Synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones

Article abstract of DOI:10.1016/j.tetlet.2010.11.150

A synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones using a combination of solution-phase and solid-phase chemistries is described. A solution-phase approach was used to produce a key piperidine intermediate that was then incorporated into a solid-phase synthesis. The combined synthetic strategy was applied to provide a series of substituted 3,8,11-triazaspiro[5,6] dodecan-7-ones in good yield and high purity.

Full text of DOI:10.1016/j.tetlet.2010.11.150

Tetrahedron Letters 52 (2011) 849–852
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones
⇑
Lan-Ying Qin , Andrew G. Cole, Axel Metzger, Kurt W. Saionz, Ian Henderson
Ligand Pharmaceuticals Inc., 3000 Eastpark Blvd., Cranbury, NJ 08512, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of novel substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones using a combination of solution-
phase and solid-phase chemistries is described. A solution-phase approach was used to produce a key
piperidine intermediate that was then incorporated into a solid-phase synthesis. The combined synthetic
strategy was applied to provide a series of substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones in good
yield and high purity.
Received 29 September 2010
Revised 24 November 2010
Accepted 29 November 2010
Available online 4 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Triazaspiro[5,6]dodecan-7-one
Solid phase
The triazaspirone core structure is present in molecules that
exhibit a wide range of biological activities. For example, the anti-
psychotic agent spiperone (1, Fig. 1) is a potent antagonist of the
dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A receptors.1
Other 1,3,8-triazaspiro[4,5]decan-4-one derivatives are reported
to be selective serotonin 5-HT2A receptor antagonists,1,2 GlyT-1
inhibitors,3 and phospholipase D inhibitors.4 Compounds incorpo-
rating the isomeric 1,4,8,-triaza[4,5]decan-2-one scaffold are useful
as cerebral function-improving agents for senile dementia and
Alzheimer’s disease.5 The ring-expanded 2,4,9-triazaspiro[5,5]
undecan-3-one core is present in monoamine receptor inverse
agonists.6 Further ring expansion elicits the 1,4,10-triazaspiro
[5,6]dodecan-5-one motif that is incorporated into selective adren-
ergic a2 receptor antagonists.7 However, this is the only report on
the synthesis and activity of molecules incorporating a [5,6]triazas-
pirone system. To allow the further investigation of this chemotype,
additional synthetic strategies need to be developed. This Letter de-
scribes the development of a robust combined solution-phase and
solid-phase synthesis of compounds incorporating a novel substi-
tuted 3,8,11-triazaspiro[5,6]dodecan-7-one system (17, Fig. 1).
An advantage of solid-phase synthesis over solution-phase syn-
thesis is that extensive reaction work ups and purifications are
avoided.8 The development of optimized reaction conditions al-
lows straightforward draining of excess reagents and subsequent
washing of the solid support upon reaction completion.9 However,
not all reactions can be performed on solid phase due to reagent
incompatibility with either the solid support or the linker that
attaches the molecule to the solid support. Also, solid-phase reac-
tions can generate undesirable impurities that remain covalently
linked to the solid support and cannot be washed away. Solu-
tion-phase synthesis does not have these particular limitations.
Reactions in solution can be performed with a wide variety of
3
R3
N
O
6
4
NH
O
1
11
3
N
7
R4
1
N
10
HN
R1
O
N
5
8
8 N
7
O
R2
1
17
F
Figure 1.
MeO C CH OH
CO H
CO Me
2
2
2
2
a
b
c
N
N
N
Boc
Boc
Boc
2
3
MeO
MeO
O
HO C
HO C
MeO C
2
2
2
OMe
OMe
H
f,g
d,e
N
N
N
Boc
Fmoc
Boc
4
5
6
Scheme 1. Reagents and conditions: (a) CH3OCOCl, Et3N, CH2Cl2, 0 °C, then
anhydrous MeOH, 25 °C, 4 h; (b) LDA, Et2O, ꢀ78 °C, then (CH2O)n, THF, ꢀ78 °C,
4 h; (c) (COCl)2, DMSO, iPr2NEt, CH2Cl2, ꢀ78 °C, 45 min; (d) p-toluenesufonic acid
monohydrate, MeOH, HC(OMe)3, 60 °C, 4 h; (e) KOH, H2O, MeOH, reflux, 4 h; (f)
trifluoroacetic acid, CH2Cl2, 25 °C, 30 min; (g) Fmoc-Cl, Na2CO3, THF, H2O, 25 °C,
20 h.
⇑
Corresponding author. Tel.: +1 609 720 0599; fax: +1 609 655 4187.
E-mail address: lan-ying.qin@bms.com (L.-Y. Qin).
In 2008, Pharmacopeia, Inc. was acquired by Ligand Pharmaceuticals, Inc.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.150

