Asymmetric synthesis of tetrahydroquinoline derivative, a building block of martinellines, via intramolecular allylic amination using 9-PBN

Article abstract of DOI:10.3987/COM-01-S(K)46

A tetrahydroquinoline derivative, a core structure of martinellines, was prepared through intramolecular allylic amination of the racemic precursor with a stereogenic center using 9-PBN and palladium. The reaction proceeded in a reagent-controlled manner

Full text of DOI:10.3987/COM-01-S(K)46

HETEROCYCLES, Vol. 56, 2002, pp. 97-100, Received, 6th June 2001
ASYMMETRIC
SYNTHESIS
OF
TETRAHYDROQUINOLINE
DERIVATIVE, A BUILDING BLOCK OF MARTINELLINES, VIA
†
INTRAMOLECULAR ALLYLIC AMINATION USING 9-PBN
Yasumasa Hamada*, Iyo Kunimune, and Osamu Hara
Graduate School of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba 263-8522,
Japan (E-mail address: hamada@p.chiba-u.ac.jp)
Abstract – A tetrahydroquinoline derivative, a core structure of martinellines,
was prepared through intramolecular allylic amination of the racemic precursor
with a stereogenic center using 9-PBN and palladium. The reaction proceeded
in a reagent-controlled manner based on the chiral phosphine to give two
diastereomeric products with moderate enantioselectivities.
Heterocycles bearing a nitrogen atom, quinolines and piperidines, constitute the core structure of a
number of biologically interesting alkaloids. Among them, pyrroloquinolines have a unique structure
of fused tetrahydroquinoline and pyrrolidine rings, and certain derivatives have attracted attention for
their interesting pharmacological activities.1 Recently, martinelline (1) and martinellic acid (2) bearing
the pyrroloquinoline nucleus and two prenylguanidines were isolated as the first example of
pyrroloquinolines of natural origin from the roots of the tropical plant, Martinella iquitosensis.2 These
alkaloids also are the first naturally occurring nonpeptide bradykinin receptor antagonists.
Their
intriguing structures as well as biological activities have prompted several groups to investigate the
synthesis of the pyrroloquinoline nucleus.3 Recently, our efforts have demonstrated that the new
monodentate chiral phosphines, (1R, 2S, 5R, 6S)-2,6-dimethyl-9-phenyl-9-phosphabicyclo[3.3.1]nonane
and its enantiomer, ((R)-(-)- and (S)-(+)-9-
PBNs), are valuable ligands for transition-
HN
metal catalyzed asymmetric synthesis, and
O HN
N
these phosphines in combination with
palladium are efficient catalysts for
formation of carbon-carbon, carbon-nitrogen,
and c arbo n-ox ygen bond s th roug h
asymmetric allylic substitution reaction.4
P
R O
H
H
N
N
N
H
NH
Martinelline (1) R = H
Martinellic acid (2) R =
(-)-9-PBN
H
H2N
N
NH
† Dedicated to Professor James P. Kutney on the occasion of his 70th birthday.

1) SOCl2, MeOH
2) TsCl, Py
TBDMSO
CO2Me
NHTs
TBDMSO
CHO
HO
CO2H
NH2
1) LiBH4
2) PDC, CH2Cl2
86%
NHTs
3) TBDMSCl, imidazole
85%
3
4
Br
CO2Me
Zn, I2, Et2O-C6H6
reflux, 96%
OH
OH
TBDMSO
CO2Me
TBDMSO
CO2Me
5a : 5b = 1: 1
+
or
NHTs
NH
Ts
5b
Br
CO2Me
5a
CrCl2, THF, rt
55%
5a : 5b = 70 : 30
Scheme 1
As an expansion of our investigation along this line, we focused on an intramolecular version of the
asymmetric allylic substitution reaction for construction of heterocylces.5 We describe here the
synthetic studies towards total synthesis of martinelline (1) and martinellic acid (2) using our developed
phosphine, 9-PBN.
The synthesis of the substrate for the asymmetric allylic substitution reaction was carried out in a
straightforward manner from a commercially available 5-hydroxyanthranilic acid (Scheme 1). First, 5-
hydroxyanthranilic acid was converted into fully protected derivative (3) in three steps with 85 % yield:
(1) esterification using thionyl chloride in methanol, (2) N-tosylation, and (3) silyl protection of the
phenolic function. For the chain elongation, ester (3) was reduced with lithium borohydride and the
resulting alcohol was oxidized with pyridinium dichromate (PDC) to produce aldehyde (4) in 86 % yield.
Vinylogous Reformatsky reaction of aldehyde (4) using methyl 4-bromocrotonate in the presence of zinc
and iodine in ether-benzene smoothly proceeded under refluxing conditions, but gave, unsurprisingly, a
mixture of regioisomers (5a) and (5b) with the ratio of 1:1 in 96 % yield.6 In the case of employing
chromous chloride instead of zinc,7 the ratio was moderately improved to 70:30, but a significant
decrease in yield was observed. Fortunately, the desired regioisomer (5a) was separable by column
chromatography.
butylchlorodimethylsilane, the conversion of the allylic alcohol into the substrate for the key allylic
substitution reaction was performed in two steps. Reduction of 5a with diisobutylaluminum hydride
After purification and protection of the hydroxy group with t-
(DIBALH) afforded the allylic alcohol in 80 % yield. Acetylation of the alcohol under the standard
conditions, acetic anhydride and pyridine, was surprisingly difficult for the concomitant acetylated
product at the sulfonamide function.
Finally, reaction of 5a with acetic acid and
dicyclohexylcarbodiimide (DCC) in the presence of dimethylaminopyridine (DMAP) in methylene

