Synthesis of enantiomerically pure (+)-(1S,2R,5S,6R)-endo,endo-2,6-diaminobicyclo[3.3.1]nonane

Article abstract of DOI:10.1081/SCC-120018786

Enantiospecific synthesis of enantiomerically pure (+)-(1S,2R, 5S,6R)-endo,endo-2,6-diaminobicyclo[3.3.1]nonane was accomplished via a reaction sequence including stereospecific synthesis of the corresponding dinitro compound and the subsequent reduction of the latter with LiAlH₄. The title diamine wasalso obtained in a direct reduction of the corresponding dioxime with sodium in ethanol with high stereoselectivity.

Full text of DOI:10.1081/SCC-120018786

This article was downloaded by: [Thammasat University Libraries]
On: 09 October 2014, At: 16:32
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Enantiomerically Pure (+)-(1S,2R,5S,6R)-
endo,endo- 2,6-Diaminobicyclo[3.3.1]nonane
a
Eugenius Butkus a , Julė Malinauskienė , Edvinas Orentas a & Albinas Žilinskas a
a Department of Organic Chemistry , Vilnius University , Vilnius, Lithuania
Published online: 16 Aug 2006.
To cite this article: Eugenius Butkus , Julė Malinauskienė , Edvinas Orentas & Albinas Žilinskas (2003) Synthesis of
Enantiomerically Pure (+)-(1S,2R,5S,6R)-endo,endo- 2,6-Diaminobicyclo[3.3.1]nonane, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:9, 1595-1602, DOI: 10.1081/SCC-120018786
To link to this article: http://dx.doi.org/10.1081/SCC-120018786
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1595–1602, 2003
Synthesis of Enantiomerically Pure
(Q)-(1S,2R,5S,6R)-endo,endo-
2,6-Diaminobicyclo[3.3.1]nonane
*
Eugenius Butkus, Jule Malinauskiene, Edvinas Orentas,
_
and Albinas Zilinskas
_
Department of Organic Chemistry,
Vilnius University, Vilnius, Lithuania
ABSTRACT
Enantiospecific synthesis of enantiomerically pure (þ)-(1S,2R,
5S,6R)-endo,endo-2,6-diaminobicyclo[3.3.1]nonane was accompl-
ished via a reaction sequence including stereospecific synthesis of
the corresponding dinitro compound and the subsequent reduction
of the latter with LiAlH4. The title diamine was also obtained in a
direct reduction of the corresponding dioxime with sodium in etha-
nol with high stereoselectivity.
*Correspondence: Eugenius Butkus, Department of Organic Chemistry, Vilnius
University, Naugarduko 24, 2006 Vilnius, Lithuania; Fax: 370-2-330987; E-mail:
eugenijus.butkus@chf.vu.lt.
1595
DOI: 10.1081/SCC-120018786
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1596
Butkus et al.
INTRODUCTION
Polycyclic compounds containing amino groups are of considerable
interest for pharmacological evaluation, for example as potential anti-
influenza agents by blocking the ion channel of the M-2 protein,[1] and
also as anti-HIV and anti-Parkinson’s agents.[2] The amino group can be
readily introduced into a suitable molecule by a reduction of a nitro
group. In turn, nitrocycloalkanes are powerful synthetic tools in organic
chemistry,[3] and of particular interest are polycyclic molecules containing
nitro groups because of their potential use as high-energy materials.[4]
Various successful approaches have been applied for the synthesis of
this class of compounds, and a review on the synthesis of polynitrocyclic
derivatives has been published.[5] The aim of this work was the enantio-
specific synthesis of 2,6-dinitrobicyclo[3.3.1]nonane and study of the
stereoselectivity of reduction of the nitro to amino group. This bicyclic
system is interesting, as it can be chiral by virtue of a substitution pattern
of this skeleton. This framework is quite common in nature as a con-
stituent of many natural and biologically active products or their meta-
bolites.[6] Biosynthetic pathways to many naturally occurring materials
involve formation and transformation of bicyclo[3.3.1]nonanes and
the latter are found to possess interesting biological activity.[7]
Therefore the access to stereochemically defined compounds of this
system is important in synthesis of many natural compounds of potential
biological activity.
