Preparation of Spirocyclic β-Proline Esters: Geometrically Restricted Building Blocks for Medicinal Chemistry

Article abstract of DOI:10.1055/s-0036-1588902

A series of novel N-Bn-protected spirocyclic β-proline esters were prepared using [3+2] cycloaddition and subsequently converted into their corresponding aldehydes. In addition, two novel N-Cbz-protected spirocyclic β-proline esters were prepared using intramolecular cyclization starting from simple precursors.

Full text of DOI:10.1055/s-0036-1588902

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
K. Fjelbye et al.
Letter
Synlett
Preparation of Spirocyclic β-Proline Esters: Geometrically
Restricted Building Blocks for Medicinal Chemistry
Kasper Fjelbyea,b
Mauro Marigoa
Rasmus Prætorius Clausenb
Karsten Juhl*a
X
5 examples
n
CO2R
TMS OMe
[3+2]
cycloaddition
♦
♦
♦
24–81% yield
X = O, N-Boc, N-Bn
n = 1, 2
CO2R
n
n
X
+
N
n
N
Bn
Bn
a Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej
9, 2500 Valby, Copenhagen, Denmark
KAJU@Lundbeck.com
1) condensation
CO2Et
2 examples
b Department of Drug Design and Pharmacology, Faculty of
Health and Medical Sciences, University of Copenhagen,
2 Universitetsparken, 2100 Copenhagen, Denmark
2) intramolecular
cyclization
O
♦
12–17% yield
over 3 steps
X = O, CH
CO2Et
+
♦
X
2
N
3) N-protection
NH3Cl
X
Cbz
Received: 17.08.2016
Accepted after revision: 05.10.2016
Published online: 17.10.2016
for the construction of the spirocyclic frameworks rely on
forming the tetrasubstituted carbon prior to the cyclization
step yielding the spirocycles, possibly as a consequence of
the difficulties associated with formation of the spirocar-
bon. Herein, a practically useful preparation of a series of
novel spirocyclic β-proline esters with concomitant forma-
tion of both the spirocycle and the spirocarbon is presented
using either a cycloaddition or intramolecular cyclization
as the key step. Although the use of 1,3-dipolar cycloaddi-
tions between olefins and ylides for the construction of
five-membered heterocycles is well-known, it is acknowl-
edged that trisubstituted olefins show significantly lower
reactivity toward such transformations.8 We have demon-
strated the possibility of constructing highly attractive spi-
rocyclic building blocks by means of [3+2] cycloaddition
between an azomethine ylide and an α,β-unsaturated ester
(Scheme 1). The ylide is readily generated in situ, in the
presence of a catalytic amount of TFA, from commercially
available N-(methoxymethyl)-N-(trimethylsilylmethyl)ben-
zylamine. The cycloadditions proceeded in practically use-
ful yields to provide both spiro[3.4]octane and spiro[4.5]de-
cane frameworks (Scheme 2).
In the case of 1b and 1e, the N-Boc azetidine and piperi-
dine units tolerated the acidic conditions allowing 1b and
1e to be isolated in high yields. Access to orthogonally pro-
tected diazaspiro[3.4]octane and diaza[4.5]decane building
blocks as 1b and 1e forms the basis for further controlled
functionalization on either ring nitrogen after chemoselec-
tive deprotection.9
Furthermore, a novel 2-pyrrolidinone bioisostere; the
N-protected 2-oxa-5-aza[3.4]octane structure 1f was pre-
pared along with a spirocyclobutane analogue 1g using an
intramolecular cyclization as the key step (Scheme 3). The
construction of α-monosubstituted β-proline esters using a
TiCl4/Et3N reagent system to facilitate intramolecular cy-
DOI: 10.1055/s-0036-1588902; Art ID: st-2016-b0534-l
Abstract A series of novel N-Bn-protected spirocyclic β-proline esters
were prepared using [3+2] cycloaddition and subsequently converted
into their corresponding aldehydes. In addition, two novel N-Cbz-pro-
tected spirocyclic β-proline esters were prepared using intramolecular
cyclization starting from simple precursors.
