Stereoselective synthesis and application of tridentate aminodiols derived from (+)-pulegone

Article abstract of DOI:10.1016/j.tetasy.2016.04.009

A library of tridentate aminodiols, derived from naturally occurring (R)-(+)-pulegone, was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The reduction of pulegone furnished pulegol, which was transformed into

Full text of DOI:10.1016/j.tetasy.2016.04.009

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis and application of tridentate aminodiols
derived from (+)-pulegone
b
c
a,d,
Tímea Gonda a, Zsolt Szakonyi a, , Antal Csámpai , Matti Haukka , Ferenc Fülöp
⇑
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
b Institute of Chemistry, Eötvös Loránd University, PO Box 32, H-1518 Budapest-112, Hungary
c Department of Chemistry, University of Jyväskylä, POB 35, 40351 Jyväskylä, Finland
d MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, 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:
A library of tridentate aminodiols, derived from naturally occurring (R)-(+)-pulegone, was synthesized
and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The reduction of pulegone
furnished pulegol, which was transformed into allylic trichloroacetamide via Overman rearrangement of
the corresponding trichloroacetimidate. The protected enamine was subjected to dihydroxylation with
OsO4/NMO system resulting in a 1:1 mixture of (1R,2R,4R)- and (1S,2S,4R)-aminodiol diastereomers.
After the removal of the trichloroacetyl protecting groups, the obtained primary aminodiols were trans-
formed into secondary ones. The regioselectivity of the ring closure of the N-benzyl substituted aminodi-
ols with formaldehyde was investigated resulting in both the 1,3-oxazine and oxazolidine rings. The
tautomerism of the spiro and fused ring systems was observed and its mechanism was studied by
detailed DFT analysis by employing an IEFPCM solvent model to provide a more realistic representation
of the experimental conditions. The obtained potential catalysts were applied to the reaction of benzalde-
hyde and diethylzinc with moderate to good enantioselectivity (up to 90% ee).
Received 1 April 2016
Accepted 22 April 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Aminodiols, which combine the chemical properties of 1,2- and
1,3-aminoalcohols derived from naturally occurring terpenes are
Naturally occurring monoterpenes, produced primarily by a
wide variety of plants, are excellent and inexpensive sources of chi-
rality. The most commonly available members, a- and b-pinene, 2-
also excellent starting materials and catalysts of stereoselective
syntheses.11–15 Over the last decade, they have been proven to be
excellent building blocks in the synthesis of various 1,3-oxazines
and oxazolidines, depending on which hydroxyl group is involved
in the ring closure reaction. The resulting bicyclic heterocycles con-
tain a free hydroxyl group which can contribute to a higher rigidity
in the transition state of the catalytic reaction, resulting in higher
enantioselective inductions in asymmetric addition reactions.13,16
The reaction of benzaldehyde and diethylzinc, which provides
enantiomerically pure secondary alcohols, has been well investi-
gated with monoterpene-based chiral aminoalcohol and aminodiol
catalysts, and serves as a model reaction to estimate the efficiency
of the used catalyst.13,14,17–19
Herein our aim was to develop a library of 2-hydroxy substi-
tuted analogues of the (ꢀ)-8-aminomenthol, applying commer-
cially available natural (+)-pulegone as an inexpensive chiral
source, to study the regioselectivity of the ring closure of the
resulting aminodiols, and to apply them in the model reaction of
diethylzinc and benzaldehyde.
and 3-carene, limonene, and pulegone are very important starting
materials for the synthesis of bi- and trifunctional chiral com-
pounds and heterocycles.1–3 Monoterpene based 1,2- and 1,3-
aminoalcohols are of great importance as starting materials and
catalysts of stereoselective syntheses.1,4 In 1987, the three step syn-
thesis of (ꢀ)-8-aminomenthol, a natural (+)-pulegone based chiral
1,3-aminoalcohol, was reported by Eliel et al.5 The Eliel-aminoalco-
hol became exceptionally widely used since it can be converted into
a variety of useful compounds,1 for example, it has been applied as a
chiral auxiliary for intramolecular alkyllithium addition reactions,6
for intramolecular Diels–Alder reactions7,8 and for Grignard addi-
tions as well.9,10 Based on the usage of (ꢀ)-aminomenthol as a
source of chirality, a wide range of enantioselective syntheses have
been established resulting in diverse chiral compounds.
⇑
Corresponding authors. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
http://dx.doi.org/10.1016/j.tetasy.2016.04.009
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
T. Gonda et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
The obtained compounds 5a and 5b were separated by column
2. Results and discussion
chromatography, and in addition to NMR measurements, the struc-
tures were confirmed by X-ray crystallography (Fig. 2).
