A chemoenzymatic route to the (+)-form of the amaryllidaceae alkaloid narseronine

Article abstract of DOI:10.1071/CH14520

The enzymatically derived and enantiopure cis-1,2-dihydrocatechol 1 has been converted, over 14 one-pot operations, into the (+)-form of the alkaloid narseronine (2). The present study, which complements earlier work that established a route from metaboli

Full text of DOI:10.1071/CH14520

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 241–247
Full Paper
http://dx.doi.org/10.1071/CH14520
A Chemoenzymatic Route to the (1)-Form
of the Amaryllidaceae Alkaloid Narseronine*
A
A B
,
A
Shuxin Yang, Martin G. Banwell,
Anthony C. Willis,
A
and Jas S. Ward
A
Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra, ACT 2601, Australia.
B
Corresponding author. Email: martin.banwell@anu.edu.au
The enzymatically derived and enantiopure cis-1,2-dihydrocatechol 1 has been converted, over 14 one-pot operations, into
the (þ)-form of the alkaloid narseronine (2). The present study, which complements earlier work that established a route
from metabolite 1 to enantiomer (ꢀ)-2, involves an N-bromosuccinimide/tri-n-butyltin hydride-mediated cyclisation
reaction to construct the unsaturated B-ring lactone of the target compound.
Manuscript received: 26 August 2014.
Manuscript accepted: 7 September 2014.
Published online: 3 November 2014.
OMe
OMe
Introduction
D
C
A
cis-1,2-Dihydrocatechols such as 1 are readily obtained in
enantiomerically pure form (viz. .99.8 % ee) through the
whole-cell biotransformation of the corresponding arene
(bromobenzene in this case) using mutant forms of bacteria that
produce toluene dioxygenase (TDO), the enzyme responsible
for this fascinating conversion.[1,2] Metabolites such as 1 have
proved to be particularly effective starting materials for
the chemical synthesis of a remarkably diverse range of chiral,
non-racemic natural products and/or biologically active com-
pounds.[2] However, an ongoing issue associated with this
(chemoenzymatic[3]) approach to the construction of such target
systems is the seeming confinement of it to the generation of a
single enantiomeric form of a given target molecule.[4] As part
of an effort to address such constraints, Hudlicky and his
coworkers demonstrated that the ‘latent’ symmetry elements
associated with compound 1 and certain of its congeners[2a,d]
allow their use in the enantiodivergent synthesis of, inter alia,
cyclitols.[5] Similarly, we have shown that various cis-1,2-
dihydrocatechols can participate in a range of Diels–Alder
cycloaddition processes that permit the assembly of either
enantiomeric form of certain polycyclic frameworks, including
those associated with sesquiterpenoid natural products.[6] In a
related vein, we now detail the outcomes of a study that has
culminated in the identification of a method for the assembly of
the (þ)-form of the Amaryllidaceae alkaloid narseronine (2)[7]
from compound 1, work that complements our recently reported
synthesis[8] of its optical antipode [viz. (ꢀ)-narseronine] from
the same starting material (Chart 1).
OH
OH
N
Me
N
O
O
O
Me
B
O
Br
O
O
O
O
1
(ϩ)-2
Chart 1.
(Ϫ)-2
The product alcohol 4 (96 %)[9] was then deoxygenated using
the Barton–McCombie protocol[10] so as to afford the bromo-
alkene 5 (82 %) that participates in a Suzuki–Miyaura cross-
coupling reaction with the arylboronate 6[9] to give compound 7
(75 %). Various manipulations of this last compound includ-
ing the Raney-cobalt mediated reduction of the associated
nitrile residue[9,11] afforded, over eight steps and in 16 % overall
yield, the a-arylated cyclohexenone 8 carrying a protected
secondary amine residue tethered through the g-carbon. Finally,
treatment of compound 8 with (Ph3P)4Pd in the presence of
dimedone resulted in cleavage of the Alloc group, thus allowing
the resulting secondary amine 9 (which was not isolated) to
undergo an intramolecular hetero-Michael addition reaction/
trans-acylation sequence and so affording (ꢀ)-narseronine
[(ꢀ)-1] (82 %), the structure of which was secured by single-
crystal X-ray analysis. Unfortunately, the specific rotation for
the natural product obtained by Bastida et al.[7] was not reported
and so it has not been possible to establish its absolute
configuration.
