Practical and divergent synthesis of 1- and 5-substituted 3,9-diazaspiro[5.5]undecanes and undecan-2-ones

Article abstract of DOI:10.1016/j.tetlet.2008.08.086

A divergent synthesis of 1- and 5-substituted 3,9-diazaspiro[5.5]undecanes and undecan-2-ones is described, in which the key step is an efficient Michael addition of a lithium enolate to a tetrasubstituted olefin acceptor. A variety of substituents (butyl, phenyl, and propoxyl) were introduced at C-1(5) in this manner. In addition, an asymmetric synthesis of one member of this series was achieved using an Evans oxazolidinone chiral auxiliary reagent.

Full text of DOI:10.1016/j.tetlet.2008.08.086

Tetrahedron Letters 49 (2008) 6371–6374
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical and divergent synthesis of 1- and 5-substituted
3,9-diazaspiro[5.5]undecanes and undecan-2-ones
*
Hanbiao Yang , Xiao-Fa Lin, Fernando Padilla, David M. Rotstein
3431 Hillview Avenue, Roche Palo Alto LLC, Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A divergent synthesis of 1- and 5-substituted 3,9-diazaspiro[5.5]undecanes and undecan-2-ones is
described, in which the key step is an efficient Michael addition of a lithium enolate to a tetrasubstituted
olefin acceptor. A variety of substituents (butyl, phenyl, and propoxyl) were introduced at C-1(5) in this
manner. In addition, an asymmetric synthesis of one member of this series was achieved using an Evans
oxazolidinone chiral auxiliary reagent.
Received 21 June 2008
Revised 22 August 2008
Accepted 22 August 2008
Available online 28 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Conformationally constrained heterocyclic multi-ring systems
have received considerable attention from the practioners of drug
discovery.1 This can be attributed to the ability of such entitites to
direct pharmacophores to well-defined 3D space,2 and to their im-
proved pharmacokinetic (PK) profile as a consequence of reduction
in the number of rotatable bonds.3 Bemis and Murcko analyzed
5120 marketed drugs using graph theory analysis.4 They found
that only 32 frameworks are needed to account for 50% of all
known drug molecules. Further analysis of the 32 common frame-
works revealed that 23 of them contain at least two fused or linked
six-membered rings and only three of them contain more than five
rotatable bonds.
O
O
N
S
H
N
N
O
N
F
N
N
O
O
O
NH
O
H2N
Spiperone
L-387,384
MK-0667
Spiropiperidines belong to an important constrained ring sys-
tem class and are found in a number of bioactive molecules, such
as Spiperone—a drug for the treatment of Schizophrenia, L-
Figure 1. Spiropiperidine-containing bioactive molecules.
387,384—a
a
-opioid ligand,5 and MK-0667—a GH secretagogue6
5
1
4
8
7
8
7
5
4
(Fig. 1). Therefore, the design and synthesis of novel spiropiperi-
3
dines are of continued interest to medicinal chemists.7
HN
9
NH
HN
NH
9
3
In connection with one of our drug discovery programs, we
were interested in employing 3,9-diaza-spiro[5.5]undecane 1 and
undecan-2-one 2 as central templates (Fig. 2). Based on our previ-
ous SAR and target homology model, we reasoned that a side chain
to the spirocenter would enhance ligand/protein binding affinity.
Although 3,9-diazaspiro[5.5]undecane 1 has been used extensively
2
2
1
O
1
2
Figure 2. 3,9-Diazaspiro[5.5]undecane 1 and undecan-2-one 2.
8
in drug discovery, to the best of our knowledge, there were no
Surprisingly, only one synthesis of the unsymmetrically N-
substituted congeners of both the 3,9-diazaspiro[5.5]undecane9
and the 3,9-diazaspiro[5.5]undecan-2-one10 systems has been
reported (Scheme 1). Di-ester 3, the key intermediate leading to
3,9-diazaspiro[5.5]undecane skeleton, was prepared from
N-methyl 4-piperidone and ethyl cyanoacetate in a three-step
sequence involving cycolcondensation, hydrolysis and esterifica-
tion. Conversion of 3 into the imide 4, and reduction thereof with
lithium aluminum hydride (LAH) gave the diazaspiroundecane 5.
