Synthesis of Orthogonally Protected 2,6-Diazaspiro[35]nonane and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building Blocks in Medicinal Chemistry

Article abstract of DOI:10.1055/s-0034-1378722

A novel and efficient synthesis of orthogonally protected spirocyclic amines is described for the first time.

Full text of DOI:10.1055/s-0034-1378722

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1815–1818
letter
1815
D. Orain et al.
Letter
Synlett
Synthesis of Orthogonally Protected 2,6-Diazaspiro[3.5]nonane
and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building
Blocks in Medicinal Chemistry
David Oraina
Boc
N
Samuel Hintermanna
Maciej Pudelko*b
Diego Carballab
COOEt
N
N
Anna Jedrzejczakb
Bn
Bz
Boc
a Novartis Pharma AG, Werk Klybeck, Postfach, 4002 Basel,
N
COOMe
Switzerland
N
b Selvita S.A., Park Life Science, Bobrzynskiego 14, 30-348 Cracow,
N
Poland
Bn
Bn
maciej.pudelko@selvita.com
26–53% yield over 6 steps
Received: 25.03.2015
Accepted after revision: 07.05.2015
Published online: 25.06.2015
noting that some of the building blocks based on the above-
mentioned spirocyclic amines are commercially available at
quite expensive price. For our purpose we were interested
in developing a reliable synthetic route to obtain gram
quantities of these spirocyclic amines. For some of the pre-
viously published strategies6,7 to synthesize similar spiro-
cyclic diamines the reasoning was based on the functional-
ization of the azetidine building block and then construct-
ing the pyrrolidine or piperidine ring. Thus, we attempted
to form the spirocyclic lactam intermediate (Scheme 1) in a
sequence of steps starting from azetidine derivative 1. First,
the acetal-protected side chain was introduced via classical
deprotonation followed by quenching with an appropriate
alkyl bromide to access 2; however, its deprotection to al-
dehyde 3 failed (no conversion of 2). In another approach,
similar deprotonation and subsequent alkylation with 3-
bromopropionitrile did not provide nitrile 4, which was ex-
pected to be further reduced with Raney nickel to form the
desired lactam (Scheme 1). Those approaches via azetidine
chemistry were not further pursued since a parallel ap-
proach was more promising.
DOI: 10.1055/s-0034-1378722; Art ID: st-2015-b0210-l
Abstract A novel and efficient synthesis of orthogonally protected spi-
rocyclic amines is described for the first time.
Key words spirocyclic amine, 2,6-diazaspiro[3.5]nonane, 2,6-di-
azaspiro[3.4]octane, azetidine deprotection, orthogonal protecting
groups
Constrained spirocyclic amines are common structural
motifs in many natural products and drug molecules such
as sanglifehrin, azaspiroacid,1 and varenicline.2 They are
providing very rigid systems with three-dimensional struc-
tures associated with low molecular weights and they are
very efficient in terms of atom economy. A vast number of
active compounds generated in pharma industry is based
on five- and six-membered aliphatic rings that are either
fused or linked.3 In comparison to those, four-membered
rings are found less frequently. A number of spirocyclic
amino
oxetanes,4
azetidine-thietanes,4
2,6-di-
azaspiro[3.3]heptanes,4 1,6-diazaspiro[3.4]octanes,6 and
2,7-diazaspiro[3.5]nonanes[5,8] are known in medicinal
chemistry and their syntheses are described in the litera-
ture. In addition, a review compiling multiple syntheses of
constrained diamine systems including several spirocycles,
for example, 1,6-diazaspiro[3.3]heptane has been pub-
lished.7
For our purposes, we were particularly interested in de-
veloping a reliable and efficient synthesis of 2,6-di-
azaspiro[3.5]nonane and 2,6-diazaspiro[3.4]octane systems
orthogonally protected on the respective nitrogen atoms.
The synthesis of 2,6-diazaspiro[3.5]nonane was not previ-
ously published. The synthesis of 6-benzyl-2,6-di-
azaspiro[3.4]octane was published before;9 however, the
reported yields were lower than reported herein. It is worth
In a parallel synthetic plan, we considered the reverse
approach that we thought to be more viable and which
would start from readily available and cheap starting mate-
rials. First, we pursued the synthesis towards the benzyl-
protected 2,6-diazaspiro[3.5]nonane 11 (Scheme 2).
