Stereoselective synthesis of carane-based aminodiols as chiral ligands for the catalytic addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2011.06.013

Key intermediate epoxy alcohol 4 was prepared regio- and stereoselectively from (+)-3-carene 1 via carene oxide 2 and (-)-trans-allyl alcohol 3. The lithium perchlorate-catalysed ring opening of 4 with secondary and primary achiral and chiral amines resulted in primary, secondary and tertiary aminodiols. Aminodiols 5-14 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde, resulting in (R)- and (S)-1-phenyl-1-propanol with moderate enantioselectivity. N-Benzyl, N-methyl, and (S)- and (R)-N-methylbenzyl derivatives 7 and 10-13 were transformed into 1,3-oxazines 17-21 via highly regioselective ring closures. When 17-21 were applied as chiral catalysts in the addition of diethylzinc to aromatic and aliphatic aldehydes, high chiral induction in the tricyclic catalysts was observed. The effects of the substituents on the nitrogen of the aminodiols and 1,3-oxazines were studied in detail; the best enantioselectivity was observed in the case of N-methylbenzyl-substituted oxazine 19.

Full text of DOI:10.1016/j.tetasy.2011.06.013

Tetrahedron: Asymmetry 22 (2011) 1021–1027
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of carane-based aminodiols as chiral ligands
for the catalytic addition of diethylzinc to aldehydes
Zsolt Szakonyi a, Kinga Csillag a, Ferenc Fülöp a,b,
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged Eötvös utca 6, Hungary
b Research Group of Stereochemistry of The Hungarian Academy of Sciences, 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:
Key intermediate epoxy alcohol 4 was prepared regio- and stereoselectively from (+)-3-carene 1 via car-
ene oxide 2 and (ꢀ)-trans-allyl alcohol 3. The lithium perchlorate-catalysed ring opening of 4 with sec-
ondary and primary achiral and chiral amines resulted in primary, secondary and tertiary aminodiols.
Aminodiols 5–14 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benz-
aldehyde, resulting in (R)- and (S)-1-phenyl-1-propanol with moderate enantioselectivity. N-Benzyl,
N-methyl, and (S)- and (R)-N-methylbenzyl derivatives 7 and 10–13 were transformed into 1,3-oxazines
17–21 via highly regioselective ring closures. When 17–21 were applied as chiral catalysts in the addition
of diethylzinc to aromatic and aliphatic aldehydes, high chiral induction in the tricyclic catalysts was
observed. The effects of the substituents on the nitrogen of the aminodiols and 1,3-oxazines were studied
in detail; the best enantioselectivity was observed in the case of N-methylbenzyl-substituted oxazine 19.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 April 2011
Accepted 14 June 2011
Available online 19 July 2011
1. Introduction
cytokine,
species.23,24
We recently reported the transformations of enantiomerically
pure -pinene, d-pinene, apopinene and myrtenal to b-amino acid
a microbial metabolite isolated from Streptomyces
Chiral synthons that can be applied successfully in asymmetric
homogeneous and heterogeneous catalysis are of increasing impor-
tance in organic chemistry.1–3 Some of these building blocks and
chiral catalysts, such as monoterpene-based 1,2- and 1,3-amino
alcohols derived from readily available chiral terpenes, and are
widely used in enantioselective transformations.4–6 Various amino
alcohols obtained from monoterpenes, such as (+)-pulegone,4
a
derivatives, for example, amino esters and amino alcohols, which
proved to be excellent building blocks for the synthesis of monoter-
pene-fused saturated1,3-heterocycleswithnoteworthy MDRblock-
ing and antitumour activity.26 Pinane-based 1,3-amino alcohols
were also applied as chiral auxiliaries in enantioselective reac-
tions.26d As part of our systematic studies on 1,3-difunctional chiral
monoterpenic building blocks,26 we also recently reported the syn-
thesis of (+)- and (ꢀ)-2-aminomethyl-6,6-dimethylbicyclo[3.1.1]
a
- and b-pinene,7,8 and fenchone-camphor,9 have been used as
catalytic ligands for various chemical transformations. Chiral amin-
odiols, whichcombine the chemicalproperties of 1,2- and 1,3-amino
alcohols, have also proven to be excellent catalysts.10–18 Aminodiols
are similarly useful starting materials for the synthesis of 1,3-oxa-
zines or oxazolidines, depending upon which hydroxy group
undergoes ring closure with the amino group. Since the resulting
heterobicycles contain a free hydroxy group, this extra coordinative
functional group may possibly lead to higher rigidity within the
transition state, and therefore to higher enantioselective induction
in asymmetric addition reactions, for example, catalytic asymmetric
carbon–carbon bond formation, as in the dialkylzinc addition to
aldehydes, asymmetric allylic alkylation, and so on.14,19–21 Further-
more, aminodiols may serve as useful starting materials for the
synthesis of biologically active natural compounds,22–25 for
example, cytoxazone, a selective modulator of the secretion of TH2
heptane-2,3-diols from
a
-pinene enantiomers.27 The resulting
aminodiols were successfully applied as catalysts and as building
blocks in the regioselective ring closures of aminodiols, to give chiral
spiro 1,3-heterocycles.27,28
Herein, our aim was to build up an aminodiol library, starting
from readily available (+)-3-carene, and to use the resulting amin-
odiols as chiral catalysts in the enantioselective addition of dieth-
ylzinc to aromatic and aliphatic aldehydes.
