Synthesis of new enantiopure trans-3,4-diaminocaranes from (+)-3-carene

Article abstract of DOI:10.1016/j.tetasy.2011.02.027

A synthetic strategy to obtain new enantiopure trans-3,4-diaminocaranes derived from (+)-3-carene via a stereoselective methodology is described. The stereoselective preparation of 3,4-α-carene- or 3,4-β-carene-epoxide is followed by a ring opening by sodium azide to obtain the azido-alcohols. Subsequent cyclization affords the corresponding aziridine diastereoisomers, which are converted to azido amines by opening of the aziridine rings by sodium azide and then reduced to the final diamine diastereoisomers. The absolute configurations of the final diamines and of novel intermediates are established by ¹H NMR spectra correlated with conformational analysis supported by molecular modeling.

Full text of DOI:10.1016/j.tetasy.2011.02.027

Tetrahedron: Asymmetry 22 (2011) 603–608
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new enantiopure trans-3,4-diaminocaranes from (+)-3-carene
⇑
Cristina Cimarelli , Davide Fratoni, Gianni Palmieri
School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic strategy to obtain new enantiopure trans-3,4-diaminocaranes derived from (+)-3-carene via a
stereoselective methodology is described. The stereoselective preparation of 3,4-a-carene- or 3,4-b-
Received 14 February 2011
Accepted 28 February 2011
Available online 12 April 2011
carene-epoxide is followed by a ring opening by sodium azide to obtain the azido-alcohols. Subsequent
cyclization affords the corresponding aziridine diastereoisomers, which are converted to azido amines by
opening of the aziridine rings by sodium azide and then reduced to the final diamine diastereoisomers.
The absolute configurations of the final diamines and of novel intermediates are established by 1H NMR
spectra correlated with conformational analysis supported by molecular modeling.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral vicinal diamines are very important molecules which
have found application in several fields.1–4 For instance, several
synthetic diamine derivatives have been employed as medicinal
agents, in particular in chemotherapy as substitutes for cisplatin.5
Chiral 1,2-diamines are also used in catalytic asymmetric synthe-
sis,6 as chiral auxiliaries4 and in organocatalysis.7–11 They have also
found use as chelating agents to obtain coordination compounds
useful in homogeneous catalysis.12–15
2.1. Synthesis of trans-(R,R)-3,4-diamino carane 8 from 3,4-a-
carene oxide 2
The synthetic route to obtain trans-3,4-diamino carane 8 is de-
scribed in detail in Scheme 1. The starting material (+)-3-carene 1
is converted to
a-carene oxide 2 with MCPBA, according to the
procedure reported by Brown and Suzuki.29
The second step is the formation of azido-alcohols 3 and 4 from
Herein we report the synthesis of new enantiopure trans-3,4-
diaminocaranes, derived from (+)-3-carene, an enantiomerically
pure terpene, easily obtained from the ‘chiral pool’. Terpenes are
widely used in organic synthesis to obtain enantiomerically pure
compounds,16–21 chiral auxiliaries or asymmetric ligands em-
ployed in enantioselective transformations.22–28 Moreover, chiral
1,2-diamines derived from (+)-3-carene are structurally correlated
with trans-1,2-diaminocyclohexane analogues, widely used as
chiral reagents, scaffolds and ligands for catalysis.3,9
a-carene oxide 2. These products are obtained by heating a-carene
oxide 2 in methanol at reflux with sodium azide and ammonium
chloride.30 The nucleophilic attack of NaN3 on carene epoxide 2
is not diastereoselective, unlike that observed in the synthesis of
analogous amines starting from limonene oxide:28 the azido ion at-
tacks both carbon atoms of epoxide ring of a-carene oxide 2, form-
ing two possible regioisomer azido-alcohols regioisomer 3 and 4 in
similar amounts.
At this point, our aim was to prepare aziridine 5 from azido-
alcohols 3 and 4 via a pseudo-Staudinger reaction,31,32 this could
be performed by treating the azido-alcohols with triphenylphos-
phine in 1,4-dioxane. However, the reaction of azido alcohol 3 with
triphenylphosphine affords only a mixture of unidentified decom-
position products, already at room temperature, while the regio-
isomer 4 forms the aziridine 5 directly at reflux. Therefore, it was
necessary to find a method aimed to obtain exclusively azido alco-
The stereoselective epoxidation of (+)-3-carene 1 affords a-car-
ene oxide 2. The reaction of carene 1 with NaI in the presence of
sulfuric acid and hydrogen peroxide affords b-carene oxide 10.
Epoxides 2 and 10 can be converted to the corresponding azido-
alcohols 3 and 4 or 11 and 12. Subsequent cyclization of azido alco-
hol 4 affords aziridine 5 but does not take place with azido alcohol
3, and it is diastereoconvergent from azido-alcohols 11 and 12, that
both lead to aziridine 13. The opening of the aziridine rings by so-
dium azide afforded to the corresponding azido-amines 6 and 7 or
14 and 15, which can then be reduced to the final diamines diaste-
reoisomers 8 and 16.
hol 4 from a-carene oxide 2, trying to get the highest possible yield
of aziridine 5. Treating trans-carene epoxide 2 with sodium azide
in acetic acid and water enables a regioselective pH-controlled ring
opening reaction to take place, forming the only regioisomer 4,33,34
as shown in Scheme 2. The regioselectivity of this reaction can be
explained by considering that the attack of the azide ion takes
place after protonation of the epoxide, which develops a more
⇑
Corresponding author. Tel.: +39 0737 402268; fax: +39 0737 637345.
