Stereoselective additions to the exocyclic C{double bond, long}C bond of some α-alkylidene-(+)-camphor derivatives

Article abstract of DOI:10.1016/j.tetasy.2006.04.014

Stereoselective additions to the exocyclic C{double bond, long}C double bond of some (1R,3E,4S)-3-alkylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4E,5S)-4-alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones were studied. All additions took place predominantly from the less hindered endo-face of the methylidene compounds to give the corresponding exo-adducts as the major isomers. Thus, catalytic hydrogenations afforded the α-alkylated (1R,3R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4R,5R)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones in 28-100% de. Similarly, 1,3-dipolar cycloadditions of 2,4,6-trisubstituted benzonitrile oxides gave the corresponding spiro cycloadducts in 66-100% de. The structures were determined by 2D NMR techniques, NOESY spectroscopy and X-ray diffraction.

Full text of DOI:10.1016/j.tetasy.2006.04.014

Tetrahedron: Asymmetry 17 (2006) 1217–1237
Stereoselective additions to the exocyclic C@C bond of some
a-alkylidene-(+)-camphor derivatives
Urosˇ Grosˇelj, David Bevk, Renata Jaksˇe, 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 2 March 2006; accepted 3 April 2006
Abstract—Stereoselective additions to the exocyclic C@C double bond of some (1R,3E,4S)-3-alkylidene-1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ones and (1R,4E,5S)-4-alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones were studied. All additions took place predom-
inantly from the less hindered endo-face of the methylidene compounds to give the corresponding exo-adducts as the major isomers.
Thus, catalytic hydrogenations afforded the a-alkylated (1R,3R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4R,5R)-1,8,8-
trimethyl-2-oxabicyclo[3.2.1]octan-3-ones in 28–100% de. Similarly, 1,3-dipolar cycloadditions of 2,4,6-trisubstituted benzonitrile oxides
gave the corresponding spiro cycloadducts in 66–100% de. The structures were determined by 2D NMR techniques, NOESY spectros-
copy and X–ray diffraction.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(1R,3E,4S)-3-[(dimethylamino)methylidene]-1,7,7-trimeth-
ylbicyclo[2.2.1]heptan-2-one21 and (1R,4E,5S)-4-[(dimeth-
ylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]-
octan-3-one.22 These two reagents were used in various
synthetic applications, such as the stereoselective synthesis
of a-([1,2,4]triazolo[4,3-x]azin-3-yl) substituted camphors21
and analogous compounds,23,24 in the synthesis of terpene-
functionalised pyrazoles,25 in coupling reactions with
amines22 and Grignard reagents,26 and in the preparation
and reductions of (1R,4E,5S)-4-oximino-1,8,8-trimethyl-2-
oxabicyclo[3.2.1]octan-3-one.27 In a continuation of our
work in this field, we herein report catalytic hydrogena-
tions and 1,3-dipolar cycloadditions of stable benzonitrile
oxides to (+)-camphor derived a-alkylidene compounds
4–8 and 11.
(+)-Camphor 1 and its derivatives are among the most fre-
quently employed types of ex-chiral pool starting materials,
building blocks, ligands in various asymmetric reagents
and/or catalysts, resolving agents and as shift reagents in
NMR spectroscopy.1–4 In addition, many camphor deriva-
tives are biologically active. For example, the reaction of
3-hydroxymethylidenecamphor5 with amines, followed
by reduction of the exocyclic C@C double bond, leads to
3-aminomethylcamphor derivatives exhibiting local anes-
thetic and smooth muscle relaxant properties.6–8
Recently, a series of alkyl 2-substituted 3-(dimethyl-
amino)prop-2-enoates and alkyl 3-cyanoprop-2-enoates
have been prepared as versatile reagents for the prepara-
tion of various heterocyclic systems.9–19 Chiral cyclic ena-
mino lactams and lactones, derived from a-amino acids,
have been employed in the synthesis of functionalised het-
erocycles, such as heteroarylalanines and their analogues
and other related heterocyclic systems containing either
an a-amino acid, dipeptide, b-amino alcohol, a-hydroxy
acid or propane-1,2-diol structural element.9–12,18,19 Our
studies on ex-chiral pool derived enaminones have recently
been extended to the preparation and synthetic applica-
tions of two (+)-camphor derived enaminones,
2. Results and discussion
Starting enaminones 221 and 3,22 and a-alkylidene com-
pounds 4b,c,h and 526 were prepared from (1R)-(+)-cam-
phor 1 according to literature procedures. Treatment of 2
with KCN and 2-methyl-1H-indole under acidic conditions
afforded the corresponding dimethylamine substitu-
tion products, (E)-3-[(1R,4S)-1,7,7-trimethyl-2-oxobicy-
clo[2.2.1]heptan-3-ylidene]acetonitrile 628 and (1R,3E,4S)-
1,7,7-trimethyl-3-[(2-methyl-1H-indol-3-yl)methylidene]-
bicyclo[2.2.1]heptan-2-one 7 in 14% and 84% yield, respec-
tively. According to the previously described reactions of
*
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 ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.014

1218
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
the enamino lactone 3,26 treatment of enamino ketone 2
with Grignard reagents also resulted in the stereoselective
substitution of the dimethylamino group to give (E)-a-
alkylidene-(+)-camphors 8a,c–i in 51–95% yields. a-Benz-
ylidene-(+)-camphors 8e–i were formed as pure (E)-iso-
mers, while their a-alkylidene analogues 8a,c,d were
formed as mixtures of the major (E)-isomers 8a,c,d and
the minor (Z)-isomers 80a,c,d. Upon chromatographic
purification over silica gel, the (E)-isomers 8a,c,d were
obtained. In the same manner, compound ent-8h was
prepared in two steps from (ꢀ)-camphor ent-1 via
(1S,3E,4R)-3-[(dimethylamino)methylidene]-1,7,7-trimeth-
ylbicyclo[2.2.1]heptan-2-one ent-2. It is noteworthy that the
carbonyl group did not react, despite the presence of excess
Grignard reagent. In contrast to the previously reported
nitrosation of enamino lactone 3 with aqueous sodium
nitrite in the presence of hydrochloric acid,27 reaction of
3 with tert-butyl nitrite in anhydrous dichloromethane in
the presence of CF3COOH took place at the dimethyla-
mino group and not at the exocyclic C@C double bond
to give N-methyl-N-{[(1R,4E,5S)-1,8,8-trimethyl-3-oxo-2-
oxabicyclo[3.2.1]octan-4-ylidene]methyl}nitrous amide 11
in 50% yield. Although we do not have a firm mechanistic
explanation for this, rather unusual, nitroso-demethylation
reaction, the reaction mechanism might involve migration
of a methyl group from the nitrogen to the oxygen atom
via a Stevens-type rearrangement. Presumably, the dimeth-
ylamino group undergoes addition to the in situ formed ni-
trous acid to give zwitterionic adduct 9, followed by N!O
migration of a methyl group to form intermediate 10, from
which elimination of methanol takes place to furnish
N-methyl-N-nitrosoamino compound 11 (Scheme 1 and
Table 1).
Next, catalytic hydrogenations of a-methylidene com-
pounds 3, 4b, 7 and 11 in the presence of Pd–C under
50 bar of hydrogen were carried out. Hydrogenation of 3
in n-propanol at 60 ꢁC gave (1R,4R,5R)-1,4,8,8-tetra-
methyl-2-oxabicyclo[3.2.1]octan-3-one 13 in 83% yield
and 28% de. Formation of compound 13 could be ex-
plained by initial hydrogenolytic removal of the dimethyl-
amino group to give the a-methylidene intermediate 12,
followed by addition of hydrogen to the exocyclic C@C
double bond. This proposed reaction mechanism is sup-
ported by a related transformation of ethyl 2-benzoyl-3-
(dimethylamino)prop-2-enoate with sodium cyanoboro-
1 CN
1'
R
2'
2
6'
3'
5'
O
4'
O
O
Ref. 26
v
6
Me2N
HN
4'
NMe2
3'
4b,c,h
5
4
4
iv
v
3
Me
5
6
6
7
3
ii, iii
vi
i
8
7
O
2
Ref. 21
Ref. 22
NC
O
O 2
O
O
1
1
iv
O
Ref. 26
2
1
3
R
O
O
7
5
O
F
O
i
iv
8a,c-i
O
NMe2
ent-1
ent-2
ent-8h
OMe
O
N
O
N
HO
N
H3C
H3C
O
N
H
Me2N
N
N
N
O
H3C
Me
OH
O
vii
O
O
O
O
O
O
O
9
10
11
3
Scheme 1. Reagents and conditions: (i) bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent), DMF, reflux; (ii) AcOOH, AcOH, AcONa, rt; (iii)
bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent), decalin, reflux; (iv) RMgX, THF, ꢀ78 ꢁC ! rt; (v) KCN, AcOH, rt; (vi) 2-methyl-1H-
indole, EtOH, HCl (1 equiv), reflux; (vii) tert-butyl nitrite, CH2Cl2, CF3COOH, rt.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
Table 1. Experimental data for alkylidene compounds 4–8, 11 and 17
1219
was somewhat surprising, since the literature reported
hydrogenation of the enamino ketone 2 resulted only in
saturation of the C@C double bond.7,30 Hydrogenation
of compound 4b in ethanol at 50 ꢁC yielded (1R,4R,5R)-
1,8,8-trimethyl-4-propyl-2-oxabicyclo[3.2.1]octan-3-one 14
in 98% yield and 76% de. Crystallisation of this mixture
of isomers 14 and 140 furnished isomerically pure com-
pound 14. On the other hand, hydrogenation of 7 in etha-
nol at 50 ꢁC was highly stereoselective and gave
isomerically pure (1R,3R,4R)-3-[(2-methyl-1H-indol-3-yl)-
methyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 15 in
86% yield. Compound 15 turned out to be quite unstable
and slowly decomposed, even when kept under argon and
in the absence of light (Scheme 2 and Table 2).
Compound
R
E:Z
Yield (%)
4b
4c
Et
n-Bu
4-Fluorophenyl
—
—
—
Me
n-Bu
Cyclopentyl
Ph
2-Methylphenyl
4-Methylphenyl
4-Fluorophenyl
4-Fluorophenyl
3,5-Bis(trifluoromethyl)phenyl 100:0
—
—
100:0a
100:0a
100:0a
100:0a
100:0
100:0
98:2b
95:5b
85:15b 51c
100:0
100:0
100:0
100:0
100:0
83a
68a
64a
49a
14
4h
5
6
7
84
8/80a
8/80c
8/80d
8e
93c
95c
91
90
93
91
96
70
50
8f
8g
8h
ent-8h
8i
11
17/170
Hydrogenation of compound 11 in n-propanol at 35 ꢁC
afforded a mixture of the major (1R,4E,5S)-1,8,8-tri-
methyl-4-[(methylamino)methylidene]-2-oxabicyclo[3.2.1]-
octan-3-one 17 and its minor (1R,4Z,5S)-isomer 170 in a
ratio of 73:27 and in 97% yield. Subsequent crystallisation
furnished a mixture of 17 and 170 in a ratio of 95:5. Forma-
tion of 17 and 170 may be due to initial reduction of the ni-
troso group to give the enehydrazine intermediate 16,
followed by N–N bond fission, and partial E/Z-isomerisa-
tion of 1722 via the imino tautomeric form 1700. To our
100:0
73:27d 97
a Ref. 26.
b E:Z ratio of the crude product. CC afforded pure (E)-isomer.
c Yield of the pure (E)-isomer.
d Upon crystallisation, the E:Z ratio changed to 95:5.
hydride into ethyl 2-benzoylpropanoate, reported previ-
ously.29 Nevertheless, the loss of dimethylamino group
Me2N
Me
Me
i
O
O
O
O
O
13:13' = 64:36
and
(28% de)
O
O
O
O
3
12
13
Et
13'
Et
Et
i
O
O
14:14' = 88:12
and
(76% de)
O
O
O
4b
14
14'
HN
HN
Me
Me
N
Me
i
100% de
O
O
O
O
7
15
17''
NO
O
NH2
O
Me
Me
N
O
Me N
HN
O
Me
NH
i
O
O
O
and
O
11
16
17
17:17' = 73:27
17'
Scheme 2. Reagents and conditions: (i) H2 (50 bar), 10% Pd–C, EtOH or n-PrOH, 35–60 ꢁC, 24–120 h.

1220
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
Table 2. Selected experimental data of (cyclo)addition products 13–15 and 19–24
Reaction
R
Reaction conditions
Yield (%)
De (%)a
3 ! 13/130
—
—
—
—
—
—
Et
n-Bu
H2 (50 bar), Pd–C, n-PrOH, 60 ꢁC, 120 h
H2 (50 bar), Pd–C, EtOH, 50 ꢁC, 24 h
H2 (50 bar), Pd–C, EtOH, 50 ꢁC, 24 h
Toluene, reflux, 4 h
Toluene, 65 ꢁC, 36 h
Toluene, reflux, 5 h
Decalin, reflux, 6 h
Decalin, reflux, 6 h
Decalin, reflux, 6 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
Anisole, 215 ꢁC, MW, 3 h
83
98
86
46b
42d
40
8
10
49
27
11
30
38
23
28
29
60
9
28
76
100
100c
100c
—
100
100
76
84e
100e
89
66
90
88
92
88
92
86
86
4b ! 14/140
7 ! 15
5 + 18a ! 19 + 20
5 + 18a ! 19 + 20
6 + 18a ! 21
4b + 18a ! 22b
4c + 18a ! 22c
4h+18a ! 22h
8a + 18a ! 23a
8c + 18a ! 23c
8e + 18a ! 23e
8f + 18a ! 23f
8g + 18a ! 23g
8h + 18a ! 23h
ent-8h + 18a ! ent-23h
8i + 18a ! 23i
8f + 18b ! 24f
8h + 18b ! 24h
8i + 18b ! 24i
4-Fluorophenyl
Me
n-Bu
Ph
2-Methylphenyl
4-Methylphenyl
4-Fluorophenyl
4-Fluorophenyl
3,5-Bis(trifluoromethyl)phenyl
2-Methylphenyl
4-Fluorophenyl
3,5-Bis(trifluoromethyl)phenyl
4
17f
a Determined by 1H NMR of the crude reaction mixture.
b 19:20 = 64:36.
c De of compound 20.
d 19:20 = 76:24.
e De was determined by 1H NMR of partially purified product (upon CC and MPLC).
f Yield of the purified 24i (100% de). According to 1H NMR of the crude reaction mixture, the conversion was ꢁ23%.
surprise, hydrogenation did not take place at the exocyclic
C@C double bond (Scheme 2 and Table 1).
out. In contrast to the previously reported cycloadditions
to a-cyanomethylidene substituted c-lactams17–19 and c-
lactones,20 1,3-dipolar cycloaddition of nitrile oxide 18a
to the dipolarophile 5 gave a mixture of spiro compound
19 and the 1,2,4-oxadiazole 20 in a ratio of 64:36, respec-
1,3-Dipolar cycloadditions of 2,4,6-trimethoxybenzonitrile
oxide 18a to the unsaturated nitriles 5 and 6 were carried
OMe
OMe
MeO
OMe
N
MeO
OMe
N
O
3'
NC
4'
NC
2'
N
5
5'
6
O
i, ii
1'
19:20 = 64:36; (at 100 °C)
4
O
O
O
and
19:20 = 76:24; (at 65 °C )
3
7
O
8 O2
O
1
5
19
20
major product
minor product
OMe
MeO
N
OMe
O
N
CN
O
i
O
6
21
Scheme 3. Reagents and conditions: (i) 2,4,6-trimethoxybenzonitrile oxide (18a) (1 equiv), toluene, reflux; (ii) chromatographic purification (CC and
MPLC).

