Monoprotected Diamines Derived from 1,5-Disubstituted (Aza)spiro[2.3]hexane Scaffolds

Article abstract of DOI:10.1002/ejoc.202001614

Synthesis of monoprotected diamines derived from 1,5-disubstituted spiro[2.3]hexane and 5-azaspiro[2.3]hexane scaffolds is described. In both cases, the method relied on the cyclopropanation of the corresponding cyclobutane or azetidine derivatives. In th

Full text of DOI:10.1002/ejoc.202001614

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Monoprotected Diamines Derived from 1,5-Disubstituted
(Aza)spiro[2.3]hexane Scaffolds
Andrii Malashchuk,[a, b] Anton V. Chernykh,[a] Mariana Y. Perebyinis,[a, b] Igor V. Komarov,*[a, b]
and Oleksandr O. Grygorenko*[a, b]
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Synthesis of monoprotected diamines derived from 1,5-disub-
stituted spiro[2.3]hexane and 5-azaspiro[2.3]hexane scaffolds is
described. In both cases, the method relied on the cyclopropa-
nation of the corresponding cyclobutane or azetidine deriva-
tives. In the case of monoprotected 1,5-diaminospiro[2.3]
hexanes, the title products were obtained as single diastereom-
ers. X-Ray diffraction studies supported by exit vector plot (EVP)
analysis showed that the obtained building blocks are promis-
ing piperidine/cycloalkane isosteres with potential utility to
drug discovery. Also, conformations observed in the crystalline
state for the two different diastereomers of 1,5-diaminospiro
[2.3]hexane derivatives prompt their application in design of β-
turn and sheet-like peptidomimetics, respectively.
Introduction
Among the spirocyclic ring systems, spiro[3.3]heptanes have
received a special attention in the last decade (Figure 1).[5–11]
They have been demonstrated to be non-classical bioisosteres
of saturated six-membered rings – most popular saturated ring
systems in drug discovery.[13] Figure 2 illustrates two very recent
examples of using spiro[3.3]heptanes for the replacement of a
linear chain or piperidine ring to improve the half-life (A)[14] or
microsomal stability (B)[15] of the corresponding derivatives.
Unlike spiro[3.3]heptanes, their lower homologues – spiro
[2.3]hexanes – were not widely represented in the literature to
date (Figure 1). Meanwhile, the spiro[2.3]hexane scaffold has
similar physico-chemical properties but occupies a different
part of the chemical space in terms of its 3D structure. Also, this
template comprises a cyclopropane ring that has a proven track
Spirocyclic compounds are becoming increasingly popular in
medicinal chemistry due to their frequent occurrence in both
natural products and synthetic drugs.[1,2] They demonstrate a
wide range of biological effects, with over 47,000 active
derivatives identified against nearly 200 targets (as of 2016).[3]
Spirocyclic compounds have some physico-chemical and struc-
tural characteristics that have been recently considered as
favorable for drug design, namely, high fraction of sp3-
hybridized
carbon
atoms
and
remarkable
three-
dimensionality.[4] They also provide a good balance between
rigidity and flexibility.
[a] A. Malashchuk, Dr. A. V. Chernykh, M. Y. Perebyinis, Prof. Dr. I. V. Komarov,
Dr. O. O. Grygorenko
Enamine Ltd.
Chervonotkatska Street 78, Kyiv 02094, Ukraine
E-mail: ik214@yahoo.com
www.enamine.net
[b] A. Malashchuk, M. Y. Perebyinis, Prof. Dr. I. V. Komarov, Dr. O. O. Grygorenko
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001614
Figure 1. Disubstituted spiro[3.3]heptanes and spiro[2.3]hexanes – isosteres
of saturated six-membered rings (numbers in brackets correspond to the
results of Reaxys® Database[12] substructural search, papers/patents).
Enamine special issue.
Dr. Igor V. Komarov graduated with honors from Taras Shevchenko National University
of Kyiv in 1986, got PhD in organic chemistry in 1991 and Dr.Sci degree in 2003. He is a
Professor and a Head of the Supramolecular Chemistry Department of Institute of High
Technologies. At the same time, Igor is a scientific advisor of Enamine, and a Principal
Investigator of several EU-funded research projects where Enamine company is the
Coordinator. Igor’s research group achievements obtained jointly with Enamine (like this
paper) have served to explore how information on chemical reactivity and biological
recognition can be implemented in constrained molecular structures. By providing these
novel chemical tools and compounds, Prof. Komarov’s group is able to mimic, read-out,
manipulate and interfere with biological information processing, which is essential for
drug action and selectivity. Photo, left to right: Dr. Igor V. Komarov, Dr. Oleksandr
Grygorenko, Dr. Anton V. Chernykh, and Andrii Malashchuk.
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record in various drug discovery programs.[16] Therefore, (aza) Results and Discussion
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spiro[2.3]hexanes have great potential for possible applications
in bioorganic and medicinal chemistry, which is illustrated by
recent discoveries of very potent histone deacetylase 1/3[17] and
homeodomain-interacting protein kinase 1[18] inhibitors (Fig-
ure 2, C).
The known approaches to the synthesis of 1,5-substituted
spiro[2.3]hexanes rely on the construction of either three- or
four-membered ring,[19–23] the former strategy being more
popular (Scheme 1). In particular, Zefirov, Yashin, Averina, and
co-workers applied it to the synthesis of a series of amino
acids,[24–30] including spirocyclic GABA analogues.[25,26] Notably,
although N-Boc-protected amino acid 1 was used in the
medicinal chemistry projects,[17,18,31] its synthesis has not been
documented to date.
