Synthesis of 1-azaspirocycles via Lewis acid-mediated spirocyclization of cyclic N-acyl-N,O-acetals

Article abstract of DOI:10.1055/s-2001-17475

A new approach to 1-azaspirocycles has been developed starting from cyclic N-acyl-N,O-acetals. This sequence involves olefin-iminium cyclization mediated by Lewis acids leading to the spirocyclization products including the chlorinated products and the olefinic products. Mixtures of these products underwent catalytic hydrogenation and reductive dechlorination to produce the 1-azaspirans.

Full text of DOI:10.1055/s-2001-17475

1506
LETTER
Synthesis of 1-Azaspirocycles via Lewis Acid-Mediated Spirocyclization of
Cyclic N-Acyl-N,O-acetals
S
ynthesis of 1-A
o
zaspirocycl
s
e
s
himasa Ito, Naoki Yamazaki, Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81-426-76-4475; E-mail: kibayasi@ps.toyaku.ac.jp
Received 15 July 2001
taric anhydride (THF, -40 °C), with the amino alcohol 4
Abstract: A new approach to 1-azaspirocycles has been developed
under slow addition condition gave the cyclic N-acyl-
N,O-acetal 12 as a 6:1 diastereomeric mixture favoring
the trans isomer.
starting from cyclic N-acyl-N,O-acetals. This sequence involves
olefin-iminium cyclization mediated by Lewis acids leading to the
spirocyclization products including the chlorinated products and the
olefinic products. Mixtures of these products underwent catalytic
hydrogenation and reductive dechlorination to produce the 1-aza-
spirans.
The Lewis acid-mediated olefin-iminium spirocyclization
was examined initially using the tricyclic N-acyl-N,O-
acetal 8. Thus, 8 was treated with 2 equiv of TiCl4 in
dichloromethane at 20 °C for 2 h, affording chromato-
graphically separable spirocyclization products 13 (42%
as a 2:1 diastereomeric mixture favoring the Cl-equatorial
isomer), 14 (21%), and 15 (28%), in all cases of which the
benzylic carbon atoms were chlorinated (Scheme 2).
Compound 14 was obtained as crystals19 of good quality
for X-ray crystallography, which allowed full assignment
of its stereostructure as shown (Figure 1).
Key words: N-acyl-N,O-acetals, Lewis acid, iminium ions, spiro-
cyclization, 1-azaspirocycles
The 1-azaspirocyclic ring system is a structurally charac-
teristic component of the Dendrobatid alkaloid histrionic-
otoxin,1 erythrina alkaloids,2 and cephalotaxus alkaloids,3
and is also recently found in the marine alkaloids includ-
ing cylindricines,4 lepadiformin,5 fasicularin,6 halichlo-
rine,7 and pinnaic acid.8 The distinctive structural feature
of these natural products sharing the 1-azaspirocyclic
framework has attracted much attention in synthetic or-
ganic chemistry.9,10–14 Particularly, the 1-azaspirocyclic
structure of histrionicotoxin and its congeners has long
been of interest in development of synthetic strategies for
the efficient formation of their core ring system.1,9a,b In
view of literature precedence, we felt that formic acid in-
duced N-acyliminium ion cyclization developed indepen-
dently by the Speckamp15 and Evans16 groups would be a
potentially important method for the construction of the 1-
azaspiro ring system. In this report, we describe a new
variant of the Speckamp-Evans strategy for the construc-
tion of various 1-azaspirocycles. Our approach was based
on Lewis acid-mediated olefin-iminium cyclization start-
ing from cyclic N-acyl-N,O-acetals, which is related to
our ongoing studies on diastereoselective allylation of cy-
clic N-acyl-N,O-acetals promoted by Lewis acids.17
Formation of these azaspirocycles 13, 14, and 15 can be
rationalized as depicted in Scheme 3 via the initial forma-
tion of the iminium intermediate 15, which undergoes two
competing spirocyclization pathways through chlorina-
tion (path a) and deprotonation (path b) leading to the 7-
chlorinated products 13 and the olefinic product 15, re-
spectively. The subsequent addition of HCl to 15 would
