Stereoselective synthesis of pinane-type tridentate aminodiols and their application in the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2012.01.020

A library of pinane-based aminodiols were prepared from commercially available (1R)-(-)-myrtenol (-)-1. Compound (-)-1 was transformed into allyl trichloroacetamide (+)-2 via the acetimidate, followed by the Overman rearrangement. In order obtain the amin

Full text of DOI:10.1016/j.tetasy.2012.01.020

Tetrahedron: Asymmetry 23 (2012) 144–150
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Stereoselective synthesis of pinane-type tridentate aminodiols and their
application in the enantioselective addition of diethylzinc to benzaldehyde
⇑
⇑
Kinga Csillag, Lukács Németh, Tamás A. Martinek, Zsolt Szakonyi , Ferenc Fülöp
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 December 2011
Accepted 27 January 2012
A library of pinane-based aminodiols were prepared from commercially available (1R)-(ꢀ)-myrtenol (ꢀ)-
1. Compound (ꢀ)-1 was transformed into allyl trichloroacetamide (+)-2 via the acetimidate, followed by
the Overman rearrangement. In order obtain the aminodiol structure, (+)-2 was subjected to stereoselec-
tive dihydroxylation with OsO4, resulting in dihydroxy trichloroacetamide (+)-3. The trichloroacetyl
group was removed from (+)-3 with aqueous HCl, and the (1R,2R,3S,5R)-3-amino-2-hydroxymethyl-
6,6-dimethylbicyclo[3.1.1]heptan-2-ol hydrochloride (ꢀ)-4 obtained was transformed to primary, sec-
ondary and tertiary aminodiols by reductive amination, N-alkylation of aminodiol (+)-9 and debenzyla-
tion of N-benzyl aminodiol (+)-10, respectively. In the reactions of (+)-9 and (+)-14 with formaldehyde,
highly regioselective ring closure was observed. In contrast with earlier results, the aminodiols gave
pinane-fused oxazolidines (+)-11 and (ꢀ)-15. The aminodiols and their oxazolidine derivatives 5–15 were
applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde. The best
enantioselectivity was observed in the case of the N-benzyl-substituted derivative (+)-9.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
1,3-aminoalcohols was recently reported. These synthons served
as chiral auxiliaries in the enantioselective synthesis of secondary
In recent years, aliphatic aminodiols bearing a 1,2- and a 1,3-
aminoalcohol moiety in the same molecule have proven to be use-
ful building blocks. They have been applied as chiral catalysts or
starting materials in the stereoselective synthesis of compounds
of pharmacological interest. In addition to their synthetic impor-
tance, aminodiols can also be applied as chiral ligands and auxilia-
ries in enantioselective transformations.1–9 The asymmetric
addition of diethylzinc to aldehydes has become a highly investi-
gated model reaction, with the application of chiral promoters
such as 1,2- and 1,3-difunctionalized ligands.5–9
alcohols.21–23
Many naturally occurring molecules containing an aminodiol
function exhibit a marked biological activity: myriocin, isolated
from M. albomyces, is known to be a potent immunostimulator,
while swainsonin, an acyclic aminodiol, is an inhibitor of glycopro-
tein processing.24 Some compounds containing an aminodiol moi-
ety have proven to be potential HIV protease inhibitors,25 while
others exert renin-inhibitory activity.26,27 Aminodiols are also use-
ful starting materials for the synthesis of biologically active natural
compounds, for example, (ꢀ)-cytoxazone, a selective modulator of
the secretion of TH2 cytokine, a microbial metabolite isolated from
cultures of Streptomyces species.28
Pinane- and carane-based 3-amino-1,2-diols are known to be
excellent building blocks for the synthesis of 1,3-oxazines and
oxazolidines. The formation of these noteworthy heterocyclic sys-
tems depends upon which hydroxy groups participate in the ring-
closure process. Different types of monoterpene-based aminodiols
have already been examined in order to investigate the tendencies
of monoterpene-based aminodiols to furnish either the spirooxaz-
olidine or the 1,3-oxazine ring system.21,22,29–31
Amino alcohols, and especially b-amino alcohols, have proven to
be excellent ligands for the addition mentioned above.10–12 Since
the report by Oguni and Omi in 1984,13 a great number of b-amino
alcohols have been investigated.4,14,15 The first very high enantiose-
lectivity in the addition of diethylzinc was achieved by Noyori et al.,
who used DAIB, a terpene-based chiral ligand.16 Several natural
chiral terpenes, including (+)-pulegone,17 - and b-pinene18,19 and
a
fenchone-camphor,20 have also proven to be excellent sources for
the synthesis of various amino alcohols, which were successfully
applied in enantioselective syntheses. The transformation of enan-
tiomerically pure
a
-pinene into b-amino acid derivatives such as
Our aim herein was to synthetize new chiral pinane-based
aminodiols and their ring-closed derivatives from readily available
(1R)-(ꢀ)-myrtenol and to apply them in the enantioselective syn-
thesis of 1-phenyl-1-propanol.
⇑
Corresponding authors. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail addresses: szakonyi@pharm.u-szeged.hu (Z. Szakonyi), fulop@pharm.
u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.020

K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
145
OH
OH
2. Results and discussion
ii
2.1. Syntheses of pinane-based aminodiols
(+)-12
N
H
The synthetic routes developed for aminodiols 5–15 are pre-
sented in Schemes 1 and 2. As reported in the literature,32,35,36
commercially available (1R)-myrtenol (ꢀ)-1 was transformed into
allyl trichloroacetimidate, which was followed by an Overman
rearrangement in the presence of K2CO3, resulting in allyl trichlo-
roacetamide (+)-2. In order to build up the aminodiol structure,
the exocyclic olefin function was dihydroxylated with KMnO4. De-
spite the good stereoselectivity of the reaction, the product was
isolated in only 10% yield with recovery of the unreacted starting
material. When OsO4/NMO was applied instead of KMnO4, the de-
sired aminodiol derivative (+)-3 was obtained in an 83% yield
(Scheme 1). Our NMR studies on the crude product proved that,
probably because of the sterically hindered rigid backbone of the
monoterpene, the reaction was highly stereoselective: only diaste-
reomer (+)-3 was detected and isolated.37,38 The stereochemistry
was established by NOESY.
