Regio- and Stereoselective Synthesis of Bicyclic Limonene-Based Chiral Aminodiols and Spirooxazolidines

Article abstract of DOI:10.1002/chem.201802484

A library of monoterpene-based aminodiols was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The reduction of a bicyclic α-methylene ketone, derived from natural (?)-limonene followed by epoxidation, gave the key epoxy alcohol intermediate. Ring opening of the oxirane ring with primary amines induced by lithium perchlorate afforded the required aminodiols. Substituent-dependent ring closure of the secondary aminodiols with formaldehyde resulted in both spirooxazolidines and a fused 1,3-oxazine. Cyclization reactions of the studied aminodiols, resulting in spirocyclic oxazolidines and an isomeric perhydro-1,3-oxazine-fused compound along with the possible iminium intermediates, were analyzed by a systematic series of comparative DFT models performed at the B3LYP/6-31+G(d,p) level of theory.

Full text of DOI:10.1002/chem.201802484

A Journal of
Accepted Article
Title: Regio- and stereoselective synthesis of bicyclic limonene-based
chiral aminodiols and spirooxazolidines
Authors: Tam Minh Le, Antal Csámpai, Ferenc Fülöp, and Zsolt
Szakonyi
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To be cited as: Chem. Eur. J. 10.1002/chem.201802484
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Regio- and stereoselective synthesis of bicyclic limonene-based
chiral aminodiols and spirooxazolidines
Tam Minh Le[a], Antal Csámpai[b], Ferenc Fülöp [a,c], Zsolt Szakonyi*[a,d]
intramolecular radical cyclisations,[11]
intramolecular [2+2]
Abstract:
A
library of monoterpene-based aminodiols was
photocycloaddition[12] and Grinard addition.[13,14]
synthesized and applied as chiral catalysts in the addition of
diethylzinc to benzaldehyde. The reduction of a bicyclic α-methylene
ketone, derived from natural (-)-limonene followed by epoxidation,
gave the key intermediate epoxy alcohol. Ring opening of the oxirane
ring with primary amines induced by lithium perchlorate afforded the
required aminodiols. The substituent-dependent ring closures of
secondary aminodiols with formaldehyde resulted in both
spirooxazolidines and a fused 1,3-oxazine. Cyclisation reactions of
the studied aminodiols, resulting in spirocyclic oxazolidines and an
isomeric perhydro-1,3-oxazine-fused compound along with the
possible iminium intermediates, were analyzed by a systematic series
of comparative DFT modelling carried out at B3LYP/6-31+G(d,p) level
of theory.
Furthermore, aminodiols, combining the chemical
properties of 1,2- and 1,3-amino alcohols derived from naturally
occurring terpenes, are excellent starting materials and catalysts
of stereoselective synthesis.[15–20] Moreover, aminodiols are
excellent building blocks for the synthesis of 1,3-oxazines and
oxazolidines. Depending upon the hydroxy group involved in ring
closure with the amino group, five- to six-membered rings may be
formed stereoselectively. The resulting bicyclic heterocycles
bearing
a
free hydroxy group can contribute to high
enantioselective inductions in asymmetric addition reactions.[21–24]
Besides their chemical interest, some natural
aminodiols exhibit marked biological activity. For example,
aristeromycin, first isolated from Streptomyces citricolor and its
modified derivatives belong to an important group of carbocyclic
nucleosides that exhibit a wide range of pharmacological
properties such as antiviral, anticancer and antitoxoplasma
activities. Aristeromycin analogues, in particular, are widely used
as antiviral agents against a range of viruses, including human
immunodeficiency, hepatitis B, herpes simplex, varicella-zoster,
influenza and hepatitis C virus.[25–27] Other aminodiols may serve
as starting materials for the synthesis of biologically active natural
compounds. For example, cytoxazone a microbial metabolite
isolated from Streptomyces species is a selective modulator of
secretion of TH2 cytokine.[26,27]
Introduction
Chiral synthons that can be applied successfully in
asymmetric homogenous and heterogeneous catalysis are of
increasing importance in organic chemistry.[1–3] A large number of
natural products such as α- and β-pinene,[4–6] 2- and 3-carene[7,8]
and (+)-pulegole[9,10] serve as important starting materials for the
synthesis of bi- and trifunctional chiral compounds and
heterocycles. Monoterpene-based 1,2- and 1,3-amino alcohols
have been demonstrated to be excellent chiral auxiliaries in a
wide range of stereoselective transformations including
In the present contribution we report the stereoselective
synthesis of new bicyclic 3-amino-1,2-diols as potential building
blocks and chiral auxiliaries starting from commercially available
natural (-)-limonene. In addition, we have studied the substituent-
dependent ring closure of these aminodiols with formaldehyde.
Competitive ring closure processes can provide both
spirooxazolidine ring systems and condensed 1,3-oxazines. The
results of experimental and theoretical study of these synthons
may expand our knowledge of this type of trifunctional building
blocks in the design/construction of 3D small molecules.