Readily available piperidine ethyl ester 5 was protected
as its N-benzoyl form leading to 6 in good yield (98%);10 it is
noteworthy to mention that when methyl ester was used,
ester hydrolysis was observed during workup. Deprotona-
tion of 6 with in situ formed LDA followed by quenching of
the resultant enolate with ethyl chloroformate provided di-
ester 7 in good yield (98%). Reduction of 7 with LiAlH4 solu-
tion gave N-benzyl protected diol 8 in 91% yield. For the in-
troduction of the nitrogen atom in an elegant way, we en-
visaged that reaction of the ditosylate 9 (obtained in 87%
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1815–1818

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Boc
Boc
Boc
N
O
O
a)
N
b)
N
CHO
n
n
n
Boc
O
COOMe
COOMe
N
N
3
n = 1, 2
Bn
2
COOMe
1
Boc
Boc
N
N
c)
CN
COOMe
N
H
4
Scheme 1 Reagents and conditions: a) LiHMDS, bromoacetal derivative, THF, –70 °C; b) PTSA, acetone–H2O, 50 °C; c) LDA, –78 °C, 3-bromopropio-
nitrile, THF.
yield) with an appropriately protected nitrogen equivalent
would form the azetidine ring. Unfortunately, direct con-
version of 9 with tert-butyl carbamate proved not to be suc-
cessful. When reacting ditosylate 9 with 2,4-dimethoxy-
benzylamine, the spirocyclic intermediate 21 was success-
fully obtained (Scheme 3). However, deprotection of the
azetidine nitrogen to provide intermediate 11 under vari-
ous conditions did not work. For instance TFA treatment
under reflux or microwave irradiation,11 conversion into the
sulfonamide14 as a temporary protecting group for second-
ary amines that is easily cleavable by treatment with thio-
phenol. Following this approach, intermediate 10 was ob-
tained (78% yield) by reacting ditosylate
9 with 2-
nitrobenzenesulfonamide. Compound 10 was further
deprotected with thiophenol in Cs2CO3/DMF to give the spi-
rocyclic diamine 11 in an excellent yield (89%) after purifi-
cation over a short silica plug.15 It is noteworthy to mention
that cyclization works as well with p-toluenesulfonamide
but deprotection and purification proved to be less effi-
cient. The azetidine moiety in 11 was further Boc-protected
using standard conditions (85% yield) to give intermediate
12 that constitutes a versatile building block with orthogo-
nal protecting groups that can be cleaved using standard
conditions such as catalytic hydrogenation or HCl/TFA
treatment, respectively.
14
trifluoroacetamide12 or oxidative cleavage with K2S2O8
were not successful. Fukuyama reported 2-nitrobenzene-
OH
OH
COOEt
COOEt
COOEt
b)
COOEt
a)
c)
N
N
N
N
H
Bz
Bz
Bn
5
6
7
8
OMe
O
N
NH
b)
OTs
OTs
NH
a)
OTs
OTs
S
d)
e)
N
f)
OMe
O
NO2
N
N
N
N
N
11
21
9
Bn
N
Bn
Bn
Bn
Bn
9
10
11
Bn
Scheme 3 Reagents and conditions: a) 2,4-dimethoxybenzylamine,
MeCN, DIPEA, reflux (50%); b) i): TFA, reflux, or MW irradiation; ii) Tf2O,
Et3N, CH2Cl2; iii) K2S2O8, MeCN–H2O.
Boc
Boc
N
N
g)
h)
N
N
Benzyl-protected 2,6-diazaspiro[3.4]octane 20 (Scheme
4) was synthesized following the same strategy as for
nonane derivative 12. TFA-catalyzed 1,3-dipolar cycloaddi-
tion between N-benzyl-N-(methoxymethyl)trimethylsilyl-
methylamine and methyl acrylate16 led to intermediate 14
in good yield (90%) and no ester hydrolysis was observed in
this case.