850
L.-Y. Qin et al. / Tetrahedron Letters 52 (2011) 849–852
O
Br
NO2
H
N
O
N
NH
4
NH2
N
H
2
H
NH2
a,b
c
O
4
HN
7
9
8
O
NO2
Br
=
R1
O
N
H
NO2
H
N
N
H
HN
L
NH
R1
d
O
4
10
10
O
NO2
NH
R1
Scheme 2. Reagents and conditions: (a) N-a-N-e-bis-Fmoc-Lys, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 20 h; (b) piperidine, DMF, 25 °C, 1 h; (c) 4-carboxy-2-nitrobenzyl
bromide, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 20 h; (d) R1-NH2, THF, 25 °C, 20 h.
reagents with subsequent purification to remove any undesirable
by-products. The combination of solution-phase and solid-phase
reactions in a synthetic strategy can be a powerful tool to both
utilize the respective advantages and circumvent the respective
weaknesses of each technique. The synthesis of novel 3,8,11-tri-
azaspiro[5,6]dodecan-7-ones detailed here employs such a com-
bined solution-phase and solid-phase approach.
The synthetic strategy to access the 3,8,11-triazaspiro[5,6]dod-
ecan-7-ones was initiated by the construction of 1-Fmoc-4-
(dimethoxymethyl)piperidine-4-carboxylic acid (6) in solution
(Scheme 1). Boc-protected isonipecotic acid was esterified to give
the methyl ester 2. Deprotonation of 2 with lithium diisopropyl-
amide (LDA) at ꢀ78 °C was followed by hydroxymethylation with
paraformaldehyde to generate alcohol 3. The use of a strong base
such as LDA would be incompatible with the photo-labile linker
subsequently used in the solid-phase part of this synthetic strategy
(vide infra). Swern oxidation of alcohol 3 provided aldehyde 4.
Protection of the aldehyde functionality in 4 as a dimethyl acetal
followed by hydrolysis of the ester gave 5. The Boc protecting
group in 5 was then removed and replaced with an Fmoc
Table 1
Substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones
R3
O
N
HN
R4
R1
N
N
R2
O
Compound
R1
R2
R3
R4
pmol per beada
543
Yieldb (%)
35
Purityc (%)
85
F
O
CH3
H
O
17a
S
O
F
O
17b
17c
17d
17e
17f
618
1157
337
40
75
22
20
19
85
91
83
87
71
O
Cl
Cl
O
H
N
O
O
CH3
O
NC
NC
NC
NC
NC
CH3
313
H
O
O
295
a
b
c
Based on comparison with an analytical reference.
Based on average loading per bead.
Based on HPLC analysis at 215 nm.