2. Results and discussion
2.1. Synthesis of carane-based aminodiols
The key-intermediate epoxy alcohol 4 was synthesised as
shown in Scheme 1, by a combination of literature methods.27,29,30
Starting from commercially available (+)-3-carene 1, epoxidation
⇑
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.013

1022
Z. Szakonyi et al. / Tetrahedron: Asymmetry 22 (2011) 1021–1027
i
ii
O
OH
2
1
3
iii
OH
OH
R1
R2
R1
v
iv
N
H
O
N
5,6
OH
OH
OH
13, 14
4
5-12
1
2
5: R1
8: R1
10: R1
12: R1
6
7: R1
= Me, R2 = CH2Ph; : R = R = CH2Ph;
= H, R2 = CH2Ph;
= CH2Ph, R2 = CH(Me)Ph (R);
= H, R2 = CH(Me)Ph (R);
= CH2Ph, R2 = CH(Me)Ph (S);
9: R1
11: R1
14: R1
= H, R2 = CH(Me)Ph (S);
= H, R2 = i-Pr;
: R = Me;
= H
1
13
Scheme 1. Reagents and conditions: (i) MCPBA, CHCl3, rt, 1 h, yield 60%; (ii) n-BuLi, 2,2,6,6-tetramethylpiperidine, Et2AlCl, dry toluene, Ar atm, 0 °C, 2 h, yield 58%; (iii)
MCPBA, DCM, Na2HPO4 buffer, rt, 1 h, yield 65%; (iv) 4 equiv HNR1R2, 1 equiv LiClO4, MeCN, reflux, 6–40 h, yield 18–70%; (v) 10% Pd/C, MeOH, H2, 1 atm, 13: yield 37%, 14:
yield 63%.
with MCPBA furnished epoxide 2 in a stereospecific reaction.29 3-
Carene oxide 2 underwent rearrangement to allyl alcohol 3 in
dry toluene in the presence of tetramethylpiperidine diethylalumi-
nate and n-butyllithium.30 Epoxidation of allylic alcohol 3 with
MCPBA resulted in epoxy alcohol 4 in a stereospecific reaction.27
Since our previous results clearly demonstrated that the N-sub-
stituents of 1,3-aminoalcohols and aminodiols when applied as
catalysts, definitely influenced the enantioselectivity of their cata-
lysed reactions,26d,27 an eight-membered aminodiol library 5–12
was prepared by aminolysis of 4 with secondary and primary
amines. The oxirane ring was opened with lithium perchlorate as
a catalyst.12,27,31 To study the effects of the bulky substituents,
(R)- and (S)-1-phenylethylamine and (R)- and (S)-N-benzyl-1-
phenylethylamine were utilised; the latter resulted in the expected
tertiary aminodiol 11 only in low yield, probably because of the
strong steric hindrance of the substituents (Scheme 1).
Our results are presented in Table 1. The enantiomeric purities
of the 1-phenyl-1-propanols (S)-16a and (R)-16a obtained were
determined by GC on a CHIRASIL-DEX CB column, according to lit-
erature methods.26d The observed enantioselectivities were low to
moderate and, in cases of (S)-selectivity (using compounds 6, 7, 9,
10, 13 and 14), were significantly lower than those involving (R)-
selectivity (compounds 5, 8, 11 and 12). The best, but still moder-
ate, result was obtained with N-(S)-1-phenylethyl-substituted
aminodiol 11. When compared with the previous results using
aminodiols,27 it seems that tridentate carane-based aminodiols
are less enantioselective catalysts than the tridentate pinane-based
analogues, probably because of the weaker steric hindrance of the
carane moiety as compared with the pinane ring system.
2.3. Regioselective synthesis of carane-fused 1,3-oxazines
Secondary and primary aminodiols were obtained in two differ-
ent ways: N-benzylaminodiol 5 was prepared by the reaction of 4
with benzylamine under similar conditions as applied for tertiary
aminodiols, while the N-methyl derivative 13 and primary amino-
diol 14 were synthesised by debenzylation of the corresponding
N,N-dibenzyl- and N-benzyl-N-methylaminodiols 5 and 6 under
standard conditions, by hydrogenation in the presence of a palla-
dium-on-carbon catalyst (Scheme 1).
Andrés et al. recently reported that tricyclic aminodiol deriva-
tives with rigid structures had enhanced catalyticpotential, discrim-
inating better between the two enantiotopic faces of the aldehyde
within the transition state complex.21 To prepare conformationally
more constrained structures, we attempted to incorporate one of
the hydroxy groups of our aminodiols into a spiro-oxazolidine or a
condensed 1,3-oxazine ring. When aminodiols 7 and 10–13 were
reacted with formaldehyde under mild conditions, 1,3-oxazines
17–21 were obtained in highly regioselective ring closures, with
opposite regioselectivities relative to those of the pinane-based
analogues reported recently (Scheme 3).27
2.2. Application of aminodiols 5–14 as chiral ligands for the
catalytic addition of diethylzinc to benzaldehyde
The excellent regioselectivity of the reaction could be explained
by the extended bicyclo[4.1.0]heptane structure, which makes the
equatorial 3-aminomethyl and 4-hydroxy groups preferable for the
ring closure.
The aminodiol derivatives 5–14 were used as chiral catalysts in
the enantioselective addition of diethylzinc to benzaldehyde,
resulting in chiral 1-phenyl-1-propanol (Scheme 2).
O
OH
OH
Et2Zn
H
+
10 mol% catalyst 5-14,
rt, Ar atm.
(S)-16a
(R)-16a
15a
Scheme 2. Addition of diethylzinc to benzaldehyde.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 22 (2011) 1021–1027
1023
Table 1
Addition of diethylzinc to benzaldehyde, catalysed by various types of aminodiols
Entry
Catalyst (10 mol %)
Yielda (%)
eeb (%)
Configuration of major productc
1
2
3
4
5
6
7
8
9
5
6
7
8
9
10
11
12
13
14
87
84
90
75
80
88
78
73
81
73
13
10
3
31
8
(R)
(S)
(S)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
7
37
30
16
5
10
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 specific rotation with the literature data.
OH
OH
R1
R1
i
N
H
N
O
O
OH
O
Zn
N
Zn
7, 10-13
17-21
H
O
1
1
1
Ph
17
18
19:
: R = CH2Ph; : R = Me;
R = CH(Me)Ph (R);
20: R1 = CH(Me)Ph (S); 21: R1 = i-Pr
Ph
Scheme 3. Reagents and conditions: (i) CH2O/H2O, rt,1 h, yield 63–96%.