13
12
H
Bn
Boc
OTs
OTs
N
i )
N
N
Bn
Bn
12
9
Deprotonation in the α-position of ester 14 with LDA
followed by quenching with methyl chloroformate gave di-
ester 15 (84% yield). Reduction to diol 16 with LiAlH4 (91%
yield) followed by tosyl protection in a similar fashion to
derivative 9 led to ditosyl intermediate 17 (54% yield). For-
Scheme 2 Reagents and conditions: a) BzCl, DIPEA, CH2Cl2, r.t. (98%); b)
LDA, ClCOOEt, THF, –78 °C to 0 °C (98%); c) LiAlH4, THF, 0 °C to reflux
(91%); d) TosCl, Et3N–DMAP, CH2Cl2, r.t. (87%); e) 2-nitrobenzenesulfon-
amide, K2CO3, DMF, 100 °C (78%); f) PhSH, Cs2CO3, MeCN, r.t. (89%); g)
Boc2O, NaHCO3, H2O–dioxane, r.t. (85%); h) H2 (5 bar), Pd/C, MeOH, r.t.
(95%); i), NH2Boc, K2CO3, DMF, 100 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1815–1818

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References and Notes
MeOOC
b)
MeOOC
MeOOC
OH
OH
MeOOC
a)
+
c)
(1) Carter, R. G.; Kuiper, D. L. Asymmetric Synthesis of Spiroketals,
Bisspiroketals, and Spiroaminals, In Stereoselective Synthesis 2:
Stereoselective Reactions of Carbonyl and Imino Groups; Vol. 2;
Molander, G. A., Ed.; Thieme: Stuttgart, 2011, 863–914.
(2) Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E.
P.; Huang, J.; Sands, S. B.; Davis, T. B.; Lebel, L. A.; Fox, C. B.;
Shrikhande, A.; Heym, J. H.; Schaeffer, E.; Rolemma, H.; Lu, Y.;
Mansbach, R. S.; Chambers, C. K.; Rovetti, C. C.; Schultz, D. W.;
Tingley, D.; O’Neill, B. T. J. Med. Chem. 2005, 48, 3474.
(3) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.
(4) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
Maerki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.;
Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Mueller, K.;
Carreira, E. M. Angew. Chem. Int. Ed. 2008, 47, 4512.
N
N
N
MeO
Si
N
16
15
Bn
14
Bn
Bn
Bn
OTs
O
OTs
e)
S
d)
NH
f)
N
O
NO2
N
N
Bn
Bn
17
18
19
N
Bn
N
Boc
g)
N
(5) Orr, S. T. M.; Cabral, S.; Fernando, D. P.; Makowski, T. Tetrahe-
dron Lett. 2011, 52, 3618.
Bn
20
(6) Sippy, K. B.; Anderson, D. J.; Bunnelle, W. H.; Hutchins, C. W.;
Schrimpf, M. R. Bioorg. Med. Chem. Lett. 2009, 19, 1682.
(7) Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.;
Tolmachev, A. A.; Komarov, I. V. Chem. Rev. 2011, 111, 5506.
(8) McClure, K. F.; Jackson, M.; Cameron, K. O.; Kung, D. W.; Perry,
D. A.; Orr, S. T. M.; Zhang, Y.; Kohrt, J.; Tu, M.; Gao, H.; Fernando,
D.; Jones, R.; Erasga, N.; Wang, G.; Polivkova, J.; Jiao, W.; Swartz,
R.; Ueno, H.; Bhattacharya, S. K.; Stock, I. A.; Varma, S.;
Bagdasarian, V.; Perez, S.; Kelly-Sullivan, D.; Wang, R.; Kong, J.;
Cornelius, P.; Michael, L.; Lee, E.; Janssen, A.; Steyn, S. J.;
Lapham, K.; Goosen, T. Bioorg. Med. Chem. Lett. 2013, 23, 5410.
(9) Engel, W.; Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.;
Mayer, N.; de Jonge, A. EP 417631, 1991.
(10) The benzoyl group was chosen as protecting group for the
nitrogen since protection with benzyl chloride or bromide pro-
ceeded with lower yield (69%).
(11) Holl, R.; Jung, B.; Schepmann, D.; Humpf, H.-U.; Gruenert, R.;
Bednarski, P. J.; Englberger, W.; Wuensch, B. ChemMedChem
2009, 4, 2111.