[a]
[b]
Tam Minh Le, Ferenc Fülöp, Zsolt Szakonyi
Institute of Pharmaceutical Chemistry
University of Szeged
H-6720 Szeged Eötvös utca 6
E-mail: szakonyi@pharm.u-szeged.hu
Antal Csámpai
Institute of Chemistry
Eötvös Loránd University
P.O. Box 32, H-1518 Budapest – 112, Hungary
MTA-SZTE Stereochemistry Research Group, Hungarian Academy
of Science, Eötvös u. 6, H-6720 Szeged, Hungary
Interdisciplinary Centre of Natural Products, University of Szeged, H
6720 Szeged, Hungary
[c]
[d]
Supporting information for this article is given via a link at the end of
the document
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Results and Discussion
Table 1. Epoxidation reaction of 6
6
t-BuOOH
T
t
Ratio
[7:8] [a]
Yield
[%][b]
Chiral bicyclic aminodiols were prepared from
Entry
(mol)
(mol)
[°C]
[h]
commercially available (-)-limonene 1 starting with regioselective
hydroxylation to afford allylic alcohol 2.[28–30] The resulting allylic
alcohol was oxidized to aldehyde 3,[28] which was then converted
1
2
3
4
5
1
1
1
1
1
1.5
1.5
1.5
3.0
3.0
0
25
100
0
> 96
12
4
4:1
3:1
1:1
1:1
40
60
70
60
to carboxylic acid
4
applying
a
literature method.[31–34]
Intramolecular acylation of isoperillic acid 4 performed using
earlier methods[34,35] resulted in bicyclic methylene ketone 5 as a
48
single product (Figure 1).
25
6
1:1
65
[a]
[b]
Based on 1H-NMR measurements of the crude product.
Isolated,
combined yield of 7 and 8.
When tert-butylamine was applied, the opening of the
oxirane ring failed, which clearly shows that from the point of view
of steric hindrance, the isopropyl group represents the upper limit
of the N-substituent. Accordingly, our efforts in the opening of
epoxide with secondary amines was also unsuccessful.[41]
Interestingly, during aminolysis with primary amines under the
applied conditions, epoxide 7 was transformed preferentially while
8 did not react. This is probably due to steric hindrance exerted
by the methyl group of 8 at the  position. Therefore, aminodiols
9-12 could be easily separated from 8 on a gram scale by simple
column chromatography with good yields.
Figure 1. Synthesis of bicyclic methylene ketone 5
Stereoselective reduction of 5 gave allylic alcohol 6
according to
a
literature procedure applied for similar
monoterpenic -methylene ketones.[10] Epoxidation of 6 in dry
toluene in the presence of vanadyl acetylacetonate as catalyst
gave a mixture of 7 and 8. Note that 8 exists as a 4:1 mixture of
two diastereomers (Scheme 1).[36–38] In addition, it is interesting
that the ratio of 7 and 8 depends on the temperature.
Scheme 1. (i) NaBH4, MeOH, 0 °C, 4 h, 67%; (ii) 70% t-BuOOH, VO(acac)2,
dry toluene, 25 °C, 12 h, 60% (optimised combined yield of 7 and 8).
Scheme 2. (i) RNH2, LiClO4, MeCN, 70-80 °C, 4 h, 50-67%
While at 25 °C 7 was formed as the main product, the
ratio of the two products was found to be 1:1 at 100 °C. At lower
temperature, the yield dropped dramatically despite the elongated
reaction time without any significant change in the 7 to 8 ratio
(Table 1). The yield of 7 could not be increased by either changing
the ratio of 6 and the oxidation reagent or the temperature (Table
1).
The relative configurations of compounds 9-12 were
determined by means of NOESY experiments: clear NOE signals
were observed between the H-1 and H-9, H-9 and H-6, H-6 and
H-5, H-8 as well as OH-6 and OH-7 protons (Figure 2).
Debenzylation via hydrogenolysis of compounds 9-11 over Pd/C
in MeOH resulted in primary aminodiol 13 in moderate yield
(Scheme 3).
The separation of epoxide 7 and 8 could not be
effectively performed without decomposition of the products.
Since our earlier results clearly demonstrated that
substituents at nitrogen of aminodiols definitely influenced the
efficiency of their catalytic activity,[4,39] aminodiol library 9-12 was
prepared by aminolysis of epoxide 7 with primary amines and
lithium perchlorate as catalyst (Scheme 2).[7,17,39,40]
Since the ring closure of monoterpene-based
aminodiols with rigid structures enhances their catalytic
potential,[7,8] we incorporated one of the hydroxy groups of
compounds 9-12 into
a
condensed 1,3-oxazine or
spirooxazolidine ring.[42–44] When aminodiols 9-11 were reacted
with formaldehyde at room temperature, spirooxazolidines 14-16
were obtained in a highly regioselective ring closure. In contrast,
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aminodiol 12 yielded a mixture of spirooxazolidine 17 and 1,3-
oxazine 18.[45]
iminium intermediate types 22-24 the proximal C=C double bond
in the seven-membered ring is also involved in these
systematically assembled H-bonding networks as a -donor
component.
The calculated relative energetics of the optimized
structures of spirocyclic products and their oxazine-fused
counterparts [E(spiro→oxazine, spiro*→oxazine*)=11.8-13.8
kcal/mol: Schemes 4 and 5] are obviously in line with the
experimental findings disclosing highly preferential formation of
the spirocyclic isomers. Moreover, according to Boltzmann
equation, the aforementioned large differences would principally
allow the formation of fused oxazines in hardly detectable traces.
However, under the acidic conditions employed for cyclisation,
the relative stability of relevant pairs of iminium intermediates 22/I-
24/I and 22/II-24/II with slightly different relative stability (0.2-1.9
kcal/mol), preformed for alternative modes of ring closure, might
also be of crucial importance. It must be emphasized that even
these small values are also in correlation with the preferred
formation of the spirocyclic products. Nevertheless, they allow the
formation of fused oxazines in experimentally detectable
concentrations. On the other hand, the amount of iminium cations
relative to the appropriate neutral spirooxazolidine or 1,3-oxazine
components in the reaction mixtures is highly dependent on the
acidity of the reaction mixture. This was spectacularly indicated
by the dramatic differences (even with opposite signs) in the
calculated relative energetics characterizing two selected types of
reversible cyclisation reactions 14-17+H3O+↔22+-25++H2O and
Figure 2. Determination of the aminodiol structures by NOESY
The temperature strongly affected the ratio of the two
products. At low temperature (0 °C), exclusive formation of
compound 17 was observed, while 17 and 18 were formed in a
ratio of 2:1 at 25 °C. At higher temperature, no significant changes
in the 17/18 ratio could be achieved (Scheme 3). Applying p-
toluenesulfonic acid (TsOH) as additive to decrease the pH to 1-
2, the ratio of 17 and 18 did not change significantly (17:18 =
1.7:1) and, at the same time, the product yield dropped to 40%.
