Complementary stereoselective conjugate addition reactions on indolo[2,3-a]quinolizine templates

Article abstract of DOI:10.1016/j.tetlet.2006.01.081

We report a new and highly stereoselective approach for the construction of a range of functionalized indolo[2,3-a]quinolizine targets from a readily available, nonracemic chiral template. The methods developed allow us to predetermine relative product st

Full text of DOI:10.1016/j.tetlet.2006.01.081

Tetrahedron Letters 47 (2006) 1961–1964
Complementary stereoselective conjugate addition reactions on
indolo[2,3-a]quinolizine templates
Steven M. Allin,a,* Jagjit S. Khera,a Christopher I. Thomas,a Jason Witherington,b
Kevin Doyle,c Mark R. J. Elsegooda and Mark Edgara
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bDepartment of Medicinal Chemistry, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research
Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
cOSI Pharmaceuticals, Watlington Road, Oxford OX4 6LT, UK
Received 21 November 2005; revised 6 January 2006; accepted 16 January 2006
Available online 7 February 2006
Abstract—We report a new and highly stereoselective approach for the construction of a range of functionalized indolo[2,3-a]quino-
lizine targets from a readily available, nonracemic chiral template. The methods developed allow us to predetermine relative product
stereochemistries by judicious choice of substrate sub-structure.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The indolo[2,3-a]quinolizine ring system 1 is of consider-
able interest and significance since this heterocyclic tem-
N
plate is found within a plethora of indole alkaloids,
O
including geissoschizine 2,1 geissoschizol 32 and hirsu-
N
N
H
H
tine 4.3 The presence of the lactam carbonyl in templates
such as 1 allows for possible further functionalization en
route to the natural product targets. Recent approaches
to the construction of this heterocyclic target system by
other groups have included the diastereoselective vinyl-
ogous Mannich reaction,4 Bischler–Napieralski reac-
tion,5 Fischer indole synthesis6 and an asymmetric
Pictet–Spengler reaction.7
N
H
H
MeO2C
OH
1
2
We have developed a new approach for the stereoselec-
tive synthesis of the indolo[2,3-a]quinolizine ring system
that involves the cyclization of a pendent indole substi-
tuent onto an N-acyliminium intermediate as the key
ring-forming step.8 We have recently applied our meth-
odology in natural product synthesis, and have reported
the asymmetric preparation of some simple indole alka-
loids, including deplancheine.9 In order to access more
advanced targets such as 2–4, and their synthetic ana-
logues, one would require suitable and flexible routes
for the introduction of additional functionality to the
indolo[2,3-a]quinolizine template, ideally with control
over relative and absolute stereochemistry. One
approach currently under study in our laboratory is to
N
N
N
H
N
H
H
H
Et
OMe
H
H
MeO2C
OH
4
3
introduce appropriate functionality through conjugate
addition to the lactam ring. Scheme 1 highlights the
preparation of a model substrate for this investigation
from indolizino[2,3-a]quinolizidine derivative 5,
obtained as a single diastereoisomer as previously
reported.8
*
Corresponding author. E-mail: S.M.Allin@lboro.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.081