E-mail address: cristina.cimarelli@unicam.it (C. Cimarelli).
positive charge on the tertiary
a-carbon with respect to the
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.027

604
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 603–608
OH
N3
iii
decomposition
N3
O
NH2
ii
i
3
N3
NH
OH
v
iv
7
1
2
H2N
H2N
NH2
N3
vi
4
5
8
6
Scheme 1. Reagents and conditions: (i) MCPBA, CHCl3, 0 °C, 70 min, 80%; (ii) NaN3, NH4Cl, MeOH, reflux, 32 h, 49%, 3:4 = 1:1.2; (iii) PPh3, 1,4-dioxane, rt, 24 h; (iv) PPh3,
1,4-dioxane, reflux, 24 h, 96%; (v) NaN3, CeCl3ꢀ7H2O, CH3CN/H2O, (5:1), reflux, 3 h, 37%, 6:7 = 36:1; (vi) LiAlH4, MTBE, 0 °C to rt, 4 h, 97%.
carene 1 is converted first into the haloidrine 9,36 then treated with
NaH. The synthesis of trans-(R,R)- and trans-(S,S)-3,4-diamino car-
anes 8 and 16 proceeds from b-carene oxide 10 through the same
N3
O
OH
NaN3
synthetic sequence that produces diamine 8 from a-carene oxide 2,
as described in Scheme 3.
AcOH, H2O (3:2)
30°C, 72h, 65%
The azido-alcohols 11 and 12 are obtained by treating b-carene
oxide 10 with NaN3 and NH4Cl.30 The azido group is then converted
into an aziridine again through a pseudo-Staudinger mechanism by
reaction with triphenylphosphine31,32 and also in this case a differ-
ent reactivity of the two azido-alcohols is observed: azido alcohol
11 forms aziridine 13 at room temperature, while 12 needs heating
in 1,4-dioxane at reflux to react. However, at this point the synthe-
sis is diastereoconvergent, because both azidoalcohols afford to the
same aziridine 13. The aziridine 13 reacts with sodium azide in the
presence of CeCl3ꢀ7H2O to give azido amines 14 and 15. The reduc-
tion of azido amine 14 affords diamine 8 as previously obtained in
4
2
Scheme 2.
secondary one. In this way only the more substituted
activated to attack of the nucleophile azide ion.
The nucleophilic ring opening of aziridine 5 with sodium azide
and CeCl3ꢀ7H2O as a catalyst shows very high selectivity towards
azido amine 6 (Y = 36%) with respect to 1 which is formed in very
poor yields (Y = 1%).
The last step is the reduction with LiAlH4 of the azido group in
azido amine 6 to an amine, to form trans-(R,R)-3,4-diamino carane
8. This product is stable in air and does not need to be stabilized by
salt formation with acids.
a-carbon is
the process starting from
a-carene oxide 2. Reduction of azido
amine 15 using the same conditions affords the diamine 16.
3. Stereochemistry
2.2. Synthesis of trans-(R,R)- and trans-(S,S)-3,4-diamino carane
from b-carene oxide
The absolute configuration of aziridine 5 in Scheme 1 was
attributed on the basis of the fact that either azido alcohol 3 or azi-
do alcohol 4, whose configuration is confirmed by literature data,30
afford the same product through a pseudo-Staudinger reaction,
that takes place with retention of configuration of the carbon atom
bearing the azido group, as was also observed in the case of limo-
nene derivatives.28,37,32
The synthetic route to obtain selectively trans-(R,R)- and trans-
(S,S)-3,4-diamino caranes
8 and 16 is depicted in detail in
Scheme 3.
When treating (+)-3-carene 1 with MCPBA only
a-carene oxide
2 is obtained35 (see Scheme 1). To get b-carene oxide 10 (+)-3-
H2N
OH
N3
1
N3
NH2
NH2
vii
i
iv
OH
O
NH
I
11
14
8
iii
ii
vi
N3
H2N
H2N
N3
OH
NH2
10
9
v
13
viii
15
12
16
Scheme 3. Reagents and conditions: (i) NaI, H2SO4, H2O2, H2O/THF (1:2.3), 0 °C to rt, 12 h, 82%; (ii) NaH, THF/Et2O (1:1), rt, 5.5 h, 84%; (iii) NaN3, NH4Cl, MeOH, reflux, 32 h,
72%, 11:12 = 1:1; (iv) PPh3, 1,4-dioxane, rt, 24 h, 79%; (v) PPh3, 1,4-dioxane, reflux, 36 h, 64%; (vi) NaN3, CeCl3ꢀ7H2O, CH3CN/H2O (5:1), reflux, 45 min, 92%, 14:15 = 1:2.2;
(vii) LiAlH4, MTBE, 0 °C to rt, 20 min, 85%; (viii) LiAlH4, MTBE, 0 °C to rt, 70 min, 91%.