Figure 1. Proposed transition state for the asymmetric addition with 17.
2.4. Application of 1,3-oxazines 17–21 as chiral ligands for the
catalytic addition of diethylzinc to aldehydes
O
OH
OH
When oxazines 17–21 were applied as catalysts in the addition
of diethylzinc, increased enantioselectivity was observed (Table 2).
The best result (ee = 96%) was obtained on the use of N-(R)-1-phen-
ylethyl-substituted 1,3-oxazine 19.
Et2Zn
+
R
H
R
R
10 mol% catalyst
15b-h
19
(R)-16b-h
,
(S)-16b-h
rt, Ar atm.
Scheme 4. Addition of diethylzinc to aldehydes.
Table 2
Addition of diethylzinc to benzaldehyde catalysed by various 1,3-oxazines
Entry
Catalyst (10 mol %)
Yielda (%)
eeb (%)
Configurationc
Table 3
Addition of diethylzinc to aldehydes catalysed by ligand 19
1
2
3
4
5
17
18
19
20
21
74
72
77
71
83
94
92
96
62
38
(S)
(S)
(S)
(S)
(S)
Entry
Product
R
Yielda (%)
eeb (%)
Configurationc
1
2
3
4
5
6
7
16b
16c
16d
16e
16f
(4-MeO)C6H4
(4-Me)C6H4
(3-MeO)C6H4
(3-Me)C6H4
2-Naphthyl
Cyclohexyl
n-Butyl
89
93
91
90
86
80
87
97
97
96
93
96
92
77
(S)
(S)
(S)
(S)
(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 specific rotation
16g
16h
with literature data.
a
b
c
Yields after silica column chromatography are given.
Determined on the crude product by HPLC (Chiracel OD-H).
Determined by comparing the tR of the HPLC analysis and the specific rotation
We propose the transition state shown in Figure 1 to account for
the stereoselectivity observed with chiral ligand 17. In this transi-
tion state, the transfer of the ethyl group occurs on the si-face of
the aldehyde, leading to the (S)-enantiomer of the alcohols.
With the best catalyst 19, the diethylzinc addition reaction was
extended to other aromatic and aliphatic aldehydes (Scheme 4).
Our results are presented in Table 3. The enantiomeric purities of
the 1-aryl and 1-alkyl-1-propanols obtained were determined by
GCona CHIRASIL-DEXCBcolumnor bychiral HPLCanalysisona Chi-
ralcel OD-H column, according to literature methods.19,21,26d,32–36
The results presented in Table 3 clearly show that hydroxy-
substituted 1,3-oxazine 19 proved to be an efficient catalyst in this
model reaction. High chemical conversions and enantioselectivi-
ties were observed in the addition of diethylzinc to aromatic alde-
hydes catalysed by 1,3-oxazines 17–21, while lower, but still good
yields and selectivities were obtained when aliphatic aldehydes
were applied.
with the literature data.
3. Conclusions
The new carane-based aminodiols prepared herein may serve as
chiral building blocks in the asymmetric syntheses of potential
drug candidates, and they can also be used as chiral auxiliaries
and catalysts in enantioselective syntheses. Substituent-dependent
enantioselectivity was observed in the sequence NH2 < NHR < NRR.
The ring closures of secondary aminodiols proceeded with high
regioselectivity, resulting exclusively in monoterpene-condensed
1,3-oxazines. The 1,3-oxazines obtained proved to be excellent cat-
alysts in the additions of diethylzinc to either aromatic or aliphatic
aldehydes, probably as a consequence of their conformationally
constrained structures.

1024
Z. Szakonyi et al. / Tetrahedron: Asymmetry 22 (2011) 1021–1027
4.3.1. (1S,3R,4R,6R)-3-(Benzyl(methyl)amino)methyl)-7,7-
4. Experimental
dimethylbicyclo[4.1.0]heptane-3,4-diol 5
Prepared with N-benzyl-N-methylamine at reflux for 8 h. Com-
pound 5 was purified by column chromatography on silica gel (tol-
uene/EtOH = 9:1). Compound 5: 2.26 g (65%); yellow crystals, mp
4.1. General experimental procedures
1H and 13C NMR spectra were recorded on a Bruker Avance DRX
400 spectrometer (400 MHz and 100.6 MHz, d = 0 (TMS)). Chemical
shifts are expressed in ppm (d) relative to TMS as the internal ref-
erence. J values are given in Hertz. FT-IR spectra were recorded on
a Perkin–Elmer Spectrum 100 instrument. Microanalyses were
performed on a Perkin–Elmer 2400 elemental analyser. GC mea-
surements were made on a Perkin–Elmer Autosystem XL GC, con-
63–67 °C; ½a 2D0
ꢃ
¼ þ35 (c 0.125, EtOH) 1H NMR (CDCl3) d (ppm):
0.62 (1H, dt, J = 4.4, 9.5 Hz), 0.78–0.83 (1H, m), 0.82 (3H, s), 0.87
(1H, dd, J = 4.4, 15.1 Hz), 0.99 (3H, s), 1.73 (1H, dt, J = 8.9,
15.1 Hz), 1.95–2.07 (2H, m), 2.37 (3H, s), 2.60 (2H, s), 3.35–3.46
(2H, m), 3.87 (1H, br d, J = 12.7 Hz), 7.27–7.37 (5H, m); 13C NMR
(CDCl3) d (ppm): 15.9, 16.2, 20.7, 25.9, 28.8, 30.2, 44.8, 64.7, 67.4,
70.9, 73.5, 127.7, 128.8, 129.4, 138.3. IR (KBr, cmꢀ1
) m = 3466,
sisting of
a Flame Ionisation Detector and a Turbochrom
2929, 1452, 1092, 738, 696. Anal. Calcd for C18H27NO2 (289.41):
C, 74.70; H, 9.40; N, 4.84. Found: C, 74.59; H, 9.52; N, 4.94.