2.1. Syntheses of pulegone-based aminodiols
Although several methods are known for the removal of the tri-
chloroacetic group, stirring 5a with 18% aqueous hydrochloric acid
provided the best yield.23–25 The obtained primary aminodiol 6a
was transformed into secondary ones with reductive alkylation
with benzaldehyde and 3,5-di-tert-butylbenzaldehyde, resulting
in 7a and 8a (Scheme 2).
In order to study the regioselectivity of the ring closure of the
aminodiol function, the reaction of 7a with formaldehyde was also
investigated (Scheme 2).
The synthesis of monoterpene-based aminodiols started from
commercially available (+)-pulegone 1, which was stereoselec-
tively reduced to pulegol 2 according to the literature.20 Next, 2
was transformed into allyl trichloroacetimidate 3, which without
isolation, underwent Overman rearrangement in the presence of
K2CO3 resulting in allyl trichloroacetamide 4 (Scheme 1).14,21
Contrary to our former result obtained in the similar, but regios-
elective ring closure of pinane- and carane-based aminodiols,13,26
stirring 7a with 35% aqueous formaldehyde solution furnished
the mixture of 1,3-oxazine 9a and oxazolidine 10a in a ratio 1:2.
After separation of the products obtained, since the absolute con-
figurations of 9a and 10a were determined by aminodiol 5a, their
1,3-oxazine and oxazolidine structures were assigned by 2D-NMR
techniques. In addition to HSQC and HMBC measurements, the
regioselectivity of the ring closure was determined by NOESY
experiments, where remarkable NOE effects were observed
between C2-H and C4a-OH and between C4-Me and C4a-OH for 9a.
The proportion of the ring-closed products seemed to change
via ring-chain-ring tautomerism during the reaction and during
the purification by column chromatography, even in CDCl3 solu-
tion. At the beginning of the reaction, only the formation of 10a
was detected; TLC monitoring of the progress of the reaction indi-
cated the slow formation of 9a; a ratio of 9a:10a = 1:2 was
observed after work-up of the reaction. The conversion occurred
even in crystalline state, where, after a certain amount of time,
only the oxazine form was observed, although by resolving the
substance in CDCl3, it led to a mixture of 1,3-oxazine 9a and oxa-
zolidine 10a in a ratio of 1:2. The conversion of oxazolidine to
1,3-oxazine and vice versa was so fast, that even during a longer
13C NMR measurement of the pure oxazolidine, the formation of
the 1,3-oxazine was observable (see Supporting data). Similar
types of ring-chain tautomerism in 1,3-O,N-heterocycles have been
thoroughly studied in recent decades.27–30
According to DFT modelling studies performed at the B3LYP
level of theory31–33 using 6-31+G(d,p) as basis set,34 a facile acid-
catalyzed reversible interconversion between 9a and 10a can take
place by protonation of the oxygen attached to the cyclohexane
ring (O1) associated with simultaneous opening of the spirocyclic-
or the fused ring system. This step is followed by alternative recy-
clizations of the resulting rotamer methyleneiminium cations
(11a/I or 11a/II: Scheme 3) identified as local minima separated
by a saddle point, i.e., a transition state, on the potential energy
surface [PES]. The optimized Ts structure was obtained by QST2
method35 and confirmed by IRC analysis.36 In order to determine
the thermodynamic parameters characterizing the assumed ele-
mentary steps for 9a, 10a, 11a/I, 11a/II and for the transition state
of interconversion 11a/IM11a/II, geometry optimization and sub-
sequent frequency calculations were carried out with IEFPCM sol-
vent model37 using the dielectric constant of water (e = 80.1) to
represent the experimental conditions. Thus, the calculated change
NH
(i)
(ii)
O
OH
O
CCl3
1
2
3
(iii)
(R)
(S)
(iv)
+
OH
OH
OH
(S)
O
OH
NH
NH
N
H
CCl3
O
CCl3
O
CCl3
4
5a
5b
Scheme 1. Reagents and conditions: (i) NaBH4, MeOH, 0 °C, 1 h, 94%; (ii) DBU,
CCl3CN, dry CH2Cl2, rt, 6 h; (iii) xylene, K2CO3, reflux, 12 h, 67%; (iv) OsO4, NMO, rt,
48 h, 39% (5a), 39% (5b).
In order to build the aminodiol structure, compound 4 was sub-
mitted to dihydroxylation with KMnO4 resulting in a mixture of
(1R,2R,4R)- and (1S,2S,4R)-diastereomers 5a and 5b with low yield.
