Complementary routes for the stereoselective synthesis of functionalized benzoquinolizidine targets

Article abstract of DOI:10.1016/j.tetlet.2006.06.035

We report new and complementary routes for the highly stereoselective construction of functionalized benzoquinolizidine targets from readily available, non-racemic chiral templates. The methods developed allow us to predetermine relative product stereoche

Full text of DOI:10.1016/j.tetlet.2006.06.035

Tetrahedron Letters 47 (2006) 5713–5716
Complementary routes for the stereoselective synthesis
of functionalized benzoquinolizidine targets
Steven M. Allin,a,* Liam J. Duffy,a Philip C. Bulman Page,a Vickie McKee,a Mark Edgar,a
Michael J. McKenzie,c Mercedes Amat,b Oriol Bassas,b
Maria M. M. Santosb and Joan Boschb,*
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
bLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
cCharnwood Molecular Ltd, Heritage Building, Prince William Road, Loughborough LE11 5GA, UK
Received 23 March 2006; revised 23 May 2006; accepted 2 June 2006
Available online 27 June 2006
Abstract—We report new and complementary routes for the highly stereoselective construction of functionalized benzoquinolizidine
targets from readily available, non-racemic chiral templates. The methods developed allow us to predetermine relative product ste-
reochemistries by judicious choice of substrate sub-structure, and provide ready access to alternative stereoisomers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The benzo[a]quinolizidine ring system is of considerable
interest and significance since this heterocyclic template
is found within a range of pharmacologically interesting
alkaloids. For example (ꢀ)-protoemetinol 1,1 isolated
by Battersby from Alangium lamarckii, is structurally re-
lated to psychotrine 2 and O-methylpsychotrine 3, and
indeed 1 has formed the basis of synthetic approaches
to these more functionalized derivatives.2 Alangine, 4,
a recently isolated natural product also from A. lama-
rckii differs stereochemically from compounds 1–3 in
that it has trans relative stereochemistry at positions 2
and 11b.3 Compounds 2 and 3 are known to be potent
inhibitors of HIV-1 reverse transcriptase, and such
biological significance earmarks the development of
new asymmetric routes for accessing functionalized
benzo[a]quinolizidine targets as an important task.4
Over recent years our research teams have, indepen-
dently, developed a new approach for the stereoselective
synthesis of heterocyclic ring systems that involves the
cyclization of a pendent aromatic substituent onto an
N-acyliminium intermediate as the key ring-forming
step.5 We now wish to report the development of com-
plementary routes for the highly stereoselective synthesis
of functionalized benzo[a]quinolizidine targets that
allow at will, the efficient preparation of targets with a
MeO
MeO
MeO
N
MeO
N
H
11b
N
MeO
HO
H
H
2
H
MeO
N
H
OH
OH
RO
4
1
2 (R = H)
3 (R = Me)
*
Corresponding authors. Tel.: +44 1509 222559; fax: +44 1509 223925 (S.M.A.); e-mail addresses: S.M.Allin@lboro.ac.uk; joanbosch@ub.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.035

