Syntheses and absolute configuration assignments of mono- and di-substituted chiral quinoline alkaloids obtained by asymmetric oxidation

Article abstract of DOI:10.3987/COM-08-S(D)51

Mono- and di-substituted quinoline, 2-quinolone, dihydrofuroquinoline and dihydropyranoquinoline alkaloids have been synthesised with enantiomeric excess values of > 90%, via asymmetric epoxidation, or asymmetric dihydroxylation of the corresponding alken

Full text of DOI:10.3987/COM-08-S(D)51

HETEROCYCLES, Vol. 79, 2009
831
HETEROCYCLES, Vol. 79, 2009, pp. 831 - 850. © The Japan Institute of Heterocyclic Chemistry
Received, 30th September, 2008, Accepted, 21st November, 2008, Published online, 25th November, 2008.
DOI: 10.3987/COM-08-S(D)51
SYNTHESES AND ABSOLUTE CONFIGURATION ASSIGNMENTS OF
MONO- AND DI-SUBSTITUTED CHIRAL QUINOLINE ALKALOIDS
OBTAINED BY ASYMMETRIC OXIDATION
Stephen A. Barr, Derek R. Boyd,* Narain D. Sharma, and Pui L. Loke
School of Chemistry and Chemical Engineering, The Queen’s University of
Belfast, Belfast UK BT9 5AG
E-mail: dr.boyd@qub.ac.uk
Abstract
–
Mono-
and
di-substituted
quinoline,
2-quinolone,
dihydrofuroquinoline and dihydropyranoquinoline alkaloids have been
synthesised with enantiomeric excess values of > 90%, via asymmetric
epoxidation, or asymmetric dihydroxylation of the corresponding alkene
precursors. The absolute configurations of isobalfourodine, ψ-balfourodine,
ψ-isobalfourodine, isobalfourodinium methiodide, balfourolone, hydroxylunidine,
orixine,
nororixine,
isopteleflorine,
O-acetylisopteleflorine,
O-methylhydroxylunium methiodide and hydroxylunine have been rigorously
determined by a combination of circular dichroism spectroscopy, ozonolysis, and
stereochemical correlation. Of these, the absolute configurations of six alkaloids
were previously unknown and six were assigned incorrect configurations in the
literature.
Dedicated to the memory of Dr. John Daly, a good friend and mentor
INTRODUCTION
Quinoline alkaloids are widely distributed among the Rutaceae family of plants and several hundred
members have been isolated to date. Recent comprehensive annual reviews of quinoline alkaloids1 provide
clear evidence of the diverse, and continually expanding, range of this large group of natural products,
many of which have been used in folk medicines, including some with potentially beneficial cytotoxic
activity. The majority of the known quinoline alkaloids contain substituted quinoline, 2-quinolone,
furoquinoline, dihydrofuroquinoline and dihydropyranoquinoline structures. Each of these quinoline

832
HETEROCYCLES, Vol. 79, 2009
alkaloid types can be further grouped, according to the regioselectivity (and degree) of enzyme-catalysed
aromatic hydroxylation occurring at the unsubstituted carbocyclic ring, to give mainly mono-, di-, or
tri-substituted alkaloids. Hydroxylation, often followed by alkylation, can produce the corresponding
alkaloids bearing hydroxy, methoxy, or methylenedioxy groups.
In 1968, the detection of the first arene oxide metabolite (naphthalene 1,2-oxide), as an intermediate in the
aromatic hydroxylation of naphthalene by Jerina and Daly at the National Institutes of Health (NIH),
Bethesda,2 proved to be a seminal discovery in the context of elucidating the mechanism of
enzyme-catalysed aromatic hydroxylation and its relevance to the NIH Shift.3 Later results, obtained from a
biosynthetic study by Grundon,4 led to the suggestion that hydroxylation of aromatic heterocycles,
including the parent unsubstituted furoquinoline alkaloid dictamnine, might similarly occur via
monooxygenase-catalysed epoxidation of the benzo ring to give an arene oxide intermediate, dictamnine
7,8-oxide (A). Although this arene oxide has not yet been isolated as a plant metabolite, it was assumed that
its formation as a biosynthetic intermediate, followed by isomerisation, could yield the corresponding
phenols and other substituted quinoline alkaloids. These biosynthetic proposals4 have recently been
supported by the synthesis of the relatively stable dictamnine 7,8-oxide (A), from the corresponding
cis-7,8-dihydrodiol bacterial metabolite.5 Arene oxide A was in turn readily converted into the
corresponding monosubstituted phenol, 8-hydroxydictamnine (robustine), and other furoquinoline
alkaloids including 8-methoxydictamine (γ-fagarine).5
Dioxygenase-catalysed aromatic hydroxylation of dictamnine was also proposed as a biosynthetic route to
other quinoline alkaloids.4 This possibility was realised by a bacterial dioxygenase-catalysed
cis-dihydroxylation of dictamnine at the 7,8-bond to yield a cis-dihydrodiol metabolite, followed by a
bacterial cis-diol dehydrogenase-catalysed dehydrogenation to yield 7,8-dihydroxydictamnine.
Dimethylation of this catechol using diazomethane provided a chemoenzymatic route (and possible
biosynthetic route) to the disubstituted quinoline alkaloid 7,8-dimethoxydictamnine (skimmianine).5
Epoxidation of a 3,3-dimethylallyl (prenyl) group, to give C-prenyl and O-prenyl epoxides, is a further
type of biocatalytic oxidation found in quinoline alkaloid biosynthesis. Monooxygenase-catalysed
formation of prenyl epoxides has been postulated, as a common biosynthetic route to transient
intermediates, during the formation of 2-quinolone, furoquinoline, dihydrofuroquinoline and
dihydropyranoquinoline alkaloids.1 The latter types of quinoline alkaloids are assumed to result, mainly,
from enzyme-catalysed epoxide hydrolysis to yield vic-diols, and intramolecular cyclisation to form
dihydrofurans and dihydropyrans. The C-prenyl epoxide (R)-preorixine (B)6,7 and O-prenyl epoxide
(R)-anhydroevoxine (C)8,9 are thus among the relatively few stable quinoline alkaloid epoxides to have

HETEROCYCLES, Vol. 79, 2009
833
been isolated from plants. This introduction has emphasised the important roles that enzyme-catalysed
epoxidation, vic-diol formation and arene hydroxylation can play in the biosynthesis of chiral quinoline
alkaloids.
OMe
N
OMe
N
Me
OMe
N
Me
OMe
N
O
HO
Me
OH
O
Me
O
O
Me
O
Me
O
O
O
O
O
O
Me
OMe
OMe
(R)-anhydroevoxine (C)
(R)-preorixine (B)
(7S,8R)-dictamnine 7,8-oxide (A)
(R)-evoxine (D)
OMe
OMe
OMe
OMe
OMe
OH
OAc
Me
OH
Me
Me
OH
Me
OH
Me
+
N
O
O
Me
N
O
N
N
O
N
O
Me
Me
Me
Me
OH
Me
Me
(R)-O-acetylgeibalansine (I)
(R)-platydesminium
methiodide (F)
(R)-geibalansine (H)
(R)-edulinine (G)
(R)-platydesmine (E)
Me
OH
Me
Me
OMe
OMe
O
OH
Me
O
OH
Me
OH
OH
O
Me
+
N
O
N
O
Me
N
O
Me
_
Me
Me
N
O
OH
I
Me
OMe Me
Me
N
O
Me
Me
(R)-geibalansinium
methiodide (J)
(R)-ψ-ribalinine (L)
(R)-ribalinine (K)
(R)-araliopsine (M)
(R)-lunacridine (N)
It has become evident that while most quinoline alkaloids isolated from plants are chiral, as a result of
enzyme-catalysed oxidations, not all are enantiopure. Thus, for example, recent studies of the fourteen
chiral quinoline alkaloids, isolated from Choisya ternata, showed that ee values covered the entire range
(0-100%).9 Furthermore, in the majority of cases, neither the absolute configurations nor the ee values of
chiral quinoline alkaloids, isolated from this and other plants, have been determined. In view of the
increasing evidence of the potentially useful biological activity of many quinoline alkaloids, in both
animal and microbial systems, it is desirable to have suitable methods for the synthesis of enantiopure or
highly enantioenriched members, and for assignment of their absolute configurations.
The chemical synthesis of a series of quinoline alkaloids, using asymmetric epoxidation as a key step,
was first reported more than 40 years ago.10-13 Unfortunately, the enantioselectivity of asymmetric
epoxidation achieved during these early studies, using (+)-peroxycamphoric acid, was very poor. The
resulting quinoline alkaloids were consistently isolated with low enantiomeric excess (2-10% ee) and
optical rotation values ([α]D < 5). At that time, the reliability of methods available for purification, and
unequivocal determination of absolute configurations of small quantities of chiral quinoline alkaloids
having such low ee and [α]D values, was rather limited. It was therefore not surprising to find that our

