Synthesis of an azaspirane via Birch reduction alkylation prompted by suggestions from a computer program

Article abstract of DOI:10.1016/j.tetlet.2006.07.100

With the aid of proposals from a computer program for synthesis design, a new method of synthesizing azaspiranes has been developed. In this method, one starts with a suitable benzoic acid ester, which is subjected to Birch reduction. Then the anionic int

Full text of DOI:10.1016/j.tetlet.2006.07.100

Tetrahedron Letters 47 (2006) 6733–6737
Synthesis of an azaspirane via Birch reduction alkylation
prompted by suggestions from a computer program
Akio Tanaka,* Takashi Kawai, Tetsuhiko Takabatake, Noriko Oka,
Hideho Okamotoà and Malcolm Bersohn§
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugade-naka 3-chome, Konohana-ku,
Osaka 554-8558, Japan
Received 8 May 2006; revised 19 July 2006; accepted 21 July 2006
Available online 8 August 2006
Abstract—With the aid of proposals from a computer program for synthesis design, a new method of synthesizing azaspiranes has
been developed. In this method, one starts with a suitable benzoic acid ester, which is subjected to Birch reduction. Then the anionic
intermediate is alkylated with 1,2-dibromoethane. The product is subsequently reacted with an amine to give a spiro lactam.
Ó 2006 Elsevier Ltd. All rights reserved.
An N-containing spiro structure is one of the important
skeletons in pharmaceuticals.1 In 1973, azaspirane 1 was
synthesized by Leonard M. Rice et al. to study its bio-
activity, for example, its inhibitory action in KB cells
and cells of human mammary cancer grown in tissue
culture.2 Since 1 was disclosed, many related derivatives
have been investigated and currently N,N-diethyl-8,8-
dipropyl-2-azaspiro[4,5]decane-2-propanamine 1a (1:
R1 = n-Pr, R2 = Et, SK&F106615, Atiprimod) is the
compound with the highest reported bioactivity.3,4 The
bioactivities are still being extensively studied.5 This
letter describes a novel route to 1a (Fig. 1).
R2
N
R2
N
2 HCl
R1, R2 = alkyl
R1 R1
1
1a (R1,R2 = n-Pr)
Figure 1. General structure of azaspirane and target 1a.
Two syntheses of 1a have been published. In one, 4,4-di-
n-propylcyclohexanone 3 is condensed with ethyl cyano-
acetate. The product reacted with KCN via Michael
addition. After hydrolysis, the corresponding anhydride
4 reacts with 3-diethylaminopropylamine to provide 1a
by reduction with LiAlH4.2 Another synthesis consists
of a 6-membered ring formation from 4,4-bis-(2-iodo-
ethyl)-heptane 6 and 1-(3-diethylaminopyropyl)-pyrroli-
din-2-one 7 followed by LiAlH4 reduction (Scheme 1).6
For the purpose of exploration for new efficient syn-
thetic routes, we used the synthesis design program
SYNSUP,7 which generates plausible routes in a retro-
synthetic fashion. After a chemist launches the program
with a specific goal, there is no further interaction of the
program and the chemist. The program explores for
routes in a depth first manner. A path leading from
the goal is generated step by step. At each stage, the
reaction which is judged to produce the most simplifica-
tion is chosen first, provided it has not been used before
at that stage. The greatest simplification means that
the most connections present in the final product are
made. For example, any cycloaddition reaction would
be favored over a single C–C bond forming reaction.
The starting compounds of proposed routes must be
Keywords: Heterocycles; Azaspirane; SYNSUP; Birch reduction alkyl-
ation; Synthesis design; Retrosynthesis.
*
Corresponding author; e-mail: tanakaa1@sc.sumitomo-chem.co.jp
Present address: Sumika Technical Information Service, Inc., 1-98,
Kasugade-nake 3-chome, Konohana-ku, Osaka 554-8558, Japan.
à Present address: Center for Joint Research and Development, Tottori
University, 4-109, Koyama-cho, Minami, Tottori 680-0945, Japan.
§ Department of Chemistry, University of Toronto, Ont., Canada M5S
3H6.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.100

