Synthesis of Structurally Diverse N-Substituted Quaternary-Carbon-Containing Small Molecules from α,α-Disubstituted Propargyl Amino Esters

Article abstract of DOI:10.1002/chem.201803143

N-containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable. Herein, we describe the diversity-oriented synthesis (DOS) of a diverse collection of structurally distinct small molecules featuring this three-dimensional (3D) motif. The subsequent derivatisation and the stereoselective synthesis exemplified the versatility of this strategy for drug discovery and library enrichment. Chemoinformatic analysis revealed the enhanced sp³ character of the target library and demonstrated that it represents an attractive collection of biologically diverse small molecules with high scaffold diversity.

Full text of DOI:10.1002/chem.201803143

A Journal of
Accepted Article
Title: Synthesis of structurally diverse N-substituted quaternary carbon
containing small molecules from α,α-disubstituted propargyl
amino esters
Authors: Natalia Mateu, Sarah L. Kidd, Leen Kalash, Hannah F. Sore,
Andrew Madin, Andreas Bender, and David R. Spring
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201803143
Link to VoR: http://dx.doi.org/10.1002/chem.201803143
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Synthesis of structurally diverse N-substituted quaternary carbon
containing small molecules from α,α-disubstituted propargyl
amino esters
Natalia Mateu,*,‡,[a] Sarah L. Kidd,‡,[a] Leen Kalash,[a] Hannah F. Sore,[a] Andrew Madin,[b] Andreas
Bender[a] and David R. Spring*,[a]
Dedicated to Sir Jack E. Baldwin on the occasion of this 80th birthday
Abstract: N-containing quaternary stereocenters represent
important motifs in medicinal chemistry. However, due to their
inherently sterically hindered nature, they remain underrepresented
in small molecule screening collections. As such, the development of
synthetic routes to generate small molecules that incorporate this
particular feature are highly desirable. Herein, we describe the
diversity-oriented synthesis (DOS) of
a diverse collection of
structurally distinct small molecules featuring this three-dimensional
(3D) motif. The subsequent derivatisation and the stereoselective
synthesis exemplified the versatility of this strategy for drug
discovery and library enrichment. Chemoinformatic analysis
revealed the enhanced sp3 character of the target library and
demonstrated that it represents an attractive collection of biologically
diverse small molecules with high scaffold diversity.
Figure 1. Examples of bioactive compounds containing
a N-substituted
quaternary carbon.
Studies have shown that increased complexity (e.g. sp3-rich
cycles or quaternary carbons) can correlate to an increase in the
selectivity, potency and metabolic stability of drug candidates,
along with the successful progression from clinical stages to
drug approval.[13],[14] However, due to their congested nature, the
incorporation of N-containing quaternary stereocenters into
Introduction
N-containing quaternary stereocenters are important motifs in
medicinal chemistry and are present in significant essential
medicines
including
the
antihypertensive
methyldopa
(Aldomet®) and the anaesthetic ketamine (Ketalar®) (Figure 1,
a-b).[1] The presence of this particular stereocenter in the three
small molecules currently under clinical evaluation, Ranirestat,[2]
Veliparib[3] and Verubecestat[4] (Figure 1, c-e), further highlight
its relevance in drug discovery contexts. The biological activity of
such compounds has been generally shown to be intrinsically
related to their absolute configuration.[5–10] For instance,
investigations have concluded that the presence of a N-
containing quaternary (R)-stereocenter within the core structure
is necessary for interaction of the substituents with the pockets
of the β-secretase (BACE1) binding site.[9],[10] Moreover, the
presence of such restricted elements within a small molecule
can provide conformational restrictions owing to their sterically
hindered nature, thereby increasing the molecular complexity of
a given molecule, which has been shown to be desirable
small molecules poses
a synthetic challenge for organic
chemists.[15–19] As
a
result, small molecules bearing this
particular feature are still under-represented in probe and drug
discovery screening collections.
From a synthetic perspective, despite all the advances
made in the field of asymmetric catalysis to generate α-branched
amino-containing compounds,[16–19] the majority of the reported
reactions are based on simple scaffolds with restricted structural
diversity and there has been a limited exploration into the
construction of such motifs into more complex molecules. It has,
however, been demonstrated that the use of α,α-disubstituted
amino esters as subunits to prepare complex molecules bearing
this sterically hindered motif can be particularly effective. Thus,
some examples in the literature have validated this strategy by
the target-oriented synthesis (TOS) of biologically active small
molecules.[20] More recently, allyl-containing cyclic quaternary
amino esters have also been used for the diversity-oriented
synthesis (DOS) of small molecule collections.[21],[22] However,
structurally diverse, sp3-rich and complex libraries are still under-
represented in probe and drug discovery screening collections.
