Synthesis of an azabicyclic framework towards (±)-actinophyllic acid

Article abstract of DOI:10.1016/j.tetlet.2014.01.019

Lewis acid mediated intramolecular Mannich reaction between an azocinone and a 3-formylindole was investigated as part of a study towards the synthesis of actinophyllic acid. The intramolecular Mannich reaction resulted in a single diastereomer of the 1-azabicyclo[4.2.1]nonan-5-one core framework, although single crystal X-ray structure analysis revealed that this had the undesired stereochemistry in comparison with the natural product.

Full text of DOI:10.1016/j.tetlet.2014.01.019

Tetrahedron Letters 55 (2014) 1255–1257
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of an azabicyclic framework towards ( )-actinophyllic
acid q
a,
a,
Danny Mortimer a, Matthew Whiting b, Joseph P. A. Harrity a, , Simon Jones , Iain Coldham
⇑
⇑
⇑
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
b GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Lewis acid mediated intramolecular Mannich reaction between an azocinone and a 3-formylindole was
investigated as part of a study towards the synthesis of actinophyllic acid. The intramolecular Mannich
reaction resulted in a single diastereomer of the 1-azabicyclo[4.2.1]nonan-5-one core framework,
although single crystal X-ray structure analysis revealed that this had the undesired stereochemistry
in comparison with the natural product.
Received 16 October 2013
Revised 6 December 2013
Accepted 6 January 2014
Available online 10 January 2014
Ó 2014 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Mannich
Indole
Actinophyllic acid
1-Azabicyclo[4.2.1]nonane
Azocinone
Many monoterpene indole alkaloids from the secologanin bio-
synthetic route have been discovered,1 including the novel indole
alkaloid actinophyllic acid (1) (Fig. 1), which was isolated from
the leaves of Alstonia actinophylla (Apocynaceae).2 This bioactive
alkaloid was isolated using a bioassay-guided fractionation of the
aqueous phase employing a CPU/hippuricase coupled enzyme as-
say to detect carboxypeptidase U inhibitors. Actinophyllic acid
was found to be a potent inhibitor of this enzyme assay with an
ments to the end game strategy.5 Martin and co-workers have
recently reported an alternative total synthesis which includes
structural analogues.6 Other routes towards the synthesis of
actinophyllic acid (1) have also been reported.7
The Mannich reaction is historically useful for the synthesis of
alkaloid frameworks.8 With Overman’s route in mind, an alterna-
tive approach to the 1-azabicyclo[4.2.1]nonan-5-one core 2 was
envisaged employing an intramolecular Mannich reaction. Re-
cently, Maldonado and co-workers reported a similar strategy
employing a Mannich reaction to give the azabicyclic core ring sys-
tem.7c We herein report our results as a comparable approach.
The first step in the retrosynthetic strategy disconnects the
hemi-acetal providing the malonoyl indole 3 (Fig. 2). The forward
sense of this retrosynthetic disconnection was clarified by Over-
man and co-workers.3 This known malonoyl indole 3 contains a
1,4-dicarbonyl, and could be disconnected to the azabicy-
clo[4.2.1]nonan-5-one 4. The key step towards this ring system
IC50 of 0.84
lM. Inhibition of carboxypeptidase U may facilitate
fibrinolysis (the process by which the body removes small blood
clots from circulation) and, therefore, has the potential to act as a
treatment for cardiovascular disorders.2 The structure of actino-
phyllic acid (1) contains a complex fused alkaloid ring system con-
taining an azabicycle 2 bridged to an indole.
The first total synthesis of actinophyllic acid was achieved by
Overman and co-workers.3 The key synthetic step employed an
aza-Cope Mannich reaction to achieve the desired framework.
Optical rotation and electronic circular dichroism measurements
on the separated methyl ester enantiomers allowed the absolute
configuration to be assigned.4 Overman and co-workers also re-
ported the first enantioselective total synthesis as well as improve-
OH
O
O
N
N
[Indole]
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
N
H
CO2H
2
1
1-azabicyclo[4.2.1]
nonan-5-one
Actinophyllic Acid
⇑
Corresponding authors. Tel.: +44 114 222 9496; fax: +44 114 222 9346.
E-mail addresses: j.harrity@shef.ac.uk (J.P.A. Harrity), simon.jones@shef.ac.uk
(S. Jones), i.coldham@shef.ac.uk (I. Coldham).
Figure 1. Actinophyllic acid (1) and azabicyclic core 2.
0040-4039/$ - see front matter Ó 2014 The Authors. Published by Elsevier Ltd. All rights
reserved.

