Spirocyclization of an N-acyliminium ion with substituted pyridine: Stereoselective synthesis of tetracyclic spirolactams possessing the pyridone nucleus

Article abstract of DOI:10.3987/COM-10-S(E)13

An efficient method for the stereoselective synthesis of tetracyclic spirolactams was developed based on a spirocyclization of an N-acyliminium ion with 2-methoxypyridine as the aromatic π-nucleophile. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)13

HETEROCYCLES, Vol. 82, No. 1, 2010
257
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 257 - 261. © The Japan Institute of Heterocyclic Chemistry
Received, 16th March, 2010, Accepted, 8th April, 2010, Published online, 9th April, 2010
DOI: 10.3987/COM-10-S(E)13
SPIROCYCLIZATION OF AN N-ACYLIMINIUM ION WITH
SUBSTITUTED PYRIDINE: STEREOSELECTIVE SYNTHESIS OF
TETRACYCLIC SPIROLACTAMS POSSESSING THE PYRIDONE
NUCLEUS
Hideki Abe,1 Kei-ichi Takaya,2 Kazuhiro Watanabe,1 Sakae Aoyagi,2*
Chihiro Kibayashi,2 and Tadashi Katoh1*
1Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical
University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan (e-mail:
katoh@tohoku-pharm.ac.jp); 2School of Pharmacy, Tokyo University of
Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
Dedicated to Professor Dr. Albert Eschenmoser on the occasion of his 85th
birthday
Abstract – An efficient method for the stereoselective synthesis of tetracyclic
spirolactams was developed based on a spirocyclization of an N-acyliminium ion
with 2-methoxypyridine as the aromatic !-nucleophile.
N-Acyliminium ions are an extremely important species in the synthesis of nitrogen-containing natural
products.1 A large number of reactions between N-acyliminium ions and nucleophiles such as olefins,
allylsilanes and aromatic rings have been developed.2-8 Among various reactions of N-acyliminium ions,
spirocyclizations of N-acyliminium ions with tethered pyridines as !-nucleophiles are rarely found,
because electron-withdrawing pyridine rings possess low nucleophilicity. However, in 1997, Padwa9
reported intramolecular cyclizations of N-acyliminium ions derived from N-substituted phthalimides
tethered to 2-methoxypyridines. Similarly, we reported that a spirocyclization of an N-acyliminium ion
with an activated pyridine afforded spirolactams possessing pyridine or pyridone moieties leading to
conformationally constrained nicotine analogues.10
In order to expand the scope of this methodology, we decided to examine the viability of this approach
toward the synthesis of tetracyclic compounds. Herein we report an efficient synthesis of tetracyclic