(+)-14
i
iii
O
OH
Ph
OH
O
N
Ph
N
(-)-15
(+)-13
Scheme 2. Reagents and conditions: (i) 1.08 equiv BnBr, NaH, THF, reflux, 8 h;
yield: 44%; (ii) Pd(C) 5%, H2, 1 atm, MeOH, rt, 2 h; yield: 57%; (iii) 35% HCHO/H2O,
Et2O, rt, 1 h, yield: 41%.
Several methods are already known for removal of the trichlo-
roacetyl group.39–41 We found it best to use an 18% aqueous HCl
solution for this cleavage at room temperature, with stirring for
24 h (Scheme 1). Primary aminodiol (ꢀ)-5 was transformed into
secondary ones 6, 7 and 8 by reductive amination, (ꢀ)-5 was stir-
red with different ketones, such as acetone, cyclohexanone and
diethyl ketone, and the Schiff base formed in situ was reduced with
NaBH4. Starting from (ꢀ)-4, additional secondary and tertiary
aminodiols were prepared. A bulky group was conveniently intro-
duced onto the amino moiety by the reaction of (ꢀ)-4 with benz-
aldehyde in the presence of Et3N and NaBH4. In order to increase
the steric hindrance on the nitrogen, an additional benzyl group
OH
OH
O
OH
i, ii
O
iii
N
H
CCl3
N
H
CCl3
(-)-1
(+)-2
(+)-3
iv
OH
OH
OH
OH
OH
O
vii
ix
N
N
H
Ph
NH2 HCl
(+)-9
Ph
(-)-4
(-)-5
(+)-11
v
x
viii
vi
OH
OH
OH
OH
OH
OH
N
Ph
N
Ph
R1
R2
Ph
(+)-10
(+)-12
N
H
(+)-6 R1 = R2 = Me
(+)-7 R1 = R2 = (CH2)5
(+)-8 R1 = R2 = Et
Scheme 1. Reagents and conditions: (i) 1.8 equiv CCl3CN, 1.5 equiv DBU, DCM, 0 °C; (ii) anhydrous K2CO3, dry xylene, reflux, 24 h, yield: 92%; (iii) 0.05 equiv OsO4/t-BuOH,
3 equiv NMO/H2O, acetone, rt, 24 h, yield: 83%; (iv) 18% HCl, Et2O, rt, 24 h, yield: 52%; (v) 15% KOH, CHCl3; (vi) starting from (ꢀ)-5, 6: dry acetone as solvent, 7: 10.5 equiv
cyclohexanone, dry EtOH, 8: 10.5 equiv diethyl ketone, dry EtOH, 3 equiv NaBH4, yield: 6: 59%, 7: 85%, 8: 18%; (vii) starting from (ꢀ)-4, 1.05 equiv PhCHO, Et3N, then 2 equiv
NaBH4, dry EtOH, rt, yield: 81%; (viii) 1.05 equiv BnBr, Et3N, MeCN, reflux, 24 h, yield: 30%; (ix) 35% HCHO/H2O, Et2O, rt, 1 h, yield: 97%; (x) 3 equiv LAH, THF, reflux, 1.5 h,
yield: 38%.

146
K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
was introduced by the N-benzylation of (+)-9 using benzyl bro-
mide in MeCN in the presence of Et3N. However, tertiary aminodiol
(+)-10 was isolated in only a moderate yield.
O
OH
OH
H
i
+
We recently found21,22,31 that the ring closure of pinane- or
carane-based aminodiols proceeded with high regioselectivity to
give spiro-fused oxazolidines in the case of pinane derivatives,
while the ring closure of carane-based aminodiols afforded fused
1,3-oxazines. The ring-closed products possessed higher catalytic
activities than those of the aminodiol analogues. Since aminodiols
5, 6, and 9–15 are regioisomers of those reported earlier,21,22,31 ring
closure can lead to the formation of pinane-fused oxazolidines or
1,3-oxazines. When (+)-9 was stirred with formaldehyde for 1 h,
a regioselective ring closure was observed. The NMR data on (+)-
11 indicated that the hydroxy group on the tertiary carbon atom
in (+)-9 had been incorporated into a condensed oxazolidine ring.
In order to increase the diversity in the substitution of the amine
group, N-methyl-N-benzyl aminodiol (+)-12 and N-methyl amino-
diol (+)-14 were prepared. The transformation of (+)-11 into N-
methyl-N-benzyl aminodiol (+)-12 was accomplished by reduction
with LiAlH4 at reflux. Debenzylation of (+)-12 in the presence of
palladium-on-carbon catalyst gave N-methyl aminodiol (+)-14.
Under similar reaction conditions as those used for the preparation
of (+)-11, the ring closure of (+)-14 displayed the same regioselec-
tivity, furnishing oxazolidine (ꢀ)-15 in good yields (Scheme 2).
16
17
18
Scheme 3. Reagents and conditions: (i) Et2Zn/n-hexane, 10 mol % catalyst 5–15, rt,
Ar atm, yield: 73–86%.
enantioselectivities were observed. The results were similar when
the secondary alcohol functional group underwent O-alkylation,
resulting in (+)-13 (Scheme 2). Our results suggest that tridentate
pinane-based aminodiols with a secondary amino function are
more efficient catalysts than those containing a primary or tertiary
amino group.