The key features of our previously reported synthesis of
(ꢀ)-narseronine [(ꢀ)-2] involved the initial conversion
(Scheme 1) of metabolite 1 into the well-known derivative 3
(95 %),[5] which was itself engaged in selective epoxide ring-
opening on treatment with the anion derived from acetonitrile.
Results and Discussion
The synthetic route used to effect the conversion 1 - (þ)-2,
the focus of the study reported herein, relied, in its early
*Dedicated to Des Brown in recognition of his seminal and sustained contributions to the chemistry of heterocyclic compounds.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

242
S. Yang et al.
O
Br
OH
OH
O
O
Two steps
HO
OH
OH
OH
OH
NBS
H2O/THF
Br
Br
Br
Br
1
3
1
10
LiCH2CN
2,2-DMP
p-TsOH
OH
Barton–McCombie
deoxygenation
O
O
O
O
NC
OH
Br
NC
6
HO
O
O
O
O
(i) NaH
NC
6
Br
(ii) LiCH2CN
Br
4
5
Br
Br
ϩ
12
11
O
NC
NaH, CS2
MeI
O
O
O
O
NC
B
Suzuki–Miyaura
cross-coupling
CO2Me
CO2Me
O
X
CO2Me
O
O
Compound 6
Pd0, Et3N
NC
O
O
O
O
O
Br
O
7
6
n-Bu3SnH
AIBN
13 [X ϭ OC(S)SMe]
14 (X ϭ H)
Eight steps
OMe
15
Alloc
MeN
MeHN
OMe
Scheme 2.
O
O
Pd0
Dimedone
deoxygenation reaction using tri-n-butyltin hydride and 2,20-
azobis(2-methylpropionitrile) (AIBN) in refluxing benzene and
thus generating the deoxygenated congener of alcohol 12, viz.
compound 14.[12] This was obtained in 87 % yield. Suzuki–
Miyaura cross-coupling of bromoalkene 14 with the arylbor-
onate 6[9] proceeded smoothly on using PdCl2(dppf)ꢁCH2Cl2 in
the presence of triethylamine and thereby providing the previ-
ously reported compound 15[12] in 95 % yield.
CO2Me
CO2Me
O
O
O
O
9
8
OMe
The chemistry used to complete the synthesis of (þ)-
narseronine [(þ)-2] is shown in Scheme 3 and began with the
exposure of the Suzuki–Miyaura cross-coupling product 15 to
aqueous acetic acid at 508C such that the allylic hydroxyl group
of the initially formed diol reacted with the proximate ester
residue to afford the lactone 16 (84 %).[12] The free hydroxyl
group within this last compound was protected as the corre-
sponding TBDPS-ether 17[12] (80 %) using conventional proto-
cols and this was, in turn, subjected to reaction with dihydrogen
in the presence of Raney-cobalt[13] in ammoniacal methanol
to produce the previously reported primary amine 18 (82 %).[12]
In a pivotal step of the reaction sequence, this last compound
was treated successively with 1.1 molar equivalents of NBS,
then, after 0.5 h, with tri-n-butyltin hydride (n-Bu3SnH) and
AIBN, so affording compound 19 (83 %), which now incorpo-
rates the unsaturated B-ring lactone and, therefore, the full
polycyclic framework of (þ)-narseronine [(þ)-2].