Synthesis
The synthetic part of this study started with preparation of α,β-
unsaturated ester 7 via the Horner-Wadsworth-Emmons olefina-
tion of commercially available ketone 6 according to the
previously published procedure (Scheme 2).[36] The key step of
the synthesis – cyclopropanation of 7 – relied on the Corey –
Chaikovsky reaction[37] and provided the spirocyclic intermedi-
ate 8 in moderate yield (27%), presumably due to the
competing base-promoted polymerization of the highly reactive
starting alkene. Nevertheless, the method was efficient and
allowed for the preparation of 8 on up to ca. 10 g scale in a
single run.
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In this work, we report synthesis of monoprotected
diamines[32] derived from the (aza)spiro[2.3]hexane scaffold
(compounds 2–5) – promising building blocks for bioorganic
and medicinal chemistry. The developed synthetic method-
ology is applicable on a gram scale and provides carbocyclic
representatives 4 and 5 as pure diastereomers. In addition to
that, structural characterization of 1,5-disubstituted (aza)spiro
[2.3]hexanes is performed by X-Ray diffraction studies followed
by exit vector plot (EVP) analysis.[33–35] The obtained data
provide a rationale for further possible applications of com-
pounds 2–5 in design of saturated ring bioisosteres and
peptidomimetics.
Alkaline hydrolysis of 8 proceeded smoothly and gave
carboxylic acid 1 in 92% yield. Further steps included modified
Curtius rearrangement of 1 involving diphenylphosphoryl azide
(DPPA) affording the orthogonally protected diamine 9 (71%
yield). Removal of the Cbz moiety in the molecule of 9 by
catalytic hydrogenolysis (H2, PdÀ C) appeared to be unfruitful,
possibly due to the destruction of the spirocyclic ring system.
Selective deprotection of 9 was achieved using Et3SiH –
Pd(OAc)2 in the presence of Et3N in CH2Cl2 to give compound 2
(isolated as hydrochloride, 33% yield). Alternatively, deprotec-
tion of 9 with TFA in CH2Cl2 gave 3 (isolated as trifluoroacetate
in 86% yield).
Analogously to the case of 2 and 3, synthesis of diamine
derivatives 4 and 5 required preparation of amino acid
derivative 12. Ethyl ester of 11 (compound 12) was synthesized
by Zefirov and co-workers;[26] their approach relied on rhodium-
catalyzed cyclopropanation of compound 10 which had moder-
ate efficiency (34% yield) (Scheme 3). Moreover, separation of
Scheme 1. (A) Synthesis of (aza)spiro[2.3]hexanes by construction of the
cyclopropane ring (B) Literature examples of functionalized spiro[2.3]
hexanes (C) Target compounds of this study (all as racemates; one
enantiomer is shown in each case for clarity).
Scheme 2. Synthesis of monoprotected 5-azaspiro[2.3]hexane-1-amine
derivatives 2 and 3.
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the cyclopropanation reaction. The adopted synthetic strategy
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(Scheme 4) allowed obtaining the target product 11 with
significantly improved yield. Thus, compound 14 reacted with
ethyl diazoacetate in the presence of Rh2(OAc)4 to give diester
15 in 86% yield (dr~1:1). Hydrogenolysis of 15 over palladium
on charcoal gave monoester 16 that was not isolated in pure
form but transformed into acyl azide and then subjected to the
Curtius reaction conditions in the presence of tert-butanol to
obtain compound 11 (69% yield over two steps). Finally,
alkaline hydrolysis of 11 led to target amino acid derivative 12
(89% yield).
Scheme 3. Synthesis of amino acid derivative 12 according to Zefirov et al[26]
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the diastereomers was fruitful neither for 11 nor for other
derivatives obtained. Our approach to the compound 12 relied
on a modified reaction sequence that that takes advantage of
ester 14[38] (obtained in 97% yield by esterification of known
carboxylic acid 13[39]) instead of the corresponding amine 10 for
Unfortunately, separation of the diastereomers appeared to
be possible for none of intermediates 11, 12, 15, or 16.
Nevertheless, it was achieved for orthogonally protected
diamine derivative 17 obtained after the DPPA-modified Curtius
Figure 2. Application of spiro[3.3]heptane (A, B) and spiro[2.3]hexane (C) motifs in medicinal chemistry (LSD1 – lysine-specific histone demethylase 1A;
HDAC – histone deacetylases; HIPT1 – homeodomain-interacting protein kinase 1).
Scheme 4. Synthesis of spiro[2.3]hexane-1,5-diamine derivatives 4a, 4b, 5a, and 5b (relative configurations are shown).
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rearrangement of 12 (69% yield). Relative stereochemistry of
these vectors, four geometric parameters are necessary (r, ϕ1,
ϕ2, and θ, Figure 4, B). Each disubstituted scaffold is represented
by the corresponding data point in the r – θ, ϕ1/ϕ2 – θ, and ϕ1
– ϕ2 plots (the so-called exit vector plots, EVPs) that provide a
convenient visualization of the chemical space based on the
molecular three-dimensional structure. EVP analysis of mono-
cyclic ring systems disclosed in the previous works[33,34] showed
that the corresponding scaffolds are distributed uneven ly
within the plots; some characteristic areas (α–ɛ) can be
identified (see the papers cited above for more detailed
discussion).
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the products 17a (trans) and 17b (cis) was established by
NOESY experiment with 17b and additionally confirmed by X-
Ray diffraction studies (see Figure 3).
After the chromatographic separation, both 17a and 17b
were transformed into target monoprotected diamine deriva-
tives 4a, 4b, 5a and 5b (isolated in 71% and 95% yield as
hydrochlorides) by catalytic hydrogenolysis and treatment with
HCl – MeOH, respectively.