834
HETEROCYCLES, Vol. 79, 2009
current, and earlier synthetic studies on single enantiomer quinoline alkaloids,14-16 have shown that many
of these earlier assignments,10-13 based on low ee and [α]D values, were incorrect.
In the absence of reported synthetic routes to single enantiomer quinoline alkaloids, we earlier
synthesised the nine unsubstituted chiral quinoline alkaloids platydesmine E, platydesminium
methiodide F, edulinine G, geibalansine H, O-acetylgeibalansine I, geibalansinium methiodide J,
ribalinine K, ψ-ribalinine L and araliopsine M14,15 and one monosubstituted alkaloid lunacridine N,16 in
enantiopure form. The synthetic methods employed involved, mainly, resolution of the MTPA esters of
trans-bromohydrin precursors by chromatography including preparative HPLC. A major objective of the
present study was to synthesise a wider range of enantiopure (or highly enantioenriched) monosubstituted
and 7,8-disubstituted alkaloids by modern catalytic asymmetric oxidation approaches, that would not
involve chromatographic separation of diastereoisomers, and to use unequivocal methods for the
determination of their absolute configurations.
RESULTS AND DISCUSSION
The acyclic alkene (glycolone) 1 bearing an OMe substituent at C-8 was synthesised by the literature
route.17 Treatment of glycolone 1 with NBS in diethyl ether yielded the bromodihydropyran 2 as the
major product (65%) which was readily separated from the minor isomeric bromodihydrofuran 3 by flash
chromatography (Scheme 1). Dehydrobromination of compound 2 using sodium methoxide gave pyran 4
in quantitative yield. Asymmetric epoxidation of alkene 4 first involved the formation of the
Mn(III)-(R,R)- and -(S,S)-salen catalysts with NaOCl as oxidant using the reported method.18,19 This
chiral epoxidation reagent had been used earlier on 2,2-dimethylchromene to give the corresponding
epoxide derivative in enantiopure form (>99% ee).19 Alkene 4, also having a 2,2-dimethyl (2H)-pyran
ring, was similarly oxidized using NaOCl and Mn(III)-(R,R)-salen catalyst. A small proportion of the
crude product, containing the required (3R,4R)-epoxide 5 ([α]D +121, CHCl3) was obtained after PLC
purification (ca: 19% yield). The opposite (3S,4S) enantiomer of epoxide 5 ([α]D -125, CHCl3; 20% yield)
was obtained after, using the corresponding (S,S)-salen catalyst, but again in low yield after
chromatography.
Suspecting that a significant amount of relatively unstable (3R,4R)-epoxide 5 had decomposed during the
PLC purification, a major fraction of the crude asymmetric epoxidation product, was catalytically
hydrogenated (Pd-C in MeOH) to yield (R)-9-methoxygeibalansine 6 ([α]D -23, EtOH) in good yield
(83% from alkene 4). Similarly, (S)-9-methoxygeibalansine 6 ([α]D +24, EtOH) was isolated in 89% yield
from the crude (3S,4S)-epoxide 5. Both (R)- and (S)-9-methoxygeibalansine 6 were found to be
enantiopure (>98% ee) by NMR analysis of their (+)-(α)-methoxy-(α)-trifluoromethylphenylacetates

HETEROCYCLES, Vol. 79, 2009
835
(MTPA esters). Thus, in common with the earlier asymmetric epoxidation of 2,2-dimethylchromene, 19 an
enantiopure product was obtained from the epoxidation of the (2H)-pyran 4.
OMe
OMe
OMe
NBS
Et2O
Br
Me
NaOMe
MeOH
Me
65%
98%
Me
Me
N
O
N
H
O
N
O
Me
Me
OMe
OMe
OMe
2
4
1
Mn(OAc)2
LiCl
N
N
NaOCl
NBS
Et2O
20%
35%
t-Bu
OH
HO
Bu-t
(R,R)-ligand
Bu-t
t-Bu
(R,R)-ligand
OMe
OMe
OMe
O
Pd-C
H2
OH
Me
Me
Br
Me
Me
83%
O
N
O
N
N
O
Me
Me
OMe
OMe
OMe
(3R)-6
(3R,4R)-5
3
Scheme 1
Although 9-methoxygeibalansine 6 has not yet been isolated as a plant alkaloid, the (R) enantiomer was
used as a precursor of the alkaloids (R)-isobalfourodinium methiodide 7 (6→7), (R)-balfourolone 8
(7→8), (R)-isobalfourodine 9 (6→9), (S)-ψ-balfourodine 10 (9→10) and (R)-ψ-isobalfourodine 11
(9→11) (Scheme 2). A similar series of stereochemical correlation reactions was carried out using
(S)-9-methoxygeibalansine 6 and had been used earlier for the corresponding unsubstituted (without a
methoxy group at C-8) quinoline alkaloids i.e. geibalansine H → geibalansinium methiodide J (cf: 6→7),
geibalansinium methiodide J → edulinine G (cf: 7→8), geibalansine H → ribalinine K (cf: 6→9),
ribalinine K → araliopsine M (cf: 9→10), and ribalinine K → ψ-ribalinine L (cf: 9→11).15
N-Methylation of (-)-(R)-9-methoxygeibalansine 6 was achieved by stirring a solution of MeI in benzene
for three days at ambient temperature. A precipitate of (R)-isobalfourodinium methiodide salt 7 ([α]D -14,
MeOH) was filtered off and dried (Scheme 2). The (S)-isobalfourodinium methiodide ([α]D +15, MeOH)
was similarly obtained from (+)-(S)-9-methoxygeibalansine 6 but the isolated yield for either enantiomer
was low (<30 %). Treatment of (-)-(R)-isobalfourodinium methiodide 7 with aqueous ammonia resulted
in nucleophilic attack of hydroxide at the immonium group and ring opening occurred to give

836
HETEROCYCLES, Vol. 79, 2009
(R)-balfourolone 8 ([α]D +31, MeOH) in good yield (83%). Under identical conditions,
(+)-(S)-isobalfourodinium methiodide 7 gave (S)-balfourolone 8 ([α]D -29, MeOH).
While reaction of (-)-(R)- or (+)-(S)-9-methoxygeibalansine 6 with MeI in benzene solution gave
relatively poor yields of (R)- or (S)-isobalfourodinium methiodide 7, refluxing compound (-)-6 or (+)-6
with an excess of neat MeI gave (R)-isobalfourodine 9 ([α]D -13, MeOH) or (S)-isobalfourodine 9 ([α]D
+12, MeOH) in excellent yields (88-96%) (Scheme 2).
The dihydropyran ring of (-)-(R)-isobalfourodine 9 was found to open in the presence of NaOMe in DMF
solvent and was followed by spontaneous cyclization to yield the angular dihydrofuran alkaloid
(S)-ψ-balfourodine 10 ([α]D +29, EtOH; 74% yield). However, (R)-ψ-isobalfourodine 11 ([α]D -25, EtOH;
95% yield) was obtained when ring opening and cyclization of compound (-)-9 occurred in the presence
of NaOH in MeOH solvent. The dihydrofuran 10 was assumed to have been formed with inversion of
configuration, and dihydropyran 11 with retention of configuration, both originating from a common
transient (R)-prenyl epoxide intermediate 12, as shown in Scheme 2. This mechanistic sequence had been
proposed earlier20 using isobalfourodine 9 having a low ee value (<5%), and is now confirmed by our
rigorous stereochemical assignments of the enantiopure alkaloids 7-11.
OMe
OMe
OH
Me
OH
NH3
H2O
OH
Me
O3
83%
+
O
Me
N
O
N
O
Me
Me
O
_
Me
OH
OMe Me
OMe Me I
8
13
7
(R)-balfourolone
(R)-isobalfourodinium
methiodide
MeI
C6H6
OMe
14%
O
OH
Me
OH
Me
MeI
88%
N
O
N
O
Me
Me
OMe Me
OMe
6
9
(R)-9-methoxygeibalansine
(R)-isobalfourodine
OH
Me
NaOH
MeOH
NaOMe
DMF
or
OH
Me
O
Me
O
Me
OH
O
NaOH
MeOH
NaOMe
DMF
O
99%
N
O
Me
Me
N
O
N
H
74%
OMe Me
OMe Me
OMe
11
(R)-ψ-isobalfourodine
10
12
(S)-ψ-balfourodine
Scheme 2