N
O
Me
O
O
O
(Ϫ)-2
Scheme 1.
stages (Scheme 2), on chemistry established during the course
of preparing the non-natural enantiomeric form of the
alkaloid clividine.[12] Specifically, diene 1 was treated with
N-bromosuccinimide (NBS) in wet THF, thus generating, in a
completely regio- and diastereo-selective manner, bromohydrin
10[12] that was readily protected as the corresponding acetonide
11[12] (92 % from 1) under conventional conditions. Successive
treatment of compound 11 with sodium hydride (so as to form
the corresponding epoxide) and then the anion of acetonitrile
(which was generated in situ by treating acetonitrile itself with
n-BuLi) afforded the previously reported[12] g-hydroxynitrile 12
(87 %). Conversion of compound 12 into the corresponding
methyl xanthate 13[12] (93 %) was achieved under conventional
conditions and this was then subjected to a Barton–McCombie
The exact pathway followed during the conversion 18 - 19
remains unclear at the present time but it seems likely that the
initial step involves the formation of the N-bromo-derivative
of the former compound (through halogen atom transfer from
NBS) and that this derivative reacts with n-Bu3SnH to give the
corresponding nitrogen-centred radical, which itself engages in
a 5-exo-trig cyclisation process to give the tetracyclic benzylic

A Chemoenzymatic Synthesis of (þ)-Narseronine
243
OTBDPS
OH
O
O
NC
NC
NC
AcOH/H2O
O
TBDPS-Cl
Imidazole
O
CO2Me
O
O
O
O
O
O
O
O
H2
Raney-Co
15
16
17
OH
OTBDPS
H2N
OTBDPS
5
N
(i) NBS
TBAF
N
H
O
O
O
O
O
H
(ii) n-Bu3SnH
O
AIBN
O
O
O
O
O
O
MnO2
20
19
18
O
OH
OMe
NaBH4, CeCl3•7H2O
N
H
N
H
N
KH, MeI
O
O
O
O
O
Me
O
O
O
O
O
O
O
21
22
(ϩ)-2
Scheme 3.
radical. The precise means by which this last species is con-
verted into the final, alkene-containing product remains to be
determined but it is conceivable that another bromine atom
transfer is involved, thus forming a benzylic bromide that
promptly loses the elements of HBr and thereby generating
compound 19.
C3
O21
C5
C4
C6
C2
N1
Completion of the synthesis of (þ)-narseronine [(þ)-2] from
compound 19 required inversion of configuration at C5 as well
as N- and O-methylation reactions. The best means of address-
ing the first of these requirements was to cleave the TBDPS
ether residue within the latter compound using tetra-n-butyl-
ammonium fluoride (TBAF) and then oxidising the resulting
alcohol 20 (95 %) with MnO2 and so forming the ketone 21
C20
C7
O8
C9
C19
C18
1
(78 %). All the H and 13C NMR spectral data acquired on
C10
C17
products 20 and 21 were in complete accord with the assigned
structures but final confirmation of these followed from a single-
crystal X-ray analysis on the former compound. The derived
ORTEP is shown in Fig. 1 and various crystal data are presented
in the Experimental section. Treatment of compound 21 with the
Luche reagent[14] derived from reacting sodium borohydride
and CeCl3 heptahydrate in methanol resulted in the essentially
exclusive formation of the C5 epimer of compound 20, namely
alcohol 22, which was obtained in 99 % yield and the structure
of which was also secured by single-crystal X-ray analysis.
Presumably, the stereochemical outcome of this 1,2-reduction
process derives from the steric impositions of the b-orientated
pyrrolidine ring that ensure hydride is delivered to the a-face of
the ketone carbonyl unit.
O22
C11
C16
O15
C12
O13
C14
Fig. 1. ORTEP derived from the single-crystal X-ray analysis of com-
pound 20 (CCDC no. 944982) with labelling of selected atoms. Anisotropic
displacement ellipsoids display 30 % probability levels. Hydrogen atoms are
drawn as circles with small radii.