5714
S. M. Allin et al. / Tetrahedron Letters 47 (2006) 5713–5716
range of relative product stereochemistries through
judicious choice of substrate structure and reaction
protocol.
axial attack
H
O
RO
We envisaged one route to the chosen functionalized
targets through application of conjugate addition chem-
istry to an a,b-unsaturated tetrahydroisoquinoline
substrate, since in related work on an indolo[2,3-a]quin-
olizine skeleton the use of appropriate nucleophilic
reagents in conjugate addition reactions has proved to
be very successful, proceeding with good yield and with
exclusive diastereoselectivity.6,7
N
H
MeO
OMe
Figure 1.
ane-2-carboxylate may be reversible, affording the 1:1
mixture of isomers 8a (2,11b trans, kinetic):8b (2,11b
cis, thermodynamic) under the reaction conditions
(ꢀ78 ꢁC to 25 ꢁC, 24 h).
In an attempt to influence the approach of the attacking
nucleophile we generated template 6 through TBDPS-
protection of the hydroxyl group of 5 before introducing
unsaturation (Scheme 1). Substrate 5 was obtained as a
single diastereoisomer on Lewis acid induced cyclization
of the corresponding bicyclic lactam precursor, as previ-
ously reported by our group.8 Our aim here was to
shield the ‘upper’ face of the heterocycle to encourage
attack from below, and hence produce the desired cis
product stereochemistry (relative to the H-atoms at
stereocentres 2 and 11b).
In an attempt to determine the effect, if any, of the
hydroxymethyl substituent on the stereoselectivity of
the conjugate addition process, we decided to examine
the reaction of substrate 13, having removed the
hydroxymethyl substituent by the route highlighted in
Scheme 3.
With a,b-unsaturated amide 13 in hand, we turned our
attention to the proposed functionalization of the b-
position of the unsaturated lactam through conjugate
addition chemistry using the more successful vinyl
nucleophile (Scheme 4).
The results of conjugate addition studies on template 6
are highlighted in Scheme 2, with product 7 isolated in
70% yield as a single diastereoisomer, and product 8 in
55% yield but as a 1:1 mixture of diastereoisomers.
The relative stereochemistry of 7 was confirmed by
nOe studies, and found to have trans relative stereo-
chemistry with respect to the H-atoms at the chiral
centres.9
Product 14 was isolated in good yield (67%), and we
were pleased to observe the formation of a single diaste-
reoisomer by examination of the crude reaction mixture
by 250 MHz 1H NMR spectroscopy. The relative stereo-
chemistry of 14 was confirmed by nOe studies, and
again found to have the H-atoms at the chiral centres
showing trans relative stereochemistry.9 We also at-
tempted the addition reaction with the lithiated dithio-
lane nucleophile, but in this case we only obtained an
intractable product mixture.
One possible explanation for the observed stereochemi-
cal outcome of the conjugate addition reactions to
unsaturated lactam 6 could be, as highlighted in Figure
1, an axial attack of the vinyl cuprate, under stereoelec-
tronic control, to give the kinetic product 7. However,
the conjugate addition of the enolate of ethyl 1,3-dithiol-
MeO
MeO
MeO
MeO
OH
O
OTBDPS
O
MeO
MeO
OTBDPS
O
(i)
(ii)
N
N
N
H
H
H
5
6
Scheme 1. Reagents and conditions: (i) imidazole (3 equiv), DMAP (cat.), TBDPSCl (2 equiv), DCM, rt, 24 h, (97%); (ii) LDA, PhSeBr, THF,
ꢀ78 ꢁC to rt, 24 h; then NaIO4, NaHCO3, MeOH, H2O, rt, 18 h (42%, two steps).
MeO
MeO
MeO
MeO
MeO
MeO
OTBDPS
OTBDPS
O
OTBDPS
O
(i) or (ii)
11b
N
O
N
8a:8b = 1:1
N
7
H
H
H
2
H
H
+ve nOe
6
CO2Et
S
S
Scheme 2. Reagents and conditions: (i) vinylmagnesium bromide (10 equiv), CuCN (7.5 equiv), TMSCl (7.5 equiv), THF, ꢀ78 ꢁC to rt, 24 h; (ii)
LDA (2 equiv), ethyl 1,3-dithiolane-2-carboxylate (1.2 equiv), THF, ꢀ78 ꢁC to rt, 24 h.

