Synthesis and application of monoterpene-based chiral aminodiols

Article abstract of DOI:10.1016/j.tet.2007.07.065

Primary, secondary and tertiary aminodiols were synthetized regio- and stereoselectively from (-)-α-pinene 1 via α-pinene oxide 2, (-)-trans-pinocarveol 3 and key intermediate epoxy alcohol 4. N-Benzyl derivative 5 was transformed to spiro-fused oxazolidine 13 in a highly regioselective ring closure. Aminodiols and their derivatives 5-13 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde, resulting in chiral 1-phenyl-1-propanol. The substituent effect on the nitrogen was studied in detail and the best enantioselectivity was observed in the case of N-methyl-N-benzyl-substituted derivative 8. The phenomenon was interpreted by using molecular modelling at an ab initio level.

Full text of DOI:10.1016/j.tet.2007.07.065

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1034–1039
Synthesis and application of monoterpene-based
chiral aminodiols
a
Zsolt Szakonyi, Anasztazia Hetenyi and Ferenc Fulop
a
a,b,
*
ꢀ
ꢀ
€ €
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eo€tvo€s utca 6, Hungary
bResearch Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged,
Eo€tvo€s utca 6, Hungary
Received 7 June 2007; revised 6 July 2007; accepted 19 July 2007
Available online 26 July 2007
ꢀ
Dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract—Primary, secondary and tertiary aminodiols were synthetized regio- and stereoselectively from (ꢀ)-a-pinene 1 via a-pinene oxide
2, (ꢀ)-trans-pinocarveol 3 and key intermediate epoxy alcohol 4. N-Benzyl derivative 5 was transformed to spiro-fused oxazolidine 13 in
a highly regioselective ring closure. Aminodiols and their derivatives 5–13 were applied as chiral catalysts in the enantioselective addition
of diethylzinc to benzaldehyde, resulting in chiral 1-phenyl-1-propanol. The substituent effect on the nitrogen was studied in detail and
the best enantioselectivity was observed in the case of N-methyl-N-benzyl-substituted derivative 8. The phenomenon was interpreted by using
molecular modelling at an ab initio level.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
hols and their application as chiral ligands and auxiliaries in
enantioselective transformations are currently undergoing
intensive investigation.7,11 Various amino alcohol catalysts
derived from monoterpenes, such as (+)-pulegone,12 b-
pinene,13 fenchone–camphor14 and limonene,15 have been
reported to have been used successfully in enantioselective
syntheses. Chiral aminodiols and their derivatives also find
excellent application as catalysts for enantioselective trans-
formations.16–20
Aliphatic aminodiols play important roles in drug therapy
and drug research.1–7 For example, chloramphenicol, one
of the earliest antibiotics, is an aminodiol derivative, other
aminodiols have been found to act as HIV protease inhibi-
tors,1–3 and still others have been shown to exert renin inhib-
itor activity.5,6 Furthermore, aminodiols may serve as useful
starting materials for the synthesis of biologically active
natural compounds, e.g., cytoxazone, a selective modulator
of the secretion of TH2 cytokine, a microbial metabolite
isolated from Streptomyces species.8,9 Apart from the phar-
macological interest, aminodiols are also useful starting
materials for the syntheses of oxazines or oxazolidines, de-
pending upon which hydroxy group undergoes ring closure
with the amino group.10 Since the resulting heterobicycles
contain a free hydroxy group, further ring closure can yield
heterotricyclic structures. Moreover, alicyclic aminodiols
are potentially excellent starting points for the development
of new ring–chain tautomeric systems.10
We recently reported the transformations of enantiomeri-
cally pure a-pinene and 3-carene to b-amino acid deriva-
tives, such as amino esters and amino alcohols, which
proved to be excellent building blocks for the syntheses of
monoterpene-fused saturated 1,3-heterocycles and were
also applied as chiral auxiliaries in enantioselective reac-
tions of diethylzinc with aromatic aldehydes.21–24 In the
present work, our aim was to build up an aminodiol library,
starting from readily available a-pinene, and to apply the re-
sulting aminodiols as chiral catalysts in the enantioselective
addition of diethylzinc to aromatic aldehydes.
The identification of new chiral ligands for asymmetric
syntheses is of increasing importance in organic chemistry.