The necessary N,O-dimethylation of aminoalcohol 22 so as
to generate (þ)-narseronine proved to be a remarkably difficult
transformation. So, for example, treatment of the former com-
pound with methyl iodide and silver(I) oxide (no solvent)
afforded a complex mixture of products from which a small
amount of a rather unstable crystalline compound could be
obtained. A single-crystal X-ray analysis of this material
established that it was the arene hydrate 24 (Scheme 4).[15] This
presumably arises via a two-fold N-methylation of substrate 22
to produce the methiodide salt 23 which itself fragments in the
illustrated manner to give, after loss of the elements of hydrogen
iodide, the observed product. Eventually, it was established that

244
S. Yang et al.
I Ϫ
J (Hz), relative integral] where multiplicity is defined as:
s ¼ singlet; d ¼ doublet; t ¼ triplet; q ¼ quartet; m ¼ multiplet,
or combinations of the above. The signal due to residual CHCl3
appearing at dH 7.26 and the central resonance of the CDCl3
OH
O
OH
O
ϩ
MeI
Ag2O
N
H
N
Me
Me
O
O
O
‘triplet’ appearing at dC 77.0 were used to reference 1H and 13
C
NMR spectra, respectively. Infrared spectra (nmax) were recorded
on a Perkin–Elmer 1800 Series Fourier-transform (FT)IR
spectrometer. Samples were analysed as thin films on KBr
plates. Low-resolution electrospray ionisation (ESI) mass
spectra were recorded on a Micromass LC-ZMD single quad-
rupole liquid chromatograph–mass spectrometer whereas high-
resolution measurements were conducted on an LCT Premier
time-of-flight instrument. Low- and high-resolution EI mass
spectra were recorded on an Autospec Premier Micromass
magnetic-sector machine. Optical rotations were recorded in
CHCl3 at 208C on a Perkin–Elmer Model 343 polarimeter using
a cell of 1 dm in length. Melting points were measured on an
Optimelt automated melting point system and are uncorrected.
Analytical thin-layer chromatography (TLC) was performed on
aluminium-backed 0.2-mm thick silica gel 60 F254 plates as
supplied by Merck. Eluted plates were visualised using a 254 nm
UV lamp and/or by treatment with a suitable dip followed by
heating. These dips included phosphomolybdic acid/ceric
sulfate/sulfuric acid (conc.)/water (37.5 g : 7.5 g : 37.5 g :
720 mL) or potassium permanganate/potassium carbonate/5 %
sodium hydroxide aqueous solution/water (3 g : 20 g : 5 mL :
300 mL). Flash chromatographic separations were carried out
following protocols defined by Still et al.[16] with silica gel 60
(40–63 mm) as the stationary phase and using the AR- or HPLC-
grade solvents indicated. Starting materials and reagents were
generally available from the Sigma–Aldrich, Merck, TCI,
Strem or Lancaster chemical companies and were used as sup-
plied. Drying agents and other inorganic salts were purchased
from the AJAX, BDH or Unilab chemical companies. Tetra-
hydrofuran (THF), methanol, and dichloromethane were dried
using a Glass Contour solvent purification system that is
based on a technology originally described by Grubbs et al.[17]
Where necessary, reactions were performed under an argon
atmosphere.
O
O
O
22
23
OH
Me2N
ϪHI
O
O
O
O
24
Scheme 4.
when a THF solution of compound 22 maintained at 0–188C was
treated with ,4 molar equivalents of potassium hydride and 8
equivalents of methyl iodide (Scheme 3), then a relatively clean
N,O-bismethylation reaction took place and thus finally provid-
ing (þ)-narseronine [(þ)-2] in 83 % yield after chromatographic
purification. The H and 13C NMR spectral data obtained on
1
this material matched those recorded earlier[8] for its enantiomer
but final confirmation of its structure (other than absolute
stereochemistry) followed from a single-crystal X-ray analysis.
The specific rotation of compound (þ)-2 was þ21.0 (c 0.3,
CDCl3). This compares with the value of ꢀ25.4 (c 1.6, CDCl3)
recorded[8] for its enantiomer.