1256
D. Mortimer et al. / Tetrahedron Letters 55 (2014) 1255–1257
OH
soda lime
dry Kügelrohr
distillation
CO2H
1. Na 130°C
O
O
O
O
neat
N
N
N
N
9 65%
NH
1,4-Dicarbonyl
Chemistry
80 – 300 °C
15mm/ Hg
2.
O
N
H
N
H
10
O
CO2H
CO2Me
CO2Me
3
CbzCl
K3PO4 (aq)
Toluene
1
rt, 16 h
OTBS
O
OTBS
OTBS
TBSOTf
Et3N
H Cube: Full H2
Pd(OH)2
Mannich Reaction
O
N
CH2Cl2
–78 °C, 1 h
MeOH [0.01M]
1 cycle, 50 °C
N
N
N
H
+
N
H
Cbz
11 52%
Cbz
CHO
6
CO2Me
6 95%
12 99%
CO2Me
CO2Me
N
N
CO2Me
Scheme 2. Synthesis of amine 6.
Boc
Boc
5
4
Table 1
Lewis acid screen
Figure 2. Retrosynthetic analysis.
would then be to employ an intramolecular Mannich reaction be-
tween the 3-formylindole 5 and the 8-membered ring amine 6.
The synthesis of the indole 5 started with the known transfor-
mation of oxindole to 2-chloro-3-formylindole (7) using Vilsme-
ier’s reagent.9 Subsequent nitrogen protection with Boc2O gave
the indole 8 in excellent yield. Deprotonation of dimethyl malonate
with NaHMDS in THF at 0 °C and treatment with indole 8 pleas-
ingly gave the desired indole 5 in 95% yield (see Scheme 1).
The eight-membered azocan-5-one (azocinone) ring was con-
structed by optimising the work of Miyano.10 Following the re-
ported procedure, neat pyrrolidinone was treated with elemental
O
OTBS
N
CHO
Lewis Acid
(2 eq.)
CO2Me
CO2Me
+
CO2Me
CO2Me
N
16 h
N
N
Boc
H
Boc
5
6
4
Entry
Lewis acid
Solvent
Temp (°C)
4 (%)
1
2
3
4
5
6
7
8
B(C6F5)3
BPh3
B(OMe)3
AuCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
40
40
40
40
0
8
0
0
1
2
9
0
sodium at 130 °C, and then subsequently with
c-butyrolactone
which gave carboxylic acid 9 in 65% yield.10a This was then distilled
from finely ground soda lime.10a–c It was found that this reaction
achieved the highest yield when the reaction was performed in a
Kügelrohr distillation apparatus with a bulb-to-bulb distillation,
yielding pure tetrahydropyrrolizine 10 that was immediately trea-
ted with CbzCl in biphasic aqueous 30% K3PO4 and toluene (rather
than via the reported hexahydropyrrolizinium perchlorate
salt)10d,10e to generate the N-Cbz azocinone 11 in a modest yield
from carboxylic acid 9.10f,g The required TBS enol ether 12 was pre-
pared from the N-Cbz azocinone 11 by treatment with TBSOTf and
Et3N at low temperature in excellent yield. Finally, cleaving the N-
Cbz protecting group, by subjecting O-TBS enol ether 12 to hydrog-
enolysis using the H-Cube™ with Pd(OH)2/C CatCart™, provided
amine 6 in excellent yield (see Scheme 2).
Ti(OiPr)4
Zn(BF4)2
MgBr2ÁOEt2
AgOAc
BPh3
9
CH2Cl2
1,2-Dichloroethane
PhCF3
20
14
30
40
10
11
12
BPh3
BPh3
BPh3
PhCF3/H2O (9:1)
ether. Amine 6 and aldehyde 5 were treated with a range of Lewis
acids (2 equiv) at room temperature for 16 h, giving the desired
azabicycle 4 with mixed results (Table 1).
Lewis acids B(C6F5)3, B(OMe)3,11a AuCl3
and AgOAc11c failed
to produce any of the desired product (entries 1, 3, 4 and 8,
11b
The Mannich reaction was initially attempted with Brønsted
acids ([0.1–6 M] HCl, TsOH) in protic (H2O, MeOH) or aprotic
(Et2O, toluene, THF) solvents. However, this led to recovery of in-
dole 5 and decomposition of amine 6 to tetrahydropyrrolizine 10.