In order to rationalize the experimental findings, quantum
chemical molecular modelling calculations were performed on
the Noyori l-oxo-complex formed by (+)-9. The calculation proto-
col utilized herein was described earlier,29 but this time, full RHF/
LANL2DZ optimization was carried out in the final stage (Table 2).
Two main reaction pathways were proposed based on the coordi-
nating hydroxyl groups in the
l-oxo-complex tertiary-OH and
the primary-OH. The ethyl groups were replaced by methyl groups
in order to eliminate conformational freedom because this modifi-
cation was not expected to cause significant errors in the trends of
2.2. Application of aminodiols as chiral ligands in the
enantioselective addition of diethylzinc to benzaldehyde
relative energies. The l-oxo transition state possesses four stereo-
genic centres, leading to 16 diastereomers, which were optimized
by using the transition state-searching algorithm implemented in
Gaussian03. The diastereomers are designated by their absolute
chirality on Zn1 in the heterocyclic ring, on the secondary nitrogen,
and by the syn- or anti-position of the transferring Zn2-attached al-
kyl group relative to the alkyl group on Zn1 (Fig. 2). Finally the
complexes were also distinguished on the basis of the configura-
tion of the carbon at the reaction centre.
The transition state search did not converge for the (R,S)_syn
class of complexes for steric reasons; only high energy structures
were obtained. Nevertheless, Table 2 reveals that the three low-
est-energy transition states produce an (R)-configuration within
the energy window of 2 kcal/mol. This modelling result is in good
correlation with the experimentally observed selectivity for 9.
Aminodiols and their ring-closed derivatives 5–15 were applied
as chiral ligands in the addition of diethylzinc to benzaldehyde,
resulting in 1-phenyl-1-propanol enantiomers 17 and 18 (Fig. 1,
Scheme 3).
Catalysts 5–15 were applied in a 10% molar ratio and the reac-
tions were performed at room temperature in n-hexane. The re-
sults are presented in Table 1. The enantiomeric purity of the 1-
phenyl-1-propanol obtained was determined by GC on a CHIRA-
SIL-DEX CB column, according to the literature.15,42,43 In all cases,
the (R)-enantiomer of 18 predominated, while the enantioselectiv-
ity of the reaction varied from low to moderate ee (Table 1). The
results with catalysts (ꢀ)-5, (+)-8, (+)-10 and (+)-14 were unsatis-
factory, but with (+)-6, (+)-7 and (+)-12, moderate increases in
enantioselectivity were observed. The best ee value (61%) was ob-
tained when the N-benzyl derivative (+)-9 was applied. It is inter-
esting to note that in our previous studies on regioisomeric
aminodiols,21 the addition of diethylzinc to aldehydes exhibited
the opposite selectivity, resulting in (S)-1-phenyl-1-propanol as
the major product, with the catalytic activity increasing in the se-
quence NH2 < NHR1 < NR1R2. Since the ring-closed aminodiol
derivatives in our former experiments displayed a higher catalytic
activity in the aforementioned model reaction, pinane-fused oxaz-
olidines (+)-11 and (ꢀ)-15 were also applied. However, only lower
3. Conclusions
In conclusion, we have developed a library of new chiral pi-
nane-based aminodiols 5–15, which may serve as chiral building
blocks in the asymmetric synthesis of potential pharmacons, or
be used as chiral ligands in enantioselective syntheses. The substit-
uents influence the enantioselectivity in the reaction of diethylzinc
with benzaldehyde in the sequence NH2 < NRR < NHR. The ring
OR3
OH
OH
OH
OH
O
R1
R2
NR1R2
N
N
H
R1
(-)-5: R1 = R2 = R3 = H
(+)-9: R1 = R3 = H, R2 = PhCH2
(+)-10: R1 = R2 = PhCH2, R3 = H
(+)-12: R1 = Me, R2 = PhCH2, R3 = H
(+)-13: R1 = Me, R2 = R3 = PhCH2
(+)-14: R1 = R3 = H, R2 = Me
(+)-6: R1 = R2 = Me
(+)-7: R1 = R2 = (CH2)5
(+)-8: R1 = R2 = Et
(+)-11: R1 = PhCH2
(-)-15: R1= Me
Figure 1. Chiral ligands for the enantioselective synthesis of 1-phenyl-1-propanol.

K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
147
Table 1
Asymmetric addition of diethylzinc to benzaldehyde catalysed by ligands 5–15
Entry
Catalyst (10 mol %)
Yielda (%)
eeb (%)
Configuration of major productc
1
2
3
4
5
6
7
8
(ꢀ)-5
(+)-6
(+)-7
(+)-8
(+)-9
(+)-10
(+)-11
(+)-12
(+)-13
(+)-14
(ꢀ)-15
83
79
76
81
85
80
75
73
86
82
77
1
40
19
3
61
1
27
26
6
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
9
10
11
1
8
a
b
c
Isolated yields.
Determined from the crude product by chiral GC (CHIRASIL-DEX CB column).
Determined by comparing the tR of the GC analysis and the specific rotation with the literature data.33,34
Table 2
Ab initio RHF/LanL2DZ energies calculated for l-oxo complexes 9
E(RHF) (a.u.)