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1221
tively, and in a combined yield of 46%. When the reaction
was carried out at 65 ꢁC, the ratio of products changed in
favour of the spiro compound 19 (19:20 = 76:24). Further
chromatographic separation of this product mixture af-
forded the pure spiro product 19. Furthermore, reaction of
18a with the dipolarophile 6 furnished the 1,2,4-oxadiazole
21, exclusively. Formation of 1,2,4-oxadiazoles 20 and 21
might be attributed to steric factors, since the exocyclic
C@C bond is sterically more hindered by the terpene resi-
due than the C„N bond (Scheme 3 and Table 2).
oxides, the reactions had to be performed at higher temper-
atures. Thus, within the lactone 4b,c,h series, reactions were
carried out with 18a in refluxing decalin and furnished the
expected spiro cycloadducts 22b,c,h in 8–49% yield. Com-
pounds 22b and 22c were obtained in isomerically pure
forms, while cycloadduct 22h was isolated in 76% de.
Further chromatographic separation of 22/220h afforded
isomerically enriched major isomer 22h in 35% yield and
94% de and isomerically pure minor isomer 220h in 1%
yield. On the other hand, the above mentioned reaction
conditions were not applicable for the cycloadditions of
benzonitrile oxides 18a,b to a-alkylidene ketones 8a,c–i
and ent-8h, due to low conversions and formation of vari-
ous by-products. However, when cycloadditions were
carried out in anisole under microwave irradiation at
215 ꢁC, a series of cycloadducts 23a,c,e–i, ent-23h and
Finally, 1,3-dipolar cycloadditions of 18a and 2,4,6-trim-
ethylbenzonitrile oxide 18b to a-alkylidene lactones 4b,c,h
and a-alkylidene ketones 8a,c–i and ent-8h were studied.
Since the C@C double bonds of the dipolarophiles 4 and
8 are less activated for 1,3-dipolar cycloadditions to nitrile
OMe
OMe
OMe
MeO
R
MeO
R
OMe
OMe
R
N
O
N
O
i, iii
MeO
OMe
O
O
O
and
+
C
N
O
O
O
O
22'b,c,h
22b,c,h
18a
4b,c,h
(minor isomer)
(major isomer)
R'
R'
R'
R'
R'
R
R
4'
5'
R
O
3'
R'
N
R'
R'
R'
1
6
ii, iii
N 2'
C
N
O
2
+
O
O
23 (R' = OMe)
and
O
7
5
O1'
24 (R' = Me)
3
4
18a (R' = OMe)
18b (R' = Me)
8a,c,e-i
23'a,c,e-i, 24'f,h,i
23a,c,e-i, 24f,h,i
(minor isomer)
(major isomer)
OMe
O
O
N
O
O
O
ii, iii
and
+
N
MeO
OMe
OMe
OMe
OMe
C
N
O
H
MeO
H
MeO
F
F
F
OMe
Me
18a
ent-23h
ent-23'h
ent-8h
(major isomer)
(minor isomer)
Me
H
anisole, MW, 215 °C
H
O
O
8f
8'f
(E)-isomer
(Z)-isomer
Scheme 4. Reagents and conditions: (i) decalin, reflux; (ii) anisole, 215 ꢁC (MW irradiation, 300 W, 3–5 bar); (iii) chromatographic purification (CC and/
or MPLC).

1222
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
24f,h,i was synthesised in 4–60% yields and in 66–100% de.
An exception was (1R,3E,4S)-3-(cyclopentylmethylidene)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 8d, which did
not react with nitrile oxide 18a (Scheme 4 and Table 2).
nations of the exocyclic C@C bond in compounds 3, 4b and
7 proceeded selectively from the sterically less hindered
endo-face and led to the corresponding exo-products 13–
15 as the major isomers. Similarly, 1,3-dipolar cycloaddi-
tions of benzonitrile oxides 18a and b to the dipolarophiles
4b,c,h, 5 and 8a,c,e–i took place preferentially from the less
hindered endo-face (Fig. 1).
Reductions and other transformations of camphor at the 3-
position often afford initial kinetically controlled exo-prod-
ucts, as a result of an attack of a reagent from the less
hindered endo-face of the bicyclic system. Epimerisation of
the exo-isomers, either in situ or as isolated products, can
afford thermodynamically more stable endo-isomers, which
are sterically less hindered.1,7,30–34 The literature data for
the reductions of a-methylidene camphor derivatives into
the corresponding methylene products usually report mod-
erate exo-selectivitiy, ranging from 34% de to 100% de.1,33–36
Moderate endo-selectivity, which has been reported in
the catalytic hydrogenation of 3-[(dimethylamino)methyli-
dene]camphor 2,7,30 can be explained by partial in situ
base-promoted epimerisation of the less stable exo-epimer
into the more stable endo-isomer.31–34 In our case, hydroge-
High temperatures, employed in the above mentioned 1,3-
dipolar cycloadditions of nitrile oxides 18, could cause par-
tial in situ E/Z-isomerisation of dipolarophiles 4 and 8.
Consequently, minor isomers 190 and 220–240 would not
be formed by attack of nitrile oxide 18 from the more hin-
dered exo-face of the (Z)-dipolarophiles 4 and 8 (cf. Fig. 1)
but rather by attack from the less hindered endo-face of the
(E)-dipolarophiles 40 and 80. In order to clarify this issue,
the dipolarophile 8f was heated in anisole at 215 ꢁC under
microwave irradiation for 3 h, followed by evaporation of
1
the solvent. The H NMR spectrum of the residue was
identical to the spectrum of the starting compound 8f, thus
hindered
H
R
H
R
preferential endo-addition
and
O
O
O
R
H
O
O
O
less hindered
H2-cat.
3, 4b
13', 14'
13, 14
minor endo-isomers
major exo-isomers
hindered
NH
Me
NH
endo-addition
H
Me
H
O
O
less hindered
H2-cat.
7
exo-isomer 15
hindered
H
R
O
preferential
Ar
N
O
R
H
endo-addition
and
Ar
N
O
O
O
O
O
H
R
O
less hindered
4b,c,h, 5
19
22'h
major (1R,4R,4'S,5S)-isomer
22b,c,h
minor (1R,4S,4'S,5S)-isomer
O N C Ar
major (1R,4R,4'R,5S)-isomer
18a
H
R
Ar
N
O
R
preferential endo-addition
Ar
N
and
O
H
O
H
O
O
R
less hindered
8a,c,e-i
23a,e-i, 24'f,h,i
23a,c,e-i, 24f,h,i
minor (1R,3S,4S,4'S)-isomer
major (1R,3R,4S,4'R)-isomer
O N C Ar
18a,b
Figure 1. Stereoselectivity of additions to the exocyclic C@C double bond.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1223
revealing that no E/Z-isomerisation took place. This exper-
iment supported formation of two isomeric cycloadducts
via facial differentiation and not via (otherwise possible)
Z/E-isomerisation of the dipolarophile (Scheme 4, see also
Fig. 1).
cally pure form. Compounds 13/130, 17/170, 22/220h and
23/230f were characterised as mixtures of the major isomers
13, 17, 22h and 23f and the minor isomers 80a,c,d, 130, 170,
220h and 230f. The minor isomer 220h was characterised by
1
mp, H NMR, EI-MS and HRMS, while the other minor
isomers 130, 140, 170, 230a,e–i and 24f,h,i were only charac-
terised by 1H NMR. Compound 20 could not be separated
from a mixture of isomeric products 19 and 20 and was
3. Structure determination
1
characterised by H NMR and by elemental analysis as a
The structures of compounds 6, 7, 8a,c–i, 11, 13/130, 14/140,
15, 17/170, 19–21, 22b,c, 22/220h, 23/230a,c,e–i, 23c, ent-23/
230h and 24/240f,h,i were determined by spectroscopic
mixture of isomeric compounds 19 and 20. Compounds
ent-2, 8a,c–g, 11, 13, 15, 23a,c,e–i and ent-23h were not pre-
pared in analytically pure form; their identities were con-
firmed by 13C NMR and EI–HRMS.
1
methods (IR, H and 13C NMR, 2D NMR, NOESY spec-
troscopy, MS) and by elemental analyses for C, H and N.
Compounds 6, 7, 8a,c–i, 11, 14, 15, 19, 21, 22a,b, 220h,
23a,c,e,g–i, ent-23h and 24f,h,i were prepared in isomeri-
The configuration around the exocyclic C@C double bond
in compounds 6, 8f,h,i and 21 was determined by NMR on
F
Ar
F3C
CF3
N
O
NO
N
Me
5
N
4'
CN
Me
4
H
4
3'
3
5
6
6
7
C3 O
H
H
H
H
H
8
7
C 2
C
C
C
C
O
O
O
O
O
O
2
1
1
21
11
6
8h
8i
8f
(E)-isomer
(E)-isomer
(E)-isomer
(E)-isomer
(E)-isomer
(E)-isomer
Compound 6: 3JC-H = 5.3 Hz (cis)
3
Compound 8i: JC-H = 6.0 Hz (cis)
Compound 11: 3JC-H = 5.7 Hz (cis)
Compound 21: 3JC-H = 5.9 Hz (cis)
3
Compound 8f: JC-H = 6.3 Hz (cis)
3
Compound 8h: JC-H = 6.1 Hz (cis)
n.O.e.
n.O.e.
n.O.e.
n.O.e.
n.O.e.
H
Me
H
N
H
H H2C
H
H
O
H
H
O
H
H
H
H
O
O
O
O
8c
17
8d
8'c
8'd
(E)-isomer
(E)-isomer
E)-isomer
(
(Z)-isomer
(Z)-isomer
n.O.e.
n.O.e.
R
8
9
10
9
CH3
CH3
7
8
H3C
H3C
H
R
H
Ar
4'
5
4
4'
Ar
6
3'
5'
3
5
4
O3
6
3'
5'
7
N 2'
O
N
1
1
O
1'
2
2 O
2'
1'
O
23a,c,e-i, 24f,h,i
22b,h
(1R,3R,4S,4'R)-isomers
(1R,4R,4'R,5S)-isomers
H
H
H
H
O
H
Ha
Hb
H
3
5
R
Ha
Hb
Ha
Hb
5
R
4
6
5
6
4
4
R
O
O
O
O
13, 14
15
13', 14'
(1R,4R,5R)-isomers
(1R,3R,4R)-isomer
(1R,4S,5R)-isomers
3JH3-H4 ~ 0 Hz
3JH4-H5 ~ 0 Hz
4JH4-H6a ~ 0 Hz
3JH4-H5 = 4.5-4.8 Hz
4JH3-H5 ~ 0 Hz
4JH4-H6a = 1.6-1.7 Hz
Figure 2. Structure determination by 1H NMR, HMBC and NOESY spectroscopy.