HETEROCYCLES, Vol. 79, 2009
837
The absolute configurations of the homochiral alkaloids 7-11 were determined in an unequivocal
manner by several methods including comparison of their CD spectra with those of the
corresponding unsubstituted alkaloids of known configuration.15 In this context, the CD spectra
of compounds (-)-(R)-9-methoxygeibalansine 6, (-)-(R)-isobalfourodinium methiodide 7,
(+)-(R)-balfourolone
8,
(-)-(R)-isobalfourodine
9,
(+)-(S)-ψ-balfourodine
10
and
(-)-(R)-ψ-isobalfourodine 11 were found to be very similar to the corresponding enantiomers of
alkaloids of established configuration but devoid of a MeO substituent in the carbocyclic ring
(geibalansine H, geibalansinium methiodide J, edulinine G, ribalinine K, araliopsine M,
ψ-ribalinine L).15 The (R) absolute configuration (and >98% ee value) of (+)-balfourolone 8 was
also confirmed by ozonolysis to yield the lactone 13 of established (R) absolute configuration
followed by chiral stationary phase-GC-MS (CSP-GC-MS) analysis, a method successfully
applied to other chiral quinoline alkaloids.9,21
We have employed an asymmetric oxidation approach to the synthesis of two chiral quinoline
alkaloids (>90% ee).15 Thus AD-mix-β was employed as oxidant in the dihydroxylation of an
O-prenyl group to give the chiral furoquinoline alkaloid (R)-evoxine (D, 93% ee), a precursor of
the derived (R)-anhydroevoxine (C),9 and (R)-edulinine (G, 94% ee), a precursor of
(S)-platydesmine (E) and (S)-platydesminium methiodide (F).15 As a logical extension,
asymmetric dihydroxylations of alkenes 14, 16 and 18 were also carried out using commercially
available AD-mix-α and AD-mix-β (Scheme 3). AD-mix contained a catalytic quantity of
osmium tetroxide in the presence of K3Fe(CN)6 and the chiral ligands hydroquinine
(1,4-phthalazinediyl diether, [DHQ]2PHAL; mix-α) or hydroquinidine (1,4-phthalazinediyl
diether, [DHQD]2PHAL; mix-β); all dihydroxylations were conducted in the presence of
o
methanesulfonamide in tert-butanol:water (1:1) at 0 C.

838
HETEROCYCLES, Vol. 79, 2009
OH
Me
OH
O3
AD mix-β
OH
O
Me
Me
Me
Me
O
Me
13
OMe
OMe
OMe
Me Me
Me Me
O
N
H
O
Me
O
N
N
Me
O
O
O
O
O
Me
16
O
Me
18
14
OMe
OMe
OMe
OH
OH
OH
Me
Me
O
Me
OH
Me Me
OH
N
Me
O
N
H
O
N
O
O
O
OH
O
Me
O
O
Me
15
(R)-nororixine
19
17
(R)-hydroxylunidine
(R)-orixine
Scheme 3
The AD-mix-β reagent yielded the corresponding vicinal diol products (R)-nororixine 15 ([α]D +23,
EtOH; 85% ee), (R)-hydroxylunidine 17 ([α]D +26, EtOH; 76% ee), and (R)-orixine 19 ([α]D +52, EtOH;
70% ee). The alternative quinoline alkaloid enantiomers, (S)-15 ([α]D -22, EtOH), (S)-17 ([α]D -26,
EtOH), and (S)-19 ([α]D -51, EtOH) having similar ee values were obtained when using AD-mix-α
(Scheme 3). The enantiopurity values of alkaloids 15, 17 and 19 (70-85% ee before recrystallization), and
their absolute configurations, were determined by ozonolysis followed by CSP-GC-MS analysis of the
resulting lactone 13, using the method reported earlier for other chiral quinoline alkaloids.9,21 The ee
value of orixine 19, obtained using AD mix, was found to increase (70→>95% ee) upon recrystallisation.
A similar increase in ee value (85→>90% ee) was observed for (R)-nororixine 15 which was then used as
precursor
of
the
alkaloids
(S)-isopteleflorine
22,
(S)-O-acetylisopteleflorine
23,
(S)-O-methylhydroxylunium methiodide 24 and (S)-hydroxylunine 25 (Scheme 4).
Reaction of (R)-nororixine 15 with acetoxyisobutryl bromide yielded the (R) enantiomer of the
corresponding bromoacetate derivative 20. Treatment with sodium methoxide in THF then yielded the
dihydrofuran, (S)-isopteleflorine 22 ([α]D +19, EtOH; 90% yield). Treatment of the (S)-isopteleflorine 22
with Ac2O in pyridine containing a trace of DMAP gave the corresponding acetate,
(S)-O-acetylisopteleflorine 23 ([α]D -6, CHCl3; 93% yield). It is assumed that the (S)-dihydrofuran 22 was
formed via the (R)-prenyl epoxide intermediate 21 and that, in common with the prenyl epoxide 12 which

HETEROCYCLES, Vol. 79, 2009
839
formed (S)-ψ-balfouridine 10, it would also spontaneously cyclise to a dihydrofuroquinoline alkaloid, but
in this case to the (S)-linear isomer 22.
OMe
OMe
OMe
N
OAc
NaOMe
THF
NaOMe
THF
Me
Me
OR
O
90%
Me Me
O
N
H
O
Me
Me
O
N
H
O
O
O
Br
O
O
O
Ac2O
pyridine
DMAP
(S)-22 (R=H)
isopteleflorine
(R)-21
(R)-20
90%
MeI
EtOH
91%
(S)-23 (R=Ac)
O-acetylisopteleflorine
(R)-13
AcOCMe2COBr
MeCN
76%
O3
O
OMe
OMe
OH
Me
Me
∆
Me
Pyridine
OH
OH
Me
+
Me Me
OH
N
O
O
O
_
O
N
N
85%
O
O
H
Me
O
O
O
Me
I
15
25
24
(S)-hydroxylunine
(S)-O-methylhydroxylunium
(R)-nororixine
methiodide
Scheme 4
Methylation of (S)-isopteleflorine 22, using MeI in EtOH, yielded (S)-O-methylhydroxylunium
methiodide 24 ([α]D +16, EtOH) in remarkably good yield (91%) compared with the earlier methylation
of 9-methoxygelbalansine 6 under similar conditions to yield the (R)-pyridinium salt 7 (<30% yield,
Scheme 2). O-Demethylation of the (S)-quaternary ammonium iodide 24 to yield (S)-hydroxylunine 25
([α]D +25, EtOH; 85% yield) was observed when heated in pyridine solvent.
Each of the alkaloids, derived from (R)-nororixine 15 (91% ee), i.e. (S)-isopteleflorine 22,
(S)-O-acetylisopteleflorine 23, (S)-O-methylhydroxylunium methiodide 24, and (S)-hydroxylunine 25,
were purified by recrystallisation, and were assumed to be virtually enantiopure (>95% ee). This
conclusion was supported by their optical rotation values being comparable or higher than those reported
for the naturally occurring alkaloids extracted from plant sources. The absolute configurations and % ee
values of (+)-(R)-nororixine 15, (+)-(R)-hydroxylunidine 17, (+)-(R)-orixine 19, (+)-(S)-isopteleflorine 22
and (+)-hydroxylunine 25 were confirmed by ozonolysis and CSP-GC-MS analysis of the resultant
lactone
13.
The
absolute
configurations
of
(-)-(S)-O-acetylisopteleflorine
23
and
(+)-(S)-O-methylhydroxylunium methiodide 24 were, in turn, derived by stereochemical correlation with
(+)-(S)-isopteleflorine 22.
The final phase of this programme involved a comparison of the absolute configurations of the twelve
enantiopure alkaloids, synthesised and configurationally assigned during the current study, with those