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Structural analysis
Table 1 summarizes r, ϕ1, ϕ2, and θ values for the
compounds 1, 17a, and 17b, as well as spiro[3.3]heptane-
derived scaffolds 18–20; in Figure 5, EVPs are provided that
depict the corresponding data points together with the α–ɛ
areas for monocyclic scaffolds. It is obvious from the EVP data
that while the size of (aza)spiro[2.3]hexane scaffolds is similar to
that of 1,6-disubstituted spiro[3.3]heptanes (r=3.33–3.38 Å and
3.42–3.59 Å, respectively), relative orientations of the exit
vectors are rather different. In particular, the scaffold of 17a is
located closely to the δ area characteristic for trans-1,3-
disubstituted cyclopentanes and cyclohexanes. Moreover, the
scaffolds of 17a and 18 approach the δ area from different
sides and hence they made a good set of isosteric cycloalkane
analogues with θ values varied significantly within the series
The molecular structure of the 1,5-disubstituted spiro[2.3]
hexane derivatives discussed in this work was obtained by X-
Ray diffraction studies performed with single crystals of the
compounds 1, 17a, and 17b (Figure 3). To discuss the relative
spatial orientation of the functional groups mounted onto the
spirocyclic scaffolds, exit vector plot (EVP) tool was applied.[33–35]
In our previous works, we have successfully applied this
methodology to isomeric 1,6- and 2,6-disubstituted spiro[3.3]
heptane scaffolds[40,41] (and many other bicyclic templates[42–45]
to evaluate their potential for isosteric replacements of
monocyclic ring systems.
Briefly, the EVP tool relies on representation of the main
functional groups attached to the disubstituted scaffold as exit
vectors (Figure 4, A). To define the relative spatial orientation of
)
°
°
(from 101 to 151 ).
On the contrary, the scaffolds of 1 and 17b are located
remotely from any of the “standard” EVP areas. According to
°
°
the θ value (61 and 59 , respectively), the closest analogy is
observed with the ɛ area typical for 1,3-disubstituted pyrroli-
dines and piperidines. However, the φ1 values referring to the
n1 exit vector attached to the cyclopropane ring are much
°
°
°
larger (70 and 72 , respectively, vs ~40 ). The difference in the
°
°
φ1 values for 1 and 17b is considerable (20 and 69 ,
respectively), again, the approach the ɛ area from the different
sides and hence make a good set for isosteric replacements.
The three-dimensional structure of cis-1,5-disubstituted spiro
Table 1. Values of the parameters r, ϕ1, ϕ2, and θ obtained from X-ray
diffraction studies of spiro[2.3]hexane and spiro[3.3]heptane derivatives.
Figure 3. Molecular structure of compounds 1 (A), 17a (B), and 17b (C)
(thermal ellipsoids are shown at 50% probability level)
°
°
°
Compound or scaffold
r [Å]
ϕ1 [ ]
ϕ2 [ ]
jθj [ ]
Source
1
3.38
3.33
3.34
3.42
3.59
4.12
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72
86
81
77
33
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18
69
30
46
21
61
101
59
151
25
140
this work
17a (trans)[a]
17b (cis)
18[b]
[40]
19[b]
20
[a] The values are average for the two slightly different conformers
observed in the solid state. [b] The values are average for the
corresponding stereoisomeric pairs.
Figure 4. (A) Definition of vectors n1, n2 (spiro[2.3]hexane scaffold is used as
an example). (B) Definition of geometric parameters r, φ1, φ2, and θ.
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Some additional interesting features are revealed when the
crystal packing of 17a and 17b is analyzed (Figure 6). In
particular, the molecules of 17b form intramolecular hydrogen
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°
bonds (H…O 2.157 Å; ffNÀ H…O 168.0 ) that stabilize conforma-
tion very similar to that of the β-turn in peptides (Figure 7). The
molecules are held together by intermolecular hydrogen bonds
°
(H…O 2.051 Å; ffNÀ H…O 161.4 ), forming endless chains with
only minor inter-chain contacts.
On the contrary, the molecules of 17a adopt extended
conformations and form only intermolecular hydrogen bonds
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°
(H…O 1.989–2.209 Å; ffNÀ H…O 162.6–168.5 ), which leads to
formation of molecular chains with the sheet-like structure. The
chains are held together by weak Van der Waals interactions.
The turn-like structure of 17b appeared to have limited
stability in solution. Thus, addition of DMSO-d6 to a CDCl3
solution of 17b (0.1 M) resulted in a large change of chemical
shifts for both the NHBoc and NHCbz protons (at 25% DMSO-
d6, the Δδ values were 1.93 and 0.70, respectively), which is
characteristic to a good accessibility to the solvent (Fig-
ure 8).[46–48] These results show that even if some folded
structure is present in the CDCl3 solution, it is very easily
disrupted by more polar DMSO-d6. This assumption is further
supported by large chemical shift thermal coefficients in the
DMSO-d6 solution: Δδ/ΔT=À 7.3 and À 8.3 ppb/K,[49,50] respec-
°
tively (measured at 50–75 C; at lower temperatures, interpreta-
tion of the data was complicated by the presence of rotamers).
Therefore, introducing additional amino acid residues is
required to stabilize the turn-like structure of the cis-1,5-
diaminospiro[2.3]hexane derivatives in solution.
Figure 5. Spiro[2.3]hexane and spiro[3.3]heptane derivatives shown in:
(A) r – θ plot (polar coordinates); B) θ – φ1/φ2 plot (two graphs are shown at
the same plot). The α–ɛ regions of the EVPs are shown by different colors
(see ref. [34] for more detailed description).
Conclusions
Efficient synthetic approaches to monoprotected diamines
derived from 1,5-disubstituted (aza)spiro[2.3]hexane scaffolds
are described. The methods are based on the cyclopropanation
of the appropriate methylenecyclobutane or -azetidine deriva-
tives. The carbocyclic representatives were obtained as single
[2.3]hexane scaffold (found in 17b) is truly remarkable since it
occupies the part of chemical space characteristic for 1,3-
disubstituted saturated heterocycles, which is very hardly
accessible for the carbocyclic ring systems.
