Asymmetric conversions of 10-bromo-10,11-dihydroquinines into 8-oxa-1-azabicyclo[4.3.0]nonane derivatives and related compounds

Article abstract of DOI:10.1016/S0957-4166(02)00050-2

Some transformations of (10R)- and (10S)-bromo-10,11-dihydroquinine 2a and 2b have been investigated in order to obtain insights into their unexplored chirality. The (10R)-diastereomer 2a converts stereoselectively into (4S)-(E-propenyl)-(6S,7R)-(6-methoxy-quinol-4-yl)-8-oxa-(1R)-azabicyclo [4.3.0]nonane 10, which is the product of a novel rearrangement of the parent quinine 1 and displays the N(1)-(S)-configuration (10a) in the solid state. The (10S)-diastereomer 2b afforded 10 and its (Z)-propenyl isomer 15 (in the ratio 55:45), as well as (Z)-3,10-didehydro-10,11-dihydro-quinine 19. On treatment with acid the alkaloid 10 yields [(4S)-(E)-propenyl)-(2S)-piperidinyl]-6-methoxyquinoline-(αR)-methanol 12. Closure of the oxazolidine ring in 12 gives 14, the 9,9-dimethyl-derivative of 10, with the N(1) configuration inverted. The molecular structures of 10a and 14, determined by X-ray diffraction, show their similar conformations except for the axial (E)-propenyl substituent, disordered in two orientations in 10a and ordered in another position in 14.

Full text of DOI:10.1016/S0957-4166(02)00050-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 47–57
Asymmetric conversions of 10-bromo-10,11-dihydroquinines into
8-oxa-1-azabicyclo[4.3.0]nonane derivatives and related
compounds
Jacek Thiel* and Andrzej Katrusiak
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
Received 21 December 2001; accepted 31 January 2002
Abstract—Some transformations of (10R)- and (10S)-bromo-10,11-dihydroquinine 2a and 2b have been investigated in order to
obtain insights into their unexplored chirality. The (10R)-diastereomer 2a converts stereoselectively into (4S)-(E-propenyl)-
(6S,7R)-(6-methoxy-quinol-4-yl)-8-oxa-(1R)-azabicyclo[4.3.0]nonane 10, which is the product of a novel rearrangement of the
parent quinine 1 and displays the N(1)-(S)-configuration (10a) in the solid state. The (10S)-diastereomer 2b afforded 10 and its
(Z)-propenyl isomer 15 (in the ratio 55:45), as well as (Z)-3,10-didehydro-10,11-dihydro-quinine 19. On treatment with acid the
alkaloid 10 yields [(4S)-(E)-propenyl)-(2S)-piperidinyl]-6-methoxyquinoline-(aR)-methanol 12. Closure of the oxazolidine ring in
12 gives 14, the 9,9-dimethyl-derivative of 10, with the N(1) configuration inverted. The molecular structures of 10a and 14,
determined by X-ray diffraction, show their similar conformations except for the axial (E)-propenyl substituent, disordered in two
orientations in 10a and ordered in another position in 14. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
-epiquinine by inverting the C(9) configuration using
Mitsunobu chemistry.12 9,10-Quinidine diols were
stereospecifically converted into tricyclic N,O-acetals.13
Stereospecific rearrangement of 9-chloro- and 9-bromo-
epiquinine as well as 9-chloro-epiquinidine into the
1-azabicyclo[3.2.2]nonane derivatives enabled correc-
tion of the structure of hetero-cinchona alkaloids.14
Hoffmann and collaborators found that acidic hydroly-
sis of quinine and quinidine mesylates proceeded with
inversion of configuration at C(9), whereas the configu-
ration at C(9) was retained for the same derivatives of
epiquinine and epiquinidine after similar treatment.15
Cook and his group synthesised (10R)- and (10S)-11-
dihydroxy-10,11-dihydroquinine via the Sharpless
osmylation process.16
Cinchona alkaloids have been intensively studied
because of their role as versatile catalysts and ligands in
a wide range of asymmetric processes. For example, the
alkaloids participate in the dihydroxylation1 and
aminohydroxylation2 of olefins as well as in phase-
transfer reactions.3,4 These alkaloids have been used as
surface modifiers of catalysts for asymmetric hydro-
genation,5 they mediate enantioselective fluorination6
and ring openings of prochiral cyclic meso-anhydrides.7
Quinine also catalyzes the intramolecular oxo-Michael
reaction and has been employed in syntheses of chiral
anion exchangers.8,9 These alkaloids are also used in the
preparative resolution of racemic acids.10 A review of
about 250 original papers dealing with the numerous
catalytic applications of the cinchona alkaloids and
their applications in a wide variety of asymmetric syn-
theses has been recently published.11
The so far unexplored course of the reaction during
which 10-halogeno-10,11-dihydrocinchona derivatives
afford products deficient in one carbon atom17
prompted us to study this reaction of 10-bromo-10,11-
dihydroquinines.
In contrast to the above achievements, much less atten-
tion has been devoted to the asymmetric aspects of the
stereochemistry of the alkaloids themselves. Brunner
and co-workers synthesised 9-amino-epicinchonine and
2. Results and discussion
Addition of hydrogen bromide to the vinyl group of
quinine 1 (1“2, Scheme 1) provides the diastereomeric
10-bromo-10,11-dihydroquinines 2a and 2b. Podlewski
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00050-2

48
J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
Scheme 1. Alternative reaction pathways along which the 10-bromo-10,11-dihydro-cinchona derivatives may lose their C(2)
carbon atom as formaldehyde.
1).24 In turn, the intermediate loses its C(9) carbon
atom (i.e. C(2) of the parent alkaloid) as formaldehyde
according to the proposed reaction sequence 6“7“8“
9“3 (Scheme 1).24,25 Unfortunately, no stereochemical
information concerning the formation of 6 could be
acquired since the diastereomeric 10-bromo-10,11-dihy-
dro-cinchonines were impossible to separate.
and Suszko18 found that the more levo-rotatory
diastereomer 2a ([h]D=−213.7), with (10R)-configura-
tion,19 provided niquine on treatment with alkali,
whereas the less levo-rotatory (10S)-isomer 2b ([h]D=
−52)19 was transformed into b-isoquinine, a D3,10-iso-
mer of 1.
The formation of niquine, for which the ‘planar’ struc-
ture 3 was proposed by Solomon,20 is accompanied by
loss of the C(2) carbon as formaldehyde. According to
Smith, the formation of niquine can be rationalised by
the Grob fragmentation mechanism of g-aminohalides
2“4“5“3 (Scheme 1).21 However, for such a frag-
mentation to occur, the anti-parallel oriented nitrogen
orbital containing the lone electron pair and the
C(10)ꢀBr bond from the N(1)ꢀC(2)ꢀC(3)ꢀC(10)ꢀBr
group of the substrate 2 must adopt either an
antiperiplanar, synperiplanar or synclinal position.22
Meanwhile, despite the above stereoelectronic require-
ments, (10R)-bromo-10,11-dihydroquinine with an
unfavourable anticlinal g-haloamine group22 underwent
the fragmentation.18 Analogous fragmentation prod-
ucts—nicinquine and isonicinquine 3a—23 arise from
10-bromo-10,11-dihydrocinchonine 2c, which does not
fulfil the stereoelectronic requirements either. However,
in the latter case, it was discovered that the reaction
may proceed via the intermediate product 6 (Scheme
Therefore, the more easily separable 10-bromo-10,11-
dihydroquinines seemed more promising not only for
examining the scope of this novel rearrangement (2“6,
Scheme 1) but also to investigate the stereochemistry of
the reaction.