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 603–608
605
Figure 1. Simplified representation of the more stable conformation of diastereomer aziridines 5 and 13 (minimized at the semiempirical PM3 level38).
Figure 2. Exemplified representation of the more stable conformation of diastereomer trans-(3,4)-diaminocaranes 8 and 16 (minimized at the semiempirical PM3 level14).
These considerations are confirmed by some observations on
the 1H NMR spectra of aziridine 5 compared with the one of its dia-
stereomer, aziridine 13.
Opening of aziridine 5 by sodium azide affords two regioiso-
meric azido amines 6 and 7, and the attribution of their configura-
tion was made after the 1H NMR signals were assigned on the basis
of COSY, HSAC, and NOESY experiments. The configuration of the
major product 6 was attributed on the basis of the NOESY and cou-
pling constants. A NOESY experiment on 6 confirmed the attribu-
tion, because when H-4b was irradiated, correlations were
observed with H-2b, H-5b, and Me-7b (0.95 ppm). In addition a
correlation between the Me-7a (0.99 ppm) and H-1, H-6 protons
was observed (Fig. 3).
Aziridines 5 and 13, depicted in Figure 1 in their most stable
3
conformations, show values of the coupling constants J4-5 of 7.6,
4.8 and 2.6, 2.6 Hz, respectively, in agreement with the values ex-
pected according to the Karplus rule for torsional angles / = 15°
and 130° in 5 and / = 50° and 65° in 13.
In the same way the attribution of the configurations of all the
other compounds described was made in agreement with the
interpretation of the 1H-NMR data. Compounds 4, 6, 8, 11, and
3
14 show respectively J4-5 values of 10.3, 10.7, 11.1, 11.1 and
4. Conclusion
11.1 Hz, typical of trans-diaxial hydrogen atoms (as shown for H-
4b/H-5a in compound 8, Fig. 2). On the other hand, compounds
3, 7, 12, 15, and 16 show 3J4-5 values of 3.0, 6.4, 3.0, 2.1, 6.0 Hz, typ-
ical of gauche-equatorial protons (H-4a in compound 16, Fig. 2).
Moreover in this second series of compounds the chemical shift
for proton H-4aeq is downshifted with respect to the signal of the
corresponding diastereomers with H-4b in an axial position.
Two new diamine diastereoisomers 8 and 16, derived from car-
ene were prepared selectively following two separate synthetic
routes, that start respectively from 3,4-a-carene oxide 2 and 3,4-
b-carene oxide 10. The synthetic sequence is diastereoselective
and in one step also diastereoconvergent. All the passages in the
synthetic routes are simple without using complex procedures or
expensive reagents. Generally the yields are good, with the excep-
tion of the aziridine ring opening. The configuration of the final
diamines and of novel intermediates was attributed through 1H
NMR spectra observation correlated with conformational analysis
and supported by molecular modeling. This is a convenient way
to obtain stereoselectively, and from a natural homochiral starting
material, new enantiopure vicinal diamines with a trans-1,2-diami-
nocyclohexane skeleton, that can be used as ligands in asymmetric
catalytic synthesis.
5. Experimental
5.1. General
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, with CDCl3 as solvent at ambient temperature and
Figure 3. Exemplified representation of the more stable conformation of azido
amine 6 (minimized at the semiempirical PM3 level14).

606
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 603–608
were calibrated using residual undeuterated solvents as the
internal reference. Coupling constants (J) are given in Hertz. IR
spectra were recorded using FTIR apparatus. Optical rotations were
measured in a 1 dm cell at 20 °C. All melting points were uncor-
rected. All reagents were commercially available, were purchased
at the highest quality, and were purified by distillation when
necessary.
5.2.5. Synthesis of (1S,3R,4R,6R)-4-azido-3,7,7-trimethyl-
bicyclo[4.1.0]heptan-3-amine 6 and (1R,3S,4S,6S)-4-azido-4,7,7-
trimethylbicyclo[4.1.0]heptan-3-amine 7
To a solution of aziridine 5 (0.458 g, 3.03 mmol) in CH3CN/H2O
5:1 (5.5 mL) was added NaN3 (0.236 g, 3.64 mmol) and CeCl3ꢀ7H2O
(0.559 g, 1.51 mmol) and then heated at reflux for 3 h. The reaction
was monitored by GC. After cooling, the reaction mixture was con-
centrated in vacuo to remove the solvent. The crude was diluted
with DCM and to the resulting mixture was added Na2SO4. The azi-
do-amines 6 and 7 were separated by column chromatography
(cyclohexane/AcOEt 50:50) to obtain 0.212 g of 6 (Y = 36%) and
5 mg of 7 (Y = 1%), both as yellow oils.