Conclusions
The ability to effect syntheses of both (þ)- and (ꢀ)-narseronine
[(þ)-2 and (ꢀ)-2, respectively] from the cis-1,2-dihy-
drocatechol 1 serves to further emphasise the utility of such
systems as starting materials in chemical synthesis. In this
instance, the capacity for enantiodivergence arises by virtue of
being able to readily generate the isomeric nitriles 4 and 12, the
C6 stereochemistries of which determine the orientations (a or
b) of the derived pyrrolidine or D-rings in the product enan-
tiomers (ꢀ)-2 and (þ)-2, respectively. In the case of the
reaction sequence leading to the latter form of the title alkaloid,
an inversion of configuration at C5 in compound 19 is required.
Despite this, the lengths of the two reaction sequences are
similar (viz. 14 vs 15 steps), not least because of the more
efficient means of introducing the methyl group at nitrogen in
the one reported here. Extensions of the chemistries defined
above to the assembly of both enantiomeric forms of related
alkaloids are now being pursued. Results will be reported in
due course.
Specific Synthetic Transformations
(3aS,5S,12cS)-5-[(tert-Butyldiphenylsilyl)oxy]-
2,3,3a,4,5,12c-hexahydro-[1,3]dioxolo-[40,50:6,7]
isochromeno[3,4-g]indol-7(1H)-one (19)
A magnetically stirred solution of amine 18[12] (300 mg,
0.55 mmol) in degassed benzene (20 mL) maintained at 188C
under an atmosphere of nitrogen was treated, in portions, with
NBS (108 mg, 0.61 mmol, 1.1 mol equiv.). After a further 0.5 h
the reaction mixture was placed in an oil bath heated at 858C
then treated, via syringe pump over 0.83 h, with a solution of
tri-n-butyltin hydride (194 mL, 0.72 mmol, 1.3 mol equiv.) and
AIBN (11.5 mg, 0.07 mmol, 0.13 mol equiv.) in benzene
(5 mL). After a further 2 h the ensuing mixture was cooled to
188C then concentrated under reduced pressure. The resulting
orange oil was subjected to flash chromatography (silica,
2 % v/v ammonia-saturated methanol/dichloromethane elution).
Concentration of the appropriate fractions (Rf 0.4) gave com-
pound 19 (246 mg, 83 %) as a white foam, [a]2D0 ꢀ3.95 (c 1.0,
CHCl3). Found: m/z 540.2206 (M þ H)þ; C32H33NO5Si requires
540.2206 (M þ H)þ. dH (400 MHz, CDCl3) 7.75–7.65 (complex
m, 4H), 7.48–7.21 (complex m, 8H), 6.04 (m, 2H), 4.42 (t,
J 3.0, 1H), 3.96 (d, J 6.0, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.88
Experimental
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded at 188C in base-filtered CDCl3 on a
Varian spectrometer operating at 400 MHz for proton and
100 MHz for carbon nuclei. 1H NMR data are recorded as
follows: chemical shift (d) [multiplicity, coupling constant(s)

A Chemoenzymatic Synthesis of (þ)-Narseronine
245
(m, 1H), 2.19 (m, 1H), 1.71 (m, 1H), 1.53 (m, 2H), 1.06 (s, 9H)
(signal due to N–H group proton not observed). dC (100 MHz,
CDCl3) 160.9 153.7 151.9 148.2 135.9(1), 135.8(7), 134.8,
133.8, 133.2, 129.7(1), 129.6(5), 127.7, 127.5, 116.3, 111.2,
107.3, 103.5, 102.2, 66.7, 56.6, 46.2, 33.7, 32.7, 31.4, 27.0, 19.4.
nmax (KBr)/cmꢀ1 2929, 2856, 1716, 1503, 1482, 1416, 1254,
1111, 1070, 1035, 937, 762. m/z (ESI, þve) 562 ([M þ Na]þ,
6 %), 540 ([M þ H]þ, 50), 267 (100).