occur regio- and stereoselectively leading to the 8-chlori-
nated product 14.
The mixture of 13, 14, and 15 obtained above was sequen-
tially subjected to catalytic hydrogenation and reductive
dechlorination with Bu3SnH and AIBN to give 17 (88%
yield). Cleavage of the N-(2-methylbenzyl) group of 17
under Birch reduction conditions was completed in ex-
tremely short reaction time (10 sec)20 to provide 1-aza-
spiro[5.5]undecan-2-one (18)21 in 88% yield (Scheme 4).
Having thus established Lewis acid–mediated olefin-imi-
nium spirocyclization of the cyclic N,O-acetal 8 to form
the 1-azaspiran, in a further experiment we extended this
reaction to the bicyclic N,O-acetal 6. When 6 was subject-
ed to the same reaction conditions as those for the spiro-
cyclization of 8 (TiCl4, CH2Cl2, 20 °C), the cyclized
products including the chlorinated products and the ole-
finic product were obtained, which is similar to the results
of the spirocyclization of 8, but the reaction gave a low
yield (40% combined) along with some decomposition of
the starting material. In this case, using ZrCl4 instead of
TiCl4 as the Lewis acid, the spirocyclization proceeded
cleanly and subsequent hydrogenation and reductive
dechlorination afforded the 1-azaspiran 19 in 82% overall
yield (Scheme 5).
The cyclic N-acyl-N,O-acetals 6-10 and 12 were readily
prepared by dehydrocondensation of the appropriate keto
acids 1, 2, and 11 with hydroxy amines 3-5 as outlined in
Scheme 1. Thus, treatment of 4-oxo-8-nonenoic acid (1)18
and 5-oxo-9-decenoic acid (2)18 with the amino alcohols
(3 and 4) and the amino phenol (5) in refluxing toluene for
2-3 h afforded the corresponding cyclic N-acyl-N,O-ace-
tals 6-10. Similar treatment of 3-methyl-5-oxo-9-deceno-
ic acid (11), prepared by the Grignard reaction of 4-
pentenylmagnesium bromide (1 equiv) and 3-methylglu-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-210X,E;2001,0,10,1506,1510,ftx,en;Y13301st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of 1-Azaspirocycles
1507
H2N
OH
3
O
N
O
6 (61%)
NH2
( )n
OH
O
N
O
O
toluene, reflux
4
( )n
OH
O
1: n = 1
2: n = 2
7: n = 1 (92%)
8: n = 2 (90%)
NH2
( )n
OH
N
O
O
5
9: n = 1 (92%)
10: n = 2 (93%)
Me
Me
O
O
Me
O
MgBr
4
O
N
O
toluene, reflux
(89%)
THF, –40 °C
(69%)
OH
O
O
11
12
trans:cis = 6:1
Scheme 1
H(Cl)
Cl(H)
O
N
O
TiCl4 (2 equiv)
CH2Cl2, 20 °C
O
N
O
N
O
N
+
+
Cl
Cl
13 (2:1, 42%)
Cl
15 (28%)
Cl
14 (21%)
8
Scheme 2
In the same manner for the cyclization of 8, the N,O-acetal 40 °C, the reaction was completed in 4 h. Subsequent two-
7 underwent efficient TiCl4-induced cyclization (CH2Cl2, step reduction sequence afforded the 1-azaspiro com-
20 °C, 2 h) to form a mixture of the 7- and 8-chlorinated pound 22 (65% yield) accompanied by a noncyclized
products (48% and 29%, respectively) and the olefinic product 23 (7% yield). Similar behavior was observed in
product (10%), which underwent hydrogenation and re- the reaction of 10; the cyclized product 24 (58%) was ob-
ductive dechlorination to produce 20 (85% yield from 7). tained along with the noncyclized product 25 (14%)
Subsequent reductive cleavage of the N-substituent by the (Scheme 5).
Birch reduction reached completion in 10 sec to give 1-
When the substrate 12 (6:1 trans/cis mixture) was submit-
ted to the TiCl4-mediated conditions (CH2Cl2, 20 °C, 2 h)
described above, extremely smooth spirocyclization took
azaspiro[4.5]decan-2-one (21)22 in 98% yield. Under the
same conditions (TiCl4, CH2Cl2, 20 °C), the reaction of 9
incorporating the phenoxy moiety in the molecule was ex-
place to afford quantitatively a mixture of the 7-chlorinat-
tremely sluggish and did not complete after 2 days. How-
ed, 8-chlorinated, and olefinic products in a ratio of
ever, when the reaction temperature was elevated to
Synlett 2001, No. 10, 1506–1510 ISSN 0936-5214 © Thieme Stuttgart · New York