RESULTS AND DISCUSSION
Most of the successful syntheses of alicyclic nitro compounds
generate this function indirectly through transformations of other
functional groups. A limited number of recent publications on the
synthesis of bicyclic structures of this class revealed that different
synthetic sequences have been used to achieve the goal. The synthesis
of the 2,6-dinitrobicyclo[3.3.1]nonane and the corresponding gem-
tetranitro derivative has been published recently, however, the stereo-
chemistry of dinitro groups in the former molecule has been not
established.[8]
We considered the use of diketoxime as appropriate precursor for the
synthesis of dinitro compound, and subsequent synthesis of bromo
nitroso and bromo nitro derivatives as the reasonable pathway of achiev-
ing the goal (Sch. 1).[9] The starting enantiomerically pure (þ)-(1S,5S)-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Pure (Q)-(1S,2R,5S,6R)-endo,endo-2,6-Diaminobicyclo[3.3.1]nonane
1597
Scheme 1. Reagents and conditions: (i) Baker’s yeast; (ii) NH2OH/EtOH,
(98%); (iii) Br2, C6H5N, CH2Cl2; (iv) HNO3 (62%); (v) NaBH4, MeOH/H2O
(20%); (vi) LiAlH4, THF (75%); (vii) Na/EtOH (75%).
bicyclo[3.3.1]nonane-2,6-dione
1 was obtained by following the
procedure described earlier.[10] The kinetic resolution of racemic 2,6-
dione 1 using baker’s yeastaffecetd mainly ( ꢀ)-(1R,5R)-enantiomer by
its reduction thus enriching the mixture with (þ)-(1S,5S)-1 (Sch. 1).
Enantiomeric excess of (þ)-1 was 93% in six days of fermentation. The
dioxime 2 was obtained in a usual manner. The reaction of bicyclo[3.3.1]-
nonane-2,6-dione dioxime 2 with bromine in pyridine afforded bromoni-
troso compound, which was oxidized in situ by concentrated nitric acid
to the corresponding bromonitro derivative 3. The exo-bromo and endo-
nitro stereochemistry follows from the analogy of stereochemical control
of exo-electrophile acceptance in bicyclo[2.2.1]heptane series.[11] The
reduction of the bromonitro derivative 3 with sodium borohydride led
to the endo-dinitro derivative 4 in a moderate yield. Isolation of pure
compound requires acidification of the reaction mixture to convert aci-
form to nitro-form which affected the yield. The sharp doublet of doub-
1
lets in the H NMR spectrum of nitro compound 4 is very remarkable
since usually only complicated multiplets are observed of the protons
attached to carbon atoms bearing substituents in substituted bicyclo[3.3.1]-
nonane system.[12] The introduction of nitro groups into a labile bicy-
clo[3.3.1]nonane framework might produce a deviation from the normal
valence and torsional angles in this structure. An interesting example of
formation of 3,7-dinitronoradamantane derivatives from the correspond-
ing diketoximes of bicyclo[3.3.1]nonane has been reported due to the
release of torsional strain.[13] We performed the optimization of the geo-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1598
Butkus et al.
metry of dinitro compound 4 by PM3 method, and a distortion of cyclo-
hexane rings and dihedral angles was proved, although the double chair
conformation of the bicyclononane framework remains the most stable.
A distortion of the molecule is observed at C3 and C2 where sp3 hybri-
dized carbon atom valence angles are 112.3ꢁ and 113.46ꢁ, respectively,
and the valence angle HC3H is 106.36ꢁ. The torsional angles between
hydrogen atom at carbon atom bearing nitro group and hydrogen
atoms at C3,7 are 47.04ꢁ and 163.38ꢁ, and hydrogen atom at C1 is
54.26ꢁ, respectively. The geometry is in agreement with the spin–spin
coupling constants observed in 1H NMR spectrum, namely 8.0, 14.4,
and 6.0 Hz, and correspond to values obtained from the Karplus
equation.[14]
The reduction of nitro groups was achieved by the reduction of 4
with NaBH4. The diastereomerically pure diaminobicyclononane
(>99% by GC–MS analysis) obtained by the reduction with NaBH4
has di-endo configuration as revealed by the 1H NMR spectrum. The
signal of proton at C2 and C6 carbon atoms are identical at ꢀ 2.94 ppm
and couplings are characteristic of the exo-protons at these positions.