For the sake of comparison with the conversion of the
cinchonine derivatives,24 each of the diastereomers 2a
and 2b was exposed to equimolar sodium bicarbonate
in refluxing 80% aqueous ethanol. The (10R)-isomer 2a
provided an analogue of the compound 6 in which the
propenyl side chain has (E)-configuration. The olefinic
protons of this fragment have JHH=15.4 Hz and its
methyl group exhibits lC=18.01.24,26
Since both (E)- and (Z)-isomers of 6 preserve the
absolute configurations of C(4), C(8) and C(9) carbons
of the parent cinchonine,24 one could assume that these
arrangements will be retained in the product derived
from 2a. Hence, cis- or trans-fusion between the pipe-

J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
49
CH3
CH3
H
H
H
H
H
H
H
H
NH
H
CH3
H3C
H
iii
H
H
N
NH
OH
CH3
H
H
OH
H
C
O
H
Q
Q
Q
14
12
13
ii
CH3
Br
H
H
H
H
H
H
H3C
H
H
N
H
H
H3C
i
N
H
H
N
O
H
H
Q
H
H
Q
H
Q
O
H
OH
10
11
2a
i
Br
H
H3C
H
H
H
H
H
H3C
N
H
H
H
H
H
N
H
O
H
i
CH3
N
H
Q
H
O
H
H
Q
H
Q
OH
iv
2b
15
16
iv
CH3
i
H
C
H3C
H
H
N
H
H3C
H
N
H
H
H
H
O
N
C
H
H
Q
H
Q
H
Q
O
H
OH
17
18
19
2a,b; 10 - 19: Q = 6-methoxyquinol-4-yl
Scheme 2. Conversions of 10-bromo-10,11-dihydroquinines 2a and 2b. Reagents and conditions: (i) NaHCO3, 80% aqueous EtOH,
11 h, reflux; (ii) (COOH)2, 96% aqueous EtOH, 80 min, reflux; (iii) acetone, 8 weeks, rt; (iv) H2, 4 atm, Adams PtO2, 4.5 h, rt.
mixture 10 = 11 (Scheme 2). A possible minor share of
the other conformer 11 in the mixture should unneces-
sarily give rise to considerable averaging of the
observed coupling constant between the C(5) and C(6)
protons (J=9.4 Hz) for which the calculated value of
the C(6)HAXꢀC(6)ꢀC(5)ꢀC(5)HAX dihedral angle is
−147.5°.27 This angle might be the result of deviation
from the normal 1,2-diaxial position of hydrogens in
the piperidine ring forced by its fusion with the five-
membered ring, as is seen in cis-hydrindane.28 It is
worth adding here that when the five-membered moiety
breaks (see the text below) the dihedral angle increases.
ridine and oxazolidine rings of the obtained alkaloid
should be taken into consideration. The cis-junction
would require the alkaloid to exist in a conformational
equilibrium of 10 = 11 (Scheme 2). The C(4) proton of
this compound has SJ=18.5 Hz. This result, preclud-
ing the 1,2-diaxial couplings with C(5)H and C(3)H,
points to the equatorial disposition of the C(4) proton.
Such a 1,2-diaxial interaction, however, occurs between
3
C(6) and C(5) protons since their JHH=9.4 Hz. The
axial C(6) and C(2) protons, apart from an NOE
1,3-diaxial enhancement, show an NOE with the pro-
penyl C(1¦) proton. In addition, the C(5) and C(3) axial
protons exhibit NOEs with one of the C(9) protons
appearing at lH=4.96 and revealing no NOE effect
with C(7)H. The two NOEs exclude the possible trans-
fusion between the six- and five-membered rings of 10.
In order to examine structure 10 found in CDCl3
solution, analysis in the solid state of the alkaloid
derived from 2a was carried out by X-ray diffraction
analysis.
The above results not only confirm the axial position of
the (E)-propenyl group but also allow us to indicate the
conformer 10 to be predominant in the equilibrium
The result was a surprise since the discussed alkaloid
exhibited trans-fusion between the piperidine and oxa-

50
J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
Figure 1. Drawing of molecule 10a showing its absolute configuration and conformation as present in the crystal structure. Two
sites of the disordered C(1¦)=C(2¦)ꢀC(3¦) 1-propenyl have been differentiated by the style of the bonds in the drawing: full bonds
and full lines to H-atoms for one position, and open bonds and dotted lines to H-atoms in the other. The methyl hydrogens in
methyl C(3¦) are additionally disordered in four positions each.
according to Altona amounts to −154°.27 The NOE
zolidine rings shown in Fig. 1 as structure 10a (dis-
between C(1¦)H and C(6)H and 1,2-diaxial coupling as
well as C(4)H resonance (broadened singlet with SJ:
24 Hz) indicates not only that 12 is the dominant
conformer in the equilibrium mixture 12 = 13 (Scheme
2) but also confirms retention of the (4S)- and (6S)-
configurations of the substrate 10. These spatial
arrangements correspond to (4S)- and (8S)-configura-
tion in the parent quinine 1.17,36
cussed in detail later in the text). This crystal structure
explains the appearance of the Bohlmann band on the
IR spectrum. The X-ray structure of trans-10a, on the
one hand, confirms the (4S,6S,7R)-configuration of 10,
but on the other hand, points to the pyramidal inver-
sion of the N(1) nitrogen atom (see Table 1). Such an
inversion is not an isolated phenomenon within struc-
tures comprising piperidine rings. For instance,
bisquinolizidine alkaloids may change their N(16) chi-
rality. In particular, lupanine, sparteine and 2-
phenylsparteine, as free bases, feature the dominant
conformer with ‘chair–chair–boat–chair’ rings,29–31
whereas their perchlorates possess the ‘all-chair’ struc-
The formation of niquine from 10 is not accompanied
by its C(a)-epimer, inferring that the C(7)ꢀO bond of
the substrate 10 has remained unscathed, whereas the
C(9)-O linkage should be broken. In such a case
niquine should feature the unchanged (7R)-configura-
tion of 10, identical to C(9R) of quinine.36 To verify
this presumption, niquine was subjected to cyclisation
via its reaction with acetone.20 In the case of cis-fusion,
the cyclisation product should feature an NOE between
the methyl group appearing at lH=1.60 and the C(5)
axial proton. Instead, this group exhibits an NOE with
the quinoline C(3%) proton, which in the cis-compound
is more remote (model inspection) than the axial C(5)H.
Occurrence of this Overhauser effect can be better
explained by accepting the trans-fusion.
ture.32–34
A
thioanalogue of lupanine, (+)-2-
thionosparteine, also shows dominance of the C-boat
form over that of the ‘all-chair’ form in solution.
Instead, asymmetric units of the crystals are composed
of both forms in a 1:1 ratio.35 Here the pyramidal
inversion is due to crystal packing forces which are
likely to give rise to trans-10a.
On treatment of 10 with acid, loss of the C(9) carbon
(corresponding to C(2) of the parent 2a) in the form of
CH2O occurs and niquine is formed. The eliminated
formaldehyde was trapped as its condensation product
with dimedone.
X-Ray diffraction analysis of the obtained isopropyl-
idine derivative of niquine, 14 (Scheme 2) showed for-
mation of the trans-junction between the piperidine and
oxazolidine rings (see Fig. 2). This fusion arose due to
inversion of configuration at N(1) in the restored 8-oxa-
1-azabicyclo-[4.3.0]-nonane ring as compared with 10.
However, in accordance with the Cahn–Ingold-Prelog
sequence rule,37 N(1) has (R)-configuration, as in 10.
Both the X-ray analysis and NMR data also confirmed
retention of the (4S,6S,7R)-configuration (see Fig. 2).
The formed niquine has the previously20 undetermined
(E)-propenyl side chain since it shows the olefinic
3JHH=15.4 Hz and the methyl group resonates at lC=
18.15.26 The propenyl substituent occupies an axial
position because its C(1¦) proton displays an NOE with
C(6)H. The C(6) proton displays a 1,2-diaxial disposi-
tion with C(5)H; their coupling constant is 10.3 Hz and
the C(6)HAXꢀC(6)ꢀC(5)ꢀC(5)HAX dihedral calculated

J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
51
Table 1. Selected torsion angles (°) for 10a and 14
10a 14
C(1¦)ꢀC(2¦). The orientations of the disordered pro-
penyl groups in 10a differ by 230°, while the position
assumed by the propenyl group in 14 is intermediate
between the two orientations in 10a. It is likely that
these conformations are related to the packing of the
molecules in the crystal lattices, rather than to the
conformational properties of the molecules.
