Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery

Article abstract of DOI:10.1002/ejoc.201900847

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug

Full text of DOI:10.1002/ejoc.201900847

A Journal of
Accepted Article
Title: Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic
Spirocycles for Fragment-Based Drug Discovery
Authors: Thomas A. King, Hannah L. Stewart, Kim T. Mortensen,
Andrew J. P. North, Hannah F. Sore, and David R. Spring
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900847
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900847
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10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
Cycloaddition Strategies for the Synthesis of Diverse
Heterocyclic Spirocycles for Fragment-Based Drug Discovery
Thomas A. King, Hannah L. Stewart, Kim T. Mortensen, Andrew J. P. North, Hannah F. Sore and
David R. Spring*
Abstract: In recent years the pharmaceutical industry has benefited
from the advances made in fragment-based drug discovery (FBDD)
with more than 30 fragment-derived drugs currently marketed or
progressing through clinical trials. The success of fragment-based
drug discovery is entirely dependent upon the composition of the
fragment screening libraries used. Heterocycles are prevalent within
marketed drugs due to the role they play in providing binding
interactions; consequently, heterocyclic fragments are important
components of FBDD libraries. Current screening libraries are
dominated by flat, sp2-rich compounds, primarily owing to their
synthetic tractability, despite the superior physicochemical properties
displayed by more three-dimensional scaffolds. Herein, we report
step-efficient routes to a number of biologically relevant, fragment-like
heterocyclic spirocycles. The use of both electron-deficient and
electron-rich 2-atom donors was explored in complexity-generating
[3+2]-cycloadditions to furnish products in 3 steps from commercially
available starting materials. The resulting compounds were primed for
further fragment elaboration through the inclusion of synthetic handles
from the outset of the syntheses.
chemical space by limiting the size (typically <300 kDa) and
physicochemical properties of screening compounds.[8,10,11]
Fragment hits, as a result of their small size, typically have weak
but high-quality binding interactions,[11] with the potential for
linking, merging and growing into high-affinity drug-like
candidates without the physical property inflation which is a
common affliction in the development of candidates identified
through more traditional methods.[12] As the FBDD field has
evolved, focus has turned to the importance of the fragment
library composition. Unfortunately, as with HTS, the robust
chemistry surrounding aromatic ring systems has led to a
significant over-representation of flat, sp2-rich scaffolds.[13,14]
In 2016, a key publication by Astex highlighted that the
various approaches to drug discovery, for example DOS and
FBDD, might not be considered orthogonal.[14] In fact, DOS might
be applied to the construction of more diverse and three-
dimensional fragment screening libraries. DOS is focused on
using short and divergent synthetic sequences from simple
starting materials to generate structurally complex and diverse
scaffolds.[15–22] DOS would provide the ideal strategy to expand
fragment libraries into three-dimensional chemical space, and this
challenge has been taken up across industry and academia.[23–29]
Within three-dimensional fragment space, spirocycles are
an important class of saturated ring systems.[30,31] The quaternary
centre provides an inherent three-dimensionality to this sub-set of
scaffolds whilst their cyclic nature provides all of the benefits of
reduced flexibility. It has been shown that these properties are
largely responsible for the biological activity observed with many
spirocyclic compounds, since they are linked to improved
physicochemical properties and decreased entropic binding
penalties.[32,33]
Introduction
Heterocycles play a vital role in drug discovery. The
incorporated heteroatoms provide potential binding interactions
and the cyclic nature limits structural flexibility, thereby reducing
the entropic penalty of binding.[1,2] Heterocycles are prevalent in
marketed drugs both as flat heteroaromatics and as saturated,
fused or spirocyclic scaffolds. However, this variety is not
representative of typical screening libraries, which are dominated
by flat heteroaromatic scaffolds as opposed to more synthetically-
challenging,
scaffolds.[2]
three-dimensional,
saturated,
heterocyclic
The failure of high throughput screening (HTS) to provide
the expected plethora of new drugs with the rise of combinatorial
chemistry can be strongly attributed to the dominance of sp2-rich,
flat compounds in HTS libraries.[3–5] This realisation has led to the
development of new strategies and approaches towards drug
discovery, including, but by no means limited to, diversity-oriented
[6,7]
synthesis
(DOS) and fragment-based drug discovery[8–10]
(FBDD). FBDD was developed as a means of efficiently sampling
T. A. King, Dr. H L. Stewart, Dr. K. T. Mortensen, Dr. A. J. P. North,
Dr. H. F. Sore, Prof. D. R. Spring
Department of Chemistry,
University of Cambridge,
Lensfield Road,
Cambridge, CB2 1EW
Figure 1. Examples of spirocycle-containing marketed drugs.[30,31]
E-mail: spring@ch.cam.ac.uk
Homepage: www-ch.spring.cam.ac.uk
Despite almost 47,000 biologically active compounds,
including a number of marketed drugs (Figure 1), containing a
spirocyclic scaffold, spirocycles are under-represented in
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900847
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COMMUNICATION
fragment screening libraries.[33] This is likely due to the synthetic
challenge posed by the generation of the quaternary centre.
Regio- and stereo-control is difficult to achieve and, historically,
has required multiple alkylation steps followed by intramolecular
coupling. Furthermore, these routes have suffered from functional
group incompatibility which, in turn, has greatly limited the
incorporation of functional handles for late-stage modification and
fragment elaboration.[34–36] Moreover, these strategies tend to
involve long linear sequences, and are therefore of limited use in
the optimisation of fragment hits.[34–36]
Despite this, due to their biological potential there has been
a recent surge of interest in the synthesis of spirocycles for drug
discovery.[26,30,37–45] In particular, Wang and Bode utilised metal
hydride hydrogen atom transfer chemistry to generate saturated
heterocyclic spirocycles in a one-pot reaction from unactivated
imines (Figure 2a).[46] Work by Griggs et al. also used a one-pot
reaction, this time to generate highly substituted 2-
spiropiperidines from N-Boc imines, by in-situ Boc-deprotection
and cyclisation onto a cyclic ketone (Figure 2b).[47] Alternatively,
the addition of trifluoroborates to oxetanyl N,O-acetals by Carreira
and co-workers provided compounds for spirocyclisation via
orthogonal activation of the oxetane and alkyne functionalities
(Figure 2c).[42]
There is a growing need for the development of step-
efficient and versatile strategies for the synthesis of these
compounds. Heterocyclic, spirocyclic scaffolds, in particular,
represent an underexplored and biologically relevant area of
chemical space.
Herein, we report the application of DOS-inspired
methodology to synthesise a diverse range of heterocyclic,
spirocyclic scaffolds. A key [3+2]-cycloaddition step has been
utilised to provide high levels of regio-selectivity and improve
previously lengthy procedures to generate the core quaternary
carbon centre. Furthermore, synthetic handles for late-stage
elaboration were incorporated from the outset to aid FBDD hit
exploration.
Results and Discussion
We envisaged that [3+2] cycloadditions could afford a range of
heterocyclic, spirocyclic scaffolds from simple starting materials in
just a few steps (Figure 3). Acyclic, electron-rich alkenes could be
reacted to introduce a heterocyclic moiety which, provided the
starting material was selected appropriately, could then be formed
into a spirocycle by the coupling of functional groups on the lower
half of the molecule (Figure 3a). Alternatively, exo-cyclic,
electron-deficient alkenes might offer a means to introduce a
quaternary carbon centre directly (Figure 3b). These later
compounds could also offer alternative routes to spirocycle
formation.