5.2. Procedures and data
5.2.1. Synthesis of (1S,3S,4R,6R)-3,4-epoxy-3,7,7-trimethyl-
bicyclo-[4.1.0]heptane 2
A solution of (+)-3-carene 1 (1.51 g, 90% pure, 10 mmol) in chlo-
roform (1.5 mL) was cooled at 0 °C. m-Chloroperbenzoic acid
(2.46 g, 77% pure, 11 mmol) in chloroform (7 mL) was added to
the solution in aliquots over 75 min. After complete addition, stir-
ring was continued at room temperature for 1 h. The progress of
the reaction was followed by GC until the starting material was
completely consumed. The excess of m-chloroperbenzoic acid
was destroyed by slow addition of sodium sulfite (10%). After
extraction, the organic layer was washed with sodium hydroxide
(10% aqueous solution), then with brine and after separation it
was dried over Na2SO4. The solvent was removed and the residue
distilled under reduced pressure to obtain 2 as a colorless oil
(1.22 g Y = 80%). Obtained spectroscopic data are confirmed by
the literature.29
5.2.5.1. (1S,3R,4R,6R)-4-Azido-3,7,7-trimethylbicyclo[4.1.0]hep-
tan-3-amine 6. Yellow oil; ½a D20
¼ ꢂ40:5 (c 0.31, CHCl3); mmax (li-
ꢁ
quid film): 3358, 2101, 1589, 1271, 1146, 1124, 812 cmꢂ1; NMR
(CDCl3): dH 0.68–0.76 (m, 2H, H-1, H-6), 0.95 (s, 3H, Me-7b), 0.99
(s, 3H, Me-7a), 1.05 (s, 3H, Me-3a), 1.10 (dd, 1H, J = 14.1, 3.8 Hz,
H-2b), 1.43 (br s, 2H, NH2), 1.78 (ddd, 1H, J = 14.5, 10.7, 8.1 Hz,
H-5a), 1.86 (dd, 1H, J = 14.1, 9.8 Hz, H-2a), 2.12 (dd, 1H, J = 14.5,
7.3 Hz, H-5b), 3.03 (dd, 1H, J = 10.7, 7.7 Hz, H-4b); dC 15.9, 17.9,
19.3, 20.3, 21.2, 25.0, 28.8, 34.8, 51.8, 69.1. Anal. Calcd for
C10H18N4, MW 194.277: C, 61.82; H, 9.34; N, 28.84. Found: C,
61.79; H, 9.48; N, 28.72.
5.2.5.2. (1R,3S,4S,6S)-4-Azido-4,7,7-trimethylbicyclo[4.1.0]hep-
tan-3-amine 7. Yellow oil; ½a D20
¼ þ37:7 (c 0.28, CHCl3); mmax (li-
ꢁ
5.2.2. Synthesis of (1S,3S,4S,6R)-4-azido-3,7,7-trimethyl-
bicyclo[4.1.0]heptan-3-ol 3 and (1R,3R,4R,6S)-4-azido-4,7,7-
trimethylbicyclo[4.1.0]heptan-3-ol 4
Products 3 (Y = 22%) and 4 (Y = 27%) were prepared according to
Ref. 12. The spectroscopic data obtained are confirmed by the
literature.30
quid film): 3346, 2105, 1388, 1248, 1108, 799 cmꢂ1; NMR (CDCl3):
dH 0.67–0.77 (m, 2H, H-1, H-6), 1.01 (s, 3H), 1.03 (s, 3H), 1.17–1.34
(m, 2H), 1.28 (s, 3H), 2.02 (dd, 1H, J = 15.0, 8.1 Hz), 2.16 (ddd, 1H,
J = 15.0, 8.5, 6.0 Hz, H-5), 2.97 (dd, 1H, J = 8.5, 6.4 Hz, H-4), 3.40
(br s, 2H); dC 15.4, 18.5, 18.7, 20.6, 22.4, 25.8, 28.5, 29.7, 54.0,
64.3. Anal. Calcd for C10H18N4, MW 194.277: C, 61.82; H, 9.34; N,
28.84. Found: C, 61.94; H, 9.52; N, 28.91.
5.2.3. Selective synthesis of (1R,3R,4R,6S)-4-azido-4,7,7-
trimethylbicyclo[4.1.0]heptan-3-ol 4
5.2.6. Synthesis of (1S,3R,4R,6R)-3,7,7-trimethyl-
At first,
a-carene oxide 2 (0.381 g, 2.5 mmol) was added to a
bicyclo[4.1.0]heptane-3,4-diamine 8
aqueous solution of NaN3 and acetic acid (0.823 g, 12.5 mmol of
NaN3 in 4 mL of water and 2.3 mL of glacial acetic acid). The heter-
ogeneous mixture was stirred for 48 h at 30 °C and followed by GC.