1962
S. M. Allin et al. / Tetrahedron Letters 47 (2006) 1961–1964
With a,b-unsaturated amide 7 in hand, we turned our
attention to the proposed functionalization of the b-
position through the conjugate addition chemistry
shown in Scheme 2.
are approaching from the outer (perhaps less hindered)
face of the bowl; that is, from the same face as the
H-atom at the proximate ring junction.
An intriguing and potentially very useful effect on the
sense of nucleophilic addition was observed on further
modification of the template sub-structure. Unsaturated
substrate 16 was prepared as a single enantiomer follow-
ing the method outlined in Scheme 3. Removal of the
hydroxymethyl substituent in this way would be a natu-
ral progression en route to final targets such as 2–4
noted at the outset of this letter, and this protocol is
now a standard transformation in our laboratory.9
The products of conjugate addition were isolated in
varying yields: 8 (52%), 9 (20%) and 10 (65%); we were
pleased to observe the formation, in each case, of the
desired product as a single diastereoisomer by exami-
1
nation of the crude reaction mixtures by 250 MHz H
NMR spectroscopy. The relative stereochemistry of
each product was confirmed by NOE studies. Protons
at positions 2 and 12b have trans relative stereochem-
istry, as seen in the natural product hirsutine, 4.3
With the structures of potential targets 2–4 in mind we
subjected compound 16 to the addition of 2 equiv of
lithiated methyl 1,3-dithiolane-2-carboxylate and were
pleased to observe the exclusive formation of the addi-
tion product 17 as a single diastereoisomer in 47% yield
(Fig. 1). Analysis of compound 17 by X-ray crystallo-
graphy10 revealed that the addition had occurred on
the opposite face to that observed in the studies outlined
All nucleophiles gave the same sense of stereochemical
induction with template 7, and although this appears
to result from the nucleophile approaching the face of
the conjugated amide that carries the large benzyloxy-
methyl-substituent, the representations shown in
Scheme 2 can be misleading, since the conformation of
molecules such as 7 is bowl-like, and the nucleophiles
H
OH
O
H
H
OBn
O
OBn
O
(ii), (iii)
(i)
N
N
N
N
H
N
N
H
H
Bn
H
Bn
6
5
7
Scheme 1. Reagents and conditions: (i) NaH (2 equiv), BnBr (2.2 equiv), DMF, rt, 1 h (90%); (ii) LDA, PhSeBr, THF, ꢀ78 ꢁC to rt, 24 h, then (iii)
NaIO4, NaHCO3, MeOH, H2O, rt, 18 h (85% for two steps).
H
OBn
O
H
H
H
OBn
O
OBn
O
OBn
O
Nu
N
N
N
12b
N
N
N
N
N
H
Bn
H
H
Bn
Bn
H
Bn
2
7
H
H
H
10
8
9
S
EtO2C
S
CO2Et
where:
Li
Na
MgBr (with CuCN additive)
S
S
Nu =
EtO2C
CO2Et
Scheme 2.
R'
R'
N
(iii)
(vi)
O
O
O
N
N
N
N
N
H
H
R
H
Boc
Boc
16
(i)
(ii)
5, R = H, R' = CH2OH
11, R = H, R' = CHO
12, R = Boc, R' = CHO
13, R = Boc, R' = CO2H
14, R = Boc, R' = COSePh
15, R = Boc, R' = H
(iv)
(v)
Scheme 3. Reagents and conditions: (i) IBX, DMSO, rt, 24 h (70%); (ii) Et3N, (Boc)2O, DMAP, THF, rt, 4 h (98%); (iii) NaClO2, NaH2PO4, 1-
methyl-1-cyclohexene, CH3CN, t-BuOH, H2O, 0 ꢁC to rt, 18 h (83%); (iv) (PhSe)2, PBu3, CH2Cl2, 0 ꢁC to rt, 18 h (83%); (v) n-Bu3SnH, AIBN,
toluene, 80 ꢁC, 2 h (73%); (vi) LDA, PhSeBr, THF, ꢀ78 ꢁC to rt, 24 h, then NaIO4, NaHCO3, MeOH, H2O, rt, 18 h (85% for two steps).