Piperidine ring
C6ꢀN1ꢀC2ꢀC3
N1ꢀC2ꢀC3ꢀC4
C2ꢀC3ꢀC4ꢀC5
C3ꢀC4ꢀC5ꢀC6
C4ꢀC5ꢀC6ꢀN1
C2ꢀN1ꢀC6ꢀC5
−61.3(4)
−62.1(3)
56.8(5)
−53.4(5)
52.2(4)
−56.7(4)
62.7(4)
54.8(4)
−50.6(3)
52.3(3)
−60.0(3)
66.0(3)
Both compounds 10 and 14 have (7R)-configuration,
the C(7)ꢀO bond of 10 could not be broken on treat-
ment with acid. Thus, formation of niquine unnecessar-
ily follows the Grob fragmentation pattern and may be
rationalised by the alternative reaction pathway 2“6“
7“8“9“3 (Scheme 1). In contrast to the highly
stereoselective conversion of the (10R)-diastereomer
(2a“10,Scheme 2) its (10S) counterpart provides a
mixture of products.
Propenyl group
C2ꢀC3ꢀC4ꢀC1¦
C2ꢀC3ꢀC4ꢀC1¦a
C3ꢀC4ꢀC1¦ꢀC2¦
C5ꢀC4ꢀC1¦ꢀC2¦
C3ꢀC4ꢀC1¦aꢀC2¦a
C5ꢀC4ꢀC1¦aꢀC2¦a
C4ꢀC1¦ꢀC2¦ꢀC3¦
C4ꢀC1¦aꢀC2¦aꢀC3¦
C1¦ꢀC4ꢀC5ꢀC6
C1¦aꢀC4ꢀC5ꢀC6
82.0(5)
62.2(11)
−128.3(8)
1.3(11)
74.1(3)
12.6(5)
137.6(4)
103(2)
−138(2)
−178.4(7)
174.1(15)
−77.2(6)
−69.8(9)
−179.0(4)
−76.4(3)
The most abundant (40%) and, at the same time, the
less polar component consists of two inseparable alka-
loids. Fortunately their 1H NMR signals overlapped
only partially, so knowing the resonances of one (i.e.
those of 10), the signals of its (Z)-isomer 15 (Scheme 2)
could be identified. Similarly the 13C NMR resonances
could be distinguished, especially those belonging to the
C(4)- and C(3¦)-carbons of 15. The two characteristi-
cally differed from analogous resonances of the alka-
loid 10. The corresponding lC values of 28.77 and
12.28, as compared with 33.51 and 18.01 ppm, respec-
tively, are due to alkene-2 g-shielding occurring only in
the (Z)-propenyl group.24,26 The mixture of alkaloids 10
and 15, with an E:Z ratio of 11:9 (1H NMR integra-
tion), undergoes catalytic hydrogenation to give the
compound with an n-propyl side chain (17 = 18,
Scheme 2). This result confirms the structure 15.
Oxazolidine ring
N1ꢀC6ꢀC7ꢀO8
C6ꢀC7ꢀO8ꢀC9
C7ꢀO8ꢀC9ꢀN1
C6ꢀN1ꢀC9ꢀO8
C9ꢀN1ꢀC6ꢀC7
35.5(3)
−12.3(4)
−16.7(5)
39.8(4)
21.7(2)
2.2(3)
−25.2(3)
40.2(3)
−46.0(3)
−38.5(2)
Piperidine–oxazolidine fusion
C4ꢀC5ꢀC6ꢀC7
C9ꢀN1ꢀC2ꢀC3
C9ꢀN1ꢀC6ꢀC5
C2ꢀN1ꢀC6ꢀC7
C5ꢀC6ꢀC7ꢀO8
C2ꢀN1ꢀC9ꢀO8
−171.6(3)
−177.5(3)
−173.5(3)
−169.8(3)
155.6(3)
−174.6(2)
174.7(2)
−164.6(2)
−167.9(2)
140.7(2)
161.6(3)
165.5(2)
Oxazolidine–quinoline
C(7)ꢀC(4%) junction
N1ꢀC6ꢀC7ꢀC4%
−83.0(3)
37.2(5)
−99.3(2)
19.7(3)
The alkaloid 15 features the C(2), C(5) and C(6) proton
3
C5ꢀC6ꢀC7ꢀC4%
signals lacking the JHH values which would indicate
C4%ꢀC7ꢀO8ꢀC9
109.3(4)
−22.9(5)
91.5(4)
155.8(3)
−89.8(4)
127.5(2)
−26.3(3)
92.1(3)
152.5(2)
−89.1(3)
1,2-diaxial couplings. Moreover, the C(4) proton reso-
nance shows SJ:29 Hz intermediate between 18.5 Hz,
characteristic of equatorial positioning of the C(4)H in
compound 10, and 42 Hz corresponding to an axial
C(4)H in the alkaloid 6.24 The above data are likely due
to averaging of the resonances caused by the conforma-
tional equilibrium 15 = 16 (Scheme 2), which might be
caused by repulsion between the methyl group and the
axial C(2) and C(6) hydrogens, which hinders the rota-
tion of the (Z)-propenyl chain about the C(1¦)ꢀC(4)
bond. A similar equilibrium probably occurs in the
hydrogenation product of the mixture of the alkaloids
10 and 15 (17 = 18, Scheme 2), since the C(2), C(5) and
C(6) protons display no 3JHH values that would indicate
1,2-diaxial interactions within the piperidine fragment.
O8ꢀC7ꢀC4%ꢀC3%
C6ꢀC7ꢀC4%ꢀC3%
O8ꢀC7ꢀC4%ꢀC4%a
C6ꢀC7ꢀC4%ꢀC4%a
Methoxyl orientation
C5%ꢀC6%ꢀO1§ꢀC2§
C7%ꢀC6%ꢀO1§ꢀC2§
3.4(8)
−177.7(5)
2.6(5)
−177.7(4)
The conformations of 10a and 14 are also shown in
Figs. 1 and 2, and compared in Table 1. The conforma-
tions are similar despite their flexibility. The methyl
substituents at C(9) induce little variation of the main
molecular skeleton. The torsion angles about the single
C(7)ꢀC(4%) bond joining two moieties in the molecules
are very similar. Some differences, of about 10°, are
observed for the oxazolidine rings, but the piperidine
rings are in the similarly distorted chair conformation.
The main apparent difference is the conformation of
the 1-propenyl substituent. In both compounds the
propenyl group is situated axially at C(4), however, in
10a it is disordered in two positions, none of which is
observed in 14. The orientation of the propenyl relative
to the piperidine ring can be conveniently measured by
torsion angles C(3)ꢀC(4)ꢀC(1¦)ꢀC(2¦) and C(5)ꢀC(4)ꢀ
The next and less abundant (ꢀ30%) product obtained
from the (10S)-diastereomer 2b is a D3,10-isomer of
quinine featuring mp 182–185°C and [h]D=−188.7.
These data are similar to those of b-isoquinine
described by Suszko (mp 188°C; [h]D=−191.45)38 and
Henry (mp 183–185°C; [h]D=−201.2)39 and also con-
sidered to be a D3,10-isomer of quinine. The discussed
alkaloid showed the methine C(4) resonance at lC=
33.32, which on comparison with the model, 3-ethyli-
dene-quinuclidine,40 points to the previously undeter-

52
J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
Figure 2. Drawing of molecule 14, as present in the crystal structure showing its molecular conformation and absolute
configuration.