In addition to these deficiencies, within the literature,
significant synthetic challenges have been identified in relation
to the development of chemistries which tolerate polar
functionalities such as amines, N-heterocycles and unprotected
chemical
feature
for
bioactive
molecules.[11],[12]
[a]
Dr. Natalia Mateu, Sarah L. Kidd, Leen Kalash, Dr. Hannah F.
Sore, Dr. Andreas Bender and Prof. David R. Spring
Department of Chemistry, University of Cambridge
Lensfield Rd, Cambridge, CB2 1EW (UK)
E-mail: spring@ch.cam.ac.uk
[b]
Dr. Andrew Madin
AstraZeneca UK Ltd.
310 Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ
(UK)
* Corresponding author ‡ Equal contributors
Supporting information for this article is given via a link at the end of the
document
polar groups.[23] Moreover, within
a fragment-based drug
discovery context, there have been recent calls for the design
and synthesis of novel compounds that feature multiple 3D
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growth vectors whilst incorporating polar functionality for
molecular recognition.[24] In response to this, notable examples
of efficient syntheses of diverse sp3-rich libraries have been
recently published[25–32], however there is still an outstanding
need for diverse libraries featuring this key N-containing
quaternary stereocenter motif.
With these points in mind, we envisioned that α,α-
disubstituted propargyl amino esters could act as a versatile and
pluripotent platform for the DOS of structurally diverse screening
commercially available chloro-oxime or the corresponding azido
ester. In turn, lactamisation of the ester moieties within 7 and 8
with the quaternary amine (Scheme 1, step e/f) afforded the
rigidified scaffolds 9 and 10. Further exploitation of the terminal
alkyne handle within 1 via Ru- or Cu- catalysis afforded the
acyclic 1,5- and 1,4-phenyl substituted triazoles 11 and 12,
respectively. Finally, Sonogashira cross-coupling of the terminal
alkyne followed by hydrogenation afforded 13 (Scheme 1, step
e).
collection featuring
a
stereogenic N-containing quaternary
Next, an exploration into intramolecular cyclisations between
the ester functionality within 1 and the terminal alkyne was
undertaken (Scheme 1, step c/d). Reduction of the carboxylic
moiety into the corresponding alcohol provided the opportunity
to introduce additional unsaturated moieties through the
alkylation of the newly generated hydroxyl group to afford the
allylic- and propargylic intermediates. Following this, metal-
catalysed intramolecular cyclisations such as Co-induced
[2+2+2] cyclotrimerisations - when starting from the dialkyne
intermediate - or a sequence of ring-closing eynyne metathesis
followed by Diels-Alder cycloaddition – when starting from the
allylic intermediate – afforded novel bi- and tricyclic oxepine-
containing scaffolds 14, 15 and 16. Additionally, ester hydrolysis
of 1 to the carboxylic acid followed by the Cu-promoted
intramolecular cyclisation afforded 17, whilst Ru-mediated
cyclisation of the amino alcohol intermediate with the terminal
alkyne generated 18.
carbon (Figure 2). In this manner, the reactivity of its three
functional vectors, namely the terminal alkyne, the amine as well
and the ester moieties could be exploited in both inter- and
intramolecular reactions.[33]
Smaller propargyl-containing fragments featuring different
polar functionalities could also be synthesised via pairing the
amino and ester moieties within 1. Pyrrole 19 was prepared via
Paal-Knorr reaction and a nitrile-based secondary branch point
was introduced to afford 20 (Scheme 1, step a, see SI).
Benzodiazepine 21 was prepared starting from the azido
benzoyl intermediate followed by azide reduction to facilitate the
lactamisation reaction with the ester functionality (Scheme 1,
steps a/b). Again, acylation of 1 proved useful in generating
acyclic intermediates which could in turn be cyclized with the
ester functionality. For example, Dieckmann condensation of the
malonyl derivative followed by decarboxylation, yielded the
substituted pyrrolidone 22. Reduction of the ester to a hydroxyl
again provided the opportunity to cyclise between this moiety
and the amino group (Scheme 1, steps c/b). In this manner,
using a single N-Boc protected amino alcohol, aziridine 23 and
oxazolidinone 26 could be both synthesized. Finally, two further
propargyl-containing scaffolds were synthesized by N-acylation
followed by hydroxyl-mediated cyclisation or vice versa, O-
acylation followed by nitrogen-mediated cyclisation, to yield
morpholinones 24 and 25, respectively.