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HETEROCYCLES, Vol. 82, No. 1, 2010
aza-spiro compounds by use of a spirocyclization between an N-acyliminium ion and a
2-methoxypyridine moiety tethered on a cyclohexane ring.
We began our spirocyclization studies by preparing the acyclic amido ketone 11, a cyclic N-acyliminium
ion precursor, starting from cyclohexanone 1, as shown in Scheme 1. Aldol reaction of 1 with
4-(4-methoxybenzyloxy)butanal11 and protection of the resulting hydroxy group of 2 as the TBS ether
gave 3 in moderate yield. Treatment of 2-methoxy-6-methylpyridine12 with n-BuLi in THF at 0 °C and
coupling of the resulting alkyllithium with 3 gave the tertiary alcohol 4 in 93% yield. Dehydration of 4
with thionyl chloride and pyridine produced the alkene 5 in 88% yield. Catalytic hydrogenation of the
double bond in 5 with palladium on carbon resulted in concomitant removal of the PMB group to yield
the primary alcohol 6. Two-step oxidation (Parikh–Doering oxidation/Pinnick oxidation) of the primary
alcohol followed by condensation of the resulting acid 8 with BnNH2 using diethyl cyanophosphonate
(DEPC) provided the N-benzylamide 9 in 94% yield. Finally, conversion of 9 to the requisite amido
ketone 11 was accomplished via cleavage of the TBS ether with TBAF followed by Swern oxidation.
OMe
O
N
O
N
OMe
a
c
d
e
OPMB
OH
OR
OPMB
1
OPMB
H
2: R = H
3: R = TBS
OTBS
b
OTBS
4
5
OMe
O
OMe
OMe
OMe
N
N
N
N
f
h
H
j
H
H
H
H
H
O
O
Bn
Bn
N
H
OH
R
N
H
H
H
O
OR
OTBS
OTBS
6
7: R = H
9: R = TBS
10: R = H
11
g
i
8: R = OH
Scheme 1. Synthesis of the N-benzylamide 11. a) LDA, THF, –78 °C, 15 min, then 4-(4-methoxybenzyloxy)butanal, –78
°C, 10 min, 67%; b) TBSCl, Imidazole, DMF, rt, 5 h, 84%; c) 2-methoxy-6-methylpyridine, n-BuLi, –78 °C to 0 °C, 30 min, then
3, 0 °C, 30 min, 93%; d) SOCl2, pyridine, CH2Cl2, 0 °C, 10 min, 88%; e) H2, 10% Pd–C, THF, rt, 48 h, 74%; f) SO3·Py, Et3N,
DMSO, rt, 30 min; g) NaClO2, 2-methyl-2-butene, NaH2PO4, tert-BuOH–H2O, rt, 1 h, 96% over 2 steps; h) BnNH2, DEPC,
Et3N, THF, rt, 12 h, 94%; i) TBAF, THF, rt, 3 h, 92%; j) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to rt, 30 min, 79%.
With the amido ketone 11 in hand, we examined the spirocyclization of 11 via a cyclic N-acyliminium
ion. On the basis of our previous report,10 11 was treated with CSA in refluxing o-dichlorobenzene for
19 h.13 TLC analysis revealed complete disappearance of the starting material and the spirocyclization
occurred to give N-methylpyridone derivative 1214 as the major product in 44% yield, along with the

HETEROCYCLES, Vol. 82, No. 1, 2010
259
N-norpyridone derivative 1315 in 27% yield. As determination of the stereochemistry of the resulting
tetracyclic compounds 12 and 13 was not possible by NMR, the relative configuration of the tetracyclic
compound 12 having a trans-fused decalin was confirmed as depicted in Figure 1 by X-ray
crystallographic analysis.16
OMe
H
H
CSA
N
H
H
o-dichlorobenzene
H
H
+
O
O
N
N
O
reflux, 19 h
Bn
Bn
N Me
O
N H
O
Bn
N
H
O
12 (44%)
11
13 (27%)
12
Figure 1. Spirocyclization of the amido ketone 11 and Chem3D drawing of the X-ray structure of 12.
The observed stereochemistry of the spirocyclization products 12 and 13 can be rationalized by
considering the isomerization of cis-configured N-acyliminium ion 14A, generated from the amido
ketone 11, to the thermodynamically more stable trans-epimer 14B through the formation of an
exo-alkene intermediate 15. Additionally, the formation of 12 and 13 are interpreted as resulting from
the thermally induced rearrangement17 or Hilbert–Johnson type reaction18 of the spirolactam 16 formed
upon spirocyclization of the N-acyliminium ion 14B (Scheme 2).
Bn
Bn
HO
N
+
N
O
+
+
N
O
11
N
OMe
H
Bn
N
N
OMe
14B
OMe
14A
15
H
H
H
H
H
H
+
O
O
O
N
N
N
Bn
Bn
Bn
N Me
O
N H
O
N
OMe
13
12
16
Scheme 2. Plausible pathway to the spirolactams 12 and 13 via spirocyclization of the cyclic N-acyliminium ions 14A, B.
In conclusion, we demonstrated the stereoselective construction of tetracyclic spirolactams having the 2-
pyridone nucleus, based on intramolecular spirocyclization between an N-acyliminium ion and the
internal pyridine ring activated by a 2-methoxy substituent.