840
HETEROCYCLES, Vol. 79, 2009
reported earlier, and determination of the unknown configurations of the chiral alkaloids isolated from
plant sources (Table 1). Absolute configurations had not been reported earlier for
(+)-9-methoxygeibalansine
6,
(+)-isobalfourodinium
methiodide
7,
(+)-nororixine
15,
(+)-hydroxylunidine 17, (+)-isopteleflorine 22, (+)-O-acetylisopteleflorine 23, and (+)-hydroxylunine 25.
The earlier assignments for (+)-balfourolone 8,12 (-)-isobalfourodine 9,12 (-)-ψ-balfouriodine 10,20
(+)-ψ-isobalfourodine 11,20 (-)-orixine 1911 and (+)-O-methylhydroxylunium methiodide 2422 were wrong
but the absolute configuration of (+)-orixine 19 was later reassigned correctly (Table 1).6,12
Table 1: Absolute configurations of the quinoline derivatives 5 and 6 and the
quinoline alkaloids 7-11, 15, 17, 19, 22-25
Monosubstituted Literature
Correct
Disubstituted Literature Correct
Ab.config Ab. Config
alkaloids
Ab.config. Ab.config. alkaloids
5a
6a
-
(+)-R
(+)-S
(+)-S
(+)-R
(-)-R
(-)-R
(+)-S
15
17
19
22
23
24
25
-
(+)-R
(+)-R
(+)-R6,12
(+)-S
-
-
7
-
(-)-R11
8
(-)-R12
(+)-R12
(+)-R20
(-)-S20
-
9
-
(-)-S22
-
(-)-S
10
11
(+)-S
(+)-S
a Alkaloid precursors
CONCLUSION
The chiral quinoline alkaloids 7-11, 15, 17, 19, 22-25 have been synthesised with >90% ee values, using
asymmetric oxidation methods involving both stable (5) and unstable (12 and 21) epoxide intermediates.
The previously unknown absolute configurations of six alkaloids, 7, 15, 17, 22, 23 and 25, have been
determined using unequivocal methods and the incorrectly reported configurations of the other six
alkaloids, 8-11, 19, 24, have been reassigned. The availability of enantiopure quinoline alkaloids, using
the described synthetic methods, will be of value in (i) elucidating the biosynthetic pathways of these and
other alkaloids and (ii) evaluating the pharmacological potential of individual alkaloid enantiomers.
EXPERIMENTAL
13
NMR (1H and C) spectra were recorded on Bruker Avance DPX-300 and DPX-500 instruments and
mass spectra were run at 70 eV, on a VG Autospec Mass Spectrometer, using a heated inlet system.

HETEROCYCLES, Vol. 79, 2009
841
Accurate molecular weights were determined by the peak matching method, with perfluorokerosene as the
standard. Elemental microanalyses were carried out on a Perkin Elmer 2400 CHN microanalyser. For
optical rotation ([α]D) measurements (ca. 20 °C, 10-1 deg cm2 g-1), a Perkin Elmer 341 polarimeter was
used. Electronic circular dichroism (ECD) spectra were recorded on a Jasco J-720 instrument in
acetonitrile solvent.
Flash column chromatography and Preparative Layer Chromatography (PLC) were performed on Merck
Kieselgel type 60 (250-400 mesh) and PF254/366 respectively. Merck Kieselgel type 60F254 analytical
plates were used for TLC. The (R,R)- and (S,S)-Mn salen ligands were prepared in accordance with the
literature method23 using commercially available reagents (Aldrich Chemical Co.). Chemically
synthesised chiral alkaloids 7-11, 15, 17, 19, 22-25 were found to have identical 1H-NMR spectra to those
reported in the literature. Additional matching spectra (NMR, IR, ECD) have been included. Absolute
configurations and ee values of chiral quinoline alkaloids 8, 15, 17, 19 and 22 were determined by
ozonolysis and CSP-GC-MS analysis of the resulting lactone 13 by the method described earlier.9,21
4,8-Dimethoxy-3-(3'-methylbut-2'-enyl)-2-quinolinone (Glycolone) 1
Glycolone 1 (0.890 g, 84%) was synthesised using the literature method.17 Rf 0.48 (2% MeOH in CHCl3),
17
mp 110-112 °C (from Pr2O) (Lit., mp 119-120 °C); νmax 3407 cm-1 (OH), 1643 cm-1 (C=O); δH (300
i
MHz, CDCl3) 1.69 (3H, s, CMe), 1.80 (3H, s, CMe), 3.39 (2H, d, J1',2' 6.7, H-1'), 3.92 (3H, s, OMe), 3.96
(3H, s, OMe), 5.27 (1H, t, J2',1' 6.6, H-2'), 6.94 (1H, d, J5,6 7.9, H-5), 7.14 (1H, dd, J6,7 8.2, J6,5 7.9, H-6),
7.35 (1H, d, J7,6 8.2, H-7), 9.10 (1H, br s, NH).
3-Bromo-3,4-dihydro-5,9-dimethoxy-2,2-dimethyl-[2H]-pyrano[2,3-b] quinoline 2
N-Bromosuccinimide (0.326 g, 1.83 mmol) was added in portions to a solution of glycolone 1 (0.50 g,
1.83 mmol) in dry Et2O (80 cm3) and the mixture stirred at ambient temperature for 20 min. The
precipitated succinimide by-product was removed, by filtration, and the solvent distilled off under
reduced pressure to give the crude products as a yellow gum. Purification by flash chromatography
(CHCl3) gave the desired product 2 as a colourless oil which solidified to a white solid (0.419 g, 65%), Rf
79
i
+
+
0.25 (CHCl3), mp 154-156 °C (from Pr2O/MeOH); (Found: M , 351.0460 C16H18NO3 Br requires M ,
351.0470); δH 300 MHz, CDCl3) 1.54 (3H, s, CMe), 1.63 (3H, s, CMe), 3.36 (1H, dd, J4,4' 17.4, J4,3 8.8,
H-4), 3.60 (1H, dd, J4',4 17.5, J4',3 5.5, H'-4), 4.01 (6H, s, 2 x OMe), 4.31 (1H, dd, J3,4 8.8, J3,4' 5.5, H-3),
6.97 (1H, d, J6,7 7.6, H-6), 7.30 (1 H, dd, J7,6 7.6, J7,8 8.7, H-7), 7.50 (1H, d, J8,7 8.7, H-8); m/z 353 (M+,
81
79
+
Br, 66%), 351 (M , Br, 64%), 272 (82%) and 216 (100%).