Br
H
CH3
CH=CH-CH3
H
Br
H3C CH
H
HCO3
N=CH2
H
HO
H
Q
N
C
N
C
OH
Q
OH
Q
H
H
H
H
20
21
22
Scheme 3. Possible transition states for oxazolidine ring-closure during the rearrangement (20, 21) and stereoselective elimination
(22) discussed in the text. The formation of 20 may be preceded by the carbonium ion 4 of Scheme 1.
mined (Z)-configuration of the side chain (in the case of
(E)-configuration, one would expect the C(4) signal to
appear at lC=26 1). Moreover, NOEs between the
C(4) and C(10) protons as well as between the C(2)
methylene and C(11) methyl protons were observed (see
19, Scheme 2).
The observed ratio of 10 to 15 may indicate that the
rearrangement of 2a and 2b proceeds via carbonium ion
4 (Scheme 1) the more so that 80% aqueous ethanol,
being the reaction medium, exhibits good ionisation
ability.22,41 The cation 4 would then convert into the
imminium cation 5 (Scheme 1), which enables an
approach of C(2) to the oxygen at C(9) to close the
oxazolidine rings of 10 and/or 15 (see 20, Scheme 3).
Because of the (8S)-configuration in 2a and 2b, forma-
tion of the oxazolidine moiety is unlikely to be a one-
step process. On the other hand, such a concerted
mechanism (21, Scheme 3) is conceivable for 10-bromo-
10,11-dihydrocinchonine 2c with (8R) arrangement.
The third component of the mixture obtained from 2b
is composed of niquine and its (Z)-isomer as it can be
inferred from the 13C NMR analysis. These alkaloids
have been, at least partially, formed by the influence of
alumina on the mixture of 10 and 15 during column
chromatography. Two remaining minor components of
the crude conversion product of 2b were very difficult
to separate.
The cation 4 could also be responsible for E1 elimina-
tion leading to the alkaloid 19, which is energetically
favourable over its (E)-isomer. In the latter compound,
the distance between the (E)-methyl group and the C(4)
hydrogen (model inspection) is smaller than that of the
(Z)-methyl group from any of the C(2) protons in 19.
However, selective formation of the alkaloid 19 would
be indicative of E2 elimination, since the (Z)-configura-
tion might result from the preceding transition state 22
(Scheme 3).
Conversions of 2a and 2b shown in Scheme 2 clearly
point out their chirality. This feature is most distinctly
revealed by the diastereomer 2a, which rearranges
almost entirely into the alkaloid 10. The rearrangement
also occurs in the case of the isomer 2b although with
much lower stereoselectivity providing 55% of 10 versus
45% of 15. Instead, high stereoselectivity in the elimina-
tion of HBr from 2b has been observed (2b“19,
Scheme 2).

J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
53
3. Conclusion
combined first and second crops were recrystallised
twice from acetone. Mp (capillary method): 155–160°C
shrinks and darkens, 166–167°C decomposes and melts;
[h]D=−213.7 (c=1.015, chloroform:ethanol/2:1 v/v).
Reported:18 mp 166–167°C decomp.; [h]D=−200 (sol-
vent as above). Anal. calcd for C20H25N2O2Br (405.336)
C, 59.26; H, 6.22; N, 6.91; found: C, 59.78; H, 6.25; N,
6.95%.
In summary, the results presented demonstrate that the
so far observed 2c“6 rearrangement not only extends
to another cinchona alkaloid but also proceeds
stereoselectively and is likely to involve a multi-stage
mechanism. Another mechanism suggested for the
acidic ‘fragmentation’ of the rearrangement product 10
has received firm support due to the retained (aR)-
configuration in 12. Stereoselectivity has also been
observed during restoration of 8-oxa-1-azabicyclo-
[4.3.0]nonane ring (12“14, Scheme 2) and elimination
of HBr from 2b. The origin of the asymmetry in the
formation of 14, 10 and 15 as well as further extending
the scope of the rearrangement are still under investiga-
tion.
The structure of 2a was confirmed by X-ray diffraction
analysis.19
4.3. (10S)-Bromo-10,11-dihydroquinine 2b
The aforementioned third crop and the residue from
concentration of the final mother liquours were crys-
tallised from benzene providing 3.85 and 0.96 g of 2b,
respectively. These fractions were combined and recrys-
tallised from benzene (40 mL) giving 2b (4.8 g, 27%).
Mp (capillary method): 142.5–144°C shrinks, decom-
poses and melts; [h]D=−51.95 (c=1.0125, chloro-
4. Experimental
4.1. General
form:ethanol/2:1).
Reported:18
mp
160–162°C,
decomp.; [h]D=−50 (solvent as above). Anal. calcd for
C20H25N2O2Br·C6H6 (483.1) C, 64.59; H, 6.46; N, 5.79;
found: C, 64.47; H, 6.27; N, 5.53%.
Melting points are uncorrected. Optical rotations were
measured on a Perkin–Elmer 243B Polarimeter and are
reported as follows: [h]D (concentration g/100 mL, sol-
vent). The IR spectra were recorded using FT-IR-
Raman Nicolette-760 spectrometer. NMR spectra were
obtained on a Varian Gemini 300 BB and Varian
Mercury spectrometers at observation frequencies 75
X-Ray diffraction analysis19 confirmed the structure of
2b.
4.4. (4S)-(E)-propenyl)-(6S,7R)-(6-methoxyquinol-4-yl)-
8-oxa-(1R)-azabicyclo[4.3.0]nonane 10
1
and 300 MHz. H NMR spectra were recorded in ppm
(l) related to tetramethylsilane and are reported as
follows: chemical shift (multiplicity, integration, cou-
pling constants in Hz, assignment). 13C NMR spectra
(l, TMS) are presented as chemical shift (assignment).
The NMR assignments were made by first-order analy-
A mixture of 2a (twice crystallised from acetone, 250
mg, 0.617 mmol) and 99.7% ethanol (16 mL) was added
to a solution of sodium bicarbonate (52 mg, 0.619
mmol) in water (4 mL) and the mixture was heated
under reflux for 11 h. Ethanol was then removed from
the warm mixture and the remainder was exhaustively
extracted with diethyl ether. The combined extracts
were dried overnight with KOH in pellets. Removal of
the solvent under reduced pressure yielded crystalline
solid of 10 (197 mg), which was near-pure by 1H NMR.
Column chromatography (15 g of neutral alumina,
Woelm, benzene 125 mL: 99.7% ethanol 1.25 mL;
benzene 100 mL: 99.7% ethanol 5 mL; 99.7% ethanol
100 mL) of the product caused its partial decomposi-
tion giving 10 (110 mg, 55%) and contaminated niquine
(ꢀ70 mg) (NMR: see Section 4.5).
1
1
sis of the H resonances and aided by DEPT, H–1H-
and 13C–1H-cosy spectra. NOEs are reported as fol-
lows: lH irradiated (lH enhanced). MS spectra were
performed on a AMD 402 instrument (AMD-INTEC-
TRA Germany). Microanalyses were performed on an
Euro EA-3000 (Euro Vector) apparatus.
4.2. (10R)-Bromo-10,11-dihydroquinine 2a
Quinine dihydrobromide (1·2HBr·3H2O crystallised
three times from water prior to use, 20 g, 37.04 mmol)
was dissolved with cooling in 62% aqueous hydro-
bromic acid (100 mL, 1326 mmol). The mixture was
placed in two sealed vials and kept for 9 h at 40°C.
After cooling, the reaction mixture was poured onto ice
(ꢀ200 g) and partially neutralised with sodium carbon-
ate. The still acidic mixture was made alkaline using
portions of ꢀ20% aqueous sodium hydroxide while
being vigorously shaken with diethyl ether (1350 mL).18
The ethereal extract was dried over anhydrous potas-
sium carbonate only for several minutes to avoid pre-
cipitation of the product, immediately decanted and left
overnight to crystallise. The crystals were isolated by
filtration and dried to afford 2a (3.07 g, 21%). The
mother liquor was concentrated to a volume of 400 mL
to give second crop (2.33 g, 16%). Distilling off a
further 200 mL of ether provided a third crop (3.76 g)
and removal of the solvent gave a solid (1.86 g). The
Data for 10: Mp (Boetius) 142–145°C (recrystal. from
diethyl ether); [h]D=−220.8 (c=1.07; 99.7% ethanol).