Workstation data system (Perkin–Elmer Corporation Norwalk,
USA). The column used for the direct separation of enantiomers
was a CHIRASIL-DEX CB column (2500 ꢁ 0.25 mm I.D.). Chiral
4.3.2. (1S,3R,4R,6R)-3-(Dibenzylamino)methyl)-7,7-
dimethylbicyclo[4.1.0]heptane-3,4-diol 6
Prepared with dibenzylamine at reflux for 29 h. Compound 6
(2.98 g, 68%); colourless crystals, mp 149–151 °C (n-hexane);
HPLC analysis was performed on
a Chiralcel OD-H column
(250 ꢁ 4.6 mm). UV detection was monitored at 210 nm or at
254 nm.
Optical rotations were obtained with a Perkin–Elmer 341 polar-
imeter. Melting points were determined on a Kofler apparatus and
are uncorrected. Chromatographic separations were carried out on
Merck Kieselgel 60 (230–400 mesh ASTM). Reactions were moni-
½
a 2D0
ꢃ
¼ þ31 (c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm): 0.45
(1H, dt, J = 4.1, 9.5 Hz), 0.60–0.66 (1H, m), 0.78 (3H, s), 0.93 (3H,
s), 1.02 (1H, dd, J = 4.2, 15.3 Hz), 1.64–1.73 (2H, m), 1.77–1.85
(1H, m), 2.43 (1H, d, J = 14.2 Hz), 2.54 (1H, d, J = 14.2 Hz), 2.98–
3.07 (1H, m), 3.61 (2H, d, J = 14.1 Hz), 3.67 (2H, d, J = 14.4 Hz),
3.80 (1H, s), 4.62 (1H, d, J= 5.3 Hz), 7.25–7.35 (10H, m); 13C NMR
(DMSO-d6) d (ppm): 16.1, 17.4, 22.3, 27.3, 29.7, 30.3, 59.8, 61,6,
tored with Merck Kieselgel 60
F254-precoated TLC plates
(0.25 mm thickness). All of the chemicals and solvents were used
as supplied. Compounds 2 and 3 were prepared from (1S,6R)-(+)-
3-carene (Sigma–Alrich Co.) according to literature methods.27,29,30
70.9, 71.4, 72.3, 127.6, 129.0, 129.6, 140.2. IR (KBr, cmꢀ1
= 3341, 2941, 1453, 741, 700. Anal. Calcd for C24H31NO2
)
m
4.2. (1S,20R,4R,6R)-7,7-Dimethylspiro[bicyclo[4.1.0]heptane-
(365.51): C, 78.86; H, 8.55; N, 3.83. Found: C, 78.61; H, 8.79; N, 4.04.
3,20-oxiran]-4-ol 4
4.3.3. (1S,3R,4R,6R)-3-(Benzylamino)methyl)-7,7-
dimethylbicyclo[4.1.0]heptane-3,4-diol 7
To a solution of (ꢀ)-(1R,3R,6S)-4-methylene-7,7-dimethylbicy-
clo[4.1.0]-heptan-3-ol 3 (2.01 g, 13.2 mmol) in 50 mL CH2Cl2 and
Na2HPO4ꢂ2H2O (6.91 g, 44.3 mmol) in 130 mL water, m-chloroper-
benzoic acid (75% purity, 23.7 mmol) was added at 0 °C and the
mixture was stirred at room temperature. When the reaction
was complete, as indicated by TLC (1 h), the mixture was sepa-
rated and the aqueous phase was extracted with CH2Cl2
(100 mL). The organic layer was washed with 5% KOH solution
(3 ꢁ 50 mL), dried (Na2SO4) and evaporated. The residue was
purified by vacuum distillation (bp: 125 °C at 4 mbar), to afford
4. Isolated compound: 1.44 g (65%); colourless crystals, mp: 23–
Prepared with benzylamine at reflux for 14 h. Compound 7 was
purified by column chromatography on silica gel (CHCl3/MeOH =
9:1). Compound 7: 2.31 g (70%); yellow crystals, mp 49–54 °C;
½
a 2D0
ꢃ
¼ þ23 (c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm): 0.52 (1H,
dt, J = 4.5, 9.8 Hz), 0.64–0.70 (1H, m), 0.85 (3H, s), 0.95 (3H, s), 1.07
(1H, dd, J = 4.3, 15.2 Hz), 1.67–1.73 (2H, m), 1.84 (1H, dd, J = 9.8,
15.0 Hz), 2.47 (2H, d, J = 11.3 Hz), 2.53 (2H, d, J = 11.3 Hz), 3.21
(1H, t, J = 8.2 Hz), 3.69–3.78 (2H, m), 3.89 (1H, br s), 7.23–7.35 (5H,
m); 13C NMR (DMSO-d6) d (ppm): 16.2, 17.6, 22.2, 27.2, 29.7, 30.7,
34.9 54.4, 58.4, 70.8, 72.3, 127.4, 128.7, 129.1, 141.5. IR (KBr,
cmꢀ1
) m = 2839, 1944, 1454, 732, 698. Anal. Calcd for C17H25NO2
25 °C, ½a 2D0
ꢃ
¼ ꢀ48 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm):
(275.39): C, 74.14; H, 9.15; N, 5.09. Found: C, 73.98; H, 9.30; N, 5.23.