+
14-17+H9O4 ↔22+-25++4H2O [+(52.0-80.7) kcal/mol and –(2.2-
30.9) kcal/mol, respectively: Schemes 4 and 5]. Consequently, it
can be assumed that under appropriate acidic conditions the
aforementioned relative population of iminium cations 22+-24+/I,
22+-24+/II, 25+/I, 25+/II, and 25+/III might indirectly control the
detectable relative amounts of the spirocyclic oxazolidines and
fused 1,3-oxazines. Note that their interconversion under neutral
conditions is prevented or significantly slowed down by high
activation barriers (24.7-42.7 kcal/mol: Schemes 4 and 5).
Consequently, it can be assumed that under appropriate
Scheme 3. from 9-11, 5% Pd/C, MeOH, H2, 1 atm, 25 °C, 20 h, 70%, (ii) R =
35% HCHO sol., Et2O, 0 °C, 1 h, 60-70%
In order to get insight into the experienced substrate
dependence of the acid-catalyzed, formaldehyde-mediated
cyclisation reactions of the studied aminodiols, all resulting
spirocyclic oxazolidines and isomeric perhydro-1,3-oxazine-fused
compound 18 along with the possible iminium intermediates
(Schemes 4 and 5) were analyzed by a systematic series of
comparative DFT modelling carried out at B3LYP/6-31+G(d,p)
level of theory.[46,47]
acidic conditions the aforementioned relative population of
iminium cations 22+-24+/I, 22+-24+/II, 25+/I, 25+/II, and 25+/III might
indirectly control the detectable relative amounts of the spirocyclic
oxazolidines and fused 1,3-oxazines. Note that their
interconversion under neutral conditions is prevented or
significantly slowed down by high activation barriers (24.7-42.7
kcal/mol: Schemes 4 and 5).
Each optimized structure, representing global or local
minimum on the potential energy surfaces, features
a
characteristic intramolecular hydrogen-bond network involving
the skeletal OH groups. Of note that in the optimized structures of
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Scheme 4. Pathways, energetics and activation barriers (kcal/mol) calculated for the interconversion of 14-16, 19-21 and the relevant iminium cationic intermediates
involving the inversions of the nitrogen stereogenic centre present in the neutral molecules.
The slightly enhanced tendency of isopropyl-substituted
model 12 to afford fused oxazine product 18 might be due to acid-
catalyzed formation of iminium cation 25+/II, the unique
intermediate that is preformed to alternative modes of cyclisation,
in concentration comparable to those of its rotamers 25+/I and
25+/III preformed to single modes of ring closure (Scheme 5). The
assumed modes of ring closure of iminium cations are in accord
with the partial bonding interactions involving the appropriate
hydroxy groups and the carbenium centre as disclosed by the
analysis of their bonding MO’s (Figure 3). Partial C---O
interactions involving the tertiary hydroxy group were disclosed in
cations 22+/I and 25+/I (cf. HOMO-5 and HOMO-9, respectively),
while similar interactions between the cationic centre and the
secondary hydroxy group are represented by HOMO-14 and
HOMO-10 in cations 22+/II and 25+/III, respectively. On the other
hand, it is of pronounced interest that in cation 25+/II a three-
centred interaction of the carbenium centre with both hydroxy
groups spectacularly visualized by HOMO-15 gives plausible
support to the view about the abovementioned alternative
directions of cyclisation of this intermediate.
All calculations were carried out by using Gaussian 09
program packege.[48] Upon request, the optimized structures are
provided by the authors.
Transition states were localized on the potential energy
surfaces by QST2 method[49] at B3LYP level of theory using 6-
31+G(d,p) basis set.
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Scheme 5. Pathways, energetics and activation barriers (kcal/mol) calculated for the interconversion of 17,18 and the relevant iminium cationic intermediates
involving the inversions of the nitrogen stereogenic centre present in the neutral molecules.
The aminodiol derivatives (9-18) were applied as chiral
catalysts in the enantioselective addition of diethylzinc to
benzaldehyde (26) to form (S)- and (R)-1-phenyl-1-propanol 27
(Scheme 6).
These results are in good correlation with those observed with
pinane- or sabinane-based spirooxazolidines and carane-fused
1,3-oxazines in our earlier studies.[44,52,53]
Table 2. Addition of diethylzinc to benzaldehyde, catalyzed by aminodiols,
oxazolidines and 1,3-oxazines
Entry
Liganda
Yieldb (%)
eec (%)
16
24
40
55
35
30
6
Configurationd
1
2
9
80
85
87
89
87
85
88
83
90
87
(R)
(R)
(R)
(R)
(R)
(R)
(R)
-
10
3
11
Scheme 6. Model reaction for enantioselective catalysis.
4
12
5
13
The results are presented in Table 2. The enantiomeric
purity of 1-phenyl-1-propanols (S)-27 and (R)-27 was determined
by GC on a CHIRASIL-DEX CB column using literature
methods.[7,8,50,51] Low to good enantioselectives were observed.