(E-Emin) (kcal/mol)
Product configuration
(S,R)_syn_CH2OH
(S,S)_anti_OH
(S,R)_anti_OH
(S,R)_syn_CH2OH
(R,R)_anti_CH2OH
(S,S)_syn_CH2OH
(S,S)_anti_OH
ꢀ1450.829635
ꢀ1450.826875
ꢀ1450.826494
ꢀ1450.825875
ꢀ1450.82567
ꢀ1450.825244
ꢀ1450.823476
ꢀ1450.823133
ꢀ1450.822738
ꢀ1450.820994
ꢀ1450.820820
ꢀ1450.819587
ꢀ1450.819388
ꢀ1450.817439
ꢀ1450.817112
ꢀ1450.816756
ꢀ1450.815029
ꢀ1450.814432
ꢀ1450.812966
ꢀ1450.812954
ꢀ1450.811653
ꢀ1450.810544
ꢀ1450.810184
ꢀ1450.807678
ꢀ1450.798307
ꢀ1450.77621
ꢀ1450.772119
0.00
1.73
1.97
2.36
2.49
2.76
3.86
4.08
4.33
5.42
5.53
6.30
6.43
7.65
7.86
8.08
9.17
(R)
(R)
(R)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(S)
(R)
(S)
(R)
(S)
(S)
(S)
(R)
(S)
(R)
(S)
(S,R)_anti_OH
(R,R)_syn_CH2OH
(S,S)_syn_CH2OH
(R,R)_anti_CH2OH
(S,R)_anti_CH2OH
(S,R)_syn_OH
(S,S)_anti_CH2OH
(R,S)_anti_CH2OH
(R,R)_anti_OH
(R,R)_anti_OH
(R,R)_syn_OH
(R,S)_anti_CH2OH
(R,R)_syn_CH2OH
(R,R)_syn_OH
(S,R)_syn_OH
(S,S)_syn_OH
(R,S)_anti_OH
(R,S)_anti_OH
(S,S)_syn_OH
(S,R)_anti_CH2OH
9.54
10.46
10.47
11.28
11.98
12.21
13.78
19.66
33.52
36.09
of (R)-1-phenyl-1-propanol, with a selectivity opposite to that re-
ported recently for their regioisomeric analogues.21
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 an appropriate sol-
vent. Chemical shifts are expressed in ppm (d) relative to TMS as
internal reference. J values are given in Hz. FT-IR spectra were re-
corded on a Perkin-Elmer Spectrum 100 instrument. Microanalyses
were performed on a Perkin-Elmer 2400 elemental analyser. 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-
Figure 2. The lowest-energy transition state [(S,R)_syn_CH2OH, (R)] obtained for
the -oxo complex of 9.
l
closure of the aminodiols proceeds with excellent regioselectivity,
resulting exclusively in pinane-fused oxazolidines. Amongst these
pinane-based aminodiols, derivatives bearing a secondary amino
group proved to be good catalysts in the enantioselective synthesis

148
K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
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. For the ab initio cal-
culations, the molecular structure, stereochemistry and geometry
(1H, m), 7.70 (2H, s) 13C NMR (DMSO-d6) d (ppm): 23.59, 26.81,
27.44, 32.21, 38.05, 39.76, 45.85, 48.60, 68.24, 74.21. IR (KBr,
cmꢀ1
) m = 3231, 2940, 1599, 1522, 841. Anal. Calcd for C10H20ClNO2
(221,12): C, 54.17; H, 9.09; N, 6.32. Found: C, 54.45; H, 9.24; N,
6.03.
of the
l-oxo complex were defined exclusively in terms of their
z-matrix internal coordinate system. The transition state optimiza-
tions were carried out in two stages. We used the transition state
search algorithm as implemented in the Gaussian 03 program
suite. The initial structures were preoptimized at the PM3 level
of theory, then the production run was performed using the RHF
method, with the LanL2DZ basis set. The converged structures con-
tained a single negative value in their Hessian. Compound (+)-2
was prepared from commercially available (1R)-(ꢀ)-myrtenol (Sig-
ma–Aldrich) according to the literature;32 all its spectroscopic data
and physical properties were similar to those reported therein.
4.3.1. Preparation of (1R,2R,3S,5R)-3-amino-2-hydroxymethyl-
6,6-dimethylbicyclo[3.1.1]heptan-2-ol (ꢀ)-5
To compound (ꢀ)-4 (1.46 g, 6.6 mmol) were added 5 mL of 15%
aqueous KOH solution and the mixture was extracted with CHCl3
(3 ꢁ 30 mL). The organic layer was dried (Na2SO4) and evaporated,
resulting in (ꢀ)-5. Compound (ꢀ)-5: 0.99 g (81%); colourless crys-
talline powder, mp 124–128 °C; ½a D20
ꢂ
¼ ꢀ11:0 (c 0.125, MeOH); 1H
NMR (DMSO-d6) d (ppm): 0.91 (3H, s), 1.19 (3H, s), 1.25 (1H, dd,
J = 2.8, 6.9 Hz), 1.28 (1H, d, J = 9.6 Hz), 1.76–1.80 (1H, m), 1.89
(1H, t, J = 5.7 Hz), 1.99–2.05 (1H, m), 2.24–2.31 (1H, m), 3.12 (1H,
d, J = 10.9 Hz), 3.18 (1H, dd, J = 6.7, 9.6 Hz), 3.27 (1H, d,
J = 10.9 Hz). 13C NMR (DMSO-d6) d (ppm): 23.82, 27.64, 28.02,
4.2. Preparation of 2,2,2-trichloro-N-((1R,2R,3S,5R)-2-hydroxy-
2-hydroxymethyl-6,6-dimethylbicyclo[3.1.1]heptan-3-
yl)acetamide (+)-3
37.50, 37.97, 40.37, 45.87, 48.80, 69.69, 73.95. IR (KBr, cmꢀ1
)
m
= 3359, 2910, 1603, 1485, 1059, 938. Anal. Calcd for C10H19NO2
(185.26): C, 64.83; H, 10.34; N, 7.56. Found: C, 64.62; H, 10.14;
Method A: 2,2,2-trichloro-N-((1R,3S,5R)-6,6-dimethyl-2-methy-
lenebicyclo[3.1.1]heptan-3-yl)acetamide (+)-2 (1.00 g, 3.37 mmol)
in EtOH (17 mL) was added dropwise to KMnO4 (1.04 g,
6.75 mmol) and MgSO4 (0.81 g, 6.75 mmol) in H2O (3 mL) at 0 °C.