0.76 (1H, dt, J = 3.7, 9.3 Hz), 0.93 (3H, s), 1.04 (3H, s), 1.04–1.05
(1H, m), 1.48 (1H, dd, J = 1.4, 15.2 Hz), 1.71 (1H, dt, J = 3.7,
15.3 Hz), 2.16–2.23 (2H, m), 2.33 (1H, dd, J = 8.4, 15.0 Hz), 2.60
(1H, d, J = 5.0 Hz), 2.75 (1H, dd, J = 0.8, 4.8 Hz), 3.29 (1H, t,
J = 4.3 Hz); 13C NMR (CDCl3) d (ppm): 15.6, 16.7, 21.2, 24.3,
4.3.4. (1S,3R,4R,6R)-3-(Benzyl((R)-1-phenylethyl)amino)methyl-
7,7-dimethylbicyclo[4.1.0]heptane-3,4-diol 8
Prepared with benzyl ((R)-1-phenylethyl)amine at reflux for
16 h. Compound 8 was purified by column chromatography on sil-
ica gel (Et2O/AcOH = 99:1). Compound 8: 1.73 g (38%); a yellow oil;
27.9, 28.7, 34.9, 54.6, 60.5, 69.7. IR (KBr, cmꢀ1
) m = 3435, 2865,
1434, 1079, 856. Anal. Calcd for C10H16O2 (168.23): C, 71.39; H,
9.59. Found: C, 71.28; H, 9.67.
½
a 2D0
ꢃ
¼ þ56 (c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm): 0.48 (1H,
dt, J = 4.4, 9.8 Hz), 0.60–0.66 (1H, m), 0.74 (3H, s), 0.90 (1H, dd,
J = 4.6, 15.4 Hz), 0.94 (3H, s), 1.35 (3H, d, J = 7.1 Hz), 1.60–1.76
(2H, m), 1.91 (1H, dd, J = 9.8, 15.4 Hz), 2.22 (1H, d J = 14.0 Hz),
2.66 (1H, d, J = 13.9 Hz), 2.88–2.99 (1H, m), 3.51 (1H, d,
J = 14.3 Hz), 3.75 (1H, s), 3.82 (1H, d, J = 14.3 Hz), 4.95–4.05 (1H,
m), 4.65 (1H, d, J = 5.8 Hz) 7.24–7.39 (10H, m); 13C NMR (DMSO-
d6) d (ppm): 15.6, 16.1, 17.4, 17.5, 22.2, 27.3, 29.7, 30.3, 56.3,
56.9, 57.7, 71,9, 72.1, 127.5, 127.6, 128.6, 129.0, 129.1, 129.2,
4.3. General procedure for the epoxide ring opening with
secondary and primary amines
To a solution of epoxy alcohol 4 (12.0 mmol, 2.00 g) in MeCN
(150 mL) was added
a solution of the appropriate amine
(48.0 mmol) in MeCN (15 mL) and LiClO4 (12 mmol, 1.30 g). The
mixture was refluxed for 1–3 days. When the reaction was com-
pleted (indicated by TLC), the mixture was evaporated to dryness,
and the residue was dissolved in water (50 mL) and extracted with
CHCl3 (3 ꢁ 50 mL). The organic layer was dried (Na2SO4), filtered
and concentrated. The crude product was purified by recrystallisa-
tion (6, 10, 11 and 12) or by column chromatography on silica gel
with an appropriate solvent mixture (5, 7–9), resulting in com-
pounds 5–12.
141.4, 142.5. IR (KBr, cmꢀ1
) m = 3434, 2927, 1452, 731, 699. Anal.
Calcd for C25H33NO2 (379.25): C, 79.11; H, 8.76; N, 3.69. Found:
C, 79.23; H, 8.63; N, 3.80.
4.3.5. (1S,3R,4R,6R)-3-(Benzyl((S)-1-phenylethyl)amino)methyl-
7,7-dimethylbicyclo[4.1.0]heptane-3,4-diol 9
Prepared with benzyl ((S)-1-phenylethyl)amine at reflux for
40 h. Compound 9 was purified by column chromatography on sil-

Z. Szakonyi et al. / Tetrahedron: Asymmetry 22 (2011) 1021–1027
1025
ica gel (Et2O/AcOH = 99:1). Compound 9: 0.32 g (29%); a yellow oil;
through a Celite pad and the solution was evaporated to dryness,
resulting in 13 or 14.
½
a 2D0
ꢃ
¼ ꢀ8 (c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm): 0.39 (1H,
dt, J = 4.2, 9.5 Hz), 0.58–0.63 (1H, m), 0.78 (3H, s), 0.91 (3H, s),
0.93 (1H, dd, J = 4.4, 14.6 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.51 (1H,
dd, J = 9.8, 15.1 Hz), 1.62–1.72 (2H, m), 2.29 (1H, d J = 13.9 Hz),
2.61 (1H, d, J = 14.1 Hz), 2.95–3.02 (1H, m), 3.63–3.72 (3H, m),
3.96–4.01 (1H, m), 4.53 (1H, d, J = 5.9 Hz), 7.22–7.31 (10H, m).
13C NMR (DMSO-d6) d (ppm): 13.8, 16.2, 17.4, 17.5, 22.2, 27.3,
29.6, 30.1, 56.4, 56.9, 58.0, 71,1, 72.2, 127.5, 128.7, 129.0, 129.5,
4.4.1. (1S,3R,4R,6R)-7,7-Dimethyl-3-((methylamino)methyl)
bicyclo[4.1.0]heptane-3,4-diol 13
Compound 13 (0.15 g, 37%); colourless crystals, mp: 70–73 °C
(n-hexane); ½a 2D0
ꢃ
¼ þ24 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm):
0.66 (1H, dt, J = 4.3, 9.5 Hz), 0.84–0.96 (4H, m), 0.95–1.09 (5H, m),
1.66–1.79 (1H, m), 1.94–2.06 (2H, m), 2.45 (3H, s), 2.55 (1H, d,
J = 12.4 Hz), 2.82 (1H, d, J = 12.4 Hz), 3.18 (1H, s), 3.50–3.54 (1H,
m); 13C NMR (CDCl3) d (ppm): 15.8, 16.3, 21.0, 26.4, 29.0, 30.3,
141.4, 143.2. IR (KBr, cmꢀ1
) m = 3434, 2924, 1451, 749, 699. Anal.