Figure 2. Recent advances in the synthesis of heterocyclic spirocycles (a)
Wang and Bode generated unactivated imines and utilised metal hydride
hydrogen atom transfer chemistry with manganese to generate a C-centered
radical, which underwent addition to the unactivated imine to generate the
spirocycle with an N-centered radical from which the unprotected-N was
unveiled by a second hydrogen atom transfer: 19 spirocycles with R = alkyl or
aryl; X = NCbz, S or CH2; n = 5 or 6;[46] (b) Griggs et al. formed highly substituted
2-spiropiperidines in a one-pot reaction from N-Boc imines via the addition of
Chan’s diene under Maitland-Japp conditions followed by in-situ Boc-
deprotection and a sodium bicarbonate catalysed cyclisation onto a cyclic
ketone: 10 spirocycles with R = alkyl or aryl; X = NCbz, O, S or CH2; n = 4, 5 or
6;[47] (c) Brady and Carreira used the addition of trifluoroborates to oxetanyl N,O-
acetals to generate products with oxetane and alkyne functionalities from which
spiro heterocycles can be generated by orthogonal activation, such as
intramolecular opening of the oxetane by the alcohol followed by catalytic
Figure 3. The use of both acyclic (a) and exo-cyclic (b) starting materials
allowed the efficient synthesis of heterocyclic spirocyclic compounds. Based on
the cyclisation approach taken, different functional handles in the final
compounds (for example, ester (blue and pink), carbonyl (yellow and green),
and aromatic (pink and green) moieties) were available for further modifications.
intramolecular alkyne hydroalkoxylation to close the spirocyclic ring:
spirocycles with R = alkyl, aryl or TMS.[42]
5
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In keeping with the goal of generating diverse scaffolds, we
aimed to carry out [3+2]-cycloadditions on both acyclic, electron-
rich (1) and exo-cyclic, electron-deficient (5) alkenes. Our initial
studies focused on the cycloadditions of nitrile-oxide dipole 13
with both the acyclic alkene and exo-cyclic alkene (Figure 3).
Spirocycle 3 could be built after the key cycloaddition produced
isoxazole 2, whereas spirocycle 7 could be formed during the key
cycloaddition step on a saturated heterocycle (5 or 6).
stereoisomers. The major isomers from these reactions, isolated
in 41% and 26% yield respectively, were carried forward for the
subsequent cyclisation. For asymmetrical ketone 4e, the
increased flexibility afforded by the 7-membered ring reduced the
chromatographic separation of the two isomers (E:Z) such that
they were carried forward as a mixture in the ratio 3:2. Critically,
these intermediates contained both an amine and an ester moiety
enabling opportunities for further fragment elaboration.
Each building block was synthesised in 1-2 step from
inexpensive, commercially available starting materials (Scheme 1,
Table 1). Treatment of benzaldehyde (11) with hydroxylamine to
give the corresponding oxime, followed by addition of N-
chlorosuccinimide, proceeded smoothly to yield chlorooxime 12
in an excellent 99% yield (Scheme 1a).[48] This was used directly,
generating 13 in situ, or converted to dipole 13 before addition.
We imagined that 1,1-disubstituted alkenes such as 1 could
act as suitable [3+2]-cycloaddition partners. The functional groups
present provided the synthetic handles necessary for cyclisation
to form the second ring. As such, following work by Ramesh et al.,
serine ethyl ester 14 was first Boc-protected before an elimination
reaction using mesyl chloride and triethylamine provided the
desired 1,1-disubstituted alkene 1 in an excellent yield (Scheme
1b).[49] The amino acid starting material provided both an amine
and ester as the synthetic handles required for cyclisation of the
second ring, with the potential for a range of cyclisation strategies.
Table 1. Generation of electron-deficient alkenes for [3+2]-cycloadditions
Product
Structure
Yield (%)
53
Ratio
(E:Z)
5a
N/A
N/A
1:2
5b
5c
5d
94
65[a]
47[a]
5:4
5e
80[b,c]
3:2
Reaction conditions: (i) 4 (1.0 equiv.), 16 (1.1 equiv.), DCM, reflux, 6-44h.[51]
Notes: [a] Yield corresponding to both isomers combined; [b] Yield
corresponding to the inseparable mixture of both isomers; [c] 5 equiv. of 16
used.
Scheme 1. Formation of key dipole (a) and acyclic (b) starting materials: (i) 11
(1.0 equiv.), NH2OH (2.0 equiv.), EtOH, rt, 10min; then NCS (1.1 equiv.), DMF,
rt, 0.5h, 99%; (ii) 12 (1.0 equiv.), NEt3 (1.0 equiv.), DCE, 0 °C, 3 min, used
immediately; (iii) 14 (1.0 equiv.), Boc2O (0.95 equiv.), K2CO3 (1.5 equiv.), EtOAc,
H2O, rt, 12h, 93%; (iv) 15 (1.0 equiv.), MsCl (1.25 equiv.), NEt3 (3.0 equiv.),
DCM, -15 °C - rt, 2h, 94%.
The [3+2]-cycloaddition was initially tested on acyclic,
electron-rich alkene 1 (Scheme 2). The desired nitrile-oxide dipole
was generated in situ from previously prepared chlorooxime (12)
using triethylamine in dichloromethane.[52,53] Pleasingly, this
provided isoxazole heterocycle 2 in a 58% yield with the regio-
chemistry predicted as proposed by transition state TS-I and
similar literature strategies.[54–56] The highly reactive ester and
Boc-protected amine provide the scope for a wide range of ring-
closing strategies. In this case, by way of an example, carbamate
formation was achieved through ester reduction, using sodium
borohydride, followed by base-mediated intramolecular ring
closure. This method furnished spirocycle 3 in moderate yield.
The crystal structure of spirocycle 3 conclusively confirmed the
regio-chemical assignment (see SI).
The exo-cyclic alkene cycloaddition partners were
synthesised from a range of commercially available Boc-
protected N-heterocyclic ketones. Heating with Wittig reagent 16
generated electron-deficient alkenes of general structure 5 in
good to excellent yields (Table 1). As might be expected, the
yields obtained closely followed the trend in ring strain; the 4- and
7-membered cycles reacted with the highest yields, whilst the
relatively unstrained 6-membered rings proceeded least
effectively.[50] For symmetrical ketones 4a and 4b the reaction
proceeded smoothly to yield the 6- and 4-membered heterocycles
5a and 5b in 94% and 53% respectively. For asymmetrical
ketones 4c and 4d the reaction led to a separable mixture of
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COMMUNICATION
Table 2. Synthesis of isoxazole-based spirocycles 7 using freshly-prepared
nitrile-oxide dipole
Product
Reaction
i
Structure
Yield (%)
50
Scheme 2. Synthesis of isoxazole-based spirocycle 3, via [3+2]-cycloaddition
with nitrile-oxide dipole generated in situ, followed by carbamate formation: (i) 1
(1.0 equiv.), 12 (6.0 equiv.) NEt3 (6.8 equiv.), DCM, rt, 1h, 58%; (ii) 2 (1.0 equiv.),
NaBH4 (1.0 equiv.), CH3OH/THF (1:8), 0 °C - rt, 12h, 55%; (iii) 2’ (1.0 equiv.),
KOtBu (2.0 equiv.), THF, 0 °C, 1h, 56%.
7a
On reviewing the literature, it was hoped that the reaction
conditions developed for the acyclic alkene could be used on the
exo-cyclic, electron-deficient alkenes 5a-e.[39,57–61] Unfortunately,
the reactions of substrates 5a-e failed to proceed under these
conditions unlike the substitutions performed on the acyclic, di-
substituted alkenes, and alkenes in strained ring systems,
reported elsewhere. The lack of progress observed at room
temperature was taken to be a consequence of the higher level of
steric crowding around the tri-substituted alkene. We therefore
looked to explore higher temperatures and pressures. Despite
furnishing the desired spirocycles, this provided its own
challenges due to the decomposition of the nitrile oxide dipole (13)
at higher temperatures. Optimisation of these conditions led to the
realisation that, similar to Zheng et al., pre-forming the nitrile oxide
dipole (13) using triethylamine at 0 °C was required (Scheme
1a).[62] The generated dipole was then added to the alkene (5a-e)
portion-wise over 90 minutes under microwave conditions at
100 °C. Unfortunately, despite optimising to these conditions, it
was not possible to push the reaction to completion and, as such,
the desired spirocycles 7 were all isolated in low to moderate
yields ranging between 7% and 62% (Table 2).