The reactivity of both 19 and 20 could be further exploited to
generate five different scaffolds in a synthetically efficient
manner. Unexpectedly, when extending the reaction time for the
formation of 19, an alternative intramolecular cyclisation was
observed between the terminal alkyne and the in situ hydrolysed
methyl ester, giving rise to 27. Moreover, gold catalysis
promoted the intramolecular cyclisation between the terminal
alkyne and a pyrrole within 19 to afford dihydroindolizine 28. We
next sought to explore the reactivity of cyano functionality within
20. A novel one-step approach to synthesise tricyclic pyrrole-
containing scaffolds was developed via Co-catalysed [2+2+2]
Figure 2. Synthetic versatility of α,α-disubstituted amino esters for the DOS of
N-substituted quaternary carbon containing small molecules.
Results and discussion
Synthesis of the DOS library
To validate our hypothesis, we initially selected the racemic -
methyl propargylglycine 1 (R = Me) as a model substrate to
perform the reagent-based DOS outlined in this work (Scheme
1). Our investigations began via alkylation of the amino group in
1 through the introduction of a tert-butyl carbamate, propargyl, 2-
azido benzoyl or an acyl group to generate the first set of highly
functionalised intermediates (S2-6, for all intermediates see
Scheme S1). Subsequent pairing of the functionalities present in
these intermediates with the terminal alkyne could be achieved
through different metal-catalysed cyclisations (Scheme 1, steps
a/f). Accordingly, Co-induced [2+2+2] cyclotrimerisation afforded
2 and 3, whilst hydroamination using gold catalysis yielded 4
and 6. Finally, intramolecular Ru-mediated click chemistry gave
rise to compound 5.
In a similar fashion, Ru-mediated 1,5-click chemistry could
be used to generate acyclic compounds 7 and 8, through
intermolecular reaction of a protected form of 1 with the
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Scheme 1. Synthesis of structurally diverse N-substituted quaternary carbon containing small molecules from α,α-disubstituted amino ester 1: a) amine
derivatisation; b) pairing of the amino and ester moieties; c) ester derivatisation; d) pairing of the alkyne and ester moieties; e) alkyne derivatisations; f) pairing of
the amino and alkyne moieties. For reaction conditions see Supporting Information.
Using the strategy outlined above we synthesised
a
cyclotrimerization. Thus, starting from 20 CpCo(CO)2 and
cyclopropylacetylene could be utilised to furnish fused
heterocycles 29 and 30. Further scaffold exploration using this
approach is currently being investigated in our research group.
Finally, Pd-catalysed reduction of the nitrile moiety within 20,
allowed the intramolecular cyclisation affording the propyl-
substituted pyrrolopiperazine 31.
Finally, the terminal alkyne within 25 and 26 could be further
modified to generate two conformationally restricted small
molecules 32 and 33 via vinyl iodide formation followed by
Buchwald coupling.[34]
To demonstrate the synthetic potential of the propargyl-
containing warheads for library enumeration, the alkyne handle
within 19, 21-23 and 26 was further modified (Figure 3, A). Thus,
Cu-catalysed click reaction gave the 1,4-substituted triazoles
19a, 21a, 22a, and 26a; Sonogashira cross-coupling afforded
21b and 22b; hydrogenation of the alkyne produced saturated
derivatives 21c and 22c and, finally, Ru-mediated click reaction
afforded the 1,5- triazole 23d.
structurally diverse library of 40 compounds based around 27
molecular frameworks relevant for drug discovery (see Figure
S1) featuring a N-containing quaternary stereocenter. Each
compound was obtained in no more than five synthetic steps
(with an average of only three steps) starting from 1, which
demonstrates the efficiency of this process. Importantly, the
flexibility of this methodology was further exemplified via the
synthesis of the phenyl-derivative 10’ (Figure 3, B). The ability to
synthesise the asymmetric version of any compound from the
library was also validated through the synthesis of the optically
pure triazolodiazepine (R)-10 (Figure 3, C) from (R)-1 (see SI).
