A highly stereoselective synthesis of the indolo[2,3-a]quinolizine ring system and application to natural product synthesis

Article abstract of DOI:10.1002/ejoc.200500412

We present a facile and highly stereoselective approach to the indolo[2,3-a]quinolizine ring system from a readily available, non-racemic chiral template. We demonstrate the potential for application of this methodology to natural product synthesis throug

Full text of DOI:10.1002/ejoc.200500412

FULL PAPER
A Highly Stereoselective Synthesis of the Indolo[2,3-a]quinolizine Ring System
and Application to Natural Product Synthesis
Steven M. Allin,*[a] Christopher I. Thomas,[a] James E. Allard,[a] Kevin Doyle,[b] and
Mark R. J. Elsegood[a]
Keywords: Natural products / Heterocycles / Lactams / Asymmetric synthesis
We present a facile and highly stereoselective approach to
sentative indole alkaloids with high enantiomeric purity in
the indolo[2,3-a]quinolizine ring system from a readily avail- both enantiomeric series.
able, non-racemic chiral template. We demonstrate the po-
tential for application of this methodology to natural product
synthesis through conversion of the template to some repre-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
The indolo[2,3-a]quinolizine ring system 1 is of great precursor in a stereoselective approach to the indolo[2,3-a]
interest and significance since this heterocyclic template is quinolizine ring system.
found within a plethora of highly bioactive indole alkaloids,
Our approach to the synthesis of the required bicyclic
including geissoschizine (2),[1] vellosimine (3)[2] and ajmalic- lactam substrate 5 followed the general method previously
ine (4).[3] The presence of the lactam carbonyl in templates used in our group.[8] The β-amino alcohol derivative of (S)-
such as 1 would allow for possible further functionalisation tryptophan was reacted under Dean–Stark conditions in
en route to the natural product targets. Recent approaches toluene with an appropriate functionalised substrate for
to the construction of this heterocyclic target system by 48 h (Scheme 1). Under these reaction conditions we were
other groups have included the diastereoselective vinylog- able to isolate the expected bicyclic lactam in 69% yield as
ous Mannich reaction,[4] Bischler–Napieralski reaction,[5] a 5:1 mixture of separable diastereoisomers, 5a and 5b.
Fischer indole synthesis[6] and the asymmetric Pictet–
Spengler reaction.[7]
The relative stereochemistry of the major diastereoiso-
mer 5a was determined by single-crystal X-ray analysis.[9]
We have recently developed a new and general approach This indole-containing bicyclic lactam is a novel example
for the stereoselective synthesis of a range of non-racemic of the fused 5,6-ring system favoured by Amat and
heterocycles that involves the cyclisation of pendent aro- Bosch,[10] and the relative stereochemistry observed for the
matic substituents onto N-acyliminium intermediates as the major isomer 5a is consistent with results obtained both by
key ring-forming step.[8] Based on our novel approach to these researchers and in our own previous work in other
the indolizino[8,7-b]indole ring system,[8a] we recognised areas.[8b]
that a suitably substituted bicyclic lactam could act as a
In a previous communication we noted briefly that treat-
ment of the initial mixture of diastereoisomers of substrate
5 with TiCl4 gave the desired indolo[2,3-a]quinolizine target
6 in 54% yield, but with only a poor level of product dia-
stereoselectivity (5:2).[8a] We have since discovered that sim-
[a] Department of Chemistry, Loughborough University,
Loughborough, Leicestershire, LE11 3TU, England
E-mail: s.m.allin@lboro.ac.uk
[b] OSI Pharmaceuticals,
Watlington Road, Oxford, OX4 6LT, England
Eur. J. Org. Chem. 2005, 4179–4186
DOI: 10.1002/ejoc.200500412
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J. Elsegood
FULL PAPER
Scheme 1.
ply treating the mixture of bicyclic lactam substrate dia-
Our previous method to remove the hydroxymethyl
stereoisomers, 5a and 5b, with 2  HCl in ethanol at room group from templates such as 7 has involved a rhodium-
temperature for 20 hours gives an excellent yield of 95% for induced decarbonylation sequence.[8a] Due to the rather
the cyclisation reaction, and leads to the formation of the long reaction times generally needed for our substrates in
desired indolo[2,3-a]quinolizine product as a single dia- this protocol we have now applied an easier approach that
stereoisomer (Scheme 2).
relies upon a decarboxylation strategy. Compound 7 was
oxidised to the carboxylic acid derivative 8 through the cor-
responding aldehyde; from 8 we generated the acyl selenide
derivative and subsequently performed a tin-mediated deac-
ylation to yield the indolo[2,3-a]quinolizine ring system 9.
Deprotection of the indole nitrogen gave the known com-
pound (S)-10 in Ͼ95% ee by comparison of optical rotation
data.[12a] Reductive removal of the lactam carbonyl group
completed the synthesis of the natural product. Target (S)-
(–)-11 was found to have an ee of 95% and the same abso-
lute configuration as the natural product by comparison of
optical rotation data.[12b]
In order to further extend the application of our method-
ology we chose to pursue the synthesis of deplancheine, 14,
an alkaloid isolated from the New Caledonian plant Al-
stonia deplanchei.[13] As a consequence of the work of Mey-
ers in 1986 that described an asymmetric approach to de-
plancheine, the absolute configuration of the natural pro-
duct was determined to be R.[13a]
Scheme 2.
The relative stereochemistry of the single diastereoisomer
6 was determined by single-crystal X-ray analysis[9] and was
found to be as favoured in the TiCl4-mediated cyclisation
reaction that had previously given only a 5:2 ratio of pro-
duct diastereoisomers.
To highlight the synthetic utility of this methodology in
the target synthesis of complex indole alkaloids and their
synthetic analogues, we undertook the synthesis of a simple
indole alkaloid, (S)-(–)-1,2,3,4,6,7,12,12b-octahydroin-
dolo[2,3-a]quinolizine (11), the main constituent of Dracon-
tomelum mangiferum B1.[11] In order to access the natural
A successful synthesis of deplancheine would require us
(S)-enantiomer of the target we were required to work with to further functionalise the lactam ring of the template.
the enantiomer of the template. Hence compound 7 was Construction of the requisite ethylidene moiety was
prepared as a single diastereoisomer from (R)-tryptophan achieved through a three-step procedure involving genera-
by analogous chemistry to that described above. Our syn- tion of the lithium enolate from (R)-9, prepared by analo-
thetic route to the natural product 11 from 7 is highlighted gous chemistry to that described in Scheme 3 but starting
in Scheme 3.
from (S)-tryptophan. Subsequent aldol reaction with acet-
Scheme 3. (i) 1-Hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX), DMSO, room temp., 24 h (60%); (ii) Et3N, (Boc)2O, DMAP, THF,
room temp., 4 h (63%); (iii) NaClO2, NaH2PO4, 1-methyl-1-cyclohexene, CH3CN, tBuOH, H2O, 0 °C to room temp., 18 h (70%); (iv)
(PhSe)2, PBu3, CH2Cl2, 0 °C to room temp., 18 h (66%); (v) nBu3SnH, AIBN, toluene, 80 °C, 2 h (98%); (vi) TBAF, THF, ∆, 9 h (63%);
(vii) LiAlH4, THF, ∆, 3 h then room temp., 12 h (96%).