After stirring for 2 h, the mixture was filtered through a Celite
pad and washed with EtOAc. The EtOH was evaporated off from
the mixture under reduced pressure and the residue obtained
was dissolved in H2O and extracted with EtOAc (3 ꢁ 20 mL). The
combined organic phase was dried (Na2SO4) and evaporated. The
crude product was purified by column chromatography (n-hex-
ane/EtOAc = 2:1).
N, 7.66.
4.4. Preparation of (1R,2R,3S,5R)-3-isopropylamino-2-
hydroxymethyl-6,6-dimethylbicyclo[3.1.1]heptan-2-ol (+)-6
A solution of (ꢀ)-5 (0.25 g, 1.35 mmol) in dry acetone (15 mL)
was stirred for 2 h at room temperature and then evaporated to
dryness. After evaporation of the solvent, the residue was dissolved
in dry EtOH (15 mL), and NaBH4 (0.15 g, 4.05 mmol) was added
cautiously. The reaction mixture was stirred for 24 h at room tem-
perature. The solvent was then removed and the residue was dis-
solved in H2O and extracted with CHCl3 (3 ꢁ 20 mL). The organic
layer was dried (Na2SO4) and evaporated. The crude product was
purified by column chromatography (CHCl3/MeOH = 2:1). Com-
pound (+)-6: 0.18 g (59%); orange crystals, mp 36–38 °C;
Method B: to 2,2,2-trichloro-N-((1R,3S,5R)-6,6-dimethyl-2-
methylenebicyclo[3.1.1]heptan-3-yl)acetamide
(+)-2
(0.60 g,
2.0 mmol) in acetone (10 mL) were added 4-methylmorpholine-
4-oxide (1.24 mL, 50% aqueous solution) and OsO4 (1.28 mL, 2.0%
t-BuOH solution). The reaction mixture was stirred for 24 h at
room temperature. The reaction was then quenched by the addi-
tion of saturated aqueous Na2SO4 (20 mL) and extracted with
EtOAc (3 ꢁ 50 mL). The combined organic phase was dried
(Na2SO4) and evaporated. The crude product was purified by col-
umn chromatography (n-hexane/EtOAc = 2:1). Compound (+)-3:
Method A: 0.11 g (10%); Method B: 0.55 g (83%), yellow crystalline
½
a 2D0
ꢂ
¼ þ14:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.94
(3H, s), 1.08 (3H, d, J = 6.3 Hz), 1.12 (3H, d, J = 6.3 Hz), 1.23–1.25
(4H, m), 1.35–1.41 (1H, m), 1.86–1.91 (1H, m), 2.14–2.22 (2H,
m), 2.55–2.63 (2H, m), 2.86–2.95 (2H, m), 3.42 (2H, q, J = 10.7,
14.9 Hz), 3.72 (2H, s). 13C NMR (CDCl3) d (ppm): 23.51, 23.76,
24.09, 27.56, 27.79, 39.23, 40.76, 48.46, 48.60, 51.52, 63.85,
70.52, 74.34. IR (KBr, cmꢀ1
) m = 3359, 2920, 1408, 1069, 891. Anal.
powder, mp 85–88 °C, ½a D20
ꢂ
¼ þ18:0 (c 0.125, MeOH); 1H NMR
Calcd for C13H25NO2 (227.34): C, 68.68; H, 11.08; N, 6.16. Found: C,
68.45; H, 11.28; N, 6.01.
(DMSO-d6) d (ppm): 0.96 (3H, s), 1.17 (1H, t, J = 7.2 Hz), 1.24 (3H,
s, CH3), 1.44 (1H, d, J = 9.7 Hz), 1.53 (1H, dd, J = 6.6, 13.7 Hz),
1.87–1.90 (1H, m), 1.98 (1H, s), 2.10–2.18 (2H, m), 3.93–3.98
(1H, m), 4.03 (1H, q, J = 7.5 Hz), 4.70 (1H, t, J = 5.6 Hz), 5.02 (1H,
s), 8.30 (1H, d, J = 6.56 Hz). 13C NMR (DMSO-d6) d (ppm): 23.66,
27.46, 27.69, 35.24, 38.07, 39.96, 46.38, 48.40, 59.69, 67.51,
4.5. General procedure for the synthesis of (+)-7 and (+)-8
To a solution of (ꢀ)-5 (0.10 g, 0.54 mmol) in dry EtOH (25 mL)
was added the appropriate ketone (5.67 mmol) and the mixture
was stirred at room temperature. After 2 h, the solvent was re-
moved under reduced pressure. The residue was dissolved in dry
EtOH (25 mL), after which NaBH4 (0.04 g, 1.08 mmol) was added,
and the solution was stirred for 24 h at room temperature. The sol-
vent was evaporated off and the residue was dissolved in H2O and
extracted with CHCl3 (3 ꢁ 30 mL). The organic layer was dried
(Na2SO4) and evaporated. The crude product was purified by col-
umn chromatography [(+)-7: toluene/EtOH = 1:1, (+)-8: CHCl3/
MeOH = 2:1].