Chemoinformatic assessment
In order to assess the molecular shape distribution of the
resulting library, a principal moments of inertia (PMI) analysis
was conducted (Figure 4).[35] Pleasingly, analysis of the DOS
library showed a broad distribution of molecular shape space,
with 93% of the library out of ‘flatland’[36] and possessing
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Figure 3. (A) Exemplification of the synthesis of other derivatives via alkyne modifications. Reaction conditions: 19a, 21a, 22a, 26a: azidobenzene, CuSO4·5H2O,
t-BuOH:H2O, rt, 72-92%; 21b and 22b: PdCl2(PPh3)2, CuI, Et3N, benzyl 2-iodobenzoate, DMF, rt, 16h, 60% and 26%, respectively; 21c and 22c: Pd/C, H2, MeOH,
rt, 2h, 69% and 87%, respectively; 23d: ethyl 2-azidoacetate, Cp*RuCl(COD), PhMe, rt - 60 ºC, 21h, 42% (B) Synthesis of the phenyl-containing derivative.
Reaction conditions: i) Boc2O, THF, 70 ºC, o/n, 84%; ii) ethyl 2-azidoacetate, Cp*RuCl(COD), PhMe, 80 ºC, 1h, 87%; iii) TFA, CH2Cl2, 2h then NaHCO3,
(quantitative yield); iv) PhMe, 150 ºC, o/n, 76%. (C) Synthesis of an enantiopure component of the library. Reaction conditions: i) Boc2O, THF, 70 ºC, o/n, 90%; ii)
ethyl 2-azidoacetate, Cp*RuCl(COD), PhMe, 50 ºC, 1h, 76%; iii) TFA, CH2Cl2, 2h then NaHCO3, 93%; iv) PhMe, 150 ºC, o/n, 79%.
considerable 3D character. In order to investigate the influence
of the substituent at the quaternary center on the shape, a virtual
collection based on the phenyl-derivatives (DOS Library Ph, see
SI) was plotted in the same graph (Figure 4). Comparative
analysis between the two DOS libraries highlighted a shift to the
right-hand side of the plot and more 3D character when
modifying the quaternary substituent. This data suggests that
installation and substituent modification of the N-containing
quaternary sp3 stereocenter represents a useful strategy for
‘tuning’ the 3D molecular shape (and thus target binding profile)
data for a large number of drug-like bioactive compounds. The
molecular weight range of the bioactive compounds selected for
the analysis was between 200 and 700, and the compounds
covered different target classes.[42] Then, their Morgan
fingerprints[43] were generated for multi-dimensional scaling
(MDS). Our DOS library (Figure 5, shown in black) covers a
wider area of biologically relevant chemical space compared to
the targeted libraries, overlapping with areas occupied by kinase
inhibitors, ion channels blockers, membrane receptors ligands
of
a given molecule. Finally, the commercially available
Maybridge ‘Rule of 3’ core fragment library comprising 1,000
screening compounds (see SI and Figure 4) was analysed and
compared to the DOS library. Importantly, only 28% of the
Maybridge library appeared out of ‘flatland’ with
a high
proportion of ‘disk’ and ‘rod’ type compounds, which highlights
the increased diversity and more 3D character displayed by the
DOS library. Interestingly, only two compounds within the
Maybridge collection featured a N-containing quaternary carbon,
exemplifying the limited inclusion of this moiety within traditional
screening collections.
In addition to PMI analysis, calculation of the mean values
for physicochemical properties related to the ‘Rule of three’
guidelines[37] commonly adopted within fragment library
generation (Table 1) was conducted. Notably the DOS library
featured a low mean SlogP (1.37), higher mean number of chiral
centres (1.1) and low fraction of aromatic atoms per molecule
(0.29), compared to commercial libraries (See SI),
demonstrating the amenability of the DOS library to fragment-
based drug discovery approaches.[38]
Figure 4. Comparative PMI plot analysis of DOS library (blue circles),
Maybridge core 1000-member Ro3 Fragment library (green triangles) and the
DOS Ph virtual library (red squares). Compounds within ‘flatland’ (represented
by npr1 + npr2 value < 1.1, dashed line) could also be identified; the further
from this area the molecules move the more they extend into three-
dimensional space.[36]
Whilst PMIs are a common way of assessing shape diversity,
the relationship to bioactivity coverage appears to be more
complex.[39] To assess the coverage of our DOS library in
bioactivity space, we compared it to two previously reported
focused synthetic libraries,[40],[41] as well as bioactive compounds
retrieved from ChEMBL a database of binding and functional
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library through modifications to the alkyne-containing scaffolds,
Table 1. Mean physicochemical properties of fragment collections
the synthesis of
a phenyl-containing derivative and the
Maybridge
Ideal
Property [a]
This work
'Ro3' Core
collection
Chembridge
Range [b]
asymmetric version of an analogue, all of which can be applied
to library enumeration. Finally, cheminformatic analysis has
shown a broad molecular shape distribution, the importance of
the quaternary sp3 carbon in modifying the molecular shape and
the increased diversity and 3D character of the library when
compared to a commercial library. The analysis of the resulting
bioactivity space coverage showcases that the target library
represents an attractive screening collection of biologically
diverse small molecules.