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Stereoselective Synthesis of the Indolo[2,3-a]quinolizine Ring System
FULL PAPER
Scheme 4. Asymmetric synthesis of deplancheine: (i) LDA, CH3CHO, THF, –78 °C to room temp., 24 h; (ii) Et3N, MsCl, DCM, –40 °C
to room temp., 3 h; (iii) DBN, THF, room temp., 16 h (65% for 3 steps); (iv) TBAF, THF, ∆, 9 h (63%); (v) Me3OBF4, 2,6-di-tBu-Py,
DCM, room temp., 21 h; (vi) NaBH4, MeOH, 0 °C, 0.5 h (77% for 2 steps).
aldehyde, activation of the hydroxy group by mesylation ture of the product (R)-14 was obtained and is presented
and finally DBN-induced elimination gave the initial target Figure 1.
12 (Scheme 4). We found that whereas a THF/DCM solvent
The crystals were obtained by slow evaporation of a
mixture in the elimination step gave only a 4.7:1 ratio in dichloromethane solution of the compound. The asymmet-
favour of the desired E-isomer 12, if the elimination pro- ric unit comprises two molecules of 14 and one molecule of
cedure was carried out in THF alone as solvent the E-re- water. The water molecule links together three molecules of
gioisomer of the ethylidene product 12 was obtained exclu- 14 by strong H bonds, while the NH on N(27) forms a weak
sively.[14] TBAF-induced deprotection of the indole nitrogen N–H···π interaction to the ring C(22B)–C(26) on a sym-
atom liberated the lactam intermediate 13.[15]
metry related molecule.
The synthesis of (R)-deplancheine was completed
To demonstrate the potential synthetic utility of our
through removal of the lactam carbonyl group as described methodology we have also undertaken an asymmetric syn-
in Scheme 4 through application of a route described by thesis of the enantiomer of deplancheine. Our route mirrors
Martin and co-workers.[16] The desired target, (R)-(+)-de- that described in Scheme 4, but uses the (R)-enantiomer of
plancheine (14), was obtained with an ee of Ͼ95% and the tryptophan as the starting material. The desired target, (S)-
same absolute configuration as the natural product by com- (–)-deplancheine (Scheme 4), was isolated with an ee of
parison of optical rotation data.[13a] An X-ray crystal struc- Ͼ95% by comparison of optical rotation data.[13a]
Figure 1. X-ray crystal structure of (R)-14.
Eur. J. Org. Chem. 2005, 4179–4186
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J. Elsegood
Minor Isomer (3S,8aR)-5b: Isolated as a pale yellow oil. [α]D
FULL PAPER
=
In summary, we report a facile and highly stereoselective
approach to the important indolo[2,3-a]quinolizine tem-
plate from readily available non-racemic substrates, and
have demonstrated the structural modification of the tem-
plate to deliver indole alkaloids with high enantiomeric pu-
rity in both enantiomeric series. Current work is focused on
extending the methodology described in this paper to other,
more complex indole alkaloid targets. Our progress will be
reported in due course.
+14.3 (c = 2.0, CH2Cl2) C16H18N2O2: calcd. C 71.09, H 6.71, N
10.36; found C 70.97 H, 6.69, N 10.35. IR (thin film, DCM, cm–1):
ν
=3279 (NH), 1628 (NC=O). 1H NMR (400 MHz, CDCl3):
˜
max
1.33–1.42 [m, 1 H, CH(H)CH2CH2C=O], 1.51–1.59 [m, 1 H,
CH2CH(H)CH2C=O], 1.80–1.88 [m, 1 H, CH2CH(H)CH2C=O],
2.14–2.18 [m, 1 H, CH(H)CH2CH2C=O], 2.27–2.37 [m, 1 H,
CH(H)C=O], 2.53 [dd, J = 16, 8 Hz, CH(H)C=O, 1 H], 3.05 [dd,
J = 16, 8 Hz, CH(H)C=C, 1 H], 3.32 [dd, J = 16, 4 Hz, 1 H, CH(H)
C=C], 3.69 [dd, J = = 8.8, 7.2 Hz, 1 H, CH(H)O], 4.04–4.09 [m, 1
H, CH(H)O], 4.46 (dd, J = 8, 4 Hz, 1 H, NCHOCH2), 4.60–4.67
(m, 1 H, NCHCH2O), 7.01 (d, J = 4 Hz, 1 H, C=CHNH), 7.10–
7.14 (m, 1 H, ArH), 7.17–7.21 (m, 1 H, ArH), 7.36 (d, J = 8 Hz, 1
H, ArH), 7.69 (d, J = 8 Hz, 1 H, ArH), 8.34 (br. s, 1 H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.2 (CH2), 27.6 (CH2), 28.2
(CH2), 31.4 (CH2), 54.5 (CH), 69.7 (CH2), 87.3 (CH), 111.1 (CH),
111.2 (C), 119.2 (CH), 119.5 (CH), 122.2 (CH), 122.6 (CH), 127.8
(C), 136.3 (C), 168.8 (NC=O) ppm. MS (EI): m/z (%) = 270 (23.3)
[M+] (found: M+, 270.13690. C16H18N2O2 requires 270.13683).
Experimental Section
General Information: Solvents and Reagents: All solvents where
necessary were dried, distilled and stored over 4-Å molecular sieves
prior to use. IBX = 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide.
Chromatographic Procedures: Analytical thin-layer chromatog-
raphy (TLC) was carried out using aluminium-backed plates coated
with silica (0.2 mm). Plates were visualised under UV light (λ =
254 nm) or by staining with either potassium permanganate solu-
tion or PMA (phosphomolybdic acid). Flash column chromatog-
raphy was carried out using Merck Kieselgel (70–230 Mesh
ASTM). Samples were applied as saturated solutions in an appro-
priate solvent or pre-adsorbed onto the minimum quantity of silica.