(3aS,5R,12cS)-5-Hydroxy-2,3,3a,4,5,12c-hexahydro-
[1,3]dioxolo[40,50:6,7]isochromeno[3,4-g]indol-
7(1H)-one (22)
A magnetically stirred solution of ketone 21 (73 mg,
0.25 mmol) and CeCl3ꢁ7H2O (92 mg, 0.38 mmol, 1.5 equiv.) in
methanol (10 mL) was cooled to ꢀ788C and, after 0.25 h, treated
with sodium borohydride (11.3 mg, 0.03 mmol, 1.2 mol equiv.)
then, after 0.03 h, with sodium bicarbonate (2 mL of a saturated
aqueous solution). The resulting mixture was extracted with
dichloromethane (5 ꢂ 10 mL), the combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced
pressure, with the residue thus obtained being subjected to flash
chromatography (silica, 96 : 4 v/v dichloromethane/ammonia-
saturated methanol). Concentration of the appropriate fractions
(Rf 0.4) gave compound 22 (73 mg, 99 %) as a white, crystalline
solid, mp 168–1698C. [a]D20 þ83.9 (c 1.0, CDCl3). Found: m/z
302.1031 (M þ H)þ; C16H15NO5 requires 302.1028 (M þ H)þ.
dH (400 MHz, CDCl3) 7.57 (s, 1H), 7.34 (s, 1H), 6.10 (m, 2H),
4.65 (dd, J 12.0, 6.0, 1H), 3.86 (d, J 3.0, 1H), 3.32 (m, 1H), 3.05
(m, 1H), 2.43 (m, 1H), 2.15–2.02 (complex m, 3H), 1.78–1.63
(complex m, 2H) (signal due to N–H group proton not
observed). dC (100 MHz, CDCl3) 161.3, 154.1, 152.6, 148.2,
135.0, 115.3, 107.4, 103.5, 102.3, 65.9, 57.1, 46.0, 35.7, 33.1,
31.8 (one signal obscured or overlapping). nmax (KBr)/cmꢀ1
3316, 2926, 2870, 1709, 1621, 1502, 1481, 1416, 1283, 1256,
1165, 1094, 1034. m/z (ESI, þve) 324 ([M þ Na]þ, 40 %) 302
([M þ H]þ, 100), 241 (35).
(3aS,5S,12cS)-5-Hydroxy-2,3,3a,4,5,12c-hexahydro-
[1,3]dioxolo[40,50:6,7]isochromeno[3,4-g]indol-
7(1H)-one (20)
A magnetically stirred solution of compound 19 (215 mg,
0.4 mmol) in THF (40 mL) maintained under an atmosphere
of nitrogen was cooled to 08C then treated with tetra-n-
butylammonium fluoride (0.8 mL of a 1 M solution in THF,
0.8 mmol, 2.0 mol equiv.). The ensuing mixture was warmed to
188C, stirred at this temperature for 18 h then quenched with
sodium bicarbonate (5 mL of a saturated aqueous solution) and
diluted with dichloromethane (3 ꢂ 10 mL). The combined
organic extracts were washed with brine (3 ꢂ 10 mL) before
being dried (Na2SO4), filtered, and then concentrated under
reduced pressure to afford a light-yellow oil. Subjecting this
material to flash chromatography (silica, 4 % v/v ammonia-
saturated methanol/dichloromethane) and concentration of the
appropriate fractions (Rf 0.4) gave compound 20 (114 mg, 95 %)
as a white, crystalline solid, mp 1638C. [a]2D0 þ82.5 (c 1.0,
CHCl3). Found: m/z 302.1027 (M þ H)þ; C16H15NO5 requires
302.1028 (M þ H)þ. dH (400 MHz, CDCl3) 7.33 (s, 1H), 7.17
(s, 1H), 6.06 (s, 1H), 6.03 (s, 1H), 4.43 (s, 1H), 3.76 (d, J 6.0,
1H), 3.25 (m, 1H), 3.01 (m, 1H), 2.69 (m, 1H), 2.13 (m, 1H),
1.90–1.71 (complex m, 2H), 1.59 (m, 1H) (signals due to N–H
and O–H group protons not observed). dC (100 MHz, CDCl3)
161.3, 153.7, 152.3, 148.1, 134.6, 115.6, 110.9, 107.1, 103.3,
102.3, 64.3, 56.4, 46.1, 32.7, 32.5, 31.2. nmax (KBr)/cmꢀ1 3416,
3330, 2927, 1706, 1654, 1502, 1483, 1418, 1282, 1255, 1115,
1037. m/z (ESI, þve) 324 ([M þ Na]þ, 13 %) 302 ([M þ H]þ,
22), 267 (100), 242 (60), 241 (48).