At the end of the reaction, the mixture was treated with DCM and
the excess of acetic acid was neutralized with NaOH (10%). The or-
ganic layer was dried with Na2SO4 and concentrated under reduced
pressure to give the crude azido-alcohol 4 which was purified
by column chromatography (cyclohexane/AcOEt 95:5), giving
0.295 g of a white crystalline solid. Y = 65%. Obtained spectroscopic
data are confirmed by the literature.33,34
The azido-amine 6 (0.212 g, 1.09 mmol) was dissolved in anhy-
drous MTBE (2 mL) and stirred at 0 °C in an ice-water bath. The
solution was treated with LiAlH4 (0.05 g, 1.31 mmol). The reaction
was stirred for 4 h until it reached room temperature. The reaction
was monitored by GC. The excess of LiAlH4 was eliminated with
H2O. The mixture was dried with Na2SO4, filtered, washed with
DCM, and evaporated in vacuo to give the diamine 8 (0.185 g,
Y = 99%) as a colorless oil: ½a D20
ꢁ
¼ ꢂ12:3 (c 0.29, CHCl3);
mmax (liquid
film): 3281,1586, 1376, 1146, 810 cmꢂ1; NMR (CDCl3): dH 0.63 (t,
1H, J = 9.0 Hz, H-6), 0.68 (td, 1H, J = 9.4, 4.7 Hz, H-1), 0.94 (s, 3H,
Me), 0.96 (s, 3H, Me), 1.00 (s, 3H, Me), 1.07 (dd, 1H, J = 14.5,
4.7 Hz, H-2b), 1.27 (br s, 4H, 2 NH2), 1.40 (ddd, 1H, J = 14.5, 11.1,
7.7 Hz, H-5a), 1.86 (dd, 1H, J = 14.1, 9.4 Hz, H-2a), 2.00 (dd, 1H,
J = 14.5, 6.8 Hz, H-5b), 2.25 (dd, 1H, J = 11.1, 6.8 Hz, H-4b); dC
15.7, 17.7, 19.3, 20.0, 20.9, 29.0, 29.3, 36.3, 52.2, 56.1. Anal. Calcd
for C10H20N2, MW 168.279: C, 71.37; H, 11.98; N, 16.65. Found:
C, 71.25; H, 12.15; N, 16.63.
5.2.4. Synthesis of (1S,3R,4S,6R)-3,4-aza-3,7,7-trimethylbicyclo-
[4.1.0]-heptane 5
The azido-alcohol 4 (0.576 g, 2.95 mmol) and triphenylphos-
phine (0.928 g, 3.54 mmol) were dissolved in dioxane (4 mL). The
mixture was heated at reflux for 24 h. The reaction was followed
by GC. The solvent was removed in vacuo and the resulting crude
was diluted with DCM. The solution was washed with citric acid
(0.744 g, 10% aqueous solution, 3.54 mmol) then the organic layer
was washed with Na2CO3 (0.450 g, 10% aqueous solution,
4.25 mmol), dried over Na2SO4, and concentrated under reduced
5.2.7. Synthesis of (1S,3R,4R,6R)-4-iodo-3,7,7-trimethyl-
bicyclo[4.1.0]heptan-3-ol 9
(+)-3-Carene 1 (2.22 g, 90% pure, 14.68 mmol) and NaI (2.20 g,
14.68 mmol) were dissolved in THF/H2O (50 mL, 7:3). The mixture
was cooled in an ice-water bath and stirred; H2SO4 (8.64 g,
88.08 mmol) was then added dropwise. After complete addition
H2O2 was added dropwise (3.88 mL, 35% aqueous solution,
44.04 mmol). An exothermic reaction and development of a dark
red color in the reaction mixture were observed. After complete
addition, stirring was continued at room temperature until the
solution turned colorless (about 12 h). The progress of the reaction
pressure to give
5 as a colorless oil (0.428 g, Y = 96%);
½
a 2D0
ꢁ
¼ þ42:7 (c 0.31, CHCl3); mmax (liquid film): 3264, 1460, 1368,
1301, 821 cmꢂ1; NMR (CDCl3): dH 0.54–0.66 (m, 3H), 0.73 (dd,
1H, J = 14.8, 7.2 Hz), 0.80 (s, 3H), 0.87 (br s, 1H), 0.94 (s, 3H), 1.27
(s, 3H), 1.90 (dd, 1H, J = 7.6, 4.8 Hz, H-4a), 1.97 (dd, 1H, J = 15.2,
5.2 Hz), 2.25 (m, 1H); dC 14.9, 20.0, 21.1, 21.3, 21.9, 26.7, 27.2,
28.7, 35.8, 38.2. Anal. Calcd for C10H17N, MW 151.249: C, 79.41;
H, 11.33; N, 9.26. Found: C, 79.55; H, 11.18; N, 9.15.

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 603–608
607
was followed by GC. THF was then removed under vacuo. The
5.2.10. Synthesis of (1S,3S,4R,6R)-3,4-aza-3,7,7-trimethyl-
bicyclo-[4.1.0]heptane 13
resulting mixture was treated with Na2S2O3 (4.58 g, 5% aqueous
solution, 29 mmol) and extracted with DCM. The organic layer
was washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The crude was purified by silica gel column chro-
matography with cyclohexane/AcOEt (97:3) to give a brown oil
(3.39 g, 12.11 mmol, Y = 82%). Obtained spectroscopic data are con-
firmed by the literature.36
From azido-alcohol 11: a solution of 11 (0.060 g, 0.31 mmol) in
dioxane (1 mL) was poured into a round bottomed flask equipped
with magnetic stirring and mixed at room temperature with tri-
phenylphosphine (0.097 g, 0.37 mmol) for 24 h. The reaction was
followed by GC. The solvent was removed in vacuo and the result-
ing crude was diluted with DCM. The solution was washed with
citric acid (0.078 g, 10% aqueous solution, 0.37 mmol), then, the or-
ganic layer was washed with Na2CO3 (0.047 g, 10% aqueous solu-
tion, 0.45 mmol), dried over Na2SO4 and concentrated under
reduced pressure to give 13 as a colorless oil (0.047 g, Y = 79%).