IR (KBr) 3032, 3003 (aromatic wC–H), 2952, 2930,
2855 (aliphatic wC–H), 2830, 2816, 2786, 2756, 2714
(Bohlmann band), 1621, 1592, 1507, 1433 (quinoline
wCꢁC), 1472, 1461, 1383 (aliphatic lC–H), 1240, 1225
(wC–O–C) cm−1. Anal. calcd for C20H24N2O2 (324.2) C,
74.04; H, 7.46; N, 8.63; found: C, 74.23; H, 7.49; N,
8.71%.
MS m/z 324 (M+, 1.29), 137 (100), 122 (28.59), 116
(5.87), 108 (10.92), 94 (21.51); HRMS calcd for
C20H24N2O2: 324.18378; found 324.18535. 1H NMR
(CDCl3): 8.77 (d, 1H, 3J=4.4, H-2%), 7.57 (dd, 1H,
4
4
3J=4.4, J:0.5, H-3%), 7.13 (d, 1H, J=2.8, H-5%), 7.37

54
J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
3
4
3
(dd, 1H, J=9.2, J=2.9, H-7%), 8.04 (d, 1H, J=9.1,
H-5%), 7.38 (dd, 1H, 3J=9.1, 4J=2.7, H-7%), 7.96 (d, 1H,
3J=9.1, H-8%), 4.85 (N-H), 5.37 (dd?, 1H, 3J=4.9, H-a),
3.35 (ddd, 1H, 3J=10.3, 3J=4.9, 3J=3.0, H-2), 1.41
2
2
H-8%), 4.96 (d, 1H, J=3.0, H-9), 4.24 (d, 1H, J=3.0,
H-9), 5.73 (dd?, 1H, 3J=7.9, H-7), 3.27 (ddd, 1H,
3J=9.4, 3J=7.8, 3J=3.6, H-6), 1.04 (ddd, 1H, 2J=13.6,
2
3
3
(m, 1H, H-3), 1.74 (ddd, 1H, J=13.3, J=10.3, J=
4.9, H-3), 2.50 (bs, 1H, SJ:24, H-4), 5.51 (ddq, 1H,
3J=9.2, J=4.5, H-5), 1.49 (dddd, 1H, J=13.3, J=
3
2
3
4.8, 3J=3.7, 4J=1.0, H-5), 1.95 (m, 1H, SJ=18.5,
3J=15.5, J=6.6, J=1.5, H-1¦), 5.26 (dqd, 1H, J=
15.4, 3J=6.3, 4J=1.5, H-2¦), 1.52 (dt, 3H, 3J=6.3,
4J=1.4, H-3¦), 3.93 (s, 3H, OMe), 1.65 (m, 1H, H-5),
1.44 (m, 1H, H-5), 2.82 (m, 2H, H-6); 13C NMR
(acetone-d6): 148.28 (C-2%), 120.29 (C-3%), 147.68 (C-4%),
103.18 (C-5%), 158.23 (C-6%), 121.74 (C-7%), 132.39 (C-8%),
145.43 (C-8%a), 127.99 (C-4%a), 73.09 (C-a), 56.24 (C-2),
31.84 (C-3), 34.98 (C-4), 32.31 (C-5), 42.42 (C-6), 55.91
(OMe), 135.21 (C-1¦), 124.73 (C-2¦), 18.15 (C-3¦).
NOE: 3.35 (5.51, 2.82, 5.26, 1.41, 1.74, 5.37, 7.58, 7.55),
5.51 (5.26, 3.35, 2.82, 2.50, 1.52).
3
4
3
H-4), 1.64 (tt, 1H, J=3J=10.2, J=4.4, H-3), 1.48 (m,
2
3
1H, H-3), 2.97 (ddd, 1H, 2J=11.0, 3J=4.9, 3J=4.4,
2
3
3
H-2), 2.56 (ddd, 1H, J=11.0, J=10.2, J=3.3), 3.94
(s, 3H, OMe), 5.37 (ddq, 1H, 3J=15.4, 3J=6.3, 4J=1.4,
3
3
4
H-1¦), 5.21 (dqd, 1H, J=15.4, J=6.3, J=1.4, H-2¦),
1.61 (dt, 3H, 3J=6.1, 4J=1.4, H-3¦). 13C NMR
(CDCl3): 147.87 (C-2%), 119.67 (C-3%), 143.99 (C-4%),
126.96 (C-4%a), 101.79 (C-5%), 157.34 (C-6%), 120.86 (C-
7%), 131.79 (C-8%), 144.73 (C-8%a), 86.71 (C-9), 77.16
(C-7), 60.28 (C-6), 30.73 (C-5), 33.51 (C-4), 29.02 (C-3),
44.64 (C-2), 55.55 (OMe), 133.53 (C-1¦), 124.85 (C-2¦),
18.01 (C-3¦). NOE: 1.04 (1.49, 1.95, 3.27, 4.96, 5.73,
7.13, 7.57); 2.56 (5.37, 5.21, 4.96, 4.24, 2.97, 3.27, 1.48,
7.57); 3.27 (5.73, 5.37, 5.21, 4.24, 1.49, 1.04); 4.96 (2.97,
2.56, 7.57, 4.24, 1.64, 1.04).
4.5.1.
2,2%-Methylene-di-(5,5-dimethylcyclohexan-1,3-
dione). The above ethanolic distillates were added to a
solution of dimedone (1 g) in water (125 mL) yielding
the condensation product (181 mg). Mp (Boetius) 189–
192°C (reported:20 190–192°C). MS m/z 292 (M+
80.50), 277 (13.54), 233 (11.46), 208 (14.87), 191 (15.59),
180 (22.83), 177 (10.97), 165 (100), 152 (28.51), 140
(24.00), 137 (19.47), 124 (33.47), 112 (21.17), 97 (25.37).
HRMS calcd for C17H24O4: 292.16745; found
292.16806.
4.5. [(4S)-(1E)-Propenyl)-(2S)-piperydynyl]-6-
methoxyquinoline-(aR)-methanol—‘niquine’ 12
A solution of almost pure 10 (1.115 g, 3.44 mmol,
obtained as above from 1.47 g of 2a twice recrystallised
from acetone) in 96% aqueous ethanol (10 mL) and a
solution of oxalic acid (COOH)2·2H2O (0.44 g, 3.49
mmol) in the same solvent were heated under reflux for
80 min. No formaldehyde was detected while forcing
the vapours through a gas-washing bottle filled with
water solution of dimedone. Ethanol was removed in
vacuo and the remaining syrup, giving off an odour of
formaldehyde, was dissolved in 99.7% ethanol (25 mL).
The solvent was again distilled off in vacuo. The
residue was heated under reflux for 10 min with a
solution of oxalic acid (0.44 g, 3.49 mmol) in ethanol
(25 mL) and left overnight to isolate niquine by precip-
itating it as its acid oxalate.18,20 The salt was filtered off
washed with ethanol and air dried to afford 12 (1.04 g,
58%).
4.5.2. (4S)-(E)-Propenyl)-(6S,7R)-(6-methoxyquinol-4-
yl)-9,9-dimethyl-8-oxa-(1R)-azabicyclo-[4.3.0]nonane—
‘isopropylidene-niquine’ 14. A solution of niquine 12 (90
mg, 0.288 mmol) in acetone (5 mL) was kept for 8
weeks at ambient temperature in a stoppered flask. The
progress of the reaction was monitored by TLC (alu-
mina, Merck 5581; benzene:99.7% ethanol/9:1 v/vol).
