Synthesis of spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amines via stereoselective cycloadditions of trimethylenemethane to (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones

Article abstract of DOI:10.1016/j.tetasy.2007.09.018

Stereoselective [3+2] cycloadditions of trimethylenemethane (TMM) to the exocyclic C{double bond, long}O and C{double bond, long}N double bonds of (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones gave the corresponding spiro[bicyclo[2.2.

Full text of DOI:10.1016/j.tetasy.2007.09.018

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2365–2376
Synthesis of spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-amines via
stereoselective cycloadditions of trimethylenemethane to
(1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones
*
ˇ
ˇ
Uros Groselj, Anton Meden, Branko Stanovnik and Jurij Svete
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia
Received 24 August 2007; accepted 14 September 2007
Available online 10 October 2007
Abstract—Stereoselective [3+2] cycloadditions of trimethylenemethane (TMM) to the exocyclic C@O and C@N double bonds of
(1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones gave the corresponding spiro[bicyclo[2.2.1]heptane-2,20-furan] and
spiro[bicyclo[2.2.1]heptane-3,20-pyrrolidine] derivatives. Further stereoselective reductions of the C@N or C@O bond in these cyclo-
adducts furnished new chiral amines, diamines, and a new aminoalcohol. All cycloadditions and reductions of the C@N double bonds
took place from the less hindered endo-face of the (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones, exclusively, thus
giving the corresponding products in 100% de. The structures were determined by NMR, NOESY spectroscopy, and by X-ray
diffraction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
NMe2
OH
Camphor and its derivatives belong among the most fre-
quently employed types of chiral pool starting materials,
building blocks, resolving agents, shift reagents in NMR
spectroscopy, and ligands in various asymmetric reagents
and/or catalysts.1–4 For example, Noyori’s (ꢀ)-3-exo-di-
methylaminoisoborneol [(ꢀ)-DAIB]5 and its morpholino-
modified analogue6 are highly enantioselective ligands for
the dialkylzinc addition to aldehydes. Similarly, (1R,2R)-
N,N0-bis{[(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]-
heptan-1-yl]methylsulfonyl}cyclohexane-1,2-diamine was
used in the asymmetric addition of diphenylzinc to
ketones,7 whereas various camphor based P,N-ligands8,9
and P,P-ligands10 were used in asymmetric hydrogenations
(Fig. 1).
OH
(-)-DAIB
Ref. 5
Ref. 6
O
S
O
S
O
NH NH
Ref. 7
O
OH
HO
PR2
N
PR2
R1
R2
S
Recently, a series of 3-(dimethylamino)prop-2-enoates and
related enaminones have been prepared as versatile
reagents in the synthesis of heterocyclic systems, including
functionalized heterocycles and natural product ana-
logues.11–22 Within this context, (+)-camphor derived
enaminones were used in the stereoselective synthesis of
R'2P
Ref. 10
Refs. 8, 9
Figure 1. Some examples of (+)-camphor derived chiral ligands.
3-([1,2,4]triazolo[4,3-x]azin-3-yl)-(+)-camphors and their
analogues;23–25 the synthesis of terpene functionalized
pyrazoles;26 coupling reactions with amines27 and
*
Corresponding author. Tel.: +386 1 2419 100; fax: +386 1 2419 220;
e-mail: jurij.svete@fkkt.uni-lj.si
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.018

2366
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
Grignard reagents,28 in the preparation and reductions of
(1R,4E,5S)-4-oximino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]-
octan-3-one;29 in 1,3-dipolar cycloaddition reactions of
a-alkylidene-(+)-camphors and analogues30 and (+)-cam-
phor derived pyrazolidin-3-ones;31 and in the preparation
of b-campholenolactone derivatives.32 In continuation of
this work, we herein report the acid-catalyzed transforma-
tions of (1S)-(+)-camphorquinone 1 with anilines 2a–e into
3-iminocamphor derivatives 3a–e, stereoselective 1,3-di-
polar cycloadditions of trimethylenemethane 4 to dipolaro-
philes 3a–e, and further reductions of the so formed spiro
cycloadducts 5 and 6 into novel non-racemic amines 8a,b;
diamines 8c,d, 9d, 10d; and aminoalcohol 11d.
3''
3'
4'
2
1
1
2
O
6
O
O
O
5'
2'
6
5
i
ii
7
7
4'
O1'
and
3'
3
3''
5'
5
3
N
Ar
N
4
4
N
2'
1'
Ar
1
Ar
5a-e
6c,d
3a-e/3'a-e
major product
minor product
ii
5a
7
iii
(R = Ph)
TMM =
O
and
O
O
O
7'
7
2. Results and discussion
Scheme 1. Reagents and conditions: (i) R–NH2, 2a–e (1 equiv), p-TsOH,
toluene, reflux; (ii) [2-(acetoxymethyl)allyl]-trimethylsilane 4 (1.4 equiv),
Pd(OAc)2, (i-PrO)3P, toluene, reflux; (iii) HCl, MeOH, H2O, 0 ꢁC!rt.
The starting compounds, (1S,3EZ,4R)-3-arylimino-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ones 3a–e/30a–e, were pre-
pared as mixtures of the major (3E)-isomers 3a–e and the
minor (3Z)-isomers 30a–e by condensation of (1S)-(+)-
camphorquinone 1 with anilines 2a–e in the presence of
catalytic amounts of p-toluenesulfonic acid according to
a slightly modified literature procedure.33 Carbocyclic
1,3-dipolar cycloadditions of trimethylenemethane
(TMM), formed in situ from the [2-(acetoxymethyl)allyl]-
trimethylsilane 4, Pd(OAc)2, and (i-PrO)3P,34,35 to 3-imino-
camphors 3a–e/30a–e were endo-selective and proceeded
predominantly at the C@O double bond giving the corre-
sponding spiro[bicyclo[2.2.1]heptane-2,20-furans] 5a–e as
the major products and spiro[bicyclo[2.2.1]heptane-3,20-
pyrrolidines] 6d,e as the minor products. Cycloadditions
to imines 3a–c/30a–c gave spirofurans 5a–c as the only
products, whilst the reactions of TMM with 3d,e/30d,e gave
mixtures of the major spirofurans 5d,e and the minor spiro-
pyrrolidines 6d,e. Further chromatographic separation of a
mixture of 5d and 6d furnished pure compounds 5d and 6d,
whilst a mixture of compounds 5e and 6e could not be sep-
arated, either by crystallization, or by using chromato-
graphic techniques. Chemoselectivity depended on the
electronic and steric properties of the aryl group. The elec-
tron-rich phenylimines 3a/30a and naphthylimines 3b/30b
and the electron-deficient ortho-nitrophenylimines 3c/30c
reacted at the C@O group exclusively, while electron-defi-
cient para- and meta-nitrophenylimines 3d/30d and 3e/30e
also reacted at the C@N double bond. The position of
the electron withdrawing nitro group markedly influenced
the chemoselectivity of the additions, ranging from
5d:6d = 56:44 (para) to 5e:6e = 86:14 (meta) and 5c:6c
100:0 (ortho). The formation of 5c as the sole product could
be rationalized by the steric hindrance imposed by the
ortho-nitro group in imines 3c/30c, which efficiently disables
the addition to the C@N double bond. Finally, cycloaddi-
tion of TMM to (1S)-(+)-camphorquinone 1 was carried
out. It proceeded endo-selectively, yet without any regiose-
lectivity, giving products 7 and 70 in a ratio of 1:1. The for-
mation of 7 was additionally confirmed by acid-catalyzed
hydrolysis of imine 5a (Scheme 1, Table 1).
be the reagent of choice for this purpose. Thus, the reduc-
tion of imines 5a and 5b gave the corresponding secondary
amines 8a and 8b in 77% and 94% yield, respectively.
Similarly, treatment of 2-nitrophenylimine 5c with excess
LiAlH4 yielded the corresponding diamine 8c in 63% yield.
On the other hand, the reduction of 4-nitrophenylimine 5d
afforded a mixture of diamine 8d, azo compound 9d, and
azoxy compound 10d in a ratio of 77:17:6, respectively.
Subsequent chromatographic separation afforded prod-
ucts 8d, 9d, and 10d in 51%, 3%, and 5% yield, respec-
tively. Reduction of spiropyrrolidine 6d with LiAlH4
gave an inseparable mixture of products. However, sequen-
tial reduction of 6d with Na2S2O4 and LiAlH4 followed by
chromatographic workup gave aminoalcohols 11d and 110d
in a ratio of 88:12 and in 20% yield (Scheme 2, Table 1).
The transformation of camphor at the 3-position often
afforded initial kinetically controlled exo-products as a
result of the attack of a reagent from the less hindered
endo-face of the bicyclic system. Epimerization of the
exo-isomers can afford thermodynamically more stable
endo-products, which are sterically less hindered.1–4,36–40
Accordingly, [3+2] cycloadditions of TMM (cf. Scheme 1)
as well as LiAlH4 reductions of the C@N and C@O bonds
(cf. Scheme 2) proceeded from the less hindered endo-face
of substrates to afford the corresponding exo-products.
Epimerization at the newly formed stereogenic center did
not take place, since cycloadducts 5–7 are not epimerizable
because of the low acidity of the a-position in amines 8–10
and alcohol 11d. The endo-stereocontrol in (cyclo)addition
reactions at the C@N and C@O bonds in compounds 1, 3,
5, and 6 was also in agreement with that reported for 1,3-
dipolar cycloadditions of benzonitrile oxides to a-alkylid-
ene-(+)-camphor derivatives (Fig. 2).30
3. Structure determination
Next, reductions of spirofurans 5 and spiropyrrolidines 6
were studied in order to prepare new chiral non-racemic
amines, diamines, and amino alcohols. LiAlH4 proved to
The structures of compounds 3a–e/30a–e, 5a–e, 6d,e, 7, 70,
8a–d, 9d, 10d, and 11d/110d were determined by spectro-

U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
2367
Table 1. Selected experimental data for compounds 3a–e/30a–e, 5a–e, 6d,e, 7/70, 8a–d, and 9d–11d
Reaction
Ar
Ratio of isomersa
Yieldb (%)
1+2a!3a/30a
1+2b!3b/30b
1+2c!3c/30c
1+2d!3d/30d
1+2e!3e/30e
3a+4!5a
Phenyl
96:4c
66 (3a:30a = 96:4)c
1-Naphthyl
2-Nitrophenyl
4-Nitrophenyl
3-Nitrophenyl
Phenyl
1-Naphthyl
2-Nitrophenyl
4-Nitrophenyl
3-Nitrophenyl
—
—
Phenyl
1-Naphthyl
2-Aminophenyld
4-Aminophenyld
4-Aminophenyld
97:3c
19 (3b:30b = 97:3)c
75:25c
45 (3c:30c = 75:25)c
90:10c
54 (3d:30d = 90:10)c
89:11c
64 (3e:30e = 89:11)c
100:0
100:0
100:0
5d:6d = 56:44
5e:6e = 87:13
7:70 = 1:1
7:70 = 100:0
100:0
100:0
100:0
8d:9d:10d = 77:17:6
11d:110d = 86:14
91
35
77
3b+4!5b
3c+4!5c
3d+4!5d+6d
3e+4!5e+6e
1+4!7/70
5a!7
43 (5d), 34 (6d)
58 (5e:6e = 86:14)e
95 (7:70 = 1:1)
61
77
94
63
5a!8a
5b!8b
5c!8c
5d!8d/9d/10d
51 (8d), 3 (9d), 5 (10d)
20 (11d:110d = 88:12)e
6d!11d/110d
a Determined by 1H NMR of the crude reaction mixture or after FC (unless otherwise stated).
b Isolated yield of the isomerically pure compound (unless otherwise stated).
c After crystallization from EtOH.
d Obtained by concomitant reduction of the nitro group.
e After purification by column chromatography.
scopic methods (IR, H and 13C NMR, NOESY spectro-
scopy, MS) and by elemental analyses for C, H, and N.