1224
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
Table 3. Selected 1H NMR data for compounds 6–8, 13–15, 20 and 22–24
3
0
the basis of long-range coupling constants, JC(2)–H(3 ), be-
tween the methylidene proton (H–C(30)) and the carbonyl
carbon atom (O@C(2)), measured from the antiphase split-
ting of cross peaks in the HMBC spectrum. Generally, the
magnitude of coupling constants, 3JC–H, for nuclei with cis-
configuration around the C@C double bond are smaller (2–
6 Hz) than that for trans-oriented nuclei (8–12 Hz).13,37–47
The magnitude of the coupling constant in compounds 6,
8f,h,i and 21 (3JC–H = 5.3–6.3 Hz) was in agreement with
the (E)-configuration. In the same manner, the (E)-config-
Solvent
d (ppm)
H–C(30)
H–C(4)
(1R,3E,4S)-Isomers 6–8
6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
6.20
7.44
6.42
6.36
6.29
7.24
7.41
7.18
7.19
7.24
2.98
3.04
2.71
2.69
2.71
3.11
2.93
3.10
3.05
3.00
7
8a
8c
8d
8e
8f
8g
8h
8i
uration of compound 11 was established on the basis of the
magnitude of coupling constant, JC(3)–H(4 ) = 5.7 Hz, be-
tween the carbonyl carbon atom (O@C(3)) and the methyl-
3
0
idene proton (H–C(40)) (Fig. 2).
(1R,3Z,4S)-Isomers 80
80a
80c
80d
CDCl3
CDCl3
CDCl3
5.83
5.75
5.65
2.39
2.39
2.37
Additionally, the configuration around the exocyclic C@C
double bond in isomeric compounds 8c,d and 80c,d was
established by NOESY spectroscopy. The NOE between
the allylic proton(s) and H–C(4) indicated the (E)-config-
uration of 8c,d, while the NOE between H–(30) and H–
C(4) in the minor isomers 80c,d was in agreement with
the (Z)-configuration. Similarly, the NOE between N–H
and H–C(5) suggested the (E)-configuration of compound
17. The E/Z-configuration of compounds 17 and 170 was
also established by correlation of chemical shifts d for H–
C(40) and NH with typical values, reported previously for
a series of closely related (1R,5S)-4-alkylaminomethylid-
ene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones.22 In
the spiro cycloadduct series, the NOE between H–C(40)
and the bridge methyl group in compounds 22b,h,
23a,c,e–i, ent-23h and 24f,h,i supported the proposed con-
figuration at the newly formed stereogenic centres
(Fig. 2).
d (ppm)
JH–H (Hz)
4–5 4–6
H–C(4)
(1R,4R,5R)-Isomers 13, 14
13
14
CDCl3
CDCl3
2.49
2.27
0
0
0
0
(1R,4S,5R)-Isomers 130, 140
130
140
CDCl3
CDCl3
2.87
2.66
4.8
4.5
1.7
1.6
d (ppm)
JH–H (Hz)
H–C(3)
2.21
3–4
0
3–5
0
(1R,3R,4R)-Isomer 15
CDCl3
d (ppm)
H–C(40)
(1R,4R,40S,5S)-Isomer 19 and (1R,4R,40R,5S)-isomers 22
H–C(5)
The configuration at the 4-position in compounds 13, 130,
14 and 140, as well as at the 3-position in compound 15,
was determined by NMR on the basis of vicinal coupling
19
22b
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
5.19
3.87
3.86
5.20
5.36
ꢁ2.8a
ꢁ2.5a
ꢁ2.5a
ꢁ2.2a
2.08
22c
22h
3
3
constants, JH(3)–H(4) and JH(4)–H(5). The dihedral angles
between H–C(4) and H–C(5) in the major exo-isomers 13
and 14 and between H–C(3) and H–C(4) in the exo-isomer
15 are close to 90ꢁ and, following the Karplus equation,48
no appreciable coupling between these protons would
be expected. Accordingly, negligible coupling constants,
(1R,4S,40S,5S)-Isomer 220h
H–C(40)
H–C(4)
(1R,3R,4S,40R)-Isomers 23, 24
23a
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.57
3.60
4.80
5.14
4.78
4.79
4.94
4.79
4.47
4.63
2.39
2.43
3JH3–H4 ꢁ 0 Hz and JH4–H5 ꢁ 0 Hz, were observed in the
23c
23e
3
2.02
1H NMR spectra of the exo-isomers 13–15. On the other
hand, a coupling constant, 3JH4–H5 = 4.5–4.8 Hz was char-
acteristic for the minor endo-isomers 130 and 140, due to a
smaller dihedral angle (ꢁ30ꢁ) between H–C(4) and H–C(5).
Furthermore, a long-range coupling, JH4–H6a = 1.6–1.7 Hz,
between H–C(4) and Ha–C(6), by the virtue of the ‘W’ con-
figuration,49 was observed in minor endo-isomers 130 and
140. Similar patterns of multiplicities for H–C(4) and mag-
nitudes of coupling constants, JH4–H5 and JH4–H6a, were
also reported in the literature for analogous compounds
(Fig. 2 and Table 3).21,23,24,27,50,51
23f
23g
ꢁ2.36a
2.01
23h and ent-23h
1.99
23i
24f
24h
24i
ꢁ1.78a
2.49
2.20
ꢁ1.82a
H–C(40)
H–C(4)
(1R,3S,4S,40S)-Isomers 230, 240
23a
a
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.43
4.61
5.03
4.59
4.59
4.72
4.66
4.34
4.49
23e
23f
a
a
a
a
a
a
a
The structures of compounds 8h, 19, 22b, 23a, 23f, 23g, ent-
23h and 24h were determined by X-ray diffraction (Figs. 3–
10).
23g
23h and ent-23h
23i
24f
24h
24i
Data for the known compounds 6,28 8a,54 8c,55 8e,54,56 8g31
and 8h57 were consistent with the literature data.
a Overlapped by other signals.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1225
Figure 3. The asymmetric unit of compound 8h. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
4. Conclusion
addition took place at the exocyclic C@C bond, as well as
at the cyano group to give a mixture of spiro compound 19
and 1,2,4-oxadiazole 20. The ratio between products 19
and 20 was temperature dependent. On the other hand,
1,3-dipolar cycloadditions of 18a,b to a-alkylidene lactones
4b,c,h and a-alkylidene camphors 8a,c,e–i were diastereo-
selective and afforded the corresponding spirolactones
22b,c,h and spirocamphors 23a,c,e–i and 24f,h,i in low to
moderate yields and in 66–100% de. The exo-selectivity of
the additions to the exocyclic C@C bond is in agreement
with the literature data and seems to be dependent on the
substituent attached to the methylidene carbon atom, as
well as on the type of the terpene residue. Spiro compounds
Catalytic hydrogenation of a-alkylidene compounds 3, 4b
and 7 proceeded stereoselectively from the sterically less
hindered endo-face to afford the major exo-isomers of
hydrogenation products 13–15 in 28–100% de. On the
other hand, catalytic hydrogenation of compound 11 took
place only at the nitroso group to furnish a mixture of
isomers 17 and 170. 1,3-Dipolar cycloadditions of stable
benzonitrile oxides 18a,b to the dipolarophiles 4b,c,h, 5, 6
and 8a,c,e–i led to two types of products. In the case of
the unsaturated nitrile 6, 1,2,4-oxadiazole 21 was the only
product, while in the case of the lactone analogue 5, cyclo-
Figure 4. The asymmetric unit of compound 19. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.

1226
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
Figure 5. The asymmetric unit of compound 22b. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
Figure 6. The asymmetric unit of compound 23a. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
19 and 22–24 might be useful intermediates for further
reductive transformations into novel nonracemic camphor
derived c-amino alcohols.
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. Microwave irradiations were performed
on a CEM Discover laboratory microwave oven.
5. Experimental
5.1. General methods
Column chromatography (CC) was performed on silica gel
(Fluka, silica gel 60, 0.04–0.06 mm). Medium pressure
liquid chromatography (MPLC) was performed with a
Melting points were determined on a Kofler microhot
Buchi isocratic system with detection on silica gel;
¨
detection: UV 254 nm; sample amount: 100–150 mg of iso-
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. Mass spectra were
Donation of Alexander von Humboldt Foundation.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1227
Figure 7. The asymmetric unit of compound 23f. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
Figure 8. The asymmetric unit of compound 23g. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
meric mixture per each run. MPLC column characteristics:
(a) dry filled column: 15 · 460 mm, Merck, silica gel 60, 15–
035 lm, backpressure ꢁ12 bar; (b) wet filled column:
15 · 460 mm, Merck, LiChrospherꢂ, 12 lm, backpressure
Et2O), [3,5-bis(trifluoromethyl)phenyl]magnesium bromide
(0.5 M in THF), MeMgCl (3 M in THF), n-BuMgCl (2 M
in THF), cyclopentylmagnesium chloride (2 M in Et2O),
potassium cyanide, 2-methyl-1H-indole and tert-butyl
nitrite are commercially available (Fluka AG). (1R,3E,4S)-
3-[(Dimethylamino)methylidene]-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-one 2,21 (1R,4E,5S)-4-[(dimethylamino)
methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-
one 3,22 (1R,4E,5S)-1,8,8-trimethyl-4-propylidene-2-oxabi-
1
ꢁ26 bar. Ratio of isomers and de were determined by H
NMR.
PhMgBr (1 M in THF), 4-Me–C6H4MgBr (1 M in Et2O),
2-Me–C6H4MgCl (1 M in THF), 4-F–C6H4MgBr (2 M in

1228
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
Figure 9. The asymmetric unit of compound ent-23h. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
Figure 10. The asymmetric unit of compound 24h. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of arbitrary radii.
cyclo[3.2.1]octan-3-one 4b, (1R,4E,5S)-1,8,8-trimethyl-4-
pentylidene-2-oxabicyclo[3.2.1]octan-3-one 4c, (1R,4E,
5S)-4-(4-fluorobenzylidene)-1,8,8-trimethyl-2-oxabicyclo-
[3.2.1]octan-3-one 4h and (1R,4E,5S)-4-(cyanomethylid-
Sources of chirality: (a) (+)-camphor (1) (Fluka AG),
product number 21,300, purum, natural, P97.0%
20
(GC, sum of enantiomers), ½aꢂ546 ¼ þ54:5 ꢃ 2:5 (c 10,
20
EtOH), ½aꢂD ¼ þ42:5 ꢃ 2:5 (c 10, EtOH), mp 176–180 ꢁC,
ene)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one
5,26
ee not specified; (b) (ꢀ)-camphor (ent-1) (Fluka AG), prod-
2,4,6-trimethoxybenzonitrile oxide 18a and 2,4,6-trim-
ethylbenzonitrile oxide 18b52,53 were prepared according
to the literature procedures.
uct number 21,295, purum, natural, P95.0% (GC, sum
20
of enantiomers), ½aꢂD ¼ ꢀ43 ꢃ 2 (c 10, EtOH), mp and ee
not specified.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1229
5.2. (1S,3E,4R)-3-[(Dimethylamino)methylidene]-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-one ent-2
5.5. General procedure for the preparation of (1R,3E,4S)-3-
alkylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones 8a,c–i
and (1S,3E,4R)-3-(4-fluorobenzylidene)-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-one ent-8h
This compound was prepared from (1S)-(ꢀ)-camphor ent-1
(5 g, 33 mmol) and Bredereck’s reagent (8.9 ml, 43 mmol)
in refluxing DMF (40 ml) according to the literature proce-
dure for the preparation of its (1R,2E,4S)-enantiomer 2.21
A solution of 2 or its enantiomer ent-2 (1.037 g, 5 mmol) in
anhydrous THF (15 ml) was cooled to ꢀ78 ꢁC under argon
and a solution of Grignard reagent in THF or Et2O
(15 mmol) then added slowly over a period of 5 min. The
mixture was stirred at ꢀ78 ꢁC for 1 h, warmed up to rt,
and stirred at rt for an additional 24 h. Then saturated
aq NH4Cl (30 ml) was added, the mixture was stirred at
rt for 1 h, poured into brine (70 ml) and the product ex-
tracted with CH2Cl2 (3 · 70 ml). The organic phases were
combined, dried over anhydrous Na2SO4, filtered and the
filtrate evaporated in vacuo to give the crude 8/80 and
ent-8/80h.à The residue was purified by column chromatog-
raphy (CC). Fractions containing the product were com-
bined and evaporated in vacuo to give 8a,c–i and ent-8h.
The following compounds were prepared in this manner.
Yield: 2.183 g (32%) of a dirty white solid; mp 60–63 ꢁC,
21
lit.21 mp 59–62 ꢁC; ½aꢂD ¼ ꢀ455:7 (c 0.19, CH2Cl2). m/z
(EI) = 207 (M+); m/z (HRMS) found: 207.162650 (M+);
C13H21NO requires: m/z = 207.162314 (Found: C, 75.28;
H, 10.50; N, 7.85. C13H21NO requires: 75.32; H, 10.21;
1
N, 6.76.) H NMR and IR data for ent-2 were identical
to the literature data for its (1R,3E,4S)-enantiomer 2.21
5.3. (E)-3-[(1R,4S)-1,7,7-Trimethyl-2-oxobicyclo[2.2.1]-
heptan-3-ylidene]acetonitrile 6
KCN (0.130 g, 2 mmol) was added to a solution of 2
(0.207 g, 1 mmol) in acetic acid (100%, 3 ml) and the mix-
ture was stirred at rt for 120 h. Volatile components were
evaporated in vacuo and the residue suspended in CH2Cl2
(50 ml). The so formed suspension was filtered, the undis-
solved material washed with CH2Cl2 (50 ml) and the filtrate
evaporated in vacuo. The residue was purified by CC
(Et2O) and MPLC (dry filled column, EtOAc–hexanes,
1:10). Fractions containing the product were combined
and evaporated in vacuo to give 6. Yield: 27 mg (14%) of
5.5.1. (1R,3E,4S)-3-Ethylidene-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one 8a and its (1R,3Z,4S)-isomer 80a. Prepared
from 2 and MeMgCl (3 M in THF); 8a:80a = 98:2. CC
(EtOAc–hexanes, 1:30) afforded isomerically pure 8a.
5.5.1.1. Data for the major (1R,3E,4S)-isomer
8a. Yield: 0.829 g (93%) of a colourless oil, lit.54 mp 28–
21
a
white solid; mp 40–45 ꢁC, lit.28 mp 46–47 ꢁC;
29 ꢁC; 8a:80a = 100:0; ½aꢂD ¼ þ185:1 (c 1.51, CHCl3),
23
20
1
½aꢂD ¼ þ183:7 (c 0.40, CH2Cl2). H NMR (DMSO-d6): d
0.75, 0.93, 0.99 (9H, 3s, 1:1:1, 3 · Me); 1.34–1.44, 1.78–
1.85 and 2.11–2.20 (4H, 3m, 2:1:1, 2 · CH2); 2.98 (1H, d,
J = 4.1 Hz, H–C(4)); 6.20 (1H, d, J = 0.8 Hz, H–C(30)).
13C NMR (CDCl3): d 9.4, 18.2, 21.2, 26.4, 30.2, 46.2,
51.4, 58.5, 95.6, 116.4, 162.7, 204.2 (Found: C, 75.90; H,
8.24; N, 7.13. C12H15NO requires: 76.16; H, 7.99; N,
7.40.) mmax (KBr) 2962, 2222 (C„N), 1740 (C@O), 1645,
lit.54 ½aꢂD ¼ þ178:6 (C6H6). m/z (EI) = 178 (M+); m/z
(HRMS) found: 178.136120 (M+); C12H18O requires: m/
1
z = 178.135765. H NMR (CDCl3): d 0.78, 0.96 (9H, 2s,
1:2, 3 · Me); 1.29–1.44 (2H, m, 2H of CH2); 1.61–1.73
(1H, m, 1H of CH2); 1.77 (3H, d, J = 7.2 Hz, Me); 1.95–
2.07 (1H, m, 1H of CH2); 2.71 (1H, d, J = 4.1 Hz, H–
C(4)); 6.42 (1H, dq, J = 0.7, 7.2 Hz, H–C(30)). 13C NMR
(CDCl3): d 9.6, 14.5, 18.7, 20.8, 26.6, 30.8, 46.4, 47.6,
58.2, 125.7, 144.1, 207.4. mmax (NaCl) 2959, 1730 (C@O),
1667 (C@O), 1445, 1390, 1372, 1323, 1255, 1170, 1105,
1450, 1375, 1323, 1257, 1107, 1065 cmꢀ1
.
5.4. (1R,3E,4S)-1,7,7-Trimethyl-3-[(2-methyl-1H-indol-3-yl)-
methylidene]bicyclo[2.2.1]heptan-2-one 7
1068, 933, 874, 795 cmꢀ1
.
5.5.1.2. NMR data for the minor (1R,3Z,4S)-isomer
80a. 1H NMR (CDCl3): d 2.39 (1H, d, J = 4.1 Hz, H–
C(4)); 5.83 (1H, q, J = 7.2 Hz, H–C(30)).
Hydrochloric acid (37%, 0.10 ml, ꢁ1 mmol) was added to a
solution of 2 (0.207 g, 1 mmol) and 2-methyl-1H-indole
(0.131 g, 1 mmol) in anhydrous ethanol (3 ml) and the mix-
ture was heated under reflux for 5 h. Volatile components
were evaporated in vacuo and the residue was purified by
CC (EtOAc–hexanes, 1:3). Fractions containing the prod-
uct were combined and evaporated in vacuo to give 7.
5.5.2. (1R,3E,4S)-3-Pentylidene-1,7,7-trimethyl-bicyclo[2.2.1]-
heptan-2-one 8c and its (1R,3Z,4S)-isomer 80c. Prepared
from 2 and n-BuMgCl (2 M in THF); 8c:80c = 95:5. CC
(EtOAc–hexanes, 1:30) afforded isomerically pure 8c.
Yield: 247 mg (84%) of a yellow solid; mp 175–182 ꢁC
22
(diethyl ether–n-hexane); ½aꢂD ¼ þ261:9 (c 0.26, CH2Cl2).
1H NMR (CDCl3): d 0.85, 0.98, 1.04 (9H, 3s, 1:1:1,
3 · Me); 1.50–1.59, 1.67–1.82 and 2.15–2.26 (4H, 3m,
1:2:1, 2 · CH2); 2.48 (3H, s, Me); 3.04 (1H, d, J = 4.1 Hz,
H–C(4)); 7.11–7.20 and 7.28–7.32 (3H, 2m, 2:1, 3H of in-
dole); 7.44 (1H, s, H–C(30)); 7.67–7.70 (1H, m, 1H of
indole); 8.30 (1H, s, NH). 13C NMR (CDCl3): d 9.9, 13.1,
18.9, 21.0, 27.6, 31.0, 47.0, 50.5, 58.0, 110.0, 111.2, 120.4,
120.7, 121.7, 122.3, 127.3 136.1, 138.3, 139.1, 208.9 (Found:
C, 82.10; H, 8.00; N, 4.50. C20H23NO requires: 81.87; H,
7.90; N, 4.77.); mmax (KBr) 3242, 2957, 1700 (C@O),
5.5.2.1. Data for the major (1R,3E,4S)-isomer 8c.
Yield: 1.047 g (95%) of a colourless oil, lit.55 bp 139–
21
141 ꢁC/12 Torr; 8c:80c = 100:0; ½aꢂD ¼ þ158:9 (c 0.53,
20
CHCl3), lit.55 ½aꢂD ¼ þ116:5 (neat). m/z (EI) = 220 (M+);
m/z (HRMS) found: 220.183450 (M+); C15H24O requires:
1
m/z = 220.182716. H NMR (CDCl3): d 0.78 (3H, s, Me);
à 1H NMR of the residue was taken in order to establish the isomer
composition. NMR data for the minor isomers 80a,c,d were acquired
from these spectra.
1612, 1492, 1459, 1388, 1328, 1250, 1159, 1067 cmꢀ1
.