SlogP
MW
1.37
237
1.92
182
1.31
222
0-3
<300
<3
HBA
HBD
2.63
0.78
1.10
0.29
1.83
1.01
0.14
0.52
1.81
1.04
0.27
0.42
<3
-
Chiral
centres
Fraction Ar
-
Experimental Section
General Remarks.
[a] MW = molecular weight, HBA = number of hydrogen bond acceptors, HBD
= number of hydrogen bond donors. [b] Ideal range based on guidelines of
Fragment ‘Rule of three‘[37]. Green = inside ideal range. Yellow = extreme of
ideal range.
All reagents and solvents were purchased from commercial
sources and used without further purification unless otherwise
stated. All the experiments were carried out under a nitrogen
atmosphere unless otherwise stated. Melting points were
measured using a Bꢀchi B545 melting point apparatus and are
uncorrected. Thin layer chromatography (TLC) was performed
on precoated Merck silica gel GF254 plates. Flash column
chromatography was performed on silica gel (230–400 mesh).
1H NMR and 13C NMR were recorded on a Bruker Avance 500
MHz instrument in CDCl3 and MeOD. HRMS was recorded on a
Micromass Q-TOF mass spectrometer or a Waters LCT Premier
Time of Flight mass spectrometer.
and ligands of other protein classes.
Currently, the DOS library is being screened via high-
throughput X-Ray crystallography methods in collaboration with
the XChem fragment screening facility at the Diamond Light
Source synchrotron. Hits against three different target classes
including hydrolases, the TGF-beta family of growth factors, and
peptidases have been successfully identified. Further biological
results from these initial campaigns will be published in due
course.
Conclusions
Methyl
3-methyl-7-phenyl-1,2,3,4-tetrahydro-2,6-
naphthyridine-3-carboxylate (2) and methyl 3-methyl-6-
phenyl-1,2,3,4-tetrahydro-2,7-naphthyridine-3-carboxylate
In summary, we have developed a new, efficient reagent-based
DOS approach using α-methyl-α-propargyl amino esters to
generate a library of 40 structurally diverse small molecules.
Importantly, throughout this sp3-rich library we have installed a
N-containing quaternary stereocenter, polar functionalities and
N-based heterocycles, answering key calls from within the field.
The resultant library also adheres to the fragment rule of three
guidelines, highlighting the amenability to this method of
screening. Furthermore, we have demonstrated the scope of our
(3):
A solution of methyl 2-((tert-butoxycarbonyl)amino)-2-
methylpent-4-ynoate (S2) (150 mg, 0.62 mmol) in DMF (3.0 mL)
was added to a suspension of sodium hydride (60% in mineral
oil, 30 mg, 0.74 mmol) in DMF(3.2 mL) cooled to 0 ºC. After 10
minutes stirring, propargyl bromide (80 wt. % in toluene, 0.138
Figure 5. Bioactive space coverage of
the DOS library, compared to two
targeted compound libraries and seven
different bioactivity classes of common
protein targets obtained from ChEMBL
(based on Morgan fingerprints and
Multi-Dimensional
Scaling,
MDS;
ellipses cover 90% of the data in each
class. It can be seen that the DOS
library displays significantly wider
coverage in bioactivity space than the
two targeted libraries, covering all
common classes of drug targets used
for comparison
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minutes stirring, propargyl bromide (80 wt. % in toluene, 0.138
mL, 1.24 mmol) was added and the mixture was warmed to
room temperature and stirred for 4 hours. Then, the mixture was
diluted with saturated aqueous solution of NH4Cl and the
and the reaction was stirred at 90 ºC. After 5 minutes, 2,5-
dimethoxytetrahydrofuran (0.13 mL, 0.99 mmol) was added and
the mixture was stirred at the same temperature overnight.