The readily available chiral terpenes and their derivatives
are widely used as chiral auxiliaries in enantioselective
transformations. The syntheses of 1,2- and 1,3-amino alco-
2. Results and discussion
2.1. Synthesis of aminodiols 5–13
The enantiomeric epoxy alcohol 4 was synthetized stereose-
lectively by a combination of literature methods.25–27 The
synthetic route for epoxy alcohol 4 is shown in Scheme 1.
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705; e-mail:
fulop@pharm.u-szeged.hu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.065

Z. Szakonyi et al. / Tetrahedron 64 (2008) 1034–1039
1035
OH
O
OH
Starting from commercially available (ꢀ)-a-pinene 1,
Ph
Ph
N
NR1R2 ii
N
i
Ph
epoxidation with MCPBA furnished epoxide 2 in a stereo-
specific reaction.25 In the presence of 1 mol % of aluminium
isopropoxide at 100–120 ꢁC, a-pinene oxide rearranges to
pinocarveol 3.27 Epoxidation of allylic alcohol 3 with
MCPBA resulted in epoxy alcohol 4 in a stereospecific
reaction.26
O
OH
OH
Ph
5, 7
12
13
Scheme 3. Reaction conditions (i) NaH, PhCH2Br, dry THF, rt, 24 h, 50%
from 7; (ii) CH2O/H2O, 1 h, rt, 80% from 5.
2.2. Applications of aminodiols 5–13
i
O
The aminodiol derivatives 5–13 were applied as chiral
catalysts in the enantioselective addition of diethylzinc to
benzaldehyde, resulting in chiral 1-phenyl-1-propanol
(Scheme 4).
1
2
ii
O
iii
OH
O
OH
H
Et2Zn/n-hexane
OH
OH
+
4
rt, 10 mol% catalyst
5-13, Ar atm.
3
14
(R)-15
(S)-16
Scheme 1. Reaction conditions: (i) MCPBA, DCM, rt, 6 h, 82%; (ii)
Al(OiPr)3, toluene, reflux, 2 h, 70%; (iii) MCPBA, DCM, Na2HPO4 buffer,
rt, 12 h, 60%.
Scheme 4. Addition of diethylzinc to benzaldehyde.
Our results are presented in Table 1. The enantiomeric
purities of the 1-phenyl-1-propanols 15 and 16 obtained
were determined by GC on a CHIRASIL-DEX CB column,
according to literature methods.24,28,29 The observed enan-
tioselectivities were low to good and in all cases predomi-
nantly the (S) enantiomer was formed. The best result was
attained with N-benzyl-N-methyl-substituted aminodiol 8.
In the case of piperidine derivative 9, no selectivity was
achieved. It was also found that O-alkylation of any of the
alcohol functional groups caused a decrease in enantioselec-
tivity. As compared with the previous results on 1,3-amino
alcohols,24 it seems that tridentate monoterpene-based
aminodiols are more successful catalysts than bidentate
monoterpene-based 1,3-amino alcohols24 in the reactions
of diethylzinc with aromatic aldehydes.
Aminolysis of epoxy alcohol 4 with secondary amines
towards tertiary aminodiols 6–9 was performed in two dif-
ferent ways (Scheme 2). When mixtures of 4 and secondary
amines were heated, long reaction times (7 days) and low
yields were observed, probably because of the steric hin-
drance. Shorter reaction times (1–3 days) and better yields
were achieved when lithium perchlorate was applied as
catalyst for the ring-opening process.16
Secondary and primary aminodiols were obtained in two
different ways: N-benzylaminodiol 5 was obtained by the
reaction of 4 (Scheme 1) with benzylamine under similar
conditions as applied for tertiary aminodiols, while the
N-methyl derivative and primary aminodiol were prepared
by debenzylation of the corresponding N,N-dibenzyl- and
N-benzyl-N-methylaminodiols 7 and 8 under standard
conditions by hydrogenation in the presence of palladium-
on-carbon catalyst (Scheme 2).
For the best catalyst 8, the relationship between the amount
of the catalyst and the enantioselectivity observed was also
examined. When the quantity of 8 was decreased from 10
to 5 mol %, the enantioselectivity remained at ee¼84%. A
lower amount of catalyst led to decreases both in the enantio-
selectivity and in the yield of the reaction (2.5 mol % 8:
ee¼76%, 75% yield; 1 mol % 8: ee¼70%, 62% yield).