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A. Tanaka et al. / Tetrahedron Letters 47 (2006) 6733–6737
O
NEt2
O
O
N
O
O
4 steps
2 steps
4 steps
n-Pr
n-Pr
n-Pr
N
n-Pr
2
n-Pr
n-Pr
3
4
1a
3 steps
NEt2
I
I
HO2C
CO2H
n-Pr
3 steps
LiAlH4
O
7
n-Pr
n-Pr
n-Pr
5
6
Scheme 1. Two published synthetic routes to 2, which is one of the most promising biologically active azaspiranes.
available. This means they should be in a set of catalogs
embedded in our program or else they should satisfy the
user specified definition of simplicity, such as having a
certain limited number of functional groups, of chiral
centers, and of rings. In addition, the search can be con-
strained by compulsory starting materials and/or a spec-
ification in the input that certain bonds must or must
not be made in the course of an acceptable route. The
program has been developed for more than 20 years in
order to find manufacturing processes for promising
new organic compounds used in the areas of pharma-
ceutical products, agrochemicals and electronic materi-
als. At the present time, our program has more than
5500 synthetic procedures for generating precursors. In
the real world, there are many more synthetically useful
transformations than this number, so we are constantly
adding more synthetic procedures to the repertory of the
program.
There are two reported routes of 3: the hydrogenation
of 8 and the Dieckmann reaction of dicarbonyl 9.
Although the program did not propose the hydrogena-
tion of 8, it did propose the principal skeletal transfor-
mations in the experimentally achieved routes to 3.
Scheme 3 shows a portion of the synthetic routes of 1a
from 3 proposed by SYNSUP. The routes include the
reported route via 4. From the result of the test, we
confirmed that our program generally could suggest
the reported routes.
Besides the routes in Scheme 1, routes to [4,5]-azaspir-
anes via radical cyclization of cyclohexenyl selenocarba-
mates,8 CuCl catalyzed cyclization of cyclohexene
derivatives substituted with trichloroacetoamides,9
intramolecular hydroamination of 1-allyl-1-aminometh-
ylcyclohexanes with BuLi,10 oxidative spirocyclization
of phenolic sulfonamides,11 and irradiation of amino-
ethylcyclohexanones12 have been reported.
We ran the program to see if SYNSUP would produce
the reported routes to 1a. With respect to synthetic
routes of the key intermediate 3 from 2, our program
proposed more than one hundred routes including
known routes. Scheme 2 shows an interesting excerpt
chosen from routes suggested by SYNSUP. We display
computer proposed routes with bold arrows, to distin-
guish them from experimentally accomplished schemes.
Using the proposals of SYNSUP with a focus on finding
a new route of azaspirane, an encouraging synthetic
plan was selected as shown in Scheme 4. According to
the plan, the commercially available methyl 3,5-di-
methoxybenzoate 10 is to be converted via Birch reduc-
tion alkylation with 1,2-dibromoethane to cyclohexa-
1,3-diene 11. Hydrolysis of 11 will give 12, which is then
O
CHO
O
ClCH2OMe
NCCO2Me
CO2Me
Mg
Li/NH3
O
n-Pr
n-Pr
n-Pr
n-Pr
8
CO2Me
MeO2C
CO2Me
O
BrC2H4CO2Me
SmI2
Methyl acrylate
NiCl2/Zn
MeOH
HBr
O
Br
n-Pr n-Pr
DMPU
3
2
n-Pr n-Pr
n-Pr n-Pr
9
CH2N2
MeOH
NCCH2CO2Me
5
Scheme 2. Proposed routes of 3 from 2 proposed by SYNSUP.