Dihydroxylation of 4 with OsO4 and NMO (4-methylmorpholine
N-oxide) system furnished 5a and 5b in an acceptable yield in a 1:1
ratio according to the NMR measurements on the crude product
(Scheme 1). Due to the well-known mechanism of OsO4, the forma-
tion of trans-diols could not be observed, and instead the reaction
furnished the cis (syn) diastereomers exclusively. Our presumption
is that OsO4 can attack both the Re and the Si face of the planar
p
-system since the Me-4 group has no steric influence on the reac-
tion, while the freely rotating bulky group at the 1-position (Fig. 1).
OsO4
Si
H
CCl3
N
O
Re
OsO4
in the free energy
10a?9a is in agreement with the experimental observations. The
DG1 accompanying the ring transformation of
Figure 1.
extremely favorable fissions of both the spirocyclic and fused ring
systems characterized by
DG2 and DG3 suggest that even trace
We also attempted to increase the stereoselectivity of the reac-
tion by applying AD-mix-b (a mixture of 1,4-bis[(S)-[(2R,4S,5R)-
5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)
methoxy]phthalazine, potassium carbonate, potassium ferri-
cyanide and potassium osmate dihydrate),22 but in our case no
product was observed.
amounts of any acidic species is capable of efficiently promoting
the overall isomerization process. Furthermore the ring opening
steps, the interconversion between intermediate iminium ions
11a/I and 11a/II with similar stability (cf.
cess as reflected from the relatively low activation barriers
and
G#2. On the other hand, the kinetic control of the cyclization
D
G4) is also a facile pro-
D
G1#
D
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T. Gonda et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
(
R
)
(
R
)
(S)
(
)
R
OH
OH
(S)
OH
(R)
OH
NH
NH
O
CCl3
O
CCl3
5b
5a
Figure 2. X-ray structure of 5a and 5b derivatives.
2.2. Application of pulegone-based aminodiol derivatives as
chiral ligands in the enantioselective addition of diethylzinc to
benzaldehyde
(i)
(ii)
OH
OH
OH
OH
NH
OH
NH2
OH
The aminodiol derivatives were used as chiral catalysts in the
enantioselective addition of diethylzinc to benzaldehyde resulting
in chiral 1-phenyl-1-propanol (Table 1, Scheme 5).
Catalysts were applied in a 10% molar ratio and the reactions
were performed at room temperature in n-hexane. The results
are presented in Table 1. The enantiomeric purity of the 1-phe-
nyl-1-propanol obtained was determined by GC on a CHIRASIL-
DEX CB column, according to the literature.38–42
N
Ar
H
6a
O
CCl3
7a: Ar = Ph
8a
: Ar = 3,5-di-t-BuC6H3
5a
(iii)
Ar = Ph
9a 10a
:
= 1:2
The enantioselectivity of the reaction varied from low to good.
The best ee value (ee = 90%) with an (S)-selectivity was obtained
when 10a was applied. The results obtained clearly show that
the (1R,2R,4R)-diastereoisomers have higher catalytic activities
compared with (1S,2S,4R)-ones.
4a
O1
2
OH
+
HO
O
4
N
N
3
3. Conclusions
10a
In conclusion, starting from natural (+)-pulegone, a monoter-
pene-based 3-amino-1,2-diol library has been created via the
stereoselective dihydroxylation of protected allylic amine 4, while
the reactions of aminodiols with formaldehyde resulted in cyclo-
hexane-fused 1,3-oxazines and spiro-oxazolidines in a ratio of
1:2. The ring-ring tautomerism of the spiro and fused ring systems
was observed and its mechanism was studied by detailed DFT anal-
ysis. The aminodiols and their ring-closed derivatives were suc-
cessfully applied as chiral catalysts in the enantioselective
addition of diethylzinc to benzaldehyde.
9a
Scheme 2. Reagents and conditions: (i) 18% aq HCl, Et2O, rt, 168 h, 85%; (ii) ArCHO,
dry EtOH, 2 h, then NaBH4, EtOH, 48 h, reflux, 54% (7a) and 27% (8a); (iii) 35% aq
CH2O, Et2O, rt, 1 h, isolated yield (differs from crude product ratio): 39% (9a) and
47% (10a).
might be attributed to the preferred formation of 11a/I that takes
place via the addition of a formaldehyde molecule from the exo site
of the pending benzylamino group. The rate of the condensation
reaction with a formaldehyde molecule approaching from the endo
site to the nucleophilic center, finally resulting 11a/II, is possibly
decreased relative to that leading to 11a/I. It should be noted that
in both ring systems, the OH proton is involved in a five-membered
chelate ring allowing the protonation of O1 atom in any of the
bicyclic molecules. The transformations discussed above were
repeated for diastereoisomeric aminodiol 6b obtained from 5b
with similar results (Scheme 4).