Starting from the N,N-dibenzyl derivative 7, O-benzyl deriv-
ative 12 was prepared. The reaction was accomplished by
regioselective alkylation of 7 with benzyl bromide in the
presence of sodium hydride. The quaternary hydroxy group
was incorporated into a spiro-fused oxazoline 13 with form-
aldehyde by regioselective ring closure of N-benzyl deriva-
tive 5 (Scheme 3).
Table 1. Influence of catalyst loading on the yields and enantioselectivity
according to Schemes 2 and 3
Entry Ligand
(10 mol %)
R1
R2
Yielda eeb
(%)
Major
(%) enantiomer
OH
OH
1
2
3
4
5
6
7
8
9
10
11
5
6
7
H
H
H
Et
H
Me
CH2Ph 92
Et 85
88
85
54
64
56
68
72
84
0
S
S
S
S
S
S
—
S
S
NR1R2
NR1R2
iii
i or ii
O
OH
OH
OH
5: R1 = H, R2 = CH2Ph
6: R1 = R2 = Et
10: R1 = R2 = H
4
CH2Ph CH2Ph 89
Me CH2Ph 87
11: R1 = H, R2 = Me
8
9
7: R1 = R2 = CH2Ph
(CH2)5
87
60
87
8: R1 = Me, R2 = CH2Ph
9: R1 = R2 = (CH2)5
12c
13c
32
60
a
Scheme 2. Preparation of primary, secondary and tertiary aminodiols: (i)
4 equiv HNR1R2, MeOH, reflux, 7 days, 19–40%; (ii) 4 equiv HNR1R2,
1 equiv LiClO4, MeOH, reflux, 1–3 days, 45–74%; (iii) 10% Pd/C,
MeOH, H2, 1 atm, 95%.
Yields are given after silica gel column chromatography.
Determined on the crude product by chiral GC (CHIRASIL-DEX CB
column).
See Scheme 3.
b
c

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Z. Szakonyi et al. / Tetrahedron 64 (2008) 1034–1039
In order to interpret the N-substituent-induced difference in
enantioselectivity, molecular modelling was performed for
8. Although the arsenal used for such theoretical studies
extends from the molecular mechanics force-field fine-
tuned for transition states30 to the ab initio methods at
the DFT level,31 it can be considered clear-cut that the
modelling of the Noyori m-oxo transition state following
the QM/MM ONIOM approach14,32,33 gives acceptably
accurate results for design purposes at a reasonable com-
putational cost. We therefore utilized the QM/MM ONIOM
modelling protocol in this work. The inner cores of
the transition structures were optimized ab initio (HF/
LanL2DZ), while Rappe’s universal force field (UFF)
was employed for the ligands and the phenyl groups
(Fig. 1). Ethyl groups were replaced by methyl groups to
eliminate conformational freedom because this modifica-
tion was not expected to cause significant errors in the
trends of relative energies. The m-oxo transition state
possesses three stereogenic centres (Fig. 1); one of them
is locked by the functional groups of aminodiol 8, leading
to four diastereomers, which were optimized by using
the transition state-searching algorithm implemented in
Gaussian03.
Figure 2. Lowest-energy structure (Zn-S, C-S) obtained for 8.
3. Conclusion
The monoterpene-based aminodiols prepared may serve as
chiral building blocks in the asymmetric syntheses of
potential pharmacons, and they can also be used as chiral
auxiliaries and catalysts in enantioselective syntheses. Sub-
stituent-dependent enantioselectivity was observed in the
sequence NH2<NHR<NRR, with the limitation that too
large substituents can probably inhibit the formation of
the transition complex. The theoretical calculations pro-
vided an explanation for the enantioselectivity and may
serve as the starting point for the design of further enantio-
selective catalysts.
The diastereomers are designated by their absolute chirality
on Zn, and on the carbon at the reaction centre. The geome-
tries were preoptimized by using the PM3 semi-empirical
method, and the final geometries were obtained at the
ONIOM (HF/LanL2DZ:UFF). The final structures showed
only a single imaginary frequency corresponding to the alkyl
transfer. The relative stabilities of the transition state diaste-
reomers calculated from the single-point energies at the full
HF/LanL2DZ level are given in Table 2. It is clear from these
results that the lowest-energy transition state diastereomers
are in good accordance with the experimental enantio-
selectivity. The calculations suggest that the transalkylation
most probably proceeds via diastereomer Zn-S, C-S, for 8
(Fig. 2).