Calcd for C25H33NO2 (379.25): C, 79.11; H, 8.76; N, 3.69. Found:
C, 79.30; H, 8.60; N, 3.86.
34.9, 36.93, 62.3, 70.4, 74.5. IR (KBr, cmꢀ1
) m = 3326, 2951, 1629,
1461, 1088, 1061. Anal. Calcd for C11H21NO2 (199.29): C, 66.29; H,
4.3.6. (1S,3R,4R,6R)-7,7-Dimethyl-3-(((R)-1-phenylethylamino)
methyl)bicyclo[4.1.0]heptane-3,4-diol 10
10.62; N, 7.03. Found: C, 66.01; H, 10.89; N, 7.30.
Prepared with benzyl (R)-1-phenylethylamine at reflux for 7 h.
Compound 10 (1.63 g, 47%); colourless crystals, mp 102–104 °C
4.4.2. (1S,3R,4R,6R)-3-Aminomethyl-7,7-dimethylbicyclo
[4.1.0]heptane-3,4-diol 14
(n-hexane); ½a 2D0
ꢃ
¼ þ65 (c 0.125, EtOH); 1H NMR (DMSO-d6) d
Compound 14 (1.63 g, 63%);
a
colourless oil;
½
a 2D0
ꢃ
¼ ꢀ32
(ppm): 0.39 (1H, dt, J = 4.3, 9.6 Hz), 0.62–0.69 (1H, m), 0.81 (3H,
s), 0.94 (3H, s), 1.02 (1H, dd, J = 4.3, 15.1 Hz), 1.24 (3H, d,
J = 6.5 Hz), 1.67–1.79 (3H, m), 2.22 (1H, d, J = 11.5 Hz), 2.46 (1H,
d, J = 10.2 Hz), 3.15 (1H, t, J = 8.7 Hz), 3.29 (1H, d, J = 7.2 Hz), 3.64
(1H, q, J = 6.5, 12.9 Hz), 3.87 (1H, s), 5.20 (1H, br s), 7.18–7.33
(5H, m); 13C NMR (DMSO-d6) d (ppm): 16.2, 17.4, 22.2, 25.3, 27.1,
29.7, 30.5, 57.1, 58.9, 70.6, 72.4, 127.26, 127.47, 129.2, 146.7. IR
(c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm): 0.53 (1H, dt, J = 4.3,
9.5 Hz), 0.63–0.69 (1H, m), 0.85 (3H, s), 0.95 (3H, s), 1.04 (1H, dd,
J = 4.3, 15.1 Hz), 1.20–1.22 (1H, m), 1.66–1.70 (2H, m), 1.75–1.81
(1H, m), 3.19–3.23 (2H, m); 13C NMR (DMSO-d6) d (ppm): 16.3,
17.6, 22.4, 27.4, 29.7, 29.9, 46.8, 50.8, 70.8, 71.6. IR (KBr, cmꢀ1
)
m
= 3378, 2935, 1572, 1456, 1049. Anal. Calcd for C10H19NO2
(185.26): C, 64.83; H, 10.34; N, 7.56. Found: C, 64.60; H, 10.59;
N, 7.76.
(KBr, cmꢀ1
) m = 3362, 2922, 1453, 1113, 1090, 851, 700. Anal. Calcd
for C18H27NO2 (289.41): C, 74.70; H, 9.40; N, 4.84. Found: C, 74.56;
H, 9.57; N, 4.99.
4.5. Preparation of 1,3-oxazines 17–21
At first, 20 mL 35% aqueous formaldehyde was added to the
respective secondary aminodiol (1.8 mmol) solution in 5 mL
Et2O. The mixture was stirred at room temperature. After 1 h, it
was made alkaline with 10% aqueous KOH and extracted with
Et2O (3 ꢁ 30 mL). The organic phase was dried (Na2SO4) and
evaporated. The crude products 17–21 were purified by column
chromatography.
4.3.7. (1S,3R,4R,6R)-7,7-Dimethyl-3-(((S)-1-phenylethylamino)
methyl)bicyclo[4.1.0]heptane-3,4-diol 11
Prepared with (S)-1-phenylethylamine at reflux for 7 h. Com-
pound 11 (0.63 g, 18%); colourless crystals, mp 57–58 °C (n-hex-
ane); ½a 2D0
ꢃ
¼ ꢀ4 (c 0.125, EtOH); 1H NMR (DMSO-d6) d (ppm):
0.51 (1H, dt, J = 4.3, 9.6 Hz), 0.63–0.59 (1H, m), 0.84 (3H, s), 0.95
(3H, s), 0.97 (1H, dd, J = 4.4, 15.3 Hz), 1.28 (3H, d, J = 6.6 Hz),
1.65–1.70 (2H, m), 1.86 (1H, dd, J = 9.9, 15.2 Hz), 2.27 (1H, d,
J = 11.8 Hz), 2.43 (1H, d, J = 11.6 Hz), 3.18 (1H, t, J = 8.12 Hz), 3.29
(1H, d, J = 7.2 Hz), 3.70 (1H, q, J = 6.4, 13.1 Hz), 3.89 (1H, br s),
7.23–7.37 (5H, m); 13C NMR (DMSO-d6) d (ppm): 15.8, 17.0, 21.8,
24.7, 26.6, 29.5, 30.2, 56.5, 58.4, 70.8, 71.9, 126.9,128.2, 128.7,
4.5.1. (1aR,2aR,6aR,7aS)-5-Benzyl-1,1-dimethyl-6a-
hydroxydecahydro-3-oxa-5-azacyclopropa[g]naphthalene 17
Compound 17 (0.49 g, 94%); colourless crystals, mp 60–68 °C
(n-hexane); ½a 2D0
¼ ꢀ61 (c 0.125, EtOH); column chromatography
ꢃ
on silica gel (n-hexane/EtOAc = 4:1). 1H NMR (DMSO-d6) d (ppm):
0.55 (1H, dt, J = 4.3, 9.6 Hz), 0.71 (1H, dt, J = 8.3 Hz), 0.88 (3H, s),
0.88–0.96 (1H, m), 0.97 (3H, s), 1.66–1.82 (3H, m), 2.23 (1H, d,
J = 12.0 Hz), 2.65 (1H, dd, J = 2.0, 12.2 Hz), 3.03 (1H, dd, J = 7.3,
10.3 Hz), 3.66 (1H, d, J = 13.6 Hz), 3.78 (1H, d, J = 13.6 Hz), 3.76
(1H, s), 3.83 (1H, d, J = 8.8 Hz), 4.30 (1H, dd, J = 1.9, 8.6 Hz), 7.21–
7.32 (5H, m), 13C NMR (DMSO-d6) d (ppm): 16.2, 17.2, 17.5, 21.4,
22.9, 29.6, 29.8, 57.3, 61.5, 65.9, 79.3, 84.9, 127.7, 129.0, 129.4,
146.0. IR (KBr, cmꢀ1
) m = 3309, 2928, 1452, 1114, 1040, 763, 697.