Hand bellows were used to apply pressure when required at the
column. Spectra: IR spectra were recorded in the range from 4000
to 600 cm–1. Solid samples were run as nujol mull, and liquids as
thin films. Nuclear Magnetic Resonance (NMR) spectra: Multi-
plicities were recorded as broad peaks (br.), singlets (s), doublets
(d), triplets (t), double doublets (dd) and multiplets (m). All NMR
samples were made up in deuterated chloroform with all values
quoted in ppm relative to tetramethylsilane as internal reference.
Coupling constants (J values) are reported in Hertz (Hz). Dia-
stereoisomer ratios were calculated from the integration of suitable
peaks in the proton NMR spectroscopy.
(6S,12bR)-1,2,3,6,7,12b-Hexahydro-6-(hydroxymethyl)indolo[2,3-a]-
quinolizin-4(12H)-one (6): Compound 5a (3.1 g, 11.5 mmol) was
dissolved in absolute ethanol (100 mL) under nitrogen. The re-
sulting solution was acidified to pH 1 by the addition of 2  HCl
in ethanol, and the mixture was stirred for a further 20 hours at
room temperature. After this time the reaction was quenched by
addition of saturated aqueous sodium hydrogencarbonate and ex-
tracted with ethyl acetate (3×150 mL). The organic fraction was
dried with anhydrous magnesium sulfate and the solvent removed
by rotary evaporation to yield a light brown solid (2.9 g, 95%).
1
250 MHz H NMR spectroscopy on the crude product mixture re-
vealed formation of 6 as a single diastereoisomer, which was recrys-
tallised from absolute ethanol to yield the target compound as
colourless block-like crystals, m.p. 288–290 °C. [α]D = +128.8 (c =
0.50, EtOH). C16H18N2O2: calcd. C 71.09, H 6.71, N 10.36; found
C 70.75, H 6.67, N 10.28. IR (thin film, DCM, cm–1): νmax = 3277
˜
(NH), 1618 (NC=O). 1H NMR (400 MHz, DMSO): δ = 1.52–1.62
(m, 1 H), 1.73–1.86 (m, 2 H), 2.26–2.43 (m, 2 H), 2.59–2.63 (m, 1
H), 2.66 (dd, J = 16, 8 Hz, 1 H), 2.80 (d, J = 16 Hz, 1 H), 3.35–
3.37 (m, 2 H), 4.65 (d, J = 8 Hz, 1 H), 4.81 (t, J = 4 Hz, 1 H), 5.22
(q, J = 7.5 Hz, 1 H), 6.95–6.99 (m, 1 H), 7.04–7.08 (m, 1 H), 7.32
(d, J = 8 Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H), 10.09 (br. s, 1 H) ppm.
13C NMR (100 MHz; DMSO): δ = 19.4 (CH2), 21.0 (CH2), 29.0
(CH2), 32.7 (CH2), 48.2 (CH), 50.6 (CH), 60.2 (CH2), 105.1 (C),
111.4 (CH), 118.1 (CH), 118.8 (CH), 121.3 (CH), 127.1 (C), 133.7
(C), 136.7 (C), 168.8 (NC=O) ppm. MS (EI): m/z (%) = 270 (100)
[M+] (found: M+, 270.13626. C16H18N2O2 requires 270.13683).
3-([1H-Indol-3-yl]methyl)hexahydrooxazolo[3,2-a][1,3]pyridin-5-one
(5): (2S)-2-Amino-3-(1H-indol-3-yl)propan-1-ol (3.0 g, 15.8 mmol)
and methyl 5-oxopentanoate (2.1 g, 15.8 mmol) were added to tolu-
ene (150 mL) and refluxed under Dean–Stark conditions for
48 hours. The mixture was cooled to room temperature and the
solvent removed under reduced pressure to yield the target com-
pound. 250 MHz 1H NMR spectroscopy on the crude product mix-
ture revealed the formation of 5 as a 5:1 mixture of diastereoiso-
mers. These diastereoisomers were purified and separated by flash
column chromatography over silica using ethyl acetate as eluent
(2.90 g, 69%).
Three-Step Route to Access 8
Major Isomer (3S,8aS)-5a: Isolated as a yellow solid which was
recrystallized from dichloromethane to yield colourless needles;
(6R,12bS)-1,2,3,4,6,7,12,12b-Octahydro-4-oxoindolo[2,3-a]quinol-
M.p. 152–156 °C. [α]D = –39.1 (c = 1.7, CH2Cl2). C16H18N2O2: izine-6-carbaldehyde: To a solution of 7 (5.0 g, 18.5 mmol) in di-
calcd. C 71.09, H 6.71, N 10.36; found C 71.04, H 6.69, N 10.27.
methyl sulfoxide (40 mL) was added IBX (15.4 g, 55.5 mmol) with
stirring under nitrogen. After 24 hours stirring at room temperature
the solvent was removed and the resulting solid was re-suspended
1
IR (thin film, DCM, cm–1): ν
= 3274 (NH), 1628 (NC=O). H
˜
max
NMR (400 MHz, CDCl3): δ = 1.43–1.57 (m, 1 H), 1.67–1.77 (m, 1
H), 1.96–2.01 (m, 1 H), 2.24–2.28 (m, 1 H), 2.41–2.45 (m, 2 H), in ethyl acetate (250 mL), before filtering through a small pad of
2.68 (dd, J = = 16, 8 Hz, 1 H), 3.67–3.76 (m, 2 H), 4.03 (d, J =
8 Hz, 1 H), 4.28–4.33 (m, 1 H), 4.68 (dd, J = 12, 4 Hz, 1 H), 7.03
celite. The filtrate was washed with water (3×250 mL), the organic
phase was then dried with anhydrous magnesium sulfate, filtered
(d, J = 4 Hz, 1 H), 7.05–7.22 (m, 2 H), 7.36 (d, J = 8 Hz, 1 H), and the solvents evaporated to dryness to yield the target com-
7.82 (d, J = 8 Hz, 1 H), 8.24 (br. s, 1 H) ppm. 13C NMR (100 MHz,
pound which was purified by flash column chromatography over
CDCl3): δ = 17.6 (CH2), 27.0 (CH2), 28.4 (CH2), 31.1 (CH2), 56.1 silica using ethyl acetate as eluent. The purified aldehyde was af-