Then, the reaction was cooled to room temperature, diluted with
EtOAc and washed with saturated aqueous solution of NaCl.
The organic layer was dried over Na2SO4, filtered and the
solvents were concentrated in vacuo. The crude product was
purified by flash column chromatography (silica gel; petroleum
ether/EtOAc, 9:1) to yield 115 mg of 19 (61% yield) as a white
solid. Rf = 0.28 (petroleum ether/EtOAc, 9:1); mp 55 – 57 ºC; 1H
NMR (400 MHz, CDCl3) δ 1.94 (s, 3H), 2.05 (t, J = 2.6 Hz, 1H),
3.00 (dd, J = 16.8, 2.6 Hz, 1H), 3.07 (dd, J = 16.8, 2.6 Hz, 1H),
aqueous layer was extracted with EtOAc (3x). The combined
organic layers were washed with brine, dried with Na2SO4,
filtered, and the solvents were evaporated. The crude product
was purified by flash column chromatography (silica gel
petroleum ether/EtOAc, 5:1) to yield 168 mg of methyl 2-((tert-
butoxycarbonyl)(prop-2-yn-1-yl)amino)-2-methylpent-4-ynoate
(S3) (97% yield) as a colourless oil. Rf = 0.40 (petroleum
ether/EtOAc; 5:1); 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H),
1.70 (s, 3H), 1.99 (t, J = 2.6 Hz, 1H), 2.20 (t, J = 2.4 Hz, 1H),
2.73 (dd, J = 17.1, 2.5 Hz, 1H), 3.12 (d, J = 16.6 Hz, 1H), 3.69
(s, 3H), 4.02 (d, J = 18.5 Hz, 1H), 4.26 (br s, 1H); 13C NMR (101
MHz, CDCl3) δ 22.0, 27.0, 28.3, 34.1, 52.4, 62.5, 70.9, 71.1,
80.1, 80.9, 81.7, 154.3, 174.0; HRMS (ESI): m/z calcd for
C15H22NO4 [M+H]+: 280.1543; found: 280.1534.
3.74 (s, 3H), 6.21 (t, J = 2.2 Hz, 2H), 6.83 (t, J = 2.2 Hz, 2H); 13
C
NMR (101 MHz, CDCl3) δ 22.8, 30.0, 53.1, 63.1, 72.3, 78.5,
108.8, 118.7, 172.0; HRMS (ESI): m/z calcd for C11H14NO2
[M+H]+: 192.1019; found: 192.1013.
Methyl 2-(2-cyano-1H-pyrrol-1-yl)-2-methylpent-4-ynoate (20)
Chlorosulfonyl isocyanate (0.047 mL, 0.55 mmol) was added
drop-wise to a solution of 19 (70 mg, 0.37 mmol) in MeCN (3.6
mL) at 0 ºC. After 1 hour stirring, DMF (0.14 mL, 1.85 mmol) was
added and the mixture was stirred for 2 hours. Then, saturated
aqueous solution of NaHCO3 was added and the reaction
mixture was extracted with EtOAc (3x). The combined organic
layers were dried over Na2SO4, filtered and the solvents were
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; petroleum ether/EtOAc, 4:1)
to yield 57 mg of 20 (71% yield) as colourless oil. Rf = 0.29
(petroleum ether/EtOAc; 5:1); mp 64 – 66 ºC; 1H NMR (400
MHz, CDCl3) δ 1.88– 2.08 (m, 4H), 3.09 (dd, J = 17.5, 2.7 Hz,
1H), 3.31 (dd, J = 17.5, 2.1 Hz, 1H), 3.84 (s, 3H), 6.19 (dd, J =
3.8, 3.0 Hz, 1H), 6.93 (dd, J = 3.9, 1.5 Hz, 1H), 7.07 (dd, J = 2.8,
1.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 23.8, 29.5, 53.7,
64.5, 72.8, 77.2, 102.9, 108.5, 114.1, 123.2, 125.5, 171.5;
HRMS (ESI): m/z calcd for C12H12N2NaO2 [M+Na]+: 239.0791;
found: 239.0783.