In order for these scaffolds to be used in drug discovery, it
would be necessary to remove all protecting groups. This was
demonstrated on the 6-membered spirocycle 7a, which
underwent smooth deprotection using trifluoroacetic acid in
dichloromethane to provide secondary amine 17a in 68% yield
(Table 2).
Having demonstrated the use of the nitrile oxide dipole for
[3+2]-cycloadditions on both electron-poor and electron-rich
alkenes we then looked to explore other dipoles. Initially, following
a published procedure for similar substrates, a benzyl azide [3+2]-
cycloaddition was attempted involving heating the substrates
under reflux.[63] Again, possibly due to the steric crowding around
the alkene, only starting material was isolated. It was only by
heating to 100 °C in a sealed vessel for 48 hours that the desired
triazole-based spirocycle 8 was isolated in a moderate 34% yield
(Scheme 3a). Looking beyond [3+2] cycloadditions, hydrazine
was used in a one-pot cyclisation approach (Scheme 3b).
7b
7c
i
7
i
43
29
23
68
7d
7e
i
i
17a
ii
Reaction conditions: (i) 5 (1.0 equiv.), 13 (3 x 2.0 equiv.), DCE, 100 °C (MW),
3 x 30 min; (ii) 7a (1.0 equiv.), TFA (2.0 equiv.), DCM, rt, 22h.
Pleasingly, the Michael-addition and subsequent
substitution formed hydrazide-based spirocycle 9 in a good 68%
yield.[64,65] This unusual spirocycle provides multiple handles for
further elaboration and therefore would be a valuable addition to
a fragment-screening library.
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COMMUNICATION
Table 3. Mean physicochemical properties
Property[a]
Ideal Range[b]
≤ 300
This Work
232.6
0.87
61.7
16.8
4.9
MW
clogP
0 – 2
PSA
≤ 60
HAC
10 – 16
Scheme 3. Exploring other alkene cycloadditions: (i) 5b (1.0 equiv.), BnN3 (10.0
equiv.), 100 °C, 48 h, 34%; (ii) 5a (1.0 equiv.), NH2NH2·H2O (1.2 equiv.), EtOH,
70 °C, 24h, 68%.
HBA
≤ 3
≤ 3
≤ 3
-
HBD
1.6
Finally, we looked to explore the use of imines in the place
RBC
2.6
of electron-poor alkenes in
a [2+2]-cycloaddition reaction
Fsp3
0.54
0.55
0.77
(Scheme 4). This reaction has good precedent on carbocyclic
systems and therefore it was hoped that it would translate cleanly
onto a heterocyclic system.[66] The imine (6) was generated from
the corresponding ketone 4a using para-anisidine in toluene.
Proving labile under column conditions, 6 was carried through
without purification into the [2+2]-cycloaddition. The imine was
trapped with acetoxyacetyl chloride at -78°C to yield the β-lactam
spirocycle 10 in a moderate 55% yield over the two steps. Again,
multiple handles for further elaboration make this a versatile
fragment for FBDD.
Molecular Shape Index
Molecular Complexity
-
-
[a] MW = molecular weight, PSA = polar surface area, HBA = number of
hydrogen-bond acceptors, HBD = number of hydrogen-bond donors, HAC =
heavy atom count, RBC = rotatable bond count; [b] Based on the guidelines
used by Astex Pharmaceuticals. See the Supporting Information for further
details.
Conclusions
Spirocycle synthesis remains a challenge within organic
chemistry. Heterocyclic spirocycles, are particularly synthetically
challenging; however, they represent an under-explored area of
chemical space with excellent potential within FBDD. Their
restricted conformation reduces the entropic binding penalty and
their heterocyclic nature provides opportunities for strong binding
interactions as well as potential synthetic handles for elaboration.
Overall, we successfully synthesised nine heterocyclic spirocyclic
fragments. This collection of scaffolds can be considered
substantially diverse since they incorporate [4,5], [4,6], [5,5], [5,6]
and [5,7] spirocycles. Furthermore, the types of heterocycles
incorporated in the structures varies widely across both rings,
including isoxazoles, triazoles, cyclic amines, hydrazides and
carbamates. These rings also provide varied types and positions
of heteroatoms and thus the potential to identify novel binding
interactions. Additionally, we have ensured the presence of
functional handles for further elaboration.
We have looked to explore the use of cycloadditions as a
synthetic strategy for heterocyclic spirocycle formation as they
enable regio-selective and short divergent syntheses. Despite the
challenges encountered conducting these types of reactions on
already-sterically-hindered centres, the synthesis of nine diverse,
novel spirocycles has introduced the powerful potential of this
synthetic strategy and highlights the need for further work in this
area.
Scheme 4. Exploring imine cyclisations: (i) 4a (1.0 equiv.), p-anisidine (1.0
equiv.), toluene, reflux, 20h; (ii) 6 (1.0 equiv.), acetoxyacetyl chloride (2.4 equiv.),
NEt3 (3.0 equiv.), DCM, -78 °C – rt, 20h, 55% over two steps.
Given that the final compounds will be utilised in their de-
protected forms, conditions were identified to remove all
protecting groups (Bn, Ac and PMP)[67–69] such that the prophetic
structures could be utilised for physicochemical property
calculations. A selection of properties were calculated for these
final compounds, demonstrating that almost all fragments
conformed to the so-called “Rule of Three”, which provides an
important guide to the desirable physicochemical properties of
fragment screening libraries.[70] Of particular note are the low
mean value for clogP (0.87) and the high “fraction sp3” (0.54),
mean number of chiral centres (1.20) and molecular complexity
(0.77) (Table 3). Additionally, the molecular shape index (0.55)
demonstrates the increased three-dimensionality of these
compounds (where a value of 0 represents spherical and a value
of 1 represents linear).
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10.1002/ejoc.201900847
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COMMUNICATION
(6.43 mL, 28.01 mmol, 0.95 equiv.) were dissolved in ethyl acetate (40 mL)
and water (40 mL). Potassium carbonate (6.11 g, 44.22 mmol, 1.5 equiv.)
was added to the reaction and it was left to stir overnight at rt. The layers
were then separated and the aqueous extracted with ethyl acetate (2 × 30
mL) and the combined organics were washed with brine (50 mL). This was
then dried over anh. MgSO4. This mixture was filtered and the filtrate was
concentrated in vacuo to give ethyl (tert-butoxycarbonyl)-l-serinate 15 as
Experimental Section
All reactions were carried out under nitrogen atmosphere unless
otherwise stated. Solvents and commercially available reagents were
dried and purified before use, where appropriate using standard
procedures. Toluene, hexane, diethyl ether, ethyl acetate (EtOAc),
petroleum ether (fraction 40-60), methanol, THF, and dichloromethane
(DCM) were dried and distilled using standard methods from oxygen free
from solvent dispenser units under an argon atmosphere. Analytical thin
layer chromatography (TLC) was performed using pre-coated Merck glass
backed silica gel plates (Silica gel 60 F254). Flash column chromatography
was undertaken on Fluka or Material Harvest silica gel (230–400 mesh).
Proton and carbon magnetic resonance spectra were recorded
using an internal deuterium lock (at 298 K unless stated otherwise) on
Bruker DPX (400/101 MHz; 1H-13C DUL probe), Bruker Avance III HD
(400/101 MHz; Smart probe), Bruker Avance III HD (500/126 MHz; Smart
probe) and Bruker Avance III HD (500/126 MHz; DCH Cryoprobe)
spectrometers. Chemical shifts (δH) are quoted in ppm to the nearest
0.01 ppm and are referenced to the residual non-deuterated solvent peak.