842
HETEROCYCLES, Vol. 79, 2009
Further elution gave the isomeric 2-(1-bromo-1-methylethyl)-2,3-dihydro-4,8- dimethoxyfuro [2,3-b]
i
quinoline 3 as white needles (0.225 g, 35%); Rf 0.19 (CHCl3); mp 140-141°C (from Pr2O/MeOH);
+
+
79
(Found: M , 351.0465 C16H18NO3 Br requires M , 351.0470); δH (300 MHz, CDCl3) 1.76 (3H, s, CMe),
1.93 (3H, s, CMe), 3.73-3.80 (2H, m, H-3, H-3'), 4.00 (3H, s, OMe), 4.26 (3H, s, OMe), 4.79 (1H, dd, J2,3 ,
J2,3' 7.7, H-2), 6.84 (1H, d, J5,6 7.7, H-5), 7.24 (1H, dd, J6,5 7.7, J6,7 8.3, H-6), 7.62 (1H, d, J7,6 8.3, H-7);
m/z 353 (M+, 81Br, 20%), 351 (M+, 79Br, 20%), 232 (97%) and 200 (100%).
5,9-Dimethoxy-2,2-dimethyl-[2H]-pyrano[2,3-b]quinoline 4
Sodium methoxide (0.40 g, 7.4 mmol) was added in one portion to a solution of the bromopyrano
derivative 2 (1.0 g, 2.84 mmol) in dry MeOH (200 cm3). The mixture was refluxed under nitrogen for 1.5
h and the methanol removed under reduced pressure. The residue was dispersed in water (50 cm3) and
extracted with CHCl3 (3 x 30 cm3). The combined extract was dried (MgSO ) and the solvent evaporated
4
to yield the pure title compound 4 as a viscous colourless oil which solidified to a white solid on standing
(0.77 g, 98%); Rf 0.85 (1% MeOH in CHCl3; mp 71-72 °C (from pentane); (Found: M+, 271.1209
C H NO requires M+, 271.1208); δ (300 MHz, CDCl ) 1.52 (6H, s, CMe2), 4.00 (3H, s, OMe), 4.00
16 17
3
H
3
(3H, s, OMe), 5.86 (1H, d, J3,4 10.0, H-3), 6.73 (1H, d, J4,3 10.0, H-4), 6.96 (1H, d, J6,7 7.9, H-6), 7.26 (1H,
dd, J7,6 7.9, J7,8 8.6, H-7), 7.49 (1H, d, J8,7 8.6, H-8); m/z 271 (M+, 100%) and 256 (M+-Me, 98%).
(+)-(3R,4R)- and (-)-(3S,4S)-3,4-Epoxy-3,4-dihydro-5,9-dimethoxy-2,2-dimethyl-[2H]-pyrano [2,3-b]
quinoline 5
An aqueous solution of Na2HPO4 (0.05 M, 1.2 cm3) was added to an aqeous solution of NaOCl (0.77 M, 3
cm3). The pH of the resulting buffered solution (~ 0.55 M in NaOCl) was adjusted, as required, to pH 11.3
by addition of aqueous sodium hydroxide (1 M) or aqueous hydrochloric acid (1 M). The solution, cooled
to 0 °C, was added in one portion to a solution of Mn-salen R,R-catalyst (0.05 mmol) and alkene 4 (0.32 g,
1.18 mmol) in CH2Cl2 (2 cm3) kept at 0 °C. The two phase mixture was stirred, at rt, and the progress of
the reaction was followed by TLC analysis. On completion of the reaction (3.5 h), hexane (10 cm3) was
added to the mixture, the organic phase separated, washed successively with water (2 x 5 cm3) and
saturated sodium chloride solution (5 cm3). The organic solution was dried (Na2SO4), the solvent
evaporated under reduced pressure, and the crude product purified by PLC (CHCl3: EtOAc; 4:1) to give
epoxide 5 (0.064 g, 19%) as a pale yellow viscous oil (Found: M+, 287.1159 C16H17NO4 requires M+,
287.1158); [α]D +121 (c 1.6, CHCl3); δH (300 MHz, CDCl3) 1.41 (3H, s, CMe), 1.66 (3H, s, CMe), 3.58

HETEROCYCLES, Vol. 79, 2009
843
(1H, d, J3,4 4.3, H-3), 4.00 (3H, s, OMe), 4.13 (3H, s, OMe), 4.47 (1H, d, J4,3 4.1, H-4), 7.01 (1H, d, J6,7
7.8, H-6), 7.33 (1H, dd, J7,6 7.8, J7,8 8.3, H-7), 7.54 (1H, d, J8,7 8.3, H-8); m/z 287 (M+, 100%), 258 (47%)
and 83 (84%); >95% ee.
(-)-(3S,4S)-3,4-epoxy-3,4-dihydro-5,9-dimethoxy-2,2-dimethyl-[2H]-pyrano[2,3-b]quinoline 5 : With
Mn-salen S,S-catalyst (20% yield); [α]D -125; >95% ee.
(+)-(S) and (-)-(R)-9-Methoxygeibalansine 6
A solution of crude (-)-(3S,4S)-epoxide (-)-5 (0.176 g, 0.61 mmol) in MeOH (15 cm3) containing 10%
Pd/C (0.015g) was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered
through a pad of celite and the solvent evaporated under reduced pressure to yield a viscous oil.
Purification by PLC (5% MeOH in CHCl3) gave (+)-(S)-9-methoxygeibalansine 6 as a colourless oil
24
1
(0.121 g, 89% for 2 steps), with H-NMR data similar to that of a racemic sample; [α]D +24 (c 2.27,
'
EtOH); δH (300 MHz, CDCl3) 1.42 (6H, s, CMe2), 2.94 (1H, dd, J4,4 17.2, J4,3 6.5, H-4), 3.16 (1 H, dd, J4' 4
,
'
17.2, J4',3 5.0, H-4 ), 3.92 (1H, dd, J3,4 6.5, J3,4' 5.0, H-3), 3.97 (3H, s, OMe), 3.99 (3H, s, OMe), 6.95 (1H,
d, J6,7 7.7, H-6), 7.26 (1H, dd, J7,6 7.7, J7,8 8.3, H-7), 7.47 (1H, d, J8,7 8.3, H-8); m/z 289 (M+, 11%) and 83
(100%); ECD ∆ε -2.18 (324 nm), ∆ε +2.62 (257 nm), ∆ε -11.8 (242 nm), ∆ε -16.5 (214 nm).
(-)-(R)-9-Methoxygeibalansine 6: 83% yield; [α]D -23 (c 1.28, EtOH).
(+)-(S)-and (-)-(R)-Isobalfourodine 9
A solution of (+)-(S)-9-methoxygeibalansine 6 (0.080 g, 0.28 mmol) in MeI (20 cm3, 0.32 mol) was
refluxed overnight. Removal of the solvent under reduced pressure yielded the crude product. Purification
by PLC gave (+)-(S)-isobalfourodine 9 as a white solid (0.077 g, 96%); mp 174-175 °C (from
Pr2O/MeOH, needles) (Lit., mp (rac.) 184-186 °C); [α]D +13 (c 0.83, EtOH); νmax 3318 cm-1 (OH),
24
i
1605 cm-1 (C=O); δH (300 MHz, CDCl3) 1.38 (3H, s, CMe), 1.47 (3H, s, CMe), 2.84 (1H, dd, J4,4' 17.0,
'
J4,3 5.2, H-4), 2.96 (1H, dd, J4',4 17.0, J4',3 4.8, H-4 ), 3.78-3.87 (7H, m, NMe, OMe, H-3), 7.03 (1H, d, J8,7
7.3, H-8), 7.18 (1H, dd, J7,6 8.1, J7,8 7.3, H-7), 7.95 (1H, d, J6,7 8.1, H-6); m/z 289 (M+, 58%) and 218
(100%); ECD ∆ε +14.5 (323 nm), ∆ε +1.90 (264 nm), ∆ε -7.42 (245 nm), ∆ε +10.26 (208 nm).
(-)-(R)-Isobalfourodine 9: 88% yield; [α]D -13 (c 0.6, EtOH).
(+)-(S)-ψ-Isobalfourodine 11
(+)-(S)-Isobalfourodine 9 (0.051 g, 0.176 mmol) was taken up in MeOH (4 cm3), aqueous sodium