4. Experimental
4.1. General experimental procedures
1H and 13C NMR spectra were recorded on a Bruker AV 600
spectrometer (600 MHz, d¼0 (TMS)), in an appropriate
solvent. Chemical shifts are expressed in parts per million
(d) relative to TMS as internal reference. J values are given
in hertz. Microanalyzes were performed on a Perkin–Elmer
2400 elemental analyzer. 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 Kiesel-
gel 60 (230–400 mesh, ASTM). Reactions were monitored
with Merck Kieselgel 60 F254-precoated TLC plates
(0.25 mm thickness). All the chemicals and solvents were
used as supplied.
UFF
N
O
*
Zn
O
R
O
Zn
*
*
CH3
HF/LanL2DZ
Figure 1. Favourable transition state proposed for Et2Zn addition.
GC measurements were made on a Chrompack CP-9002
system, consisting of a Flame Ionization detector 901A
and a Maestro II Chromatography data system (Chrompack
International B.V., Middelburg, The Netherlands). The col-
umn used for the direct separation of 1-phenyl-1-propanol
and for the enantiomer excess determination in the case
of epoxy alcohol was a CHIRASIL-DEX CB column
(2500ꢂ0.25 mm I.D.) operated at 80 ꢁC (4) or 120 ꢁC (15
and 16), and 140 kPa.
Table 2. Ab initio HF/LanL2DZ single-point energies calculated for m-oxo
complex of 8
Zn
C
E (RHF)/au
(EꢀEmin)/
(kcal/mol)
R
R
S
R
S
S
ꢀ1449.052971
ꢀ1449.038909
ꢀ1449.054772
ꢀ1449.044227
1.13
9.95
0.00
6.62
S
R

Z. Szakonyi et al. / Tetrahedron 64 (2008) 1034–1039
1037
Compounds 2–4 were prepared from (1S,5S)-(ꢀ)-a-pinene
(Aldrich Co.) according to literature methods (ee for com-
pound 4 was found by GC measurement to be >95%).25–27
4.2.3. (1R,2S,3S,5R)-2-Dibenzylaminomethyl-6,6-di-
methylbicyclo[3.1.1]heptane-2,3-diol (7). Compound 7
was prepared according to the general procedure given in
Section 4.2.
4.2. General procedure for the synthesis of tertiary
aminodiols 5–9
Compound 7 (Method A: 32% yield; Method B: 55% yield
(reaction time: 48 h)); mp 62–63 ꢁC; [a]D20 ꢀ10.5 (c 0.25,
MeOH); 1H NMR (CDCl3) d (ppm): 0.56 (3H, s), 1.14 (3H,
s), 1.39 (1H, d, J¼10.3 Hz), 1.54–1.61 (1H, m), 1.78–1.86
(2H, m), 2.07–2.15 (1H, m), 2.19–2.28 (1H, m), 2.58 (1H,
d, J¼13.6 Hz), 2.68 (1H, d, J¼13.6 Hz), 3.41 (1H, br s),
3.56 (2H, d, J¼13.2 Hz), 3.75 (1H, dd, J¼6.0, 9.3 Hz),
3.87 (2H, d, J¼13.2 Hz), 4.41 (1H, br s), 7.23–7.37 (10H,
m); 13C NMR (CDCl3) d (ppm): 23.8, 27.9, 28.0, 36.7,
38.5, 40.4, 52.3, 60.6, 63.3, 67.8, 74.6, 127.4, 128.5, 129.2,
138.8. Anal. Calcd for C24H31NO2 (365.51): C, 78.86; H,
8.55; N, 3.83%. Found: C, 79.02; H, 8.29; N, 3.95%.
Method A: a solution of the appropriate amine (4.8 mmol) in
MeOH (10 mL) was added to a solution of epoxy alcohol 4
(0.20 g, 1.2 mmol) in MeOH (15 mL) and the mixture was
refluxed for 7 days (the reaction was monitored by means
of TLC). Removal of the solvent provided yellow, oily prod-
ucts. The crude products were purified by flash chromato-
graphy on silica gel (toluene/EtOH¼4:1), resulting in
compounds 5–9.