The synthesis of the 3,9-diazaspiro[5.5]undecan-2-one ring system
relied upon the conjugate addition of lithio ethyl acetate to 6 to
reported syntheses of 1- or 5-substituted 3,9-diazaspiro[5.5]unde-
canes and undecan-2-ones. Presumably, steric hindrance by the
spirocenter makes such a substitution highly disfavored. Herein,
we report a divergent synthesis of 1- and 5-substituted 3,9-diaza-
spiro[5.5]undecanes and undecan-2-ones from a common inter-
mediate, and our initial study of their asymmetric syntheses.
* Corresponding author. Tel.: +1 650 855 5697; fax: +1 650 855 6585.
E-mail address: hanbiao.yang@roche.com (H. Yang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.086

6372
H. Yang et al. / Tetrahedron Letters 49 (2008) 6371–6374
NC
O
MeN
NC
O
CO2Et
CO2Et
1. H2SO4, H2O
2. H2SO4, EtOH
EtOH, NH3
MeN
N
MeN
NH
O
+
CO2Et
3
NC
O
LAH
Benzyl amine
95%
MeN
CN
MeN
N
O
83.4%
Ph
Ph
5
4
CN
1. LiCl, DMSO/H2O
86%
COOEt
COOEt
Ethyl acetate
LDA, -78 oC
25%
N
N
Ph
Ph
COOEt
O
2. Raney Nickel, H2
46%
6
7
LDA: lithium diisopropylamide
N
NH
Ph
8
Scheme 1.
give di-ester 7, which was converted into diazaspiroundecan-2-
one 8 in two steps.
CN
CN
CO2Et
b
a
N
N
6
Our initial synthetic target was the 1-butyl congener of the 3,9-
diazaspiro[5.5]undecane system. Thus, the reaction of 9 with ethyl
cyanoacetate in saturated ethanolic ammonia solution, as de-
scribed in the literature,10 gave a complex mixture, from which
small amounts of the monocondensation products 10 and 11 could
be isolated, but not containing any of the desired product 12
(Eq. 1).
CO2Et
CO2Et
Ph
Ph
X
X
13 X=CH2, 90%
14 X= O, 75%
15 X= CH2, 95%
16 X= O, 89%
e
c, d for 15
c for 16
N
N
O
N
N
CN
Ph
Ph
N
X
X
Ph
Ph
CO2NH2
N
O
n
Bu
19 X = CH2, 72%
20 X = O, 75%
17 X = CH2, 71%
18 X = O, 78%
10
+
Ph
EtOH, NH3
n
Bu
9
4 ºC
10:11 = 1: 1
< 30%
CO2NH2
CN
+
N
Scheme 2. Reagents and conditions: (a) LDA, THF, ꢀ78 °C, for X = CH2, ethyl
hexanoate; for X = O, ethyl propoxyacetate;(b) LiCl, DMSO, H2O, 200 °C; (c) NaBH4,
CoCl2, MeOH, rt; (d) toluene, reflux; (e) LAH, THF, reflux.
NC
CO2Et
ð1Þ
n
Bu
11
CN
O
N
NH
CN
Ph
CN
CO2Et
LiCl, DMSO/H2O
O
CN
n
12
Bu
N
N
ð2Þ
Not Observes
Ph
CO2Et
140 ºC, 2 h
9%
CO2Et
Ph
Ph
22
Ph
21
This result prompted us to examine the reported 3,9-diaza-
spiro[5.5]undecan-2-one synthesis, but the low yield (25%)
reported in the Michael addition step (6?7) was of concern to us
because the 1-substitued congeners of the spirocyclic system were
required in multi-gram amounts. On the assumption that the poor
yield was associated with temperature control in the enolate gen-
eration step, a pre-cooled (ꢀ78 °C) THF solution of ethyl caproate
or ethyl propoxyacetate was added to a stirred solution of a THF
solution Lithium diisopropylamide (LDA) and 6 at ꢀ78 °C. The Mi-
chael addition products 13 and 14 were thus obtained in 90% and
75% yields, respectively, (Scheme 2). Krapcho de-ethoxycarbonyla-
tion (2 equiv of LiCl, DMSO/H2O, 200 °C) of the Michael adducts
occurred selectively and in high yield, to give the mono-esters 15
and 16. Catalytic reduction (Raney Nickel, H2) of the nitrile group
of 15 and 16 took place in modest yields at best, but reduction with
a large excess of NaBH4 (15 equiv), in the presence of CoCl2 in
methanol solution,11 occurred cleanly and efficiently to give the
spirocyclic lactams 17 and 18 directly. Final LAH reduction of the
lactams readily provided the 3,9-diazaspiro[5.5]undecanes 19
and 20.