CpCo(CO)2 (6.4 mg, 0.036 mmol) and benzonitrile (0.05 mL,
0.48 mmol) were added to a solution of S3 (68 mg, 0.24 mmol)
in toluene (2.4 mL), previously degassed with argon for 15
minutes, and the mixture was heated at 110 ºC for 36 hours.
Then, the solvent was removed under reduced pressure and the
crude product was purified by column chromatography (silica
gel; petroleum ether/EtOAc, gradient from 5:1 to 3:2). The
resulting inseparable mixture of regioisomers (ca. 40:60 ratio as
determined by 1H NMR) was dissolved in CH2Cl2 (1 mL) and
TFA (0.5 mL) was then added to the solution. After 1 hour
stirring the solvent was removed under reduced pressure. The
crude product was dissolved in EtOAc (5 mL) and a saturated
aqueous solution of NaHCO3 (5 mL) was added and the mixture
was stirred for 10 minutes. Then, the organic layer was
separated, dried over Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash column
chromatography (silica gel; gradient from EtOAc:MeOH 1:0 to
9:1) to afford 20 mg of 2 (30% yield) and 18 mg of 3 (26% yield)
both as a colourless oils.
3-Methyl-5-methylene-3-(1H-pyrrol-1-yl)dihydrofuran-2(3H)-
one (27): NaOAc (26 mg, 0.32 mmol) was added to a stirred
solution of 19 (30 mg, 0.16 mmol) in a mixture 5:3: of
DCE:H2O:AcOH (1.6 mL) and the reaction was stirred at 90 ºC
for 24 hours. Then, the reaction was cooled to room
temperature, diluted with EtOAc and washed with saturated
aqueous solution of NaCl. The organic layer was dried over
Na2SO4, filtered and the solvents were concentrated in vacuo.
The crude product was purified by flash column chromatography
to yield 12 mg of 27 (42% yield) as a colourless oil. Rf = 0.22
1
Data of minor regioisomer (2): Rf = 0.21 (EtOAc): H NMR (400
MHz, CDCl3) δ 1.48 (s, 3H), 2.37 (br s, 1H), 2.83 (d, J = 16.7 Hz,
1H), 3.35 (d, J = 16.7 Hz, 1H), 3.69 (s, 3H), 4.05 – 4.18 (m, 2H),
7.39 (ddd, J = 7.3, 3.7, 1.3 Hz, 1H), 7.41 – 7.49 (m, 3H), 7.90 –
7.98 (m, 2H), 8.37 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 26.6,
37.3, 42.6, 52.5, 57.9, 120.6, 126.9, 128.3, 128.8, 128.8, 139.4,
143.2, 147.8, 155.3, 175.9; HRMS (ESI): m/z calcd for
C17H19N2O2 [M+H]+: 283.1441; found: 283.1431
1
1
Data of major regioisomer (3): Rf = 0.32 (EtOAc): H NMR (400
(petroleum ether/EtOAc, 9:1); H NMR (400 MHz, CDCl3) δ1.85
MHz, CDCl3) δ 1.48 (s, 3H), 2.03 (br s, 1H), 2.80 (d, J = 16.2 Hz,
1H), 3.33 (d, J = 16.2 Hz, 1H), 3.68 (s, 3H), 4.08 (d, J = 17.0 Hz,
1H), 4.19 (d, J = 17.1 Hz, 1H), 7.34 – 7.41 (m, 2H), 7.41 – 7.48
(m, 2H), 7.86 – 7.97 (m, 2H), 8.43 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 26.4, 34.7, 44.7, 52.6, 58.1, 117.8, 126.9, 127.8,
128.8, 129.0, 139.4, 143.3, 150.2, 155.1, 175.8; HRMS (ESI):
m/z calcd for C17H19N2O2 [M+H]+: 283.1441; found: 283.1431.
Methyl 2-methyl-2-(1H-pyrrol-1-yl)pent-4-ynoate (19): NaOAc
(97 mg, 1.19 mmol) was added to a stirred solution of 1 (140
mg, 0.99 mmol) in a mixture 5:3:1 of DCE:H2O:AcOH (2.24 mL)
(s, 3H), 3.11 (dt, J = 16.2, 1.5 Hz, 1H), 3.39 (dt, J = 16.2, 1.8 Hz,
1H), 4.51 (dt, J = 3.2, 1.7 Hz, 1H), 4.91 (dt, J = 2.8, 2.1 Hz, 1H),
6.24 (t, J = 2.2 Hz, 2H), 6.86 (t, J = 2.1 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 24.2, 41.5, 61.6, 91.2, 109.7, 118.4, 151.3,
173.5; HRMS (ESI): m/z calcd for C10H12NO2 [M+H]+: 178.0861;
found: 178.0863.