75.01, 159.97. IR (KBr, cmꢀ1
) m = 3465, 3370, 2917, 1678, 1491,
825. Anal. Calcd for C12H18Cl3NO3 (329.04): C, 43.59; H, 5.49; N,
4.24. Found: C, 43.32; H, 5.21; N, 4.27.
4.3. Preparation of (1R,2R,3S,5R)-3-amino-2-hydroxymethyl-
6,6-dimethylbicyclo[3.1.1]heptan-2-ol hydrochloride (ꢀ)-4
A solution of (+)-3 (4.22 g, 12.7 mmol) in Et2O (26 mL) was stir-
red with 106 mL of 18% aqueous HCl at room temperature. After
24 h, the mixture was evaporated to dryness, and the residue
was recrystallized from EtOH–Et2O. Compound (ꢀ)-4: 1.46 g
4.5.1. (1R,2R,3S,5R)-3-Cyclohexylamino-2-hydroxymethyl-6,6-
dimethylbicyclo[3.1.1]heptan-2-ol (+)-7
(52%); colourless crystalline powder, mp 239–245 °C; ½a D20
¼ ꢀ4:0
ꢂ
(c 0.125, MeOH); 1H NMR (DMSO-d6) d (ppm): 0.87 (3H, s), 1.20
(3H, s), 1.57 (1H, d, J = 10.4 Hz), 1.65–1.71 (1H, m), 1.83–1.90
(1H, m), 1.97 (1H, t, J = 5.3 Hz), 2.09–2.14 (1H, m), 2.23–2.29 (1H,
m), 3.27–3.33 (1H, m), 3.46–3.51 (2H, m),4.05 (2H, s) 4.99–5.02
Compound (+)-7: 0.12 g (85%); yellow crystals, mp 81–89 °C;
½
a 2D0
ꢂ
¼ þ9:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.93 (3H,
s), 0.98–1.07 (1H, m), 1.24–1.28 (9H, m), 1.34–1.39 (1H, m),
1.50–1.62 (2H, m), 1.69–1.74 (2H, m), 1.85–1.98 (2H, m), 2.16

K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
149
(1H, d, J = 5.8 Hz), 2.44–2.51 (1H, m), 2.55–2.61 (1H, m), 2.95 (1H,
dd, J = 5.4, 10.0 Hz), 3.39 (1H, s), 3.56–3.62 (1H, m). 13C NMR
(CDCl3) d (ppm): 24.10, 25.26, 25.63, 26.07, 27.59, 27.79, 34.34,
35.70, 38.61, 39.63, 40.78, 48.38, 51.11, 56.31, 70.49, 74.23. IR
4.8. General procedure for the synthesis of oxazolidines (+)-11
and (ꢀ)-15
At first, 5 mL of 35% aqueous formaldehyde was added to a solu-
tion of (+)-9 or (+)-14 (0.43 mmol) in 2 mL of Et2O. The mixture
was stirred at room temperature for 1 h, then made alkaline with
10% aqueous KOH and extracted with Et2O (3 ꢁ 15 mL). The com-
bined organic phase was dried (Na2SO4) and evaporated. The crude
product was purified by column chromatography [(+)-11: n-hex-
ane/EtOAc = 4:1, (ꢀ)-15: n-hexane/EtOAc = 3:2].
(KBr, cmꢀ1
)
m
= 3366, 2927, 1453, 1067, 893. Anal. Calcd for
C16H29NO2 (267.22): C, 71.86; H, 10.93; N, 5.24. Found: C, 71.68;
H, 10.77; N, 5.46.
4.5.2. (1R,2R,3S,5R)-3-Pentan-3-ylamino-2-hydroxymethyl-6,6-
dimethylbicyclo[3.1.1]heptan-2-ol (+)-8
Compound (+)-8: 0.02 g (18%); yellow oil; ½a D20
¼ þ5:0 (c 0.125,
ꢂ
MeOH); 1H NMR (CDCl3) d (ppm): 0.87–0.95 (9H, m), 1.25–1.31
(5H, m), 1.35–1.60 (4H, m), 1.87–1.92 (1H, m), 2.14–2.21 (2H,
m), 2.51–2.61 (2H, m), 2.97 (1H, dd, J = 5.4, 10.1 Hz), 3.42 (2H, s).
13C NMR (CDCl3) d (ppm): 9.49, 10.31, 24.17, 26.12, 26.34, 27.61,
27.79, 29.86, 38.80, 40.82, 48.61, 51.89, 60.01, 70.55, 74.64. IR
4.8.1. [(1R,2R,6S,8R)-5-Benzyl-9,9-dimethyl-3-oxa-5-
azatricyclo[6.1.1.02,6]dec-2-yl]methanol (+)-11
Compound (+)-11: 0.12 g (97%); oil; ½a D20
¼ þ3:0 (c 0.125,
ꢂ
MeOH); 1H NMR (DMSO-d6) d (ppm): 0.81 (3H, s), 1.21 (3H, s),
1.73–1.86 (3H, m), 1.91–2.09 (3H, m), 2.68 (1H, d, J = 7.9 Hz),
3.28–3.40 (2H, m), 3.53 (1H, dd, J = 5.3, 11.8 Hz), 3.91 (1H, d,
J = 13.2 Hz), 3.98 (1H, s), 4.31 (1H, s), 4.63 (1H, t, J = 7.4 Hz),
7.21–7.34 (5H, m). 13C NMR (DMSO-d6) d (ppm): 23.14, 24.12,
27.03, 32.32, 37.24, 40.25, 45.19, 54.76, 57.16, 65.33, 84.39,
(KBr, cmꢀ1
)
m
= 3420, 2924, 1630, 1462, 1065. Anal. Calcd for
C15H29NO2 (255.22): C, 70.54; H, 11.45; N, 5.48. Found: C, 70.37;
H, 11.27; N, 5.57.
88.24, 126.88, 128.18, 128.28. IR (KBr, cmꢀ1
) m = 3441, 2925,
1955, 1808, 1604, 1453, 1071, 698. Anal. Calcd for C18H25NO2
(287.19): C, 75.22; H, 8.77; N, 4.87. Found: C, 75.07; H, 8.65; N,
4.99.