An attempt to apply the methodology described in Scheme 2 to
the synthesis of the phenyl analog turned out to be problematic in
the de-ethoxycarbonylation step. The required mono-ester 22 was
obtained in very low yield, perhaps due to the loss of the benzylic
ethoxycarbonyl group.12 This problem was solved as shown in
Scheme 3, via the t-butyl ester 23. Microwave irradiation of a hexa-
fluoroisopropanol solution of this diester (1 h/130 °C) gave the
mono-ester 24 nearly quantitatively.13 This compound was con-
verted into 25 and 26 by the methods described above.
Cyanoester 15 also served as
a flexible intermediate for
the synthesis of 5-substituted-3,9-diazaspiro[5.5]undecan-2-ones
(Scheme 4). Thus, selective reduction of the ester with lithium
pyrrolidinoborohydride14 gave alcohol 27, which was converted
into the azide 28 via a Mitsunobu reaction. Staudinger reduction
of 28 gave the iminophosphorane 29, which upon vigorous acidic
hydrolysis (concd HCl/100 °C, 3 d) produced the diazaspiroundeca-
none 30 via the easily detectable (liquid chromatography–mass
spectrometry) intermediate amidine 31.

H. Yang et al. / Tetrahedron Letters 49 (2008) 6371–6374
6373
CN
CO2
CN
CN
t
Bu
b
a
N
N
N
Ph
t
Bu
CO2
Ph
Ph
CO2Et
Ph
CO2Et
Ph
Ph
23
24
c
d
N
NH
O
N
NH
Ph
Ph
25
Ph
26
Scheme 3. Reagents and conditions: (a) ethyl phenylacetate, LDA, THF, ꢀ78 °C, quant.; (b) hexafluoro-2-propanol, 130 °C, microwave, 1 h, 95%; (c) NaBH4, CoCl2, MeOH, rt,
73%; (d) LAH, THF, reflux, 65%.
viously employed Krapcho conditions (2 equiv LiCl, DMSO/H2O,
CN
CN
200 °C, 2 h), 34 was converted into the nitrile 35 in only 25% yield,
but this yield was greatly improved when the reaction was effected
with ca 1 equiv of LiCl at 140 °C. Interestingly, when the reaction
was carried out at 140 °C with 3 equiv of LiCl, the nitrile 35 was
formed cleanly, but upon further heating at 200 °C for 50 min, it
was completely converted into the oxazoline 38 (Eq. 3), the struc-
ture of which was fully confirmed by NMR experiments.17 Reduc-
tion of the nitrile group of 35 as described above gave
undecanone 36 (>99.5% ee), which on further reduction with LAH
in refluxing THF yielded undecane 37 (79% yield) with minimal
racemization (98% ee).
a
b
15
N
N
Ph
Ph
Ph
OH
N3
n
Bu
n
Bu
27
28
O
CN
d
c
N
N
NH
Ph
N
PPh3
nBu
nBu
29
30
NH
NH
In summary, a practical and divergent synthesis of 1- and
5-substituted 3,9-diazaspiro[5.5] undecanes and 3,9-diaza-
spiro[5.5]undecan-2-ones is described, in which the key synthetic
step involves an efficient Michael addition of the lithium enolates
N
Ph
n
Bu
31
of a-substituted acetic acid esters to tetrasubstituted olefin accep-
tors such as 6.18 Similar methodology using the Evans oxazolidi-
none chiral reagent 32 permitted the synthesis of the highly
optically enriched 5-butyl-3.9-diazaspiro[5.5]undecan-2-one 36.
Scheme 4. Reagents and conditions: (a) Lithium pyrrolidinoborohydride, THF, rt,
86%; (b) PPh3, diethylazodicarboxylate, diphenyl phosphoryl azide, THF, rt, 54%.