Compounds 5a–d, 6d, 7, 8a–d, 9d, and 10d were prepared
in isomerically pure form. Compounds 5e/6e and 11d/
110d were isolated and characterized as mixtures of the
major isomers 5e and 11d and the minor isomers 6e and
110d, respectively. Similarly, compounds 3a–e/30a–e were
isolated and characterized as mixtures of the major isomers
3a–e and the minor isomers 30a–e, respectively. Compound
70 could not be separated from a mixture of isomeric prod-
ucts 7 and 70 and was characterized by 1H NMR, 13C
NMR and by EI-HRMS as a 1:1 mixture of isomeric com-
pounds 7 and 70. Compounds 5a–c,e, 6e, 7/70, 8a–c,d, 9d,
and 11d were not prepared in analytically pure forms; their
identities were confirmed by 13C NMR and EI-HRMS.
8a–d, 9d, and 10d are close to 90ꢁ and, following the
Karplus equation,43 no appreciable coupling between these
protons would be expected. Accordingly, negligible
1
3
coupling constants, JH(3)–H(4) ꢁ 0 Hz, were observed in
1H NMR spectra of the secondary exo-amines 8a–d, 9d,
and 10d. Finally, the configuration of compounds 5a–e,
6d,e, 7, 70, 8a–d, 9d, and 10d was confirmed by correlation
of the chemical shifts and vicinal coupling constants, 3JH–H
(Fig. 3, Table 2).
The (E)-configuration around the exocyclic C@N double
bond in compounds 3d and 3e was determined by X-ray
diffraction (Figs. 4 and 5). On the basis of these results
and because the (E)-configuration imposes a lesser steric
strain than the (Z)-configuration around the exocyclic
C@N double bond, it seems reasonable to assume the
(E)-configuration in imines 3a–e and 5a–e.
The configurations of compounds 6d, 8a–c, and 8d–11d
were determined by NOESY spectroscopy. In spiropyrrol-
idine 6d, the NOE between the ortho-protons of the
4-nitrophenyl group and the bridge methyl group supports
the (1S,3S,4R)-configuration. Next, the NOE between
H–C(2) and Ha–C(40) and the NOE between the hydroxy
group and the bridge methyl group in compound 11d sug-
gest an exo-orientation at the C(2) and C(3) positions, that
is, the (1R,2S,3R,4S)-configuration. Similarly, the (S)-con-
figuration at the 3-position in secondary amines 8a–d, 9d,
and 10d was confirmed by NOE between H–C(3) and
Ha–C(40). Additionally, the NOE between H–N group
and the bridge methyl group reconfirmed the (S)-configura-
tion at the 3-position in secondary amines 8a–c and 9d
(Fig. 3).
4. Conclusion
[3+2] Cycloadditions of trimethylenemethane (TMM) 4 to
the exocyclic C@N and C@O double bonds of 3-iminocam-
phors 3a–e/30a–e took place preferentially at the C@O
double bond to give the corresponding spirofurans 5a–e
as the major products. In the case of imino camphors
3d,e/30d,e, the reaction also took place at the C@N double
bond to give the spiropyrrolidines 6d,e as the minor prod-
ucts. A lower reactivity of the C@N bond was not surpris-
ing, since it is sterically shielded by the aryl group, whilst
the C@O double bond is not. Electron-rich imines 3a,b/
30a,b and sterically hindered electron poor ortho-nitrophen-
ylimine 3c/30c gave the corresponding furan derivatives
5a–c, exclusively, whereas the less-hindered electron poor
para-nitrophenylimine 3d/30d and m-nitrophenylimine 3e/
30e furnished mixtures of spirofurans and spiropyrroli-
dines 5d/6d and 5e/6e, respectively. To our surprise, the
The configuration at the 3-position in secondary amines
8a–d, 9d, and 10d was determined by 1H NMR on the basis
of vicinal coupling constants (3JH(3)–H(4)) and multiplicities
for proton H–C(3).23–25,29–31,41,42 The dihedral angles
between H–C(3) and H–C(4) in the secondary exo-amines

2368
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
i, ii
i, ii
O
NHAr
O
NH
O
N
O
N
NH2
Ar
NO2
8a,b
5a,b
8c
5c
i, ii
O
NH
O
N
O
NH
O
NH
and
and
N
NO2
NH2
N
O
N
N
5d
8d
HN
O
HN
O
9d
10d
O
O
OH
OH
iii, ii
i, ii
and
N
N
N
N
H2N
O2N
H2N
H2N
11d
11'd
6d
6'd
minor isomer
major isomer
Scheme 2. Reagents and conditions: (i) LiAlH4, Et2O/THF, 55 ꢁC; (ii) chromatographic purification; (iii) Na2S2O4, K2CO3, EtOH/H2O, reflux.
hindered
O
X
exo-adducts
6 (X = NAr)
7' (X = O)
O
exo-adducts
5 (X = NAr)
7 (X = O)
O
X
1, 3
X
less hindered
endo-addition
TMM
hindered
hindered
O
O
OH
O
Ar
N
Ar
N
NHAr
NAr
6d
H
5
H
exo-adducts
less hindered
8-10
less hindered
endo-addition
endo-addition
exo-adduct
11d
LiAlH4
LiAlH4
Figure 2. Stereoselectivity of [3+2] cycloadditions of trimethylenemethane (TMM) 4 and reductions with LiAlH4 to/of exocyclic C@N and C@O double
bonds.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
2369
OH
n.O.e.
Ha
Hb
n.O.e.
O
H
NO2
H
OH
Me
1
n.O.e.
6
5
2
4'
5'
Me
N
3
3''
N
4
3'
N
1'
2'
H2N
H2N
6d
11d
11d
(1S,3S,4R)-isomer
(1R,2S,3R,4S)-isomer
(1R,2S,3R,4S)-isomer
2'
1'
3'
3''
O
O
O
1
Hb
Ha
4'
5'
6
2
3
Me
5
NHR
3
n.O.e.
4
H
4
NH
R
H
H
n.O.e.
RHN
3JH(3)-H(4) ~ 0 Hz
8a-d, 9d, 10d
(1S,2R,3S,4R)-isomers
8a-c, 9d
8a-d, 9d, 10d
(1S,2R,3S,4R)-isomers
(1S,2R,3S,4R)-isomers
Figure 3. Structure determination by 1H NMR and NOESY spectroscopy.
1
Table 2. Selected H NMR data for the prepared compounds 5a–e, 6d,e, 7, 70, 8a–d, 9d, 10d, and 11da
Compound
d (ppm)
40-CH2
3JH–H (Hz)
3-H
4-H
2.38
2.32
2.27
2.26
2.31
2.49
2.20
2.18
20-CH2
300-CH2
NH
3-4
4–5
HC(3)–NH
5a
5b
4.47/4.87
4.58/5.03
4.46/4.73
4.48/4.79
4.49/4.83
3.69/4.77
3.55/4.74
2.65/2.78
2.79/2.88
2.79/2.79
2.62/2.80
2.64/2.81
2.54/2.87
2.55/2.92
2.41/2.65
2.50/2.70
2.49/2.81
2.60/2.91
2.51/2.83
2.46/2.79
2.44/2.91
2.43/2.91
4.92/5.02
4.95/5.09
4.88/5.02
4.93/5.03
4.94/5.04
5.01/5.11
5.02/5.15
4.9
4.5
4.1
4.9
4.9
4.5
4.5
5.3
5c
5d
5e
6dd
6e
7
70
4.44/4.67
b
4.93/5.02
b
2.01
4.1
8ac,d
8bc,d
8cc,d
8dc,d
9dd
10dd
3.09
3.33
3.10
3.00
3.20
3.17/3.20
ꢁ1.7b
4.40/4.40
ꢁ4.50b
4.80/4.93
4.81/4.95
4.80/4.94
4.79/4.92
4.82/4.95
4.82/4.95
4.78
5.33
4.21
4.00
4.74
4.76/4.81
0
0
0
0
0
0
7.2
b
1.86
4.5
6.0
6.8
6.6
b
ꢁ1.7b
ꢁ1.6b
1.90
4.40/4.53
4.38/4.38
4.37/4.49
4.36/4.49
b
4.9
5.1
6.6
6.9/7.0
1.88
2-H
4-H
20-CH2
40-CH2
300-CH2
OH
4–5
CH–OH
11dc,d
110dc
2.85
b
1.77
1.65
3.41/3.91
b
2.36/3.02
b
4.88/5.03
4.80/4.94
4.31
4.60
3.9
4.2
4.9
6.1
a Unless otherwise stated, the spectra were taken in CDCl3.
b Overlapped by other signals or the position of the desired signal could not be unambiguously determined.
c The spectrum was taken in DMSO-d6.
d Determined by NOESY spectroscopy.
stereoselectivity of cycloadditions was very high—the
approach of trimethylenemethane 4 took place exclusively
from the less hindered endo-face of the dipolarophile 3 to
furnish cycloadducts 5 and 6 as single diastereomers. Sim-
ilarly, reductions of imines 5a–d with LiAlH4 took place
from the less hindered endo-face of the bicyclic system,
exclusively, thus giving diastereomerically pure exo-amines
8a–d. In the reduction of para-nitrophenylimine 5d, azo
compound 9d and azoxy compound 10d were also formed
as by-products. Upon sequential reduction of spiropyrrol-
idine 6d with Na2S2O4/LiAlH4, b-amino alcohol 11d was
isolated in 76% de.