Figure 6. Packing of the molecules of 17b (A) and 17a (B) in the crystalline state.
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crystalline state reveal that cis-1,5-diaminospiro[2.3]hexanes are
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promising building blocks for the design of β-turn peptidomi-
metics (albeit the folded structures appeared to have limited
stability in solution for the model derivatives studied).
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Experimental Section
Figure 7. Structural similarity between the frameworks of 17b and β-turn
(one enantiomer of 17b is shown).
Solvents were purified according to the standard procedures.
Compounds 7[36] and 13[39] were prepared according to the
reported procedures. Melting points were measured on an
automated melting point system. Analytical TLC was performed
using Polychrom SI F254 plates. Column chromatography was
performed using silica gel (230–400 mesh) as the stationary phase.
1H, 13C NMR spectra were recorded at 499.9 or 400.4 MHz for
protons and 124.9 or 100.4 MHz for carbon-13. Chemical shifts are
reported in ppm using the solvent residual signal as an internal
standard. MS analyses were done on an LCMS instrument with
chemical ionization (CI) or a GCMS instrument with electron
impact ionization (EI). MS analyses were done on Agilent 1100
LCMSD SL instrument with chemical ionization (CI) or Agilent 5890
Series II 5972 GCMS instrument with electron impact ionization
(EI). HRMS were obtained on Agilent 6200 TOF/6500 Q-TOF
B.08.00 instrument.
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The single crystals of 1, 17a, and 17b for the X-Ray diffraction
studies were obtained by slow evaporation of their solutions in t-
BuOMe – hexanes (for 1) and THF – hexanes (for 17a and 17b).
Deposition Numbers 2048776 (17a), 2048777 (1), and 2048778
(17b) contain the supplementary crystallographic data for this
paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinformationszen-
trum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
Figure 8. Chemical shift dependence of the NH resonances of 17b (0.1 M) as
a function of DMSO-d6 concentration (% v/v) in CDCl3.
diastereomers, which was achieved by stereoisomer separation
of the corresponding orthogonally bis-protected diamine de-
rivatives. Structural characterization of the title scaffolds based
on the X-Ray diffraction studies followed by exit vector plot
(EVP) analysis showed that these compounds significantly
extend the chemical space of three-dimensional molecules,
providing novel isosteric replacements for 1,3-disubstituted
five- and six-membered saturated carbo- and heterocyclic rings
(Figure 9). Therefore, (aza)spiro[2.3]hexanes can be considered
as a useful extension of (aza)spiro[3.3]heptanes that have been
widely used for the aforementioned purpose in recent years. In
addition to that, hydrogen bonding patterns observed in the
5-tert-Butyl 1-ethyl 5-azaspiro[2.3]hexane-1,5-dicar-
boxylate (8)
To a solution of t-BuOK (20.5 g, 183 mmol) in DMSO (250 mL)
trimethylsulfoxonium iodide (40.0 g, 182 mmol) was added por-
tionwise at rt (internal temperature control). The mixture was
stirred for 30 min. A solution of compound 7 (40.0 g, 166 mmol) in
DMSO (50 mL) was added slowly, the mixture was stirred for 16 h,
and then poured into H2O (600 mL). EtOAc (400 mL) was added,
the organic layers was separated, washed with H2O (2×250 mL),
then dried over anhydrous Na2SO4, filtered, and evaporated in
vacuo. The crude product was purified by flash chromatography
(hexanes – EtOAc (7:1) as eluent, Rf =0.37). Yield 11.4 g (27%).
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J=7.3 Hz, 2H),
4.08–3.89 (m, 4H), 1.76 (dd, J=8.6, 5.2 Hz, 1H), 1.42 (s, 9H), 1.31–
1.21 (m, 4H), 1.15 (dd, J=8.6, 5.2 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 171.3, 155.5, 79.1, 60.2, 55.0, 27.9, 23.5, 22.4, 17.3, 13.8.
HRMS (ESI-TOF) m/z [M+H]+ Calcd. For C13H22NO4: 256.1543.
Found 256.1602. LC/MS (CI): m/z=200 [MÀ H2C=C(CH3)2 +H]+, 156
[MÀ CO2-H2C=C(CH3)2)+H]+.
5-(tert-Butoxycarbonyl)-5-azaspiro[2.3]hexane-1-carboxy-
lic acid (1)
Compound 8 (11.4 g, 0.045 mol) was dissolved in MeOH (50 mL),
and the mixture was added to a solution of NaOH (5.40 g,
0.135 mol) in H2O (80 mL). The mixture was stirred for 16 h. MeOH
was evaporated in vacuo, 1 M aq NaHSO4 was added to the
aqueous solution to pH=3–4, followed by then EtOAc (100 mL).
Figure 9. Possible applications of 1,5-disubstituted (aza)spiro[2.3]hexanes in
bioorganic and medicinal chemistry (relative configurations are shown).
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The organic phase was separated, the aqueous phase was washed
with EtOAc (3×50 mL), the combined organic layers were dried
over anhydrous Na2SO4, filtered, and the solvent was evaporated
233 [M+H]+. Anal. Calcd. for C15H17F3N2O4: C 52.02; H 4.95; N 8.09.
Found: C 51.65; H 4.69; N 8.38.