(CH), 70.0 (CH2), 89.0 (CH), 111.1 (CH), 112.6 (C), 119.4 (CH),
119.6 (CH), 122.2 (CH), 122.4 (CH), 127.7 (C), 136.2 (C), 168.1
(NC=O) ppm. MS (EI): m/z (%) = 270 (100) [M+] (found: M+,
270.13690. C16H18N2O2 requires 270.13683).
forded as a pale yellow foam (3.0 g, 60%), m.p. 97.5–99 °C. [α]D
= –201.3 (c = 1.2, CH Cl ). IR (thin film, DCM, cm–1): ν
=
˜
max
2
2
3271 (NH), 1727 (CHO), 1617 (NBoc[C=O]). 1H NMR (400 MHz,
CDCl3): δ = 1.66–1.77 [m, 1 H, CH(H)CH2CH2C=O], 1.99–2.05
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Stereoselective Synthesis of the Indolo[2,3-a]quinolizine Ring System
FULL PAPER
= 3379 (OH), 1640 (NC=O). H NMR (400 MHz, CDCl3): δ
= 1.34–1.40 [m, 1 H, C=CCHCH(H)], 1.64 [s, 9 H, OC(CH3)3],
1.82–1.91 (m, 2 H, CH2CH2C=O), 2.45–2.62 [m, 1 H, CH(H)
1
(m, 2 H, CH2CH2C=O), 2.40–2.48 [m, 1 H, CH(H)CH2CH2C=O],
2.49–2.54 [m, 1 H, CH(H)C=O], 2.69–2.76 [m, 1 H, CH(H)C=O],
3.10 [ddd, J = 16, 8, 4 Hz, 1 H, CH(H)CHCHO], 3.41–3.47 [m, 1
ν
˜
max
H, CH(H)CHCHO], 4.89–4.93 (m, 1 H, C=CCH), 5.97–5.99 (m, 1 C=O], 2.45–2.62 [m, 1 H, C=CCHCH(H)], 2.45–2.62 [m, 1 H,
H, CHCHO), 7.11–7.24 (m, 2 H, ArH), 7.30–7.32 (m, 1 H, ArH), CH(H)C=O], 2.83–2.89 [m, 1 H, C=CCH(H)], 3.35–3.41 [m, 1 H,
7.53–7.55 (m, 1 H, ArH), 8.15 (br. s, 1 H, NH), 9.49 (s, 1 H, CHO) C=CCH(H)], 5.33–5.36 (m, 1 H, C=CCH), 5.98–6.0 (m, 1 H,
ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5 (CH2), 20.0 (CH2), NCHCO2H), 7.18–7.28 (m, 2 H, ArH), 7.39–7.41 (m, 1 H, ArH),
29.6 (CH2), 32.0 (CH2), 52.2 (CH), 56.8 (CH), 106.4 (C), 111.1
(CH), 118.3 (CH), 120.0 (CH), 122.6 (CH), 126.5 (C), 132.7 (C), NMR (100 MHz, CDCl3): δ = 19.0 (CH2), 23.2 (CH2), 28.2
8.03 (d, J = 8 Hz, 1 H, ArH), 8.80 (br. s, 1 H, CO2H) ppm. 13C
136.5 (C), 170.4 (NC=O), 199.3 (CHO) ppm. MS (EI): m/z (%)
= 268 (75.9) [M+], (found: M+, 268.12130. C16H16N2O2 requires
268.12118).
(3×CH3), 30.4 (CH2), 31.3 (CH2), 49.8 (CH), 54.1 (CH), 84.4 (C),
115.0 (C), 115.7 (CH), 118.4 (CH), 123.0 (CH), 124.8 (CH), 128.4
(C), 133.9 (C), 136.8 (C), 149.9 [NC(O)OtBu], 172.1 (NC=O), 173.0
[C(O)OH] ppm. MS (EI): m/z (%) = 384 (2) [M+] (found: M+,
384.16768. C21H24N2O5 requires 384.16852).
(6R,12bS)-tert-Butyl-6-formyl-1,2,3,4,6,7-hexahydro-4-oxoindolo-
[2, 3-a]quinolizine-12(12bH)-carboxylate: (6R,12bS)-
1,2,3,4,6,7,12,12b-octahydro-4-oxoindolo[2,3-a]quinolizine-6-carb-
aldehyde (3.5 g, 13.1 mmol) was dissolved in anhydrous tetra-
hydrofuran (40.0 mL) under nitrogen. Triethylamine (3.7 mL,
26.2 mmol). 4-(Dimethylamino)pyridine (0.35 g, 2.7 mmol) and di-
tert-butyl dicarbonate (3.8 g, 17.1 mmol) were added successively,
and the resulting solution was stirred at room temperature under
nitrogen for 4 hours. After this time the volatiles were removed by
rotary evaporation and the resulting residue was re-dissolved in
ethyl acetate (200 mL) and washed successively with saturated
aqueous ammonium chloride (2×200 mL), saturated aqueous so-
dium hydrogencarbonate (2×200 mL) and brine (200 mL). The or-
ganic layer was dried with anhydrous magnesium sulfate, the sol-
vent removed under rotary evaporation and the crude product was
adsorbed onto silica and purified by flash column chromatography
over silica using ethyl acetate/hexane (3:2) as eluent. The product
was isolated as a yellow oil (2.6 g, 63%). [α]D = –925.3 (c = 3.0,
Radical-Induced Decarboxylation Strategy
(6R,12bS)-tert-Butyl-1,2,3,4,6,7-hexahydro-4-oxo-6-[(phenylselan-
yl)carbonyl]indolo[2,3-a]quinolizine-12(12bH)-carboxylate: To a
flask containing compound 8 (1.9 g, 4.95 mmol) under nitrogen
was added anhydrous dichloromethane (30.0 mL) followed by di-
phenyl diselenide (2.4 g, 7.5 mmol). The resulting mixture was co-
oled to 0 °C and tributylphosphane (90 % grade) (3.1 mL,
10.1 mmol) was added dropwise. The solution was warmed to room
temperature and stirring continued for a further 18 hours at room
temperature. Dichloromethane (100 mL) and water (100 mL) were
added and the aqueous layer was extracted with a further (100 mL)
of dichloromethane. The combined organic fractions were washed
with brine (100 mL), dried with anhydrous magnesium sulfate and
the solvents evaporated to dryness to give the crude product which
was purified by flash column chromatography over silica eluting
with hexane/ethyl acetate (8:2), then ethyl acetate/hexane (3:2) giv-
ing the title compound as a pale yellow foam (1.72 g, 66%), m.p.