S. M. Allin et al. / Tetrahedron Letters 47 (2006) 5713–5716
5715
R'
MeO
MeO
R'
MeO
MeO
(iii)
(v)
MeO
MeO
N
O
N
O
N
O
H
H
H
5, R' = CH2OH
9, R' = CHO
13
11, R' = COSePh
12, R' = H
(i)
(iv)
(ii)
10, R' = CO2H
Scheme 3. Reagents and conditions: (i) IBX, DMSO, rt, 24 h (70%); (ii) NaClO2, NaH2PO4, 1-methyl-1-cyclohexene, CH3CN, t-BuOH, H2O, 0 ꢁC to
rt, 18 h (86%); (iii) (PhSe)2, PBu3, CH2Cl2, 0 ꢁC to rt, 18 h (76%); (iv) n-Bu3SnH, AIBN, toluene, 80 ꢁC, 2 h (81%); (v) LDA, PhSeBr, THF, ꢀ78 ꢁC to
rt, 24 h; then NaIO4, NaHCO3, MeOH, H2O, rt, 18 h (61% for two steps).
MeO
MeO
MeO
MeO
(i)
11b
N
O
N
O
14
H
H
2
H
H
+ve nOe
13
Scheme 4. Reagents and conditions: (i) vinylmagnesium bromide (10 equiv), CuCN (7.5 equiv), TMSCl (7.5 equiv), THF, ꢀ78 ꢁC to rt, 24 h.
Clearly the (protected) hydroxymethyl group of
substrate 6 plays no major role in determining the
approach of the nucleophile, with the inherent confor-
mation of the parent heterocyclic template being respon-
sible for the stereochemical induction, with the
nucleophile approaching from the least hindered (con-
vex) face of the ring system. In summary, products 7
and 14 are formed as single diastereoisomers and with
trans relative stereochemistry at positions 2 and 11b,
as required for alkaloids such as alangine, 4.
in DCM at reflux for 3 days, gave 17 in 36% yield as a
single product diastereoisomer (Scheme 6). X-ray crys-
tallography11 confirmed the relative stereochemistry of
this product to be as shown in Scheme 6, with the
H-atoms at the chiral centres now having cis relative
stereochemistry, as required in benzo[a]quinolizidine
targets, such as 1–3.
Removal of the hydroxymethyl moiety from 17 by an
analogous route to that described in Scheme 3 gave
the desired functionalized benzo[a]quinolizidine target
18.
An alternative route for the introduction of substituents
onto the lactam ring would involve the incorporation of
functionality at an earlier stage in the sequence. The
development of synthetic routes to prochiral or racemic
glutarates,10 such as 15, and the subsequent use of these
oxo diesters in stereoselective cyclocondensation reac-
tions with chiral amino alcohols has previously been
demonstrated.5b In this current approach, cycloconden-
sation of the appropriate substrates leads to the forma-
tion of functionalized bicyclic lactams 16a and 16b in a
process that involves the discrimination of two enantio-
topic acetate chains (Scheme 5).
MeO
MeO
MeO
MeO
N
O
N
O
H
H
H
H
CO2Me
trans 14
cis 18
In conclusion, we have developed new and highly stereo-
selective routes to functionalized benzo[a]quinolizidine
targets, both in the 2,11b-cis and -trans series. The rela-
tive stereochemistry of the products can be influenced
through appropriate selection of synthetic approach,
allowing complementary routes to diastereoisomerically
Lactams 16a,b were separable, and their relative stereo-
chemistry was established by X-ray crystallography. N-
Acyliminium ion precursor 16a, on treatment with TiCl4
Ar
O
Ar
O
MeO2C
CHO
O
MeO
MeO
O
N
Toluene, Δ
N
OH
+
H
H
NH2
24 h, 80%
CO2Me
MeO2C
16a (67%)
MeO2C
16b (13%)
15
Scheme 5.