5. Experimental
5.1. General methods
Melting points were determined on a Kofler micro hot
1
stage. The H NMR spectra were obtained on a Bruker
1
Avance DPX 300 at 300 MHz for H and 75.5 MHz for
13C nucleus, using DMSO-d6 and CDCl3, with TMS as
the internal standard, as solvents. All NMR experiments
were carried out at 302 K except for compound 3c where
NMR experiments were carried out also at 358 K. Optical
rotations were measured on a Perkin–Elmer 241MC

2370
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
Figure 4. The asymmetric unit of compound 3d. Ellipsoids are plotted at
50% probability level. H atoms are drawn as circles of arbitrary radii.
Figure 5. The asymmetric unit of compound 3e. Ellipsoids are plotted at
50% probability level. H atoms are drawn as circles of arbitrary radii.
Polarimeter. Mass spectra were recorded on an AutoSpecQ
spectrometer, IR spectra on a Perkin–Elmer Spectrum BX
FTIR spectrophotometer. Microanalyses were performed
on a Perkin–Elmer CHN Analyser 2400. Column chromato-
graphy (CC) was performed on silica gel (Fluka, silica gel
60, 0.04–0.06 mm). Medium pressure liquid chromato-
camphorquinone
1 (3 mmol, 499 mg), anilines 2a–e
(3 mmol), 4-toluenesulfonic acid monohydrate (0.3 mmol,
58 mg), and anhydrous toluene (35 mL) was heated at
reflux for 6 h. A Dean–Stark water trap was used to
remove water during the reaction. The reaction mixture
was cooled to 5 ꢁC, poured into a cooled saturated aq
NaHCO3 (150 mL, 5 ꢁC) and the product extracted with
EtOAc (2 · 100 mL). The organic phases were combined,
dried over anhydrous Na2SO4, and filtered. The filtrate
was evaporated in vacuo, and the residue crystallized from
ethanol. Compounds 3a–e/30a–e were prepared in this
manner.
graphy (MPLC) was performed with a Buchi isocratic
¨
system with detection on silica gel (Merck, silica gel 40,
0.015–0.035 mm); column dimensions (dry filled): 15 ·
460 mm; backpressure: 10–15 bar; detection: UV 254 nm;
sample amount: 100–150 mg of isomeric mixture per run.
1
Ratio of isomers and de were determined by H NMR.
(1S)-(+)-Camphorquinone 1, anilines 2a–e, 4-toluenesul-
fonic acid monohydrate, [2-(acetoxymethyl)allyl]trimethyl-
silane (TMM) 4, Pd(OAc)2, (i-PrO)3P and LiAlH4 are
commercially available (Sigma–Aldrich).
5.2.1. (1S,3E,4R)-1,7,7-Trimethyl-3-(phenylimino)bicyclo-
[2.2.1]heptan-2-one 3a and its (1S,3Z,4R)-isomer
30a. Prepared from aniline 2a (280 mg, 3 mmol);
3a:30a = 96:4. Yield: 0.478 g (66%) of a yellow solid; mp
104–106 ꢁC (from ethanol at ꢀ20 ꢁC), lit.44 mp 107–
Source of chirality: (1S)-(+)-Camphorquinone 1, 99%,
20
(Fluka AG), product number 27,207-8, ½aꢂD ¼ þ100 (c
1.9, toluene), mp 200–202 ꢁC.
23
35
5.2. General procedure for the preparation of (1S,3E,4R)-3-
(arylimino)-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ones 3a–e
and their (1S,3Z,4R)-isomers 30a–e
108 ꢁC; ½aꢂD ¼ ꢀ652:1 (c 0.14, CHCl3), lit.44 ½aꢂ589
¼
ꢀ659:8 (c 0.50, CHCl3). m/z (EI) = 241 (M+); m/z
(HRMS) Found: 241.147350 (M+); C16H19NO requires:
m/z = 241.146664. (Found: C, 79.84; H, 8.13; N, 5.70.
C16H19NO requires: C, 79.63; H, 7.94; N, 5.80.) mmax
(KBr) 2955, 1744 (C@O), 1664, 1652, 1589, 1485, 1448,
1397, 1373, 1325, 1259, 1106, 1060, 1015, 969, 795, 779,
Compounds 3a–e/30a–e were prepared according to the
modified literature procedure.33 A mixture of (1S)-(+)-
Donation of Alexander von Humboldt Foundation.
699 cmꢀ1
.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
2371
5.2.1.1. Data for major (1S,3E,4R)-isomer 3a. 1H
NMR (CDCl3): d 0.92, 0.99, and 1.11 (9H, 3s, 1:1:1,
3 · Me); 1.59–1.73, (2H, m, CH2); 1.80–1.92 and 2.04–
2.16 (2H, 2m, 1:1, CH2); 2.82 (1H, d, J = 4.5 Hz,
H–C(4)); 6.90–6.94, 7.15–7.20, and 7.34–7.39 (5H, 3m,
2:1:2, Ph). 13C NMR (CDCl3): d 9.1, 17.6, 21.0, 24.5,
30.2, 44.6, 50.2, 58.2, 120.4, 125.3, 129.0, 149.7, 171.9,
206.4.
1:1:1:1, 2 · CH2); 2.68 (1H, d, J = 4.1 Hz, H–C(4)); 6.94
(1H, d, J = 7.9 Hz, 1H of C6H4); 7.33 (1H, t, J = 7.7 Hz,
1H of C6H4); 7.67 (1H, t, J = 7.5 Hz, 1H of C6H4); 8.03
(1H, d, J = 8.3 Hz, 1H of C6H4). 13C NMR (DMSO-d6,
358 K): d 8.1, 16.7, 20.0, 22.9, 29.1, 43.6, 51.4, 57.7,
120.3, 124.2, 124.3, 133.9, 139.1, 144.3.
5.2.3.2. Data for minor (1S,3Z,4R)-isomer 30c. 1H
NMR (DMSO-d6, 302 K): d 2.83 (1H, br s, H–C(4)).
5.2.1.2. Data for minor (1S,3Z,4R)-isomer 30a. 1H
NMR (CDCl3): d 0.96, 1.02, and 1.05 (9H, 3s, 1:1:1,
3 · Me); 2.75 (1H, d, J = 4.5 Hz, H–C(4)); 6.77–6.81 (1H,
m, 1H of Ph).
5.2.4. (1S,3E,4R)-1,7,7-Trimethyl-3-[(4-nitrophenyl)imino]-
bicyclo[2.2.1]heptan-2-one 3d and its (1R,3Z,4S)-isomer
30d. Prepared from 4-nitroaniline (2d) (415 mg, 3 mmol);
3d:30d = 90:10. Yield: 0.464 g (54%) of a yellow solid; mp
23
5.2.2. (1S,3E,4R)-1,7,7-Trimethyl-3-[(1-naphthyl)imino]-
bicyclo[2.2.1]heptan-2-one 3b and its (1S,3Z,4R)-isomer
128–130 ꢁC (from ethanol); ½aꢂD ¼ ꢀ358:2 (c 0.17, CHCl3).
m/z (EI) = 286 (M+); m/z (HRMS) Found: 286.132530
(M+); C16H18N2O3 requires: m/z = 286.131743. (Found:
C, 67.41; H, 6.47; N, 9.79. C16H18N2O3 requires: C,
67.12; H, 6.34; N, 9.78.) mmax (KBr) 2956, 1755 (C@O),
1692, 1587, 1512, 1482, 1342, 1262, 1221, 1198, 1166,
30b. Prepared from 1-naphthylamine 2b (430 mg,
3 mmol); 3b:30b = 97:3. Yield: 0.167 g (19%) of a yellow
23
solid; mp 146–148 ꢁC (from ethanol); ½aꢂD ¼ ꢀ620:8 (c
0.11, CHCl3). m/z (EI) = 291 (M+); m/z (HRMS) Found:
291.163130 (M+); C20H21NO requires: m/z = 291.162314.
(Found: C, 82.48; H, 7.40; N, 4.76. C20H21NO requires:
C, 82.44; H, 7.26; N, 4.81.) mmax (KBr) 2965, 1753
(C@O), 1669, 1585, 1571, 1505, 1448, 1389, 1373, 1323,
1265, 1226, 1166, 1077, 1059, 1046, 1013, 999, 966, 807,
1105, 1015, 869, 857 cmꢀ1
.
5.2.4.1. Data for major (1S,3E,4R)-isomer 3d. 1H
NMR (CDCl3): d 0.95, 1.01, and 1.13 (9H, 3s, 1:1:1,
3 · Me); 1.54–1.62, 1.66–1.75, 1.86–1.96, and 2.05–2.17
(4H, 4m, 1:1:1:1, 2 · CH2); 2.68 (1H, d, J = 4.9 Hz,
H–C(4)); 6.97 and 8.26 (4H, 2d, 1:1, J = 8.7 Hz, C6H4).
13C NMR (CDCl3): d 9.0, 17.4, 21.1, 24.4, 30.0, 44.5,
50.4, 58.3, 120.1, 125.1, 145.0, 155.8, 173.6, 205.3.
779 cmꢀ1
.
5.2.2.1. Data for major (1S,3E,4R)-isomer 3b. 1H
NMR (CDCl3): d 0.95, 0.96, and 1.15 (9H, 3s, 1:1:1,
3 · Me); 1.58–1.66, 1.69–1.78, 1.83–1.93, and 1.98–2.10
(4H, 4m, 1:1:1:1, 2 · CH2); 2.68 (1H, d, J = 4.9 Hz,
H–C(4)); 6.75 (1H, dd, J = 0.8; 7.2 Hz, 1H of Ar); 7.41–
7.54 (3H, m, 3H of Ar); 7.67 (1H, d, J = 8.3 Hz, 1H of
Ar); 7.83–7.88 (2H, m, 2H of Ar). 13C NMR (CDCl3): d
9.2, 17.6, 21.2, 24.7, 30.3, 44.5, 50.4, 58.5, 113.3, 123.8,
125.2, 125.6, 125.9, 126.6, 126.7, 127.9, 134.1, 146.7,
173.1, 206.1.
5.2.4.2. Data for minor (1S,3Z,4R)-isomer 30d. 1.08
(3H, s, Me); 2.78 (1H, br s, H–C(4)); 6.82 (1H, br d,
J = 8.0 Hz, 2H of Ar); 8.16 (1H, br d, J = 8.0 Hz, 2H of
Ar).