Scheme 4 Reagents and conditions: a) cat. TFA, CH2Cl2, 0 °C to r.t.
(90%); b) LDA, ClCOOMe, THF –78 °C to 0 °C (84%); c) LiAlH4, THF, 0 °C
to reflux (91%); d) TosCl, Et3N–DMAP, CH2Cl2, r.t. (54%); e) 2-nitroben-
zenesulfonamide, K2CO3, DMF, 100 °C (95%); f) PhSH, Cs2CO3, MeCN,
r.t.; g) Boc2O, Et3N, CH2Cl2, r.t. (60% over two steps).
mation of the nosyl-protected azetidine 18 was high yield-
ing (95%)17 and subsequent thiophenol-mediated nosyl
group removal led to the spirocyclic amine 19 which was
Boc-protected giving intermediate 20 in 60% yield over two
steps.18
The
orthogonally
protected
2,6-di-
azaspiro[3.5]nonane and 2,6-diazaspiro[3.4]octane build-
ing blocks are ideally set up for further functionalizations.
The Boc group can be cleaved either with TFA or HCl in di-
oxane allowing functionalization of the azetidine nitrogen.
Then, the benzyl protecting group can be hydrogenolytical-
ly cleaved to functionalize the piperidine nitrogen. Alterna-
tively, the order of functionalizations can be interconverted.
In summary, we have reported for the first time the syn-
thesis of the spirocyclic amines 2,6-diazaspiro[3.5]nonane
derivative and 2,6-diazaspiro[3.4]octane which are accessi-
ble in an excellent overall yield of 53% and 26% over six
steps, respectively. The syntheses were optimized on gram
scale and are amenable for further scale-up to multigram
scale.
(12) Fyfe, M. C. T.; Gattrell, W.; Rasamison, C. M. WO 116230, 2007.
(13) Shiozaki, M.; Ishida, N.; Hiraoka, T.; Maruyama, H. Tetrahedron
1984, 40, 1795.
(14) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
(15) Typical Procedure for Nosyl Group Removal
Cs2CO3 (22.64 g, 0.069 mol) and thiophenol (5.21 mL, 0.051
mol) were successively added to a solution of nosyl-protected
spiro amine 10 (18.6 g, 0.046 mol) in MeCN (150 mL). The
mixture was stirred at r.t. for 16 h. After this time the starting
material was consumed as judged by TLC. The reaction mixture
was filtered through a short layer of Celite. The cake was
washed first with EtOAc (300 mL) and further with CH2Cl2–
MeOH–NH3 (7 M in MeOH, 80:18:2, 3 × 100 mL), and the col-
lected organic layer was concentrated to give in total 31.3 g of
the crude oil, which was absorbed on the minimum of silica gel
and poured into a chromatography column containing a 1 cm
layer of silica gel. The elution was carried out with EtOAc to
wash off unpolar impurities and then with the system CH2Cl2–
MeOH–NH3 (7 M in MeOH, 80:18:2) to give the product 11 (8.8
g, 89% yield) as yellow oil. LCMS (214 nm): tR = 7.8 min (89.1%
content), [M + H]+ = 217.0. TLC analysis: Rf = 0.07 in CH2Cl2–
MeOH–NH3 (7 M in MeOH). 1H NMR (400 MHz, CD3OD): δ =
7.36–7.19 (m, 5 H), 3.51 (s, 2 H), 3.38–3.33 (m, 4 H), 2.53–2.28
Acknowledgment
The authors would like to thank Piotr Graczyk and Przemyslaw
Zawadzki for helpful discussions.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378722.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(m, 4 H), 1.65 (s, 2 H), 1.60–1.51 (m, 2 H). 13C NMR (101 MHz,
CD3OD): δ = 137.93, 128.91, 127.92, 126.84, 62.73, 61.32, 55.05,
53.12, 38.27, 33.82, 21.78.
(17) Intermediate 18 was also obtained from the dimesyl analogue
of 17; however, the isolated yield was lower (51%).
(18) The p-toluenesulfonamide derivative of intermediate 18 was
obtained, and the deprotection to spirocyclic amine 19 was
carried out with Red-Al® in toluene under reflux; however, the
isolated yield of was lower.
(16) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 2762.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1815–1818