75–77 °C. [α]D = –84 (c = 1.0, CH2Cl2). IR (thin film, DCM, cm–1):
CH Cl ). IR (thin film, DCM, cm–1): ν
= 1729 (CHO), 1653
˜
max
2
2
(NBoc[C=O]). 1H NMR (400 MHz, CDCl3): δ = 1.41–1.50 [m, 1
H, C=CCHCH(H)], 1.67 [s, 9 H, OC(CH3)3], 1.96–2.04 (m, 2 H,
CH2CH2C=O), 2.50–2.59 [m, 1 H, CH(H)C=O], 2.61–2.65 [m, 1
H, C=CCHCH(H)], 2.71–2.78 [m, 1 H, CH(H)C=O], 2.96 [ddd, J
= 16, 8, 4 Hz, 1 H, C=CCH(H)], 3.35–3.40 [m, 1 H, C=CCH(H)],
5.26–5.29 (m, 1 H, C=CCH), 5.92–5.94 (m, 1 H, NCHCHO), 7.24–
7.34 (m, 2 H, ArH), 7.47–7.49 (m, 1 H, ArH), 8.04–8.06 (m, 1 H,
ArH), 9.52 (s, 1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.3 (CH2), 20.5 (CH2), 28.4 (3×CH3), 30.6 (CH2), 31.7 (CH2), 54.0
(CH), 56.1 (CH), 84.6 (C), 114.7 (C), 115.7 (CH), 118.2 (CH), 123.1
(CH), 125.0 (CH), 128.1 (C), 134.5 (C), 136.9 (C), 149.8 [NC(O)
OtBu], 170.9 (NC=O), 199.1 (CHO) ppm. MS (EI): m/z (%) = 368
(54.1) [M+] (found: M+, 368.17367. C21H24N2O4 requires
368.17361).
ν
˜
= 1729 (COSePh), 1654 (NC=O). 1H NMR (400 MHz,
max
CDCl3): δ = 1.44–1.54 [m, 1 H, C=CCHCH(H)], 1.70 [s, 9 H,
OC(CH3)3], 1.95–2.11 (m, 2 H, CH2CH2C=O), 2.60–2.68 [m, 1 H,
C=CCHCH(H)], 2.60–2.68 [m, 1 H, CH(H)C=O], 2.78–2.85 [m, 1
H, CH(H)C=O], 2.87–2.93 [m, 1 H, C=CCH(H)], 3.47–3.52 [m, 1
H, C=CCH(H)], 5.56–5.59 (m, 1 H, NCHCOSePh), 6.15–6.17 (m,
1 H, ArH), 7.24–7.32 (m, 5 H, ArH), 7.39–7.40 (m, 2 H, ArH),
7.43–7.46 (m, 1 H, ArH), 8.03–8.06 (m, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.0 (CH2), 22.4 (CH2), 28.3 (3×CH3),
31.1 (CH2), 31.8 (CH2), 54.1 (CH), 59.6 (CH), 84.5 (C), 114.8 (C),
115.7 (CH), 118.4 (CH), 123.1 (CH), 124.9 (CH), 125.4 (C), 128.3
(C), 128.9 (CH), 129.2 (2×CH), 133.5 (C), 136.0 (2×CH), 136.8
(C), 149.9 [NC(O)OtBu], 171.6 (NC=O), 200.3 (COSePh) ppm. MS
(CI): m/z (%) = 525 (6.7) [MH+] (found: MH+, 525.13013.
C27H29N2O4Se requires 525.12925).
(6R,12bS)-12-(tert-Butoxycarbonyl)-1,2,3,4,6,7,12,12b-octahydro-4-
oxoindolo[2,3-a]quinolizine-6-carboxylic Acid (8): A solution of
(6R,12bS)-tert-butyl-6-formyl-1,2,3,4,6,7-hexahydro-4-oxoindolo-
[2,3-a]quinolizine-12(12bH)-carboxylate (2.6 g, 7.1 mmol) in aceto-
nitrile (35.0 mL), tert-butyl alcohol (130.0 mL) and 1-methyl-1-cy-
clohexene (63.0 mL) was stirred rapidly as it was cooled to 0 °C. A
solution of sodium chlorite (80% grade) (6.3 g, 54.7 mmol) and
(12bS)-tert-Butyl-1,2,3,4,6,7-hexahydro-4-oxoindolo[2,3-a]quinol-
izine-12(12bH)-carboxylate (9): A three-necked flask fitted with a
condenser, glass stopper and a suba seal was flushed with nitrogen.
A solution of (6R,12bS)-tert-butyl1,2,3,4,6,7-hexahydro-4-oxo-6-
sodium dihydrogen phosphate (6.3 g, 49.7 mmol) in water [(phenylselanyl)carbonyl]indolo[2,3-a]quinolizine-12(12bH)-carb-
(130.0 mL) was added dropwise over a period of 10 minutes at 0 °C.
The solution was then stirred at room temperature for a further
18 hours. After this time the reaction was partitioned between ethyl
acetate (300 mL) and brine (200 mL). The ethyl acetate layer was
oxylate (1.7 g, 3.2 mmol) in anhydrous toluene (20.0 mL) was
added through a cannula. The solution was then degassed with
nitrogen for 15 minutes before adding tri-n-butyltin hydride
(3.5 mL, 13.2 mmol) via syringe. The resulting mixture was heated
then washed with 1  aqueous sodium dithionite solution to 80 °C in an oil bath whereupon azobis(isobutyronitrile) (0.1 g,
(100 mL). The organic layer was dried with anhydrous magnesium
sulfate and the solvents evaporated to dryness to give the target
compound which was purified by flash column chromatography
over silica eluting with ethyl acetate yielding a yellow oil (1.9 g,
0.6 mmol) was added portionwise over a 2 hour period at 80 °C.