Aminodiol 12 afforded the best ee value (ee = 55%) with an (R)-
selectivity (entry 4), while a 2:1 mixture of 17/18 showed the best
ee value (ee = 80%) with an (S)-selectivity (entry 10). The results
obtained clearly show that the spirooxazolidine ring has poorer
catalytic performance compared with the 1,3-oxazine ring system.
6
14
7
15
16
8
0
9
17
6
(R)
10
17/18 (2:1)
80
(S)
[a] 10 mol%. [b] After silica column chromatography. [c] Determined on the crude
product by GC (Chirasil-DEX CB column). [d] Determined by comparing the tR of
GC analysis and optical rotations with the literature date.
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Figure 3. Selected MO’s of the iminium intermediates that highlight the alternative modes of partial bonding between the nucleophilic tertiary or secondary
carbinol unit and the electrophilic carbenium centre (in 22+/I, 22+/II, 25+/I and 25+/III) and the latter’s simultaneous three-centred interaction with both hydroxy
groups (in 25+/II)
Conclusions
Experimental Section
Starting from natural (-)-limonene, a limonene-based
1
General Methods: H- and 13C- NMR spectra were recorded on
aminodiol library was created whereas the reaction of aminodiols
a Bruker Avance DRX 400 [400 and 100 MHz, respectively,  = 0
with formaldehyde resulted in bicyclic monoterpene-fused
ppm (TMS)] and Bruker Avance DRX 500 [500 and 125 MHz,
spirooxazolidines in N-substituent dependent ring closures. The
respectively,  = 0 ppm (TMS)]. Chemical shifts () are expressed
regioselective nature of the ring closure proved to be N-
in ppm relative to TMS as internal reference. J values are given
substituent-dependent, and molecular modelling was applied to
in Hz. Microanalyses were performed on a Perkin–Elmer 2400
explain this phenomenone. The aminodiols and their ring-closed
elemental analyser. GC measurements were made on Perkin-
Elmer Autosystem KL GC consisting of a Flame Ionisation
Detector and a Turbochrom Workstation data system (Perkin-
Elmer Corpotation Norwalk, USA). The separation of O-acetyl
derivatives were applied as chiral catalysts in the enantioselective
addition of diethylzinc to benzaldehyde. The 1,3-oxazine obtained
proved to be a good catalyst in the addition of diethylzinc to
benzaldehyde.
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derivatives of enantiomers was carried out on a CHIRASIL-DEX
CB column (2500 × 0.265 mm I.D).
brine before drying (Na2SO4) and evaporation. Flash column
chromatography (n-hexane:ethyl acetate 4:1) gave the mixture of
epoxides 7 and 8 as a pale yellow oil.
Optical rotations were determined with a Perkin–Elmer 341
1
polarimeter. Melting points were determined on
a
Kofler
Mixture of compound 7 and 8: 0.66 g (60%); colourless oil. H
apparatus and are uncorrected. Chromatographic separations
were carried out on Merck Kieselgel 60 (230–400 mesh ASTM).
Reactions were monitored with Merck Kieselgel 60 F254-
precoated TLC plates (0.25 mm thickness).
NMR (400 MHz, CDCl3)  (ppm): 1.36-1.42 (5H, m, minor), 1.51-
1.54 (m, minor, 1H), 1.70-1.77 (m, 5H, minor overlapped with
major), 2.11-2.18 (m, 5H, minor overlapped with major), 2.42-2.44
(m, 1H, minor overlapped with major), 2.61 (br s, 1H, minor), 2.81
(d, J = 5.2 Hz, 1H, major), 2.92 (d, J = 2.6 Hz, 1H, minor), 2.96 (d,
J = 5.2 Hz, 1H, major), 3.16 (d, J = 11.9 Hz, 1H, minor), 4.12-4.16
(m, 1H, major), 4.29-4.34 (m, 1H, minor), 4.95 (d, J = 2.2 Hz, 1H,
minor), 5.10 (s, 1H, minor), 5.33 (d, J = 1.3 Hz, 1H, major). 13C
NMR (100 MHz, CDCl3)  (ppm): 24.4 (CH3, minor), 24.7 (CH3,
major), 28.8 (CH2, major), 30.0 (CH2, major), 35.3 (CH, major),
36.6 (CH2, minor), 36.7 (CH, minor), 42.7 (CH, minor), 44.1 (CH,
major), 51.6 (CH2, major), 56.8 (CH, minor), 64.8 (Cq, major), 75.9
(CH, major), 77.4 (CH, minor), 106.3 (CH2, minor), 119.7 (CH,
major), 137.3 (Cq, major), 157.4 (Cq, minor). Anal. Calcd for
C10H14O2: C, 72.26; H, 8.49. Found: C, 72.30; H, 8.50.
Isolated compound 8: 0.16 g (15%); colourless oil. 1H NMR (400
MHz, CDCl3)  (ppm): 1.26-1.30 (m, 3H, minor), 1.36-1.42 (m, 5H,
major), 1.50-1.55 (m, 1H, major), 1.70-1.80 (m, 2H, minor), 1.96-
1.98 (m, 1H, minor), 2.10-2.18 (m, 3H, minor overlapped with
major), 2.41-2.43 (m, 1H, minor overlapped with major), 2.61 (br
s, 1H, major), 2.86 (d, J = 3.5 Hz, 1H, minor), 2.92 (d, J = 2.5 Hz,
1H, major), 3.16 (d, J = 11.9 Hz, 1H, major), 3.55 (d, J = 12.5 Hz,
1H, minor), 4.17-4.25 (m, 1H, minor), 4.29-4.34 (m, 1H, major),
4.95 (d, J = 2.1 Hz, 1H, major), 5.10 (s, 1H, major). 13C NMR (100
MHz, CDCl3)  (ppm): 24.6 (CH3, major), 30.2 (CH2, major), 36.8
(CH2, major), 36.9 (CH, major), 42.9 (CH, major), 57.0 (CH, major),
77.6 (CH, major), 106.5 (CH2, major). (Anal. Calcd for C10H14O2:
C, 72.26; H, 8.49. Found: C, 72.30; H, 8.50.