5.2.5. (1S,3E,4R)-1,7,7-Trimethyl-3-[(3-nitrophenyl)imino]-
bicyclo[2.2.1]heptan-2-one 3e and its (1S,3Z,4R)-isomer
30e. Prepared from 3-nitroaniline 2e (415 mg, 3 mmol);
5.2.2.2. Data for minor (1S,3Z,4R)-isomer 30b. 1H
NMR (CDCl3): d 2.94 (1H, d, J = 4.7 Hz, H–C(4)).
3e:30e = 89:11. Yield: 0.550 g (64%) of a yellow solid; mp
23
121–123 ꢁC (from ethanol); ½aꢂD ¼ ꢀ377:3 (c 0.11, CHCl3).
m/z (EI) = 286 (M+); m/z (HRMS) Found: 286.132520
(M+); C16H18N2O3 requires: m/z = 286.131743. (Found:
C, 67.41; H, 6.41; N, 9.78. C16H18N2O3 requires: C,
67.12; H, 6.34; N, 9.78.) mmax (KBr) 2960, 1754 (C@O),
1686, 1612, 1525, 1450, 1393, 1375, 1349, 1308, 1278,
5.2.3. (1S,3E,4R)-1,7,7-Trimethyl-3-[(2-nitrophenyl)imino]-
bicyclo[2.2.1]heptan-2-one 3c and its (1S,3Z,4R)-isomer
30c. Prepared from 2-nitroaniline 2c (415 mg, 3 mmol);
3c:30c = 75:25. Repeated crystallization from ethanol gave
isomerically pure compound 3c. Yield: 0.387 g (45%) of a
1202, 1016, 985, 804 cmꢀ1
.
23
yellow solid; mp 133–141 ꢁC (from ethanol); ½aꢂD ¼ ꢀ94:6
(c 0.11, CHCl3). m/z (EI) = 286 (M+); m/z (HRMS)
Found: 286.130950 (M+); C16H18N2O3 requires: m/z =
286.131743. (Found: C, 67.10; H, 6.37; N, 9.74.
C16H18N2O3 requires: C, 67.12; H, 6.34; N, 9.78.) mmax
(KBr) 2959, 1749 (C@O), 1678, 1605, 1575, 1533, 1476,
5.2.5.1. Data for major (1S,3E,4R)-isomer 3e. 1H
NMR (CDCl3): d 0.95, 1.02, and 1.14 (9H, 3s, 1:1:1,
3 · Me); 1.59–1.76 (2H, m, CH2); 1.87–1.96 and 2.08–
2.19 (2H, 2m, 1:1, CH2); 2.75 (1H, d, J = 4.9 Hz, H–
C(4)); 7.22–7.26 (1H, m, 1H of C6H4); 7.55 (1H, t,
J = 7.9 Hz, 1H of C6H4); 7.74 (1H, t, J = 1.9 Hz, 1H of
C6H4); 8.03–8.06 (1H, m, 1H of C6H4). 13C NMR (CDCl3):
d 9.1, 17.5, 21.2, 24.4, 30.1, 44.7, 50.3, 58.3, 115.0, 120.0,
126.5, 130.1, 148.9, 150.9, 174.1, 205.5.
1447, 1393, 1362, 1159, 1014, 970, 861, 779, 770 cmꢀ1
.
5.2.3.1. Data for major (1S,3E,4R)-isomer 3c. 1H
NMR (DMSO-d6, 302 K): d 0.91, 0.96, 1.00 (9H, 3br s,
1:1:1, 3 · Me); 1.47–1.77, 1.84–1.94, and 1.97–2.24 (4H,
3m, 2:1:1, 2 · CH2); 2.62 (1H, br s, H–C(4)); 6.89–7.08,
7.21–7.46, 7.56–7.82 (3H, 3m, 1:1:1, 3H of C6H4); 8.08
5.2.5.2. Data for minor (1S,3Z,4R)-isomer 30e. 0.97,
1.03, and 1.08 (9H, 3s, 1:1:1, 3 · Me); 2.79 (1H, d,
J = 4.6 Hz, H–C(4)); 7.05–7.09 (1H, m, 1H of Ar); 7.42
(1H, t, J = 8.1 Hz, 1H of Ar); 7.61 (1H, t, J = 2.1 Hz, 1H
of Ar); 7.91–7.98 (1H, m, 1H of Ar).
1
(1H, br d, J = 7.9 Hz, 1H of C6H4). H NMR (DMSO-
d6, 358 K): d 0.92, 0.97, 0.98 (9H, 3s, 1:1:1, 3 · Me);
1.50–1.59, 1.62–1.71, 1.84–1.93, and 2.04–2.14 (4H, 4m,

2372
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
5.3. General procedure for 1,3-dipolar cycloadditions of
trimethylenemethane to (1S)-(+)-camphorquinone 1 and
3-iminocamphors 3a–e/30a–e
5.3.3. 2-Nitro-N-{(1S,2R,3E,4R)-1,7,7-trimethyl-40-methyl-
enedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-
ylidene}aniline 5c. Prepared from compound 3c/30c
(286 mg, 1 mmol); CC (EtOAc–hexanes, 1:10); 0.262 g
23
1
(1S)-(+)-Camphorquinone 1 (1 mmol, 166 mg) or 3-imino-
camphors 3a–e/30a–e (1 mmol) and [2-(acetoxymethyl)-
allyl]trimethylsilane (TMM) 4 (1.4 mmol, 261 mg) were
dissolved in anhydrous toluene (3 mL) and heated under
argon at reflux. Then, a solution of Pd(OAc)2 (23 mg,
0.1 mmol) and (i-PrO)3P (0.139 mL, d240 ¼ 0:905 g=l,
0.6 mmol) in anhydrous THF (1 mL) was added and the
reaction mixture was heated at reflux for 3 h. Volatile com-
ponents were evaporated in vacuo and the residue was
purified by CC and/or MPLC. Fractions containing the
product were combined and evaporated in vacuo. Com-
pounds 5a–e, 6d,e, and 7/70 were prepared in this manner.
(77%) of a yellow oil; ½aꢂD ¼ þ133:9 (c 0.24, CHCl3). H
NMR (CDCl3): d 0.88, 0.96, and 1.21 (9H, 3s, 1:1:1,
3 · Me); 1.40–1.47 and 1.52–1.75 (4H, 2m, 1:3, 2 · CH2);
2.27 (1H, d, J = 4.1 Hz, H–C(4)); 2.71–2.87 (2H, m, Ha–
C(40), Hb–C(4)); 4.46 (1H, br d, J = 12.8 Hz, Ha–C(20));
4.73 (1H, br d, J = 12.8 Hz, Hb–C(20)); 4.86–4.90 (1H,
m, Ha–C(300)); 5.00–5.04 (1H, m, Hb–C(300)); 6.77 (1H,
dd, J = 1.5; 8.3 Hz, 1H of Ar); 7.10–7.15 (1H, m, 1H of
Ar); 7.46–7.52 (1H, m, 1H of Ar); 8.00 (1H, dd, J = 1.1;
8.3 Hz, 1H of Ar); 7.78–7.88 (2H, m, 2H of Ar). 13C
NMR (CDCl3): d 9.4, 19.0, 22.5, 22.6, 31.5, 38.8, 47.9,
52.4, 52.7, 72.5, 89.9, 104.0, 122.0, 123.3, 125.2, 134.0,
140.3, 146.5, 147.4, 186.2. m/z (EI) = 340 (M+); m/z
(HRMS) Found: 340.179750 (M+); C20H24N2O3 requires:
m/z = 340.178693. (Found: C, 70.28; H, 7.26; N, 9.23.
C20H24N2O3 requires: C, 70.56; H, 7.11; N, 8.23.) mmax
(NaCl) 2958, 2869, 1694, 1603, 1572, 1519, 1472, 1456,
1392, 1374, 1344, 1310, 1266, 1218, 1191, 1142, 1067,
5.3.1.
N-{(1S,2R,3E,4R)-1,7,7-Trimethyl-40-methylene-
dihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-ylidene}-
aniline 5a. Prepared from compound 3a/30a (241 mg,
1 mmol); CC (EtOAc–hexanes, 1:10); 0.269 g (91%) of a
26
colorless oil; ½aꢂD ¼ ꢀ18:0 (c 0.16, CHCl3). 1H NMR
1017, 874, 771 cmꢀ1
.
(CDCl3): d 0.84, 0.94, and 1.13 (9H, 3s, 1:1:1, 3 · Me);
1.26–1.35, 1.49–1.68, and 1.72–1.83 (4H, 3m, 1:2:1,
2 · CH2); 2.38 (1H, d, J = 4.9 Hz, H–C(4)); 2.65 (1H, br
d, J = 15.8 Hz, Ha–C(40)); 2.73–2.82 (1H, m, Hb–C(40));
4.47 (1H, br d, J = 12.4 Hz, Ha–C(20)); 4.84–4.90 (1H, m,
Hb–C(20)); 4.90–4.93 (1H, m, Ha–C(300)); 5.00–5.03 (1H,
m, Hb–C(300)); 6.71–6.74, 6.99–7.05, and 7.24–7.29 (5H,
3m, 2:1:2, Ph). 13C NMR (CDCl3): d 9.6, 19.0, 22.4, 24.2,
31.7, 39.5, 47.6, 51.7, 52.2, 72.6, 90.1, 103.7, 120.0, 123.2,
128.8, 147.9, 151.8, 185.9. m/z (EI) = 295 (M+); m/z
(HRMS) Found: 295.194350 (M+); C20H25NO requires:
m/z = 295.193615. (Found: C, 79.67; H, 8.35; N, 7.05.
C20H25NO requires: C, 81.31; H, 8.53; N, 4.74.) mmax
(NaCl) 2957, 2875, 1687, 1595, 1485, 1454, 1392, 1373,
5.3.4. 4-Nitro-N-{(1S,2R,3E,4R)-1,7,7-trimethyl-40-methyl-
enedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-
ylidene}aniline 5d and (1S,3S,4R)-1,7,7-trimethyl-40-methyl-
ene-10-(4-nitrophenyl)spiro[bicyclo[2.2.1]heptane-3,20-pyr-
rolidin]-2-one 6d. Prepared from compound 3d/30d
(286 mg, 1 mmol); CC (EtOAc–hexanes, 1:1); 5d:6d =
56:44. Subsequent separation of 5d/6d by MPLC
(EtOAc–hexanes, 1:10) furnished pure compounds 5d and
6d.
5.3.4.1. Data for compound 5d. Yield: 0.147 g (43%) of
23
a brownish-yellow solid; mp 123–135 ꢁC; ½aꢂD ¼ þ32:8 (c
1
0.19, CHCl3). H NMR (CDCl3): d 0.87, 0.95, and 1.14
1215, 1193, 1160, 1067, 1018, 878, 776, 697 cmꢀ1
.