After 2 hours stirring at 80 °C the mixture was cooled to room
temperature and the solvent removed on the rotary evaporator. The
resulting crude oil was adsorbed onto silica and purified by flash
70%). [α]D = –530 (c = 1.0, CH2Cl2). IR (thin film, DCM, cm–1): column chromatography over silica eluting with hexane followed
Eur. J. Org. Chem. 2005, 4179–4186
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4183

S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J. Elsegood
FULL PAPER
by ethyl acetate/hexane (3:1). The target compound was isolated as
a colourless oil (1.1 g, 98%). [α]D = –77.3 (c = 1.8, CH2Cl2). IR
150 °C). [α]D = –79.6 (c = 1.0, MeOH) [ref.[13a] [α]D = –86.5 2 (c
1
= 1.0, MeOH)]. IR (thin film, DCM, cm–1): νmax = 3441 (NH). H
˜
(thin film, DCM, cm–1): ν
= 1732 [NC=O(O)tBu], 1644
N M R ( 4 0 0 M H z , C D C l 3 ) : δ = 1 . 4 0 – 1 . 5 2 [ m , 1 H ,
˜
max
(NC=O). 1H NMR (400 MHz, CDCl3): δ = 1.32–1.42 [m, 1 H, C = C C H C H 2 C H ( H ) ] , 1 . 5 7 [ d d d , J = 2 4 , 1 6 , 4 H z , 1
C=CCHCH(H)], 1.67 [s, 9 H, OC(CH3)3], 1.79–1.86 (m, 2 H,
HC=CCHCH(H)], 1.69–1.77 [m, 2 H, C=CCH(CH2)2CH2], 1.85–
CH2CH2C=O), 2.34–2.43 [m, 1 H, CH(H)C=O], 2.54–2.77 [m, 1 1.89 [m, 1 H, C=CCHCH2 CH(H)], 2.02–2.05 [m, 1 H,
H, C=CCHCH(H)], 2.54–2.77 [m, 1 H, CH(H)C=O], 2.54–2.77 (m,
2 H, CH2CH2N), 2.54–2.77 [m, 1 H, CH(H)N], 5.05–5.15 [m, 1 H,
C=CCHCH(H)], 2.37 [dt, J = 8, 4 Hz, 1 HC=CCH(CH2)3CH(H)
N], 2.58–2.73 [m, 1 H, C=CCH2CH(H)N], 2.58–2.73 [m, 1 H,
CH(H)N], 5.05–5.15 (m, 1 H, C=CCH), 7.18–7.30 (m, 2 H, ArH), C=CCH(H)CH2N], 2.96–3.02 [m, 1 H, C=CCH2CH(H)N], 2.96–
7.37 (d, J = 8 Hz, 1 H, ArH), 8.06 (d, J = 8 Hz, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.5 (CH2), 21.6 (CH2), 28.1
(3×CH3), 30.2 (CH2), 32.1 (CH2), 38.8 (CH2), 56.0 (CH), 84.1 (C),
115.5 (CH), 118.2 (CH), 118.2 (C), 122.9 (CH), 124.5 (CH), 128.6
(C), 135.2 (C), 136.8 (C), 150.1 [NC(O)OtBu], 169.4 (NC=O) ppm.
MS (EI): m/z (%) = 340 (13.8)] [M+] (found: M+, 340.17884.
C20H24N2O3 requires 340.17862).
3.02 [m, 1 H, C=CCH(H)CH2N], 3.02–3.08 [m, 1 H, C=CCH(CH2)
3CH(H)N], 3.21 (d, J = 8 Hz, 1 H, HC=CCH), 7.06–7.15 (m, 2 H,
ArH), 7.28 (d, J = 8 Hz, 1 H, ArH), 7.46 (d, J = 8 Hz, 1 H, ArH),
7.73 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6
(CH2), 24.3 (CH2), 25.7 (CH2), 30.0 (CH2), 53.6 (CH2), 55.7 (CH2),
60.2 (CH), 108.2 (C), 110.7 (CH), 118.1 (CH), 119.4 (CH), 121.3
(CH), 127.5 (C), 135.1 (C), 136.0 (C) ppm. MS (EI): m/z (%) = 226
(72.3) [M+] (found: M+, 226.14700. C15H18N2 requires 226.14700).
(12bS)-1,2,3,6,7,12b-Hexahydroindolo[2,3-a]quinolizin-4(12H)-one
(10): Compound 9 (0.23 g, 0.68 mmol) was dissolved in anhydrous
tetrahydrofuran (10.0 mL) under nitrogen. A 1.0  solution of tet-
rabutylammonium fluoride in tetrahydrofuran (6.8 mL, 6.8 mmol)
was then added, and the mixture was heated under reflux for
9 hours. After this time the mixture was cooled to room tempera-
(12bR)-(E)-tert-Butyl-3-ethylidene-1,2,3,4,6,7-hexahydro-4-oxo-
indolo[2,3-a]quinolizine-12(12b)-carboxylate (12): To a stirred solu-
tion of diisopropylamine (1.3 mL, 8.8 mmol) in anhydrous tetra-
hydrofuran (10.0 mL) was added n-butyllithium (2.5  solution in
hexanes) (3.5 mL, 8.8 mmol) dropwise at 0 °C under nitrogen. The
ture and water (40.0 mL) was added. The mixture was extracted reaction mixture was stirred for 15 min at 0 °C and then cooled
with ethyl acetate (2 ×70.0 mL), and the organic fractions were
dried with anhydrous magnesium sulfate and the solvent removed
on the rotary evaporator. The crude product was adsorbed onto
silica and purified by flash column chromatography over silica
using ethyl acetate as eluent to give the target compound as an off-
to –78 °C whereupon a solution of (12bR)-tert-butyl-1,2,3,4,6,7-
hexahydro-4-oxoindolo[2,3-a]quinolizine-12(12b)-carboxylate (R)-
9 (1.0 g, 2.9 mmol) in anhydrous tetrahydrofuran (15.0 mL) was
added through a cannula. The resulting mixture was stirred for a
further 30 min at –78 °C after which time acetaldehyde (1.6 mL,
29.0 mmol) was added dropwise via syringe. The reaction was
warmed to room temperature overnight and then quenched by the
white solid (0.1 g, 63%), m.p. 238–240 °C. [α]D = –286 (c = 1.0,
1
CHCl3). IR (thin film, DCM, cm–1): ν
= 1651 (NC=O). H
˜
max
NMR (400 MHz, CDCl3): δ = 1.76–1.89 [m, 1 H, CH(H) addition of saturated aqueous ammonium chloride solution
CH2C=O], 1.76–1.89 [m, 1 H, CH(H)CH2CH2C=O], 1.95–2.01 [m,
1 H, CH(H)CH2C=O], 2.36–2.47 [m, 1 H, CH(H)CH2CH2C=O],
2.36–2.47 [m, 1 H, CH(H)C=O], 2.57–2.62 [m, 1 H, CH(H)C=O],
(30.0 mL) and extracted with ethyl acetate (2×50 mL). The com-
bined organic extracts were dried with anhydrous magnesium sul-
fate and the solvent was removed under reduced pressure to yield
2.72–2.82 [m, 1 H, CH(H)CH2N], 2.84–2.89 [m, 1 H, CH(H) a yellow oil. The crude oil was dissolved in anhydrous dichloro-
CH2N], 2.84–2.89 [m, 1 H, CH(H)N], 4.76–4.80 (m, 1 H, C=CCH),
5.14–5.22 [m, 1 H, CH(H)N], 7.11–7.21 (m, 2 H, ArH), 7.33–7.36
(m, 1 H, ArH), 7.51 (d, J = 8 Hz, 1 H, ArH), 7.85 (br. s, 1 H, NH)
methane (15.0 mL) under nitrogen. Triethylamine (1.2 mL,
8.7 mmol) was added and the mixture cooled to –40 °C before add-
ing methanesulfonyl chloride (0.34 mL, 4.4 mmol). After 20 min-
ppm. 13C NMR (100 MHz, CDCl3): δ = 19.4 (CH2), 21.0 (CH2), utes stirring at –40 °C the reaction was warmed to room tempera-
29.1 (CH2), 32.5 (CH2), 40.1 (CH2), 54.4 (CH), 109.8 (C), 110.9 ture and stirred for an additional 3 hours. After this time the sol-
(CH), 118.5 (CH), 119.9 (CH), 122.2 (CH), 127.0 (C), 133.3 (C), vent was removed and the mesylate dissolved in anhydrous tetra-
136.2 (C), 169.1 (NC=O) ppm. MS (EI): m/z (%) = 240 (100.0) hydrofuran (35.0 mL) to which 1,5-diazabicyclo[4.3.0]non-5-ene
[M+] (found: M+, 240.12632. C15H16N2O requires 240.12626).