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°
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9
in vacuo. Yield 9.10 g (92%). Colorless solid; m.p. =115–117 C (t-
BuOMe – hexanes). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br. s, 1H),
3.98–3.79 (m, 4H), 1.76 (dd, J=8.6, 5.3 Hz, 1H), 1.38 (s, 9H), 1.19
(dd, J=8.6, 5.3 Hz, 1H), 1.07 (t, J=5.3 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 176.9, 156.2, 80.1, 55.6, 28.4, 24.7, 22.7, 18.4. HRMS (ESI-
TOF) m/z [MÀ H]À Calcd. For C11H16NO4 226.1085. Found 226.1082.
LC/MS (CI): m/z=226 [MÀ H]À .
Benzyl 3-methylenecyclobutanecarboxylate (14)
To the solution of compound 13 (18.7 g, 167 mmol) in CH2Cl2
(200 mL), CDI (29.6 g, 183 mmol) was added portionwise at rt
upon stirring. The resulting mixture was stirred at rt for 1 h. BnOH
(19.8 g, 183 mmol) was added dropwise, and the resulting solution
was stirred at rt for 16 h. Then the mixture was washed with H2O
(100 mL) and 1 M aq HCl (100 mL). The organic layer was
separated, dried over anhydrous Na2SO4, filtered and evaporated
in vacuo. Yield 32.7 g (97% yield). Yellowish liquid. 1H NMR
(400 MHz, CDCl3) δ 7.40–7.27 (m, 5H), 5.13 (s, 2H), 4.80 (d, J=
2.5 Hz, 1H), 4.79 (d, J=2.5 Hz, 1H), 3.23–3.10 (m, 1H), 3.07–2.84 (m,
4H); 13C NMR (126 MHz, CDCl3) δ 174.9, 144.2, 136.0, 128.6, 128.2,
128.2, 106.9, 66.4, 35.5, 33.2. HRMS (ESI-TOF) m/z [M+H]+ Calcd.
For C13H15O2 203.1067. Found 203.1067. LC/MS (CI): m/z=203 [M+
H]+.
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tert-Butyl 1-(((benzyloxy)carbonyl)amino)-5-azaspiro[2.3]
hexane-5-carboxylate (9)
Compound 1 (9.30 g, 0.041 mol) was dissolved in toluene (80 mL),
and triethylamine (7.00 mL, 0.050 mol), BnOH (11.0 g, 0.102 mol),
and diphenylphosphorylazide (12.4 g, 0.045 mol) were added. The
resulting mixture was heated to reflux carefully, then refluxed for
16 h, cooled to rt, saturated aq NaHCO3 (150 mL) and EtOAc
(50 mL) were added. The organic phase was separated, dried over
anhydrous Na2SO4, and evaporated in vacuo. The crude product
was purified by flash chromatography (hexanes – EtOAc (4:1) as
eluent, Rf =0.18). Yield 9.64 g (71%). Yellowish oil. 1H NMR
(400 MHz, CDCl3) δ 7.33 (s, 5H), 5.09 (s, 2H), 4.95 (br. s, 1H), 4.03–
3.82 (m, 4H), 2.61 (br. s, 1H), 1.42 (s, 9H), 1.04 (t, J=7.1 Hz, 1H),
0.69 (br. s, 1H); 13C NMR (126 MHz, CDCl3) δ 157.1, 156.0, 136.2,
128.6, 128.2, 128.1, 79.5, 77.3, 67.0, 30.7, 28.4, 20.8, 16.3. HRMS
(ESI-TOF) m/z [MÀ H]À Calcd. For C18H23N2O4 331.1663. Found
331.1655. LC/MS (CI): m/z=331 [MÀ H]À .
5-Benzyl 1-ethyl spiro[2.3]hexane-1,5-dicarboxylate (15)
Compound 14 (20.0 g, 99.0 mmol) was dissolved in CH2Cl2
(200 mL), and rhodium diacetate (0.840 g, 1.90 mmol) was added.
A solution of ethyldiazoacetate (22.8 g, 200 mmol) in CH2Cl2
(60 mL) was added dropwise at rt over 4 h. The resulting solution
was filtered through a thin layer of silica; the solvent was
evaporated in vacuo. The crude product was purified by flash
chromatography (hexanes – EtOAc (8:1), Rf =0.43). Yield 24.4 g
1
(86%); ca. 1:1 mixture of diastereomers. Colorless liquid; H NMR
(400 MHz, CDCl3,) δ 7.33 (s, 5H), 5.13 (s, 0.5×2H), 5.11 (s, 0.5×2H),
4.23–3.93 (m, 2H), 3.41–3.11 (m, 1H), 2.64–2.17 (m, 4H), 1.68–1.44
(m, 1H), 1.30–1.13 (m, 4H), 1.09–0.95 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 175.0 and 174.7, 172.4 and 172.3, 136.1 and 136.0, 128.6,
128.2, 128.1 and 128.1, 66.4 and 66.3, 60.3, 33.6 and 33.4, 33.2 and
33.1, 31.6 and 30.6, 27.0 and 26.3, 25.1 and 24.3, 20.8 and 20.2,
14.4; LC/MS (CI): m/z=289 [M+H]+; Anal. Calcd. for C17H20O4: C
70.81; H 6.99. Found: C 70.77; H 7.23.
5-(tert-Butoxycarbonyl)-5-azaspiro[2.3]hexan-1-aminium
chloride (2·HCl)
Triethylamine (4 μL, 0.03 mmol) was added to a stirred solution of
triethylsilane (350 mg, 3.00 mmol) in CH2Cl2 (10 mL), followed by
palladium diacetate (17.0 mg, 0.076 mmol). After 5 min, com-
pound 5 (500 mg, 1.50 mmol) was added, and the mixture was
stirred for 16 h. Then saturated aq NaHCO3 (10 mL) was added, the
organic layer was separated, dried over anhydrous Na2SO4, filtered,
and the solvent was evaporated. The residue was purified by flash
chromatography (hexanes – EtOAc (1:2), Rf =0.36). The resulting
product was dissolved in diethyl ether (5 mL), and then HCl in
diethyl ether (21% wt) was added dropwise until pH=5–6. The
precipitate was filtered and dried in vacuo. Yield 165 mg (33%).