1508
T. Ito et al.
LETTER
Figure 1
Cl–
a
+
N
O
N
O
TiCl4
O
b
H
X
8
16 (X = OTi–Cl4)
path a
path b
Cl
O
N
O
N
X
X
13 (X = Cl)
15 (X = Cl)
HCl
O
N
Cl
X
14 (X = Cl)
Scheme 3
1
54:28:18 by H NMR. This mixture underwent the two- to provide 4-methyl-1-azaspiro[5.5]undecan-2-one (27)23
step reduction sequence to provide the spiro compound 26 in 90% yield (Scheme 5).
in excellent yield (99% from 12). Subsequent exposure to
the Birch reduction conditions in short reaction time (10
sec) led to cleavage of the N-(2-methylbenzyl) substituent
In summary, we have developed a new approach to the 1-
azaspirocycles starting from the cyclic N-acyl-N,O-ace-
Synlett 2001, No. 10, 1506–1510 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Azaspirocycles
1509
tals. This sequence involves olefin-iminium cyclization
mediated by Lewis acids leading to mixtures of the spiro-
cyclization products including the chlorinated products
and the olefinic products, which underwent catalytic hy-
drogenation and reductive dechlorination to produce 1-
azaspiro[4.5]decan-2-one, 1-azaspiro[5.5]undecan-2-one,
and 4-methyl-1-azaspiro[5.5]undecan-2-one.
References and Notes
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1) H2/Pd–C, EtOH
2) Bu3SnH, AIBN, benzene, 80 °C
(88%)
O
N
13/14/15
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Me
17
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H
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18
Scheme 4
1) ZrCl4 (2 equiv), CH2Cl2, 20 °C
O
N
O
O
N
N
O
2) H2/Pd–C, EtOH, then Bu3SnH, AIBN
HO
6
19 (82%)
O
Na/NH3, EtOH, –78 °C
N
O
1) TiCl4 (2 equiv), CH2Cl2, 20 °C
O
N
(98%)
2) H2/Pd–C, EtOH, then Bu3SnH, AIBN
H
21
Me
7
20 (85%)
( )n
N
( )n
N
( )n
O
O
N
O
O
O
1) TiCl4 (2 equiv), CH2Cl2, 40 °C
+
2) H2/Pd–C, EtOH, then Bu3SnH, AIBN
OH
9: n = 1
10: n = 2
23: n = 1 (7%)
25: n = 2 (14%)
22: n = 1 (65%)
24: n = 2 (58%)
Me
N
Me
Me
Na/NH3, EtOH, –78 °C
(90%)
1) TiCl4 (2 equiv), CH2Cl2, 20 °C
O
O
O
N
2) H2/Pd–C, EtOH, then Bu3SnH, AIBN
O
N
H
27
Me
26 (99%)
12
trans:cis = 6:1
Scheme 5
Synlett 2001, No. 10, 1506–1510 ISSN 0936-5214 © Thieme Stuttgart · New York

1510
T. Ito et al.
LETTER
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