Slow evaporation of the solvent gave a resin, which
began to solidify after freezing in liquid nitrogen. The
partially solidified product was left for 72 h in a dessic-
cator and the obtained solid was crystallised from
acetone yielding 14 (50 mg, 44%). Mp (Boetius) 149–
154°C decomp.; [h]D=−115.3 (c=1.084, 99.7% etha-
nol). IR (KBr) 3092, 3078, 3022 (aromatic wC–H),
2957, 2920, 2898, 2852 (aliphatic wC–H), 1619, 1591,
1504, 1430 (quinoline wCꢁC), 1470, 1455 (aliphatic
lC–H), 1381, 1367 (geminal dimethyl groups), 1234,
1224 (wC–O and/or wC–O–C). MS m/z 352 (M+, 7.08),
337 (19.37), 295 (30.68), 166 (14.99), 165 (100), 150
(35.28), 110 (24.39). HRMS calcd for C22H28N2O2:
Niquine acid oxalate (0.66 g, 1.17 mmol) were dissolved
in 2N aqueous HCl, made alkaline with ꢀ20% aqueous
KOH and exhaustively extracted with diethyl ether (300
mL and 3×50 mL). The combined extracts were dried
overnight with KOH in pellets. After removal of the
solvent the crude niquine was crystallised from acetone
to afford pure 12 (155 mg, 42%). Mp (Boetius) 136.5–
138°C; [h]D=−128.65 (c=1.02, ethanol 99.7%). IR
(KBr) 3500–2500 (wO–H, N–H), 3023 (aromatic wC–
H), 2945, 2916, 2884, 2840 (aliphatic wC–H), 1620,
1592, 1509, 1433 (quinoline wCꢁC), 1470, 1363
(aliphatic l C–H), 1255, 1242 (wC–O and C–O–C)
cm−1. Anal. calcd for C19H24N2O2 (312.413) C, 73.05;
H, 7.74; N, 8.97; found: C, 72.56; H, 7.78; N, 8.84%.
MS m/z 311 (M+−H, 0.18), 189 (100), 174 (11.0), 160
(12.74), 145 (6.61), 124 (58.0), 117 (10.43) 89 (4.86) 56
(45.57); MSFAB m/z 313.1 (M+H+, 23); HRMS.FAB
1
352.21509; found 352.21410. H NMR (CDCl3): 8.75
3
3
4
(d, 1H, J=4.4, H-2%), 7.56 (dd, J=4.4, J:0.7, H-3%),
7.18 (d, 1H, 4J=3.0, H-5%), 7.35 (dd, 1H, 3J=9.1,
4J=2.8, H-7%), 8.02 (d, 1H, 3J=9.3), 5.77 (d, 1H,
3J=8.0, H-7), 3.50 (ddd, 1H, 3J=11.6, 3J=8.4, 3J=2.8,
2
3
4
H-6), 1.39 (dtd, 1H, J=12.7, J=2.5, J=1.1, H-5),
2
3
3
0.75 (ddd, 1H, J=12.6, J=11.8, J=4.9, H-5), 2.27
(bs, 1H, SJ:21, H-4), ꢀ1.61 (m, 1H, H-3), ꢀ1.65 (m,
2
3
1H, H-3), 2.74 (dt, 1H, J=10.7, J=3.6, H-2), 2.50
(td, 1H, J=3J=10.6, J=4.7, H-2), 1.60 (d, 3H, J:
2
3
4
4
0.4, a-Me at C-9), 1.31 (d, 3H, J:0.4, b-Me at C-9),
3
3
3.93 (s, 3H, OMe), 5.54 (ddq, 1H, J=15.4, J=6.4,
1
3
3
4
calcd for C19H25N2O2: 313.19159; found 313.19302. H
4J=1.4, H-1¦), 5.37 (dqd, 1H, J=15.4, J=6.2, J=
NMR (acetone-d6): 8.70 (d, 1H, 3J=4.2, H-2%), 7.58
1.4, H-2¦), 1.68 (dt, 3H, J=6.0, J=1.4, H-3¦). 13C
NMR (CDCl3); 147.73 (C-2%), 119.90 (C-3%), 143.82
3 4
3
4
4
(dd, 1H, J=4.5, J:0.7, H-3%), 7.55 (d, 1H, J=2.7,

J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
55
(C-4%), 127.10 (C-4%a), 101.79 (C-5%), 157.11 (C-6%),
120.81 (C-7%), 131.54 (C-8%), 144.79 (C-8%a), 75.56 (C-7),
57.11 (C-6), 32.40 (C-5), 33.56 (C-4), 29.68 (C-3), 41.41
(C-2), 94.85 (C-9), 133.27 (C-1¦), 124.95 (C-2¦), 18.26
(C-3¦), 55.61 (OMe), 18.74 (C-9 a-Me), 26.04 (C-9
b-Me). NOE: 3.50 (5.77, 5.54, 2.50, 1.39, 1.31, 5.37),
0.75 (2.27, 1.61, 1.39, 7.56), 2.50 (5.54, 5.37, 3.50, 2.74,
1.60, 1.31), 5.54 (5.37, 3.50, 2.50, 2.27, 1.68, 1.39), 7.56
(8.75, 5.77, 1.60, 0.75).
(31 mg) on crystallisation from benzene. Mp (Boetius)
182–185°C; [h]D=−188.7 (c=0.5125, 99.7% ethanol).
IR (KBr): 3690–2350 broad absorption with extrema at
3347, 3125, 2737, 2591 (hydrogen bonded wOH), 3090,
3040, 3008 (wC–H aromatic), 2952, 2929, 2895, 2860
(wC–H aliphatic), 1622, 1591, 1566, 1511 (quinoline
wCꢁC), 1458, 1382 (lC–H aliphatic), 1261, 1242 (wC–O
and/or wC–O–C) cm−1. MS m/z 324 (M+, 89.96), 309
(19.25), 189.0 (56.43), 188 (34.29), 172 (27.65), 160
(23.18), 137 (67.88), 136 (100), 122 (25.34), 117 (25.17),
108 (22.06), 81 (26.75), 68 (31.80), 56 (25.50). HRMS
4.6. Reaction of 2b with sodium bicarbonate
1
calcd for C20H24N2O2 324.18378; found 324.18282. H
3
NMR (CDCl3): l 8.57 (d, 1H, J=4.4, H-2%), 7.49 (d,
A mixture of 2b (600 mg, 1.23 mmol—the equivalent of
500 mg of benzene-free 2b), NaHCO3 (103 mg, 1.23
mmol), water (10 mL) and 99.7% ethanol (40 mL) were
heated under reflux for 11 h. Ethanol was removed
under reduced pressure and the residue was exhaustively
extracted with diethyl ether. The combined ethereal
extracts were dried over anhydrous potassium carbon-
ate. Removal of the solvent under reduced pressure gave
a foamy solid (436 mg), which on TLC (see above)
showed the spots A, B, C, D, E marked in accordance
with their decreasing polarity. Column chromatography
(40 g neutral alumina partially deactivated by treatment
with water (1.2 mL); benzene 100 mL: 99.7% ethanol 0.5
mL; benzene 400 mL: 99.7% ethanol 4 mL; benzene 100
mL: 99.7% ethanol 10 mL; 99.7% ethanol 100 mL)
yielded 163 mg of the alkaloids E (10, 15), ꢀ5 mg of D
(with unreadable 1H NMR spectrum), 31 mg of the
alkaloids D+C (aproximately 1:1), 51 mg of C contam-
inated by D, 41 mg of C (alkaloid 19), 17 mg of
predominantly C+B, 70 mg of the alkaloids A contam-
inated by B and C. The alkaloids A consist of 12 (13C
NMR see: Section 4.5) and its (Z)-counterpart showing
the lC values of 72.95, 56.25, 31.83, 29.85, 133.69,
123.61, 12.92, 32.13 as well as 6-methoxyquinol-4-yl
resonances common with those of 12.