4.6. Preparation of (1R,2R,3S,5R)-3-benzylamino-2-
hydroxymethyl-6,6-dimethylbicyclo[3.1.1]heptan-2-ol (+)-9
To a mixture of (ꢀ)-4 (0.20 g, 0.9 mmol) and Et3N (0.18 g,
1.8 mmol) in dry EtOH (15 mL), benzaldehyde (0.10 g, 0.95 mmol)
was added, and the mixture was stirred for 2 h at room tempera-
ture. After evaporation of the solvent, the residue was dissolved
in dry EtOH (15 mL), after which NaBH4 (0.068 g, 1.8 mmol) was
added portionwise. The reaction mixture was stirred for 24 h at
room temperature, the solvent was then removed and the residue
was dissolved in H2O and extracted with CHCl3 (3 ꢁ 20 mL). The
combined organic layer was dried (Na2SO4) and evaporated. The
crude product was purified by column chromatography (CHCl3/
MeOH = 9:1). Compound (+)-9: 0.20 g (81%); colourless crystalline
4.8.2. [(1R,2R,6S,8R)-5,9,9-Trimethyl-3-oxa-5-
azatricyclo[6.1.1.02,6]dec-2-yl]methanol (ꢀ)-15
Compound (+)-15: 0.03 g (41%); colourless crystalline powder,
mp 44–46 °C; ½a 2D0
ꢂ
¼ ꢀ11:0 (c 0.125, MeOH); 1H NMR (CDCl3) d
(ppm): 0.86 (3H, s), 1.29 (3H, s), 1.17–1.85 (3H, m), 1.92–1.98
(1H, m), 2.00–2.08 (1H, m), 2.12–2.20 (1H, m), 2.28 (1H, t,
J = 5.5 Hz), 2.33 (3H, s), 2.37–2.43 (1H, m), 3.56 (1H, d,
J = 11.5 Hz), 3.65 (1H, d, J = 11.5 Hz), 3.99 (1H, s), 4.60 (1H, s). 13C
NMR (CDCl3) d (ppm): 23.77, 24.68, 27.32, 31.40, 36.60, 37.96,
40.98, 45.28, 60.38, 66.34, 86.27, 89.37. IR (KBr, cmꢀ1
) m = 3425,
powder, mp 74–78 °C, ½a D20
ꢂ
¼ þ10:0 (c 0.125, MeOH); 1H NMR
2926, 1458, 1067. Anal. Calcd for C12H21NO2 (211.16): C, 68.21;
H, 10.02; N, 6.63. Found: C, 68.49; H, 10.15; N, 6.57.
(CDCl3)
d (ppm): 0.90 (3H, s), 1.25 (3H, s), 1.32 (1H, d,
J = 10.3 Hz), 1.46 (1H, ddd, J = 2.6, 5.7, 13.7 Hz), 1.88–1.92 (1H,
m), 2.15 (1H, t, J = 5.9 Hz), 2.18–2.24 (1H, m), 2.48–2.55 (1H, m),
3.02 (1H, dd, J = 5.7, 9.9 Hz), 3.43 (2H, dd, J = 10.8, 24.2 Hz), 3.90
(2H, s), 7.27–7.37 (5H, m). 13C NMR (CDCl3) d (ppm): 24.07,
27.63, 27.78, 37.68, 38.53, 40.77, 48.84, 52.97, 53.62, 70.70,
4.9. Preparation of (1R,2R,3S,5R)-3-benzyl(methyl)amino-2-
hydroxymethyl-6,6-dimethylbicyclo[3.1.1]heptan-2-ol (+)-12
To a stirred suspension of LiAlH4 (0.48 g, 12.63 mmol) in dry
THF (90 mL), a solution of (+)-11 (1.45 g, 5.05 mmol) in THF
(15 mL) was added at 0 °C. The reaction mixture was refluxed for
1.5 h, and a mixture of H2O (0.5 mL) and THF (25 mL) was then
added dropwise with cooling. The inorganic material was filtered
off and washed with THF. The filtrate was dried (Na2SO4) and evap-
orated. The crude product was purified by column chromatography
(toluene/EtOH = 4:1). Compound (+)-12: 0.56 g (38%); oil;
74.77, 127.68, 128.42, 128.81. IR (KBr, cmꢀ1
) m = 3345, 2904,
1935, 1862, 1798, 1740. Anal. Calcd for C17H25NO2 (275.39): C,
74.14; H, 9.15; N, 5.09. Found: C, 73.97; H, 8.99; N, 5.19.
4.7. Preparation of (1R,2R,3S,5R)-3-dibenzylamino-2-
hydroxymethyl-6,6-dimethylbicyclo[3.1.1]heptan-2-ol (+)-10
½
a 2D0
ꢂ
¼ þ8:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.91 (3H,
To a solution of (+)-9 (0.10 g, 0.36 mmol) and Et3N (0.11 g,
1.1 mmol) in dry MeCN (5 mL), benzyl bromide (0.065 g,
0.42 mmol) was added. When the reaction was complete (moni-
tored by means of TLC), the mixture was evaporated to dryness,
and the residue was dissolved in H2O (3 mL) and extracted with
CHCl3 (3 ꢁ 5 mL). The combined organic layer was dried (Na2SO4)
and evaporated. The crude product was purified by column chro-
matography (n-hexane/EtOAc = 2:1). Compound (+)-10: 0.04 g
s), 1.26 (3H, s), 1.39 (1H, d, J = 10.6 Hz), 1.96–2.11 (3H, m), 2.15
(1H, t, J = 5.5 Hz), 2.21–2.27 (1H, m), 2.43 (3H, s), 3.20 (1H, s),
3.32 (2H, s), 3.66 (1H, d, J = 13.1 Hz), 3.88 (1H, d, J = 13.1 Hz),
7.27–7.37 (5H, m). 13C NMR (CDCl3) d (ppm): 23.98, 24.59, 27.19,
27.84, 38.50, 39.65, 40.74, 46.87, 58.40, 61.57, 70.22, 77.42,
127.78, 128.75, 129.23. IR (KBr, cmꢀ1
) m = 3433, 2913, 1946,
1602, 1457, 700. Anal. Calcd for C18H27NO2 (289.41): C, 74.70; H,
9.40; N, 4.84. Found: C, 74.35; H, 9.06; N, 5.16.
