Tetrahedron Letters
Synthesis of 5,6-dihydrophenanthridines via N,O-acetal TMS ethers
Won-Il Lee a, Jong-Wha Jung b, Jaebong Jang a, Hwayoung Yun a, Young-Ger Suh a,
⇑
a College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
b College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 701-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and high-yielding protocol for the synthesis of 5,6-dihydrophenanthridines is disclosed. The
key feature includes a sequential reduction-cyclization reaction of N-acylcarbamates via N,O-acetal
TMS ethers as a stable N-acyliminium ion precursor.
Received 24 April 2013
Revised 1 July 2013
Accepted 5 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
5,6-Dihydrophenanthridine
N,O-Acetal TMS ether
N-Acyliminium ion
Intramolecular aromatic substitution
Phenanthridine and 5,6-dihydrophenanthridine alkaloids are
found throughout a wide range of natural resources, exhibiting var-
ious biological activities including antibiotic, anti-inflammatory,
and anticancer activity.1 Thus, there have been continuous endeav-
ors to secure the classes of phenanthridines and 5,6-dihydrophe-
nanthridines occupying biologically relevant chemical spaces. For
instance, phenanthridines including aza-phenanthridines and
benzophenathridines have been reported to be promising candi-
dates for drug development and the related biological studies2
although 5,6-dihydrophenanthridines were less explored. A recent
report revealed that the natural alkaloid-based 5,6-dihydrophenan-
thridines possess potent inhibitory activities against acetylcholine
esterase.3 In addition, development of the 5,6-dihydrophenanthri-
dine derivatives as bradykinin B1 antagonist has been reported.4
5,6-Dihydrophenanthridines as potassium channel inhibitors and
as immunosuppressants were also reported.1h Figure 1 Notably
5,6-dihydrophenanthridines often exhibited distinct biological
properties compared to the structurally related phenanthridines
owing to the absence of electrophilic C@N double bond.5
OMe
OMe
OMe
OMe
CHO
N
N
O
O
assoanine
acetylcholine esterase inhibitor
dihydrochelerythrinylacetaldehyde
cytotoxic
N
N
N
O
N
H
O
O
5,6-dihydrophenanthridine
Compared to the well developed phenanthridine syntheses,6
only a few synthetic methods for the preparation of 5,6-dihydr-
ophenanthridines were reported. In addition, the 5,6-dihydrophe-
nanthridine syntheses often suffered from low yields due to the
limited functional group tolerance7 and the undesirable in situ oxi-
dation.8 Modified Pictet-Spengler reaction for the synthesis of 5,6-
dihydrophenanthridine-6-carboxylates,9 a sequential multicompo-
nent reaction involving intramolecular C–H functionalization10 and
potassium channel inhibitor
MeO
O
O
N
O
N
SO2
N
H
Cl
Cl
N
Et
Et
bradykinin B1 antagonist
acetylcholine esterase inhibitor
⇑
Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649.
Figure 1. Selected 5,6-dihydrophenanthridines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.