OTBDMS
OTBDMS
Pd(dba)2 (5 mol%)
Bu3P (10 mol%)
1) TBDMSCl, imidazole
84 %
TBDMSO
TBDMSO
OAc
5a
2) DIBALH, 80 %
3) DCC, AcOH, quant.
NHTs
THF, rt, 92%
N
H
(±)-7
6
OTBDMS
OTBDMS
OTBDMS
TBDMSO
Pd(dba) (2 mol%)
TBDMSO
2
TBDMSO
OAc
(-)-9-PBN (5 mol%)
N
N
H
NHTs
H
BSA(3eq), LiOAc(1eq)
THF, rt, 48 h, 42 %
6
8
7
Scheme 2
chloride at –20°C was found to furnish allyl ester (6) in quantitative yield.
Preliminary cyclization of 6 using allylic substitution reaction was examined by use of 10 mol% of
tributylphosphine and 5 mol% of bis(dibenzylideneacetone)palladium (Pd(dba)2) in tetrahydrofuran
(THF) at room temperature. The reaction stereoselectively took place in a substrate-controlled manner
to afford exclusively the cis-substituted tetrahydroquinoline (7) as the sole product in 92 % yield. With
this satisfactory result in hand, the key cyclization of 6 using (-)-9-PBN in place of tributylphosphine
was carried out in the presence of lithium acetate and bistrimethylsilylacetamide (BSA). The reaction
was somewhat sluggish but provided two cyclic products (7) and (8) with 60 %ee each in the ratio of
1
68:32.8 Both stereostructures were confirmed by their H NMR spectra. The values of the coupling
constants of 7 and 8 at the C-4 hydrogen are 11 Hz and 4 Hz, and 10 Hz and 6 Hz, respectively. These
values show that both C-4 hydrogens are placed on the pseudo-axial position. While the values of the
coupling constants of 7 at the C-2 hydrogen are 11 Hz and 8 Hz, the values of 8 at the C-2 hydrogen are
5 Hz and 3 Hz. These results show that C-2 hydrogen of 7 and 8 is placed on the axial and equatorial
positions, respectively.
In summary, we have described that the intramolecular asymmetric allylic amination of the racemic
substrate (6) with a stereogenic center using our developed phosphine, 9-PBN, and Pd(dba)2 proceeds in
a reagent-controlled manner based on the chiral phosphine to produce two tetrahydroquinolines in
moderate enantioselectivities. During this work, we have observed that cyclization of the same
substrate (6) using achiral phosphine takes place in substrate-controlled manner to afford the cis-
J H-4-H-3= 11 Hz, 4 Hz
H
H
J
H-4-H-3= 10 Hz, 6 Hz
O
H
4
H
O
H
3
2
N
H
N
H
J H-2-H-3= 5 Hz, 3 Hz
H
J H-2-H-3= 11 Hz, 8 Hz
8
7
Figure

substituted tetrahydroquinoline as the sole product. Further investigations towards total synthesis of
martinellines are in progress in our labaratories.
ACKNOWLEDGEMENT
This work was financially supported in part by Grants-in Aid for Scientific Research (C) (No. 12672048)
from the Ministry of Education, Culture, Sports, Sciences and Technology, Japan.
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Optical purity was determined by HPLC analysis using Daicel Chiralpak AD.