(1.1 mL, 8.7 mmol) was added and stirred at room temperature for
16 hours. The solvent was removed and the residue re-dissolved in
dichloromethane (80 mL) which was washed with saturated aque-
ous ammonium chloride solution (60 mL). The organic fraction
was dried with anhydrous magnesium sulfate and the solvents evap-
orated to dryness to give the crude product. 250 MHz 1H NMR
spectroscopy of the crude product revealed formation of the pro-
duct as a single trans geometrical isomer which was purified by
flash column chromatography over silica using hexane/ethyl acetate
(5:1) as eluent (0.70 g, 65%).
(12bS)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine (11):
Lithium aluminium hydride (0.07 g, 1.68 mmol) was weighed into a
pre-dried three-necked flask fitted with a condenser under nitrogen.
Anhydrous tetrahydrofuran (13.0 mL) was added and the suspen-
sion was cooled to 0 °C with an ice bath. Compound 10 (0.07 g,
1.68 mmol) in anhydrous tetrahydrofuran (4.0 mL) was added
dropwise to the hydride solution at 0 °C. The resulting mixture was
heated under reflux for 3 hours and then stirred at room tempera-
ture for a further 12 hours. Ether (5.0 mL) was added, and the reac-
tion was quenched by the careful addition of saturated aqueous
sodium potassium tartrate solution. The mixture was stirred for
another 1 hour before the addition of anhydrous magnesium sulfate
prior to filtration through a celite pad. The reaction vessel was
washed out with ethyl acetate and filtered through the celite pad.
The filtrate was evaporated under reduced pressure to yield the
crude product which was adsorbed onto silica and purified by flash
column chromatography over silica using ethyl acetate as eluent to
give the target compound as a yellow solid (0.09 g, 96%), a small
portion of which was recrystallised from dichloromethane to yield
yellow plate-like crystals; m.p. 146–148 °C (ref.[13a] M.p. 149–
trans Isomer 12: Isolated as a pale yellow oil. [α]D = +140.4 (c =
2.0, CH Cl ). IR (thin film, DCM, cm–1): ν
= 1734 [NC=O(O)
˜
max
2
2
1
tBu] 1591 (C=C). H NMR (400 MHz, CDCl3): δ = 1.47–1.52 (m,
1 H), 1.70 (s, 9 H), 1.77 (d, J = 8 Hz, 3 H), 2.40–2.49 (m, 1 H),
2.58–2.64 (m, 1 H), 2.71–2.72 (m, 1 H), 2.73–2.76 (m, 2 H), 2.84–
2.90 (m, 1 H), 5.13–5.23 (m, 2 H), 7.00–7.05 (m, 1 H), 7.23–7.32
(m, 2 H), 7.43–7.46 (m, 1 H), 8.06–8.08 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.7 (CH3), 21.5 (CH2), 23.4 (CH2), 28.2
(3xCH3), 30.3 (CH2), 39.1 (CH2), 55.1 (CH), 84.2 (C), 115.6 (CH),
118.2 (C), 118.3 (CH), 123.0 (CH), 124.5 (CH), 128.6 (C), 129.3
(C), 134.2 (CH), 135.0 (C), 136.7 (C), 150.2 [NC(O)OtBu], 164.9
4184
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4179–4186

Stereoselective Synthesis of the Indolo[2,3-a]quinolizine Ring System
(NC=O) ppm. MS (EI): m/z (%) = 366 (8.9) [M+] (found: M+, amine. The target compound was isolated as a yellow solid (0.23 g,
FULL PAPER
366.19484. C22H26N2O3 requires 366.19434). When the DBN elimi-
nation was carried out in a 1:1 mixture of tetrahydrofuran and
dichloromethane, a 4.7:1 mixture of trans:cis geometrical isomers
was obtained; these were separated by column chromatography
over silica using hexane/ethyl acetate (5:1) as eluent.
77%), a portion of which was recrystallised from dichloromethane
to yield yellow needles; m.p. 139.5–140.5 °C (ref.[13a] m.p. 140 °C).
[α]D = +52.0 (c = 1.0, CHCl3) [ref.[13a] [α]D = +56 2 (c = 1.0,
1
CHCl )]. IR (thin film, DCM, cm–1): νmax = 3455 (NH). H NMR
˜
3
(400 MHz, CDCl3): δ = 1.52–1.60 (m, 1 H), 1.63 (d, J = 8 Hz, 3
H), 1.95–2.02 (m, 1 H), 2.15–2.20 (m, 1 H), 2.61–2.75 (m, 2 H),
2.80–2.84 (m, 1 H), 2.98–3.11 (m, 3 H), 3.32–3.35 (m, 1 H), 3.38–
3.41 (m, 1 H), 5.43 (q, J = 8 Hz, 1 H), 7.06–7.15 (m, 2 H), 7.30–
7.33 (m, 1 H), 7.46–7.48 (m, 1 H), 7.76 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3) 12.7 (CH3), 21.6 (CH2), 25.9 (CH2), 30.3 (CH2),
52.9 (CH2), 60.2 (CH), 63.5 (CH2), 108.4 (C), 110.7 (CH), 118.2
(CH), 119.4 (CH), 119.4 (CH), 121.3 (CH), 127.4 (C), 134.0 (C),
134.6 (C), 136.0 (C) ppm. MS (EI): m/z (%) = 252 [M+, 98.6%]
(found: M+, 252.16261. C17H20N2 requires 252.16265).
cis Isomer: Isolated as a yellow oil. [α]D = +218.4 (c = 4.0, CH2Cl2).