To prevent the formation of tetrahydropyrrolizine 10, milder reac-
tion conditions were investigated. There are reports of Lewis acid
mediated Mannich reactions,11 and the use of silyl enol ethers as
reagents.8,12 Efforts towards accessing azabicycle 4 were con-
ducted with a Lewis acid that could promote iminium ion forma-
tion, but was not so strong that it would deprotect the silyl enol
respectively). However, the desired amine 4 was obtained in 8%,
1%, 2% and 9% yield using BPh3,11d Ti(OiPr)4, Zn(BF4)2
and
11e
MgBr2ÁOEt2,11f respectively (entries 2, 5–7). Elevating the tempera-
ture to 40 °C, when employing BPh3, increased the yield from 8% to
20% (entry 9).13 Changing the solvent to 1,2-dichloroethane failed
to improve the reaction (entry 10). Interestingly, changing to
trifluorotoluene improved the yield to 30% (entry 11), with the
addition of trace quantities of water improving the yield further
(entry 12).14
Azabicycle 4 was isolated as a single diastereomer with the
molecular structure being confirmed by HSQC and ROSEY 2D
NMR experiments. The relative stereochemistry was confirmed as
anti by single crystal X-ray analysis. This is different from that re-
quired for the synthesis of actinophyllic acid.15 The X-ray crystal
structure shows a hydrogen bonding interaction between the
amine and the C–H of the malonate. Maldonado and co-workers
also reported anti selectivity (see Fig. 3).7c
CO2Me
POCl3
DMF
CHO
CHO
Cl
CO2Me
CO2Me
CO2Me
O
NaHMDS
THF
0 °C, 10 min
N
H
CH2Cl2
0 °C, 1 h
N
N
Boc
R
5 95%
7 R = H 75%
Boc2O, DMAP
THF, rt, 1 h
8 R = Boc 99%
The cyclisation is likely to occur by nucleophilic attack of the
silyl enol ether onto the indole 13 (or possibly the iminium ion).
Scheme 1. Synthesis of indole malonate 5.

D. Mortimer et al. / Tetrahedron Letters 55 (2014) 1255–1257
1257
3. Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 7568–
7569.
4. Taniguchi, T.; Martin, C. L.; Monde, K.; Nakanishi, K.; Berova, N.; Overman, L. E.
J. Nat. Prod. 2009, 72, 430–432.
5. Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894–
4906.
6. Butler, J. D.; Hua, B.; Knezevic, C. E.; Parkinson, E. I.; Hergenrother, P. J.; Martin,
S. F. J. Am. Chem. Soc. 2013, 135, 12984–12986.
O
7. (a) Vaswani, R. G.; Day, J. J.; Wood, J. L. Org. Lett. 2009, 11, 4532–4535; (b)
Zaimoku, H.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2012, 14, 1656–1658; (c)
Galicia, I. Z.; Maldonado, L. A. Tetrahedron Lett. 2013, 54, 2180–2182.
8. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044–
1070.
H
H
N
H
CO2Me
9. Pedras, M. S. C.; Suchy, M.; Ahiahonu, P. W. K. Org. Biomol. Chem. 2006, 4, 691–
701.
N
CO2Me
Boc
10. (a) Miyano, S.; Fujii, S.; Yamashita, O.; Toraishi, N.; Sumoto, K. J. Heterocycl.
Chem. 1982, 19, 1465–1468; (b) Sumoto, K.; Fujii, S.; Yamashita, O.; Somehara,
T.; Miyano, S. J. Heterocycl. Chem. 1981, 18, 413–414; (c) Miyano, S.; Sumoto, K.;
Satoh, F.; Shima, K.; Hayashimatsu, M.; Morita, M.; Aisaka, K.; Noguchi, T. J.
Med. Chem. 1985, 28, 714–717; (d) Miyano, S.; Somehara, T.; Nakao, M.;
Sumoto, K. Synthesis 1978, 701–702; (e) Miyano, S.; Mibu, N.; Fujii, S.; Abe, N.;
Sumoto, K. J. Chem. Soc., Perkin Trans. 1 1985, 2611–2613; (f) Sumoto, K.; Mibu,
N.; Irie, M.; Abe, N.; Miyano, S. Chem. Pharm. Bull. 1990, 38, 577–580; (g)
Miyano, S.; Mibu, N.; Irie, M.; Sumoto, K. Heterocycles 1986, 24, 2121–2125.
11. (a) Tanaka, Y.; Hidaka, K.; Hasui, T.; Suginome, M. Eur. J. Org. Chem. 2009, 1148–
1151; (b) Xu, L. W.; Xia, C. G.; Li, L. J. Org. Chem. 2004, 69, 8482–8484; (c)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
3734–3735; (d) Tanaka, Y.; Hasui, T.; Suginome, M. Synlett 2008, 1239–1242;
(e) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron
Lett. 2003, 44, 9189–9192; (f) Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010,
12, 3502–3505.