L.-Y. Qin et al. / Tetrahedron Letters 52 (2011) 849–852
851
O
O
O
NHBoc
O
NHBoc
NHBoc
NH2
a,b
c,d
f,g
e
L
N
L
NH
R1
L
N
OMe
OMe
N
L
R1
R1
R1
N
NH
10
11
13
12
R2
R2
N
Fmoc
R3
N
R3
N
O
O
R3
N
O
O
H
N
i,j
L
N
L
N
h
k
L
N
HN
N
R4
R1
N
R4
R1
R1
R2
NFmoc
NFmoc
R1
N
N
N
N
R2
R2
R2
O
O
O
O
17
14
15
16
Scheme 3. Reagents and conditions: (a) N-
a
-Boc-N-b-Fmoc-diaminopropionic acid, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 20 h; (b) piperidine, DMF, 25 °C, 1 h; (c) R2-
CHO, THF, 25 °C, 20 h; (d) NaCNBH3, MeOH, CH3COOH, 25 °C, 20 h; (e) 1-Fmoc-4-(dimethoxymethyl)piperidine-4-carboxylic acid (6), BOPCl, iPr2NEt, CH2Cl2, 25 °C, 3 d; (f)
TFA, CH2Cl2, H2O, 25 °C, 30 min; (g) NaCNBH3, CH3 COOH, DMF, 25 °C, 20 h; (h) benzenesulfonyl chloride, methyl chloroformate, acetic anhydride, or allyl chloroformate,
iPr2NEt, CH2Cl2, 25 °C, 20 h; or paraformaldehyde, or benzaldehyde, NaCNBH3, MeOH, CH3COOH, 25 °C, 20 h; (i) piperidine, DMF, 25 °C, 1 h; (j) isopropyl isocyanate, acetic
anhydride, or phenyl chloroformate, iPr2NEt, CH2Cl2, 25 °C, 20 h; or paraformaldehyde, NaCNBH3, MeOH, CH3COOH, 25 °C, 20 h; (k) isopropanol/H2O/TFA (80:20:3), h
(330 nm), 50 °C, 1 h.
m
protecting group to give 6 in order to be compatible with the sub-
sequent solid-phase synthesis.
benzyl bromide 9 with a primary amine provides the resin-bound
secondary amine 10. A large excess of amine was utilized in order
to minimize undesired cross-linking between unreacted benzylic
bromide functionality and the secondary amine formed during this
reaction. A range of primary amines were successfully utilized
(Table 1). The secondary amine 10 was then acylated with
Solid-phase synthesis was initiated by acylating aminomethyl-
terminated ArgogelÒ resin
7 with N-a-N-e-bis-Fmoc-lysine
followed by Fmoc deprotection to generate 8 (Scheme 2). This
increases the loading capacity of the resin by doubling the number
of amino groups for further derivatization. The double-loaded resin
8 was subsequently acylated with the photo-labile linker precursor
4-carboxy-2-nitrobenzyl bromide to give 9. This linker allows
cleavage of intermediates and product from solid phase via photol-
ysis at 330 nm, and is compatible with all the chemistry utilized in
the solid-phase part of this synthetic strategy.10 Reaction of the
N-
a-Boc-N-b-Fmoc-diaminopropionic acid, followed by Fmoc
deprotection to give 11 (Scheme 3). Both enantiomers of N-
a
-Boc-
N-b-Fmoc-diaminopropionic acid were successfully utilized. The
resin-bound primary amine 11 was further derivatized through
reductive alkylation with an aldehyde (R2-CHO) to give 12. To
insure mono-alkylation of the primary amine, a two-step reductive
Figure 2. (A) HPLC profile of the standard of 17b at 215 nm. (B) HPLC profile of the crude bead eluent of 17b at 215 nm.