Data are reported as: chemical shift, multiplicity (br = broad; s = singlet; d
= doublet; t = triplet; q = quartet; qn = quintet; sp = septet; m = multiplet;
or a combination thereof), coupling constants, number of nuclei, and
assignment.
a pure colourless oil (6.41 g, 27.49 mmol, 93%); Rf: 0.07 (Pet. Ether 40-
–1
̃
60/EtOAc 4:1); IR (thin film) 흂/cm : 3383 (O-H, br s), 2978 (C-H, w), 1714
(C=O ester, s), 1692 (C=O carbamide, s), 1158 (C-O, s); 1H NMR (400
MHz, CDCl3) δ/ppm: 5.44 (br s, 1H), 4.36 (br s, 1H), 4.24 (q, J = 7.0 Hz,
2H), 3.98–3.89 (m, 2H), 2.30 (br s, 1H), 1.46 (s, 9H), 1.30 (t, J = 7.0 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ/ppm: 170.7, 155.8, 80.3, 63.8, 61.8,
55.8, 28.3, 14.1; HRMS (ESI) C10H19NO5Na m/z: [M+Na]+ 256.1151 (calc.
[ ]ퟐퟎ
256.1155). 훂 –17.2 (c = 1.0, CHCl3). Data agree with that reported in
퐃
the literature.[71]
Ethyl 2-((tert-butoxycarbonyl)amino)acrylate (1): Ethyl (tert-
butoxycarbonyl)-l-serinate 15 (6.4 g, 27.44 mmol, 1.0 equiv.) was
dissolved in dichloromethane (70 mL) at -15 °C. Mesyl chloride (2.65 mL,
34.30 mmol, 1.25 equiv.) was added dropwise followed by triethylamine
(11.41 mL, 82.31 mmol, 3.0 equiv.). The reaction was stirred for 30 min
before being warmed to rt and stirred for a further 2 h. Then one third molar
HCl (30 mL) was added. The mixture was washed with water and the
combined organics were dried over anh. MgSO4. This mixture was filtered,
and the filtrate was concentrated in vacuo to give the crude product. This
was filtered through Celite with dichloromethane to afford ethyl 2-((tert-
butoxycarbonyl)amino)acrylate 1 as a yellow oil (5.5667 g, 25.86 mmol,
Infrared (IR) spectra were recorded on a Perkin Elmer 1FT-IR
Spectrometer fitted with an ATR sampling accessory as either solids or
neat films, either through direct application or deposited in CDCl3.
Absorption maxima (νmax) are reported in wavenumbers (cm–1) with the
following abbreviations: w, weak; m, medium; s, strong; br, broad. High-
resolution mass spectra (HRMS) were measured on a Micromass LCT
Premier spectrometer using electron spray ionization (ESI) techniques.
Masses are quoted within the 5 ppm error limit. Melting points were
obtained on a Buchi B-545 melting point apparatus and are uncorrected.
Chiral products had their optical rotation recorded on an Anton-Paar MCP
100 polarimeter. [훂]퐃ퟐퟎ values are reported in °g–1cm–210–1 at the sodium
D-line of 598 nm, concentration (c) is given in g(100 mL)–1 in the solvent
stated.
94%); Rf: 0.60 (Pet. Ether 40-60/EtOAc 4:1); IR (thin film) 흂/cm–1: 3420 (N-
̃
H, w), 2980 (C-H, w), 1733 (C=O carbamate, m), 1707 (C=O ester, s),
1638 (C=C, w), 1152 (C-O, s); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.02 (br
s, 1H), 6.14 (br s, 1H), 5.72 (d, J = 1.5 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H),
1.48 (s, 9H), 1.33 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ/ppm:
164.0, 152.6, 131.5, 104.8, 80.6, 62.0, 28.2, 14.1; HRMS (ESI)
C10H17NO4Na m/z: [M+Na]+ 238.1046 (calc. 238.1050). Data agree with
that reported in the literature.[49]
General procedure for synthesis of α,β-unsaturated esters (5): N-Boc
heterocyclic ketone 4 (1 equiv.) and ethyl (triphenylphosphoranylidine)
acetate 16 (1.1 equiv.) were dissolved in dichloromethane and refluxed.
Upon complete conversion of starting material, the mixtures were
concentrated in vacuo and submitted to flash column chromatography to
yield the pure products.
N-hydroxybenzimidoyl chloride (12): Benzaldehyde 11 (1.5 g, 14.1
mmol, 1.0 equiv.) was dissolved in diethyl ether (12 mL) and
hydroxylamine (50% w/w in H2O, 1.73 mL, 29.3 mmol, 2.0 equiv.) was
added. The reaction was stirred for 10 minutes, dried (MgSO4), filtered and
concentrated in vacuo. The residual oil was redissolved in N,N-
dimethylformamide (12 mL), N-chlorosuccinimide (2.1 g, 15.6 mmol, 1.1
equiv.) was added and the reaction was stirred for 30 minutes. The
reaction was diluted with water (10 mL) and extracted with ethyl acetate (2
x 10 mL). The combined organic extracts were washed with water (20 mL)
and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to
give the crude product as a yellow oil, which was used directly without
further purification (2.2 g, 14.0 mmol, 99%); Rf: 0.45 (Pet. Ether 40-
tert-Butyl 4-(2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate (5a):
tert-Butyl 4-oxopiperidine-1-carboxylate 4a (3.50 g, 17.6 mmol, 1.0 equiv.)
and ethyl (triphenylphosphoranylidene)acetate 16 (6.73 g, 19.3 mmol, 1.1
equiv.) were dissolved in dichloromethane (50 mL) and refluxed for 17
hours. The reaction was concentrated in vacuo and submitted to column
chromatography (Pet. Ether 40-60/EtOAc 9:1 to 4:1) to yield the product,
tert-butyl 4-(2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate 5a as a
colourless, crystalline solid (2.53 g, 9.4 mmol, 53%); Rf: 0.24 (Pet. Ether
60/EtOAc 4:1); IR (thin film) ν /̃
cm–1: 3246 (O-H, m), 3058 (Ar-H, m), 1650
(C=N, s); 1H NMR (400 MHz, CDCl3, 25°C) δ /ppm: 8.94 (br s, 1H), 7.89-
7.86 (m, 2H), 7.47-7.41 (m, 3H); HRMS (ESI) C7H7NOCl m/z: [M+H]+
156.0220 (calc. 156.0126). Data agree with that reported in the
literature.[48]
40-60/EtOAc 4:1); IR (thin film) ν /
̃
cm–1: 2972 (C-H, w), 1706 (C=O ester,
1
s), 1676 (C=O carbamate, s), 1143 (C-O, s); H NMR (400 MHz, CDCl3,
25°C) δ /ppm: 5.71 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.49 (app. quin, J =
5.7 Hz, 4H), 2.93 (t, J = 5.5 Hz, 2H), 2.27 (t, J = 5.6 Hz, 2H) 1.47 (s, 9H),
1.28 (t, J = 7.1, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 166.5, 158.0,
Ethyl (tert-butoxycarbonyl)-l-serinate (15): L-serine ethyl ester
hydrochloride 14 (5 g, 29.48 mmol, 1.0 equiv.) and di-tert-butyl dicarbonate
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
154.7, 115.4, 80.0, 59.9, 36.6, 29.7, 28.5, 14.4; m.p. 84-86 °C (Lit. Value
84-86 °C); HRMS (ESI) C14H23NO4Na m/z: [M+Na]+ 292.1515 (calc.