5716
S. M. Allin et al. / Tetrahedron Letters 47 (2006) 5713–5716
Ar
O
OMe
HO
O
N
TiCl4
O
N
H
OMe
DCM, Δ, 3 days
H
36%
H
MeO2C
16a
MeO2C
17
Scheme 6.
9. For compounds 7 and 14, a positive NOE effect was
observed between the proton at position 11b and a proton
of the newly added vinyl substituent. No positive NOE
effect was observed between the proton substituents at
positions 11b and 2.
substituted products 14 and 18 as single diastereoiso-
mers.12 The absolute stereochemistry of such products
can, if required, be tuned by the choice of appropriate
enantiomer of the b-aminoalcohol starting material.
´
10. Amat, M.; Bassas, O.; Canto, M.; Llor, N.; Santos, M. M.
M.; Bosch, J. Tetrahedron 2005, 61, 7693–7702.
Acknowledgements
11. X-ray data for 17: Data collected at 150 K on a Bruker
SMART 1000 diffractometer; solution by direct methods
and refinement by full-matrix least-squares on F2 using all
the data.13 Non-hydrogen atoms refined with anisotropic
atomic displacement parameters; hydrogen atoms inserted
at calculated positions using a riding model, except for the
alcohol proton which was located and refined with a fixed
isotropic displacement parameter. Crystal dimensions
0.36 · 0.24 · 0.22 mm3, monoclinic, P21, a = 5.1398(4),
The Loughborough group thanks the EPSRC and Charn-
wood Molecular for an industrial CASE award to L.J.D.
The Barcelona group thanks the Ministry of Science and
Technology (Spain)-FEDER through project BQU2003-
00505. Thanks are also due to DURSI, Generalitat de
Catalunya, for Grant 2005-SGR-00603, the Ministry of
Education and Science (Spain) for a fellowship to O.B.,
˚
b = 11.7652(8), c = 14.524(1) A, b = 94.274(1)ꢁ and V =
and the Fundac¸ao para a Cieˆncia e Tecnologia (Portugal)
˜
for a postdoctoral grant to M.M.M.S.
875.8(1) A , Z = 2, qcalcd = 1.378 M g/m3. 7592 Refl.,
3
˚
2156 independent (Rint = 0.0212), l = 0.102 mmꢀ1
,
F(000) = 388, 238 least-squares parameters, R1 =
0.0303, wR = 0.0777 (2r data). CCDC 297432 contains
supplementary 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).
References and notes
1. Battersby, A. R.; Kapil, R. S.; Bhakuni, B. S.; Popli, S. P.;
Merchant, J. R.; Salgar, S. S. Tetrahedron Lett. 1965,
4965–4971.
2. Takacs, J. M.; Boito, S. C. Tetrahedron Lett. 1995, 36,
2941–2944, and references therein.
3. Itoh, A.; Ikuta, Y.; Tanahashi, T.; Nagakura, N. J. Nat.
Prod. 2000, 63, 723–725; Takayama, H.; Arai, M.;
Kitajima, M.; Aimi, N. Chem. Pharm. Bull. 2002, 50,
1141–1143.
4. Tan, G. T.; Kinghorn, A. D.; Hughes, S. H.; Pezzuto, J.
M. J. Biol. Chem. 1991, 266, 23529–23536.
5. For recent examples, see: (a) Allin, S. M.; Thomas, C. I.;
Doyle, K.; Elsegood, M. R. J. J. Org. Chem. 2005, 70,
357–359; (b) Bassas, O.; Llor, N.; Santos, M. M. M.;
Griera, R.; Molins, E.; Amat, M.; Bosch, J. Org. Lett.
2005, 7, 2817–2820.
6. Allin, S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.;
Doyle, K.; Elsegood, M. R. J.; Edgar, M. Tetrahedron
Lett. 2006, 47, 1961–1964.
22
12. Data for selected compounds: Compound 14: ½aꢁD +43.0
(c 1.0, CHCl3); dH (400 MHz; CDCl3) 2.02–2.08 (1H, m),
2.30–2.37 (1H, m), 2.54 (2H, t, J = 4), 2.63 (1H, dt,
J = 2.8, 15.2), 2.67–2.73 (1H, m), 2.78–2.85 (1H, m), 2.91–
2.90 (1H, m), 3.86 (3H, s), 3.87 (3H, s), 4.63–4.66 (1H, m),
4.83–4.88 (1H, m), 5.12–5.18 (2H, m), 5.91–6.00 (1H, m),
6.62 (1H, s), 6.64 (1H, s); dC (100 MHz; CDCl3) 28.5, 33.1,
34.8, 36.3, 40.1, 53.5, 55.9, 56.1, 107.8, 11.7, 115.4, 127.6,
129.0, 139.4, 146.8, 146.9, 169.0 (Found (EI): M+
288.15935. C17H21NO3 requires 288.15940). Compound
22
18: ½aꢁD +124.9 (c 1.6, CHCl3); dH (400 MHz; CDCl3)
1.34–1.43 (1H, m), 2.07 (1H, dd, J = 17, 12), 2.34–2.36
(2H, m), 2.43–2.49 (1H, m), 2.55–2.68 (3H, m), 2.74–2.92
(2H, m), 3.70 (3H, s), 3.83 (3H, s), 3.84 (3H, s), 4.65 (1H,
dd, J = 11, 4), 4.81–4.85 (1H, m), 6.59 (1H, s), 6.63 (1H,
s); dC (100 MHz; CDCl3) 28.4 (2C), 37.0, 38.1, 39.5, 39.9,
51.7, 55.8, 56.0, 56.1, 108.2, 111.5, 127.1, 128.6, 147.7,
147.8, 168.1, 172.1 (Found (EI): M+, 333.1576.
C18H23NO5 requires 333.1576).
´
7. For related conjugate additions, see: Amat, M.; Perez, M.;
Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J.
J. Org. Chem. 2004, 69, 8681–8693.
8. Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard, J. E.;
Smith, T. A. D.; McKee, V.; Martin, W. P. Tetrahedron
Lett. 2002, 43, 3661–3663.
13. Sheldrick, G. M. SHELXTL version 6.12, Bruker-AXS,
Madison WI, 2001.