Methyl 5-methyl-5,6-dihydroindolizine-5-carboxylate (28): A
solution of AuSPhos(MeCN)SbF6 (4.8 mg, 5 mol%) in DCE (0.1
mL) was added drop-wise to a solution of 19 (21 mg, 0.11 mmol)
and ethanol (0.032 mL, 0.55 mmol) in DCE (1.0 mL). The
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10.1002/chem.201803143
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resulting solution was heated for 2 hours at 40 ºC and then the
solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (silica gel;
petroleum ether /EtOAc, 4:1) to yield 17 mg of 28 (81% yield) as
a colourless oil. Rf = 0.24 (petroleum ether/EtOAc, 5:1); 1H NMR
(400 MHz, CDCl3) δ 1.80 (s, 3H), 2.49 (dt, J = 16.9, 2.7 Hz, 1H),
2.95 (dd, J = 16.9, 6.1 Hz, 1H), 3.64 (s, 3H), 5.58 – 5.69 (m, 1H),
6.12 (d, J = 2.5 Hz, 1H), 6.22 (t, J = 3.2 Hz, 1H), 6.46 (dd, J =
9.7, 2.8 Hz, 1H), 6.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
24.0, 35.8, 52.9, 61.3, 107.4, 108.9, 117.1, 118.9, 120.8, 130.3,
174.0; HRMS (ESI): m/z calcd for C11H14NO2 [M+H]+: 192.1019;
found: 192.1012.
CDCl3) δ 14.0, 17.4, 26.4, 39.8, 43.7, 62.9, 102.8, 109.8, 115.9,
122.1, 172.2; HRMS (ESI): m/z calcd for C11H17N2O [M+H]+:
193.1335; found: 193.1328.
Acknowledgements
Our research is supported by the EPSRC, BBSRC, MRC,
Wellcome Trust, and ERC (FP7/2007-2013; 279337/DOS). N. M.
thanks the EU for a Marie Curie Fellowship (2013-IEF-626191).
S.L.K. thanks AstraZeneca for funding. L.K thanks the IDB
Cambridge International Scholarship. The authors would like to
thank Prof. Frank von Delft, Dr. Romain Talon and Dr. Anthony
Aimon at XChem for enabling library screening using their facility
and collaborators Dr. Marko Hyvönen and Prof. Christopher
Dowson.
Methyl
2-cyclopropyl-6-methyl-5,6-dihydropyrrolo[1,2-
h][1,7]naphthyridine-6-carboxylate (29) and methyl 3-
cyclopropyl-6-methyl-5,6-dihydropyrrolo[1,2-
h][1,7]naphthyridine-6-carboxylate (30): CpCo(CO)2 (13.3 mg,
0.038 mmol) and cyclopropylacetylene (0.048 mL, 0.57 mmol)
were added to a solution of 20 (40 mg, 0.19 mmol) in toluene
(3.5 mL), previously degassed with argon for 15 minutes, and
the mixture was heated at 110 ºC for 36 hours. Then, the solvent
was removed under reduced pressure and the crude product
was purified by column chromatography (silica gel; gradient from
petroleum/EtOAc, gradient from 4:1 to 2:1) to afford 14 mg of 29
(27% yield) and 5 mg of 30 (10% yield) both as a white solids.
Keywords: diversity-oriented synthesis • medicinal chemistry •
molecular diversity • drug discovery • quaternary stereocenters
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Natalia Mateu,* Sarah L. Kidd, Leen
Kalash, Hannah Sore, Andrew Madin,
Andreas Bender and David R. Spring*
Page No. – Page No.
Synthesis of structurally diverse N-
substituted quaternary carbon containing
small molecules from α,α-disubstituted
propargyl amino esters,
A reagent-based diversity-oriented synthesis approach to generate a small molecule library, starting from α, α -disubstituted
propargyl amino esters, is reported. The strategy exploited the different reactivity of the alkyne, the amine and the ester moieties. The
target library represents an attractive screening collection of small molecules with high scaffold diversity covering broad areas of both
molecular shape space and bioactive space.
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