1H, 3J=4.5, H-3%), 7.22 (d, 1H, 4J=2.7, H-5%), 7.29 (dd,
3
4
3
1H, J=9.0, J=2.7, H-7%), 7.94 (d, 1H, J=9.3, H-8%),
3
3
3
5.61 (d, 1H, J=3.7, H-9), 3.09 (td, 1H, J=8.8, J=
3.8, H-8), 1.95 (ddd, 1H, 2J=12.2, 3J=8.6, 3J=1.2,
2
H-7), 1.38 (dm, 1H, J=12.4, H-7), 3.57 (m, 1H, H-6),
2.70 (dd?, 1H, 2J=13.1, 3J=9.6, H-6), 1.77 (m, 1H,
H-5), 1.55 (m, 1H, H-5), 2.33 (bs, 1H, SJ=9, H-4), 3.45
2
2
(dbs, 1H, J=17.3, H-2), 3.34 (dbs, 1H, J=17.0, H-2),
5.16 (qt, 1H, 3J=6.7, 4J=2.5, H-10), 1.43 (dt, 3H,
3J=6.8, J=1.4, H11), 3.88 (s, 3H, OMe), ꢀ4.6 (OH).
5
13C NMR (CDCl3): l 147.42 (C-2%), 118.38 (C-3%),
147.82 (C-4%), 101.33 (C-5%), 157.58 (C-6%), 121.33 (C-7%),
131.38 (C-8%), 126.48 (C-9%), 144.00 (C-10%), 71.81 (C-9),
60.74 (C-8), 28.04 (C-7), 43.93 (C-6), 27.82 (C-5), 33.32
(C-4), 140.82 (C-3), 56.70 (C-2), 114.56 (C-10), 12.36
(C-11), 55.64 (OMe). NOE: 3.39 (1.43, 3.09, 2.70), 2.33
(5.16, 1.95), 5.16 (2.33, 1.43).
4.7. (4S)-Propyl-(6S,7R)-(6-methoxyquinol-4-yl)-8-oxa-
(1R)-azabicyclo[4.3.0]nonane 17
A mixture of 10 and 15 (61 mg, 0.188 mmol, from the
above 163 mg fraction of the alkaloids E) was dissolved
in 99.7% ethanol (10 mL) and hydrogenated by shaking
with Adams catalyst (PtO2, 10 mg, 0.044 mmol) under
hydrogen (4 2 atm) at room temperature for 4.5 h. The
catalyst was then removed by filtration and the solvent
was evaporated under reduced pressure. The remainder
was dissolved in diethyl ether and filtered. Removal of
the ether from the filtrate yielded non-crystalline 17 (53
mg, 87%). [h]D=−216.8 (c=0.505, 99.7% ethanol). MS
m/z 326 (M+, 2.44), 189 (8.38), 159 (4.74), 153 (11.41),
139 (100), 124 (7.22), 110 (8.91), 96 (28.04), 69 (8.27).
HRMS calcd for C20H26O2N2: 326.19943; found
326.20066. 1H NMR (CDCl3): 8.73 (d, 1H, 3J=4.6,
H-2%), 7.61 (dd, 1H, 3J=4.6, 4J:0.8, H-3%), 7.10 (d, 1H,
4J=2.7, H-5%), 7.38 (dd, 1H, 3J=9.2, 4J=2.6, H-7%), 8.03
4.6.1. (4S)-(Z)-Propenyl)-(6S,7R)-(6-methoxyquinol-4-
yl)-8-oxa-(1R)-azabicyclo[4.3.0]nonane 15. This alkaloid
1
makes 45% of the above 163 mg fraction. H NMR
(CDCl3): 8.78 (d, 1H, 3J=4.6, H-2%), 7.64 (dd, 1H,
4
4
3J=4.4, J:0.7, H-3%), 7.09 (d, 1H, J=2.5, H-5%), 7.37
3
4
3
(dd, 1H, J=9.2, J=2.5, H-7%), 8.04 (d, 1H, J=9.2,
3
2
H-8%), 5.67 (d, 1H, J=8.2, H-7), 4.96 (d, J=3.3, H-9),
2
4.35 (d, J=3.8, H-9), 3.92 (s, 3H, OMe), 3.46 (td, 1H,
3J=7.8, 3J=4.4, H-6), 1.38 (m, 1H, H-5), 1.22 (ddd, 1H,
2J=13.6, J=7.7, J=4.2, H-5), 2.03 (m, 1H, SJꢀ29,
H-4), 1.37 (m, 1H, H-3), 1.57 (m, 1H, H-3), 3.04 (ddd,
1H, 2J=11.0, 3J=7.1, 3J=3.8, H-2), 2.68 (ddd, 1H,
3
3
3
2
(d, 1H, J=9.3, H-8%), 4.92 (d, 1H, J=3.8, H-9), 4.34
2J=11.1, J=8.1, J=3.2, H-2), ꢀ5.28 (m, 1H, H-1¦),
ꢀ5.24 (m, 1H, H-2¦), 1.03 (d, 3J=4.9, H-3¦). 13C NMR
(CDCl3): 147.77 (C-2%), 119.37 (C-3%), 144.04 (C-4%),
126.88 (C-4%a), 101.67 (C-5%), 157.22 (C-6%), 121.00 (C-
7%), 131.68 (C-8%), 145.09 (C-8%a), 86.98 (C-9), 76.66
(C-7), 60.68 (C-6), 30.52 (C-5), 28.77 (C-4), 29.83 (C-3),
45.65 (C-2), 55.57 (OMe), 132.66 (C-1¦), 124.81 (C-2¦),
12.28 (C-3¦).
3
3
2
3
(d, 1H, J=4.1, H-9), 5.64 (d, 1H, J=8.0, H-7), 3.45
(td, 1H, 3J=7.9, 3J=4.7, H-6), 1.38 (ddd, 1H, 2J=13.6,
3
3J=6.6, J=4.7, H-5), 1.23 (m, 1H, H-5), 0.92 (m, 1H,
H-4), 1.51 (m, 1H, H-3), 1.25 (m, 1H, H-3), 2.96 (ddd,
1H, 2J=11.0, 3J=7.4, 3J=3.8, H-2), 2.63 (ddd, 1H,
2J=11.1, J=8.1, J=3.2, H-2), 1.05 (m, 2H, H-1¦),
0.86 (m, 2H, H-2¦), 0.60 (t, 3H, 3J=7.0, H-3¦). 13C
NMR (CDCl3): 147.60 (C-2%), 119.23 (C-3%), 143.78
(C-4%), 126.81 (C-4%a), 101.63 (C-5%), 157.11 (C-6%),
120.93 (C-7%), 131.53 (C-8%), 145.26 (C-8%a), 45.67 (C-2),
29.46 (C-3), 30.39 (C-4), 29.94 (C-5), 60.45 (C-6), 76.58
(C-7), 86.82 (C-9), 35.69 (C-1¦), 19.88 (C-2¦), 13.88
(C-3¦), 55.55 (OMe).
3
3
NMR data for the 55% component 10, see Section 4.4.
4.6.2. (Z)-3,10-Didehydro-10,11-dihydroquinine, ‘(Z)-
D
3,10-isoquinine’ 19. The above 41 mg fraction gave 19

56
J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
Table 2. Crystal data and structure refinement for 10a
and 14
References
1. Kolb, H. C.; Nieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
10a
14
2. Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207–1217.
3. Dehmlow, E. V.; Wagner, S.; Muller, A. Tetrahedron
1999, 55, 6335–6346.
Empirical formula
Formula weight
Crystal system/
space group
C20H24N2O2
324.41
Orthorhombic/
P212121
C22H28N2O2
352.46
Orthorhombic/
P212121
Unit cell dimensions
4. Hofstetter, C.; Stone, P. S.; Pochapsky, T. C. J. Org.
Chem. 2000, 64, 8794–8800.