Brownish amorphous solid. 1H NMR (500 MHz, D2O) δ 4.05–3.88
(m, 4H), 2.67 (dd, J=8.0, 4.7 Hz, 1H), 1.32 (s, 9H), 1.14 (t, J=8.0 Hz,
1H), 0.95 (dd, J=8.0, 4.7 Hz, 1H).13C NMR (101 MHz, D2O) δ 157.7,
82.1, 29.6, 29.1, 27.5, 18.1, 12.7. HRMS (ESI-TOF) m/z [MÀ H]À Calcd.
For C10H17N2O2 199.1441 Found 199.1432.
Ethyl 5-((tert-butoxycarbonyl)amino)spiro[2.3]
hexane-1-carboxylate (11)
Compound 15 (24.4 g, 84.7 mmol) was dissolved in EtOAc
(250 mL), and palladium on charcoal (10%, 5.00 g) was added. The
suspension was placed under a hydrogen atmosphere at normal
pressure and stirred at rt for 16 h. The mixture was filtered, and
the solvent was evaporated in vacuo to give 16 as a colorless
liquid (16.0 g) that was used in the next step without character-
ization. It was dissolved in CH2Cl2 (150 mL), and DMF (590 mg,
8.10 mmol) was added. Oxalyl chloride (12.3 g, 96.9 mmol) was
added to this solution dropwise at rt. The resulting solution was
stirred for 1 h, and then the solvent was evaporated in vacuo. The
acyl chloride obtained was immediately dissolved in acetone
(100 mL) and a solution of sodium azide (15.8 g, 243 mmol) in H2O
Benzyl 5-azaspiro[2.3]hexan-1-ylcarbamate
2,2,2-trifluoroacetate (3·TFA)
Compound 9 (500 mg, 1.51 mmol) was dissolved in CH2Cl2 (8 mL),
and trifluoroacetic acid (4 mL) was added. The mixture was stirred
at rt for 2 h, and then the solvent was evaporated in vacuo. The
crude product was dissolved in H2O (4 mL), the solvent was
evaporated, and the residue was dried in vacuo. Yield 450 mg
(86%). Brownish oil; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (br. s, 2H),
7.57 (br. s, 1H), 7.43–7.25 (m, 5H), 5.15–4.98 (m, 2H), 3.97 (m, 3H),
3.89 (d, J=8.4 Hz, 1H), 2.69–2.61 (m, 1H), 1.08 (dd, J=8.2, 6.6 Hz,
1H), 0.75 (dd, J=6.6, 4.7 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ
156.3 (q, J=31.0 Hz), 155.2, 135.1, 126.6, 126.1, 126.0, 116.0 (q, J=
281.6 Hz), 63.8, 50.0, 47.7, 38.7, 28.5, 19.3, 12.9. LC/MS (CI): m/z=
°
(150 mL) was added dropwise at 0 C. The solution was stirred at
the same temperature for 1 h, EtOAc (200 mL) and H2O (100 mL)
were added, the organic phase was separated, and the aqueous
phase was washed with EtOAc (2×50 mL). The combined organic
layers were washed with brine (100 mL), dried over anhydrous
Na2SO4, filtered, and the solvent was evaporated in vacuo to ca.
80 mL of the remaining volume. This solution was added dropwise
°
to a mixture of toluene (150 mL) and t-BuOH (70 mL) at 90 C, and
the mixture was stirred at this temperature for 16 h. The solvent
was evaporated in vacuo, and the crude product was purified by
flash chromatography (hexanes – EtOAc, Rf =0.62). Yield 15.5 g
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(69% for 2 steps); ca. 1:1 mixture of diastereomers. Colorless oil;
cis-Isomer 17b
1
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3) 4.77 (br. s, 0.5×1H) and 4.71 (br. s, 0.5×
1H), 4.25 (br. s, 1H), 4.15–4.03 (m, 2H), 2.49 (m, 1H), 2.44–2.28 (m,
1H), 2.22–2.04 (m, 2H), 1.62–1.54 (m, 1H), 1.41 (s, 9H), 1.24 (t, J=
7.1 Hz, 0.5×3H), 1.24 (t, J=7.1 Hz, 0.5×3H), 1.20 (t, J=5.0 Hz, 0.5×
1H) and 1.11 (t, J=5.0 Hz, 0.5×1H), 1.04 (dd, J=8.5, 5.0 Hz, 0.5×
1H), 0.96 (dd, J=8.5, 5.0 Hz, 0.5×1H).13C NMR (126 MHz, CDCl3) δ
172.6 and 172.5, 155.0, 79.3, 60.3 and 60.2, 39.4 and 39.2, 37.5 and
37.4, 35.6 and 35.1, 28.4, 25.1 and 24.7, 24.1 and 23.5, 20.5, 14.4.
HRMS (ESI-TOF) m/z [M+H]+ Calcd. For C14H24NO4: 270.1700.
Found 270.1688. LC/MS (CI): m/z=169 [MÀ CO2-H2C=C(CH3)2 +H]+.