4. Experimental
4.1. General
Commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
Melting points were determined on a Kofler apparatus and are
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4
T. Gonda et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
H
Ph
H
H
1
O
O
Ph
O
2
ΔG2= −32.4 kcal/mol
O
N
N
+H2O
+H3O
11a/I
ΔG2
CH2O /H
fast
10a
#
#
=
ΔG1
=
−
7.4 kcal/mol
−6.6 kcal/mol
ΔG1= −4.7 kcal/mol
7a
ΔG4=
+0.8 kcal/mol
slow
H
CH2O /H
2
H
H
1
Ph
Ph
O
Δ
−
G3= 26.9 kcal/mol
O
N
O
O
N
+H3O
+H2O
11a/II
9a
Scheme 3. Proton-catalyzed ring–ring tautomerism of oxazine 9a and oxazolidine 10a.
HO
HO
O
H
(i)
(i)
7b
: Ar = Ph
(
S
)
( )
R
5b
6b
8b: Ar = 3,5-di-t-BuC6H3
Et2Zn, n-hexane
+
10 mol% catalyst
(iii)
Ar = Ph
9b 10b
:
= 1:2
Scheme 5. Model reaction for enantioselective catalysis.
9b + 10b
4.2. (4R)-2,2,2-Trichloro-N-[1-methyl-1-(4-methylcyclohex-1-
enyl)-ethyl]-acetamide 4
Scheme 4. Reagents and conditions: (i) 18% aq HCl, Et2O, rt, 168 h, 83%; (ii) ArCHO,
dry EtOH, 2 h, then NaBH4, EtOH, 48 h, reflux, 51% (7b) and 43% (8b); (iii) 35% aq
CH2O, Et2O, rt, 1 h, 48% (9b) and 21% (10b).
To a solution of pulegol (5.00 g, 32.4 mmol) prepared according
to the literature in dry CH2Cl2 (100 mL), 1,8-diazabicycloundec-7-
ene (7 mL, 46.8 mmol) and CCl3CN (6 mL, 59.8 mmol) were added
at 0 °C. The reaction mixture was then allowed to warm to room
temperature and stirred for 6 h. When the reaction was completed
(monitored by means of TLC), the mixture was concentrated to a
volume of 40 mL and then filtered through a short pad of silica
gel washing with CH2Cl2. Evaporation of the solvent in vacuo gave
a brown oil, which was immediately dissolved in dry xylene
(250 mL). To this solution, anhydrous K2CO3 (1.30 g, 9.4 mmol)
was added and the mixture was refluxed overnight. The obtained
solution was then filtered through a Celite pad, washed and con-
centrated in vacuo. The obtained crude product was purified by
column chromatography on silica gel (n-hexane/EtOAc = 9/1). Iso-
lated compound: 6.49 g (67%); yellow crystals; mp: 50–53 °C;
uncorrected. The 1H and 13C NMR spectroscopic data were
recorded with a Bruker Avance DRX 400 MHz spectrometer. Chem-
ical shifts are reported in (ppm) units relative to tetramethylsilane
as the internal standard. Optical rotations were measured with a
Perkin-Elmer 341 polarimeter. Chromatographic separations were
carried out on Merck Kieselgel 60 (230–400 mesh ASTM). Reac-
tions were monitored with Merck Kieselgel 60 F254-precoated
TLC plates (0.25 mm thickness). Elemental analyses were per-
formed on a Perkin-Elmer 2400 Elemental Analyzer. GC measure-
ments 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 Chi-
rasil-DEX CB column (2500 ꢁ 0.25 mm I.D.). Pulegol 2 was pre-
pared according to the literature method, and was identical with
product reported therein.20
½
a 2D0 = +39 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d 0.95
ꢂ
(3H, d, J = 6.3 Hz), 1.13–1.28 (1H, m), 1.50 (6H, s), 1.55–1.79 (3H,
m), 1.95–2.23 (3H, m), 5.69 (1H, t, J = 2.3 Hz), 6.53 (1H, br s). 13C
NMR (100 MHz, CDCl3) d 21.7, 24.4, 26.2, 26.4, 28.2, 31.4, 34.0,
58.4, 76.8, 121.5, 139.5, 160.0. Anal. Calcd for C12H18Cl3NO: C,
48.26; H, 6.08; Cl, 35.61; N, 4.69. Found: C, 48.37; H, 6.02; Cl,
35.55; N, 4.70.