852
L.-Y. Qin et al. / Tetrahedron Letters 52 (2011) 849–852
alkylation was performed. This involved imine formation, removal
of excess aldehyde, and subsequent imine reduction with sodium
cyanoborohydride.
quantitatively analyzed versus an analytically pure sample of the
corresponding 3,8,11-triazaspiro[5,6]dodecan-7-one.12 Released
compound yields ranged from 19% to 75% (Table 1). The purity lev-
els of crude 17a–f were high, which is exemplified by the HPLC
chromatogram in Figure 2.
In conclusion, a robust and general combined solution-phase
and solid-phase method exploiting the advantages of each tech-
nique for the synthesis of 3,8,11-triazaspiro[5,6]dodecan-7-ones
has been developed. The synthesis performed well with a range
of R1, R2, R3, and R4 components and provided a high level of purity.
This synthetic strategy can be readily applied to additional analogs
and also the construction of both parallel and combinatorial
3,8,11-triazaspiro[5,6]dodecan-7-one libraries.
A number of aromatic aldehydes were used (Table 1). The next
step involving acylation of the resin-bound secondary amine 12
with 6 is the point at which the solution-phase and solid-phase
methods converged. This reaction proved challenging due to the
sterically-hindered carboxylic acid functionality in 6. Typical
acylation conditions including carboxylic acid activation with
N,N0-diisopropylcarbodiimide (DIC)/hydroxybenzotriazole (HOBt),
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), and bromo-tri-pyrrolidinophospho-
nium hexafluorophosphate (PyBrOP) did not achieve a complete
reaction. The use of bis(2-oxo-oxazolidinyl)phosphinic chloride
(BOPCl) in the presence of iPr2NEt at room temperature for 3 days
gave complete conversion to amide 13 as evidenced by a negative
bromophenol blue test. Subsequent concomitant acid-mediated re-
moval of the Boc and the acetal protecting groups from 13 was fol-
lowed by the spontaneous formation of a seven-membered cyclic
imine. Reduction of this imine with sodium cyanoborohydride
gave the triazaspiro[5,6]dodecan-7-one ring system 14. The sec-
ondary amine in 14 was derivatized (R3) with a set of electrophilic
reagents including benzenesulfonyl chloride, methyl chlorofor-
mate, acetic anhydride, paraformaldehyde, benzaldehyde, and allyl
chloroformate to give 15 (Table 1). The allyl carbamate formed
here was later removed just prior to photolysis ultimately produc-
ing the secondary amine 17f.11 Fmoc deprotection of 15 was fol-
lowed by an additional N-derivatization (R4) utilizing isopropyl
isocyanate, phenyl chloroformate, paraformaldehyde, and acetic
anhydride to give 3,8,11-triazaspiro[5,6]dodecan-7-ones 16. The
secondary amine was also left underivatized. Cleavage of the de-
sired substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones 17 from
the solid support was accomplished via photolysis of 16 at
330 nm. Substituted 3,8,11-triazaspiro[5,6]dodecan-7-ones 17a–f
were successfully produced using a range of combinations of R1,
R2, R3, and R4 groups (Table 1).
References and notes
1. Metwally, K. A.; Dukat, M.; Egan, C. T.; Smith, C.; DuPre, A.; Gauthier, C. B.;
Herrick-Davis, K.; Teitler, M.; Glennon, R. A. J. Med. Chem. 1998, 41, 5084–
5093.
2. Samnick, S.; Brandau, W.; Noelken, G.; Gerhards, H. J.; Schober, O. Nucl. Med.
Biol. 1997, 24, 295–303.
3. Ceccarelli, S. M.; Pinard, E.; Stalder, H. WO2005040166.
4. Lavieri, R.; Scott, S. A.; Lewis, J. A.; Selvy, P. E.; Armstrong, M. D.; Brown, H. A.;
Lindsley, C. W. Biorg. Med. Chem. Lett. 2009, 19, 2240–2243.
5. Goto, G.; Nagaoka, A. JP01207291.
6. Schlienger, N. WO2003057698.
7. Baldwin, J. J.; Huff, J. R.; Vacca, J. P.; Young, S. D.; De Solms, J.; Guare, J. P.
EP204254.
8. Dolle, R. E. J. Comb. Chem. 2000, 2, 383–433.
9. A typical washing protocol after a solid-phase reaction involves sequentially
washing two times each with the reaction solvent, MeOH, DMF, and CH2Cl2.
Prior to the initiation of a solid-phase reaction the resin is typically washed two
times with the reaction solvent.
10. (a) Rich, D. A.; Gurwara, S. K. J. Am. Chem. Soc. 1975, 97, 1575–1579; (b) Barany,
G.; Albericio, F. J. Am. Chem. Soc. 1985, 107, 4936–4942.
11. The Alloc protecting group was removed under the following conditions: a THF
solution of 1,3-dimethylbarbituric acid (5.0 equiv) was degassed with argon
prior to the addition to the resin. Tetrakis(triphenylphosphine)palladium(0)
(0.25 equiv) was then added as a solid and the resulting resin suspension
shaken for 18 h at 25 °C.
12. Analytical standards of 17a–f were synthesized using the combined solution-
phase and solid-phase approach described in this Letter, and purified by semi-
preparative HPLC. Analytical HPLC analysis was conducted using a PDA-linked
Waters Millenium 2690 and Phenomenex Luna 3um 50 ꢁ 3 mm C8 column.
To determine the yields and purities of 17a–f following the pho-
tolysis, the combined eluent from 20 beads of each compound was