4
Figure 3. X-ray crystal structure (ORTEP) of 4.
OTBS
[Indole]
H
N
H
H
[Indole]
OTBS
CO2Me
CO2Me
OTBS
N
N
N
Boc
13
14
15
12. (a) Kobayashi, S.; Ishitani, H.; Komiyama, S.; Oniciu, D. C.; Katritzky, A. R.
Tetrahedron Lett. 1996, 37, 3731–3734; (b) Danishefsky, S.; Kahn, M.; Silvestri,
M. Tetrahedron Lett. 1982, 23, 1419–1422.
Figure 4. Possible diastereoselectivity rationale.
13. Boranes have been reported to promote iminium ion formation, see: (a)
Suginome, M.; Uehlin, L.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 13196–
13197; (b) Suginome, M. Pure Appl. Chem. 2006, 78, 1377–1387.
14. Synthesis of 4: BPh3 (100 mg) was added in one portion to a stirred solution of
The diastereoselectivity must arise either from a thermodynamic
preference for the isomer 4, or from a preference for a transition
state of general structure 14 rather than 15. The latter has a steric
clash between the indole unit and the OTBS group (see Fig. 4).
In conclusion, the synthesis of the azabicycle 4 core system with
anti diastereoselectivity was achieved using a BPh3-mediated
intramolecular Mannich reaction. Current investigations are
underway using an approach in which the 1,4-dicarbonyl function-
ality is set up prior to the transannular Mannich reaction.
aldehyde
5 (78 mg, 0.21 mmol) and amine 6 (50 mg, 0.21 mmol) in
trifluorotoluene (4 mL) at 40 °C under nitrogen. After 16 h, the reaction
mixture was combined with H2O (5 mL) and CH2Cl2 (5 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and the
combined organic extracts were dried (MgSO4) and evaporated. Purification by
column chromatography on silica, eluting with petrol–EtOAc (1:1) gave indole
4 (40 mg, 40%) as needles; mp 177–178 °C; Rf [petrol–EtOAc (1:1)] 0.1; IR mmax
/
cmÀ1 3050, 2930, 1740, 1690, 1640, 1440; 1H NMR (400 MHz, CDCl3) d = 7.96
(d, J = 8.0 Hz, 1H, Ar), 7.60 (s, 1H, CH), 7.33 (d, J = 8.0 Hz, 1H, Ar), 7.23 (t,
J = 8.0 Hz, 1H, Ar), 7.15 (t, J = 8.0 Hz, 1H, Ar), 4.97 (s, 1H, CH), 3.65 (s, 3H, CH3),
3.62 (s, 3H, CH3), 3.48 (d, J = 8.5 Hz, 1H, CH), 3.12–2.99 (m, 3H, CH2 + CHAHB),
2.93–2.87 (m, 1H, CHAHB), 2.81 (td, J = 16.0, 2.5 Hz, 1H, CHAHB), 2.58 (dd,
J = 16.0, 5.0 Hz, 1H, CHAHB), 2.08–1.95 (m, 3H, CH2 + CHAHB), 1.66–1.62 (m, 1H,
CHAHB), 1.56 (s, 9H, CH3); 13C NMR (100 MHz, CDCl3) d = 213.4 (CO), 167.9
(CO), 167.5 (CO), 150.6 (CO), 135.6 (C), 129.1 (C), 127.8 (C), 124.5 (CH), 122.5
(CH), 119.5 (CH), 117.8 (C), 116.0 (CH), 84.5 (C), 66.3 (CH), 60.1 (CH), 57.2
(CH2), 52.5 (CH3), 52.4 (CH3), 50.2 (CH2), 47.7 (CH), 41.7 (CH2), 31.3 (CH2), 28.1
(CH3), 23.7 (CH2); MS (ESI) m/z 485 [(M+H)+ 100]; HRMS (ESI) calcd for
Acknowledgments
We would like to thank GSK and EPSRC for funding and Harry
Adams for the X-ray crystallographic analysis.
C
26H33N2O7 (M+H)+ 485.2288 found 485.2295.
References and notes
15. Crystallographic data (excluding structure factors) for the structure in this
Letter has been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 949237. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
1. Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 27, 1630–1680.
2. Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.; Forster, P. I. J. Org.
Chem. 2005, 70, 1096–1099.