Table 1
Addition of diethylzinc to benzaldehyde, catalyzed by aminodiols, oxazolidines and
1,3-oxazines
Entry
Ligand
Yielda (%)
eeb (%)
Configurationc
4.3. General procedure for the preparation of 5a and 5b
1
2
3
4
5
6
7
8
9
10
6a
6b
7a
7b
8a
8b
9a
9b
10a
10b
87
85
75
89
87
85
88
83
90
87
28
0
(S)
—
To 4 (2.30 g, 7.70 mmol) in acetone (50 mL) were added 4-
methylmorpholine N-oxide (9 mL, 50% aqueous solution) and
OsO4 (2.8 mL, 2% t-BuOH solution). The reaction mixture was stir-
red for 48 h at room temperature. The reaction was then quenched
by the addition of saturated aqueous Na2SO3 (50 mL) and extracted
with EtOAc (3 ꢁ 50 mL). The organic layer was dried (Na2SO4) and
evaporated. According to the 1H NMR measurement of the crude
product, it was a mixture of 5a and 5b in 1:1 diastereomeric ratio.
The separation of diastereoisomers was accomplished by column
chromatography on silica gel (n-hexane/EtOAc = 4/1).
67
36
12
54
64
46
90
44
(R)
(S)
(R)
(S)
(R)
(S)
(S)
(S)
a
b
c
Yields after silica column chromatography are given.
Determined on the crude product by GC (Chirasil-DEX CB column).
Determined by comparing the tR of the GC analysis and the optical rotation with
the literature data.41,42
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T. Gonda et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.3.1. (1R,2R,4R)-2,2,2-Trichloro-N-[1-(1,2-dihydroxy-4-methyl-
cyclohexyl)-1-methyl-ethyl]-acetamide 5a
solved in H2O and extracted with CH2Cl2 (3 ꢁ 30 mL). The com-
bined organic layer was dried (Na2SO4), filtered and evaporated
to dryness. The obtained crude product was purified by column
chromatography on silica gel (toluene/ethanol = 4/1).
Isolated compound: 1.0 g (39%); white crystals; mp: 155–
157 °C; ½a 2D0
ꢂ
= +27 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
0.94 (3H, d, J = 6.0 Hz), 1.53 (3H, s), 1.54 (3H, s), 1.20–1.56 (5H,
m), 1.69–1.81 (2H, m), 2.00 (1H, d, J = 6.9 Hz), 2.84 (1H, s), 3.83–
3.92 (1H, m), 8.11 (1H, br s). 13C NMR (100 MHz, CDCl3) d 21.6,
21.8, 22.8, 29.4, 30.9, 31.1, 40.7, 63.3, 72.2, 76.2, 93.9, 161.7. Anal.
Calcd for C12H20Cl3NO3: C, 43.33; H, 6.06; Cl, 31.97; N, 4.21. Found:
C, 43.47; H, 6.11; Cl, 31.80; N, 4.07.
4.5.1. (1R,2R,4R)-1-(1-Benzylamino-1-methylethyl)-4-methyl-
cyclohexane-1,2-diol 7a
Isolated compound: 0.40 g (54%); white crystals; mp: 125–
128 °C; ½a 2D0
ꢂ
= +27 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
0.92 (3H, d, J = 6.3 Hz), 1.21 (3H, s), 1.27 (3H, s), 1.18–1.29 (3H,
m), 1.34–1.48 (2H, m), 1.67–1.77 (2H, m), 3.76 (2H, q, J = 12.3,
12.3 Hz), 3.98 (1H, dd, J = 4.7, 11.4 Hz), 7.21–7.35 (5H, m). 13C
NMR (100 MHz, CDCl3) d 19.9, 21.8, 22.0, 29.8, 30.3, 30.6, 39.0,
46.3, 61.3, 72.4, 75.8, 127.5, 128.6, 128.8, 139.4. Anal. Calcd for
4.3.2. (1S,2S,4R)-2,2,2-Trichloro-N-[1-(1,2-dihydroxy-4-methyl-
cyclohexyl)-1-methyl-ethyl]-acetamide 5b
Isolated compound: 1.0 g (39%); white crystals; mp: 172–
174 °C. ½a 2D0
ꢂ
= ꢀ18 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.71; H, 10.00;
N, 5.09.