A. Tanaka et al. / Tetrahedron Letters 47 (2006) 6733–6737
6735
HO
Br
OH
Br
CBr4
PPh3
H2N
NEt2
n-Pr n-Pr
LiAlH4
n-Pr n-Pr
NEt2
NEt2
NH2
O
CO2H
CO2H
N
MeO2C
CH2(CO2Me)2
CO2Me
O
KCN
H+
TiCl4
1a
4
3
n-Pr n-Pr
n-Pr n-Pr
H+
n-Pr n-Pr
NEt2
NEt2
OH
NEt2
NEt2
O
N
HN
HN
NaCN
CN
NHAc
BuLi
TMSCl
NaI
NH
AlCl3
O
O
n-Pr n-Pr
n-Pr n-Pr
n-Pr n-Pr
Scheme 3. Proposed routes of 1a from 3 proposed by SYNSUP.
Br
O
Br
CO2Me
CO2Me
Br
Br
CO2Me
MeO
OMe
O
MeO
OMe
10
11
12
NEt2
NEt2
N
N
O
O
H2N
NEt2
n-PrI
O
O
1a
O
n-Pr n-Pr
O
13
14
Scheme 4. An encouraging new synthetic route to 1a proposed by SYNSUP.
reacted with a diamine to effect ring closure, as shown in
Scheme 4. Diketone 13 is doubly alkylated with 2 mol of
1-propyl iodide to give 14, which is then deoxygenated
to give 1a, the final product.
ply reduced product 18 was obtained in 91% yield
(Scheme 6).
NEt2
The plan was confirmed by experiments, done with a
slight alteration in the order of operations. The starting
material 10 was treated with 1,2-dibromoethane to pro-
duce 11 quantitatively. 11 was reacted with the diamine
to give 15 via cyclization in moderate yield (Scheme 5).13
N
O
a
b
10
11
MeO
OMe
15
Incidentally, SYNSUP also proposed another synthetic
route for 15, that is, from 16. However, the attempted
Birch reduction alkylation of benzoyl amide 17 with
1,2-dibromoethane was unsuccessful and only the sim-
Scheme 5. The first part of the experimental route to 1a. Reagents and
conditions: (a) 1. t-BuOH, NH3, Li, THF, À78 °C; 2. Br(CH2)2Br
(96%) and (b) H2N(CH2)3NEt2, NEt3, DMF, reflux (70%).

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A. Tanaka et al. / Tetrahedron Letters 47 (2006) 6733–6737
15
NEt2
NEt2
CO2H
O
NH
a
b
O
NH
MeO
OMe
MeO
OMe
MeO
OMe
16
17
18
Scheme 6. An unsuccessful trial to generate 15 based on another proposal by SYNSUP. Reagents and conditions: (a) H2N(CH2)3NEt2, DCC, THF
(88%) and (b) 1. t-BuOH, NH3, Li, THF, À78 °C; 2. Br(CH2)2Br (91%).
Dialkylation of 15 was done using standard procedures:
a THF solution of n-BuLi was added to 15 in the pres-
ence of HMPA at À78°C. Alkylation with 1-propyl
iodide gave 19, which was reduced by LiAlH4. Depro-
tection of 20 with acid yielded 21 quantitatively (Scheme
7).14
we succeeded via hydrogenation of dithioketals in the
presence of Raney nickel. Even using this method,
simultaneous conversion of the diketone of 21 into the
corresponding bis-dithioketal failed, probably because
of steric hindrance. Accordingly, 1a was obtained by
stepwise deoxygenation (Scheme 8).
Deoxygenation of 21 proved to be very difficult. Under
typical reduction conditions, both the Wolff–Kishner
reduction15 and reduction with NaBH3CN to the corre-
sponding tosylhydrazone16 completely failed. Finally,
In an effort to decrease the trouble of the deoxygenation,
the racemic diol 23 from 19 was converted to tosylate 24
for deoxygenation (Scheme 9). But deoxygenations with
17
LiEt3BH or LiAlH4 did not proceed. In addition, the
NEt2
NEt2
NEt2
N
O
N
N
a, b
c
d
15
MeO
OMe
MeO
OMe
O
O
n-Pr n-Pr
n-Pr n-Pr
n-Pr n-Pr
19
20
21
Scheme 7. The second part of the experimental route to 1a. Reagents and conditions: (a) 1. t-BuLi, HMPA, THF, À78 °C; 2. n-PrI; (b) 1. t-BuLi,
HMPA, THF, À78 °C; 2. n-PrI (quant.); (c) LiAlH4, THF, reflux (93%) and (d) 1 N HCl (95%).
NEt2
b
NEt2
c
NEt2
N
N
N
a
d
21
1a
S
S
O
n-Pr
O
S
n-Pr
S
n-Pr n-Pr
n-Pr
n-Pr
Scheme 8. The successful deoxgenation of 21 to produce the final goal azaspirane 1a. Reagents and conditions: (a) HS(CH2)2SH, BF3–OEt2, 90 °C
(42%); (b) Raney Nickel, EtOH, reflux (39%); (c) HS(CH2)2SH, BF3–OEt2, 90 °C (64%) and (d) Raney Nickel, EtOH, reflux (43%).
NEt2
c
NEt2
d
N
N
a
b
1a
19
14
HO
OH
TsO
OTs
n-Pr n-Pr
n-Pr n-Pr
23
24
Scheme 9. Another failed trial of deoxygenation of diketone via the corresponding diol 23 to 1a. Reagents and conditions: (a) 1 N HCl, acetone
(99%); (b) LiAlH4, THF (91%) and (c) LiEt3BH or LiAlH4.