Starting materials: (S)-Limonene 1 is available commercially
from Merck Co. All chemicals and solvents were used as supplied.
THF and toluene were dried over Na wire. (S)-Isoperillyl alcohol
(2), (S)-p-mentha-1,8-dien-9-al (3), (S)-p-mentha-1,8-dien-9-oic
acid (4) and (1S,5S)-4-methyl-7-methylenebicyclo[3.2.1]oct-3-en-
6-one (5) were prepared according to literature procedures, and
all spectroscopic data were similar as described therein.[28],[34]
(1S,5S,6R)-4-Methyl-7-methylenebicyclo[3.2.1]oct-3-en-6-ol (6):
A suspension of NaBH4 (1.5 g, 39.65 mmol) in MeOH (21 mL) was
added dropwise to an ice-cooled solution of 5 (1.5 g, 10.12 mmol)
in MeOH (18 mL). Stirring was continued for 4 h at 0 °C. When
the reaction was complete, the mixture was poured into brine and
the product was extracted with diethyl ether (3 × 100 mL). The
combined extracts were washed with water and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo and the
crude product was used for the next step without further
purification.
Compound 6: 1.02 g (67%); white crystals; mp: 50-53 °C; [α]D
=
20
1
-188 (c 0.20, MeOH). H NMR (400 MHz, CDCl3)  (ppm): 1.64-
1.70 (m, 3H), 1.76 (s, 3H), 1.93 (d, J = 16.8 Hz, 1H), 2.39-2.47 (m,
2H), 2.80 (s, 1H), 4.58 (s, 1H), 5.14 (s, 1H), 5.19 (s, 1H), 5.32 (s,
1H). 13C NMR (100 MHz, CDCl3)  (ppm): 25.0 (CH3), 30.6 (CH2),
38.5 (CH2), 38.9 (CH), 44.4 (CH), 81.3 (CH), 108.6 (CH2), 120.1
(CH), 137.7 (Cq), 160.0 (Cq). Anal. Calcd for C10H14O: C,79.96; H,
9.39. Found: C, 79.93, H, 9.40.
General methods for epoxide ring opening with primary
amines: To a solution of the mixture of epoxide 7 and 8 (0.66 g,
3.97 mmol) in MeCN (50 mL) was added a solution of the
appropriate amine (7.94 mmol) in MeCN (15 mL) and LiClO4 (0.07
g, 0.66 mmol). The mixture was kept at reflux temperature for 4
hours. When the reaction was completed (indicated by TLC), the
mixture was evaporated to dryness, and the residue was
dissolved in water (15 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic phase was dried (Na2SO4), filtered and
concentrated. The crude product was purified by column
chromatography on silica gel with an appropriate solvent mixture
(1S,2'R,5S,7R)-2-Methylspiro[bicyclo[3.2.1]oct[2]ene-6,2'-
oxiran]-7-ol (7)
and
(1R,6R,8R)-2-methyl-7-methylene-3-
oxatricyclo[4.2.1.02,4]nonan-8-ol (8): To a stirred pale red
solution of 6 (1.0 g, 6.56 mmol) and vanadyl acetylacetonate (7
mg) in dry toluene (30 mL), briefly (Na2CO3) dried t-BuOOH (70%
solution in H2O, 1.30 g, 10.1 mmol) in dry toluene (30 mL) was
added dropwise at 25 °C. The red colour of the solution darkened
during the addition then faded to brownish yellow. Stirring was
continued (20 h), whereupon potassium hydroxide (0.55 g, 9.8
mmol) in brine (25 mL) was added. The mixture was extracted
with toluene (3 × 100 mL) and the organic layer was washed with
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(CHCl3:MeOH 19:1). The crude products after purification were
recrystallized in diethyl ether resulting in compounds 9-12.
(1S,5S,6R,7R)-6-((Benzylamino)methyl)-2-
(500 MHz, DMSO-d6)  (ppm): 1.24 (d, J = 6.2 Hz, 6H), 1.50 (d, J
= 11.7 Hz, 1H), 1.56-1.58 (m, 1H), 1.63 (s, 3H), 2.02 (d, J = 16.8
Hz, 1H), 2.20-2.26 (m, 3H), 2.75 (d, J = 12.4 Hz, 1H), 2.93 (d, J =
12.5 Hz, 1H), 3.28-3.30 (m, 1H), 3.77 (t, J = 5.4 Hz, 1H), 4.05 (s,
methylbicyclo[3.2.1]oct-2-ene-6,7-diol (9): 0.54 g (50%); white
1
crystals; mp: 190-200 °C; [α]D = -62 (c 0.24, MeOH). H NMR
20
1H), 5.15 (br s, 1H), 5.52 (d, J = 5.6 Hz, 1H), 8.01 (br s, 2H). 13
C
(400 MHz, DMSO-d6)  (ppm):1.45 (m, 2H), 1.61 (s, 3H), 1.97 (d,
J = 17.2 Hz, 1H), 2.17-2.24 (m, 3H), 2.73 (d, J = 12.5 Hz, 1H),
2.81 (d, J = 12.5 Hz, 1H), 3.84 (t, J = 5.5 Hz, 1H), 4.01 (br s, 1H),
4.12 (s, 2H), 5.11 (s, 1H), 5.65 (d, J = 5.5 Hz, 1H), 7.38-7.60 (m,
5H), 8.97 (br s, 1H). 13C NMR (100 MHz, DMSO-d6)  (ppm): 24.8
(CH3), 27.9 (CH2), 28.2 (CH2), 39.9 (CH), 43.3 (CH), 50.6 (CH2),
54.5 (CH2), 74.8 (Cq), 76.9 (CH), 118.8 (CH), 128.5 (CH Ar), 128.8
(CH Ar), 130.4 (CH Ar), 131.8 (Cq Ar), 137.2 (Cq). Anal. Calcd for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.73; H, 8.45;
N, 5.08.