Key words spirocycles, β-proline esters, oxetanes, 1,3-dipolar cy-
cloaddition, intramolecular cyclization
The continuing discovery and synthesis of novel hetero-
cyclic structures provide medicinal chemists with an in-
creasing repertoire of building blocks for the design and
synthesis of active pharmaceutical ingredients.1 Spirocycles
have recently gained increased attention and are consid-
ered as attractive frameworks to incorporate in compounds
of interest in medicinal chemistry.2 The spirocyclic motifs,
especially the smaller rings, provide a spatially fixed struc-
ture with the possibility of well-defined vectorization in all
three dimensions.3 However, the density and rigidity of the
spirocyclic substructures that make them attractive also
bring high synthetic difficulty. Thus, spirocyclic scaffolds
have been recognized as being among the most challenging
structural motifs to synthesize.4 A particularly intriguing
case is the spirocyclic oxetane ring, being bioisoteric with
both gem-dimethyl and carbonyl groups that are widely en-
countered motifs in biologically active compounds.5 Fur-
thermore, cyclic amines bearing a spirocyclic oxetanyl
group adjacent to the nitrogen have been reported as non-
hydrolyzable lactam analogues, providing interesting alter-
natives in molecule design from a medicinal chemistry
point of view.6 Spirocyclic diamines (diazaspiroalkanes)
have also attracted attention, and reports of their prepara-
tion are starting to emerge in literature.7 Most procedures
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
K. Fjelbye et al.
Letter
Synlett
O
CO2Et
CO2Et
O
TMS OMe
O
O
O
O
EtO2C
CO2Et
and
+
+
+
N
N
N
PR2
2 steps
3 steps
NHCl
Bn
Pg
Pg
Scheme 1 Rapid access to novel N-protected oxaazaspiro[3.4]octane carboxylic acid esters
X
In our case, applying the TiCl4/Et3N combination for the
intramolecular cyclization of 2f,g did not afford the desired
spirocycles. Despite a moderate overall yield, it was possi-
ble to facilitate the intramolecular cyclization of 2f,g using
LiHMDS at –78 °C, which ultimately provided access to
rather advanced and biologically interesting motifs 1f,g
from the inexpensive commercially available ethyl 4-ami-
nobutanoate hydrochloride and a cyclic ketone. The con-
densation step (Scheme 3, a) generally proceeded quantita-
tively, as judged by NMR analysis, although 2f,g degraded
during silica gel chromatography. To circumvent the stabili-
ty issue the intermediates were used directly in the intra-
molecular cyclization step. Unfortunately, construction of
spirotetrahydropyranyl and -piperidinyl β-proline esters
using this three-step procedure only provided trace
amounts of the desired products.
CO2R
n
TMS OMe
CO2R
cat. TFA
n
n
+
X
N
toluene (0.4 M)
N
n
Bn
Bn
1a–e
Boc
O
O
N
CO2Et
CO2Me
CO2Me
N
N
N
Bn
Bn
1b
81% yield
Bn
1c
1a
55% yield
24% yield
Bn
Boc
N
N
CO2Et
CO2Et
To further extend the products’ synthetic versatility, the
spirocyclic β-proline esters 1a–e were converted into their
corresponding aldehydes featuring carbamate-based pyrro-
lidine N-protecting groups (Scheme 4). The aldehyde 6a
was synthesized by reduction of 1a followed by palladium-
catalyzed transfer hydrogenation to yield amino alcohol 4.
The amino alcohol 4 was Cbz-protected and oxidized using
a water-accelerated Dess–Martin periodinane (DMP) proto-
col.11 The orthogonally protected diazaspirooctane 1b was
subjected to chemoselective removal of the N-benzyl group,
followed by Cbz protection and reduction of the methyl es-
ter using LiBH4 to yield the prolinol 8 that was oxidized us-
ing Swern conditions to furnish 6b. The oxaazaspiro[4.5]de-
cane 1c was reduced using LiAlH4 and subsequently N-de-
benzylated on an autoclave to yield the corresponding
amino alcohol that was Boc protected and after DMP oxida-
tion provided the aldehyde 11c. Attempts towards intro-
ducing the Boc group one pot in the hydrogenation step on
the autoclave resulted in formation of carbonate byprod-
ucts. The diazaspiro[4.5]decane 11d was prepared starting
from 1d using transfer hydrogenation, Boc protection, and
LiBH4 as a milder reducing agent compared to LiAlH4 leav-
ing the two N-Boc protecting groups intact. The aldehydes
6a,b and 11c,d could all be purified using silica gel chroma-
tography. However, a significant amount of hydrate forma-
tion resulted in a loss of yield during the purification of 11c.