1230
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
0.90 (3H, t, J = 7.2 Hz, CH2CH2CH2CH3); 0.96, 0.97 (6H,
2s, 1:1, 2 · Me); 1.26–1.47 (6H, m, 6H of CH2); 1.64–1.73
(1H, m, 1H of CH2); 1.95–2.05 (1H, m, 1H of CH2); 2.13
(2H, deg q, J = 7.2, 7.5 Hz, CH2CH2CH2CH3); 2.69 (1H,
d, J = 3.8 Hz, H–C(4)); 6.36 (1H, dq, J = 0.7; 7.7 Hz, H–
C(30)). 13C NMR (CDCl3): d 9.5, 14.2, 18.6, 20.8, 22.7,
26.8, 28.7, 30.7, 31.3, 46.3, 47.9, 58.1, 130.8, 143.2, 207.5.
mmax (NaCl) 2959, 1732 (C@O), 1666, 1453, 1389, 1371,
(C@O), 1643, 1493, 1447, 1388, 1367, 1325, 1257, 1059,
1017, 926, 748, 693 cmꢀ1
.
5.5.5. (1R,3E,4S)-3-(2-Methylbenzylidene)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one 8f. Prepared from 2 and 2-
methylphenylmagnesium chloride (1 M in THF);
8f:80f = 100:0; CC (EtOAc–hexanes, 1:30). Yield: 1.145 g
(90%) of a white solid; mp 77–78 ꢁC (from n-heptane at
21
1324, 1255, 1106, 1069, 1010, 940 cmꢀ1
.
ꢀ20 ꢁC); ½aꢂD ¼ þ397:1 (c 0.24, CHCl3). m/z (EI) = 254
(M+); m/z (HRMS) found: 254.168110 (M+); C18H22O re-
1
5.5.2.2. NMR data for the minor (1R,3Z,4S)-isomer
80c. 1H NMR (CDCl3): d 0.81, 0.91, 0.93 (9H, 3s, 1:1:1,
3 · Me); 2.39 (1H, d, J = 4.1 Hz, H–C(4)); 2.50–2.77 (2H,
m, CH2CH2CH2CH3); 5.75 (1H, t, J = 7.9 Hz, H–C(30)).
13C NMR (CDCl3): d 9.7, 14.3, 18.9, 20.8, 22.7, 27.7,
28.0, 30.3, 31.9, 46.5, 53.0, 59.7, 136.8, 141.8, 209.2.
quires: m/z = 254.167066. H NMR (CDCl3): d 0.81, 0.98,
1.03 (9H, 3s, 1:1:1, 3 · Me); 1.49–1.64 (2H, m, 2H of CH2);
1.74–1.85 (1H, m, 1H of CH2); 2.08–2.22 (1H, m, 1H of
CH2); 2.35 (3H, s, Me); 2.93 (1H, d, J = 4.5 Hz, H–C(4));
7.17–7.24 (3H, m, 3H of Ar); 7.29–7.34 (1H, m, 1H of
Ar); 7.41 (1H, s, H–C(30)). 13C NMR (CDCl3): d 9.72,
18.7, 20.4, 21.0, 26.7, 31.0, 46.9, 49.2, 57.9, 126.0, 126.2,
128.9, 130.8, 135.1, 138.5, 143.2, 208.4 (Found: C, 84.41;
H, 8.60. C18H22O requires: C, 84.99; H, 8.72.) mmax (KBr)
2957, 1723 (C@O), 1638, 1473, 1440, 1400, 1390, 1323,
1288, 1257, 1154, 1105, 1067, 1015, 961, 914, 805, 747,
5.5.3. (1R,3E,4S)-3-Cyclopentylmethylidene-1,7,7-trimeth-
ylbicyclo[2.2.1]heptan-2-one 8d and its (1R,3Z,4S)-isomer
80d. Prepared from 2 and cyclopentylmagnesium chloride
(2 M in Et2O); 8d:80d = 85:15. CC (EtOAc–hexanes, 1:40)
afforded isomerically pure 8d.
720 cmꢀ1
.
5.5.3.1. Data for the major (1R,3E,4S)-isomer 8d.
Yield: 0.593 g (51%) of a colourless oil; 8d:80d = 100:0;
5.5.6. (1R,3E,4S)-3-(4-Methylbenzylidene)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one 8g. Prepared from 2 and 4-
methylphenylmagnesium bromide (1 M in Et2O);
8g:80g = 100:0; CC (EtOAc–hexanes, 1:20). Yield: 1.182 g
21
½aꢂD ¼ þ162:6 (c 0.83, CHCl3). m/z (EI) = 232 (M+); m/z
(HRMS) found: 232.183450 (M+); C16H24O requires:
1
m/z = 232.182716. H NMR (CDCl3): d 0.78, 0.95, 0.96
(93%) of a white solid; mp 94–98 ꢁC (from n-heptane
21
at ꢀ20 ꢁC), lit.31 mp 98.5–99.5 ꢁC; ½aꢂD ¼ þ458:1 (c 0.28,
24
(9H, 3s, 1:1:1, 3 · Me); 1.25–1.45 (4H, m, 4H of CH2);
1.52–1.87 (7H, m, 7H of CH2); 1.95–2.08 (1H, m, 1H of
CH2); 2.54–2.68 (1H, m, H–C(1) of cyclopentyl); 2.71
(1H, d, J = 4.1 Hz, H–C(4)); 6.29 (1H, d, J = 9.4 Hz, H–
C(30)). 13C NMR (CDCl3): d 9.6, 18.7, 20.9, 25.8, 25.9,
27.1, 30.8, 33.6, 33.7, 40.0, 46.4, 48.2, 58.2, 135.8, 141.8,
208.1. mmax (NaCl) 2958, 1731 (C@O), 1664 (C@O), 1474,
1451, 1390, 1370, 1327, 1254, 1107, 1064, 1012, 950,
CHCl3), lit.31 ½aꢂD ¼ þ412 (c 1.35, C6H6). m/z (EI) = 254
(M+); m/z (HRMS) found: 254.167550 (M+); C18H22O re-
1
quires: m/z = 254.167066. H NMR (CDCl3): d 0.80, 0.99,
1.03 (9H, 3s, 1:1:1, 3 · Me); 1.46–1.62 (2H, m, 2H of CH2);
1.73–1.84 (1H, m, 1H of CH2); 2.12–2.22 (1H, m, 1H of
CH2); 2.37 (3H, s, Me); 3.10 (1H, d, J = 4.1 Hz, H–C(4));
7.18 (1H, s, H–C(30)); 7.19–7.21 (2H, m, 2H of Ar); 7.36–
7.40 (2H, m, 2H of Ar). 13C NMR (CDCl3): d 9.7, 18.8,
21.0, 21.8, 26.4, 31.2, 47.1, 49.7, 57.5, 128.0, 129.8, 130.2,
133.3, 139.3, 141.7, 208.6 (Found: C, 84.42; H, 8.86.
C18H22O requires: C, 84.99; H, 8.72.) mmax (KBr) 2961,
1721 (C@O), 1642, 1608, 1511, 1444, 1324, 1254, 1152,
800 cmꢀ1
.
5.5.3.2. Data for the minor (1R,3Z,4S)-isomer 80d. 1H
NMR (CDCl3): d 0.81, 0.91, 0.93 (9H, 3s, 1:1:1, 3Me);
2.37 (1H, d, J = 3.8 Hz, H–C(4)); 3.71–3.85 (1H, m, H–
C(40)); 5.65 (1H, d, J = 9.8 Hz, H–C(30)). 13C NMR
(CDCl3): d 9.7, 18.9, 20.9, 25.8, 25.9, 27.7, 30.3, 33.8,
33.9, 38.6, 46.4, 52.9, 59.6, 140.4, 141.6, 209.0.
1106, 1064, 1015, 959, 919, 814 cmꢀ1
.
5.5.7. (1R,3E,4S)-3-(4-Fluorobenzylidene)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one 8h. Prepared from 2 and 4-fluor-
ophenylmagnesium bromide (2 M in Et2O); 8h:80h = 100:0;
CC (EtOAc–hexanes, 1:30). Yield: 1.176 g (91%) of a white
solid; mp 97–99 ꢁC (from n-heptane at ꢀ20 ꢁC), lit.57 mp
5.5.4. (1R,3E,4S)-3-Benzylidene-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one 8e. Prepared from 2 and phenylmagnesium
bromide (1 M in THF); 8e:80e = 100:0; CC (EtOAc–hex-
anes, 1:15). Yield: 1.094 g (91%) of a white solid; mp 74–
75 ꢁC (from n-heptane at ꢀ20 ꢁC), lit.56 mp 71–73 ꢁC;
21
20
97 ꢁC; ½aꢂD ¼ þ413:4 (c 0.19, CHCl3), lit.57 ½aꢂD ¼ þ387:5
(dioxane). m/z (EI) = 258 (M+). 1H NMR (CDCl3): d
0.80, 1.00, 1.03 (9H, 3s, 1:1:1, 3 · Me); 1.47–1.61 (2H, m,
2H of CH2); 1.75–1.85 (1H, m, 1H of CH2); 2.11–2.23
(1H, m, 1H of CH2); 3.05 (1H, d, J = 4.1 Hz, H–C(4));
7.04–7.11 (2H, m, 2H of Ar); 7.19 (1H, s, H–C(30)); 7.42–
7.48 (2H, m, 2H of Ar). 13C NMR (CDCl3): d 9.6, 18.7,
20.9, 26.3, 31.1, 47.1, 49.5, 57.5, 116.1 (d, J = 86.9 Hz),
126.7, 131.9 (d, J = 32.0 Hz), 132.2 (d, J = 11.4 Hz),
142.2 (d, J = 9.2 Hz), 163.2 (d, J = 994.2 Hz), 208.3 (Found:
C, 78.72; H, 7.37. C17H19FO requires: C, 79.04; H, 7.41.)
mmax (KBr) 2963, 1712 (C@O), 1641, 1601, 1508, 1369,
1325, 1228, 1163, 1104, 1065, 1016, 963, 914, 868, 841,
21
20
½aꢂD ¼ þ446:6 (c 0.30, CHCl3), lit.56 ½aꢂD ¼ þ418
20
(EtOH), lit.54 ½aꢂD ¼ þ426:6 (C6H6). m/z (EI) = 240
(M+); m/z (HRMS) found: 240.151950 (M+); C17H20O
requires: m/z = 240.151415. 1H NMR (CDCl3): d 0.81,
1.00, 1.03 (9H, 3s, 1:1:1, 3 · Me); 1.48–1.64 (2H, m, 2H
of CH2); 1.74–1.82 (1H, m, 1H of CH2); 2.10–2.24 (1H,
m, 1H of CH2); 3.11 (1H, d, J = 4.1 Hz, H–C(4)); 7.24
(1H, s, H–C(30)); 7.30–7.42 (3H, m, 3H of Ph); 7.45–7.50
(2H, m, 2H of Ph). 13C NMR (CDCl3): d 9.7, 18.7, 21.0,
26.4, 31.1, 47.1, 49.6, 57.5, 127.9, 129.0, 129.1, 130.2,
136.1, 142.5, 208.5 (Found: C, 84.40; H, 8.35. C17H20O
requires: C, 84.96; H, 8.39.) mmax (KBr) 2959, 1726
820 cmꢀ1
.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1231
5.5.8. (1S,3E,4R)-3-(4-Fluorobenzylidene)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one ent-8h. Prepared from ent-2
and 4-fluorophenylmagnesium bromide (2 M in Et2O);
ture was filtered through a short pad of Celiteꢂ, washed
with ethanol (50 ml) and the filtrate evaporated in
vacuo. The residue was purified by CC or/and crystallisa-
tion. Fractions containing the product were combined
and evaporated in vacuo to give 13/130, 14/140, 15 and
17/170. The following compounds were prepared in this
manner.
ent-8h:ent-80h = 100:0; CC (EtOAc–hexanes, 1:30). Yield:
21
1.240 g (96%) of a white solid; ½aꢂD ¼ ꢀ399:4 (c 0.34,
CHCl3). m/z (EI) = 258 (M+); m/z (HRMS) found:
258.142440 (M+); C17H19FO requires: m/z = 258.141994
(Found: C, 79.26; H, 7.62. C17H19FO requires: C, 79.04;
1
H, 7.41.). H NMR and IR spectral data were identical
5.7.1. (1R,4R,5R)-1,4,8,8-Tetramethyl-2-oxabicyclo[3.2.1]-
octan-3-one 13 and its (1R,4S,5R)-isomer 130. Prepared
from compound 3 (0.223 g, 1 mmol) in n-propanol; 10%
Pd–C (90 mg); 60 ꢁC, 120 h; CC (EtOAc–hexanes, 1:7).
to those given above for its enantiomer 8h (see Section
5.5.7).
5.5.9. (1R,3E,4S)-3-[3,5-Bis(trifluoromethyl)benzylidene]-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
Yield: 151 mg (83%) of a colourless oil; 13:130 = 64:36
19
8i. Prepared
(28% de); ½aꢂD ¼ ꢀ31:4 (c 0.17, CHCl3). m/z (EI) = 182
from 2 and 3,5-bis(trifluoromethyl)phenyl]magnesium bro-
(M+); m/z (HRMS) found: 182.131020 (M+); C11H18O2 re-
quires: m/z = 182.130680. 13C NMR (CDCl3): d 14.3, 17.4,
17.8, 18.5, 19.6, 20.2, 24.0, 24.1, 30.4, 36.3, 38.6, 43.9, 44.3,
45.4, 48.3, 48.7, 92.5, 93.2, 175.0, 175.5 (Found: C, 70.34;
H, 9.70; N, 4.40. C11H18O2 requires: C, 72.49; H, 9.95;
N, 0.00.) mmax (NaCl) 2980, 1725 (C@O), 1472, 1395,
mide (0.5 M in THF); 8i:80i = 100:0; CC (EtOAc–hexanes,
1:15). Yield: 1.318 g (70%) of a dirty white solid; mp 85–
21
87 ꢁC (from n-heptane at ꢀ20 ꢁC); ½aꢂD ¼ þ242:0 (c 0.27,
CHCl3). m/z (EI) = 376 (M+); m/z (HRMS) found:
376.127320 (M+); C19H18F6O requires: m/z = 376.126185.
1H NMR (CDCl3): d 0.82, 1.04, 1.05 (9H, 3s, 1:1:1,
3 · Me); 1.51–1.64 (2H, m, 2H of CH2); 1.79–1.90 (1H,
m, 1H of CH2); 2.18–2.30 (1H, m, 1H of CH2); 3.00 (1H,
d, J = 4.1 Hz, H–C(4)); 7.24 (1H, s, H–C(30)); 7.82–7.85
(3H, m, 3H of Ar). 13C NMR (CDCl3): d 9.4, 18.4, 20.9,
26.1, 30.8, 47.0, 49.5, 57.5, 122.1–122.3 (m), 123.5 (q,
J = 1084.5 Hz), 124.2, 129.3–129.5 (m), 132.5 (q,
J = 133.7 Hz), 138.3, 145.9, 207.3 (Found: C, 60.81; H,
4.89. C19H18F6O requires: C, 60.64; H, 4.82.) mmax (KBr)
2965, 1732 (C@O), 1652, 1617, 1468, 1450, 1386, 1350,
1327, 1280, 1210, 1136, 1107, 1065, 1019, 982, 949, 899,
1377, 1343, 1252, 1223, 1148, 1060, 1012 cmꢀ1
.
5.7.1.1. Data for the major (1R,4R,5R)-isomer 13. 1H
NMR (CDCl3): d 0.97, 1.06, 1.30 (9H, 3s, 1:1:1, 3 · Me);
1.38 (3H, d, J = 7.5 Hz, Me); 1.47–1.56 (1H, m, 1H of
CH2); 1.80 (1H, d, J = 5.3 Hz, H–C(5)); 1.91–2.20 (3H,
m, 3H of CH2); 2.49 (1H, q, J = 7.5 Hz, H–C(4)).
5.7.1.2. Data for the minor (1R,4S,5R)-isomer 130. 1H
NMR (CDCl3): d 1.02, 1.09 (6H, 2s, 1:1, 2 · Me); 1.23
(3H, d, J = 7.2 Hz, Me); 1.27 (3H, s, Me); 2.87 (1H, ddq,
J = 1.7, 4.8, 7.2 Hz, H–C(4)).
847, 706, 679 cmꢀ1
.
5.6. N-Methyl-N-{[(1R,4E,5S)-1,8,8-trimethyl-3-oxo-2-oxa-
bicyclo[3.2.1]octan-4-ylidene]methyl}nitrous amide 11
5.7.2.
(1R,4R,5R)-4-Propyl-1,8,8-trimethyl-2-oxabicyclo-
[3.2.1]octan-3-one 14 and its (1R,4S,5R)-isomer 140. Pre-
pared from compound 4b (0.208 g, 1 mmol) in ethanol;
10% Pd–C (60 mg); 50 ꢁC, 24 h. Yield: 206 mg (98%) of a
white solid; 14:140 = 88:12 (76% de). Crystallisation from
a mixture of diethyl ether and n-heptane afforded isomeri-
cally pure 14.
tert-Butyl nitrite (92%, 0.2 ml, ꢁ1.5 mmol) was added to a
solution of 3 (0.223 g, 1 mmol) in anhydrous dichlorometh-
ane (4 ml), followed by the addition of trifluoroacetic acid
(0.5 ml, ꢁ6.5 mmol) and the mixture was stirred at rt for
24 h. Volatile components were evaporated in vacuo and
the residue purified by CC (EtOAc–hexanes, 1:4). Frac-
tions containing the product were combined and evapo-
5.7.2.1. Data for the major (1R,4R,5R)-isomer 14.
Yield: 112 mg (53%) of a white solid; 14:140 = 100:0; mp
23
rated in vacuo to give 11. Yield: 119 mg (50%) of a
92–95 ꢁC (Et2O–n-heptane); ½aꢂD ¼ ꢀ11:9 (c 0.19, CHCl3).
22
yellow oil; ½aꢂD ¼ þ462:3 (c 0.22, CH2Cl2). m/z
1H NMR (CDCl3):
d
0.93 (3H, t, J = 7.2 Hz,
(EI) = 209 (M+); m/z (FAB) = 239 (MH+). 1H NMR
(CDCl3): d 1.01, 1.03, 1.36 (9H, 3s, 1:1:1, 3 · Me); 1.65–
1.76 and 2.04–2.30 (4H, 2m, 1:3, 2 · CH2); 3.15 (1H, d,
J = 6.0 Hz, H–C(5)); 3.24 (3H, s, NMe); 7.95 (1H, s, H–
C(40)). 13C NMR (CDCl3): d 18.6, 18.9, 23.7, 28.5, 34.6,
37.1, 44.7, 47.9, 93.6, 122.8, 136.0, 167.2 (Found: C,
59.96; H, 7.51; N, 13.10. C12H18N2O3 requires: 60.49; H,
7.61; N, 11.76.) mmax (NaCl) 2974, 1713 (C@O), 1634,
CH2CH2CH3); 0.97, 1.04, 1.29 (9H, 3s, 1:1:1, 3 · Me);
1.36–1.57 (4H, m, CH2CH2CH3); 1.90–2.20 (5H, m,
2 · CH2, H–C(5)); 2.27 (1H, dd, J = 4.1, 8.7 Hz, H–C(4)).
13C NMR (CDCl3): d 14.2, 19.0, 19.1, 22.1, 24.7, 31.0,
36.6, 37.0, 44.3, 46.5, 51.5, 92.7, 175.9 (Found: C, 73.96;
H, 10.83; N, 0.00. C13H22O2 requires: C, 74.24; H, 10.54;
N, 0.00.) mmax (KBr) 2985, 1715 (C@O), 1467, 1450, 1394,
1382, 1335, 1265, 1239, 1222, 1205, 1153, 1072, 1020 cmꢀ1
.
1470, 1274, 1204, 1147, 1067, 1019, 972, 944, 904 cmꢀ1
.
5.7.2.2. Data for the minor (1R,4S,5R)-isomer 140. 1H
NMR (CDCl3): d 1.03, 1.07, 1.27 (9H, 3s, 1:1:1, 3 · Me);
2.66 (1H, ddt, J = 1.6, 4.5, 5.8 Hz, H–C(4)).
5.7. General procedure for catalytic hydrogenation of
alkylidene compounds 3, 4b, 7 and 11
A mixture of methylidene compound 3, 4b, 7 or 11
(1 mmol) and 10% Pd–C (60–100 mg) in anhydrous n-pro-
panol or ethanol (15 ml) was hydrogenated in an autoclave
(50 bar of H2, 35–60 ꢁC) for 24–120 h. The reaction mix-
5.7.3. (1R,3R,4R)-3-[(2-Methyl-1H-indol-3-yl)methyl]-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one 15. Prepared from
compound 7 (0.293 g, 1 mmol) in ethanol; 10% Pd–C
(100 mg); 50 ꢁC, 24 h; CC (EtOAc–hexanes, 1:2). Yield:

1232
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
23
254 mg (86%) of a colourless oil; ½aꢂD ¼ þ12:1 (c 0.78,
CHCl3). m/z (EI) = 295 (M+); m/z (HRMS) found:
295.194260 (M+); C20H25NO requires: m/z = 295.193615.
1H NMR (CDCl3): d 0.92, 0.95, 1.05 (9H, 3s, 1:1:1,
3 · Me); 1.09–1.17, 1.38–1.49, 1.54–1.64 and 1.78–1.89
(4H, 4m, 1:1:1:1, 2 · CH2); 1.93 (1H, d, J = 4.1 Hz, H–
C(4)); 2.21 (1H, dd, J = 9.8; 3.8 Hz, H–C(3)); 2.36 (3H, s,
Me); 2.66 (1H, dd, J = 14.7; 9.8 Hz, Ha–C(30)); 3.25 (1H,
dd, J = 14.7; 3.8 Hz, Hb–C(30)); 7.04–7.12, 7.21–7.24 and
7.50–7.53 (4H, 3m, 2:1:1, 4H of indole); 7.88 (1H, br s,
NH). 13C NMR (CDCl3): d 9.9, 12.2, 21.0, 22.4, 26.4,
29.7, 29.8, 47.3, 47.6, 56.9, 58.2, 110.7, 111.5, 118.4,
119.6, 121.4, 128.9, 131.6, 135.8, 221.9. mmax (NaCl) 3403,
2959, 1729 (C@O), 1462, 1445, 1385, 1301, 1239, 1101,
5.8.1. (1R,4R,40S,5S)-30-(2,4,6-Trimethoxyphenyl)-1,8,8-tri-
methyl-3-oxo-40H-2-oxaspiro[bicyclo[3.2.1]octane-4,50-iso-
xazole]-40-carbonitrile 19 and (1R,4E,5S)-4-{[3-(2,4,6-tri-
methoxyphenyl)-1,2,4-oxadiazol-5-yl]mehyilidene}-1,8,8-tri-
methyl-2-oxabicyclo[3.2.1]octan-3-one 20. Prepared from
compound 5 (0.205 g, 1 mmol) in toluene; reflux for 4 h;
19:20 = 64:36; CC (EtOAc–hexanes, 1:2). Yield: 191 mg
(46%) of a greyish solid (Found: C, 63.97; H, 6.46; N,
6.52. C22H26N2O6 requires: 63.76; H, 6.32; N, 6.76.) Fur-
ther purification by MPLC (EtOAc–hexanes, 1:2) afforded
pure compound 19.
5.8.1.1. Data for the major compound 19. Yield: 50 mg
22
(12%) of a white solid; mp 183–185 ꢁC; ½aꢂD ¼ ꢀ338:3 (c
1074, 1018 cmꢀ1
.
0.09, CHCl3). m/z (EI) = 414 (M+); m/z (FAB) = 415
(MH+); m/z (HRMS) found: 414.180250 (M+);
C22H26N2O6 requires: m/z = 414.179087. 1H NMR
(CDCl3): d 1.11, 1.19, 1.36 (9H, 3s, 1:1:1, 3Me); 1.99–
2.29 and 2.46–2.61 (4H, 2m, 3:1, 2 · CH2); 2.77–2.82
(1H, m, H–C(5)); 3.84 (9H, s, 3 · OMe); 5.19 (1H, s, H–
C(40)); 6.15 (2H, s, C6H2) (Found: C, 63.83; H, 6.42; N,
6.67. C22H26N2O6 requires: 63.76; H, 6.32; N, 6.76.) mmax
(KBr) 2965, 2242 (C„N), 1737 (C@O), 1608, 1587, 1471,
1459, 1416, 1343, 1261, 1237, 1212, 1193, 1161, 1130,
5.7.4. (1R,4E,5S)-4-[(Methylamino)methylidene]-1,8,8-tri-
methyl-2-oxabicyclo[3.2.1]octan-3-one 17 and its (1R,4Z,
5S)-isomer 170. Prepared from compound 11 (0.238 g,
1 mmol) in n-propanol; 10% Pd–C (80 mg); 35 ꢁC, 48 h;
CC (EtOAc). Yield: 203 mg (97%), 17:170 = 77:23. Crystal-
lisation from CH2Cl2–n-hexane gave isomerically enriched
17. Yield: 172 mg (82%) of a white solid; 17:170 = 95:5;
20
mp 140–150 ꢁC; ½aꢂD ¼ þ155:9 (c 0.26, CH2Cl2) (Found:
1067 cmꢀ1
.
C, 69.00; H, 8.83; N, 6.55. C12H19NO2 requires: C, 68.87;
H, 9.15; N, 6.69.) mmax (KBr) 3304, 2985, 1683 (C@O),
5.8.1.2. NMR data for the minor compound 20. 1H
NMR (CDCl3): d 1.03, 1.07, 1.38 (9H, 3s, 1:1:1, 3 · Me);
1.62–1.71 and 2.03–2.43 (4H, 2m, 1:3, 2 · CH2); 3.79 and
3.88 (9H, 2s, 2:1, 3 · OMe); 4.03 (1H, br d, J = 6.4 Hz,
H–C(5)); 6.21 (2H, s, C6H2); 7.55 (1H, s, H–C(40)).
1579, 1430, 1277, 1171, 1133, 1060, 1007, 970 cmꢀ1
.
5.7.4.1. Data for the major (1R,4E,5S)-isomer 17. 1H
NMR (CDCl3): d 0.99, 1.28 (9H, 2s, 2:1, 3 · Me); 1.46–
1.61 and 1.89–2.21 (4H, 2m, 1:3, 2 · CH2); 2.25 (1H, d,
J = 4.9 Hz, H–C(5)); 2.97 (3H, d, J = 4.5 Hz, MeNH);
4.15 (1H, br s, NH); 7.33 (1H, d, J = 14.3 Hz, H–C(40)).
13C NMR (CDCl3): d 18.8, 19.0, 23.8, 32.4, 35.1, 38.1,
43.5, 50.3, 91.0, 97.2, 151.1, 170.3.
5.8.2.
(1R,3E,4S)-3-{[3-(2,4,6-Trimethoxyphenyl)-1,2,
4-oxadiazol-5-yl]methylidene}-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one 21. Prepared from compound 6 (0.189 g,
1 mmol) in toluene; reflux for 5 h; CC (EtOAc–hexanes,
1:3) and MPLC (EtOAc–hexanes, 1:4). Yield: 159 mg
5.7.4.2. Data for the minor (1R,4Z,5S)-isomer 170. 1H
NMR (CDCl3): d 0.96, 0.98, 1.27 (9H, 3s, 1:1:1, 3 · Me);
2.93 (1H, d, J = 4.9 Hz, MeNH); 6.38 (1H, d,
J = 12.8 Hz, H–C(40)); 7.79 (1H, br s, NH).
(40%) of
a
greyish solid; mp 90–95 ꢁC (Et2O);
21
½aꢂD ¼ ꢀ346:6 (c 0.32, CH2Cl2). 1H NMR (CDCl3): d
0.86, 1.04, 1.05 (9H, 3s, 1:1:1, 3 · Me); 1.47–1.60, 1.76–
1.84 and 2.17–2.25 (4H, 3m, 2:1:1, 2 · CH2); 3.69 (1H, d,
J = 4.1 Hz, H–C(4)); 3.78 and 3.86 (9H, 2s, 2:1,
3 · OMe); 6.20 (2H, s, C6H2); 7.09 (1H, d, J = 0.8 Hz,
H–C(30)). 13C NMR (CDCl3): d 9.6, 18.4, 21.4, 26.4,
30.7, 46.3, 50.8, 55.9, 56.5, 58.0, 91.3, 108.8, 153.8, 160.6,
163.8, 165.3, 174.1, 207.0 (Found: C, 66.60; H, 6.80; N,
6.93. C22H26N2O5 requires: 66.32; H, 6.58; N, 7.03.) mmax
(KBr) 2969, 1753 (C@O), 1608, 1470, 1416, 1340, 1232,
5.8. General procedure for 1,3-dipolar cycloadditions of
2,4,6-trimethoxybenzonitrile oxide 18a to alkylidene
compounds 4b,c,h, 5 and 6
A mixture of alkylidene compound 4b,c,h, 5 or 6 (1 mmol)
and 2,4,6-trimethoxybenzonitrile oxide 18a (0.209 g,
1 mmol) in anhydrous toluene (6 ml) or decalin (4 ml)
was heated at 65 ꢁC or at reflux for 4–36 h. Volatile compo-
nents were evaporated in vacuo and the residue§ purified by
CC and MPLC (dry filled column). Fractions containing
the product were combined and evaporated in vacuo to
give 19–22. The following compounds were prepared in this
manner.
1207, 1159, 1130 cmꢀ1
.
5.8.3. (1R,4R,40R,5S)-40-Ethyl-30-(2,4,6-trimethoxyphenyl)-
1,8,8-trimethyl-40H-2-oxaspiro[bicyclo-[3.2.1]octane-4,50-iso-
xazol]-3-one 22b. Prepared from compound 4b (0.208 g,
1 mmol) in decalin; reflux for 6 h; CC (EtOAc–hexanes,
1:1) then MPLC (EtOAc–hexanes, 1:2). Yield: 33 mg
(8%) of a white solid; 22b:220b = 100:0 (100% de); mp
23
145–152 ꢁC; ½aꢂD ¼ ꢀ402:2 (c 0.09, CHCl3). m/z (EI) =
1
417 (M+). H NMR (CDCl3): d 0.71 (3H, t, J = 7.5 Hz,
§ 1H NMR spectra of the crude reaction mixtures before chromatographic
separation were taken in order to establish the de as accurately as
possible. In the case of very complex spectra, the de were determined
after the chromatographic purification.
CH2CH3); 1.05, 1.10, 1.31 (9H, 3s, 1:1:1, 3 · Me); 1.36–
1.68 and 1.90–2.05 (4H, 2m, 1:1, 2 · CH2); 2.12–2.27
(1H, m, 1H of CH2); 2.48–2.57 (2H, m, 1H of CH2, H–
C(5)); 3.81 and 3.83 (9H, 2s, 2:1, 3 · OMe); 3.87 (1H, dd,