A. Tanaka et al. / Tetrahedron Letters 47 (2006) 6733–6737
6737
attempted photosensitized electron-transfer reaction18
of the di-m-trifluorobenzoate of 23 produced only an
intractable mixture.
Hanna, N.; Mirabelli, C. K. J. Med. Chem. 1990, 33,
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The overall yield of the six steps from the starting mate-
rial 10 to diketone 21 was 59%. However, the total yield
of 1a was only 3%, which is lower than the approximately
25% achieved by the reported route in Scheme 1. The low
yield was due to the inefficient stepwise deoxygenation
and also to the fact that we did not do any optimization
of the yields. The computer program does not estimate
yields. It attempts to minimize chemically erroneous
reaction steps by inspecting the functional groups in
the molecule and determining from its stored data
whether or not any of them would be damaged by the
reagent used. It also notes the influence of aromatic sub-
stituents on the orientation of substitution, assesses steric
hindrance, etc. At the end, there is a qualitative decision,
that is, to proceed with this reaction or not.
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In summary, with the aid of the SYNSUP program, a
new synthetic route to azaspiranes was found, using
Birch reduction alkylation followed by lactamization
with an amine.
13. 1H NMR: d (ppm), CDCl3, coupling constants J in Hz.
Compound 11: 2.31 (2H, t, J = 8.3 Hz), 2.76 (2H, t,
J = 1.5 Hz), 3.21–3.27 (2H, m), 3.61 (6H, s), 3.69 (3H, s),
4.63 (2H, s). Compound 15: 1.02 (6H, t, J = 6.9 Hz),
1.71–1.75 (2H, m), 2.03–2.08 (2H, m), 2.41–2.57 (6H, m),
2.79–3.00 (2H, m), 3.30–3.41 (4H, m), 3.57 (6H, s), 4.47
(2H, s).
References and notes
14. 1H NMR: d (ppm), CDCl3, coupling constants J in Hz.
Compound 19: 0.80–0.85 (6H, m), 0.97–1.03 (3H, m),
1.21–1.26 (2H, m), 1.49–1.57 (4H, m), 1.70–1.76 (2H, m),
2.00 (2H, t, J = 6.9 Hz), 2.40–2.56 (6H, m), 3.29–3.39 (4H,
m), 3.50 (6H, s), 4.53 (2H, s). Compound 20: 0.77–0.83
(6H, m), 0.89–1.05 (10H, m), 1.44–1.50 (4H, m), 1.63–1.71
(2H, m), 1.76–1.81 (2H, t), 2.39–2.57 (6H, m), 2.61–2.69
(6H, m), 3.47 (6H, s), 4.75 (2H, s). Compound 21: 0.83–
0.93 (6H, m), 0.96–1.15 (10H, m), 1.53–1.73 (6H, m), 2.32–
2.73 (18H, m).
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