In summary, we have reported the preparation of a se-
ries of novel spirocyclic β-proline esters 1a–g through ei-
ther [3+2] cycloaddition or intramolecular cyclization.
Moreover, we have exemplified the transformation of N-Bn-
protected β-proline esters 1a–e into their corresponding
N
N
Bn
Bn
1d
48% yield
1e
69% yield
Scheme 2 Synthesis of spirocyclic N-benzyl β-proline esters. See the
Supporting Information for further experimental details. X = O, N-Boc,
N-Bn; n = 1, 2; R = Et, Me.
clization has previously been described for aldimines.10
However, the analogous intramolecular cyclization of ke-
timines is unprecedented.
CO2Et
O
NH2•HCl
3 steps
+
X
N
X = O, 17% yield
X = CH2, 12% yield
CO2Et
X
Cbz
1f: X = O
1g: X = CH2
a)
c)
CO2Et
X
b)
N
CO2Et
X
N
intramolecular
cyclization
H
2f,g
3f,g
Scheme 3 Reagents and conditions: a) Et3N, CH2Cl2, MS (3 Å), 66 h or
K2CO3, toluene, 60 °C, 18 h; b) LiHMDS, THF, –78 °C; c) Cbz-Cl, THF. See
the Supporting Information for further details.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
K. Fjelbye et al.
Letter
Synlett
HO
HO
O
O
O
O
CO2Et
CHO
1) LiAlH4, THF, 0 °C
Cbz-Cl, Et3N
DMP, H2O
2) NH4HCO2, Pd/C
MeOH, 80 °C
CH2Cl2
34%
CH2Cl2
63%
N
Bn
1a
N
N
N
H
76%
(two steps)
Cbz
Cbz
5
4
6a
Boc
Boc
Boc
Boc
HO
N
N
N
N
CHO
CO2Me
CO2Me
1) NH4HCO2, Pd/C
MeOH, 80 °C
(COCl)2, DMSO
(i-Pr)2NEt
LiBH4
toluene, 0–40 °C
65%
2) Cbz-Cl, Et3N
CH2Cl2
CH2Cl2, –78 °C
79%
N
N
N
N
Cbz
Cbz
Bn
84%
(two steps)
Cbz
7
8
6b
1b
HO
O
O
HO
O
O
CO2Me
1) H2, Pd(OH)2/C
EtOH, 50 °C, 7 bar
CHO
LiAlH4
DMP, H2O
THF, 0 °C
87%
2) Boc2O, THF, r.t.
55%
CH2Cl2
20%
N
N
N
N
Bn
Bn
(two steps)
Boc
10
Boc
11c
9
1c
Boc
Boc
Boc
Boc
HO
N
N
N
N
1) NH4HCO2, Pd/C
MeOH, 80 °C
CO2Et
CO2Et
CHO
LiBH4
DMP, H2O
toluene, 0–60 °C
90%
CH2Cl2
85%
2) Boc2O, THF
89%
(two steps)
N
N
N
N
Boc
12
Scheme 4 DMP = Dess–Martin periodinane. All of the yields are isolated yields. See the Supporting Information for further details.
Bn
1e
Boc
Boc
11d
13
N-Boc and N-Cbz β-proline aldehydes 6a,b and 11c,d, re-
spectively. These products are versatile candidates for sev-
eral chemical transformations including multicomponent
reactions, reductive amination, and olefination. Their facile
preparation12 provides medicinal chemists with an in-
creased collection of building blocks for the construction of
compounds with potential pharmaceutical applicability.