(9H, 3s, 1:1:1, 3 · Me); 1.23–1.36, 1.51–1.60, 1.62–1.72,
and 1.76–1.87 (4H, 4m, 1,:1:1:1, 2 · CH2); 2.26 (1H, d,
J = 4.9 Hz, H–C(4)); 2.62 (1H, br d, J = 15.8 Hz,
Ha–C(40)); 2.76–2.85 (1H, m, Hb–C(40)); 4.48 (1H, br d,
J = 12.8 Hz, Ha–C(20)); 4.79 (1H, br d, J = 12.8 Hz,
Ha–C(20)); 4.93 (1H, br s, Hb–C(300)); 5.03 (1H, br s,
Hb–C(300)); 6.79–6.83 and 8.14–8.19 (4H, 2m, 1:1, C6H4).
5.3.2.
N-{(1S,2R,3E,4R)-1,7,7-Trimethyl-40-methylene-
dihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-ylidene}-
naphthalen-1-amine 5b. Prepared from compound 3b/30b
(291 mg, 1 mmol); CC (EtOAc–hexanes, 1:10); 0.121 g
26
1
(35%) of a colorless oil; ½aꢂD ¼ ꢀ36:8 (c 0.19, CHCl3). H
NMR (CDCl3): d 0.82, 0.99, and 1.17 (9H, 3s, 1:1:1,
3 · Me); 1.28–1.37 and 1.56–1.80 (4H, 2m, 1:3, 2 · CH2);
2.32 (1H, d, J = 4.5 Hz, H–C(4)); 2.79 (1H, br d,
J = 15.8 Hz, Ha–C(40)); 2.84–2.92 (1H, m, Hb–C(40));
4.58 (1H, br d, J = 12.8 Hz, Ha–C(20)); 4.93–4.97 (1H, m,
Ha–C(300)); 5.00–5.07 (1H, m, Hb–C(20)); 5.08–5.11 (1H,
m, Hb–C(300)); 6.67 (1H, dd, J = 0.8; 7.2 Hz, 1H of Ar);
7.34–7.49 (3H, m, 3H of Ar); 7.54 (1H, d, J = 8.3 Hz, 1H
of Ar); 7.78–7.88 (2H, m, 2H of Ar). 13C NMR (CDCl3):
d 9.5, 18.9, 22.4, 24.4, 31.7, 39.7, 47.6, 51.7, 52.2, 72.7,
90.2, 103.8, 113.5, 123.3, 123.8, 125.3, 125.8, 126.1, 127.0,
127.8, 134.1, 147.8, 147.9, 186.8. m/z (EI) = 345 (M+);
m/z (HRMS) Found: 345.210150 (M+); C24H27NO
requires: m/z = 345.209265. (Found: C, 82.96; H, 8.23; N,
3.74. C24H27NO requires: C, 83.44; H, 7.88; N, 4.05.) mmax
(NaCl) 2956, 2876, 1687, 1682, 1588, 1574, 1505, 1483,
1455, 1391, 1373, 1283, 1269, 1226, 1192, 1065, 1035,
13C NMR (CDCl3):
d 9.3, 18.8, 22.3, 24.0, 31.3,
39.3, 47.7, 52.2, 72.4, 89.8, 104.0, 120.1, 124.9, 143.7,
147.2, 157.7, 187.5. m/z (EI) = 340 (M+); m/z (HRMS)
Found: 340.179520 (M+); C20H24N2O3 requires: m/z =
340.178693. (Found: C, 70.79; H, 7.28; N, 8.17.
C20H24N2O3 requires: C, 70.56; H, 7.11; N, 8.23.) mmax
(KBr) 2998, 2954, 2931, 2866, 1683, 1598, 1586, 1508,
1481, 1450, 1390, 1375, 1339, 1313, 1296, 1285, 1265,
1220, 1191, 1160, 1102, 1066, 1017, 883, 866, 741, 703,
647 cmꢀ1
.
5.3.4.2. Data for compound 6d. Yield: 0.116 g (34%) of
23
a brownish-yellow solid; mp 65–80 ꢁC; ½aꢂD ¼ ꢀ237:5 (c
1
0.12, CHCl3). H NMR (CDCl3): d 0.90, 0.93, and 1.00
(9H, 3s, 1:1:1, 3 · Me); 1.45–1.53, 1.59–1.75, and 1.91–
2.02 (4H, 3m, 1:2:1, 2 · CH2); 2.49 (1H, d, J = 4.5 Hz,
H–C(4)); 2.54 (1H, dt, J = 1.5; 16.2 Hz, Ha–C(40)); 2.87
(1H, ddd, J = 2.3; 4.5; 16.2 Hz, Hb–C(40)); 3.65–3.73
1014, 877, 799, 776 cmꢀ1
.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
2373
(1H, m, Ha–C(20)); 4.73–4.81 (1H, m, Hb–C(20)); 4.99–5.03
(1H, m, Ha–C(300)); 5.09–5.13 (1H, m, Hb–C(300)); 7.04–
7.10 and 8.09–8.14 (4H, 2m, 1:1, C6H4). 13C NMR
37.4, 39.3, 46.1, 46.3, 51.5, 52.3, 58.4, 59.8, 71.7, 72.2,
87.4, 88.6, 104.13, 104.14, 146.2, 146.3, 219.1, 219.6. m/z
(EI) = 220 (M+); m/z (HRMS) Found: 220.147100 (M+);
C14H20O2 requires: m/z = 220.146330. (Found: C, 73.23;
H, 7.44; N, 3.92. C14H20O2 requires: C, 76.33; H, 9.15;
N, 0.00.) mmax (NaCl) 2960, 2872, 1748 (C@O), 1671,
1485, 1456, 1426, 1393, 1374, 1325, 1310, 1239, 1156,
(CDCl3):
d 9.8, 20.0, 22.4, 24.2, 31.0, 41.2, 46.6,
49.7, 59.5, 61.8, 75.3, 106.7, 124.6, 125.2, 143.0,
145.2, 157.4, 218.5. m/z (EI) = 340 (M+); m/z (HRMS)
Found: 340.179550 (M+); C20H24N2O3 requires: m/z =
340.178693. (Found: C, 70.79; H, 7.22; N, 8.20.
C20H24N2O3 requires: C, 70.56; H, 7.11; N, 8.23.) mmax
(KBr) 2990, 2957, 2929, 2878, 1737 (C@O), 1586, 1507,
1488, 1458, 1392, 1339, 1318, 1247, 1177, 1111, 1024,
1105, 1068, 1025, 1015, 1002, 985, 939, 883, 852 cmꢀ1
.
5.3.6.1. Data for compound 7. 1H NMR (CDCl3): d
0.94, 0.95, 1.11 (9H, 3s, 1:1:1, 3 · Me); 1.36–1.55, 1.67–
1.77, and 1.86–1.98 (4H, 3m, 2:1:1, 2 · CH2); 2.18 (1H, d,
J = 5.3 Hz, H–C(4)); 2.38–2.45 (1H, m, Ha–C(40)); 2.60–
2.69 (1H, m, Hb–C(40));0 4.40–4.48 (1H, m, Ha–C(20));
4.62–4.71 (1H, m, Hb–C(2 )); 4.91–4.95 (1H, m, Ha–C(300));
5.00–5.04 (1H, m, Hb–C(300)).
1000, 975, 956, 943, 895 cmꢀ1
.
5.3.5. 3-Nitro-N-{(1S,2R,3E,4R)-1,7,7-trimethyl-40-methyl-
enedihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-
ylidene}aniline 5e and (1S,3S,4R)-1,7,7-trimethyl-40-methyl-
ene-10-(3-nitrophenyl)spiro[bicyclo[2.2.1]heptane-3,20-pyr-
rolidin]-2-one 6e. Prepared from compound 3e/30e
(286 mg, 1 mmol); CC (EtOAc–hexanes, 1:1); 5e:6e =
5.3.6.2. Data for compound 70. 1H NMR (CDCl3): d
0.91, 0.97, 1.08 (9H, 3s, 1:1:1, 3 · Me); 2.01 (1H, d,
J = 4.1 Hz, H–C(4)); 2.50 (1H, br d, J = 15.8 Hz,
Ha–C(40)); 2.66–2.75 (1H, m, Hb–C(40)).
87:13; CC (EtOAc–hexanes, 1:25); 5e:6e = 86:14; 0.198 g
23
(58%) of a yellow oil; ½aꢂD ¼ 0 (c 0.45, CHCl3). m/z
(EI) = 340 (M+); m/z (HRMS) Found: 340.179350
(M+); C20H24N2O3 requires: m/z = 340.178693. (Found:
C, 68.45; H, 7.27; N, 7.59. C20H24N2O3 requires: C,
70.56; H, 7.11; N, 8.23.) mmax (NaCl) 2959, 2929, 2871,
1744 (C@O), 1682, 1612, 1575, 1526, 1472, 1455, 1392,
1372, 1348, 1308, 1284, 1217, 1192, 1161, 1067, 1017,
5.4. Synthesis of (1S,2R,4R)-1,7,7-trimethyl-40-methylene-
dihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-one 7
by hydrolysis of imine 5a
Hydrochloric acid (37%, 0.38 mL, ꢁ2.5 mmol) was added
to a cooled solution (0 ꢁC) of 5a (1 mmol, 295 mg) in a mix-
ture of MeOH and H2O (3:1, 20 mL). The reaction mixture
was stirred at 0 ꢁC for 1 h and then at room temperature
for 24 h. Methanol was evaporated in vacuo, the aqueous
residue was poured into EtOAc (100 mL), and the organic
phase was washed subsequently with saturated aq NaHSO4
(100 mL) and water (100 mL). The organic phase was dried
over anhydrous Na2SO4, filtered, and the filtrate evapo-
rated in vacuo. The residue was purified by CC (EtOAc–
hexanes, 1:10). Fractions containing the product were
887, 806, 738, 696 cmꢀ1
.