Anal. Calcd for C18H27NO2 (289.41): C, 74.70; H, 9.40; N, 4.84.
Found: C, 74.59; H, 9.50; N, 4.97.
4.3.8. (1S,3R,4R,6R)-3-(Isopropylamino)methyl-7,7-dimethyl
bicyclo[4.1.0]heptane-3,4-diol 12
Prepared with isopropylamine at reflux for 40 h. Compound 12
(0.85 g, 31%); colourless crystals, mp 96–99 °C (n-hexane);
139.4. IR (KBr, cmꢀ1
) m = 3505, 2918, 1454, 1081, 742, 696. Anal.
Calcd for C18H25NO2 (287.40): C, 75.22; H, 8.77; N, 4.87. Found:
C, 75.03; H, 8.99; N, 4.98.
½
a 2D0
ꢃ
¼ þ44 (c 0.125, EtOH); 1H NMR (CDCl3) d (ppm): 0.67 (1H,
dt, J = 4.5, 9.5 Hz), 0.81–0.90 (4H, m), 1.00 (3H, s), 1.03 (1H, dd,
J = 4.3, 15.5 Hz), 1.14 (3H, d, J = 4.3 Hz), 1.15 (3H, d, J = 4.3 Hz),
1.70–1.78 (1H, m), 1.94–2.05 (2H, m), 2.65 (1H, d, J = 12.2 Hz),
2.84–2.91 (2H, m), 3.49 (1H, dd, J = 7.6, 9.2 Hz); 13C NMR (CDCl3)
d (ppm): 15.9, 16.5, 21.1, 22.4, 22.5, 26.0, 26.5, 29.1, 30.5, 50.2,
4.5.2. (1aR,2aR,6aR,7aS)-6a-Hydroxy-1,1,5-trimethyldecahydro-
3-oxa-5-azacyclopropa[g]naphthalene 18
56.8, 70.2, 74.6. IR (KBr, cmꢀ1
)
m
= 3342, 2933, 2614, 1434, 1040,
Compound 18 (0.32 g, 84%); a colourless oil; ½a D20
¼ ꢀ13 (c
ꢃ
867. Anal. Calcd for C13H25NO2 (227.34): C, 68.68; H, 11.08; N,
6.16. Found: C, 68.56; H, 11.21; N, 6.29.
0.125, EtOH); column chromatography on silica gel (toluene/
EtOH = 4:1). 1H NMR (DMSO-d6) d (ppm): 0.56 (1H, dt, J = 4.3, 9.6
Hz), 0.70 (1H, dt, J = 8.5 Hz), 0.88 (3H, s), 0.93–0.98 (4H, m),
1.64–1.82 (3H, m), 2.04 (1H, d, J = 11.6 Hz), 2.20 (3H, s), 2.61 (1H,
dd, J = 1.7, 11.5 Hz), 2.94 (1H, dd, J = 7.6, 10.2 Hz), 3.58 (1H, d,
J = 8.1 Hz), 3.62 (1H, d, J = 1.7 Hz), 4.25 (1H, dd, J = 1.8, 8.1 Hz);
13C NMR (DMSO-d6) d (ppm): 16.2, 17.2, 17.5, 21.4, 22.8, 29.6,
4.4. Preparation of aminodiols 13 and 14
To a suspension of palladium-on-carbon (5% Pd, 0.22 g) in
MeOH (50 mL) was added aminodiol 5 or 6 (14.0 mmol) in MeOH
(100 mL), and the mixture was stirred under a H2 atmosphere at
room temperature and normal pressure. When the reaction was
completed (as monitored by TLC, 5 h), the mixture was filtered
29.7, 41.1, 64.4, 65.7, 78.6, 86.8. IR (KBr, cmꢀ1
) m = 3467, 2939,
1633, 1464, 1087, 895. Anal. Calcd for C12H21NO2 (211.30): C,
68.21; H, 10.02; N, 6.63. Found: C, 68.01; H, 10.18, N, 6.84.