292.1519). Data agree with that reported in the literature.[72,73]
27.7, 25.4, 14.4; (Z)-isomer: IR (thin film) ν /̃
cm–1: 2978 (C-H, w), 1692
(C=O ester, s), 1662 (C=O carbamate, s), 1212 (C-O, s), 1154 (C-O, s);
1H NMR (400 MHz, CDCl3, 25°C) δ /ppm: 5.65 (br s, 1H), 4.60 (s, 2H), 4.16
(q, J = 7.1 Hz, 2H), 3.47 (m, 2H), 2.33 (m, 2H), 1.71 (m, 2H), 1.44 (s, 9H),
1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 165.9, 155.0,
154.6, 115.5, 79.9, 60.1, 43.4, 34.2, 28.5, 27.6, 25.6, 14.4; HRMS (ESI)
C14H23NO4Na m/z: [M+Na]+ 292.1521 (calc. 292.1519). Data agree with
that reported in the literature.[75]
tert-Butyl 3-(2-ethoxy-2-oxoethylidene) azetidine-1-carboxylate (5b):
tert-Butyl 3-oxoazetidine-1-carboxylate 4b (2.90 g, 16.9 mmol, 1.0 equiv.)
and ethyl (triphenylphosphoranylidene)acetate 16 (6.49 g, 18.6 mmol, 1.1
equiv.) were dissolved in dichloromethane (56 mL) and refluxed for 6 h.
The reaction was concentrated in vacuo and submitted to column
chromatography (Pet. Ether 40-60/EtOAc 4:1) to yield the pure product,
tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate 5b as a
colourless oil (3.85 g, 16.0 mmol, 94%);. Rf: 0.29 (Pet. Ether 40-60/EtOAc
tert-Butyl 3-(2-ethoxy-2-oxoethylidene)azepane-1-carboxylate (5e):
tert-Butyl 3-oxoazepane-1-carboxylate 4e (0.50 g, 2.34 mmol, 1.0 equiv.)
and ethyl (triphenylphosphoranylidene)acetate 16 (4.08 g, 11.7 mmol, 5.0
equiv.) were dissolved in toluene (20 mL) and refluxed for 44 hours. The
reaction was concentrated in vacuo and submitted to column
chromatography (Pet. Ether 40-60/EtOAc 19:1 to 4:1) to yield an isomeric
mixture of the products, (E)- and (Z)-tert-Butyl 3-(2-ethoxy-2-
oxoethylidene)azepane1-carboxylate 5e as an orange oil (0.52 g, 1.85
4:1); IR (thin film) 흂/cm–1: 2978 (C-H, w), 1725 (C=O carbamate, s), 1704
̃
1
(C=O ester, s), 1197 (C-O, s); H NMR (400 MHz, CDCl3, 25°C) δ /ppm:
5.76 (quin, J = 2.2 Hz, 1H), 4.81 (m, 2H), 4.58 (m, 2H), 4.17 (q, J = 7.1 Hz,
2H), 1.45 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
/ppm: 165.2, 156.2, 152.6, 113.7, 80.1, 60.4, 57.8, 28.3, 14.3; HRMS (ESI)
C12H19NO4Na m/z: [M+Na]+ 264.1215 (calc. 264.1212). Data agree with
that reported in the literature.[41]
mmol, 80%); Rf: 0.51 (Pet. Ether 40-60/EtOAc 7:3); IR (thin film) ν /̃ :
cm–1
2936 (C-H, w), 1689 (C=O ester, s), 1645 (C=O carbamate, s), 1152 (C-
O, s); 1H NMR (400 MHz, CDCl3, 25°C) δ /ppm: 5.73 & 5.70 (s, 1H), 4.16
& 4.15 (q, J = 7.1 Hz, 2H), 4.12 & 4.04 (s, 2H), 3.29 & 3.20 (m, 2H), 2.79
& 2.74 (m, 2H), 1.75-1.74 (m, 4H), 1.47 & 1.45 (s, 9H), 1.28 & 1.27 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 166.2, 166.1, 161.4,
160.8, 155.7, 155.1, 116.7, 116.3, 80.0, 79.8, 59.9, 59.8, 55.5, 54.7, 47.4,
47.2, 30.2, 29.7, 29.0, 28.9, 28.6, 28.5, 27.8, 27.3, 14.4, 14.4; HRMS (ESI)
C15H25NO4Na m/z: [M+Na]+ 306.1678 (calc. 306.1676). Data agree with
that reported in the literature.[75]
tert-Butyl
3-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate
(5c): tert-Butyl 3-oxopyrrolidine-1-carboxylate 4c (0.50 g, 2.69 mmol, 1.0
equiv.) and ethyl (triphenylphosphoranylidene)acetate 16 (1.03 g, 2.97
mmol, 1.1 equiv.) were dissolved in dichloromethane (9 mL) and refluxed
for 20 h. The reaction was concentrated in vacuo and submitted to column
chromatography (Pet. Ether 40-60/EtOAc 9:1 to 3:1) to yield the E/Z
isomers of the product tert-butyl 3-(2-ethoxy-2-oxoethylidene) pyrrolidine-
1-carboxylate 5c as colourless oils. (0.45 g, 1.76 mmol, combined E/Z yield
65%); Rf: 0.23 (E) and 0.18 (Z) (Pet. Ether 40-60/EtOAc 4:1); (E)-isomer:
Ethyl 4-((tert-butoxycarbonyl)amino)-3-phenyl-4,5-dihydroisoxazole-
4-carboxylate (2): Triethylamine (2.2 mL, 15.80 mmol, 6.8 equiv.) was
added to a mixture of ethyl 2-((tert-butoxycarbonyl)amino)acrylate 1 (500
mg, 2.32 mmol, 1.0 equiv.) and N-hydroxybenzimidoyl chloride 12 (2.17 g,
13.94 mmol, 6.0 equiv.) in dichloromethane (40 mL) and the reaction was
stirred at rt for 1 h. Water (30 mL) was added and the organic layer was
washed with water (30 mL) and brine (30 mL). The combined organics
were dried over anh. MgSO4. This mixture was filtered, and the filtrate was
concentrated in vacuo to give the crude product. This was purified by
column chromatography (Pet. Ether 40-60/Et2O 4:1) to give ethyl 4-((tert-
butoxycarbonyl)amino)-3-phenyl-4,5-dihydroisoxazole-4-carboxylate 2, as
off-white amorphous solid (448.6 mg, 1.34 mmol, 58%); Rf: 0.12 (20%
IR (thin film) ν /
̃
cm–1: 2979 (C-H, w), 1710 (C=O ester, s), 1670 (C=O
1
carbamate, s), 1212 (C-O, s), 1165 (C-O, s); H NMR (400 MHz, CDCl3,
25°C) δ /ppm: 5.82 (br s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.11 (br s, 2H), 3.56
(br s, 2H), 3.11 (br s, 2H), 1.46 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ /ppm: 166.1, 154.4, 122.4, 112.8, 83.8, 80.0, 77.4,
60.5, 45.7, 28.6, 14.4; (Z)-isomer: IR (thin film) ν /̃
cm–1: 2978 (C-H, w),
1702 (C=O ester, s), 1676 (C=O carbamate, s), 1215 (C-O, s), 1163 (C-O,
1
s); H NMR (400 MHz, CDCl3, 25°C) δ /ppm: 5.80 (m, 1H), 4.41 (s, 2H),
4.16 (q, J = 7.1 Hz, 2H), 3.50 (m, 2H), 2.73 (m, 2H), 1.46 (s, 9H), 1.27 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 166.1, 160.6, 154.5,
113.0, 79.8, 60.2, 50.6, 43.8, 32.9, 28.6, 14.4; HRMS (ESI) C13H21NO4Na
m/z: [M+Na]+ 278.1356 (calc. 278.1363). Data agreed with that reported in
the literature.[74]
diethyl ether in pet. ether); IR (thin film) ν /
̃
cm–1: 3410 (N-H, m), 2976 (C-
1
H, w), 1741 (C=O, m), 1721 (C=N, s), 1484 (C=C, s), 1308 (N-O, s); H
NMR (400 MHz, CDCl3) δ/ppm: 7.70–7.66 (m, 2H, H11), 7.43–7.38 (m, 3H,
H12&13), 6.08 (br s, 1H, NH), 4.32 (q, J = 7.0 Hz, 2H), 3.91 (br s, 2H), 1.40
(s, 9H), 1.32 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ/ppm: 167.6,
156.3, 153.3, 130.4, 129.8, 128.7, 126.9, 92.4, 81.2, 63.4, 42.7, 28.2, 14.0;
HRMS (ESI) C17H23N2O5 m/z: [M+H]+ 335.1591 (calc. 335.1607).