1
°
White solid. m.p.=154–157 C (THF – hexanes). H NMR (400 MHz,
CDCl3) δ 7.36–7.31 (m, 5H), 5.86 (br. s, 1H), 5.12 (d, J=11.4 Hz, 1H),
5.09 (d, J=11.4 Hz, 1H), 4.93 (s, 1H), 4.27 (br. s, 1H), 2.45 (br. s, 2H),
2.39 (br. s, 1H), 1.99–1.91 (m, 1H), 1.85–1.77 (m, 1H), 1.43 (s, 9H),
0.85 (t, J=7.0 Hz, 1H), 0.43 (br. s, 1H); 13C NMR (101 MHz, CDCl3) δ
157.5, 155.5, 136.3, 128.6, 128.3, 128.3, 78.9, 67.0, 42.8, 38.3, 34.1,
32.5, 28.5, 22.0, 17.0. HRMS (ESI-TOF) m/z [MÀ H]À Calcd. For
C19H25N2O4: 345.1820. Found 345.1812. LC/MS (CI): m/z=291
[MÀ H2C=C(CH3)2 +H]+, 91 [C7H7]+.
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General procedure for the synthesis of 4a·HCl and 4b·HCl
5-((tert-Butoxycarbonyl)amino)spiro[2.3]hexane-1-carboxylic
acid (12)
Palladium on charcoal (10%, 100 mg) was added to a stirred
solution of compound 17a or 17b (500 mg, 1.44 mmol) in MeOH
(10 mL), and H2 gas was bubbled through the reaction mixture for
3 h. The catalyst was filtered off through a celite pad. The filtrate
was evaporated in vacuo and dissolved in diethyl ether (20 mL).
Then HCl in diethyl ether (20% wt, 250 mg) was added dropwise,
the precipitate was filtered, dissolved in acetonitrile (1 mL), then
diethyl ether (15 mL) was added dropwise, and the mixture was
stirred for 15 min. The precipitate was filtered and dried in vacuo.
Compound 11 (15.5 g, 0.058 mol) was dissolved in MeOH (50 mL),
and the mixture was added to a solution of NaOH (7.00 g,
0.175 mol) in H2O (80 mL). The mixture was stirred at rt for 16 h.
The solvent was evaporated in vacuo, 1 M aq NaHSO4 was added
to the aqueous solution to pH=3–4, and then EtOAc (100 mL)
was added. The organic phase was separated, the aqueous phase
was washed with EtOAc (3×50 mL), the combined organic layers
were dried over anhydrous Na2SO4, filtered, and the solvent was
evaporated in vacuo. Yield 12.4 g (89%); ca. 1:1 mixture of
°
diastereomers. Yellowish solid; m.p.=120–122 C (t-BuOMe
–
trans-5-((tert-butoxycarbonyl)amino)spiro[2.3]
hexan-1-aminium chloride (4a·HCl)
1
hexanes); H NMR (400 MHz, CDCl3) δ 4.80 (br. s, 1H), 4.25 (br. s,
1H), 2.57 (br. s, 1H), 2.42 (br. s, 1H), 2.25–2.08 (m, 2H), 1.65–1.55
(m, 1H), 1.45–1.38 (m, 9H), 1.29–1.14 (m, 1H), 1.13–1.00 (m, 1H);
COOH is exchanged with HDO. 13C NMR (101 MHz, CDCl3) δ 178.5,
155.0, 79.5, 42.2 and 41.7, 39.3 and 39.0, 37.4 and 35.7, 28.4, 26.3
and 25.1, 24.5 and 23.5, 21.3. HRMS (ESI-TOF) m/z [M+H]+ Calcd.
For C12H20NO4: 242.1387. Found 242.1378. LC/MS (CI): m/z=241
[MÀ H]À .
Yield 232 mg (71%). White solid; m.p.=231–233 C (MeCN). 1H
°
NMR (500 MHz, DMSO-d6) δ 8.42 (br. s, 3H), 7.23 (d, J=7.7 Hz, 1H),
4.21–4.01 (m, 1H), 2.41 (br. s, 1H), 2.35–2.25 (m, 1H), 2.17–2.11 (m,
1H), 2.11–2.03 (m, 2H), 1.35 (s, 9H), 0.82–0.63 (m, 2H). 13C NMR
(126 MHz, DMSO-d6) δ 155.0, 78.1, 42.1, 37.9, 33.5, 30.7, 28.7, 18.1,
13.5. HRMS (ESI-TOF) m/z [M+H]+ Calcd. For C11H21N2O2: 213.1598.
Found 213.159.
Benzyl tert-butyl spiro[2.3]hexane-1,5-diyldicarbamate (17)
cis-5-((tert-Butoxycarbonyl)amino)spiro[2.3]hexan-1-aminium
chloride (4b·HCl)
Compound 12 (12.4 g, 0.036 mol) was dissolved in toluene
(80.0 mL), and triethylamine (8.80 mL, 0.063 mol), BnOH (13.8 g,
0.128 mol), and diphenylphosphorylazide (15.4 g, 0.056 mol) were
added. The resulting mixture was heated to reflux carefully, then
refluxed for 16 h, cooled to rt, and saturated aq NaHCO3 (150 mL)
and EtOAc (50 mL) were added. The organic phase was separated,
dried over anhydrous Na2SO4, and evaporated in vacuo. The crude
product was purified by flash chromatography. Yield 12.3 g (69%),
ca. 1:1 mixture of diastereomers. The mixture was separated by
column chromatography (hexanes – EtOAc (3:1) as eluent, Rf
(17a)=0.24, Rf (17b)=0.34). Yield of 17a – 7.0 g (40%). Yield of
17b – 3.7 g (21%)
Yield 255 mg (71%). White solid; m.p.=212–213 C (MeCN). 1H
°
NMR (400 MHz, DMSO-d6) δ 8.34 (br. s, 3H), 7.29 (br. s, 1H), 4.07
(br. s, 1H), 2.39 (br. s, 1H), 2.31–2.24 (m, 1H), 2.21 (br. s, 1H), 2.15–
2.02 (m, 2H), 1.36 (s, 9H), 0.95–0.74 (m, 2H). 13C NMR (126 MHz,
DMSO) δ 154.7, 77.7, 41.6, 36.8, 34.0, 28.8, 28.3, 18.1, 15.1. HRMS
(ESI-TOF) m/z [M+H]+ Calcd. For C11H21N2O2: 213.1598. Found
213.159.