NMR (125 MHz, DMSO-d6)  (ppm): 18.30 (CH3), 24.8 (CH3), 27.8
(CH2), 28.2 (CH2), 39.3 (CH), 43.3 (CH), 50.4 (CH), 52.3 (CH2),
74.7 (Cq), 77.3 (CH), 119.0 (CH), 137.1 (Cq). Anal. Calcd for
C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C, 69.30; H,
10.25; N, 6.25.
General procedure for the ring closure of compound 9-12
with formaldehyde
Method A: To a solution of aminodiol 9-12 (1.8 mmol) in 5 mL
diethyl ether was added 20 mL of aqueous formaldehyde (35%)
and the mixture was stirred at room temperature. After 1 h, it was
made alkaline with 10% aqueous KOH and extracted with diethyl
ether (3 × 30 mL). After drying (Na2SO4) and solvent evaporation
crude products 14-18 were purified by column chromatography
(CHCl3:MeOH 19:1).
(1S,5S,6R,7R)-2-Methyl-6-((((S)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-2-ene-6,7-diol (10):
0.68 g (60%); white crystals; mp: 190-195 °C; [α]D20 = -87 (c 0.21,
MeOH). 1H NMR (400 MHz, DMSO-d6)  (ppm): 1.39-1.43 (m, 2H),
1.60 (s, 3H), 1.65 (d, J = 6.7 Hz, 1H), 1.90-1.99 (m, 2H), 2.17-2.23
(m, 2H), 2.46 (d, J = 12.4 Hz, 1H), 2.78 (d, J = 12.4 Hz, 1H), 3.95
(s, 1H), 3.99 (br s, 1H), 4.31 (m, 1H), 5.10 (s, 1H), 5.67 (br s, 1H),
7.35-7.60 (m, 5H), 8.84 (br s, 1H). 13C NMR (100 MHz, DMSO-d6)
 (ppm) 19.9 (CH3), 24.7 (CH3), 27.9 (CH2), 28.1 (CH2), 40.3 (CH),
43.4 (CH), 54.5 (CH2), 58.4 (CH), 74.8 (Cq), 76.6 (CH), 118.7 (CH),
127.9 (CH Ar), 128.5 (CH Ar), 128.7 (CH Ar), 137.2 (Cq). Anal.
Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.28;
H, 8.65; N, 4.89.
Method B: To a solution of aminodiol 12 (1.8 mmol) in 5 mL
diethyl ether was added 20 mL aqueous formaldehyde (30%). The
mixture was stirred at 0 °C for 1 h, then it was made alkaline with
10% aqueous KOH and extracted with diethyl ether (3 × 30 mL).
The organic phase was dried (Na2SO4) and the solvent
evaporated. The crude product was purified by column
chromatography (CHCl3:MeOH 19:1) to afford 17.
(1S,5S,5'R,7R)-3'-Benzyl-2-methylspiro[bicyclo[3.2.1]oct[2]ene-
6,5'-oxazolidin]-7-ol (14): Prepared by method A; 0.31 g (60%);
yellow oil; [α]D20 = -43 (c 0.17, MeOH). 1H NMR (400 MHz, CDCl3)
 (ppm): 1.66 (d, J = 11.8 Hz, 1H), 1.71 (d, J = 1.4 Hz, 1H), 2.06-
2.11 (m, 1H), 2.21 (br s, 1H), 2.30-2.36 (m, 2H), 2.82 (d, J = 10.9
Hz, 1H), 3.07 (d, J = 10.9 Hz, 1H), 3.71-3.83 (m, 3H), 4.27 (d, J =
4.4 Hz, 1H), 4.55 (d, J = 4.4 Hz, 1H), 5.30 (s, 1H), 7.26-7.36 (m,
5H) . 13C NMR (100 MHz, CDCl3)  (ppm): 24.9 (CH3), 28.9 (CH2),
29.2 (CH2), 43.4 (CH), 44.1 (CH), 57.3 (CH2), 65.8 (CH2), 82.2
(CH), 85.2 (Cq), 87.9 (CH2), 119.8 (CH), 127.5 (CH Ar), 128.6 (CH
Ar), 128.9 (CH Ar), 137.4 (Cq). Anal. Calcd for C18H23NO2: C,
75.76; H, 8.12; N, 4.91. Found: C, 75.77; H, 8.09; N, 4.95.
(1S,5S,6R,7R)-2-Methyl-6-((((R)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-2-ene-6,7-diol (11):
0.74 g (65%); white crystals; mp: 215-220 °C; [α]D20 = -65 (c 0.20,
MeOH). 1H NMR (400 MHz, DMSO-d6)  (ppm): 1.24-1.33 (m, 2H),
1.59 (s, 3H), 1.64 (d, J = 6.1 Hz, 3H), 1.96 (d, J = 18.2 Hz, 1H),
2.15-2.25 (m, 3H), 2.37 (d, J = 12.5 Hz, 1H), 2.81 (d, J = 12.3 Hz,
1H), 3.68 (t, J = 5.40 Hz, 1H), 3.98 (s, 1H), 4.27 (br s, 1H), 5.10
(s, 1H), 5.67 (br s, 1H), 7.36-7.63 (m, 5H), 8.97 (br s, 1H). 13C
NMR (100 MHz, DMSO-d6)  (ppm) 24.7 (CH3), 28.0 (CH2), 28.1
(CH2), 43.3 (CH), 54.2 (CH2), 58.3 (CH), 74.8 (Cq), 76.9 (CH),
118.7 (CH), 127.8 (CH Ar), 128.5 (CH Ar), 128.7 (CH Ar), 137.2
(Cq). Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87.