S. M. Allin et al. / Tetrahedron Letters 47 (2006) 1961–1964
1963
O
N
N
H
CO2Me
S
Boc
H
17
S
Figure 1.
O
N
12b
H
N
H
2
CO2Me
20
2 eq.
S
H
19
S
CO2Me
S
Li
S
O
N
N
H
H
18
O
4 eq.
N
OLi
N
N
N
O
H
H
H
H
quench onto
XS methylester
H
S
H
S
S
S
MeO2C
MeO2C
S
S
20
Scheme 4.
above, with the protons at positions 2 and 12b now
having cis relative stereochemistry, as in the natural
products geissoschizine 21 and geissoschizol 3.2
required for a future synthesis of hirsutine, 4, as
confirmed by X-ray crystallography (Scheme 4).11
In conclusion, we have found that the relative stereo-
chemistry of the products of conjugate addition to indo-
lo[2,3-a]quinolizine molecules can be influenced through
careful selection of the template structure, allowing
complementary approaches to diastereoisomeric addi-
tion products.12 With either the hydroxymethyl auxil-
iary group present, or judicious choice of indole
N-protection, nucleophilic addition occurs to give cis
relative stereochemistry between the newly added substi-
tuent and the proton at ring junction 12b. An alternative
manipulation of the template structure can lead to the
introduction of trans relative stereochemistry between
these two groupings. In addition, we have discovered
that the use of a dithiolane reagent in a domino-type
process can lead to highly efficient and stereoselective
functionalization of our template. 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.
A remarkable manipulation in the sense of stereochemi-
cal induction can be achieved with template 18, that
lacks any N-protection at the indole nitrogen (obtained
through formic acid-mediated deprotection of 16 [neat,
rt, 22 h, 71% yield]). In this case, addition of the lithiated
dithiolane nucleophile (2 equiv) led to selective forma-
tion of product 19 in which the protons at positions 2
and 12b were found to be of trans relative stereochemis-
try, as seen previously with template 7, and as required
in the natural product hirsutine, 4.3
The full potential of our approach for the efficient stereo-
selective total synthesis of indole natural products can
be demonstrated with the addition of an excess of the
lithiated dithiolane nucleophile (4 equiv) to substrate
18. We reasoned that the dithiolane moiety could serve
a dual role: as both a nucleophile and subsequently, in
the same pot, as an electrophile for derivatization of
an intermediate lactam enolate. This domino process
would provide a highly economic route to access
advanced heterocyclic templates. We were pleased to
isolate product 20 in 64% yield and as a single
diastereoisomer (Scheme 4). Product 20 has the correct
relative stereochemistry at all three chiral centres
Acknowledgements
One of the authors (C.I.T.) thanks Loughborough Uni-
versity and OSI Pharmaceuticals, for a joint studentship