844
HETEROCYCLES, Vol. 79, 2009
hydroxide (30%, 4 cm3) was added and the solution stirred under reflux for 7 h. The reaction mixture was
cooled, diluted with water and the product extracted into CHCl3 (3 x 15 cm3). The extract was dried
(MgSO4) and the solvent removed to yield the crude product as a colourless viscous oil. Purification by
PLC (5% MeOH in CHCl3) gave (+)-(S)-ψ-isobalfourodine 11 as a white solid (0.051 g, 97%); mp
189-191°C (from Pr2O/ MeOH) (Lit., mp [rac.] 190-191°C); [α]D +25 (c 1.04, EtOH); νmax 3301 cm-1
20
i
(OH), 1628 cm-1 (C=O); δH (300 MHz, CDCl3) 1.38 (3H, s, CMe), 1.44 (3H, s, CMe), 2.64 (1H, br s, OH),
'
2.71 (1H, dd, J4,4' 18.0, J4,3 5.6, H-4), 2.91 (1H, dd, J4',4 17.9, J4',3 5.0, H-4 ), 3.85-3.88 (7H, m, NMe, OMe,
H-3), 7.01 (1H, d, J10,9 7.7, H-10), 7.13 (1H, dd, J9,10 7.7, J9,8 7.9, H-9), 7.61 (1H, d, J8,9 7.9, H-8); m/z
289 (M+, 47%), 230 (40%), 218 (41%) and 69 (100%); ECD ∆ε -0.33 (323 nm), ∆ε -4.94 (291 nm), ∆ε
-12.01 (254 nm), ∆ε +1.42 (226 nm).
(-)-(R)-ψ-Isobalfourodine 11: 95% yield; [α]D -25 (c 1.35, EtOH).
(+)-(S)- and (-)-(R)-ψ-Balfourodine 10
A solution of (-)-(R)-isobalfourodine 9 (0.027 g, 0.09 mmol.) in DMF (3 cm3) was stirred, at rt overnight,
with sodium methoxide (0.075 g, 1.39 mmol). Water (20 cm3) was added and the product extracted into
CHCl3 (3 x 15 cm3). The extract was dried (MgSO ), concentrated under reduced pressure, and the crude
4
product purified by PLC (5% MeOH in CHCl3) to give (S)-ψ-balfourodine as colourless viscous oil
(0.020 g, 74%); [α]D +40 (c 1.36, MeOH) (Lit.,12; [α]D +3); νmax 3371 cm-1 (OH), 1655 cm-1 (C=O); δ
.
H
(300 MHz, CDCl3), 1.26 (3H, s, CMe), 1.37 (3H, s, CMe), 2.11 (1H, br s, OH), 3.15-3.94 (2H, m, CH2),
3.88-3.94 (7H, m, NMe, OMe, H-2), 7.06 (1H, d, J9,8 7.3, H-9), 7.15 (1H, dd, J8,9 7.3, J8,7 7.8, H-8), 7.39
(1H, d, J7,8 7.8, H-7); m/z 289 (M+, 83%) and 230 (100%); ECD ∆ε -11.26 (299 nm), ∆ε -8.18 (259 nm),
∆ε -17.35 (237 nm), ∆ε +33.86 (213 nm).
(-)-(R)-ψ-Balfourodine (-)-10: 69% yield; [α]D -39 (c 1.4, EtOH).
(+)-(S)-and (-)-(R)-Isobalfourodinium methiodide 7
A solution of (+)-(S)-9-methoxygeibalansine 6 (0.072 g, 0.25 mmol) in dry benzene (2 cm3) and
iodomethane (2 cm3, 0.032 mol) was kept at rt for 3 days. The precipitate formed was separated by
filtration and washed, on the filter paper, with dry benzene. (+)-(S)-Isobalfourodinium methiodide 7 was
obtained as a cream coloured solid (0.028 g, 26%); Rf 0.21 (10% MeOH in CHCl3); mp 113-115 °C;
(Found: M+, 289.1315. C17H22NO4I -MeI requires M+, 289.1314); [α]D +15 (c 1.08, MeOH); δH (300
MHz, CDCl3), 1.57 (3H, s, CMe), 1.75 (3H, s, CMe), 3.26 (1H, dd, J4,4' 17.2, J4,3 3.8, H-4), 3.67 (1H, dd,

HETEROCYCLES, Vol. 79, 2009
845
'
J4',4 17.3, J4',3 4.1, H-4 ), 4.05 (3H, s, NMe), 4.31 (3H, s, OMe), 4.36 (3H, s, OMe), 4.25-4.40 (1H, m, H-3),
7.37 (1H, d, J6,7 7.9, H-6), 7.58 (1H, dd, J7,6 7.9, J7,8 8.2, H-7), 7.80 (1H, d, J8,7 8.2, H-8); m/z 289
(M+-MeI, 60%) and 218 (100%); ECD ∆ε +2.30 (324 nm), ∆ε -0.63 (293 nm), ∆ε +13.33 (253 nm),
∆ε -40.26 (211 nm).
(-)-(R)-Isobalfourodinium methiodide 7: 14% yield; [α]D -14 (c 0.64, MeOH).
(-)-(S)- and (+)-(R)-Balfourolone 8
(+)-(S)-Isobalfourodinium methiodide 7 (0.022 g, 0.05 mmol) was taken up in aqueous ammonia (33%
w/w, 5 cm3) and the mixture stirred at rt for 3 h. The reaction mixture was diluted with water (10 cm3),
saturated with sodium chloride, and the solution extracted with CHCl3 (3 x 10 cm3). The organic extract
was washed with water (10 cm3), dried (MgSO4), and the solvent removed under reduced pressure. The
crude product obtained was purified by PLC (5% MeOH in CHCl3) to give (-)-(S)-balfourolone 8 as a
colourless viscous oil (0.014 g, 85%); [α]D -29 (c 1.27, MeOH) (Lit.,25; [α]D +32); νmax 3399 cm-1 (OH),
1630 cm-1 (C=O); δH (500 MHz, CDCl3), 1.31 (3H, s, CMe), 1.31 (3H, s, CMe), 2.72 (1H, dd, J1',1 13.7,
J1,2' 10.3, H-1), 3.10 (1H, dd, J1',1 13.7, J1',2' 2.1, H-1'), 3.59 (1H, dd, J2',1' 10.3, J2',1 2.1, H-2'), 3.92 (3H, s,
NMe), 3.93 (3H, s, OMe), 3.98 (3H, s, OMe), 5.27 (1H, br s, OH), 7.09 (1 H, dd, J5,6 7.9, J5,7 1.1, H-5),
7.23 (1H, dd, J6,5 = J6,7 7.9, H-6), 7.46 (1H, dd, J7,6 7.9, J7,5 1.5, H-7); m/z 321 (M+, 0.6%), 303 (M+-H2O,
11%) and 262 (100%); ECD ∆ε -10.56 (286 nm), ∆ε +3.96 (260 nm), ∆ε -14.34 (242 nm), ∆ε 1.50
(227 nm).
(+)-(R)-Balfourolone (+) 11: 83% yield; [α]D +31 (c 0.84, MeOH).
(+)-(R)-Hydroxylunidine 17
The crude product obtained by the dihydroxylation of alkene 16 using AD mix-β on purification, by PLC
(5% MeOH in CHCl3), afforded (+)-(R)-hydroxylunidine 17: (0.090 g, 81 %) colourless crystals; Rf 0.25;
mp 120.5-121.5 °C (from EtOH) (Lit.,26 mp 124-125 °C); [α]D +29 (c 0.16, EtOH) (Lit.,26 [α]D +28,
EtOH); δH (500 MHz, CDCl3) 1.30 (3H, s, CMe), 1.61 (3H, s, CMe), 2.60 (1H, s, OH), 2.69 (1H, dd,
J1'a,1'b 13.9, J1'a,2' 10.2, H-1a'), 3.06 (1H, d, J1a',1b' 13.9, J1b',2' 2.0, H-1b'), 3.56 (1H, ddd, J2',1a' 10.2, J2',OH 3.5,
J2',1'b 2.0, H-2'), 3.91 (3H, s, NMe), 3.92 (3H, s, OMe), 5.02 (1H, d, JOH,2' 3.5, CH2CHOH), 6.07 (2H, s,
OCH2O), 6.87 (1H, d, J4,5 8.6, H-4), 7.40 (1H, d, J5,4 8.6, H-5); m/z 336 (M++1, 1 %), 276 (100%); ECD
data: ∆ε +7.40 (301 nm), ∆ε -1.56 (261 nm), ∆ε +1.91 (215 nm), ∆ε -2.92 (204 nm).
(-)-(S)-Hydroxylunidine 17: With AD mix-α; [α]D –29 (c 0.92, EtOH).