5.3.5.1. Data for compound 5e. 1H NMR (CDCl3): d
0.87, 0.96, and 1.14 (9H, 3s, 1:1:1, 3 · Me); 1.28–1.37,
1.51–1.72, and 1.77–1.88 (4H, 3m, 1:2:1, 2 · CH2); 2.31
(1H, d, J = 4.9 Hz, H–C(4)); 2.64 (1H, br d, J = 15.8 Hz,
Ha–C(40)); 2.76-2.85 (1H, m, Hb–C(40)); 4.49 (1H, br d,
J = 12.8 Hz, Ha–C(20)); 4.79–4.86 (1H, m, Hb–C(20));
4.91–4.96 (1H, m, Ha–C(300)); 5.02–5.07 (1H, m, Hb–
C(300)); 7.03–7.06 (1H, m, 1H of Ar); 7.43 (1H, t,
J = 8.1 Hz, 1H of Ar); 7.58 (1H, t, J = 2.1 Hz, 1H of
Ar); 7.88–7.92 (1H, m, 1H of Ar). 13C NMR (CDCl3): d
9.3, 18.9, 22.4, 24.1, 31.5, 39.4, 47.8, 51.9, 52.2, 72.5,
90.0, 104.0, 115.0, 118.2, 126.3, 129.7, 147.4, 148.8, 152.7,
188.5.
combined and evaporated in vacuo to give 7. Yield:
27
0.135 g (61%) of a colorless oil; ½aꢂD ¼ þ122:8 (c 0.23,
CHCl3). 1H NMR (CDCl3): d 0.94, 0.95, 1.11 (9H, 3s,
1:1:1, 3 · Me); 1.36–1.54, 1.67–1.77, 1.86–1.98 (4H, 3m,
2:1:1, 2 · CH2); 2.18 (1H, d, J = 5.3 Hz, H–C(4)); 2.37-
2.45 (1H, m, Ha–C(40)); 2.60-2.69 (1H, m, Hb–C(40));
4.41–4.47 (1H, m, Ha–C(20)); 4.63–4.70 (1H, m, Hb–C(20));
4.91–4.95 (1H, m, Ha–C(300)); 5.00–5.03 (1H, m,
Hb–C(300)). 13C NMR (CDCl3): d 9.2, 18.8, 22.1, 22.2,
31.5, 37.6, 46.5, 51.8, 60.0, 72.4, 88.9, 104.4, 146.5, 219.6.
m/z (EI) = 220 (M+); m/z (HRMS) Found: 220.147020
(M+); C14H20O2 requires: m/z = 220.146330. (Found: C,
73.36; H, 9.14; N, 0.00. C14H20O2 requires: C, 76.33; H,
9.15; N, 0.00.) mmax (NaCl) 2961, 2872, 1748 (C@O),
1672, 1484, 1456, 1425, 1393, 1374, 1326, 1281, 1240,
5.3.5.2. Data for compound 6e. 1H NMR (CDCl3): d
0.93 (3H, s, Me); 1.90–1.97 (1H, m, 1H of CH2); 2.20
(1H, d, J = 4.5 Hz, H–C(4)); 2.51–2.59 (1H, m, Ha–C(40));
2.92 (1H, ddd, J = 2.6; 4.9; 16.9 Hz, Hb–C(40)); 3.52–3.59
(1H, m, Ha–C(20)); 4.70–4.78 (1H, m, Hb–C(20)); 5.00–
5.03 (1H, m, Ha–C(300)); 5.13–5.16 (1H, m, Hb–C(300));
7.34–7.38 (1H, m, 1H of Ar); 7.95–7.99 (1H, m, 1H of
Ar). 13C NMR (CDCl3): d 9.7, 19.8, 22.5, 24.2, 31.1,
40.5, 46.7, 49.4, 59.4, 62.8, 75.4, 106.7, 119.6, 122.1,
129.6, 133.8, 146.1, 148.6, 153.0, 218.9.
1156, 1107, 1071, 1014, 883 cmꢀ1
.
5.3.6. (1S,2R,4R)-1,7,7-Trimethyl-40-methylenedihydro-30H-
spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-one 7 and (1S,3S,
4R)-1,7,7-trimethyl-40-methylenedihydro-30H-spiro[bicyclo-
tane-3,20-furan]-2-one 70. Prepared from (1S)-(+)-cam-
phorquinone 1 (166 mg, 1 mmol); CC (EtOAc–hexanes,
1:1); 7:70 = 1:1; CC (EtOAc–hexanes, 1:15) 7:70 = 1:1.
Yield: 0.210 g (95%) of a colorless oil. 13C NMR (CDCl3):
d 8.9, 9.2, 18.5, 19.6, 21.87, 21.88, 22.0, 23.3, 30.0, 31.3,
5.5. General procedure for reduction of compounds 5a–d with
LiAlH4
To a solution of compounds 5a–d (0.5 mmol) in anhydrous
Et2O (15 mL) under argon was added a solution of LiAlH4
(5 mL, 1 M in THF) and the reaction mixture was heated
at 55 ꢁC for 2–5 h. The reaction mixture was cooled to
0 ꢁC and the unreacted LiAlH4 was quenched carefully

2374
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
25
with saturated aq Na2SO4 (just enough to quench all
LiAlH4). The reaction mixture was filtered through a short
column (d = 1 cm) consisting of Celiteꢂ (bottom layer,
h = 3 cm) and anhydrous Na2SO4 (top layer, h = 3 cm) in
dichloromethane and washed with dichloromethane
(200 mL). The combined filtrates were evaporated in vacuo
and the residue was purified by CC. Fractions containing
the products were combined and evaporated in vacuo.
Compounds 8a–d, 9d, and 10d were prepared in this
manner.
(63%) of a black solid; mp 95–103 ꢁC; ½aꢂ589 ¼ þ150:0 (c
0.09, CHCl3). 1H NMR (DMSO-d6): d 0.78, 0.85, and
1.14 (9H, 3s, 1:1:1, 3 · Me); 1.19–1.28 and 1.32–1.48 (3H,
2m, 1:2, 3H of CH2); 1.61–1.74 (2H, m, 1H of CH2,
H–C(4)); 2.51 (1H, Ha–C(40)); 2.83 (1H, br d,
J = 15.5 Hz, Hb–C(40)); 3.10 (1H, d, J = 6.8 Hz, H–C(3));
4.11 (2H, br s, NH2); 4.21 (1H, d, J = 6.8 Hz, NH); 4.40
(1H, br d, J = 12.8 Hz, Ha–C(20)); 4.53 (1H, br dd,
J = 1.9; 13.2 Hz, Hb–C(20)); 4.80 (1H, br s, Ha–C(300));
4.94 (1H, br s, Hb–C(300)); 6.24 (1H, dd, J = 0.75; 7.9 Hz,
1H of Ar); 6.38 (1H, dt, J = 1.1; 7.5 Hz, 1H of Ar); 6.55
(1H, dt, J = 1.5; 7.5 Hz, 1H of Ar); 6.63 (1H, dd, J = 1.5;
7.5 Hz; 1H of Ar). 13C NMR (CDCl3): d 10.1, 21.8, 22.4,
26.1, 31.7, 43.1, 48.9, 49.3, 52.4, 69.1, 73.4, 94.2, 104.6,
111.4, 116.9, 117.0, 121.0, 133.5, 137.6, 146.8. m/z
(EI) = 312 (M+); m/z (HRMS) Found: 312.220850 (M+);
C20H28N2O requires: m/z = 312.220164. (Found: C,
75.72; H, 9.12; N, 10.39. C20H28N2O requires: C, 76.88;
H, 9.03; N, 8.97.) mmax (KBr) 3405, 2992, 2939, 2865,
1623, 1598, 1517, 1426, 1401, 1386, 1312, 1271, 1073,
5.5.1. (1S,2R,3S,4R)-1,7,7-Trimethyl-40-methylene-N-phenyl-
dihydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-amine
8a. Prepared from compound 5a (148 mg, 0.5 mmol);
t = 2 h; CC (EtOAc–hexanes, 1:40); 0.115 g (77%) of a col-
27
orless oil; ½aꢂ589 ¼ þ141:5 (c 0.27, CHCl3). 1H NMR
(DMSO-d6): d 0.78, 0.85, and 1.10 (9H, 3s, 1:1:1,
3 · Me); 1.17–1.47 (3H, m, 3H of CH2); 1.60–1.72 (2H,
m, 1H of CH2, H–C(4)); 2.49 (1H, Ha–C(40)); 2.81 (1H,
br d, J = 15.5 Hz, Hb–C(40)); 3.09 (1H, d, J = 7.2 Hz,
H–C(3)); 4.40 (2H, br s, Ha–C(20), Hb–C(20)); 4.78 (1H,
br d, J = 7.2 Hz, NH); 4.80 (1H, br s, Ha–C(300)); 4.93
(1H, br s, Hb–C(300)); 6.45–6.54 and 7.00–7.06 (5H, 2m,
3:2, Ph). 13C NMR (CDCl3): d 10.0, 21.6, 22.4, 26.0,
31.7, 43.0, 48.8, 49.2, 52.3, 68.9, 73.1, 93.9, 104.5, 112.7,
116.0, 129.2, 146.5, 147.4. m/z (EI) = 297 (M+); m/z
(HRMS) Found: 297.210500 (M+); C20H27NO requires:
m/z = 297.209265. mmax (NaCl) 3434, 3048, 2953, 2886,
1672, 1600, 1504, 1485, 1427, 1389, 1371, 1323, 1312,
1263, 1194, 1179, 1153, 1074, 1045, 1028, 992, 885, 746,
1039, 1026, 884, 777, 759, 738, 720 cmꢀ1
.
5.5.4. N1-{(1S,2R,3S,4R)-1,7,7-Trimethyl-40-methylenedi-
hydro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}benz-
ene-1,4-diamine 8d, (E)-1,2-bis(4-{(1S,2R,3S,4R)-1,7,7-tri-
methyl-40-methylenedihydro-30H-spiro[bicyclo[2.2.1]heptane-
2,20-furan]-3-ylamino}phenyl)diazene 9d and (E)-1,2-bis(4-
{(1S,2R,3S,4R)-1,7,7-trimethyl-40-methylenedihydro-30H-
spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-ylamino}phenyl)-
diazene-1-oxide 10d. Prepared from compound 5d
(170 mg, 0.5 mmol); t = 3 h; 8d:9d:10d = 77:17:6 (crude
reaction mixture); CC (first EtOAc–hexanes, 1:3, 9d/10d,
the first fraction; then EtOAc–hexanes, 1:1, 8d, the second
fraction). The mixture of compounds 9d and 10d was sep-
arated by MPLC (EtOAc–hexanes, 1:10). Fractions con-
taining the products were combined and evaporated in
vacuo to give pure compounds 9d and 10d.
692 cmꢀ1
.
5.5.2.