Method B: a solution of the appropriate amine (48 mmol) in
MeCN (15 mL) and LiClO4 (1.28 g, 12 mmol) was added to
a solution of epoxy alcohol 4 (2.00 g, 12 mmol) in MeCN
(150 mL) and the mixture was refluxed for 1–3 days (the re-
action was monitored by means of TLC). When the reaction
was completed, the mixture was evaporated to dryness, and
the residue was dissolved in water (50 mL) and extracted
with CHCl3 (3ꢂ50 mL). The organic layer was dried
(Na2SO4), filtered and concentrated. The crude product
was purified by flash column chromatography on silica gel
(toluene/EtOH¼4:1), resulting in compounds 5–9.
4.2.4. (1R,2S,3S,5R)-2-[(Benzylmethylamino)methyl]-
6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol (8). Compound
8 was prepared according to the general procedure given in
Section 4.2.
Compound 8 (Method A: 30% yield; Method B: 50% yield
(reaction time: 24 h)); an oil; [a]2D0 ꢀ18.0 (c 0.25, MeOH);
1H NMR (CDCl3) d (ppm): 0.79 (3H, s), 1.21 (3H, s), 1.46
(1H, d, J¼10.3 Hz), 1.64–1.73 (1H, m), 1.84–1.91 (1H,
m), 1.93 (1H, t, J¼5.7 Hz), 2.12–2.21 (1H, m), 2.31–2.35
(1H, m), 2.38 (3H, s), 2.53 (1H, d, J¼13.1 Hz), 2.64 (1H,
d, J¼13.1 Hz), 3.58 (1H, d, J¼13.1 Hz), 3.67 (1H, d,
J¼13.1 Hz), 3.92 (1H, dd, J¼5.3, 9.1 Hz), 7.23–7.37 (5H,
m); 13C NMR (CDCl3) d (ppm): 24.1, 27.8, 37.3, 38.7,
40.4, 44.8, 52.8, 64.3, 67.4, 68.2, 74.0, 127.4, 128.4,
129.1, 138.4. Anal. Calcd for C18H27NO2 (289.41): C,
74.70; H, 9.40; N, 4.84%. Found: C, 74.38; H, 9.46;
N, 5.19%.
4.2.1. (1R,2S,3S,5R)-2-Benzylaminomethyl-6,6-di-
methylbicyclo[3.1.1]heptane-2,3-diol (5). Compound 5
was prepared according to the general procedure given in
Section 4.2.
Compound 5 (Method A: 40% yield; Method B: 63% yield
(reaction time: 72 h)); mp 53–55 ꢁC; [a]D20 ꢀ11.0 (c 0.25,
1
MeOH); H NMR (CDCl3) d (ppm): 0.84 (3H, s), 1.23
(3H, s), 1.45 (1H, d, J¼10.3 Hz), 1.65 (1H, ddd, J¼2.2,
5.9, 13.9 Hz), 1.87–1.92 (1H, m), 1.96 (1H, t, J¼5.9 Hz),
2.16–2.22 (1H, m), 2.38–2.45 (1H, m), 2.67 (2H, dd,
J¼1.0, 12.3 Hz), 3.25 (1H, br s), 3.82 (2H, dd, J¼13.2,
19.9 Hz), 4.10 (2H, dd, J¼5.9, 9.4 Hz), 7.23–7.35 (5H, m);
13C NMR (CDCl3) d (ppm): 24.2, 28.0, 28.1, 37.1, 38.7,
40.6, 51.3, 54.2, 59.0, 67.7, 74.6, 127.2, 128.2, 128.5,
139.8. Anal. Calcd for C17H25NO2 (275.39): C, 74.14; H,
9.15; N, 5.09%. Found: C, 73.82; H, 9.09; N, 5.41%.
4.2.5. (1R,2S,3S,5R)-6,6-Dimethyl-2-piperidin-1-yl-
methylbicyclo[3.1.1]heptane-2,3-diol hydrochloride (9).
Compound 9 was prepared according to the general proce-
dure given in Section 4.2, with the modification that it was
purified as the hydrochloride. The base liberated for catalytic
usage was a viscous oil.