tert-Butyl 3-(2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate (5d):
tert-Butyl 3-oxopiperidine-1-carboxylate 4d (4.00 g, 20.1 mmol, 1.0 equiv.)
and ethyl (triphenylphosphoranylidene)acetate 16 (7.69 g, 22.1 mmol, 1.1
equiv.) were dissolved in dichloromethane (50 mL) and refluxed for 18
hours. The reaction was concentrated in vacuo and submitted to column
chromatography (Pet. Ether 40-60/EtOAc 9:1 to 3:1) to yield the E/Z
isomers of the product, tert-butyl 3-(2-ethoxy-2-oxoethylidene) piperidine-
1-carboxylate 5d as colourless oils (2.55 g, 9.5 mmol, combined E/Z yield
47%); Rf: 0.32 (E) and 0.25 (Z) (Pet. Ether 40-60/EtOAc 4:1); (E)-isomer:
tert-Butyl
(4-(hydroxymethyl)-3-phenyl-4,5-dihydroisoxazol-4-
yl)carbamate (2’): Ethyl 4-((tert-butoxycarbonyl)amino)-3-phenyl-4,5-
dihydroisoxazole-4-carboxylate 2 (100 mg, 0.30 mmol, 1.0 equiv.), was
dissolved in an 8:1 THF/methanol mixture (1.8 mL). This was cooled to
0 °C and sodium borohydride (2.83 mg, 0.07 mmol, 0.25 equiv.) were
added. The reaction was stirred for 4 h before further sodium borohydride
(8.49 mmol, 0.21 mmol, 0.75 equiv.) was added. The reaction was stirred
overnight. It was quenched with sat. aq. NH4Cl (2 mL), and extracted with
dichloromethane (3 × 5 mL). The combined organics were then dried over
IR (thin film) ν /
̃
cm–1: 2978 (C-H, w), 1692 (C=O ester, s), 1659 (C=O
1
carbamate, s), 1150 (C-O, s); H NMR (400 MHz, CDCl3, 25°C) δ /ppm:
5.73 (br s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.92 (br s, 2H), 3.47 (m, 2H), 2.92
(m, 2H), 1.68 (m, 2H), 1.44 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ /ppm: 166.5, 154.7, 115.7, 80.0, 60.0, 51.4, 44.5, 28.5,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
anh. MgSO4. This mixture was filtered, and the filtrate was concentrated in
vacuo to give the crude product. This was purified via column
chromatography (Hexane/EtOAc 1:1) to give tert-butyl (4-(hydroxymethyl)-
3-phenyl-4,5-dihydroisoxazol-4-yl)carbamate 2’ as a white powder (54.0
129.2, 129.0, 126.5, 87.0, 80.0, 62.3, 62.0, 36.8, 31.2, 28.6, 14.2; HRMS
(ESI) C21H28N2O5Na m/z: [M+Na]+ 411.1888 (calc. 411.1890).
2-(tert-Butyl) 8-ethyl 7-phenyl-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2,8-
dicarboxylate (7b): Following the general procedure for N-
hydroxybenzimidoyl chloride cycloaddition, tert-butyl 3-(2-ethoxy-2-
oxoethylidene)azetidine-1-carboxylate 5b (50 mg, 0.21 mmol) furnished
the product, 2-(tert-butyl) 8-ethyl 7-phenyl-5-oxa-2,6-diazaspiro[3.4]oct-6-
mg, 0.18 mmol, 62%); Rf: 0.29 (55% ethyl acetate in hexane); IR (thin film)
–1
̃
흂/cm : 3408 (N-H, w), 3278 (O-H, w), 2970 (C-H, w), 1717 (C=O, s), 1545
(C=C, s); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.66–7.64 (m, 2H), 7.40–7.37
(m, 3H), 5.74 (br s, 1H), 3.90–3.86 (m, 2H), 3.77–3.73 (m, 1H), 3.30 (d, J
= 17.5 Hz, 1H), 3.05 (br s, 1H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ/ppm: 157.3, 154.1, 130.3, 129.6, 128.7, 126.7, 95.4, 80.9, 66.2, 40.4,
28.2; HRMS (ESI) C15H21N2O4 m/z: [M+H]+ 293.1498 (calc. 293.1501).
ene2,8-dicarboxylate 7b, as
submissions (5.4 mg, 0.01 mmol, 7%); Rf: 0.31 (Pet. Ether 40-60/EtOAc
2:1); IR (thin film) ν /
cm–1: 2978 (C-H, w), 1736 (C=O ester, s), 1698 (C=O
a colourless oil after 3 consecutive
̃
carbamate/C=N, s), 1392 (N-O, s), 1153 (C-O, s); 1H NMR (400 MHz,
CDCl3, 25°C) δ /ppm: 7.68 (m, 2H), 7.42 (m, 3H), 4.45 (s, 1H), 4.34 (dd, J
= 10.8 Hz, 0.8 Hz, 1H), 4.27-4.15 (m, 4H), 4.05 (dd, J = 9.8 Hz, 0.9 Hz,
1H), 1.46 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
/ppm: 167.0, 155.9, 154.8, 130.8, 128.9, 128.0, 126.8, 83.4, 80.3, 64.7,
62.4, 60.5, 57.3, 28.3, 14.0; HRMS (ESI) C19H25N2O5 m/z: [M+H]+
361.6087 (calc. 361.6085).
3-Phenyl-1,8-dioxa-2,6-diazaspiro[4.4]non-2-en-7-one (3): To
a
solution of potassium tert-butoxide (30.7 mg, 0.27 mmol, 2.0 equiv.) in THF
(1.4 mL) at 0 °C was added tert-butyl (4-(hydroxymethyl)-3-phenyl-4,5-
dihydroisoxazol-4-yl)carbamate 2’ (40 mg, 0.14 mmol, 1.0 equiv.) and the
reaction was stirred for 1 h. This was then diluted with sat. aq. NH4Cl (5
mL) and extracted with dichloromethane (3 × 5 mL). The combined
organics were dried over anh. MgSO4, filtered and concentrated in vacuo
to give the crude product. This was purified by column chromatography
(60% ethyl acetate in hexane) to give 3-phenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one 3 as a white powder (17 mg, 0.08 mmol,
7-(tert-Butyl) 4-ethyl 3-phenyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-
4,7-dicarboxylate (7c): Following the general procedure for N-
hydroxybenzimidoyl chloride cycloaddition, tert-butyl 3-(2-ethoxy-2-
oxoethylidene)pyrrolidine-1-carboxylate 5c (50 mg, 0.20 mmol) furnished
the product, 7-(tert-butyl) 4-ethyl 3-phenyl-1-oxa-2,7-diazaspiro[4.4]non-2-
56%); Rf: 0.16 (Hexane/EtOAc 2:3); IR (thin film) ν /̃
cm–1: 3226 (N-H, w),
1765 (C=O, s), 1048 (C-O, s); 1H NMR (400 MHz, CDCl3) δ/ppm: 7.64–
7.62 (m, 2H), 7.48–7.41 (m, 3H), 5.97 (br s, 1H), 4.77 (d, J = 10.0 Hz, 1H),
4.59 (d, J = 10.0 Hz, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.49 (d, J = 18.0 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ/ppm: 156.3, 156.2, 131.1, 129.1, 128.2,
126.6, 96.1, 73.9, 42.8; HRMS (ESI) C11H10N2O3Na m/z: [M+Na]+
241.0576 (calc 241.0584). m.p. 178–179 °C. For crystallographic data, see
SI.
ene4,7-dicarboxylate 7c, as
submissions (24 mg, 0.09 mmol, 43%); Rf: 0.24 (Pet. Ether 40-60/EtOAc
7:3); IR (thin film) ν /
cm–1: 3375 (Ar-H, w), 2980 (C-H, m), 1728 (C=O ester,
a colourless oil after 3 consecutive
̃
s), 1704 (C=O carbamate/C=N, s), 1148 (C-O, s); 1H NMR (400 MHz,
CDCl3, 25°C) δ /ppm: 7.66 (m, 2H), 7.41 (m, 3H), 4.83 (s, 1H), 4.19 (m,
2H), 3.86 (m, 2H), 2.45 (m, 1H), 2.19 (m, 1H), 1.55 (s, 9H), 1.19 (t, J = 7.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 169.0, 167.6, 155.3, 150.0,
130.8, 129.0, 127.1, 90.8, 84.2, 62.4, 57.2, 43.5, 28.6, 28.1, 27.0, 14.2;
HRMS (ESI) C20H26N2O5Na m/z: [M+Na]+ 397.1738 (calc. 397.1734).