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1233
J = 3.4; 8.7 Hz, H–C(40)); 6.14 (2H, s, C6H2) (Found: C,
65.91; H, 7.68; N, 3.57. C23H31NO6 requires: 66.17; H,
5.9. General procedure for 1,3-dipolar cycloadditions of
2,4,6-trisubstituted benzonitrile oxides 18a,b to a-alkyli-
dene camphors 8a,c,e–i and ent-8h
7.48; N, 3.35.) mmax (KBr) 2978, 1733 (C@O), 1624, 1605,
1584, 1465, 1416, 1228, 1205, 1155, 1126 cmꢀ1
.
A mixture of alkylidene compound 8a,c,e–i or ent-8h
(1 mmol) and 2,4,6-trimethoxybenzonitrile oxide 18a
(0.251 g, 1.2 mmol) or 2,4,6-trimethylbenzonitrile oxide
18b (0.194 g, 1.2 mmol) in anhydrous anisole (5 ml) under
argon was irradiated in a laboratory microwave oven
(P = 300 W, T = 215 ꢁC, P = 3–5 bar) for 3 h. Volatile
components were evaporated in vacuo and the residue§
purified by CC and MPLC (wet filled column). Fractions
containing the product were combined and evaporated in
vacuo to give diastereomerically pure compounds 23c and
24i and isomeric mixtures 23/230a,e–i, ent-23/230h and 24/
240f,h. Repeated crystallisation of isomeric mixtures affor-
ded diastereomerically enriched compound 23/230f (90%
de) and diastereomerically pure compounds 23a,e,g–i,
ent-23h and 24f,h. The following compounds were prepared
in this manner.
5.8.4. (1R,4R,40R,5S)-40-Butyl-30-(2,4,6-trimethoxyphenyl)-
1,8,8-trimethyl-40H-2-oxaspiro[bicyclo-[3.2.1]octane-4,50-iso-
xazol]-3-one 22c. Prepared from compound 4c (0.236 g,
1 mmol) in decalin; reflux for 6 h; CC (CHCl3–MeOH,
100:1 ! 20:1) and MPLC (EtOAc–hexanes, 1:2). Yield:
45 mg (10%) of a white solid; 22c:220c = 100:0 (100% de);
23
mp 145–151 ꢁC; ½aꢂD ¼ ꢀ358:7 (c 0.14, CHCl3). m/z
(EI) = 445 (M+); m/z (HRMS) found: 445.247500 (M+);
C25H35NO6 requires: m/z = 445.246438. 1H NMR
(CDCl3): d 0.72 (3H, t, J = 7.2 Hz, CH2CH2CH2CH3);
0.96–1.20 (4H, m, 2 · CH2); 1.05, 1.09, 1.31 (9H, 3s,
1:1:1, 3Me); 1.36–1.54 and 1.89–2.05 (4H, 2m, 1:1,
2 · CH2); 2.11–2.26 (1H, m, 1H of CH2); 2.49–2.56 (2H,
m, 1H of CH2, H–C(5)); 3.80 and 3.83 (9H, 2s, 2:1,
3 · OMe); 3.86 (1H, dd, J = 3.0; 8.7 Hz, H–C(40)); 6.13
(2H, s, C6H2) (Found: C, 67.66; H, 8.12; N, 3.13.
C25H35NO6 requires: 67.39; H, 7.92; N, 3.14.) mmax (KBr)
2959, 1737 (C@O), 1606, 1585, 1464, 1415, 1383, 1228,
5.9.1.
(1R,3R,4S,40R)-1,40,7,7-Tetramethyl-30-(2,4,6-tri-
methoxyphenyl)-40H-spiro[bicyclo[2.2.1]heptane-3,50-isoxa-
zol]-2-one 23a and its (1R,3S,4S,40S)-isomer 230a.
Prepared from 8a (0.178 g, 1 mmol) and 18a (0.251 g,
1.2 mmol); CC and MPLC (EtOAc–hexanes, 1:3). Yield:
1206, 1158, 1130 cmꢀ1
.
5.8.5. (1R,4R,40R,5S)-40-(4-Fluorophenyl)-30-(2,4,6-trimeth-
oxyphenyl)-1,8,8-trimethyl-40H-2-oxaspiro[bicyclo[3.2.1]oc-
tane-4,50-isoxazol]-3-one 22h and (1R,4S,40S,5S)-isomer
220h. Prepared from compound 4h (0.274 g, 1 mmol), in
decalin; reflux for 6 h; 22h:220h = 88:12 (76% de); CC
(EtOAc–hexanes, 1:2). Yield: 237 mg (49%) of a white so-
lid; 22h:220h = 88:12 (76% de). Further purification by
MPLC (EtOAc–hexanes, 1:3) afforded isomerically en-
riched 22h (first fraction) and isomerically pure 220h (sec-
ond fraction).
105 mg (27%) of
a
white solid; 23a:230a = 92:8
(84% de). Upon repeated crystallisation from EtOAc–
n-heptane, diastereomerically pure compound 23a was
obtained.
5.9.1.1. Data for major (1R,3R,4S,40R)-isomer
23a. Yield: 0.023 g (6%) of a white solid; mp 169–
19
173 ꢁC; 23a:230a = 100:0 (100% de); ½aꢂD ¼ ꢀ421:3 (c
0.15, CHCl3). m/z (EI) = 387 (M+); m/z (HRMS) found:
387.205540
(M+);
C22H29NO5
requires:
m/z =
1
5.8.5.1. Data for the major (1R,4R,40R,5S)-isomer
387.204573. H NMR (CDCl3): d 0.86, 0.95 (6H, 2s, 1:1,
2 · Me); 1.02 (3H, d, J = 7.5 Hz, Me); 1.04 (3H, s, Me);
1.64–1.88 (3H, m, 3H of CH2); 2.26–2.35 (1H, m, 1H of
CH2); 2.39 (1H, d, J = 3.8 Hz, H–C(4)); 3.57 (1H, q,
J = 7.5 Hz, H–C(40)); 3.81, 3.82 (9H, 2s, 2:1, 3 · OMe);
6.13 (2H, s, C6H2). 13C NMR (CDCl3): d 10.0, 14.4, 19.3,
21.6, 21.7, 31.3, 43.9, 48.9, 50.0, 55.8, 56.6, 57.9, 90.2,
91.5, 100.7, 157.6, 160.6, 162.8, 215.7 (Found: C, 67.85;
H, 7.62; N, 4.45. C22H29NO5 requires: C, 68.20; H, 7.54;
N, 3.61.) mmax (KBr) 2966, 1754 (C@O), 1604, 1586, 1456,
1412, 1343, 1225, 1205, 1157, 1126, 1007, 948, 884, 812,
22h. Yield: 169 mg (35%) of a white solid; 22h:220h =
21
97:3 (94% de); mp 95–105 ꢁC; ½aꢂD ¼ ꢀ352:9 (c 0.14,
1
CH2Cl2). H NMR (CDCl3): d 0.73, 0.89, 1.28 (9H, 3s,
1:1:1, 3Me); 1.77–1.98 (2H, m, 2H of CH2); 2.15–2.27
(2H, m, 1H of CH2, H–C(5)); 2.48–2.56 (1H, m, 1H of
CH2); 3.73 and 3.75 (9H, 2s, 1:2, 3 · OMe); 5.20 (1H, s,
H–C(40)); 5.98 (2H, s, C6H2); 6.85–7.23 (4H, m, C6H4)
(Found: C, 67.11; H, 6.22; N, 2.96. C27H30FNO6 requires:
67.07; H, 6.25; N, 2.90.) mmax (KBr) 3416, 2980, 1738
(C@O), 1607, 1509, 1460, 1384, 1227, 1202, 1155,
1132 cmꢀ1
.
746 cmꢀ1
.
5.8.5.2. Data for the minor (1R,4S,40S,5S)-isomer
220h. Yield: 6 mg (1%) of a white solid; 22h:220h = 0:100
(100% de); mp 103–107 ꢁC. m/z (EI) = 483 (M+); m/z
(HRMS) found: 483.206950 (M+); C27H30FNO6 requires:
5.9.1.2. Data for minor (1R,3S,4S,40S)-isomer 230a. 1H
NMR (CDCl3): d 0.97 (3H, s, Me); 1.12 (3H, d, J = 7.2 Hz,
Me); 1.20 (3H, s, Me); 3.43 (1H, q, J = 7.2 Hz, H–C(40)).
1
m/z = 483.205716. H NMR (CDCl3): d 0.87 (3H, s, Me);
5.9.2. (1R,3R,4S,40R)-40-Butyl-30-(2,4,6-trimethoxyphenyl)-
1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]heptane-3,50-isoxaz-
ol]-2-one 23c. Prepared from 8c (0.220 g, 1 mmol) and 18a
(0.251 g, 1.2 mmol); CC and MPLC (EtOAc–hexanes, 1:3).
0.88–0.95 (1H, m, 1H of CH2); 1.32 and 1.33 (6H, 2s,
1:1, 2 · Me); 1.45–1.54, 1.72–1.83 and 1.91–2.01 (3H, 3m,
1:1:1, 3H of CH2); 2.08 (1H, d, J = 7.5 Hz, H–C(5)); 3.74
and 3.78 (9H, 2s, 1:2, 3 · OMe); 5.36 (1H, s, H–C(40));
6.00 (2H, s, C6H2); 6.88–6.94 (2H, m, 2H of C6H4); 7.05–
7.24 (2H, m, 2H of C6H4). mmax (KBr) 3417, 2936, 1734
(C@O), 1606, 1509, 1466, 1383, 1229, 1206, 1160,
Yield: 48 mg (11%) of a colourless oil; 23c:230c = 100:0
19
(100% de); ½aꢂD ¼ ꢀ470:5 (c 0.42, CHCl3). m/z (EI) = 429
(M+); m/z (HRMS) found: 429.252750 (M+); C25H35NO5
requires: m/z = 429.251524. 1H NMR (CDCl3): d 0.73
(3H, deg t, J = 6.8, 7.2 Hz, CH2CH2CH2CH3); 0.84, 0.94,
1131 cmꢀ1
.