The 13C NMR spectrum corresponds with the C2 symmetry of the
molecule. GC–MS analysis shows the only peak with m/z 154 and the
elemental analysis of the obtained diamine 5 shows that it is a highly
hygroscopic compound. Earlier 2,6-diamino bicyclo[3.3.1]nonane 5 has
been obtained from dioxime derivative 2 by reduction with sodium in
ethanol, and the stereochemistry of the product has been assigned to be
trans in respect of both amino groups only on the basis of elimination
of ammonia.[15] Reinvestigation of the reduction of dioxime led to the
product, which was identical by spectral and analytical data with the di-
endo diamino compound obtained from 4. Consequently, a reduction of
the dioxime 2 proceeds with high stereoselectivity and the configuration
of the resultant diamine 5 is di-endo in contrary with the previous
observation.
In conclusion, an enantiospecific synthesis of di-endo-2,6-(þ)-
1S,2R,5S,6R-dinitrobicyclo[3.3.1]-nonane via ketoxime and bromo
nitro compounds was achieved, and the stereoselective reduction of
the nitro group afforded the corresponding di-endo-amine. A direct
reduction of the dioxime 2 proceeds with high stereoselectivity and
the configuration of the resultant diamine is di-endo in contrary with the
previous observation. A suggested synthetic scheme opens way to
the synthesis of chiral bicyclic ligand to be used in building of new
catalysts and a powerful block for the construction of supramolecular
structures.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Pure (Q)-(1S,2R,5S,6R)-endo,endo-2,6-Diaminobicyclo[3.3.1]nonane
1599
EXPERIMENTAL
Melting points were recorded with a Koefler melting apparatus and
are not corrected. IR spectra obtained in KBr on a Perkin Elmer Spectrum
1
BX spectrometer in KBr. H and 13C NMR spectra were recorded on
Varian (300 MHz) and Tesla BS-587A (80 MHz) instruments in deuterio-
chloroform and are reported as chemical shifts (ꢀ) in ppm relative to
(CH3)4Si, and J values are given in Hz. GLC analysis was carried out
on a Varian 3700 instrument (FID) by using 30 m long column (9% silicon
on Chromosorb W-AW). Mass spectra were run by GC–MS on a Hewlett-
Packard 5890 Series II instrument with mass selective detector using
HP-1701 capillary column (30 m ꢂ 0.25 mm ꢂ 0.25 mm). Optical rotations
[ꢁ] were measured on a polarimeter Polamat-A (Carl Zeiss) at 546 nm.
Semi-empirical and Molecular Mechanics calculations were performed
using SPARTAN Plus program package.[17]
Dioxime of (Q)-(1S,5S )-bicyclo[3.3.1]nonane-2,6-dione (2): Dioxime 2
was obtained from 1 by a slightly modified procedure described pre-
viously[16] using sodium hydroxide solution instead of sodium carbonate.
M.p. 230ꢁC. [ꢁ]20 þ300.5 (C2H5OH, c 0.05). IR: 3402 (br), 1651,
1457 (cmꢀ1). Anal. calcd. for C9H14N2O2: C, 59.32; H, 7.74; N, 15.37.
Found: C, 59.61; H, 8.00; N, 15.62.
(Q)-(1S,5S )-2,6-exo,exo-dibromo-endo,endo-dinitrobicyclo[3.3.1]nonane
(3): To a solution of dioxime 2 (0.74 g, 4.0 mmol) in pyridine (2.4 mL,
30mmol) and dichloromethane (35 mL) a solution of bromine (1.3 g,
14mmol) in dichloromethane (6 mL) was added dropwise during 30min
at0 ꢁC. The reaction was stirred vigorously for 1.5 h. A green solution was
washed three times with water until a neutral media of washing water.
The mixture was concentrated to 1/3 of initial volume and a solution of
concentrated nitric acid (6 mL, 70%) was added. The reaction mixture was
stirred until blue color disappeared and poured into 10 mL of water. The
mixture was extracted with CH2Cl2, the combined organic extracts were
washed sequentially with NaOH (50%), water and brine, and dried
(Na2SO4). The removal of the solvent in vacuo afforded 3 (0.77 g, 51%),
which was used without further purification.