From azido-alcohol 12: a solution of 12 (0.127 g, 0.65 mmol) in
dioxane (2 mL) was stirred and heated at reflux with triphenyl-
phosphine (0.205 g, 0.78 mmol) for 36 h. The reaction was followed
by GC. The solvent was removed in vacuo and the resulting crude
was diluted with DCM. The solution was washed with citric acid
(0.164 g, 10% aqueous solution, 0.78 mmol), then, the organic layer
was washed with Na2CO3 (0.099 g, 10% aqueous solution,
0.94 mmol), dried over Na2SO4 and concentrated under reduced
pressure to give 13 as colorless oil (0.063 mg, Y = 64%):
5.2.8. Synthesis of (1S,3R,4S,6R)-3,4-epoxy-3,7,7-trimethyl-
bicyclo-[4.1.0]heptane 10
A solution of 9 (1.581 g, 5.6 mmol) in THF/Et2O (25 mL, 1:1)
anhydrous under an N2 atmosphere was stirred at room tempera-
ture. The solution was treated with NaH (0.176 g, 7.3 mmol). The
progress of the reaction was followed by GC. After 5.5 h the reac-
tion was complete. The excess NaH was destroyed with cold water
added dropwise. The mixture was extracted with DCM and washed
with brine. The organic layer was dried with Na2SO4 and concen-
trated under reduced pressure. The reaction mixture was purified
over column chromatography with cyclohexane/AcOEt (97:3) to
give 10 as a colorless oil (0.714 g, 4.7 mmol, Y = 84%). Spectral data
obtained are confirmed by the literature. 1H NMR (CDCl3): dH 0.51
(td, 1H, J = 8.1, 2.1 Hz), 0.55 (td, 1H, J = 7.7, 2.1 Hz), 0.91 (s, 3H),
0.95 (s, 3H), 1.29 (s, 3H), 1.76 (d, 1H, J = 16.6 Hz), 1.77 (d, 1H,
J = 15.7 Hz), 2.05 (dd, 1H, J = 16.6, 9.0 Hz, H-2), 2.26 (ddd, 1H,
J = 15.7, 9.0, 5.5 Hz, H-5); 2.86 (d, 1H, J = 5.5 Hz, H-4).
½
a 2D0
ꢁ
¼ þ21:0 (c 0.40, CHCl3); mmax (liquid film): 3256, 1306, 1270,
1205, 1164, 1136, 1074, 920, 825 cmꢂ1; NMR (CDCl3): dH 0.31 (td,
1H, J = 9.0, 3.4 Hz, H-6), 0.42 (td, 1H, J = 9.0, 3.8 Hz, H-1), 0.71 (s,
3H), 0.98 (s, 3H), 1.10 (s, 3H), 1.24 (br s, 1H), 1.31 (dd, 1H,
J = 15.4, 3.4 Hz, H-2b), 1.52 (dt, 1H, J = 15.8, 3.0 Hz, H-5b), 1.70 (t,
1H, J = 2.6 Hz, H-4b), 1.99 (dd, 1H, J = 15.4, 9.4 Hz, H-2a), 2.13
(ddd, 1H, J = 15.8, 9.4, 2.1 Hz, H-5a); dC 13.0, 14.9, 15.7, 16.5, 18.2,
23.3, 25.0, 28.0, 36.7, 72.8. Anal. Calcd for C10H17N, MW 151.249:
C, 79.41; H, 11.33; N, 9.26. Found: C, 79.25; H, 11.46; N, 9.37.
5.2.9. Synthesis of (1S,3R,4R,6R)-4-azido-3,7,7-trimethyl-
bicyclo[4.1.0]heptan-3-ol 11 and (1R,3S,4S,6S)-4-azido-4,7,7-
trimethylbicyclo[4.1.0]heptan-3-ol 12
A solution of b-carene oxide 10 (0.300 g, 1.97 mmol) in meth-
anol was mixed with NaN3 (0.275 g, 3.95 mmol) and NH4Cl
(0.105 g, 1.97 mmol). The resulting mixture was heated at reflux
for 14 h. The reaction was monitored by GC. The mixture was al-
lowed to cool to room temperature, and the solvent was removed
in vacuo. The resulting mixture was diluted with DCM and fil-
tered on Na2SO4. The azido-alcohols 11 and 12 were separated
by silica gel column chromatography with cyclohexane/AcOEt
(95:5) to give 11 (0.142 g, Y = 36%) and 12 (0.141 g, Y = 36%) as
yellow oils. Obtained spectroscopic data are confirmed by the
literature.30
5.2.11. Synthesis of (1R,3R,4R,6S)-4-azido-4,7,7-trimethyl-
bicyclo[4.1.0]heptan-3-amine 14 and (1S,3S,4S,6R)-4-azido-
3,7,7-trimethylbicyclo[4.1.0]heptan-3-amine 15
To a solution of aziridine 13 (0.329 g, 2.18 mmol) in CH3CN/H2O
5:1 (4.4 mL) was added NaN3 (0.170 g, 2.61 mmol) and CeCl3ꢀ7H2O
(0.406 g, 1.09 mmol) and heated at reflux for 45 min. The reaction
was monitored by GC. After cooling, the reaction mixture was con-
centrated in vacuo to remove the solvent. The crude was diluted
with DCM and to the mixture resulting was added Na2SO4. The
solution was filtered on Na2SO4. The azido-amines 14 and 15 were
separated on column chromatography (cyclohexane/AcOEt 10:90)
to obtain 0.131 g of 14 (Y = 31%) as a yellow oil and 0.284 g of 15
(Y = 67%) as a white solid.