0.98 (3H, d, J = 7.3 Hz), 1.28–1.36 (1H, m), 1.54 (3H, s), 1.55 (3H,
s), 1.57–1.64 (3H, m), 1.79–1.91 (2H, m), 1.98 (1H, d, J = 7.1 Hz),
2.02–2.12 (1H, m), 2.88 (1H, s), 4.01–4.14 (1H, m), 8.10 (1H, br
s). 13C NMR (100 MHz, CDCl3) d 17.7, 21.7, 22.9, 25.9, 26.2, 27.3,
37.8, 63.4, 68.1, 76.8, 161.8. Anal. Calcd for C12H20Cl3NO3: C,
43.33; H, 6.06; Cl, 31.97; N, 4.21. Found: C, 43.51; H, 6.01; Cl,
32.03; N, 4.15.
4.5.2. (1S,2S,4R)-1-(1-Benzylamino-1-methylethyl)-4-methyl-
cyclohexane-1,2-diol 7b
Isolated compound: 0.38 g (51%); white crystals, mp: 138–
140 °C; ½a 2D0
ꢂ
= ꢀ26 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
0.99 (3H, d, J = 7.4), 1.21 (3H, s), 1.28 (3H, s), 1.24–1.33 (1H, m),
1.45–1.67 (4H, m), 1.79–1.90 (1H, m), 1.98–2.08 (1H, m), 3.73
(2H, q, J = 11.8, 18.6 Hz), 4.21 (1H, dd, J = 6.0, 10.8 Hz), 7.22–7.37
(5H, m). 13C NMR (100 MHz, CDCl3) d 17.7, 19.8, 21.9, 25.0, 26.5,
27.1, 35.7, 46.4, 61.1, 67.8, 76.5, 127.4, 128.4, 128.8, 140.0. Anal.
Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.47;
H, 10.03; N, 5.13.
4.4. General procedure for the hydrolysis of trichloroacetyl
protecting group
A solution of 5a or 5b (0.5 g, 1.5 mmol) in Et2O (10 mL) was stir-
red with 18% aqueous HCl solution (15 mL) at room temperature.
After 168 h, the aqueous and organic phases were separated and
the aqueous phase was washed with Et2O (2 ꢁ 50 mL) and then
evaporated to dryness. To the obtained crude product 10% KOH
solution was added (50 mL) and the mixture was extracted with
CH2Cl2 (3 ꢁ 50 mL). The organic layer was dried (Na2SO4) and
evaporated.
4.5.3. (1R,2R,4R)-1-[1-(3,5-Di-tert-butylbenzylamino)-1-methyl-
ethyl]-4-methylcyclohexane-1,2-diol 8a
Isolated compound: 0.28 g (27%); white crystals; mp: 122–
123 °C; ½a 2D0
ꢂ
= +15 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
0.92 (3H, d, J = 6.2), 1.14 (2H, q, J = 12.0, 23.8 Hz), 1.27 (4H, s),
1.22 (3H, s), 1.32 (18H, s), 1.34–1.48 (2H, m), 1.69–1.80 (2H, m),
3.70 (2H, q, J = 11.3, 15.2 Hz), 4.00 (1H, dd, J = 4.7, 12.0 Hz), 7.10
(2H, d, J = 1.8 Hz), 7.33 (1H, t, J = 1.9 Hz). 13C NMR (100 MHz,
CDCl3) d 19.9, 21.8, 22.0, 29.9, 30.2, 30.6, 31.6, 35.0, 39.1, 47.0,
60.8, 72.2, 75.8, 121.5, 122.8, 139.0, 151.3. Anal. Calcd for
4.4.1. (1R,2R,4R)-1-(1-Amino-1-methylethyl)-4-methylcyclohex-
ane-1,2-diol 6a
Isolated compound: 0.24 g (85%); colourless oil; ½a D20
ꢂ
= +26 (c
d 0.92 (3H, d,
0.250, MeOH). 1H NMR (400 MHz, CDCl3)
J = 6.2 Hz), 1.18 (3H, s), 1.20 (3H, s), 1.15–1.28 (3H, m), 1.32–1.46
(2H, m), 1.66–1.75 (2H, m), 3.94 (1H, dd, J = 4.9, 11.4 Hz). 13C
NMR (100 MHz, CDCl3) d 22.1, 25.7, 28.5, 29.9, 30.3, 30.8, 39.0,
57.0, 72.4, 74.9. Anal. Calcd for C10H21NO2: C, 64.13; H, 11.30; N,
7.48. Found: C, 64.02; H, 11.51; N, 7.40.
C25H43NO2: C,77.07; H, 11.12; N, 3.60. Found: C, 77.14; H, 11.01;
N, 3.58.