(1S,2R,3S,4R)-1,7,7-Trimethyl-40-methylene-N-
(naphthalen-1-yl)dihydro-30H-spiro[bicyclo-[2.2.1]heptane-2,
20-furan]-3-amine 8b. Prepared from compound 5b
(173 mg, 0.5 mmol); t = 2 h; CC (EtOAc–hexanes, 1:20);
25
0.164 g (94%) of a colorless oil; ½aꢂ589 ¼ þ211:6 (c 0.07,
1
CHCl3). H NMR (DMSO-d6): d 0.80, 0.92, 1.16 (9H, 3s,
1:1:1, 3 · Me); 1.30–1.54 (3H, m, 3H of CH2); 1.68–1.78
(1H, m, 1H of CH2); 1.86 (1H, d, J = 4.5 Hz, H–C(4));
2.60 (1H, d, J = 15.5 Hz, Ha–C(40)); 2.91 (1H, br d,
J = 15.1 Hz, Hb–C(40)); 3.33 (1H, d, J = 6.0 Hz, H–C(3));
4.44–4.55 (2H, m, Ha–C(20), Hb–C(20)); 4.81 (1H, br s,
Ha–C(300)); 4.95 (1H, br s, Hb–C(300)); 5.33 (1H, d,
J = 6.0 Hz, NH); 6.34 (1H, d, J = 7.5 Hz, 1H of Ar); 7.10
(1H, d, J = 8.3 Hz, 1H of Ar); 7.29 (1H, t, J = 7.9 Hz,
1H of Ar); 7.41–7.48 (2H, m, 2H of Ar); 7.71–7.81 (2H,
m, 1H of Ar). 13C NMR (CDCl3): d 10.1, 21.9, 22.4,
26.0, 31.8, 43.2, 48.4, 49.3, 52.5, 68.5, 73.5, 94.4, 103.6,
104.9, 115.5, 119.9, 123.3, 124.6, 125.7, 127.0, 128.8,
134.7, 142.4, 146.4. m/z (EI) = 347 (M+); m/z (HRMS)
5.5.4.1. Data for compound 8d. Yield: 0.080 g (51%) of
25
a black solid; mp 70–77 ꢁC; ½aꢂ589 ¼ þ417:2 (c 0.06,
CHCl3). 1H NMR (DMSO-d6): d 0.76, 0.83, and 1.09
(9H, 3s, 1:1:1, 3 · Me); 1.13–1.24 and 1.29–1.45 (3H, 2m,
1:2, 3H of CH2); 1.58–1.68 (2H, m, 1H of CH2, H–C(4));
2.46 (1H, Ha–C(40)); 2.79 (1H, br d, J = 15.1 Hz,
Hb–C(40)); 3.00 (1H, br d, J = 6.6 Hz, H–C(3)); 4.00 (1H,
br d, J = 6.6 Hz, NH); 4.23 (2H, br s, NH2); 4.38 (2H, br
s Ha–C(20), Hb–C(20)); 4.79 (1H, br s, Ha–C(300)); 4.92
(1H, br s, Hb–C(300)); 6.29 and 6.40 (2H, 2 br d, 1:1,
J = 8.3 Hz, C6H4). 13C NMR (CDCl3): d 10.1, 21.7, 22.4,
26.2, 31.7, 43.1, 49.0, 49.2, 52.3, 70.2, 73.2, 94.0, 104.4,
114.1, 117.2, 136.5, 141.3, 146.8. m/z (EI) = 312 (M+);
m/z (HRMS) Found: 312.221030 (M+); C20H28N2O
requires: m/z = 312.220164. (Found: C, 75.69; H, 9.04; N,
10.29. C20H28N2O requires: C, 76.88; H, 9.03; N, 8.97.)
mmax (KBr) 3423, 3332, 2950, 2888, 1616, 1516, 1478,
1463, 1416, 1388, 1332, 1307, 1262, 1194, 1151, 1073,
Found:
347.225450
(M+);
C24H29NO
requires:
m/z = 347.224915. (Found: C, 78.31; H, 8.05; N, 5.55.
C24H29NO requires: C, 82.95; H, 8.41; N, 4.03.) mmax
(NaCl) 3457, 3058, 2952, 2885, 1582, 1524, 1476, 1456,
1410, 1389, 1371, 1339, 1313, 1278, 1252, 1148, 1072,
1050, 1036, 886, 782, 765 cmꢀ1
.
1043, 1023, 900, 881, 817 cmꢀ1
.
5.5.3. N1-{(1S,2R,3S,4R)-1,7,7-Trimethyl-40-methylenedihy-
dro-30H-spiro[bicyclo[2.2.1]heptane-2,20-furan]-3-yl}benzene-
1,2-diamine 8c. Prepared from compound 5c (170 mg,
0.5 mmol); t = 5 h; CC (EtOAc–hexanes, 1:10); 0.099 g
5.5.4.2. Data for compound 9d. Yield: 0.010 g (3%) of a
25
yellow solid; mp 207–212 ꢁC; ½aꢂ589 ¼ þ100:0 (c 0.04,
1
CHCl3). H NMR (CDCl3): d 0.83, 0.90, and 1.14 (18H,
3s, 1:1:1, 6 · Me); 1.16–1.26, 1.34–1.51, and 1.73–1.84

U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
2375
(8H, 3m, 1:2:1, 4 · CH2); 1.90 (2H, d, J = 4.9 Hz, 2 · H–
C(4)); 2.44 (2H, d, J = 15.1 Hz, 2 · Ha–C(40)); 2.91 (2H,
br d, J = 15.4 Hz, 2 · Hb–C(40)); 3.20 (2H, d, J = 6.6 Hz,
2 · H–C(3)); 4.34–4.41 (2H, m, 2 · Ha–C(20)); 4.49 (2H,
br d, J = 12.8 Hz, 2 · Hb–C(20)); 4.74 (2H, br d,
J = 6.6 Hz, 2 · NH); 4.82 (2H, br s, 2 · Ha–C(300)); 4.95
(2H, br s, 2 · Hb–C(300)); 6.48–6.53 and 7.68–7.73 (8H,
2m, 1:1, 2 · C6H4). 13C NMR (CDCl3): d 10.1, 21.8, 22.4,
26.1, 31.7, 43.1, 49.2, 49.4, 52.5, 68.7, 73.2, 93.9, 105.0,
112.5, 124.4, 144.6, 146.2, 148.8. m/z (EI) = 620 (M+);
m/z (HRMS) Found: 620.411520 (M+); C40H52N4O2
requires: m/z = 620.409027. (Found: C, 74.29; H, 8.22; N,
9.30. C40H52N4O2 requires: C, 77.38; H, 8.44; N, 9.02.) mmax
(KBr) 3429, 2953, 1597, 1512, 1474, 1460, 1427, 1400, 1389,
h = 3 cm) and anhydrous Na2SO4 (top layer, h = 3 cm) in
dichloromethane and washed with dichloromethane
(200 mL). The combined filtrates were evaporated in vacuo
to give the crude aminoalcohols 11d and 110d in a ratio of
86:14. The raw product 11d/110d was purified by CC
(EtOAc–hexanes, 1:1). Fractions containing the products
were combined and evaporated in vacuo to give amino
alcohols 11d and 110d in a ratio of 88:12. Yield: 0.063 g
26
(20%) of a brownish solid; mp 155–170 ꢁC; ½aꢂ589 ¼ ꢀ80:2
(c 0.17, CHCl3). m/z (EI) = 312 (M+); m/z (HRMS)
Found: 312.220650 (M+); C20H28N2O requires: m/z =
312.220164. (Found: C, 75.91; H, 9.50; N, 8.54.
C20H28N2O requires: C, 76.88; H, 9.03; N, 8.97.) mmax
(KBr) 3436, 3331, 2968, 2946, 1629, 1513, 1463, 1436,
1399, 1389, 1368, 1279, 1256, 1181, 1093, 1071, 1052,
1332, 1312, 1194, 1145, 1071, 1044, 1024, 888, 827 cmꢀ1
.
1028, 1015, 884, 840 cmꢀ1
.
5.5.4.3. Data for compound 10d. Yield: 0.016 g (5%) of
25
5.6.1. Data for major (1R,2S,3R,4S)-isomer 11d. 1H
NMR (DMSO-d6): d 0.60, 0.80, and 1.00 (9H, 3s, 1:1:1,
3 · Me); 1.04–1.11, 1.31–1.42, and 1.46–1.56 (4H, 3m,
1:2:1, 2 · CH2); 1.77 (1H, d, J = 3.9 Hz, H–C(4)); 2.36
(1H, d, J = 15.9 Hz, Ha–C(40)); 2.85 (1H, br d,
J = 4.9 Hz, H–C(2)); 2.99–3.06 (1H, m, Hb–C(40)); 3.41
(1H, d, J = 16.2 Hz, Ha–C(20)); 3.88–3.95 (1H, m,
Hb–C(20)); 4.31 (1H, br d, J = 4.9 Hz, OH); 4.88 (3H, s,
Ha–C(300), NH2); 5.03 (1H, s, Hb–C(300)); 6.43–6.48 and
6.80–6.85 (4H, 2m, 1:1, C6H4). 13C NMR (CDCl3): d
12.1, 22.1, 23.3, 24.7, 33.1, 47.1, 49.2, 51.07, 51.12, 65.1,
77.4, 87.7, 105.7, 115.3, 129.9, 143.2, 144.0, 147.5.
a yellow solid; mp 219–224 ꢁC; ½aꢂ589 ¼ þ85:3 (c 0.03,
1
CHCl3). H NMR (CDCl3): d 0.83, 0.90, and 1.13 (18H,
3s, 1:1:1, 6 · Me); 1.34–1.60 and 1.73–1.84 (8H, 2m, 3:1,
4 · CH2); 1.88 (2H, t, J = 5.1 Hz, 2 · H–C(4)); 2.43 (2H,
d, J = 15.1 Hz, 2 · Ha–C(40)); 2.91 (2H, br d,
J = 15.1 Hz, 2 · Hb–C(40)); 3.17 (1H, d, J = 6.9 Hz,
H–C(3)); 3.20 (1H, d, J = 7.0 Hz, H–C(3)); 4.33–4.40
(2H, m, 2 · Ha–C(20)); 4.49 (2H, br d, J = 12.8 Hz,
2 · Hb–C(20)); 4.76 (1H, br d, J = 6.4 Hz, NH); 4.81 (1H,
NH); 4.82 (2H, br s, 2 · Ha–C(300)); 4.95 (2H, br s,
2 · Hb–C(300)); 6.42–6.51, 8.03–8.09, and 8.17–8.23 (8H,
3m, 2:1:1, 2 · C6H4). 13C NMR (CDCl3): d 10.0, 21.74,
21.76, 22.3, 26.1, 31.65, 31.67, 43.0, 49.1, 49.3, 49.39,
49.40, 52.5, 68.5, 68.7, 73.2, 77.4, 93.9, 105.02, 105.05,
111.6, 112.0, 123.6, 128.2, 135.1, 146.13, 146.17, 148.0,
149.1. m/z (EI) = 636 (M+); m/z (HRMS) Found:
5.6.2. Data for minor (1R,2R,3R,4S)-isomer 110d. 1H
NMR (DMSO-d6): d 0.71, 0.75, and 1.28 (9H, 3s, 1:1:1,
3 · Me); 1.65 (1H, d, J = 4.2 Hz, H–C(4)); 2.69 (1H, br
d, J = 16.8 Hz); 3.69–3.72 (1H, m); 3.82 (1H, br d,
J = 16.5 Hz); 4.60 (1H, d, J = 6.1 Hz, OH); 4.74 (2H, br
s, NH2); 4.80 (1H, s, Ha–C(300)); 4.94 (1H, s, Hb–C(300));
6.39–6.43 and 6.72–6.76 (4H, 2m, 1:1, C6H4).