5.2.9.1. (1S,3R,4R,6R)-4-Azido-3,7,7-trimethylbicyclo[4.1.0]hep-
tan-3-ol 11. Yellow oil, ½a D20
¼ ꢂ26:2 (c 0.20, CHCl3), mmax (liquid
ꢁ
film): 3430, 2104, 1255, 1117, 1007, 946 cmꢂ1; NMR (CDCl3): dH
0.66 (t, 1H, J = 8.5 Hz, H-6), 0.75 (td, 1H, J = 9.0, 5.1 Hz, H-1), 0.98
(s, 6H), 1.20 (s, 3H), 1.27 (ddd, 1H, J = 9.8, 4.7, 0.8 Hz, H-2b), 1.75
(ddd, 1H, J = 14.5, 11.1, 8.1 Hz, H-5a), 1.94 (br s, 1H), 1.98 (dd,
1H, J = 14.5, 9.8 Hz, H-2a), 2.14 (dd, 1H, J = 14.5, 7.3 Hz, H-5b),
3.21 (dd, 1H, J = 11.1, 7.3 Hz, H-4b); dC 15.9, 19.9, 20.0, 20.7, 25.6,
26.4, 28.8, 33.7, 67.4, 72.8. Anal. Calcd for C10H17N3O, MW
195.261: C, 61.51; H, 8.78; N, 21.52. Found: C, 61.37; H, 8.82; N,
21.68.
5.2.11.1.
(1R,3R,4R,6S)-4-Azido-4,7,7-trimethylbicyclo[4.1.0]-
heptan-3-amine 14. Yellow oil, ½a D20
¼ ꢂ74:2 (c 0.21, CHCl3), mmax
ꢁ
(liquid film): 3323, 2096, 1378, 1256, 1099, 805, 770 cmꢂ1; NMR
(CDCl3): dH 0.64 (t, 1H, J = 8.1 Hz, H-6), 0.72 (td, 1H, J = 9.8,
4.7 Hz, H-1), 0.95 (s, 3H), 0.98 (s, 3H), 1.18 (br s, 2H), 1.23 (s,
3H), 1.30 (dd, 1H, J = 14.1, 4.7 Hz, H-2b), 1.42 (ddd, 1H, J = 14.7,
11.5, 8.1 Hz, H-5a), 2.00 (dd, 1H, J = 14.7, 6.8 Hz, H-5b), 2.08 (dd,
1H, J = 14.1, 9.8 Hz, H-2a), 2.43 (dd, 1H, J = 11.5, 7.3 Hz, H-4b); dC
15.1, 15.7, 18.2, 19.2, 20.4, 28.0, 28.9, 31.8, 54.1, 65.7. Anal. Calcd
for C10H18N4, MW 194.277: C, 61.82; H, 9.34; N, 28.84. Found: C,
61.64; H, 9.25; N, 28.68.
5.2.9.2. (1R,3S,4S,6S)-4-Azido-4,7,7-trimethylbicyclo[4.1.0]hep-
tan-3-ol 12. Yellow oil, ½a D20
¼ þ93:4 (c 0.31, CHCl3), mmax (liquid
ꢁ
film): 3467, 2106, 1376, 1258, 1049, 824 cmꢂ1; NMR (CDCl3): dH
0.61 (td, 1H, J = 9.4, 3.0 Hz, H-6), 0.72 (td, 1H, J = 9.4, 6.0 Hz, H-1),
1.02 (s, 3H), 1.04 (s, 3H), 1.27 (s, 3H), 1.36 (dd, 1H, J = 15.4,
6.4 Hz, H-2b), 1.42 (dt, 1H, J = 15.8, 3.0 Hz, H-5a), 1.47 (br s, 1H),
1.89 (ddd, 1H, J = 15.8, 9.0, 0.9 Hz, H-2a), 2.29 (ddd, 1H, J = 15.8,
9.0, 6.8 Hz, H-5b), 3.56 (dd, 1H, J = 6.8, 3.0 Hz, H-4a); dC 15.2,
18.1, 18.4, 18.7, 22.8, 26.4, 26.5, 28.9, 63.5, 70.3. Anal. Calcd for
5.2.11.2. (1S,3S,4S,6R)-4-Azido-3,7,7-trimethylbicyclo[4.1.0]hep-
tan-3-amine 15. Crystals mp 50–54 °C, ½a D20
¼ þ138:8 (c 0.27,
ꢁ
CHCl3), mmax (Nujol): 3388, 2098, 1607, 1269, 1008, 805,
773 cmꢂ1; NMR (CDCl3): dH 0.56 (td, 1H, J = 9.0, 2.1 Hz, H-6), 0.71
(td, 1H, J = 9.4, 6.4 Hz H-1), 1.01 (s, 3H), 1.03 (s, 3H), 1.08 (s, 3H),
1.18 (dd, 1H, J = 15.0, 6.0 Hz, H-2b), 1.34 (br s, 2H), 1.54 (ddd, 1H,
J = 15.0, 9.8, 1.3 Hz, H-2a), 1.66 (dt, 1H, J = 14.1, 2.1 Hz, H-5a),
2.36 (ddd, 1H, J = 16.2, 9.0, 7.7 Hz, H-5b), 3.23 (dt, 1H, J = 7.7,
2.1 Hz, H-4a); dC 15.2, 17.1, 18.4, 18.5, 22.3, 27.4, 28.9, 29.1, 50.6,
C10H17N3O, MW 195.261: C, 61.51; H, 8.78; N, 21.52. Found: C,
61.42; H, 8.55; N, 21.70.