Compound 9 (Method A: 19% yield; Method B: 74% yield
(reaction time: 24 h)); mp 233–234 ꢁC; [a]D20 ꢀ3.0 (c 0.25,
1
4.2.2. (1R,2S,3S,5R)-2-Diethylaminomethyl-6,6-di-
methylbicyclo[3.1.1]heptane-2,3-diol (6). Compound 6
was prepared according to the general procedure given in
Section 4.2.
MeOH); H NMR (CDCl3) d (ppm): 0.90 (3H, s), 1.27
(3H, s), 1.39 (1H, d, J¼10.9 Hz), 1.43–1.51 (1H, m), 1.76–
1.86 (4H, m), 1.90–1.94 (1H, m), 2.02 (1H, t, J¼5.6 Hz),
2.16–2.27 (2H, m), 2.40–2.54 (2H, m), 2.81–2.90 (2H, m),
2.92 (1H, dd, J¼7.7, 13.5 Hz), 3.12 (1H, d, J¼13.6 Hz),
3.58 (1H, d, J¼12.0 Hz), 4.15 (1H, d, J¼12.0 Hz), 4.29–
4.34 (1H, m), 5.11 (1H, s), 6.27 (1H, d, J¼6.8 Hz); 13C
NMR (CDCl3) d (ppm): 21.8, 22.0, 22.2, 24.3, 26.4, 27.3,
36.9, 38.1, 39.8, 53.4, 27.2, 27.7, 64.9, 73.8. Anal. Calcd
for C15H28ClNO2 (289.84): C, 62.16; H, 9.74; N, 4.83%.
Found: C, 62.46; H, 9.83; N, 5.00%.
Compound 6 (Method A: 25% yield; Method B: 74% yield
(reaction time: 60 h)); an oil; [a]2D0 ꢀ10.0 (c 0.25, MeOH);
1H NMR (CDCl3) d (ppm): 0.92 (3H, s), 1.03 (6H, t,
J¼7.1 Hz), 1.25 (3H, s), 1.47 (1H, d, J¼10.2 Hz), 1.73
(1H, ddd, J¼2.7, 4.8, 13.9 Hz), 1.88–1.93 (1H, m), 1.96
(1H, t, J¼5.9 Hz), 2.14–2.22 (1H, m), 2.36–2.45 (1H, m),
2.62 (1H, d, J¼10.5 Hz), 2.64 (4H, dd, J¼7.1, 17.6 Hz),
3.92 (1H, dd, J¼4.9, 9.1 Hz); 13C NMR (CDCl3) d (ppm):
12.0, 24.2, 27.7, 27.8, 37.9, 38.7, 40.4, 48.5, 53.3,
64.4, 68.9, 72.8. Anal. Calcd for C14H27NO2 (241.37): C,
69.66; H, 11.27; N, 5.80%. Found: C, 69.43; H, 11.33;
N, 6.27%.
4.3. General procedure for the synthesis of aminodiols
10 and 11
To a suspension of palladium-on-carbon (10%, 0.10 g) in
MeOH (10 mL) was added aminodiol 7 or 8 (1.3 mmol) in

1038
Z. Szakonyi et al. / Tetrahedron 64 (2008) 1034–1039
MeOH (15 mL), and the resulting mixture was stirred under
a H2 atmosphere at room temperature. When the reaction
was complete, as indicated by TLC, the solution was filtered
through a Celite pad and the solvent was removed, affording
a colourless oily product 10 or 11, which crystallized upon
standing at ca. 4 ꢁC. The crystalline product was recrystal-
lized from n-hexane.
7.43 (15H, m); 13C NMR (CDCl3) d (ppm): 23.5, 27.4,
27.5, 35.5, 38.0, 40.4, 50.7, 60.8, 62.3, 71.2, 73.4, 12.8,
127.7, 127.8, 128.1, 128.4, 129.6, 140.0. Anal. Calcd for
C31H37NO2 (455.63): C, 81.72; H, 8.19; N, 3.07%. Found:
C, 81.55; H, 8.37; N, 3.41%.
4.5. (1R,2S,3S,5R)-30-Benzyl-6,6-dimethylspiro-
[bicyclo[3.1.1]heptane-2,50-oxazolidin]-3-ol (13)
4.3.1. (1R,2S,3S,5R)-2-Aminomethyl-6,6-dimethyl-
bicyclo[3.1.1]heptane-2,3-diol (10). Compound 10 was
prepared according to the general procedure given in
Section 4.3.