(2) (a) Kumar, S.; Thornton, P. D.; Painter, T. O.; Jain, P.; Downard,
J.; Douglas, J. T.; Santini, C. J. Org. Chem. 2013, 78, 6529.
(b) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med Chem. Lett.
2014, 24, 3673.
(3) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014, 114, 8257.
(4) Sannigrahi, M. Tetrahedron 1999, 55, 9007.
(5) (a) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.;
Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052.
(b) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew.
Chem. Int. Ed. 2006, 45, 7736.
Acknowledgment
(6) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler,
F.; Schneider, J.; Alker, A.; Schweizer, B. W.; Müller, K.; Carreira,
E. M. Angew. Chem. Int. Ed. 2008, 47, 4512.
(7) (a) Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.;
Tolmachev, A. A.; Komarov, I. V. Chem. Rev. 2011, 111, 5506.
(b) Orain, D.; Hintermann, S.; Pudelko, M.; Carballa, D.;
Jedrzejczak, A. Synlett 2015, 26, 1815.
The work was financially supported by The Ministry of Higher Educa-
tion and Science and H. Lundbeck A/S. We would like to thank Dr.
Henrik Pedersen from H. Lundbeck A/S for assistance with the acqui-
sition of HRMS data.
Supporting Information
(8) (a) Srihari, P.; Yaragorla, S. R.; Basu, D.; Chandrasekhar, S. Syn-
thesis 2006, 2646. (b) Stachel, S. J.; Steele, T. G.; Petrocchi, A.;
Haugabook, S. J.; McGaughey, G.; Holloway, M. K.; Allison, T.;
Munshi, S.; Zuck, P.; Colussi, D.; Tugasheva, K.; Wolfe, A.;
Graham, S. L.; Vacca, J. P. Bioorg. Med. Chem. Lett. 2012, 22, 240.
(9) Compound 1e is mentioned in a Japanese patent application:
Yoshida, K.; Ochiai, H.; Tani, K.; Shibayama, S.; Kasano, M. WO
2010147094, 2010.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588902.
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References and Notes
(1) Lamberth, C.; Dinges, J. Bioactive Heterocyclic Compound
Classes; Wiley-VCH: Weinheim, 2012, 1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
K. Fjelbye et al.
Letter
Synlett
(10) Suresh, S.; Periasamy, M. Tetrahedron Lett. 2004, 45, 6291.
(11) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(12) General Procedure for the Synthesis of β-Proline Esters
Using Cycloaddition
raphy to provide the desired cycloaddition product 1a–e.
Ethyl 6-Benzyl-2-oxa-6-azaspiro[3.4]octane-8-carboxylate (1a)
The general procedure A over 12 h provided 1a (5.3 g, 19.25
mmol, 55% yield) as a colorless oil. 1H NMR (600 MHz, CDCl3):
δ = 7.33–7.29 (m, 4 H), 7.27–7.24 (m, 1 H), 4.72–4.64 (m, 2 H),
4.51–4.43 (m, 2 H), 4.23–4.15 (m, 2 H), 3.66–3.60 (m, 2 H), 3.21
(d, J = 9.2 Hz, 1 H), 3.10–3.02 (m, 2 H), 2.74 (dd, J = 9.3, 0.8 Hz, 1
H), 2.62–2.59 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H). 13C NMR (151
MHz, CDCl3): δ = 173.0, 138.5, 128.6, 128.3, 127.1, 84.0, 77.9,
64.3, 60.9, 59.6, 56.5, 50.4, 47.9, 14.3. ESI-HRMS: m/z calcd for
To a stirred solution of an unsaturated ester (1 equiv) in toluene
(0.4 M w.r.t. the ester) was added N-benzyl-1-methoxy-N-
[(trimethylsilyl)methyl]methanamine (1.5 equiv) at 0 °C under
argon. After 10 min, a solution of TFA (0.1 equiv) in CH2Cl2 (1 M
w.r.t. TFA) was added to the mixture, and stirring was continued
for 2–18 h while allowing the temperature to slowly reach r.t.
Subsequently, the volatiles were removed in vacuo, and the
resulting crude residue was purified using silica gel chromatog-
C
16H22NO3 [MH+]: 276.1594; found: 276.1599.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D