1026
Z. Szakonyi et al. / Tetrahedron: Asymmetry 22 (2011) 1021–1027
4.5.3. (1aR,2aR,6aR,7aS)-6a-Hydroxy-1,1-dimethyl-5-((R)-1-
phenylethyl)decahydro-3-oxa-5-azacyclopropa[g]naphthalene
19
(R)-isomer]34 and 3-heptanol 16h [tR1 = 3.3 min for the (S)-isomer,
tR2 = 3.9 min for the (R)-isomer].34 Identification of 16b and 16d–f
was done by chiral HPLC analysis on a Chiralcel OD-H column and
the data are as follows: 1-(4-methoxyphenyl)-1-propanol 16b;
Compound 19 (0.52 g, 96%); colourless crystals, mp 61–65 °C
(n-hexane); ½a 2D0
ꢃ
¼ ꢀ18:0 (c 0.125, EtOH); column chromatography
V(n-hexane)/V(2-propanol) = 95:5, 0.7 mL/min, 210 nm, tR1
15.3 min for the (R)-isomer, tR2 = 16.9 min for the (S)-isomer.21 1-
(4-Tolyl)-1-propanol 16c V(n-hexane)/V(2-propanol) = 95:5,
=
on silica gel (n-hexane/EtOAc = 4:1). 1H NMR (DMSO-d6) d (ppm):
0.55 (1H, dt, J = 4.3, 9.5 Hz), 0.70 (1H, d, J = 8.1 Hz), 0.86 (3H, s),
0.92–0.96 (1H, m), 0.96–0.98 (3H, s), 1.26 (3H, d, J = 6.8 Hz),
1.66–1.81 (3H, m), 2.08 (1H, d, J = 11.5 Hz), 2.68 (1H, dd, J = 1.9,
11.4 Hz), 2.95 (1H, dd, J = 7.4, 10.1 Hz), 3.60 (1H, d, J = 1.5 Hz),
3.69 (1H, d, J = 8.4 Hz), 3.80 (1H, q, J = 7.2, 13.6 Hz), 4.39 (1H, dd,
J = 1.9, 8.4 Hz), 7.23–7.38 (5H, m); 13C NMR (DMSO-d6) d (ppm):
16.2, 17.2, 17.5, 20.3, 21.4, 22.9, 29.5, 29.7, 59.1, 59.4, 65.8, 79.2,
0.5 mL/min, tR1 = 10.4 min for the (R)-isomer, tR2 = 14.9 min for
the (S)-isomer.21 1-(3-Methoxyphenyl)-1-propanol 16d; V(n-hex-
ane)/V(2-propanol) = 98:2, 0.4 mL/min, 210 nm, tR1 = 64.7 min for
the (R)-isomer, tR2 = 70.7 min for the (S)-isomer.34 1-(3-Tolyl)-1-
propanol 16e; V(n-hexane)/V(2-propanol) = 95:5, 0.7 mL/min,
210 nm, tR1 = 10.1 min for the (R)-isomer, tR2 = 11.5 min for the
(S)-isomer.36 1-(Naphthyl)-1-propanol 16f; V(n-hexane)/V(2-pro-
panol) = 95:5, 0.4 mL/min, 210 nm, tR1 = 29.9 min for the (S)-iso-
mer, tR2 = 33.1 min for the (R)-isomer.21 The direction of the
optical rotations of the products was also checked. The spectro-
scopic data on the alcohols prepared were, in all cases, similar to
those reported in the literature.19,21,26d,32–35
83.5, 129.0, 128.1, 127.7, 144.6. IR (KBr, cmꢀ1
) m = 3522, 2917,
1597, 1268, 885. Anal. Calcd for C19H27NO2 (301.42): C, 75.71; H,
9.03; N, 4.65. Found: C, 75.57; H, 9.17; N, 4.81.
4.5.4. (1aR,2aR,6aR,7aS)-6a-Hydroxy-1,1-dimethyl-5-((S)-1-
phenylethyl)decahydro-3-oxa-5-azacyclopropa[g]naphthalene
20
Compound 20 (0.44 g, 81%); a colourless oil; ½a D20
¼ ꢀ44 (c
ꢃ
Acknowledgements
0.125, EtOH); column chromatography on silica gel (n-hexane/
EtOAc = 4:1). 1H NMR (CDCl3) d (ppm): 0.71 (1H, dt, J = 4.4,
9.7 Hz), 0.84–0.91 (4H, m), 0.95–1.03 (4H, m), 1.42 (3H, d,
J = 6.5 Hz), 1.85–1.95 (4H, m), 2.78 (1H, d, J = 10.8 Hz), 2.96 (1H,
t, J = 8.6 Hz), 3.62–3.72 (2H, m), 4.65 (1H, dd, J = 1.9, 7.8 Hz),
7.23–7.34 (5H, m); 13C NMR (CDCl3) d (ppm): 16.2, 17.2, 17.5,
20.3, 21.4, 22.9, 29.5, 29.7, 59.1, 59.4, 64.8, 79.3, 83.5, 127.7,
We are grateful to the Hungarian Research Foundation (OTKA
NK81371) and TÁMOP-4.2.1/B-09/1/KONV-2010–0005- for finan-
cial support and acknowledge the receipt of a Bolyai János Fellow-
ship for Zsolt Szakonyi.
128.1, 129.0, 141.9. IR (KBr, cmꢀ1
) m = 3459, 2955, 1453, 1081,
700. Anal. Calcd for C19H27NO2 (301.42): C, 75.71; H, 9.03; N,
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decahydro-3-oxa-5-azacyclopropa[g]naphthalene 21
Compound 21 (0.27 g, 63%); a yellow oil; ½a D20
¼ ꢀ22 (c 0.125,
ꢃ
MeOH); column chromatography on silica gel (n-hexane/
EtOAc = 4:1). 1H NMR (CDCl3) d (ppm): 0.75 (1H, dt, J = 4.4, 9.7
Hz), 0.83–0.91 (3H, m), 0.93 (3H, s), 0.99–1.07 (9H, m), 1.85–1.90
(2H, m), 1.99 (1H, dd, J = 9.8, 15.2 Hz), 2.16 (1H, d, J = 10.8 Hz),
2.72 (1H, dd, J = 2.2, 10.9 Hz), 2.79–2.89 (1H, m), 2.99 (1H, t,
J = 8.9 Hz), 3.86 (1H, d, J = 7.7 Hz), 4.49 (1H, dd, J = 2.2, 7.6 Hz);
13C NMR (CDCl3) d (ppm): 15.8, 16.5, 17.5, 18.6, 19.9, 21.2, 22.8,
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2862, 1452, 1083, 890. Anal. Calcd for C14H25NO2 (239.35): C,
70.25; H, 10.53; N, 5.85. Found: C, 70.02; H, 10.79; N, 5.99.
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