Amino alcohol 5 (0.25 g, 0.9 mmol) was stirred with 10 mL
of 35% aqueous formaldehyde at room temperature for 1 h.
The mixture was made alkaline with 10% aqueous KOH and
extracted with Et2O (3ꢂ30 mL). The combined organic
phase was dried (Na2SO4) and evaporated to give an almost
colourless oil, which was purified by flash chromatography
on silica gel (n-hexane/EtOAc¼3:2, Rf¼0.45), resulting in
compound 13.
Compound 10 (0.35 g, 70% yield); mp 62–64 ꢁC; [a]D20 ꢀ7.0
(c 0.25, EtOH); 1H NMR (CDCl3) d (ppm): 0.91 (3H, s), 1.24
(3H, s), 1.44 (1H, d, J¼10.3 Hz), 1.66 (1H, ddd, J¼2.5, 5.5,
13.9 Hz), 1.87–1.93 (1H, m), 1.98 (1H, t, J¼5.8 Hz), 2.20
(1H, dtd, J¼2.2, 6.0, 14.6 Hz), 2.39–2.49 (1H, m), 2.67
(1H, d, J¼12.5 Hz), 2.72 (1H, d, J¼12.5 Hz), 3.29 (2H, br
s), 4.06 (2H, dd, J¼5.6, 9.4 Hz); 13C NMR (CDCl3)
d (ppm): 24.3, 27.9, 28.0, 37.6, 38.7, 40.6, 50.4, 51.3,
66.8, 74.8. Anal. Calcd for C10H19NO2 (185.26): C, 64.83;
H, 10.34; N, 7.56%. Found: C, 65.21; H, 9.98; N, 7.36%.
Compound 13 (0.24 g, 93% yield); an oil; [a]2D0 +6.0 (c 0.25,
MeOH); 1H NMR (CDCl3) d (ppm): 0.80 (3H, s), 1.26 (3H,
s), 1.54 (1H, d, J¼10.3 Hz), 1.86 (1H, td, J¼3.2, 14.2 Hz),
1.90–1.96 (1H, m), 2.12 (1H, t, J¼5.6 Hz), 2.18–2.25 (1H,
m), 2.30–2.39 (1H, m), 2.82 (1H, d, J¼11.0 Hz), 2.96 (1H,
d, J¼11.0 Hz), 3.66 (1H, d, J¼4.8 Hz), 3.76 (1H, d,
J¼13.1 Hz), 3.82 (2H, d, J¼13.1 Hz), 3.98–4.04 (1H, m),
4.32 (1H, d, J¼4.4 Hz), 4.38 (1H, d, J¼4.4 Hz), 7.23–7.35
(5H, m); 13C NMR (CDCl3) d (ppm): 23.2, 26.7, 27.0,
37.1, 38.9, 39.8, 51.6, 57.5, 65.3, 69.4, 85.2, 85.5, 127.3,
128.4, 128.5, 138.5. Anal. Calcd for C18H25NO2 (287.40):
C, 75.22; H, 8.77; N, 4.87%. Found: C, 75.23; H, 8.39;
N, 5.30%.
4.3.2. (1R,2S,3S,5R)-6,6-Dimethyl-2-methylamino-
methylbicyclo[3.1.1]heptane-2,3-diol (11). Compound 11
was prepared according to the general procedure given in
Section 4.3.
Compound 11 (0.60 g, 86% yield); mp 78–79 ꢁC; [a]D20 ꢀ4.0
1
(c 0.25, MeOH); H NMR (CDCl3) d (ppm): 0.95 (3H, s),
1.26 (3H, s), 1.45 (1H, d, J¼10.4 Hz), 1.65–1.75 (1H, m),
1.86–2.05 (3H, m), 2.14–2.26 (1H, m), 2.66 (3H, s), 2.72
(1H, d, J¼12.0 Hz), 3.04 (1H, d, J¼12.0 Hz), 3.46 (1H, s),
4.36 (1H, dd, J¼4.9, 9.0 Hz), 5.60 (1H, s); 13C NMR
(CDCl3) d (ppm): 24.3, 27.5, 27.6, 34.8, 37.5, 38.3, 40.4,
51.9, 60.6, 64.9, 73.5. Anal. Calcd for C11H21NO2
(199.29): C, 66.29; H, 10.62; N, 7.03%. Found: C, 66.60;
H, 10.49; N, 7.35%.