General procedure for the synthesis of 5a·HCl and 5b·HCl
Compound 17a or 17b (500 mg, 1.45 mmol) was added to 2 M
HCl in MeOH (10 mL). The mixture was stirred at rt for 2 h, then
the solvent was evaporated in vacuo, the solid residue was
washed with hexanes, filtered, and dried in vacuo.
trans-Isomer 17a
1
°
White solid. m.p.=135–137 C (THF – hexanes). H NMR (400 MHz,
CDCl3) δ 7.41–7.22 (m, 5H), 5.08 (br. s, 2H), 4.88 (br.. s, 1H), 4.79 (br.
s, 1H), 4.29 (br. s, 1H), 2.48 (br. s, 1H), 2.30 (br. s, 2H), 2.11–1.92 (m,
2H), 1.41 (br. s, 9H), 0.82 (br. s, 1H), 0.40 (br. s, 1H); 13C NMR
(101 MHz, CDCl3) δ 157.0, 154.9, 136.5, 128.5, 128.2, 128.1, 79.2,
66.7, 42.6, 38.2, 34.1, 32.5, 28.4, 20.4, 16.6. HRMS (ESI-TOF) m/z
[MÀ H]À Calcd. For C19H25N2O4: 345.1820. Found 345.1816. LC/MS
(CI): m/z=291 [MÀ H2C=C(CH3)2 +H]+, 247 [MÀ CO2-H2C=C(CH3)2)+
H]+.
trans-1-(((Benzyloxy)carbonyl)amino)spiro[2.3]
hexan-5-aminium chloride (5a·HCl)
°
Yield 340 mg (95%). White powder; m.p.=177–180 C
1
(MeCNÀ MeOH). H NMR (400 MHz, D2O) δ 7.25 (s, 5H), 4.95 (s, 2H),
3.78 (br. s, 1H), 2.33 (br. s, 1H), 2.22 (br. s, 2H), 2.09 (br. s, 2H), 0.79
(br. s, 1H), 0.43 (br. s, 1H).13C NMR (101 MHz, D2O) δ 159.5, 136.3,
128.8, 128.4, 127.6, 66.9, 42.1, 33.7, 31.5, 30.1, 19.7, 15.2. HRMS
(ESI-TOF) m/z [M+H]+ Calcd. For C14H19N2O2: 247.1441. Found
247.1439 LC/MS (CI): m/z=247 [MÀ HCl+H]+.
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11, 1213–1220.
[16] T. T. Talele, J. Med. Chem. 2016, 59, 8712–8756.
cis-1-(((Benzyloxy)carbonyl)amino)spiro[2.3]hexan-5-aminium
chloride (5b·HCl)
1
2
3
4
5
6
7
8
9
°
[17] W. Yu, J. Liu, Y. Yu, V. Zhang, D. Clausen, J. Kelly, S. Wolkenberg, D.
Beshore, J. L. Duffy, C. C. Chung, R. W. Myers, D. J. Klein, J. Fells, K.
Holloway, J. Wu, G. Wu, B. J. Howell, R. J. O. Barnard, J. Kozlowski,
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W. Wang, B. Wei, A. Zhou, M. W. Cartwright, E. Gancia, G. Jones, M.
Lainchbury, A. Madin, E. Seward, D. Favor, K. C. Fong, A. Good, Y. Hu, B.
Hu, A. Lu, U. S. Patent 2018282328, 2018.
Yield 339 mg (95%). White powder; m.p.=248–250 C (dec.)
(MeCNÀ MeOH). H NMR (400 MHz, D2O) δ 7.26 (s, 5H), 4.98 (s, 2H),
1
3.81 (br. s, 1H), 2.35 (br. s, 2H), 2.30–2.23 (m, 1H), 2.14–2.07 (m,
1H), 1.92–1.84 (m, 1H), 0.83 (t, J=7.2 Hz, 1H), 0.48 (br. s, 1H); 13C
NMR (126 MHz, D2O) δ 159.8, 136.3, 128.8, 128.4, 127.6, 67.1, 42.8,
33.3, 31.2, 30.4, 20.5, 15.7. HRMS (ESI-TOF) m/z [M+H]+ Calcd. For
C14H19N2O2: 247.1441. Found 247.1430. LC/MS (CI): m/z=247
[MÀ HCl+H]+.
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Acknowledgements
The work was funded by Enamine Ltd. Additional funding was
received from Ministry of Education and Science of Ukraine
(Grants No. 19BF037-03 and 21BF037-01M). The authors thank Dr.
Eduard Rusanov for X-Ray diffraction studies, Ms. Yuliya Kuchkov-
ska for her help with manuscript preparation, Dr. Andriy Kozytskiy
for NMR measurements, and Prof. Andrey A. Tolmachev for his
encouragement and support.
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Conflict of Interest
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Manuscript received: December 12, 2020
Revised manuscript received: January 30, 2021
Accepted manuscript online: February 4, 2021
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A. Malashchuk, Dr. A. V. Chernykh,
M. Y. Perebyinis, Prof. Dr. I. V.
Komarov*, Dr. O. O. Grygorenko*
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1 – 11
Monoprotected Diamines Derived
from 1,5-Disubstituted (Aza)spiro
[2.3]hexane Scaffolds
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Synthesis of monoprotected diamines
derived from 1,5-disubstituted (aza)
spiro[2.3]hexane scaffolds is
described. Structural characterization
of the obtained spirocyclic
compounds provided a rationale for
their applications in design of
saturated ring isosteres and peptido-
mimetics.