General method for the cycloaddition of α,β-unsaturated esters with
N-hydroxybenzimidoyl chloride (7): To
a stirred solution of N-
hydroxybenzimidoyl chloride 12 (6 equiv.) in dichloroethane (2 mL) at 0°C
was added triethylamine (6 equiv.) dropwise. The resulting suspension
was stirred for 5 minutes and then washed with water (2 x 2 mL), dried
(MgSO4) and filtered to leave a solution of nitrile oxide intermediate 13 in
dichloroethane at 0°C. A solution of α,β-unsaturated ester 3 (1 equiv.) was
prepared in dichloroethane (2 mL). To this solution was added
approximately 1 equivalent of the nitrile oxide solution and the mixture was
heated at 100°C (MW) for 30 minutes. Further additions and resubmission
to heating conditions were performed if the reaction looked incomplete.
The mixture was then concentrated and submitted to flash column
chromatography to yield the pure products.
7-(tert-Butyl) 4-ethyl 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-4,7-
dicarboxylate (7d): Following the general procedure for N-
hydroxybenzimidoyl chloride cycloaddition, tert-butyl 3-(2-ethoxy-2-
oxoethylidene)piperidine-1-carboxylate 5d (50 mg, 0.19 mmol) furnished
the product, 7-(tert-butyl) 4-ethyl 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-
ene4,7-dicarboxylate 7d, as
submissions (21 mg, 0.06 mmol, 29%); Rf: 0.29 (Pet. Ether 40-60/EtOAc
2:1); IR (thin film) ν /
cm–1: 2975 (C-H, m), 1732 (C=O ester, s), 1687 (C=O
a colourless oil after 3 consecutive
̃
carbamate/C=N, s), 1150 (C-O, s); 1H NMR (400 MHz, CDCl3, 25°C) δ
/ppm: 7.64 (m, 2H), 7.40 (m, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.05 (m, 1H),
3.59 (m, 2H), 3.32 (m, 2H), 1.99 (m, 2H), 1.83 (m, 1H), 1.66 (m, 1H), 1.45
(br s, 9H), 1.18 (t, J = 7.12, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 167.8,
155.4, 154.8, 130.5, 129.1, 129.0, 126.6, 86.9, 80.3, 62.0, 61.2, 58.8, 43.2,
29.9, 28.4, 22.8, 14.1; HRMS (ESI) C21H28N2O5Na m/z: [M+Na]+ 411.1901
(calc. 411.1890).
8-(tert-Butyl) 4-ethyl 3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-4,8-
dicarboxylate (7a): Following the general procedure for N-
hydroxybenzimidoyl chloride cycloaddition, tert-butyl 4-(2-ethoxy-2-
oxoethylidene)piperidine-1-carboxylate 5a (50 mg, 0.19 mmol) furnished
the product, 8-(tert-butyl) 4-ethyl 3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-
ene4,8-dicarboxylate 7a, as
submissions (36 mg, 0.09 mmol, 50%); Rf: 0.18 (Pet. Ether 40-60/EtOAc
4:1); IR (thin film) ν /
cm–1: 2978 (C-H, m), 1732 (C=O ester, s), 1687 (C=O
carbamate/C=N, s), 1139 (C-O, s); 1H NMR (400 MHz, CDCl3, 25°C) δ
/ppm: 7.61 (m, 2H), 7.39 (m, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.10 (s, 1H),
3.95 (m, 2H), 3.28 (m, 2H), 1.98-1.61 (m, 4H), 1.47 (s, 9H), 1.19 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 167.7, 155.2, 154.7, 130.4,
a
colourless oil after
3
consecutive
7-(tert-Butyl) 4-ethyl 3-phenyl-1-oxa-2,7-diazaspiro[4.6]undec-2-ene-
4,7-dicarboxylate (7e): Following the general procedure for N-
hydroxybenzimidoyl chloride cycloaddition, tert-butyl 3-(2-ethoxy-2-
oxoethylidene)azepane-1-carboxylate 5e (50 mg, 0.18 mmol) furnished
̃
the
product,
7-(tert-butyl)
4-ethyl
3-phenyl-1-oxa-2,7-
diazaspiro[4.6]undec-2-ene-4,7- dicarboxylate 7e, as a colourless oil after
3 consecutive submissions (17 mg, 0.04 mmol, 23%); Rf: 0.33 (Pet. Ether
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
40-60/EtOAc 2:1); IR (thin film) ν /
̃
cm–1: 2931 (C-H, m), 1722 (C=O ester,
154.6, 79.8, 61.1, 43.0, 40.2, 34.5, 28.4; HRMS (ESI) C12H21N3O3Na m/z:
[M+Na]+ 278.1479 (calc. 278.1475).
s), 1682 (C=O carbamate/C=N, s), 1158 (C-O, s); 1H NMR (400 MHz,
CDCl3, 25°C) δ /ppm: 7.64 (m, 2H), 7.38 (m, 3H), 4.80 & 4.38 (s, ’1H’),
4.16 (m, 2H), 3.77 (m, 1H), 3.76 & 3.39-3.02 (m, 2H), 1.99 (m, 1H), 1.80
(m, 3H), 1.62 (m, 2H), 1.49 & 1.31 (s, ’9H’), 1.18 (m, 3H); 13C NMR (100
MHz, CDCl3) δ /ppm: 168.2, 155.7, 155.5, 130.4, 129.0, 127.0, 126.6, 92.4,
80.7, 61.9, 59.3, 53.4, 48.7, 34.4, 28.5, 28.3, 22.3, 14.2; HRMS (ESI)
C22H30N2O5Na m/z: [M+Na]+ 425.2048 (calc. 425.2047).
tert-Butyl 4-((4-methoxyphenyl)imino)piperidine-1-carboxylate (6): To
a solution of tert-butyl 4-oxopiperidine-1-carboxylate 4a (0.50 g, 2.5 mmol,
1.0 equiv.) in toluene (10 mL) was added para-anisidine (0.31 g, 2.5 mmol,
1.0 equiv.) and the mixture heated to vigorous reflux in Dean-Stark
apparatus. After 20 hours, the mixture was cooled and solvent removed in
vacuo to yield the crude product, which was used directly in the following
reaction, without purification; Rf: 0.33 (Pet. Ether 40-60/EtOAc 2:3); IR
Ethyl
3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-4-carboxylate
solution of 8-(tert-butyl) 4-ethyl 3-phenyl-1-oxa-2,8-
(17a): To
a
(thin film) ν /̃
cm–1: 3357 (Ar-H, w), 2976 (C-H, m), 1685 (C=O carbamate
diazaspiro[4.5]dec-2-ene-4,8-dicarboxylate 7a (50 mg, 0.13 mmol, 1
equiv.) in dichloromethane (2 mL) was added trifluoroacetic acid (20 µL,
0.26 mmol, 2 equiv.) and the solution stirred for 22 hours. The mixture was
quenched with saturated aqueous sodium bicarbonate (20 mL) and
extracted with dichloromethane (3 x 7 mL). The combined organic extracts
were dried (MgSO4), filtered and solvent removed in vacuo. The crude
mixture was purified by flash column chromatography (Pet. Ether 40-
60/EtOAc 1:0 to 1:1 followed by DCM/MeOH 9:1) to yield the pure product,
ethyl 3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-4-carboxylate 17a as a
white amorphous solid (26 mg, 0.09 mmol, 68%); Rf: 0.14 (DCM/MeOH
and imine, s), 1510 (C=C Ar, s), 1234 (C-O, s), 1160 (C-O, s); 1H NMR
(400 MHz, CDCl3, 25°C) δ /ppm: 6.84 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8
Hz, 2H), 3.78 (s, 3H), 3.69 (m, 2H), 3.48 (m, 2H), 2.54 (m, 1H), 2.43 (m,
1H), 2.33 (m, 2H), 1.47 (br s, ’9H’); HRMS (ESI) C17H25N2O3 m/z: [M+H]+
305.1874 (calc. 305.1865).