608
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 603–608
66.0. Anal. Calcd for C10H18N4, MW 194.277: C, 61.82; H, 9.34; N,
28.84. Found: C, 61.95; H, 9.28; N, 28.77.
References
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bicyclo[4.1.0]heptane-3,4-diamine 8
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The azido-amine 14 (0.129 g, 0.66 mmol) was dissolved in
anhydrous MTBE (1 mL) and stirred at 0 °C in an ice-water bath.
The solution was treated with LiAlH4 (0.033 g, 0.86 mmol). The
reaction was stirred for 20 min until room temperature was
reached. The reaction was monitored by GC. The excess of LiAlH4
was eliminated with H2O saturated with Na2SO4. The mixture
was treated with Na2SO4, filtered, washed with DCM, and evapo-
rated under reduced pressure to give the diamine 8 (0.093 g,
Y = 85%) as a colorless oil: ½a D20
ꢁ
¼ ꢂ12:3 (c 0.29, CHCl3);
mmax (liquid
film): 3281,1586, 1376, 1146, 810 cmꢂ1; NMR (CDCl3): dH 0.63 (t,
1H, J = 9.0 Hz, H-6), 0.68 (td, 1H, J = 9.4, 4.7 Hz, H-1), 0.94 (s, 3H,
Me), 0.96 (s, 3H, Me), 1.00 (s, 3H, Me), 1.07 (dd, 1H, J = 14.5,
4.7 Hz, H-2b), 1.27 (br s, 4H, 2 NH2), 1.40 (ddd, 1H, J = 14.5, 11.1,
7.7 Hz, H-5a), 1.86 (dd, 1H, J = 14.1, 9.4 Hz, H-2a), 2.00 (dd, 1H,
J = 14.5, 6.8 Hz, H-5b), 2.25 (dd, 1H, J = 11.1, 6.8 Hz, H-4b); dC
15.7, 17.7, 19.3, 20.0, 20.9, 29.0, 29.3, 36.3, 52.2, 56.1. Anal. Calcd
for C10H20N2, MW 168.279: C, 71.37; H, 11.98; N, 16.65. Found:
C, 71.25; H, 12.15; N, 16.63.
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5.2.13. Synthesis of (1S,3S,4S,6R)-3,7,7-trimethyl-
bicyclo[4.1.0]heptane-3,4-diamine 16
The azido-amine 15 (0.239 g, 1.23 mmol) was dissolved in
anhydrous MTBE (2 mL) and stirred at 0 °C in an ice-water bath.
The solution was treated with LiAlH4 (97 mg, 1.60 mmol). The
reaction was stirred for 70 min until room temperature was
reached. The reaction was monitored by GC. The excess of LiAlH4
was eliminated with H2O. The mixture was treated with Na2SO4,
filtered, washed with DCM, and evaporated under vacuo to give
the diamine 16 (0.187 g, Y = 91%) as a colorless oil; ½a D20
¼ þ33:3
ꢁ
(c 0.47, CHCl3), mmax (liquid film): 3282, 1651, 1574, 1558,
1152 cmꢂ1; NMR (CDCl3): dH 0.60 (td, 1H, J = 8.5, 4.7 Hz, H-1),
0.67 (td, 1H, J = 9.4, 6.8 Hz, H-6), 1.00 (ddd, 1H, J = 15.4, 10.2,
5.6 Hz, H-5a), 0.99 (s, 3H), 1.00 (s, 3H), 1.04 (s, 3H), 1.27 (dd, 1H,
J = 15.0, 6.4 Hz, H-2b), 1.41 (br s, 4H), 1.54 (dd, 1H, J = 15.0,
8.6 Hz, H-2a), 2.14 (ddd, 1H, J = 15.4, 8.6, 6.8 Hz, H-5b), 2.67
(ddd, 1H, J = 6.8, 6.0, 0.9 Hz, H-4a); dC 15.7, 18.1, 18.8, 19.6, 26.4,
26.7, 28.9, 30.6, 51.5, 55.8. Anal. Calcd for
C10H20N2, MW
168.279: C, 71.37; H, 11.98; N, 16.65. Found: C, 71.46; H, 12.08;
N, 16.72.
Acknowledgments
The financial support of this research by a grant from University
of Camerino and from MIUR-PRIN is gratefully acknowledged.