(Q)-(1S,2R,5S,6R)-endo,endo-2,6-dinitrobicyclo[3.3.1]nonane (4): To a
stirred solution of sodium borohydride (1.66 g, 0.052 mol) in
methanol and water mixture (40 mL, 3:1) a solution of dibromodinitro
derivative 3 (0.77 g, 2.1 mmol) in methanol was added dropwise
cautiously. The reaction mixture was stirred until evolution of gas was
over (for ꢃ15 min) and neutralized with an excess of KOH solution.
Methanol was evaporated and the residue was neutralized with aqueous
hydroxylamine hydrochloride (15% solution). The mixture was extracted

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1600
Butkus et al.
with petrol ether and the combined organic layers were washed sequen-
tially with phosphoric acid, water, and dried (Na2SO4). Following the
removal of the solvent, the resultant solid was purified by column
chromatography on silica gel. Isolation of the band at Rf 0.65 (benzene)
yielded 0.085 g (20.0%) of the nitro derivative 4, m.p. 97–98ꢁC.
[ꢁ]20 þ47.3 (CHCl3, c 0.02). IR: 1540, 1380, 975 (cmꢀ1). 1H NMR:
ꢀ 4.38 (2H, ddd, J 8.0, 14.4 and 6.0, H-C-NO2), 2.56 (2H, m, H-C1,5),
2.36–1.50 (10H, m, bicyclic protons). 13C NMR: 23.9 (C4,8), 24.3 (C3,7),
30.9 (C1,5), 32.9 (C9), 86.6 (C2,6). Calcd. for C9H14N2O4: C, 50.46; H, 6.59;
N, 13.07. Found: C, 50.79; H, 6.81; N, 12.75.
(Q)-(1S,2R,5S,6R)-endo,endo-2,6-diaminobicyclo[3.3.1]nonane (5): (a)
Reduction of 4 with LiAlH4. A solution of lithium aluminium hydride
(0.12 g, 3.2 mmol) in dry THF (20 mL) was refluxed for 0.5 h and portions
of solution of nitro derivative 4 (0.085 g, 0.41 mmol) in 10 mL of THF
was added dropwise. Reflux was maintained for 3 h and then reaction
mixture was allowed to cool to room temperature. The mixture was
washed sequentially with water, NaOH (15%), and water. The diamine
was isolated by the continuous extraction with ether. The solution was
dried (CaCl2) and a dry HCl was passed through it. Diamine was isolated
as hydrochloride (0.08 g). The solid was mixed with KOH (0.14 g) and
distilled in vacuo to give 0.06 g (75%) of diamine 5, b.p. 128–130ꢁC/
14 torr. [ꢁ]20 þ 30.5 (C2H5OH, c 0.045). IR: 3349, 3275, 1592 (cmꢀ1).
1H NMR (300 MHz): ꢀ 2.94 (2H, m, H-C-NH2), 2.25 (2H, br s, NH2),
1.96 (2H, dd, J 12, H-C1,5), 1.80–1.2 (10H, m). 13C NMR: 52.3 (C2, 6),
34.0 (C9), 33.4 (C1, 5), 31.5 (C3,7), 22.6 (C C4, 8). MS: m/z 154 (15), 137
(45.6), 122 (10.4), 112 (11.0), 108 (25.5), 96 (24.2), 94 (32.0), 82 (35.2),
69 (15.8), 56 (100). Anal. calcd. for C9H14N2O4ꢄH2O: C, 70.08; H, 11.76,
N, 18.16. Found: C, 70.19; H, 11.81; N, 18.65.
(b) Reduction of 1 with sodium in ethanol. To a boiling solution of
bisoxime (þ)-1 (0.25 g, 1.3 mmol) in dry ethanol (6.0 mL) portions of
sodium (0.6 g, 0.026 mol) were added cautiously and the reaction mixture
was refluxed until sodium dissolved. Ethanol was evaporated and the
residue was water steam distilled. The distillate was collected into a
flask containing solution of HCl. The obtained solution was evaporated
till dryness yielding the diamine hydrochloride (0.23 g, 75%). Free amine
was obtained by mixing with KOH and distillation in vacuo to give a
sample identical with the diamine 5 obtained from the dinitro
compound 4.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Pure (Q)-(1S,2R,5S,6R)-endo,endo-2,6-Diaminobicyclo[3.3.1]nonane
1601
ACKNOWLEDGMENTS
We thank the Lithuanian science and studies foundation for partial
financial supportof ht is work.