846
HETEROCYCLES, Vol. 79, 2009
(+)-(R)-Nororixine 15
The crude product formed by the dihydroxylation of alkene 14 using AD mix-β, on purification by PLC
(6% MeOH-CHCl3), gave (+)-(R)-nororixine 15 (0.15 g, 70%); Rf 0.2; mp 198-199 °C (from EtOH)
(Lit.,26 mp 199-200 °C); [α]D +24 (c 0.76, EtOH) (Lit.,26 [α]D +27, EtOH); δH (500 MHz, CDCl3) 1.24
(3H, s, CMe), 1.59 (3H, s, CMe), 2.64 (1H, s, OH) 2.67 (1H, dd, J1'a,1'b 14.3, J1'a,2' 10.0, H-1'a), 3.13 (1H, d,
J1'b,1'a 14.2, H-1'b), 3.58 (1H, d, J2',1'a 9.8, H-2'), 3.97 (3H, s, OMe), 5.20 (1H, s, OH), 6.16 and 6.17 (2H, s,
OCH2O), 6.85 (1H, d, J4,5 8.6, H-4), 7.33 (1H, d, J5,4 8.6, H-5); δC (125 MHz, CDCl3) 167.5, 164.0, 149.3,
133.5, 122.3, 119.3, 117.6, 113.5, 105.4, 103.0, 79.5, 73.2, 62.7, 27.6, 25.8, 24.3; ECD : ∆ε + 0.46 (296
nm), ∆ε -1.80 (262 nm), ∆ε +1.81 (212 nm).
(-)-(S)-Nororixine 15: With AD mix-α; [α]D -22 (c 0.8, EtOH).
(+)-(R)-Orixine 19
The dihydroxylation complex was generated by adding methane sulfonamide (0.035 g, 0.36 mmol) into a
stirring solution of AD mix-β (0.5 g) in tert-butanol (2 cm3) and water (2 cm3) at 0 °C. Alkene 18 (0.10 g,
0.33 mmol) was added to the mixture and stirring was continued at 0 °C for 24 h. After completion of the
reaction (TLC analysis), a saturated Na2S2O5 solution (1 cm3) was added and the mixture stirred for 1h at
rt. The reaction mixture was saturated with NaCl and then extracted with EtOAc (3 x 20 cm3). The
organic extract was dried (Na2SO4) and concentrated under reduced pressure. Purification by PLC (5%
MeOH-CHCl3) afforded (+)-(R)-orixine 19 as a white solid (0.080 g, 73%); (Rf 0.2); mp 146-147 °C
(from EtOAc-hexane) (Lit.,26 mp 153 °C); [α]D +64 (c 0.5, CHCl3) (Lit.,27 [α]D +83); δ (500 MHz,
H
CDCl3) 1.33 and 1.36 (3H, s, CMe), 2.24 (1H, s, OH), 2.56 (1H, d, JOH,2' 4.4, OH), 2.83 (1H, dd, J1'a,1'b
13.7, J1'a,2' 10.2, H-1'a), 2.98 (1H, dd, J1'b,1'a 13.7, J1'b,2' 2.5, H-1'b), 3.67 (1H, ddd, J2',1'a 10.2, J2',OH 4.4,
J2',OH 2.5, H-2'), 4.11 (1H, s, OMe), 4.12 (1H, s, OMe), 6.20 (2H, s, OCH2O), 7.06 (1H, d, J4,5 8.7, H-4),
7.48 (1H, d, J5,4 8.7, H-4); m/z 335 (40%), 246 (100); ECD: ∆ε +6.21 (254 nm), ∆ε + 3.23 (211 nm), ∆ε
-2.34 (193 nm).
(-)-(S)-Orixine 19: With AD mix-α; [α]D -61 (c 0.52, CHCl3).
(-)-(R)-1'-Bromo-3'-(6-methoxy-8-oxo-8,9-dihydro[1,3]dioxolo[4,5-h]quinolin-7-yl)-1',1'-
dimethylpropyl acetate 20
To a solution of (+)-(R)-nororixine 15 (0.12 g, 0.374 mmol) in anhydrous MeCN (2 cm3) at 0 °C,
1-bromocarbonyl-1-methylethyl acetate (0.066 cm3, 0.449 mmol) was added. The mixture was stirred at 0
°C for 2 h and at rt for 2 h. Most of the MeCN was removed under reduced pressure, the residue taken up in
EtOAc (15 cm3) and thoroughly washed with a solution of aqueous NaHCO3 (2.5%, 20 cm3). The aqueous

HETEROCYCLES, Vol. 79, 2009
847
basic layer was back-extracted with EtOAc (20 cm3). The organic layers were combined, dried (Na2SO4)
and concentrated under reduced pressure to give the crude bromo acetate 20 as a yellow oil. Purification by
PLC (50% EtOAc in hexane) gave (-)-(R)-bromoacetate 20 as colourless oil which solidified on standing
(0.13 g, 76%); Rf 0.5; mp 137-138 °C (from CHCl3); [α]D - 4 (c 0.14, CHCl3); (Found: M+ 345.1219.
C18H19NO6 requires 345.1212); δ H (500 MHz, CDCl3) 1.54 (3H, s, CMe), 1.63 (3H, s, CMe), 1.97 (3H, s,
OCOMe), 3.49 (1H, dd, J3'a,3'b 15.8, J3'a,2' 6.7, H-3'a), 3.61 (1H, dd, J3'b,3'a 15.8, J3'b,2' 9.3, H-3'b), 4.24 (3H, s,
OMe), 4.98 (1H, dd, J2', 3'b 9.3, J2',3'a 6.7, H-2'), 6.15 (2H, s, OCH2O), 6.94 (1H, d, J4,5 8.7, H-4), 7.59 (1H, d,
J5,4 8.7, H-5); δ (125 MHz, CDCl3) 170.2, 169.4, 147.8, 140.1, 133.9, 116.6, 115.6, 106.6, 102.1, 99.7,
C
84.0, 82.1, 58.3, 28.9, 22.3, 22.2, 20.8; m/z 345 (M+-HBr, 15%).
(+)-(S)-1'-Bromo-3'-(6-methoxy-8-oxo-8,9-dihydro[1,3]dioxolo[4,5-h]quinolin-7-yl)-1',1'-
dimethylpropyl acetate 20: [α]D +5 (c 0.31, CHCl3).
(+)-(S)-Isopteleflorine 22
To a solution of (-)-(R)-bromoacetate 20 (0.1 g, 0.235 mmol) in dry Et2O (30 cm3) anhydrous NaOMe
(0.5 g) was added. After stirring the reaction mixture (24 h) at rt, it was filtered through a pad of celite to
remove the inorganic salts. The filtrate was concentrated under reduced pressure and the residue purified
by multiple elution PLC (75% EtOAc in hexane). (+)-(S)-Isopteleflorine 22 was obtained as white solid
(0.064 g, 90%); Rf 0.3; mp 164-165 °C (from CHCl3) (Lit.,28 mp 163-166 °C); [α]D +19 (c 0.35, CHCl3)
(Lit.,29 [α]D -18, CHCl3); Anal.Calcd for C16H17NO5: C, 63.4; H, 5.6; N, 4.6%. Found: C, 63.5; H, 5.5; N,
4.3 ; δH (500 MHz, CDCl3) 1.26 (3H, s, CMe), 1.41 (3H, s, CMe), 3.54 (1H, dd, J7a,7b 15.4, J7a,8 8.8, H-7a),
3.56 (1H, dd, J7b,7a 15.4, J7b,8 7.7, H-7b), 4.21 (3H, s, OMe), 4.62 (1H, dd, J8,7a 8.8, J8,7b 7.8, H-8), 6.13
(1H, d, J 2.4, OCH2O), 6.15 (1H, J 2.4, OCH2O), 6.93 (1H, d, J4,5 8.7, H-4), 7.58 (1H, d, J5,4 8.7, H-5); δC
(125 MHz, CDCl3) 24.7, 26.5, 29.3, 58.7, 71.9, 86.8, 100.6, 102.5, 107.0, 116.4, 117.1, 134.2, 140.4,
148.1, 159.7, 169.8; m/z 303 (60%); ECD: ∆ε -0.94 (250 nm), ∆ε +2.98 (224 nm), ∆ε +2.02 (199 nm).
(-)-(R)-Isopteleflorine 22: [α]D -18 (c 0.72, CHCl3).
(-)-(S)-O-Acetylisopteleflorine 23
A mixture of (+)-(S)-isopteleflorine 22 (0.01 g, 0.033 mmol), acetic anhydride (1cm3), pyridine (1cm3) and
DMAP (0.002 g) was heated (1.5 h) under reflux and then strirred (12 h) at rt. The reaction mixture was
concentrated under reduced pressure and the crude product obtained purified by PLC (50% EtOAc in
hexane). (-)-Acetylisopteleflorine 23 was obtained as a white solid (0.010 g, 91%); mp 129-130 °C (from
EtOAc-hexane); Rf 0.3; [α]D -6.4 (c 0.45, CHCl3) (Lit.,30 [α]D +6.4, CHCl3); δH (500 MHz, CDCl3) 1.55 (3H,
s, CMe), 1.62 (3H, s, CMe), 1.97 (3H, s, OCOMe) 3.49 (1H, dd, J7a,7b 15.9, J7a,8 6.8, H-7a), 3.62 (1H, dd,