Found: C, 75.30; H, 8.57; N, 4.90.
(1S,5S,5'R,7R)-2-Methyl-3'-((S)-1-
phenylethyl)spiro[bicyclo[3.2.1]oct[2]ene-6,5'-oxazolidin]-7-ol
(15): Prepared by method A; 0.38 g (70%); yellow oil; [α]D20 = -51
(c 0.28, MeOH). 1H NMR (400 MHz, CDCl3)  (ppm): 1.33 (d, J =
6.5 Hz, 3H), 1.32-1.38 (m, 1H), 1.59 (d, J = 11.8 Hz, 1H), 1.70 (d,
(1S,5S,6R,7R)-6-((Isopropylamino)methyl)-2-
methylbicyclo[3.2.1]oct-2-ene-6,7-diol (12): 0.60 g (67%); white
1
crystals; mp: 195-200 °C; [α]D = -64 (c 0.28, MeOH). H NMR
20
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10.1002/chem.201802484
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J = 1.7 Hz, 3H), 2.05-2.13 (m, 2H), 2.25-2.33 (m, 2H), 2.46 (d, J
= 9.9 Hz, 1H), 2.81 (br s, 1H), 2.87 (d, J = 9.9 Hz, 1H), 3.42 (q, J
= 6.5, 13.0 Hz, 1H), 3.75 (d, J = 5.5 Hz, 1H), 4.13 (d, J = 2.9 Hz,
1H), 4.66 (d, J = 2.9 Hz, 1H), 5.28 (d, J = 1.1 Hz, 1H), 7.24-7.35
(m, 1H). 13C NMR (100 MHz, CDCl3)  (ppm): 23.3 (CH3), 24.9
(CH3), 28.8 (CH2), 29.5 (CH2), 43.2 (CH), 44.1 (CH), 61.8 (CH),
64.2 (CH2), 81.3 (CH), 86.3 (Cq), 86.8 (CH2), 119.7 (CH), 127.2
(CH Ar), 127.4 (CH Ar), 128.7 (CH Ar), 137.4 (Cq), 144.9 (Cq).
Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C,
76.30; H, 8.39; N, 4.70.
NMR (500 MHz, DMSO-d6)  (ppm): 1.24-1.28 (m, 6H, minor
overlapped with major), 1.63 (s, 3H, minor overlapped with major),
1.50-1.58 (m, 2H, minor overlapped with major), 1.99-2.26 (m, 2H,
minor overlapped with major), 2.18 (s, 1H, minor), 2.38 (s, 1H,
major), 2.80-2.93 (m, 2H, minor), 3.27-3.30 (m, 1H, minor), 3.30
(m, 1H, major), 3.19-3.70 (m, 2H, major), 3.85 (d, J = 5.1 Hz, 1H,
minor), 3.94 (br s, 1H, major), 4.59-4.71 (m, 2H, minor overlapped
with major), 5.01 (s, 1H, major), 5.07 (s, 1H, minor), 5.14 (s, 1H,
minor overlapped with major), 13C NMR (125 MHz, DMSO-d6) 
(ppm): 18.3 (CH3, minor), 18.5 (CH3, major), 24.7 (CH3, major),
24.9 (CH3, minor), 27.9 (CH2, minor), 28.0 (CH2, minor), 28.2 (CH2,
major), 28.3 (CH2, major), 41.5 (CH, minor), 43.4 (CH, major),
50.5 (CH, minor), 52.3 (CH2, minor), 55.2 (CH, major), 59.2 (CH2,
major), 74.7 (Cq, minor), 77.1 (CH, minor), 80.9 (CH, major), 80.9
(CH2, minor), 82.7 (CH2, major), 87.4 (Cq, major), 118.8 (CH,
minor), 118.9 (CH, major), 136.7 (Cq, minor), 137.3 (Cq, major).
Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found: C,
70.80; H, 9.75; N, 5.89.
(1S,5S,5'R,7R)-2-Methyl-3'-((R)-1-
phenylethyl)spiro[bicyclo[3.2.1]oct[2]ene-6,5'-oxazolidin]-7-ol
(16): Prepared by method A; 0.36 g (67%); yellow oil; [α]D20 = -35
(c 0.26, MeOH). 1H NMR (400 MHz, CDCl3)  (ppm):1.35 (d, J =
6.5 Hz, 3H), 1.40-1.44 (m, 1H), 1.63 (d, J = 11.8 Hz, 1H), 1.70 (d,
J = 1.8 Hz, 3H), 2.03-2.10 (m, 1H), 2.19-2.29 (m, 3H), 2.65 (d, J
= 10 Hz, 1H), 2.79 (d, J = 9.0 Hz, 1H), 3.03 (d, J = 9.9 Hz, 1H),
3.46 (q, J = 6.4, 12.8 Hz, 1H), 3.80 (q, J = 5.7, 8.8 Hz, 1H), 4.12
(d, J = 3.4 Hz, 1H), 4.40 (d, J = 3.5 Hz, 1H), 5.26 (s, 1H), 7.24-
7.34 (m, 5H). 13C NMR (100 MHz, CDCl3)  (ppm): 23.8 (CH3),
24.9 (CH3), 29.0 (CH2), 29.3 (CH2), 43.0 (CH), 44.2 (CH), 61.4
(CH), 64.2 (CH2), 81.9 (CH), 86.1 (Cq), 86.7 (CH2), 119.7 (CH),
127.2 (CH Ar), 127.4 (CH Ar), 128.7 (CH Ar), 137.5 (Cq), 144.9
(Cq Ar). Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68.
