dimethylbicyclo[3.1.1]hep-
tane-3-carboxylic acid 19
To a solution of 15 (100 mg, 0.5 mmol) in Et2O (5 mL), 10% aque-
ous HCl (5 mL) was added. The mixture was stirred vigorously for
3 days at room temperature (the reaction was monitored by means
of TLC). The aqueous layer was then extracted with Et2O (3 ꢁ 30 mL).
The combined organic layer was dried (Na2SO4), filtered and evapo-
rated to dryness. 19: 60 mg (65%); white crystals; mp: 59–62 °C
4.1.19. (1R,2S,3S,5R)-3-Benzylaminomethyl-6,6-dimethylbicyclo
[3.1.1]heptan-2-ol 23
To a slurry of LiAlH4 (176 mg, 4.6 mmol) in freshly distilled THF
(10 mL), 22 (0.40 g, 1.54 mmol) in freshly distilled THF (15 mL)
was added dropwise at room temperature. The mixture was refluxed
for 2 h (the reduction was monitored by means of TLC), after which
the mixture was then decomposed with H2O (0.2 g) in THF (3 mL)
underice cooling. The inorganicmaterial was filtered off and washed
with THF, and the filtrate was dried (Na2SO4), filtered and evapo-
rated to dryness. The crude product obtained was purified by col-
umn chromatography on silica gel (toluene/ethanol = 4:1). 23:
[a]
20 = +2 (c 0.250, MeOH); 1H NMR (CDCl3) d (ppm): 1.09 (3H, s),
D
1.18 (1H, d, J = 10.0 Hz), 1.24 (3H, s), 1.98–2.11 (2H, m), 2.21–2.31
(2H, m), 2.37–2.46 (1H, m), 3.31 (1H, dd, J = 9.4, 18.0 Hz), 4.63 (1H,
dd, J = 4.5, 8.1 Hz). 13C NMR (CDCl3) d (ppm): 22.7, 26.3, 26.9, 27.8,
38.7, 40.4, 46.9, 72.9, 179.7. Anal. Calcd for C10H16O3 (184.23): C,
65.19; H, 8.75. Found: C, 65.37; H, 8.52.
4.1.16. (1R,2S,3S,5R)-2-Hydroxy-6,6-dimethylbicyclo[3.1.1]hep-
tane-3-carboxylic acid 20
To a solution of 16 (0.50 g, 2.52 mmol) in THF (20 mL), H2O
(20 mL) and LiOHꢂH2O (0.21 g, 5.00 mmol) were added. The mix-
0.26 g, (57%); white crystals; 36–39 °C; [a]
20 = +46 (c 0.255,
D
MeOH); 1H NMR (CDCl3) d (ppm): 1.03 (3H, s), 1.16 (1H, d,
J = 10.0 Hz), 1.21 (3H, s), 1.28 (1H, d, J = 14.1 Hz), 1.43–1.53
(1H, m), 1.84–1.95 (2H, m), 2.12–2.20 (1H, m), 2.21–2.28 (1H, m),

Z. Szakonyi et al. / Tetrahedron: Asymmetry 25 (2014) 1138–1145
1145
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4.1.20. 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 Ar atmosphere at
room temperature. The reaction was stirred for 25 min at room
temperature or 0 °C (see Table 3), and benzaldehyde (1 mmol)
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a chiral stationary phase
(Chirasil-Dex CB column) at 90 °C.40,41
4.1.21. Selective synthesis of 8 in a flow hydrogenation mesore-
actor
For the CF reactions, the catalyst cartridge (internal dimensions:
30 mm ꢁ 4 mm) was filled with 100 mg of the appropriate hydroge-
nation catalyst (see Table 2). For small-scale test reactions, 10 mg of
6a were dissolved in 10 mL of MeOH/AcOH = 99:1. The solution was
homogenized by sonication, and then pumped through the H-CubeÒ
reactor under the selected conditions. Between the two reactions,
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with a mixture of toluene/EtOH = 4:1 as eluent, and the solvent
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and finally evaporated. The products were identified by 1H NMR as 7
and 8.
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Acknowledgements
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We are grateful to the Hungarian Research Foundation (OTKA
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