1234
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1.04 (9H, 3s, 1:1:1, 3 · Me); 1.02–1.21 (4H, m, 4H of CH2);
1.43–1.50 (2H, m, 2H of CH2); 1.63–1.88 (3H, m, 3H of
CH2); 2.25–2.34 (1H, m, 1H of CH2); 2.43 (1H, d,
J = 3.8 Hz, H-C(4)); 3.60 (1H, deg t, J = 6.0, 5.7 Hz, H–
C(40)); 3.81, 3.82 (9H, 2s, 2:1, 3 · OMe); 6.13 (2H, s,
C6H2). 13C NMR (CDCl3): d 10.0, 14.2, 19.3, 21.7, 21.8,
23.2, 28.5, 29.1, 31.3, 44.0, 48.7, 53.7, 55.7, 56.6, 57.8.
90.4, 91.6, 101.9, 157.0, 160.5, 162.7, 215.5. mmax (KBr)
2960, 1751 (C@O), 1606, 1586, 1458, 1415, 1340, 1228,
2.31–2.41 (2H, m, 1H of CH2, H–C(4)); 3.68, 3.73 (9H,
2s, 2:1, 3 · OMe); 5.14 (1H, s, H–C(40)); 5.95 (2H, s,
C6H2); 6.92–6.96, 7.00–7.06, 7.09–7.14 and 7.22–7.25 (4H,
4m, 1:1:1:1, C6H4). 13C NMR (CDCl3): d 10.1, 19.1, 19.5,
21.7, 21.8, 31.7, 44.0, 50.0, 55.6, 56.5, 56.6, 58.6, 91.2,
91.3, 100.9, 125.5, 127.5, 130.4, 132.1, 134.4, 136.2, 156.5,
160.3, 162.6, 215.6.
5.9.4.2. NMR data for the minor (1R,3S,4S,40S)-isomer
230f. 1H NMR (CDCl3): d 0.57, 0.83 (6H, 2s, 1:1, 2 · Me);
3.75 (6H, s, 2 · OMe); 5.03 (1H, s, H–C(40)); 5.99 (2H, s,
C6H); 6.84–6.87 (1H, m, 1H of C6H4).
1206, 1159, 1130, 1065, 1038, 1019, 944, 893, 814 cmꢀ1
.
5.9.3. (1R,3R,4S,40R)-40-Phenyl-30-(2,4,6-trimethoxyphen-
yl)-1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]heptane-3,50-is-
oxazol]-2-one 23e and its (1R,3S,4S,40S)-isomer 230e.
Prepared from compound 8e (0.240 g, 1 mmol) and 18a
(0.251 g, 1.2 mmol); 23e:230e = 94.5:5.5 (89% de); CC and
MPLC (EtOAc–hexanes, 1:2). Yield: 138 mg (30%) of a
white solid; 23e:230e = 95:5 (90% de). Repeated crystallisa-
tion of 23/230e from EtOAc–n-hexane furnished diastereo-
merically pure compound 23e.
5.9.5.
(1R,3R,4S,40R)-40-(4-Methylphenyl)-30-(2,4,6-tri-
methoxyphenyl)-1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]-hep-
tane-3,50-isoxazol]-2-one 23g and its (1R,3S,4S,40S)-isomer
230g. Prepared from 8g (0.254 g, 1 mmol) and 18a
(0.251 g, 1.2 mmol); 23g:230g = 95:5 (90% de); CC
(EtOAc–hexanes, 1:2) and MPLC (EtOAc–hexanes, 1:3).
Yield: 107 mg (23%) of a white solid; 23g:230g = 95:5
(90% de). Repeated crystallisation from CHCl3–n-heptane
furnished diastereomerically pure compound 23g.
5.9.3.1. Data for major (1R,3R,4S,40R)-isomer 23e.
0.050 g (11%) of
a
white solid; mp 222–225 ꢁC;
21
23e:230e = 100:0 (100% de); ½aꢂD ¼ ꢀ508:9 (c 0.09, CHCl3).
5.9.5.1. Data for major (1R,3R,4S,40R)-isomer 23g.
m/z (EI) = 449 (M+); m/z (HRMS) found: 449.221820
Yield: 0.033 g (7%) of a white solid; mp 205–208 ꢁC;
19
(M+); C27H31NO5 requires: m/z = 449.220223. H NMR
23g:230g = 100:0 (100% de); ½aꢂD ¼ ꢀ496:4 (c 0.14,
1
(CDCl3): d 0.70, 0.82, 0.95 (9H, 3s, 1:1:1, 3 · Me); 1.63–
1.88 (3H, m, 3H of CH2); 2.02 (1H, d, J = 3.4 Hz, H–
C(4)); 2.24–2.35 (1H, m, 1H of CH2); 3.72, 3.74 (9H, 2s,
1:2, 3 · OMe); 4.80 (1H, s, H–C(40)); 5.97 (2H, s, Ar);
7.04–7.25 (5H, m, C6H2). 13C NMR (CDCl3): d 10.0,
19.0, 21.7, 22.5, 31.5, 44.0, 49.7, 55.6, 56.6, 58.6, 61.8,
91.1, 91.5, 101.0, 127.8, 128.2, 130.7, 136.1, 156.2, 160.4,
162.6, 215.3 (Found: C, 72.18; H, 6.97; N, 3.83.
C27H31NO5 requires: C, 72.14; H, 6.95; N, 3.12.) mmax
(KBr) 2966, 1752 (C@O), 1606, 1455, 1415, 1340, 1234,
CHCl3). m/z (EI) = 463 (M+); m/z (HRMS) found:
463.237020
(M+);
C28H33NO5
requires:
m/z =
1
463.235874. H NMR (CDCl3): d 0.70, 0.83, 0.95 (9H, 3s,
1:1:1, 3 · Me); 1.62–1.87 (3H, m, 3H of CH2); 2.01 (1H,
d, J = 3.4 Hz, H–C(4)); 2.23–2.33 (1H, m, 1H of CH2);
2.26 (3H, s, Me); 3.72, 3.74 (9H, 2s, 1:2, 3 · OMe); 4.78
(1H, s, H–C(40)); 5.98 (2H, s, C6H2); 6.90–7.05 (4H, m,
C6H4). 13C NMR (CDCl3): d 10.0, 19.0, 21.5, 21.7, 22.5,
31.5, 44.0, 49.7, 55.6, 56.6, 58.6, 61.4, 91.0, 91.6, 101.2,
129.0, 130.5, 133.0, 137.3, 156.3, 160.4, 162.5, 215.5
(Found: C, 72.07; H, 7.18; N, 4.10. C28H33NO5 requires:
C, 72.55; H, 7.18; N, 3.02.) mmax (KBr) 2954, 1751
(C@O), 1608, 1583, 1455, 1405, 1340, 1322, 1220, 1203,
1209, 1163, 1129, 1071, 1031, 819, 707 cmꢀ1
.
5.9.3.2. Data for minor (1R,3S,4S,40S)-isomer 230e. 1H
NMR (CDCl3): d 0.92, 0.99, 1.22 (9H, 3s, 1:1:1, 3 · Me);
3.67, 3.72 (9H, 2s, 2:1, 3 · OMe); 4.61 (1H, s, H–C(40)).
1180, 1155, 1130, 1022, 908, 876, 838, 811, 782 cmꢀ1
.
5.9.5.2. Data for minor (1R,3S,4S,40S)-isomer 230g. 1H
NMR (CDCl3): d 0.91, 0.98, 1.21 (9H, 3s, 1:1:1, 3 · Me);
3.69, 3.73 (9H, 2s, 2:1, 3 · OMe); 4.59 (1H, s, H–C(40));
7.06–7.10 (2H, m, 2H of C6H4).
5.9.4.
(1R,3R,4S,40R)-40-(2-Methylphenyl)-30-(2,4,6-tri-
methoxyphenyl)-1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]hep-
tane-3,50-isoxazol]-2-one 23f and its (1R,3S,4S,40S)-isomer
230f. Prepared from 8f (0.254 g, 1 mmol) and 18a
(0.251 g, 1.2 mmol); 23f:230f = 83:17 (66% de); CC and
MPLC (EtOAc–hexanes, 2:3). Yield: 177 mg (38%) of a
white solid; 23f:230f = 90:10 (80% de). Repeated crystallisa-
tion of 23/230f from EtOAc–n-hexane furnished diastereo-
merically enriched compound 23f. Yield: 0.047 g (10%) of a
5.9.6. (1R,3R,4S,40R)-40-(4-Fluorophenyl)-30-(2,4,6-trimeth-
oxyphenyl)-1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]heptane-
3,50-isoxazol]-2-one 23h and its (1R,3S,4S,40S)-isomer
230h. Prepared from compound 8h (0.258 g, 1 mmol)
and 18a (0.251 g, 1.2 mmol); 23h:230h = 94:6 (88% de);
CC and MPLC (EtOAc–hexanes, 1:2). Yield: 131 mg
(28%) of a white solid; 23h:230h = 96:4 (92% de). Repeated
crystallisation from EtOAc–n-hexane furnished diastereo-
merically pure compound 23h.
white solid; 23f:230f = 95:5 (90% de); mp 249–252 ꢁC;
21
½aꢂD ¼ ꢀ533:6 (c 0.12, CHCl3). m/z (EI) = 463 (M+); m/z
(HRMS) found: 463.236980 (M+); C28H33NO5 requires:
m/z = 463.235874 (Found: C, 71.90; H, 7.05; N, 4.75.
C28H33NO5 requires: C, 72.55; H, 7.18; N, 3.02.) mmax
(KBr) 2966, 1746 (C@O), 1604, 1581, 1456, 1417, 1340,
5.9.6.1. Data for major (1R,3R,4S,40R)-isomer 23h.
1234, 1209, 1162, 1128, 1072, 900, 876, 820, 764 cmꢀ1
.
Yield: 56 mg (12%) of a white solid; mp 204–207 ꢁC;
21
23h:230h = 100:0; ½aꢂD ¼ ꢀ469:9 (c 0.16, CHCl3). m/z
5.9.4.1. NMR data for the major (1R,3R,4S,40R)-isomer
23f. 1H NMR (CDCl3): d 0.61, 0.84, 0.96 (9H, 3s, 1:1:1,
3 · Me); 1.63–1.92 (3H, m, 3H of CH2); 2.08 (3H, s, Me);
(EI) = 467 (M+); m/z (HRMS) found: 467.211950 (M+);
C27H30FNO5 requires: m/z = 467.210802. 1H NMR
(CDCl3): d 0.69, 0.84, 0.95 (9H, 3s, 1:1:1, 3 · Me); 1.64–