(R)-2-(2-(Dimethylamino)ethyl)-4-hydroxy-3,4-
dihydro-6H-[1,3]dioxolo[40,50:4,5]benzo-[1,2-c]
chromen-6-one (24)
A magnetically stirred mixture of compound 22 (42 mg,
0.14 mmol) and methyl iodide (1 mL, 16 mmol) maintained
under a nitrogen atmosphere at 188C was treated with silver(I)
oxide (323 mg, 1.4 mmol) and the resulting mixture stirred in a
sealed tube at 508C for 16 h before being cooled, filtered, and
concentrated under reduced pressure. The resulting yellow oil
was subjected to flash chromatography (silica, 95 : 5 - 90 : 10
v/v dichloromethane/ammonia-saturated methanol gradient
elution) and concentration of the relevant fractions (Rf 0.3 in
90 : 10 v/v dichloromethane/ammonia-saturated methanol) gave
an unstable oil (30 mg), a portion of which crystallised on
standing. A crystal of this material was subjected to single-
crystal X-ray analysis and this revealed it to be compound 24.
The very small quantities of compound 24 obtained by this
means precluded the acquisition of any other spectral data.
(3aS,12cS)-1,2,3,3a,4,12c-Hexahydro-[1,3]dioxolo
[40,50:6,7]isochromeno[3,4-g]indole-5,7-dione (21)
Manganese dioxide (455 mg, 5.2 mmol, 15 mol equiv.) was
added in one portion to a magnetically stirred solution of alcohol
20 (105 mg, 0.35 mmol) in dichloromethane (25 mL). The
ensuing mixture was heated to 308C for 22 h while being
maintained under a nitrogen atmosphere then cooled to 188C
before being filtered through a pad of CeliteTM. The filtrate was
concentrated under reduced pressure and the resulting brown oil
subjected to flash chromatography (silica, ,2–3 % v/v ammo-
nia-saturated methanol/dichloromethane). Concentration of the
appropriate fractions (Rf 0.5) gave compound 21 (81 mg, 78 %)
as a white solid, mp 142–1438C. [a]2D0 þ88.8 (c 1.0, CDCl3).
Found: m/z 300.0871 (M þ H)þ; C16H13NO5 requires 300.0872
(M þ H)þ. dH (400 MHz, CDCl3) 7.67 (s, 1H), 7.42 (s, 1H), 6.16
(m, 2H), 4.30 (d, J 4.0, 1H), 3.32 (m, 1H), 3.15 (m, 1H), 2.90
(m, 1H), 2.73–2.62 (complex m, 2H), 2.20 (m, 1H), 1.84 (broad
s, 1H), 1.71 (m, 1H). dC (100 MHz, CDCl3) 188.7, 159.3, 153.9,
150.5, 143.1, 132.5, 124.6, 119.3, 108.3, 104.7, 102.8, 56.0,
46.2, 39.3, 37.4, 31.5. nmax (KBr)/cmꢀ1 3349, 2931, 2876, 1714,
1677, 1501, 1484, 1416, 1322, 1274, 1254, 1145, 1026. m/z
(ESI, þve) 621 ([2M þ Na]þ, 77 %), 599 ([2M þ H]þ, 99), 322
([M þ Na]þ, 46), 300 ([M þ H]þ, 80), 283 (100).