REFERENCES
1. Miller, J.A.; Ullah, G.M.; Welsh, G.M.; Hall, A.C. Tetrahedron
Lett. 2001, 42, 7503–7507, and references cited therein.
2. (a) Knoll, W.; Bobek, M.M.; Giester, G.; Brinker, U.H.
Tetrahedron Lett. 2001, 42, 9161–9165; (b) Hagers Handbuch der
Pharmazeutischen Praxis; von Bruchhausen, F., Dannhardt, G.,
Eibel, S., Frahm, A.W., Hackenthal, E., Holzgraber, U., Eds.;
Springer: Berlin, 1993; Vol. 9, 1097.
3. For some recentexamples, see: (a) Zhang, D.; Miller, M.J. J. Org.
Chem. 1998, 63, 755–759; (b) Ballini, R.; Petrini, M.; Polinati, O.
J. Org. Chem. 1995, 61, 5652–5655; (c) Ballini, R.; Papa, F.; Abate,
C. Eur. J. Org. Chem. 1999, 87–90.
4. Lukin, K.A.; Li, J.; Eaton, P.E.; Kanomata, N.; Hain, J.;
Punzalan, E.; Gilardi, R. J. Am. Chem. Soc. 1997, 119, 9591–9599.
5. Marchand, A.P. Tetrahedron 1988, 24, 2377–2395.
6. For recentexamples of bicyclo[3.3.1]nonanes found in natural sub-
stances, see: (a) Shi, J.-G.; Shi, Y.-P.; Jia, Z.-J. Phytochemistry 1997,
45, 343–347; (b) Paula de, J.R.; Vieira, I.J.C.; Silva, M.F.;
das, G.F.da; Rodrigues, Fo E.; Fernandes, J.B.; Vieira, P.C.;
Pinheiro, A.L.; Vilela, E.F. Phytochemistry 1997, 44, 1449–1454;
(c) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm.
Bull. 1997, 45, 947–949; (d) Govindachari, T.R.; Krishna Kumari,
G.N. Phytochemistry 1998, 47, 1423–1425; (e) Hu, L.-H.; Sim,
K.-Y. Tetrahedron 2000, 56, 1379–1386.
7. See for example: (a) Srikrishna, A.; Vijaykumar, D. J. Chem. Soc.,
Perkin Trans. 1 1999, 1265–1272; (b) Aleu, J.; Hernandez-Galan, R.;
Hanson, J.R.; Hitchcock, P.B.; Collado, I.G. J. Chem. Soc., Perkin
Trans. 1 1999, 727–730; (c) Geirsson, J.K.F.; Eiriksdottir, E.G.
Synlett 2001, 664–666; (d) Butkus, E. Synlett 2001, 1827–1835,
and references cited therein.
8. Archibald, T.G.; Baum, K. J. Org. Chem. 1988, 53, 4645–4649.
9. Marchand, A.P.; Reddy, D.S. J. Org. Chem. 1984, 49, 4078–4080.
10. Hoffman, G.; Wiartalla, R. Tetrahedron Lett. 1982, 23, 3887–3888.
11. Ranganathan, S.; Raman, H.; Srinivasan, C.V. Tetrahedron 1978,
34, 3129–3132.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1602
Butkus et al.
12. (a) Berg, U.; Butkus, E.; Stoncius, A. J. Chem. Soc., Perkin Trans. 2
1995, 97–102; (b) Butkus, E.; Malinauskiene, J.; Kadziauskas, P.
Z. Chem. 1980, 20, 103.
13. Zajac, W.W.; Speier, G.J.; Buzby, J.H.; Walters, T.R. J. Org. Chem.
1995, 61, 3545–3547.
14. (a) Karplus, M. J. Chem. Phys. 1959, 30, 11; (b) Bother-By, A.B.
Adv. Magn. Reson. 1965, 1, 195.
15. Meerwein, H.; Kiel, F.; Klosgen, G.; Schoch, E. J. Prakt. Chem.
1922, 212, 161–206.
16. Meerwein, H.; Schurmann, W. Justus Liebigs Ann. Chem. 1913,
398, 196–250.
¨
17. SPARTAN Plus, Version 1, Wavefunction, Inc. 1840 Von Karman
Avenue, Suite 370, Irvine, CA 92612.