An asymmetric synthesis based on the above methodology was
then devised. Michael addition of the lithium enolate15 of the opti-
cally pure ester 32 to 6 occurred in excellent yield (88%) to give a
1:13, readily separable (flash column chromatography), mixture of
the stereoisomeric adducts 33 and 34 (Scheme 5). 16 Under the pre-
Acknowledgments
We thank Dr. Joseph Muchowski for proof-reading this Letter
and Mr. Saul Jaime-Figueroa for the helpful discussion.
References and notes
then 200 oC
CN
O
1. For recent examples, see: (a) Mustazza, C.; Borioni, A.; Sestili, I.; Sbraccia, M.;
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2008, 18, 1374; (c) Costanzo, M. J.; Yabut, S. C.; Zhang, H.-C.; White, K. B.;
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V.; Page, C. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett 2008, 18, 2114.
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S.; Chaung, L. P.; Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu, S. L.; Smith, R. G.
Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001.
7. For recent examples, see: (a) Pfefferkorn, J. A.; Choi, C. Tetrahedron Lett. 2008,
49, 4372; (b) Tang, F.-Y.; Qu, L.-Q.; Xu, Y.; Ma, R.-J.; Chen, S.-H.; Li, G. Synth.
Commun. 2007, 37, 3793; (c) Laras, Y.; Pietrancosta, N.; Moret, V.; Marc, S.;
Garino, C.; Rolland, A.; Monnier, V.; Kraus, J.-L. Aust. J. Chem. 2006, 59, 812.
8. For recent patents, see: (a) Schudok, M.; Wagner, M.; Bauer, A.; Kohlmann, A.
WO 2007137738, 2007; Chem Abstr. 2007, 148, 34023.; (b) Berk, S. C.; Close, J.;
Hamblett, C.; Heidebrecht, R. W.; Kattar, S. D.; Kliman, L. T.; Mampreian, D. M.;
Methot, J. L.; Miller, T.; Sloman, D. L.; Stanton, M. G.; Tempest, P.; Zabierek, A. A.
U.S. Patent. 2,007,117,824, 2007; Chem Abstr. 2007, 147, 9884; (c) Boerjesson,
L.; Connolly, S.; Johansson, H.; Kristoffersson, A.; Linnanen, T.; Shamovsky, I.;
3 eq. LiCl
(3)
BnN
34
35
DMSO/H2O, 140 oC
N
Ph
n-Bu
Ph
38
O
O
n
Bu
CN
CN
N
O
CO2Et
O
32
CO2Et
Ph
N
N
O
+
O
6
O
Ph
a
N
nBu
N
O
n
Bu
O
34 (88%)
33 (7%)
Ph
Ph
b
CN
O
c
d
N
N
NH
N
NH
O
O
Ph
Ph
Ph
N
n
Bu
n
Bu
37
n
Bu
36
O
35
Ph
Scheme 5. Reagents and conditions: (a) LDA, THF, ꢀ78 °C, then 21, ꢀ78 °C, 88%
yield for the R-isomer; (b) LiCl, DMSO, H2O, 140 °C, 89%; (c) NaBH4, CoCl2, MeOH, rt,
80% yield, >99.5% ee; (d) LAH, THF, reflux, 79% yield, 98% ee.

6374
H. Yang et al. / Tetrahedron Letters 49 (2008) 6371–6374
Skrinjar, M. WO 2007030061, 2007; Chem Abstr. 2007, 146, 337739; (d)
Connolly, S.; Linnanen, T.; Skrinjar, M. WO 2006107253, 2006; Chem Abstr.
2006, 145, 418956.
2.70–2.60 (m, 2H), 2.41–2.13 (m, 4H), 1.80–1.13 (m, 11H), 0.89 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 75 MHz) d 172.4, 138.6, 129.6, 128.6, 127.4, 63.7, 49.3,
49.2, 42.5, 41.5, 38.6, 35.2, 33.8, 31.8, 30.9, 26.1, 23.2, 14.4; IR (neat film) 3421,
3195, 3060, 2948, 2932, 2869, 2799, 2762, 1670, 1505, 1451, 1411, 1366, 1341,
1313, 1121, 736 cmꢀ1; HRMS Cacld for C20H31N2O [M+H]+ 315.2436. Found:
9. (a) Rice, L. M.; Grogan, C. H.; Freed, M. E. J. Heterocycl. Chem. 1964, 1, 125; (b)
McElvain, S. M.; Lyle, R. E., Jr. J. Am. Chem. Soc. 1950, 72, 384.