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1235
1.88 (3H, m, 3H of CH2); 1.99 (1H, d, J = 3.4 Hz, H–C(4));
2.24–2.34 (1H, m, 1H of CH2); 3.74, 3.75 (9H, 2s, 1:2,
3 · OMe); 4.79 (1H, s, H–C(40)); 5.98 (2H, s, C6H2);
6.86–6.94 (2H, m, 2H of C6H4); 7.06 (2H, br s, 2H of
C6H4). 13C NMR (CDCl3): d 10.0, 19.0, 21.7, 22.5, 31.4,
44.0, 49.7, 55.6, 56.6, 58.6, 61.1, 90.9, 91.5, 100.7, 115.2
(d, J = 84.5 Hz), 132.0 (d, J = 13.7 Hz), 132.2 (d,
J = 32.0 Hz), 156.1, 160.4, 162.5 (d, J = 980.5 Hz), 162.7,
215.1 (Found: C, 69.80; H, 6.67; N, 3.07. C27H30FNO5 re-
quires: C, 69.36; H, 6.47; N, 3.00.) mmax (KBr) 2974, 1749
(C@O), 1603, 1586, 1508, 1458, 1410, 1346, 1231, 1220,
3 · Me); 1.66–1.90 (4H, m, 3H of CH2, H–C(4)); 2.28–
2.35 (1H, m, 1H of CH2); 3.74 and 3.76 (9H, 2s, 1:2,
3 · OMe); 4.94 (1H, s, H–C(40)); 5.99 (2H, s, C6H2); 7.57
(2H, br s, 2H of C6H3); 7.73 (1H, br s, 1H of C6H3). 13C
NMR (CDCl3): d 9.9, 18.9, 21.7, 22.6, 31.1, 44.2, 49.7,
55.6, 56.3, 58.7, 61.1, 91.0, 91.2, 99.4, 121.9–122.1 (m),
123.5 (q, J = 1085.7 Hz), 130.7 (br s), 131.7 (q,
J = 134.8 Hz), 139.1, 155.2, 160.3, 163.1, 213.9.
5.9.8.2. NMR data for the minor (1R,3S,4S,40S)-isomer
230i. 1H NMR (CDCl3): d 0.94, 1.01 (6H, 2s, 1:1, 2 · Me);
4.72 (1H, s, H–C(40)).
1207, 1158, 1132, 1021, 850, 810 cmꢀ1
.
5.9.6.2. Data for minor (1R,3S,4S,40S)-isomer 230h. 1H
NMR (CDCl3): d 0.93, 0.99, 1.22 (9H, 3s, 1:1:1, 3 · Me);
4.59 (1H, s, H–C(40)).
5.9.9. (1R,3R,4S,40R)-40-(2-Methylphenyl)-1,7,7-trimethyl-
30-(2,4,6-trimethylphenyl)-40H-spiro[bicyclo[2.2.1]heptane-
3,50-isoxazol]-2-one 24f and its (1R,3S,4S,40S)-isomer
240f. Prepared from compound 8f (0.254 g, 1 mmol) and
18b (0.194 g, 1.2 mmol); 24f:240f = 96:4 (92% de); first
CC (CHCl3–MeOH, 300:1 ! 100:1), second CC (EtOAc–
hexanes, 1:10). Yield: 37 mg (9%) of a white solid;
24f:240f = 96:4 (92% de). Repeated crystallisation from
CHCl3–n-heptane furnished diastereomerically pure com-
pound 24f.
5.9.7. (1S,3S,4R,40S)-40-(4-Fluorophenyl)-30-(2,4,6-trimeth-
oxyphenyl)-1,7,7-trimethyl-40H-spiro[bicyclo[2.2.1]heptane-
3,50-isoxazol]-2-one ent-23h and its (1S,3R,4R,40R)-isomer
ent-230h. Prepared from compound ent-8h (0.258 g,
1 mmol) and 18a (0.251 g, 1.2 mmol); ent-23h:ent-
230h = 96:4 (92% de); CC and MPLC (EtOAc–hexanes,
1:2). Yield: 136 mg (29%) of a white solid; ent-23h:ent-
230h = 97:3 (94% de). Repeated crystallisation from
EtOAc–n-hexane furnished diastereomerically pure com-
pound ent-23h.
5.9.9.1. Data for major (1R,3R,4S,40R)-isomer
24f. Yield: 0.015 g (3%) of a white solid; mp 223–
21
226 ꢁC; 24f:240f = 100:0 (100% de); ½aꢂD ¼ ꢀ534:4 (c 0.28,
CHCl3). m/z (EI) = 415 (M+); m/z (HRMS) found:
5.9.7.1. Data for major (1S,3S,4R,40S)-isomer ent-
415.252350
(M+);
C28H33NO2
requires:
m/z =
1
23h. Yield: 0.054 g (11%) of a white solid; mp 204–
415.251130. H NMR (CDCl3): d 0.66, 0.88, 0.97 (9H, 3s,
1:1:1, 3 · Me); 1.70–1.94 (3H, m, 3H of CH2); 1.96, 2.18
(6H, 2s, 1:1, 2 · Me); 2.21 (6H, br s, 2 · Me); 2.32–2.43
(1H, m, 1H of CH2); 2.49 (1H, d, J = 3.8 Hz, H–C(4));
4.79 (1H, s, H–C(40)); 6.71 (2H, s, C6H2); 6.96–6.99,
7.09–7.14, 7.17–7.22 and 7.34–7.37 (4H, 4m, 1:1:1:1,
C6H4). 13C NMR (CDCl3): d 10.0, 19.0, 19.8, 20.5, 21.4,
21.6, 21.8, 31.8, 44.0, 49.7, 57.5, 58.8, 91.8, 125.5, 126.0,
128.2, 128.9, 131.0, 131.9, 133.3, 136.3, 138.1, 138.9,
161.7, 216.0 (Found: C, 80.97; H, 8.08; N, 3.60.
C28H33NO2 requires: C, 80.93; H, 8.00; N, 3.37.) mmax
(KBr) 2962, 1744 (C@O), 1610, 1469, 1448, 1393, 1374,
21
207 ꢁC; ent-23h:ent-230h = 100:0 (100% de); ½aꢂD ¼ þ498:9
(c 0.09, CHCl3). m/z (EI) = 467 (M+); m/z (HRMS) found:
467.211500 (M+); C27H30FNO5 requires: m/z =
467.210802 (Found: C, 69.40; H, 6.56; N, 4.05.
C27H30FNO5 requires: C, 69.36; H, 6.47; N, 3.00.). 1H
NMR and IR spectral data for ent-23h were identical to
the data for the (1R,3R,4S,40R)-enantiomer 23h (see Sec-
tion 5.9.6.1).
5.9.7.2. NMR data for minor (1S,3R,4R,40R)-isomer ent-
1
230h. H NMR data for ent-230h were identical to the
data for the (1R,3S,4S,40S)-enantiomer 230h (see Section
1306, 1285, 1103, 1029, 903, 875, 856, 837, 757 cmꢀ1
.
5.9.6.2).
5.9.9.2. Data for minor (1R,3S,4S,40S)-isomer 240f. 1H
NMR (CDCl3): d 0.96, 1.01 (6H, 2s, 1:1, 2 · Me); 4.66 (1H,
s, H–C(40)); 7.56–7.60 (1H, m, 1H of C6H4).
5.9.8. (1R,3R,4S,40R)-40-[3,5-Bis(trifluoromethyl)phenyl]-30-
(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-40H-spiro[bicyclo-
[2.2.1]heptane-3,50-isoxazol]-2-one 23i and its (1R,3S,
4S,40S)-isomer 230i. Prepared from 8i (0.376 g, 1 mmol)
and 18a (0.251 g, 1.2 mmol); first CC (EtOAc–hexanes,
1:2); 23i:230i = 94:6 (88% de); second CC (CHCl3–MeOH,
5.9.10. (1R,3R,4S,40R)-40-(4-Fluorophenyl)-1,7,7-trimethyl-
30-(2,4,6-trimethylphenyl)-40H-spiro[bicyclo[2.2.1]heptane-
3,50-isoxazol]-2-one 24h and its (1R,3S,4S,40S)-isomer
240h. Prepared from compound 8h (0.258 g, 1 mmol)
and 18b (0.194 g, 1.2 mmol); 24h:240h = 93:7 (86% de);
CC (EtOAc–hexanes, 1:15) and MPLC (EtOAc–hexanes,
1:13). Yield: 17 mg (4%) of a white solid; 24h:240h = 99:1
(98% de). Repeated crystallisation from CHCl3–n-heptane
furnished diastereomerically pure compound 24h.
100:1). Yield: 0.352 g (60%) of a greyish semisolid;
21
23i:230i = 93:7 (86% de); mp 64–70 ꢁC; ½aꢂD ¼ ꢀ309:3 (c
0.162, CHCl3). m/z (EI) = 585 (M+); m/z (HRMS) found:
585.196520 (M+); C29H29F6NO5 requires: m/z =
585.194993 (Found: C, 60.38; H, 5.48; N, 2.28. C29H29-
F6NO5 requires: C, 59.49; H, 4.99; N, 2.39.) mmax (KBr)
2965, 1752 (C@O), 1605, 1585, 1468, 1458, 1416, 1376,
1341, 1278, 1230, 1207, 1131, 1034, 947, 911, 877, 831,
5.9.10.1. Data for major (1R,3R,4S,40R)-isomer
814, 710, 681 cmꢀ1
.
24h. Yield: 0.007 g (1.5%) of a white solid; mp 196–
21
208 ꢁC; 24h:240h = 100:0 (100% de); ½aꢂD ¼ ꢀ509:7 (c
5.9.8.1. NMR data for the major (1R,3R,4S,40R)-isomer
23i. 1H NMR (CDCl3): d 0.70, 0.86, 0.97 (9H, 3s, 1:1:1,
0.06, CHCl3). m/z (EI) = 419 (M+); m/z (HRMS) found:
419.227320 (M+); C27H30FNO2 requires: m/z =

1236
U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
1
419.226058. H NMR (CDCl3): d 0.67, 0.87, 0.96 (9H, 3s,
1:1:1, 3 · Me); 1.69–1.92 (3H, m, 3H of CH2); 2.18 (3H,
s, Me); 2.20 (1H, d, J = 3.8 Hz, H–C(4)); 2.28–2.40 (1H,
m, 1H of CH2); 2.29 (6H, s, 2 · Me); 4.47 (1H, s,
H · C(40)); 6.74 (2H, s, C6H2); 6.92–6.98 (2H, m, 2H of
C6H4); 7.02–7.10 (2H, m, 2H of C6H4). 13C NMR (CDCl3):
d 9.9, 19.0, 21.0, 21.3, 21.8, 22.1, 31.5, 44.1, 49.6, 58.8, 62.1,
91.5, 115.9 (d, J = 86.9 Hz), 125.2, 129.3, 130.9 (d,
J = 13.7 Hz), 132.1 (d, J = 32.0 Hz), 138, 139.1, 161.2,
162.8 (d, J = 985.1 Hz), 215.5 (Found: C, 77.50; H, 7.24;
N, 3.65. C27H30FNO2 requires: C, 77.30; H, 7.21; N,
3.34.) mmax (KBr) 2972, 1746 (C@O), 1604, 1509, 1455,
1396, 1374, 1309, 1224, 1163, 1101, 1024, 911, 844,
positions of the hydrogen atoms were geometrically calcu-
lated and their positional and isotropic atomic displace-
ment parameters not refined. Absorption correction was
not necessary. Regina63 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 289084, 289085 and 299415–
299420. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
796 cmꢀ1
.
5.9.10.2. Data for minor (1R,3S,4S,40S)-isomer
1
240h. H NMR (CDCl3): d 4.34 (1H, s, H–C(40)).
Acknowledgements
5.9.11. (1R,3R,4S,40R)-40-[3,5-Bis(trifluoromethyl)phenyl]-
1,7,7-trimethyl-30-(2,4,6-trimethyl-phenyl)-40H-spiro[bicyclo-
[2.2.1]heptane-3,50-isoxazol]-2-one 24i and its (1R,3S,4S,
40S)-isomer 240i. Prepared from compound 8i (0.376 g,
1 mmol) and 18b (0.194 g, 1.2 mmol); 24i:240i = 93:7
(86% de); CC and MPLC (EtOAc–hexanes, 1:30) afforded
diastereomerically pure compound 24i.
Financial support from the Slovenian Research Agency,
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), and Boehringer-Ingelheim Pharma (Biberach,
Germany).
5.9.11.1. Data for major (1R,3R,4S,40R)-isomer 24i.
The authors wish to express their gratitude to the Alexan-
der von Humboldt Foundation, Germany, for the dona-
tion of a Buchi medium pressure liquid chromatograph.
¨
Yield: 92 mg (17%) of a white solid; mp 147–155 ꢁC;
21
24i:240i = 100:0 (100% de); ½aꢂD ¼ ꢀ401:1 (c 0.09, CHCl3).
m/z (EI) = 537 (M+); m/z (HRMS) found: 537.212020
(M+); C29H29F6NO2 requires: m/z = 537.210249. 1H
NMR (CDCl3): d 0.67, 0.89, 0.98 (9H, 3s, 1:1:1, 3 · Me);
1.71–1.94 (4H, m, 3H of CH2, H–C(4)); 2.19, 2.31 (9H,
2s, 1:2, 3 · Me); 2.29–2.43 (1H, m, 1H of CH2); 4.63 (1H,
s, H–C(40)); 6.76 (2H, s, C6H2); 7.52 (2H, br s, 2H of
C6H3); 7.79 (1H, s, 1H of C6H3). 13C NMR (CDCl3): d
9.8, 18.9, 20.9, 21.3, 21.8, 22.2, 31.2, 44.3, 49.6, 58.9,
62.1, 91.6, 122.5–122.7 (m), 123.3 (q, J = 1085.7 Hz),
124.4, 129.6, 130.2–130.4 (m), 132.3 (q, J = 132.6 Hz),
137.8, 138.1, 139.6, 160.3, 214.3 (Found: C, 64.78; H,
5.40; N, 2.83. C29H29F6NO2 requires: C, 64.80; H, 5.44;
N, 2.61.) mmax (KBr) 2979, 1754 (C@O), 1613, 1455, 1395,
1374, 1276, 1179, 1133, 1107, 1032, 903, 874, 859,
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.
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Single crystal X-ray diffraction data of compounds 8h, 19,
22b, 23a, 23f, 23g, ent-23h and 24h were collected at room
temperature on a Nonius Kappa CCD diffractometer using
the Nonius Collect Software.58 DENZO and SCALE-
PACK59 were used for indexing and scaling of the data
and the structures were solved by means of SIR97.60
Refinement was done using Xtal3.461 program package
and the crystallographic plots were prepared by ORTEP
III.62 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

U. Grosˇelj et al. / Tetrahedron: Asymmetry 17 (2006) 1217–1237
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