4.5.4. (1S,2S,4R)-1-[1-(3,5-Di-tert-butylbenzylamino)-1-methyl-
ethyl]-4-methylcyclohexane-1,2-diol 8b
Isolated compound: 0.45 g (43%); white crystals; mp: 114–
4.4.2. (1S,2S,4R)-1-(1-Amino-1-methylethyl)-4-methylcyclohex-
ane-1,2-diol 6b
116 °C; ½a 2D0
ꢂ
= ꢀ20 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d
0.99 (3H, d, J = 7.4 Hz), 1.13 (3H, s), 1.30 (3H, s) 1.32 (18H, s),
1.24–1.34 (1H, m), 1.46–1.64 (4H, m), 1.80–1.91 (1H, m), 2.97–
1.09 (1H, m), 3.70 (2H, q, J = 11.6, 16.4 Hz), 4.23 (1H, dd, J = 6.3,
10.5 Hz), 7.10 (2H, d, J = 1.8 Hz), 7.33 (1H, t, J = 1.8 Hz). 13C NMR
(100 MHz, CDCl3) d 17.7, 19.7, 21.9, 25.0, 26.5, 27.2, 31.6, 35.0,
35.8, 47.1, 61.1, 67.7, 76.5, 121.5, 122.8, 138.9, 151.3. Anal. Calcd
for C25H43NO2: C,77.07; H, 11.12; N, 3.60. Found: C, 76.95; H,
11.31; N, 3.54.
Isolated compound: 0.23 g (83%); white crystals; mp: 72–75 °C;
½
a 2D0
ꢂ
= ꢀ36 (c 0.250, MeOH). 1H NMR (400 MHz, CDCl3) d 0.97 (3H,
d, J = 7.3 Hz), 1.18 (3H, s), 1.23 (3H, s), 1.24–1.30 (1H, m), 1.40–1.71
(4H, m), 1.79–1.90 (1H, m), 1.99–2.08 (1H, m), 4.16 (1H, dd, J = 5.2,
11.6 Hz). 13C NMR (100 MHz, CDCl3) d 17.7, 25.1, 25.7, 26.5, 27.3,
28.3, 35.7, 57.2, 67.9, 75.6. Anal. Calcd for C10H21NO2: C, 64.13;
H, 11.30; N, 7.48. Found: C, 64.29; H, 11.07; N, 7.46.
4.5. General procedure for the reductive alkylation of
aminodiols
4.6. General procedure for the ring closure of monobenzyl
substituted aminodiols
To
a
solution of primary aminodiols 6a and 6b (0.50 g,
To a solution of 7a or 7b (0.30 g, 1.6 mmol) in Et2O (6 mL), 35%
aqueous formaldehyde solution (5 mL) was added. The reaction
mixture was stirred for 1 h at room temperature, after which was
added alkaline with 10% cool aqueous KOH solution and extracted
with Et2O (3 ꢁ 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 was purified
by column chromatography on silica gel (n-hexane/EtOAc = 9/1).
2.7 mmol) in dry ethanol (25 mL), was added the appropriate alde-
hyde (2.8 mmol) in one portion, and the solution was stirred at
room temperature for 1 h and then evaporated to dryness. The
residual product was dissolved in dry ethanol (25 mL) and stirred
for a further 1 h. Next NaBH4 (0.30 g, 7.9 mmol) was added in small
portions to the mixture under ice cooling. After refluxing for 48 h,
the mixture was evaporated to dryness and the residue was dis-
Please cite this article in press as: Gonda, T.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.04.009

6
T. Gonda et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.6.1. (4aR,7R,8aR)-3-Benzyl-4,4,7-trimethylhexahydrobenzo[e]
[1,3]oxazin-4a-ol 9a
using a chiral stationary phase (Chirasil-Dex CB column) at
90 °C.41,42
Isolated compound: 91 mg (39%); white crystals; mp: 110–
113 °C; ½a 2D0
ꢂ
= ꢀ73 (c 0.250, MeOH). 1H NMR (400 MHz, DMSO-
4.8. X-ray structure determination
d6) d 0.85 (3H, d, J = 6.4 Hz), 0.93 (3H, s), 1.04–1.26 (3H, m), 1.29
(3H, s), 1.32–1.40 (1H, m), 1.41–1.50 (2H, m), 1.51–1.59 (1H, m),
3.32 (1H, d, J = 13.4 Hz), 3.51 (1H, dd, J = 4.3, 11.2 Hz), 3.97 (1H,
d, J = 13.4 Hz), 4.00 (1H, d, J = 1.3 Hz), 4.25 (1H, d, J = 1.2 Hz), 5.97
(1H, s), 7.21–7.34 (5H, m). 13C NMR (100 MHz, DMSO-d6) d 15.2,
21.2, 22.8, 30.0, 30.6, 31.2, 39.9, 48.8, 64.2, 73.0, 83.5, 86.6,
128.1, 128.9, 129.4, 139.2. Anal. Calcd for C18H27NO2: C, 74.70; H,
9.40; N, 4.84; Found: C, 74.35; H, 9.30; N, 5.05.