1964
S. M. Allin et al. / Tetrahedron Letters 47 (2006) 1961–1964
measured, Rint = 0.0208, wR2 = 0.0705 for all 5875 unique
data, R1 = 0.0287 for 5417 data with F2 P 2r(F2). Abso-
lute structure parameter = ꢀ0.03(5)—thus reliably deter-
mined. H-bonded chains along a via N(12)–H(12)ꢁ ꢁ ꢁO(10),
CCDC 286787.
and J.S.K. thanks Loughborough University and GSK
Pharmaceuticals, for a joint studentship.
References and notes
12. Data for selected compounds: Compound 7: dH
(400 MHz; CDCl3) 2.21–2.30 (1H, m), 2.52–2.59 (1H,
m), 3.02 (1H, ddd, J 16, 8, 4), 3.15 (1H, d, J 16), 3.30–3.38
(2H, m), 4.45 (2H, s), 4.59–4.63 (1H, m, C@CCH), 5.23
(2H, dd, J 36, 16), 5.42–5.46 (1H, m), 6.06 (1H, dd, J 8, 4),
6.49–6.50 (1H, m), 6.83–6.85 (2H, m), 7.14–7.23 (11H, m),
7.60–7.62 (1H, m); dC (100 MHz, CDCl3) 21.9 (CH2), 32.0
(CH2), 47.3 (CH), 48.3 (CH2), 49.8 (CH), 68.0 (CH2), 72.5
(CH2), 107.6 (C), 109.8 (CH), 118.7 (CH), 119.9 (CH),
122.3 (CH), 125.6 (2 · CH), 125.9 (CH), 127.0 (C), 127.3
(2 · CH), 127.3 (CH), 127.5 (CH), 128.2 (2 · CH), 128.9
(2 · CH), 132.6 (C), 137.0 (C), 138.1 (C), 138.2 (C), 138.2
(CH), 164.9 (NC@O); MS (EI) m/z 448 [M+, 100.0%]
(Found: M+, 448.21406. C30H28N2O2 requires 448.21507).
Compound 16: dH (400 MHz, CDCl3) 1.69 (9H, s), 2.13–
2.22 (1H, m), 2.72–2.80 (2H, m), 2.82–2.92 (1H, m), 3.03
(1H, ddd, J 17.2, 6.6, 3.8), 5.02 (1H, ddd, J 12.5, 4.8, 1.4),
5.24–5.30 (1H, m), 6.09 (1H, dd, J 9.7, 1.5), 6.67–6.71 (1H,
m), 7.26–7.35 (2H, m), 7.47–7.49 (1H, m), 8.08 (1H, d, J
8.0); dC (100 MHz, CDCl3) 21.5 (CH2), 28.2 (3 · CH3),
31.6 (CH2), 37.6 (CH2), 53.3 (CH), 84.5 (C), 115.8 (CH),
118.0 (C), 118.4 (CH), 123.1 (CH), 124.7 (CH), 125.4
(CH), 128.5 (C), 134.1 (C), 136. 6 (C), 139.2 (CH), 150.0
(NC(O)OtBu), 164.8 (NC@O); MS (EI) m/z 338 [M+,
24.4%] (Found: M+, 338.16318. C20H22N2O3 requires
338.16384). Compound 17: dH (400 MHz, CDCl3) 1.38–
1.47 (1H, m), 1.70 (9H, s), 2.53 (1H, dd, J 17.4, 11.7),
2.69–2.80 (2H, m) 2.81–2.85 (2H, m), 2.87–2.89 (1H, m),
2.95–3.03 (1H, m), 3.28–3.33 (2H, m), 3.35–3.39 (2H, m),
3.81 (3H, s), 5.10–5.17 (2H, m), 7.23–7.33 (2H, m), 7.43–
7.45 (1H, m), 8.02–8.04 (1H, m); dC (100 MHz, CDCl3)
21.7 (CH2), 28.1 (3 · CH3), 33.8 (CH2), 35.7 (CH2), 38.4
(CH), 39.0 (CH2), 40.1 (CH2), 40.3 (CH2), 53.5 (CH3),
55.4 (CH), 74.1 (C), 84.5 (C), 115.5 (CH), 118.4 (CH),
118.7 (C), 123.1 (CH), 124.8 (CH), 128.5 (C), 134.7 (C),
136.8 (C), 150.3 (NC(O)OtBu), 168.7 (C@O), 171.9
(NC@O); MS (EI) m/z 502 [M+, 3.5%] (Found: M+,
502.15989. C25H30N2O5S2 requires 502.15962). Com-
pound 20: dH (400 MHz, CDCl3) 2.29–2.33 (1H, m),
2.79–2.89 (2H, m), 2.79–2.89 (1H, m), 3.15–3.27 (4H,
m), 3.35–3.37 (2H, m), 3.45–3.48 (2H, m), 3.49–3.52 (1H,
m), 3.88 (3H, s), 4.33–4.36 (1H, m), 4.98 (1H, t , J 8.4),
5.11–5.13 (1H, m), 5.92 (1H, s), 7.10–7.20 (2H, m), 7.32–
7.34 (1H, m), 7.49 (1H, d, J 7.6), 7.87 (1H, br s); dC
(100 MHz, CDCl3) 20.9 (CH2), 29.3 (CH2), 30.9 (CH),
38.2 (CH2), 38.3 (CH2), 39.1 (CH2), 40.4 (CH2), 41.3
(CH2), 51.0 (CH), 53.8 (CH3), 54.8 (CH), 56.3 (CH), 73.9
(C), 109.7 (C) 110.9 (CH), 118.4 (CH), 119.9 (CH),
122.2 (CH), 126.8 (C), 131.9 (C), 136.3 (C), 164.8 (C@O),
171.8 (NC@O), 198.1 (C@O); MS (FAB) m/z 535 [MH+,
5.2%] (Found: MH+, 535.08460. C24H26N2O4S4 requires
535.08537).
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10. Crystallography for 17: C25H30N2O5S2, M = 502.63,
monoclinic, P21, a = 10.5505(7), b = 9.3807(6), c =
3
˚
˚
12.4921(8) A, b = 100.281(2)ꢁ, V = 1216.51(14) A , Z =
2, 10,789 data measured, Rint = 0.0192, wR2 = 0.0905 for
all 5594 unique data, R1 = 0.0379 for 5007 data with
F2 P 2r(F2). Absolute structure parameter = ꢀ0.03(6)—
thus reliably determined. CCDC 286786 contains supple-
mentary crystallographic data in cif format. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033,
e-mail: deposit@ccdc.cam.ac.uk.).
11. Crystallography for 20: C24H26N2O4S4, M = 534.71,
orthorhombic, P212121, a = 7.6895(7), b = 17.2611(16),
3
˚
˚
c = 18.2799(17) A, V = 2426.3(4) A , Z = 4, 21508 data