5. Szabo, A.; Kunzle, M.; Mallat, T.; Baiker, A. Tetra-
hedron: Asymmetry 1999, 10, 61–76.
6. Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc.
2000, 122, 10728–10729.
7. Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org.
Chem. 2000, 65, 6984–6991.
,
a (A)
7.8441(7)
8.0804(7)
28.183(2)
1786.3(3)
4
1.206
696
17662
4669
8.190(2)
15.134(3)
16.076(3)
1992.6(7)
4
1.175
760
14047
1702
,
b (A)
,
c (A)
Volume (A )
Z
3
,
Calculated density (g/cm3)
F(000)
Reflections collected
Reflections unique
Completeness to q
Data/parameters
Goodness-of-fit on F2
Final R1/wR2 indices
[I\2|(I)]
R1/wR2 indices (all data)
Absolute structure
parameter
8. Tanaka, T.; Kumamoto, T.; Ishikawa, T. Tetrahedron:
Asymmetry 2000, 11, 4633–4637.
q=29.86° 93.1% q=23.56° 99.0%
4669/220
1.135
1702/276
1.203
0.0370/0.0859
9. Zarbl, E.; Lammerhofer, M.; Hammerschmidt, F.; Wug-
genig, F.; Hanbauer, M.; Maier, N. M.; Sajovic, L.;
Lindner, W. Anal. Chim. Acta 2000, 404, 169–177.
10. Wakita, H.; Yoshiwara, H.; Kitano, Y.; Nishiyama, H.;
Nagase, H. Tetrahedron: Asymmetry 2000, 11, 2981–2989.
11. Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961–998.
12. Brunner, H.; Bugler, J.; Nuber, B. Tetrahedron: Asymme-
try 1995, 6, 1699–1702.
0.0689/0.0647
0.1292/0.0700
−0.1(2)
0.0421/0.0863
0.0(2)
13. von Riesen, C.; Jones, P. G.; Hoffmann, H. M. R. Chem.
Eur. J. 1996, 2, 673–679.
4.8. X-Ray diffraction crystallography
The crystals of 10a were recrystallised from diethyl
ether, those of 14 from acetone by slow evaporation.
The crystal data (see Table 2) were measured using a
KM4-CCD diffractometer equipped with a graphite
monochromator. The structures were solved by
straightforward direct methods42 and refined (Table 2)
by full-matrix least-squares.43 In the 10a structure a
disorder of the 1-propenyl C(1¦)=C(2¦)ꢀC(3¦) in two
nearly coplanar positions with clearly discriminated
partly occupied sites of C(1¦) and C(2¦), but a common
site of C(3¦) has been observed, as illustrated in Fig. 1.
The occupation of the sites denoted C(1¦)=C(2¦)ꢀC(3¦)
and C(1¦a)=C(2¦a)ꢀC(3¦) was refined to 0.58(2) and
0.42(2), respectively. The positions of all hydrogen
atoms, except those of the methyl groups, were deter-
mined from molecular geometry—their positions,
including the protons of the methyl groups, were rede-
termined after each cycle of refinement; in the methyl
C(3¦) of 10a a disordered model has been assumed with
the hydrogen atoms disordered in two orientations, one
at 60° to the other. Crystallographic data for 10a and
14 have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publications
numbered CCDC 175709 and CCDC 175710, respec-
tively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1233-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
14. Braje, W. M.; Wartchow, R.; Hoffmann, H. M. R.
Angew. Chem., Int. Ed. 1999, 38, 2540–2543.
15. Braje, W. M.; Holzgrefe, J.; Wartchow, R.; Hoffmann,
H. M. R. Angew. Chem., Int. Ed. 2000, 39, 2085–2087.
16. Zheng, T.; Flippen-Anderson, J.; Yu, P.; Wang, T.; Mir-
ghani, R.; Cook, J. M. J. Org. Chem. 2001, 66, 1509–
1511.
17. Turner, R. B.; Woodward, R. B. In The Alkaloids;
Manske, R. H. F.; Holmes, H. L., Eds. Chemistry of the
Cinchona Alkaloids; Academic Press: New York, 1953;
Vol. 3, pp. 1–63.
18. Podlewski, J. K.; Suszko, J. Rec. Trav. Chim. Pays-Bas
1936, 55, 392–400.
19. Borowiak, T.; Dutkiewicz, G.; Thiel, J.; Z. Naturforsch.
in press.
20. Solomon, W. J. Chem. Soc. 1941, 77–83 and the refer-
ences therein.
21. Smith, M. B. Organic Synthesis; McGraw-Hill: New
York, 1994; pp. 171–174.
22. Grob, C. A. Angew. Chem., Int. Ed. 1969, 8, 535–546.
23. Thiel, J. J. Mol. Struct. 1994, 319, 153–159.
24. Thiel, J.; Fiedorow, P. J. Mol. Struct. 1998, 440, 203–212.
25. Borowiak, T.; Dutkiewicz, G.; Thiel, J. Z. Naturforsch.
2000, 55b, 1020–1024.
26. Couperus, P. A.; Clague, A. D. H.; van Dongen, J. P. C.
M. Org. Magn. Res. 1976, 8, 426–431.
27. Haasnoot, C. A. G.; de Leeuw, C.; Altona, C. Tetra-
hedron 1980, 36, 2783–2792.
28. Nasipuri, D. Stereochemistry of Organic Compounds.
Principles and Applications; J. Wiley & Sons: New York,
Chichester, Brisbane, Toronto, Singapore, 1991; p. 315.
29. Wiewio´rowski, M.; Edwards, O. E.; Bratek-
Wiewio´rowska, M. D. Can. J. Chem. 1967, 45, 1447–
1457.
Acknowledgements
We thank Professor Władysław Boczon´ for supporting
this study from his grant and Jolanta Kubik for her
exploratory work.

J. Thiel, A. Katrusiak / Tetrahedron: Asymmetry 13 (2002) 47–57
57
30. Haasnoot, C. A. G. J. Am. Chem. Soc. 1993, 115, 1460–
1468.
Sons: New York, Chichester, Brisbane, Toronto, Singa-
pore, 1994; pp. 103–112.
38. Suszko, J. Bull. Acad. Polon., Ser. A: Sci. Mat. 1925,
129–151.
31. Katrusiak, A.; Figas, E.; Kaluski, Z.; Lesiewicz, D. Acta
Crystallogr. 1989, C45, 1758–1760.
39. Henry, T. A.; Solomon, W.; Gibbs, E. M. J. Chem. Soc.
1935, 966–971.
40. van Binst, G.; Tourve, D. Org. Magn. Res. 1972, 4,
625–631.
32. Skrzypczak-Jankun, E.; Hoser, A.; Kaluski, Z.;
Perkowska, A. Acta Crystallogr. 1980, B36, 1517–1520.
33. Borowiak, T.; Bokiy, N. G.; Struchkov, Yu. T. Zh.
Strukt. Khim. 1973, 14, 387–388.
41. March, J. Advanced Organic Chemistry—Reactions,
Mechanisms and Structure, 4th ed.; J. Wiley & Sons: New
York, Chichester, Brisbane, Toronto, Singapore, 1992; p.
359.
34. Kubicki, M.; Borowiak, T.; Boczon, W. J. Crystallogr.
Spectrosc. Res. 1991, 21, 575–579.
35. Wysocka, W.; Kolanos, R.; Borowiak, T.; Korzanski, A.
J. Mol. Struct. 1999, 474, 207–214.
42. Sheldrick, G. Shelxs-97. Program for crystal structure
determination, University of Go¨ttingen, 1997.
43. Sheldrick, G. Shelxl-97. Program for crystal structure
refinement, University of Go¨ttingen, 1997.
36. Lyle, G. G.; Keefer, L. K. Tetrahedron 1967, 23, 3253–
3263.
37. Eliel, E. L.; Wilen, S. H. with a contribution by Mander,
L. N. Stereochemistry of Organic Compounds; J. Wiley &