636.406200
(M+);
C40H52N4O3
requires:
m/z =
636.403942. (Found: C, 75.13; H, 8.32; N, 9.03.
C40H52N4O3 requires: C, 75.44; H, 8.23; N, 8.80.) mmax
(KBr) 3408, 2951, 1599, 1510, 1481, 1459, 1442, 1403,
1387, 1331, 1314, 1261, 1159, 1072, 1045, 1023, 887, 880,
826 cmꢀ1
.
5.7. X-ray structure analysis for compounds 3d and 3e
5.6. Synthesis of (1R,2S,3R,4S)-10-(4-aminophenyl)-4,7,7-
trimethyl-40-methylenespiro[bicyclo[2.2.1]heptane-2,20-pyrr-
olidin]-3-ol 11d and its (1R,2R,3R,4S)-isomer 110d
Single crystal X-ray diffraction data of compounds 3d and
3e were collected at room temperature on a Nonius Kappa
CCD diffractometer using the Nonius Collect Software.45
46
A mixture of compound 6d (340 mg, 1 mmol), Na2S2O4
(1740 mg, 10 mmol), K2CO3 (414 mg, 3 mmol), ethanol
(50 mL), and water (1 mL) was heated at reflux for 3 h.
Volatile components were evaporated in vacuo, the residue
was suspended in CH2Cl2 (200 mL), and the organic phase
was washed with water (100 mL). The organic phase was
dried over anhydrous Na2SO4, filtered, and the filtrate
was evaporated in vacuo. The residue was purified by CC
(EtOAc–hexanes, 3:1). Fractions containing the product
were combined and evaporated in vacuo to give the crude
amine 60d, which was dissolved in anhydrous Et2O
(15 mL). Then, a solution of LiAlH4 (6 mL, 1 M in THF)
was added and the reaction mixture was heated under
argon at 55 ꢁC for 2 h. The reaction mixture was cooled
to 0 ꢁC and the unreacted LiAlH4 was carefully quenched
with saturated aq Na2SO4 (just enough to quench all
LiAlH4). The reaction mixture was filtered through a short
column (d = 1 cm) consisting of Celiteꢂ (bottom layer,
DENZO and SCALEPACK were used for indexing and scal-
ing of the data and the structures were solved by means of
SIR97.47 Refinement was done using Xtal3.448 program
package and the crystallographic plots were prepared by
ORTEP III.49 Crystal structures were refined on F values
using the full-matrix least-squares procedure. The non-
hydrogen atoms were refined anisotropically in all cases,
while the positions of hydrogen atoms were geometrically
calculated and their positional and isotropic atomic dis-
placement parameters were not refined. Absorption correc-
tion was not necessary. Regina50 weighting scheme was
used in all cases.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC 649283 and 649284. Copies
of the data can be obtained, free of charge, on application

2376
U. Grosˇelj et al. / Tetrahedron: Asymmetry 18 (2007) 2365–2376
22. Wagger, J.; Golicˇ Grdadolnik, S.; Grosˇelj, U.; Meden, A.;
Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2007, 18,
464–475.
to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
23. Grosˇelj, U.; Recˇnik, S.; Svete, J.; Meden, A.; Stanovnik, B.
Tetrahedron: Asymmetry 2002, 13, 821–833.
24. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Stanovnik, B.;
Svete, J. Tetrahedron: Asymmetry 2006, 17, 79–91.
25. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Stanovnik, B.;
Svete, J. Tetrahedron: Asymmetry 2005, 16, 2927–2945.
26. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Recˇnik, S.; Meden, A.;
Stanovnik, B.; Svete, J. Tetrahedron 2005, 61, 3991–3998.
27. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Pirc, S.; Recˇnik,
S.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2004, 15,
2367–2383.
28. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Recˇnik, S.;
Stanovnik, B.; Svete, J. Synthesis 2005, 1087–1094.
29. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Pirc, S.; Stanovnik, B.;
Svete, J.; Meden, A. Tetrahedron: Asymmetry 2005, 16, 2187–
2197.
Acknowledgments
The financial support from the Ministry of Science and
Technology, Slovenia, through grants P0-0502-0103, P1-
0179, and J1-6689-0103-04 is gratefully acknowledged.
We acknowledge with thanks the financial support from
pharmaceutical companies Krka d.d. (Novo mesto, Slove-
nia) and Lek d.d., a new Sandoz company (Ljubljana,
Slovenia). The authors wish to express their gratitude to
the Alexander von Humboldt Foundation, Germany, for
the donation of
chromatograph.
a Buchi medium pressure liquid
¨
Crystallographic data were collected on the Kappa CCD
Nonius diffractometer in the Laboratory of Inorganic
Chemistry, Faculty of Chemistry and Chemical Technol-
ogy, University of Ljubljana, Slovenia. We acknowledge
with thanks the financial contribution of the Ministry of
Science and Technology, Republic of Slovenia through
grant Packet X-2000 and PS-511-102, which thus made
the purchase of the apparatus possible.
30. Grosˇelj, U.; Bevk, D.; Jaksˇe, R.; Meden, A.; Stanovnik, B.;
Svete, J. Tetrahedron: Asymmetry 2006, 17, 1217–1237.
31. Grosˇelj, U.; Recˇnik, S.; Meden, A.; Stanovnik, B.; Svete, J.
Acta Chim. Slov. 2006, 53, 245–256.
ˇ
32. Grosˇelj, U.; Tavcˇar, G.; Bevk, D.; Meden, A.; Zemva, B.;
Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2006, 17,
1715–1727.
33. Denmark, S. E.; Rivera, I. J. Org. Chem. 1994, 59, 6887–
6889.
34. Trost, B. M.; Marrs, C. M. J. Am. Chem. Soc. 1993, 115,
6636–6645.
35. Chan, D. M. T. In Recent Advances in Palladium-Catalyzed
Cycloadditions Involving Trimethylenemethane and its Ana-
logs; Kobayashi, S., Jørgensen, K. A., Eds.; Cycloaddition
Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2001; pp 57–84.
36. McClure, N. L.; Dai, G.-Y.; Mosher, H. S. J. Org. Chem.
1988, 53, 2617–2620.
37. Richer, J.-C.; Rossi, A. Can. J. Chem. 1972, 50, 1376–
1385.
References
1. Money, T. Nat. Prod. Rep. 1985, 253–289.
2. Oppolzer, W. Tetrahedron 1987, 43, 1969–2004.
3. Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250.
4. Money, T. In Remote Functionalization of Camphor: Appli-
cation to Natural Product Synthesis. In Organic Synthesis:
Theory and Applications; JAI Press, 1996; Vol. 3, pp 1–83.
5. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071–6072.
38. Van Toan, V.; Lightner, D. A. Tetrahedron 1987, 43, 5769–
5774.
6. Nugent, W. Chem. Commun. 1999, 1369–1370.
39. Nevalainen, M.; Nevalainen, V. Tetrahedron: Asymmetry
2001, 12, 1771–1777.
40. Oppolzer, W.; Chapius, C. Tetrahedron Lett. 1984, 25, 5383–
5386.
41. Abraham, R. J.; Fisher, J. Magn. Reson. Chem. 1985, 23,
862–871.
42. Abraham, R. J.; Fisher, J. Magn. Reson. Chem. 1986, 24,
451–459.
43. Karplus, M. J. Chem. Phys. 1959, 30, 11–15.
44. Singh, B. K.; Basu-Mallik, H.; Bhaduri, B. J. Indian Chem.
Soc. 1931, 8, 95–117.
45. Collect Software. Nonius, BV, Delft, The Netherlands,
1998.
´
7. Garcıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641–3644.
8. Bunlaksananusorn, T.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 3941–3943.
9. Bunlaksananusorn, T.; Knochel, P. J. Org. Chem. 2004, 69,
4595–4601.
10. Kadyrov, R.; Ilaldinov, I. Z.; Almena, J.; Monsees, A.;
Riermeier, T. H. Tetrahedron Lett. 2005, 46, 7397–7400.
11. Stanovnik, B.; Svete, J. Targets Heterocycl. Syst. 2000, 4,
105–137.
12. Stanovnik, B.; Svete, J. Synlett 2000, 1077–1091.
13. Svete, J. J. Heterocycl. Chem. 2002, 39, 437–454.
14. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480, and
references cited therein.
46. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276,
307–326.
15. Svete, J. Monatsh. Chem. 2004, 135, 629–647.
16. Stanovnik, B.; Svete, J. Mini-Rev. Org. Chem. 2005, 2, 211–
224.
17. Pirc, S.; Bevk, D.; Jaksˇe, R.; Recˇnik, S.; Golicˇ, L.; Golobicˇ,
A.; Meden, A.; Stanovnik, B.; Svete, J. Synthesis 2005, 2969–
2988.
47. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori,
G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115–119.
48. Hall, S. R.; King, G. S. D.; Stewart, J. M. The Xtal3.4 User’s
Manual; University of Western Australia: Lamb, Perth, 1995.
49. Burnett, M. N.; Johnson, C. K. In ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure Illus-
trations, Oak Ridge National Laboratory Report ORNL-
6895, 1996.
18. Pirc, S.; Bevk, D.; Golobicˇ, A.; Stanovnik, B.; Svete, J. Helv.
Chim. Acta 2006, 89, 30–44.
19. Jaksˇe, R.; Bevk, D.; Golobicˇ, A.; Svete, J.; Stanovnik, B. Z.
Naturforsch. 2006, 61b, 1–7.
ˇ
20. Casar, Z.; Bevk, D.; Svete, J.; Stanovnik, B. Tetrahedron
50. Wang, H.; Robertson, B. E. In Structure and Statistics in
Crystallography; Wilson, A. J. C., Ed.; Adenine Press: New
York, 1985.
2005, 61, 7508–7519.
21. Wagger, J.; Bevk, D.; Meden, A.; Svete, J.; Stanovnik, B.
Helv. Chim. Acta 2006, 89, 240–248.