Found: C, 76.25; H, 8.45; N, 4.65.
General procedure for the preparation of aminodiol 13: To a
suspension of palladium-on-carbon (5% Pd, 0.22 g) in MeOH (50
mL) was added aminodiols 9-11 (14.0 mmol) in MeOH (100 mL),
and the mixture was stirred under a H2 atmosphere (1 atm) at
room temperature. When the reaction was completed (as
monitored by TLC, 20 h), the mixture was filtered through a Celite
pad and the solution was evaporated to dryness. The crude
product was crystallized in diethyl ether, resulting in 13 as white
crystals.
(1S,5S,5'R,7R)-3'-Isopropyl-2-
methylspiro[bicyclo[3.2.1]oct[2]ene-6,5'-oxazolidin]-7-ol
(17):
Prepared by method B; 0.34 g (70%); yellow oil; [α]D = -47 (c,
(1S,5S,6R,7R)-6-(Aminomethyl)-2-methylbicyclo[3.2.1]oct-2-
ene-6,7-diol (13): 1.80 g (70%); white crystals; mp: 197-210 °C;
20
1
0.15 MeOH). H NMR (500 MHz, CDCl3)  (ppm): 1.08 (dd, J =
[α]D = -51 (c 0.20 MeOH). 1H NMR (500 MHz, DMSO-d6) 
20
7.6, 12.6 Hz, 6H), 1.42-1.48 (m, 1H), 1.66 (d, J = 14.7 Hz, 1H),
1.71 (d, J = 1.8 Hz, 3H), 2.02-2.09 (m, 1H), 2.17-2.32 (m, 3H),
2.45-2.52 (m, 1H), 2.51 (d, J = 11.9 Hz, 1H), 2.79 (d, J = 10.0 Hz,
1H), 3.10 (d, J = 11.7 Hz, 1H), 3.82 (dd, J = 7.4, 9.9 Hz, 1H), 4.06
(d, J = 3.3 Hz, 1H), 4.65 (d, J = 3.4 Hz, 1H), 5.28 (s, 1H). 13C NMR
(125 MHz, CDCl3)  (ppm): 21.8 (CH3), 22.0 (CH3), 24.8 (CH3),
28.8 (CH2), 29.4 (CH2), 43.0 (CH), 43.9 (CH), 52.2 (CH), 63.7
(CH2), 81.5 (CH), 86.5 (Cq), 86.7 (CH2), 119.7 (CH), 137.2 (CH2).
Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found: C,
70.80; H, 9.75; N, 5.89.
(ppm): 1.48 (d, J = 11.7 Hz, 1H), 1.52-1.56 (m, 1H), 1.62 (s, 3H),
2.00 (d, J = 17.2 Hz, 1H), 2.15 (br s, 1H), 2.20-2.23 (m, 2H), 2.70
(d, J = 12.7 Hz, 1H), 2.80 (d, J = 12.7 Hz, 1H), 3.79 (t, J = 5.6 Hz,
1H), 3.97 (s, 1H), 5.14 (s, 1H), 5.53 (d, J = 5.7 Hz, 1H), 7.80 (br
s, 3H). 13C NMR (125 MHz, DMSO-d6)  (ppm): 24.8 (CH3), 27.8
(CH2), 28.2 (CH2), 43.4 (CH), 47.4 (CH2), 74.7 (Cq), 77.0 (CH),
118.9 (CH), 137.2 (Cq). Anal. Calcd for C10H17NO2: C, 65.54; H,
9.35; N, 7.64. Found: C, 65.55; H, 9.37; N, 7.62.
General procedure for the reaction of benzaldehyde with
diethylzinc in the presence of chiral catalysts: To the
respective catalyst (0.1 mmol), 1 M Et2Zn in n-hexane solution (3
mL, 3 mmol) was added under an argon atmosphere at room
temperature. The solution was stirred for 25 min at room
temperature then benzaldehyde (1 mmol) was added. After
(1S,5S,5'R,7R)-3'-Isopropyl-2-
methylspiro[bicyclo[3.2.1]oct[2]ene-6,5'-oxazolidin]-7-ol (17) and
(4aR,5S,9S,9aR)-3-isopropyl-8-methyl-2,3,4,4a,5,6,9,9a-
octahydro-5,9-methanocyclohepta[e][1,3]oxazin-4a-ol
(18):
1
Prepared by method A; 0.36 g (74%, 17:18 = 2:1); yellow oil. H
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10.1002/chem.201802484
Chemistry - A European Journal
FULL PAPER
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10.1002/chem.201802484
Chemistry - A European Journal
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Starting from natural (-)-limonene, a
limonene-based aminodiol library was
created whereas the reaction of
aminodiols with formaldehyde resulted
in limonene-fused spirooxazolidines in
Tam Le Minh, Antal Csámpai, Ferenc
Fülöp , Zsolt Szakonyi*
Page 1. – Page 10.
N-substituent
dependent
regio-
selective ring closures. The aminodiol
derivatives were applied as chiral
catalysts in the addition of diethylzinc
to benzaldehyde. The N-substituent-
dependent ring closure was explained
by comparative DFT modelling.
Regio- and stereoselective synthesis
of bicyclic limonene-based chiral
aminodiols and spirooxazolidines
This article is protected by copyright. All rights reserved.