4.6. Typical experimental procedure for the reaction of
aldehydes with diethylzinc in the presence of chiral
catalyst 5–14
To a solution of 5 (41 mg, 0.15 mmol) in dry n-hexane
(2 mL), 1 M Et2Zn in n-hexane solution (4.5 mL, 4.5 mmol)
was added under an Ar atmosphere at room temperature.
The reaction mixture was stirred for 25 min at room temper-
ature, and benzaldehyde (0.16 g, 1.5 mmol) in dry toluene
was then added to it for 5 min. The reaction mixture was
next stirred at room temperature for a further 20 h. The reac-
tion was quenched with saturated NH4Cl solution (20 mL)
and extracted with EtOAc (2ꢂ30 mL). The combined
organic phase was washed with water (20 mL), dried
(Na2SO4) and evaporated under vacuum. The crude alcohol
obtained was purified by flash column chromatography (n-
hexane/EtOAc¼4:1), resulting in pure 1-phenyl-1-propanol.
The enantiomeric excess and absolute configuration were
determined by chiral GC, using a chiral stationary phase
(Chirasil-Dex CB column), and the direction of the optical
rotation of the products was checked. The spectroscopic
data on the alcohols prepared were in all cases similar to
those in the literature.24,28,29
4.4. (1R,2S,3S,5R)-3-Benzyl-2-dibenzylaminomethyl-
6,6-dimethylbicyclo[3.1.1]heptane-2,3-diol (12)
To a stirred suspension of NaH (2.46 mmol) in 16 mL of dry
THF was added 3 mL of a THF solution of aminodiol 7
(0.30 g, 0.82 mmol). After 30 min, a solution of benzyl bro-
mide (0.15 g, 0.90 mmol) in 3 mL of THF was added via
a syringe and the mixture was stirred at room tempera-
ture for 24 h. The reaction was quenched by the addition
of 1 mL of water. The THF was removed under reduced
pressure and the residue was extracted with CHCl3 (3ꢂ
30 mL). The organic layer was washed with brine, dried
(Na2SO4), filtered and concentrated. The crude product was
purified by flash column chromatography on silica gel (n-
hexane/EtOAc¼2:1, Rf¼0.40), resulting in compound 12.
Compound 12 (0.20 g, 54% yield); an oil; [a]2D0 ꢀ4.5 (c 0.25,
MeOH); 1H NMR (CDCl3) d (ppm): 0.28 (3H, s), 1.14 (3H,
s), 1.49–1.53 (1H, m), 1.76–1.81 (1H, m), 1.82–1.86 (1H, m),
2.16–2.20 (1H, m), 2.23–2.29 (1H, m), 2.45 (1H, d, J¼
13.8 Hz), 2.63 (1H, d, J¼13.8 Hz), 3.66 (2H, d, J¼13.5 Hz),
3.69 (1H, dd, J¼4.5, 9.0 Hz), 3.88 (2H, d, J¼13.5 Hz),
4.67 (1H, d, J¼11.3 Hz), 4.75 (1H, d, J¼11.3 Hz), 7.23–
4.7. Computational details
All transition structures were fully optimized without con-
straints, using Morokuma’s ONIOM method implemented
in Gaussian03, combining ab initio levels (HF/LanL2DZ)
with Rappe’s universal force field (UFF) on an FSC
PRIMERGY system: 19ꢂ2ꢂ2 (dual-core dual-processor

Z. Szakonyi et al. / Tetrahedron 64 (2008) 1034–1039
1039
11. Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767–796.
RX220 boards) AMD Opteron computing nodes, 19ꢂ4 GB
standard system memory PRIMERGY TX200 S2 head-
node with Intel Xeon processor. Hydrogen atoms were
used as link atoms between the two layers (HF/LanL2DZ:
UFF). All transition structures were analyzed by frequency
computations and showed one imaginary frequency of the
methyl transfer mode.
ꢀ
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Acknowledgements
We are grateful to the Hungarian Research Foundation
(OTKA No. NF69316 and T049407) and the National
Research and Development Office, Hungary (GVOP-3.1.1-
2004-05-0255/3.0) for financial support. We thank R.
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Kovacs for her assistance in the experimental work.
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