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ACKNOWLEDGEMENTS
This work was supported in part by a grant for private universities and a grant for the High Technology
Research Program provided by the Ministry of Education, Science, Sports and Culture and The
Promotion and Mutual Aid Corporation for Private School of Japan to which we are grateful.
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13. Experimental procedure: A mixture of the amido ketone 11 (38.0 mg, 96.3 µmol) and CSA (11.0
mg, 48.2 µmol) in o-dichlorobenzene (4 mL) was heated at reflux for 19 h, and then allowed to cool
to room temperature. This mixture was basified by the addition of sat. aq. NaHCO3 and extracted
with CHCl3. The combined organic layers were washed with brine, dried (MgSO4), and

HETEROCYCLES, Vol. 82, No. 1, 2010
261
concentrated in vacuo. The residue was purified by column chromatography (CHCl3–MeOH, 30:1)
to give 12 (16.1 mg, 44%) and 13 (9.4 mg, 27%), respectively.
14. Data
for
spiro[(5S*,5aS*,9aR*)-1-methyl-5,5a,6,7,8,9,9a-octahydrobenz[g]quinoline-5,5'-(1-
benzyl)pyrrolidin-2'-one] (12): colorless prism after recrystallization from EtOH–AcOEt. mp
1
258–260 °C; IR (KBr): 1678, 1656 cm–1; H NMR (400 MHz, CDCl3): " 0.48–1.36 (6H, m),
1.52–1.90 (5H, m), 2.15 (1H, A part of ABX, J = 17.8, 10.3 Hz), 2.20–2.51 (3H, m), 2.70 (1H, B
part of ABX, J = 17.8, 5.5 Hz), 3.50 (3H, s), 3.63 and 4.84 (2H, ABq, J = 14.8 Hz), 6.43 (1H, d, J =
13
9.5 Hz), 6.96 (1H, d, J = 9.5 Hz), 7.19–7.28 (5H, m); C NMR (100.6 MHz, CDCl3): " 25.0, 25.1,
25.3, 30.4, 30.5, 30.7, 32.7, 34.3, 35.3, 43.7, 44.2, 69.4, 118.7, 118.9, 127.5, 128.3 (2C), 129.1 (2C),
137.2, 138.2, 143.9, 162.7, 175.9; HRMS (ESI–TOF): calcd for C24H29N2O2 (M+ + H) 377.2229,
found 377.2229.
15. Data
for
spiro[(5S*,5aS*,9aR*)-5,5a,6,7,8,9,9a-octahydrobenz[g]quinolin-2(1H)-one-5,5-
1
(1-benzyl)pyrrolidin-2-one] (13): white crystals. mp 293–295 °C; H NMR (400 MHz, CDCl3): "
0.49–1.41 (6H, m), 1.53–1.91 (5H, m), 2.23–2.52 (4H, m, including 1H, A part of ABX, J = 17.8,
11.0 Hz), 2.71 (1H, B part of ABX, J = 17.8, 5.3 Hz), 3.73 and 4.79 (2H, ABq, J = 14.7 Hz), 6.35
13
(1H, d, J = 9.4 Hz), 7.07 (1H, d, J = 9.5 Hz), 7.21–7.52 (5H, m), 12.8 (1H, br s); C NMR (100.6
MHz, CDCl3): " 25.1, 25.2, 25.3, 30.5, 30.9, 32.8, 34.0, 34.3, 44.2, 44.7, 68.8, 118.4, 118.9, 127.5,
128.4 (2C), 129.1 (2C), 138.2, 140.1, 164.8, 176.0.
16. Crystal data for 12: Crystal size: 0.48 # 0.43 # 0.30 mm; Cell dimension: a = 9.4640 (4) Å, b =
15.2930 (5) Å, c = 15.4750 (5) Å; Cell volume: 1924.13 (12) Å3; Z = 4.
17. T. Lister, R. H. Prager, M. Tsaconas, and K. L. Wilkinson, Aust. J. Chem., 2003, 56, 913.
18. K. Matsumoto, Y. Ikemi, M. Suda, H. Iida, and H. Hamana, Heterocycles, 2007, 72, 187.