(30%); colourless crystalline powder, mp 128–130 °C;
½
a 2D0
ꢂ
¼
þ11:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.80 (3H, s),
1.24–1.28 (4H, m, CH3, 1H), 1.47 (1H, d, J = 11.1 Hz), 1.57 (1H, s),
1.99–2.29 (5H, m), 2.98 (2H, s), 3.25 (1H, s), 3.48 (2H, d,
J = 13.0 Hz), 4.06 (2H, s), 7.26–7.35 (10H, m). 13C NMR (CDCl3) d
(ppm): 23.77, 24.91, 27.49, 27.93, 32.53, 38.40, 40.86, 47.48,
4.10. Preparation of (1R,2R,3S,5R)-3-(N-Benzyl-N-
methylamino)-2-benzyloxymethyl-6,6-
dimethylbicyclo[3.1.1]heptan-2-ol (+)-13
54.35, 56.75, 70.10, 77.67, 127.65, 128.84, 129.06. IR (KBr, cmꢀ1
)
A solution of (+)-12 (0.20 g, 0.69 mmol) in THF (5 mL) was
added to a suspension of NaH (60% in mineral oil; 0.034 g,
0.87 mmol) in THF (3 mL) at 0 °C under an Ar atmosphere. The
m
= 3431, 2921, 1630, 1452, 747. Anal. Calcd for C24H31NO2
(365.51): C, 78.86; H, 8.55; N, 3.83. Found: C, 78.50; H, 8.20; N, 4.02.

150
K. Csillag et al. / Tetrahedron: Asymmetry 23 (2012) 144–150
mixture was stirred for 30 min, and a solution of benzyl bromide
(0.75 mmol, 0.13 g) in THF (3 mL) was then added by syringe.
The mixture was stirred for 8 h at reflux temperature, after which
H2O (1 mL) was added dropwise. The THF was evaporated off, after
which H2O was added (5 mL) and the mixture was extracted with
EtOAc (3 ꢁ 15 mL). The organic layer was dried (Na2SO4) and evap-
orated. The resulting oil was purified by column chromatography
(n-hexane/EtOAc = 4:1). Compound (+)-13: 0.11 g (44%); oil;
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA
NK81371) and TÁMOP-4.2.1/B-09/1/KONV-2010-0005 for financial
support and acknowledge the receipt of a Bolyai János Fellowship
for Zsolt Szakonyi. Tamás A. Martinek acknowledges HAS Lendület
Foldamer research group.
½
a 2D0
ꢂ
¼ þ30:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.73
References
(3H, s), 1.15–1.16 (4H, m), 1.37 (1H, d, J = 10.5 Hz), 1.84–1.90
(2H, m), 1.97–2.03 (1H, m), 2.05 (1H, t, J = 5.7 Hz), 2.09–2.15 (1H,
m), 2.27 (3H, s), 3.11–3.17 (2H, m), 3.34 (1H, d, J = 11.6 Hz), 3.63
(1H, d, J = 13.5 Hz), 3.74 (1H, d, J = 13.5 Hz), 4.44 (1H, d,
J = 12.3 Hz), 4.52 (1H, d, J = 12.3 Hz), 7.16–7.26 (10 H, m). 13C
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40.78, 47.94, 58.45, 61.72, 73.65, 77.26, 78.33, 127.10, 127.59,
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127.97, 128.40, 129.06. IR (KBr, cmꢀ1
) m = 3548, 2909, 1948,
1871, 1807, 1702, 1453, 698. Anal. Calcd for C25H33NO2 (379.25):
C, 79.11; H, 8.76; N, 3.69. Found: C, 79.37; H, 8.90; N, 3.54.
4.11. Preparation of (1R,2R,3S,5R)-2-hydroxymethyl-3-
methylamino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol (+)-14
To a suspension of palladium-on-carbon (5%, 0.10 g) in MeOH
(10 mL), a solution of aminodiol (+)-12 (0.35 g, 1.21 mmol) in
MeOH (15 mL) was added. The mixture was stirred under an H2
atmosphere at room temperature and atmospheric pressure. When
the reaction was complete, as indicated by TLC, the solution was
filtered through a Celite pad and the solvent was removed. The
crude product was purified as the hydrochloride salt. The base lib-
erated was a yellow oil. Compound (+)-14: 0.13 g (57%); oil,
½
a 2D0
ꢂ
¼ þ9:0 (c 0.125, MeOH), 1H NMR (DMSO-d6) d (ppm): 0.89
(3H, s), 1.18 (3H, s), 1.22 (2H, d, J = 9.8 Hz), 1.38–1.43 (1H, m),
1.77–1.81 (1H, m), 1.96 (1H, t, J = 5.8 Hz), 1.99–2.05 (1H, m),
2.30–2.34 (4H, m), 2.67 (1H, dd, J = 5.7, 9.6 Hz), 3.17 (1H, d,
J = 11.2 Hz), 3.30 (1H, d, J = 11.2 Hz). 13C NMR (DMSO-d6)
d
(ppm): 23.78, 27.11, 27.70, 35.32, 35.94, 37.82, 40.14, 48.41,
55.10, 69.31, 74.25. IR (KBr, cmꢀ1
)
m
= 3453, 2909, 1558, 1321,
918. Anal. Calcd for C11H21NO2 (199.16): C, 66.29; H, 10.62; N,
7.03. Found: C, 65.98; H, 10.51; N, 7.47.
4.12. General procedure for the reaction of aldehydes with
diethylzinc in the presence of chiral catalyst (ꢀ)–5–(ꢀ)-15
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ane solution (3 mL, 3 mmol) was added under an argon atmo-
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at room temperature, and benzaldehyde (1 mmol) was then added
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