10. Fisher, M. J.; Jakubowski, J. A.; Masters, J. J.; Mullaney, J. T.; Paal, M.; Ruehter,
G.; Ruterbories, K. J.; Scarborough, R. M.; Schotten, T.; Stenzel, W. WO 9711940,
1997; Chem Abstr. 1997, 126, 317374.
11. Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron Lett. 1969, 10,
4555.
12. McMurry, J. Org. React 1976, 24, 187.
13. Private communication with Saul Jaime-Figueroa, Roche Palo Alto LLC.
14. Collins, C. J.; Fisher, G. B.; Reem, A.; Goralski, C. T.; Singaram, B. Tetrahedron
Lett. 1997, 38, 529.
15. For the use of titanium enolate in enantiselective Michael additions, see: Evans,
D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry, D.; Kato, Y. J. Org. Chem.
1991, 56, 5750.
315.2433. Compound 36: ½a D25
ꢁ
+32.4 (c 1.7, CH2Cl2); ee >99.5% (determined by
chrialpak AD analytical column with 85:15 hexane/EtOH at 1.4 mL/min rate).
1H NMR (CDCl3, 300 MHz) d 7.36–7.21 (m, 5H), 6.13 (br s, 1H), 3.49 (s, 2H),
3.28–3.20 (m, 2H), 2.60–2.55 (m, 2H), 2.35–2.25 (m, 2H), 2.12–2.08 (m, 1H),
1.83–1.72 (m, 1H), 1.53–1.23 (m, 11H), 0.89 (t, J = 7.1H, 3H); 13C NMR (CDCl3,
75 MHz) d 176.2, 138.7, 129.6, 128.6, 127.4, 63.8, 50.9, 49.6, 49.5, 38.6, 34.5,
34.1, 33.7, 31.7, 28.0, 26.7, 23.5, 14.4; IR (neat film) 3681, 3402, 3207, 3019,
2956, 2873, 2811, 2771, 2400, 1656, 1496, 1454, 1369, 1343, 1297, 1163, 1106,
1029, 991, 909, 701 cmꢀ1
Found: 315.2431. Compound 37: ꢁ
;
HRMS Calcd for C20H31N2O [M+H]+ 315.2436.
+55.0 (c 2.3, CH2Cl2); ee 98%
½
a 2D5
(determined by chrialpak AD analytical column with 95:05 hexane/EtOH at
1.4 mL/min rate). 1H NMR (CDCl3, 300 MHz) d 7.32–7.22 (m, 5H), 4.53 (br s,
1H), 3.49 (s, 2H), 3.02–2.88 (m, 2H), 2.85–2.76 (m, 1H), 2.62–2.52 (m, 3H),
2.26–2.09 (m, 2H), 2.02–1.88 (m, 2H), 1.60–1.40 (m, 3H), 1.36–0.95 (m, 8H),
0.87 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 138.8, 129.5, 128.6, 127.3,
63.9, 49.1, 45.6, 44.7, 41.6, 35.5, 33.3, 31.8, 31.2, 28.1, 26.5, 23.4, 14.5; IR (neat
film) 3285, 3061, 3026, 2929, 2858, 2804, 1494, 1453, 1394, 1365, 1342, 1135,
16. The stereochemistry was assigned based on related titanium enolate Michael
addition reactions in Ref. 16.
17. During the preparation of this manuscript, a similar decarboxylation reaction
of N-acyl oxazolidinone was reported by Hoye and co-workers, see: May, A. E.;
Willoughby, P. H.; Hoye, T. R. J. Org. Chem. 2008, 73, 3292.
18. Selected spectral data—compound 30: 1H NMR (CDCl3, 300 MHz) d 7.30–7.20 (m,
5H), 6.85 (s, 1H), 3.51 (s, 2H), 3.41 (dd, J = 1.5, 4.7 Hz, 1H), 3.10–3.02 (m, 1H),
1083, 1029, 993, 794, 738, 698 cmꢀ1
;
HRMS Calcd for C20H33N2 [M+H]+
301.2644. Found: 301.2614.