(3aS,5R,12cS)-5-Hydroxy-2,3,3a,4,5,12c-hexahydro-
[1,3]dioxolo-[40,50:6,7]isochromeno[3,4-g]indol-
7(1H)-one [(þ)-2, (þ)-Narseronine]
A magnetically stirred solution of alcohol 22 (18.6 mg,
0.06 mmol) in dry THF (2 mL) maintained at 08C under a
nitrogen atmosphere, was treated, in portions, with potassium
hydride (32 mg of a 30 % dispersion in mineral oil, 0.24 mmol,
4.0 mol equiv.) and then with methyl iodide (30 mL, 0.48 mmol,
8.0 mol equiv.) After a further 4 h the reaction mixture was
quenched with NH4Cl (2mL of a saturated aqueous solution)
and the separated aqueous phase extracted with dichloromethane
(3ꢂ 10mL). The combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The light-
yellow oil thus obtained was subjected to flash chromatography
(silica, 95: 5 v/v, dichloromethane/ammonia-saturated methanol

246
S. Yang et al.
elution) and concentration of the appropriate fractions (Rf 0.4)
gave (þ)-narseronine [(þ)-2] (16.8 mg, 83 %) as a white,
crystalline solid, mp 165–1668C [lit.[8] for (ꢀ)-enantiomer
167–1688C]. [a]2D0 þ21.0 (c 0.3, CHCl3). Found: m/z 330.1342
(M þ H)þ; C18H19NO5 requires 330.1341 (M þ H)þ. dH
(400 MHz, CDCl3) 7.67 (s, 1H), 7.28 (s, 1H), 6.13 (m, 2H),
4.22 (t, J 6.0, 1H), 3.82 (broad s, 1H), 3.57 (s, 3H), 3.07 (m, 1H),
2.78 (m, 1H), 2.64 (m, 1H), 2.44 (s, 3H), 2.25–2.10 (complex m,
2H), 2.01 (m, 1H), 1.90 (m, 1H). dC (100 MHz, CDCl3) 161.5,
153.7, 152.7, 148.3, 135.2, 116.4, 108.5, 107.8, 103.3, 102.4,
75.0, 62.0, 58.2, 54.3, 42.1, 35.0, 31.4, 29.5. nmax (KBr)/cmꢀ1
3449, 2927, 1718, 1623, 1502, 1482, 1413, 1282, 1256, 1161,
1102, 1035. m/z (ESI, þve) 352 ([M þ Na]þ, 8 %), 330 ([M þ
using the CRYSTALS program package.[21] Atomic coordinates,
bond lengths and angles, and displacement parameters have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC nos. 1020370, 944982, 948651, and 1017935 for com-
pounds (þ)-2, 20, 22, and 24, respectively). These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
Supplementary Material
The anisotropic displacement ellipsoid plots derived from the
single-crystal X-ray structures of compounds (þ)-2, 20, 22, and
24 together with 1H and 13C NMR spectra of compounds (þ)-2,
19, 20, 21, and 22 are available on the Journal’s website.
1
H]þ, 100), 298 (20). The H NMR, 13C NMR, and infrared
spectral data presented above were in good agreement with
those reported for the natural product[7] and for the synthetically
derived (ꢀ)-narseronine.[8] The only minor discrepancy was
observed in the 13C NMR spectra. In particular, the signal
reported at 111.5 ppm in the spectrum of the synthetically
derived (ꢀ)-enantiomer was replaced by one at 108.5 ppm in
that of (þ)-2. This difference is attributed to the differing
acidities of the media in which the samples were analysed.
Acknowledgements
We thank the Australian Research Council and the Institute of Advanced
Studies for generous financial support. The very useful ongoing advice
provided by Dr Brett Schwartz is gratefully acknowledged.
References
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