848
HETEROCYCLES, Vol. 79, 2009
J7b,7a 15.9, J7b,8 9.2, H-7b), 4.22 (3H, s, OMe), 4.97 (1H, dd, J8,7a 9.2, J8,7b 6.8, H-8), 6.14 (1H, d, J 1.5,
OCH2O), 6.16 (1H, J 1.5, OCH2O), 6.95 (1H, d, J4,5 9.7, H-4), 7.58 (1H, d, J5,4 8.7, H-5); m/z 345 (M+,
45%); ECD : ∆ε -1.55 (251 nm), ∆ε +1.53 (222 nm), ∆ε +0.57 (197 nm).
(+)-(R)-O-Acetylisopteleflorine 23: [α]D +6.4 (c 0.40, CHCl3).
(+)-(S)-O-Methylhydroxylunium methiodide 24
A solution of (+)-(S)-isopteleflorine 22 (0.05 g, 0.164 mmol) in MeI (1 cm3) and EtOH (5 cm3) was heated
(2 h) under reflux. The reaction mixture was concentrated under reduced pressure to give
(+)-(S)-methiodide 24 (0.066 g, 90%) as a yellow solid; mp 155-156 °C (from EtOH) (Lit.,28 mp
159-161 °C); [α]D +16 (c 0.25, EtOH) (Lit.,22 [α]D -18, EtOH); δH (500 MHz, CD3OD) 1.30 (3H, s, CMe),
1.44 (3H, s, CMe), 3.95 (1H, dd, J7a,7b 15.5, J7a,8 6.8, H-7a), 3.97 (1H, dd, J7b,7a 15.5, J7b,8 9.2, H-7b), 4.22
(3H, s, OMe), 4.48 (3H, s, NMe), 5.23 (1H, dd, J8,7b 9.3, J8,7a 6.9, H-8), 7.28 (1H, d, J4,5 8.8, H-4), 7.91 (1H,
d, J5,4 8.8, H-5); δC (125 MHz, CD3OD) 24.9, 26.0, 30.0, 60.6, 71.9, 95.7, 102.7, 104.7, 110.6, 116.9, 121.0,
124.6, 125.6, 153.7, 164.7, 168.6; m/z 303 (M+-MeI, 12 %), 141; Electronic CD: ∆ε -2.30 (261 nm), ∆ε
+6.15 (221 nm).
(-)-(R)-O-Methylhydroxylunium iodide 24: [α]D -16 (c 0.19, EtOH).
(+)-(S)-Hydroxylunine 25
A solution of (+)-(S)-methiodide 24 (0.05 g, 0.11 mmol) in pyridine (1 cm3) was heated (3.5 h) under
reflux in an oil bath. Pyridine was removed under reduced pressure and the residue purified by PLC (7%
MeOH in CHCl3). (+)-(S)-Hydroxylunine 25 was obtained as a white solid (0.028 g, 85%); mp
224-225 °C (from EtOH) (Lit.,28 mp 222-225 °C); Rf 0.4 [α]D +25 (c 0.45, EtOH) (Lit.,26 [α]D -6); δH (500
MHz, CDCl3) 1.26 (3H, s, CMe), 1.38 (3H, s, CMe), 3.17 (1H, dd, J7a,7b 14.5, J7a,8 9.8, H-7a), 3.25 (1H,
dd, J7b,7a 14.6, J7b,8 8.0, H-7b), 3.83 (3H, s, NMe), 4.80 (1H, dd, J8,7a 9.8, J8,7b 8.0, H-8), 6.03 (2H, s,
OCH2O), 6.85 (1H, d, J4,5 8.5, H-4), 7.98 (1H, d, J5,4 8.5, H-5);δC (125 MHz, CDCl3) 24.6, 25.9, 27.6,
34.2, 71.4, 92.0, 101.4, 105.6, 120.9, 122.9, 125.2, 134.9, 149.6, 161.8, 173.0; m/z 303 (M+, 40 %), 232
(100); ECD data: ∆ε -1.67 (239 nm), ∆ε +2.63 (215 nm).
(-)-(R)-Hydroxylunine 25:[α]D -24 (c 0.40, EtOH).
ACKNOWLEDGEMENTS
We thank the BBSRC (N.D.S) and Oxford Glycosciences (P.L.L) for funding and also DENI (S.A.B) and
Queen's University Belfast (P.L.L) for providing Postgraduate Studentships.

HETEROCYCLES, Vol. 79, 2009
849
REFERENCES
1.
J. P. Michael, Nat. Prod. Rep., 2008, 25, 166 and earlier annual reviews in this journal by the same
author.
2.
3.
4.
5.
D. M. Jerina, J. W. Daly, and B. Witkop, J. Am. Chem. Soc., 1968, 90, 6525.
D. R. Boyd, J. W. Daly, and D. M. Jerina, Biochemistry, 1972, 11, 1961.
M. F. Grundon, D. M. Harrison, and C. G. Sypropoulos, J. Chem. Soc., Perkin Trans. 1,1974, 2181.
D. R. Boyd, N. D. Sharma, C. O’Dowd, J. G. Carroll, P. L. Loke, and C. C. R. Allen, Chem.
Commun., 2005, 3989.
6.
7.
S. Funayama, K. Murata, and S. Nozoe, Chem. Pharm. Bull., 1996, 44, 1885.
C. Ito, M. Itoigawa, A. Furukawa, T. Hirano, T. Murata, N. Kaneda, Y. Hisada, K. Okuda, and H.
Furukawa, J. Nat. Prod., 2004, 67, 1800.
8.
9.
C. L. Cantrell, K. K. Schrader, L. K. Mamonov, G. T. Sitpaeva, T. S. Kustova, C. Dunbar, and D. E.
Wedge, J. Agric. Food Chem., 2005, 53, 7741.
D. R. Boyd, N. D. Sharma, P. L. Loke, J. F. Malone, W. C. McRoberts, and J. T. G. Hamilton, Org.
Biomol. Chem., 2007, 5, 2983.
10. R. M. Bowman, J. F. Collins, and M. F. Grundon, J. Chem. Soc., Chem. Commun., 1967, 1131.
11. R. M. Bowman and M. F. Grundon, J. Chem. Soc.(C), 1967, 2368.
12. R. M. Bowman, J. F. Collins, and M. F. Grundon, J. Chem. Soc., Perkin Trans.1, 1973, 626.
13. M. F. Grundon in ‘The Alkaloids: Quinoline Alkaloids Related to Anthranilic Acid’, Academic
Press, London, 1988, 32, 341.
14. S. A. Barr and D. R. Boyd, J. Chem. Soc., Chem. Commun., 1994, 153.
15. D. R. Boyd, N. D. Sharma, S. A. Barr, J. G. Carroll, D. Mackerracher, and J. F. Malone, J. Chem.
Soc., Perkin Trans. 1, 2000, 3397.
16. S. A. Barr, D. R. Boyd, N. D. Sharma, T. A. Evans, J. F. Malone, and V. D. Mehta, Tetrahedron,
1994, 50, 11219.
17. E. A. Clarke and M. F. Grundon, J. Chem Soc., 1964, 4196.
18. E. N. Jacobsen, W. Zang, A. R. Murci, J. R. Ecker, and L. Deng, J. Am. Chem. Soc., 1991, 113,
7063.
19. N. H. Lee, A. R. Murci, and E. N. Jacobsen, Terahedron. Lett., 1991, 32, 5055.
20. K. J. James and M. F. Grundon, J. Chem. Soc., Perkin Trans. 1, 1979, 1467.
21. D. R. Boyd, N. D. Sharma, P. L. Loke, J. F. Malone, W. C. McRoberts, and J. T. G. Hamilton,
Chem. Commun., 2002, 3070.
22. M. Rideau, C. Verchere, P. Hibon, J. Chenieux, P. Maupas, and C. Viel, Phytochemistry, 1979, 18,
155.

850
HETEROCYCLES, Vol. 79, 2009
23. W. Zang, J. L. Leobach, S. R. Wilson, and E. N. Jacobsen, J. Am. Chem. Soc., 1991, 113, 7063.
24. R. M. Bowman and M. F. Grundon, J. Chem. Soc. (C), 1966, 1504.
25. S. Goodwin, A. F. Smith, A. A. Smith, A. A. Velasquez, and A. C. Horning, J. Am. Chem. Soc.,
1959, 81, 6209.
26. M. Terasaka, Chem. Pharm. Bull., 1960, 8, 523.
27. M. Terasaka, Chem. Pharm. Bull., 1959, 7, 946.
28. C. F. Neville, M. F. Grundon, V. N. Ramachandran, and J. Reisch, J. Chem. Soc., Perkin Trans. 1,
1991, 259.
29. T. Noshita, M. Tando, K. Suzuki, K. Murata, and S. Funayama, Biosci. Biotechnol. Biochem., 2001,
65, 710.
30. S. Funayama, K. Murata, and S. Nozoe, Phytochemistry, 1996, 41, 1231.