The crystals of 5a and 5b were immersed in cryo-oil, mounted
in a MiTeGen loop, and measured at a temperature of 120 K. The
X-ray diffraction data were collected on a Rigaku Oxford Diffrac-
tion Supernova diffractometer using Cu K
a (k = 1.54184 Å) radia-
tion. The CrysAlisPro43 program package was used for cell
refinements and data reductions. Analytical absorption corrections
were performed by modeling the crystal faces (CrysAlisPro).43 The
structures were solved by charge flipping method using the SUPER-
FLIP software.44 Structural refinements were carried out using
SHELXL-201445 with the SHELXLE46 graphical user interfaces. In
both structures the NH and OH hydrogen atoms were located from
the difference Fourier map and refined isotropically. Other hydro-
gen atoms were positioned geometrically and constrained to ride
on their parent atoms, with C–H = 0.98–1.00 Å and Uiso = 1.2–
1.5 Ueq (parent atom). The crystallographic details are summarized
in Table S1 (see Supporting information). Deposition numbers
CCDC 1470051 and CCDC 1470052 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif].
4.6.2. (5R,6R,8R)-3-Benzyl-4,4,8-trimethyl-1-oxa-3-azaspiro[4.5]
decan-6-ol 10a
Isolated compound: 0.18 g (47%); colourless oil; ½a D20
= ꢀ56 (c
ꢂ
0.250, MeOH). 1H NMR (400 MHz, DMSO-d6) d 0.87 (3H, d,
J = 5.7 Hz), 1.13 (3H, s), 1.15 (3H, s), 1.17–1.47 (6H, m), 1.57–1.65
(1H, m), 3.26 (1H, d, J = 15.1 Hz), 3.54 (1H, d, J = 1.5 Hz), 3.68 (1H,
dd, J = 4.5, 10.5 Hz), 3.84 (1H, d, J = 9.0 Hz), 3.91 (1H, d,
J = 15.2 Hz), 4.22 (1H, d, J = 9.0 Hz), 7.14–7.38 (5H, m). 13C NMR
(100 MHz, DMSO-d6) d 15.5, 21.6, 22.0, 28.4, 29.2, 30.1, 35.5,
48.4, 59.6, 70.6, 75.2, 77.6, 126.5, 127.9, 128.1, 140.6. Anal. Calcd
for C18H27NO2: C, 74.70; H, 9.40; N, 4.84; Found: C, 74.99; H,
9.33; N, 4.75.
4.6.3. (5S,6S,8R)-3-Benzyl-4,4,8-trimethyl-1-oxa-3-azaspiro[4.5]
decan-6-ol 9b
Acknowledgement
Isolated compound: 0.15 g (48%); white crystals; mp: 79–81 °C;
½
a 2D0
ꢂ
= ꢀ28 (c 0.250, MeOH). 1H NMR (400 MHz, DMSO-d6) d 0.97
The authors are grateful for financial support from the Hungar-
ian Research Foundation (OTKA K-112442 and K-115731).
(3H, d, J = 7.4 Hz), 1.15 (7H, d, J = 5.0 Hz), 1.22–1.40 (2H, m),
1.42–1.49 (1H, m), 1.76–1.89 (2H, m), 1.92–2.04 (1H, m), 3.26
(1H, d, J = 14.3 Hz), 3.54 (1H, d, J = 1.7 Hz), 3.81–3.95 (3H, m),
4.24 (1H, d, J = 8.7 Hz), 7.17–7.39 (5H, m). 13C NMR (100 MHz,
DMSO-d6) d 16.3, 18.9, 22.4, 26.7, 27.4, 33.4, 49.3, 60.6, 72.2,
72.3, 78.6, 124.4, 128.8, 129.0, 141.5. Anal. Calcd for C18H27NO2:
C, 74.70; H, 9.40; N, 4.84; Found: C, 74.55; H, 9.41; N, 4.72.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.04.
009.
4.6.4. (4aS,7R,8aS)-3-Benzyl-4,4,7-trimethylhexahydrobenzo[e]
[1,3]oxazin-4a-ol 10b
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