IR (thin film, DCM, cm–1): ν
= 1731 [NC=O(O)tBu] 1660
˜
max
(C=C). 1H NMR (400 MHz, CDCl3): δ = 1.22–1.533 (m, 2 H), 1.69
(s, 9 H), 2.17 (d, J = 8 Hz, 3 H), 2.47–2.52 (m, 1 H), 2.57–2.62 (m,
1 H), 2.73–2.78 (m, 2 H), 2.80–2.88 (m, 1 H), 5.06–5.18 (m, 2 H),
5.92–5.97 (m, 1 H), 7.23–7.32 (m, 2 H), 7.44–7.47 (m, 1 H), 8.04–
8.06 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.8 (CH3),
21.6 (CH2), 28.2 (3xCH3), 30.3 (CH2), 30.6 (CH2), 38.8 (CH2), 55.7
(CH), 84.2 (C), 115.5 (CH), 118.3 (CH), 118.4 (C), 123.0 (CH),
124.5 (CH), 128.7 (C), 128.7 (C), 135.4 (CH), 136.8 (C), 136.8
(CH), 150.2 [NC(O)OtBu], 165.4 (NC=O) ppm. MS (EI): m/z (%)
= 366 (13.1) [M+] (found: M+, 366.19395. C22H26N2O3 requires
366.19434).
X-ray Crystal Structure of (R)-14: Crystal data for 14·1/2H2O:
C17H21N2O0.5, M = 261.36, monoclinic, P21, a = 12.7620(16), b =
6.8946(9), c = 17.222(2) Å, β = 98.533(2)°, V = 1498.5(3) Å3, Z =
4, Dc = 1.158 g cm–3, µ(Mo-Kα) = 0.070 mm–1, T = 150(2) K, yel-
low blocks; 8486 reflections measured with a Bruker SMART 1000
CCD diffractometer, of which 4933 were independent, data cor-
rected for absorption on the basis of symmetry equivalent and re-
peated data (min and max transmission factors: 0.960, 0.987) and
Lp effects, Rint = 0.032, structure solved by direct methods, F2 re-
finement, R1 = 0.043 for 3705 data with F2 Ͼ 2s(F2), wR2 = 0.105
for all data, 367 parameters. CCDC-261811 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(12bR)-(E)-3-Ethylidene-1,2,3,6,7,12b-hexahydroindolo[2,3-a]quino-
lizin-4(12H)-one (13): Compound 12 (0.7 g, 1.91 mmol) was dis-
solved in anhydrous tetrahydrofuran (8.0 mL) under nitrogen. A
1.0  solution of tetrabutyl ammonium fluoride in tetrahydrofuran
(19.1 mL, 19.1 mmol) was then added, and the mixture was heated
under reflux for 9 hours. After this time the mixture was cooled to
room temperature and water (30.0 mL) was added. The mixture
was extracted with ethyl acetate (2×50.0 mL), and the organic frac-
tions were dried with anhydrous magnesium sulfate and the solvent
removed on the rotary evaporator. The crude product was adsorbed
onto silica and purified by flash column chromatography over silica
using hexane/ethyl acetate (3:1) as eluent to give the target com- Acknowledgments
pound as a yellow solid (0.32 g, 63 %), a portion of which was
recrystallised from diethyl ether to give a yellow crystalline solid,
Loughborough University and OSI Pharmaceuticals (joint student-
ship to CIT), EPSRC (Quota studentship to JA).
m.p. 198–202 °C. [α]D = +77.2 (c = 1.0, CH2Cl2). IR (thin film,
DCM, cm–1): ν
= 3238 (NH), 1746 (NC=O). 1H NMR
˜
max
(400 MHz, CDCl3): δ = 1.72–1.82 (m, 1 H), 1.77 (dd, J = 8, 4 Hz,
3 H), 2.31–2.41 (m, 1 H), 2.50–2.58 (m, 1 H), 2.77–2.97 (m, 4 H),
4.81–4.84 (m, 1 H), 5.18–5.25 (m, 1 H), 7.00–7.06 (m, 1 H), 7.09–
7.19 (m, 2 H), 7.31–7.34 (m, 1 H), 7.49–7.51 (m, 1 H, ArH) 8.57
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.7
(CH3), 21.1 (CH2), 22.7 (CH2), 28.9 (CH2), 40.6 (CH2), 54.0 (CH),
109.4 (C), 111.0 (CH), 118.3 (C), 119.6 (CH), 122.0 (CH), 126.8
(C), 129.2 (C), 133.4 (C), 134.1 (CH), 136.4 (C), 164.7 (NC=O)
ppm. MS (EI): m/z (%) = 266 (100) [M+] (found: M+, 266.14191.
C17H18N2O requires 266.14191).
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(12bR)-(E)-3-Ethylidene-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-
quinolizine (14): A slurry of compound 13 (0.32 g, 1.2 mmol) and
trimethyloxonium tetrafluoroborate (0.48 g, 3.3 mmol) in anhy-
drous dichloromethane (40.0 mL) containing 2,6-di-tert-butylpyri-
dine (0.80 mL, 3.5 mmol) was stirred at room temperature under
nitrogen for 21 hours. After this time the reaction was cooled to
0 °C and anhydrous methanol (16.0 mL) was added. After 15 min
sodium borohydride (0.48 g, 12.0 mmol) was added carefully and
the mixture stirred at 0 °C for a further 30 minutes. The reaction
was warmed to room temperature, and saturated aqueous sodium
hydrogencarbonate solution (40.0 mL) and ethyl acetate (40.0 mL)
were added. The layers were separated and the aqueous layer ex-
tracted with ethyl acetate (2×30.0 mL). The combined organic
fractions were dried with anhydrous magnesium sulfate and the
solvent removed under reduced pressure to give the crude product
which was adsorbed onto silica and purified by flash column
chromatography over silica eluting with 98:2 ethyl acetate/triethyl-
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[9] See: S. M. Allin, C. I. Thomas, J. E. Allard, M. Duncton,
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7105; CCDC-227217 for structures 5a (R = 0.072) and CCDC-
227218 for structure 6 (R = 0.031) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Eur. J. Org. Chem. 2005, 4179–4186
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4185

S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J. Elsegood
FULL PAPER
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of δ = 5.92–5.97 ppm. This pattern is in line with reports of
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at an ee of 96%[13a]; b) Compound 11: [α]2D0 = –79.6 (c = 1,
MeOH); ref.[13a]: [α]2D0 = –84 (c = 1, MeOH).
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Received: June 8, 2005
Published Online: August 22, 2005
4186
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4179–4186