tert-Butyl
3-acetoxy-1-(4-methoxyphenyl)-2-oxo-1,7-
solution of crude
diazaspiro[3.5]nonane-7-carboxylate (10): To
a
product, containing tert-butyl 4-((4-methoxyphenyl)imino)piperidine1-
carboxylate 6 (250 mg, 0.82 mmol, 1 equiv.), in dichloromethane (6 mL) at
-78°C was added triethylamine (0.34 mL, 2.46 mmol, 3 equiv.) dropwise.
A solution of acetoxyacetyl chloride (0.22 mL, 1.98 mmol, 2.4 equiv.) in
dichloromethane (2 mL) was added dropwise over 30 minutes and the
solution was allowed to warm slowly to room temperature and stirred for
20 hours. The mixture was washed with sodium bicarbonate solution (5%,
10 mL), HCl (5%, 10 mL) and saturated aqueous sodium chloride (10 mL),
dried (MgSO4), filtered and the solvent was removed in vacuo. The mixture
was purified by flash column chromatography (Pet. Ether 40-60/EtOAc 9:1
to 4:6) to yield the product, tert-butyl 3-acetoxy-1-(4-methoxyphenyl)-2-
oxo-1,7-diazaspiro[3.5]nonane-7-carboxylate 10, as a pale yellow oil (183
mg, 0.45 mmol, 55%); Rf: 0.48 (Pet. Ether 40-60/EtOAc 4:6); IR (thin film)
9:1); IR (thin film) ν /̃
cm–1: 3385 (N-H, w), 2967 (C-H, m), 1732 (C=O ester,
s), 1671 (C=O carbamate/C=N, s), 1181 (C-O, s); 1H NMR (400 MHz,
CDCl3, 25°C) δ /ppm: 7.62 (m, 2H), 7.42 (m, 3H), 4.21 (q, J = 7.2 Hz, 2H),
4.12 (m, 1H), 3.51-3.28 (m, 4H), 2.34-2.08 (m, 4H), 2.04 (s, 1H), 1.24 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ /ppm: 167.0, 155.7, 130.9,
129.1, 128.5, 126.7, 84.0, 62.5, 62.0, 41.0, 40.7, 33.2, 28.1, 14.1; HRMS
(ESI) C16H21N2O3 m/z: [M+H]+ 289.1533 (calc. 289.1547).
2-(tert-Butyl) 8-ethyl 7-benzyl-2,5,6,7-tetraazaspiro[3.4]oct-5-ene-2,8-
dicarboxylate (8): tert-butyl 3-(2-ethoxy-2-oxoethylidene) azetidine-1-
carboxylate 5b (386 mg, 1.60 mmol, 1.0 equiv.) was dissolved in benzyl
azide (2 mL, 16.0, 10.0 equiv.) and heated in a sealed tube at 100 °C for
48 h. This was purified via column chromatography (30% ethyl acetate in
pet. ether) to give the product, 2-(tert-Butyl) 8-ethyl 7-benzyl-2,5,6,7-
tetraazaspiro[3.4]oct-5-ene-2,8-dicarboxylate 8, as a yellow oil (204 mg,
0.54 mmol, 34%); Rf: 0.49 (Pet. Ether 40-60/EtOAc 7:3); IR (thin film)
ν /̃
cm–1: 3319 (Ar-H, w), 2975 (C-H, m), 1750 (C=O ester and lactam, s),
1687 (C=O carbamate, s), 1511 (C=C Ar, s), 1215 (C-O, s), 1163 (C-O, s);
1H NMR (400 MHz, CDCl3, 25°C) δ /ppm: 7.35 (d, J = 9.1 Hz, 2H), 6.87 (d,
J = 9.1 Hz, 2H), 5.72 (s, 1H), 4.13 (m, 2H), 3.79 (s, 3H), 3.50 (m, 1H), 3.01
(m, 1H), 2.58 (m, 1H), 2.27 (m, 1H), 2.20 (s, 3H), 2.05 (m, 1H), 1.81 (m,
1H), 1.65 (m, 1H), 1.46 (s, ’9H’); 13C NMR (100 MHz, CDCl3) δ /ppm: 169.8,
162.2, 157.6, 154.7, 128.5, 122.3, 114.7, 80.8, 80.3, 79.5, 66.0, 52.1, 55.6,
33.5, 31.1, 28.5, 20.9; HRMS (ESI) C21H29N2O6 m/z: [M+H]+ 405.2019
(calc. 405.2026).
ν /̃
cm–1: 2988 (C-H, w), 1726 (C=O, s), 1631 (C=C, m), 1115 (C-O, s); 1H
NMR (400 MHz, CDCl3) δ/ppm: 7.30–7.17 (m, 5H), 5.68 (br s, 2H), 4.89
(br s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 2.65 (br s, 3H), 1.42–1.38 (m, 12H);
13C NMR (101 MHz, CDCl3) δ/ppm: 154.3, 138.1, 128.9, 128.2, 127.6,
126.8, 89.5, 79.8, 59.0, 54.8, 51.1, 50.3, 48.4, 28.4, 14.6; HRMS (ESI)
C19H26N4O4Na m/z: [M+Na]+ 397.1840 (calc. 397.1846).
Acknowledgments
tert-Butyl 3-oxo-1,2,8-triazaspiro[4.5]decane-8-carboxylate (9): To
tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate 5a (270
mg, 1.00 mmol, 1.0 equiv.) in ethanol (0.4 mL) was added hydrazine
hydrate (58 µL, 1.2 mmol, 1.2 equiv.) and the mixture heated in a sealed
tube at 70°C for 24 hours. Solvent was removed in vacuo and the mixture
purified by flash column chromatography (DCM/MeOH 19:1 to 9:1) to yield
the product, tert-butyl 3-oxo 1,2,8-triazaspiro[4.5]decane-8-carboxylate 9,
as a colourless oil (173 mg, 0.68 mmol, 68%); Rf: 0.30 (DCM/MeOH 9:1);
T. A. K. thanks BBSRC for funding. H. L. S. thanks AstraZeneca
and EPSRC for funding. K. T. M. thanks the Carlsberg Foundation
for a Postdoctoral Fellowship. A.J.P.N., H.F.S., and D.R.S.
acknowledge support from the Engineering and Physical
Sciences
Research
Council
(EP/P020291/1).
D.R.S.
acknowledges support from the Royal Society (Wolfson Research
Merit Award). The Spring lab acknowledges general lab support
from the ERC, EPSRC, BBSRC, MRC, and Royal Society. The
authors would like to thanks Dr. Andrew Bond (Department of
Chemistry, University of Cambridge) for carrying out the single-
crystal crystallography for the project.
IR (thin film) ν /̃
cm–1: 3225 (N-H, m), 2931 (C-H, m), 1668 (C=O carbamate
and acid hydrazide, br s), 1148 (C-O, s); 1H NMR (400 MHz, CDCl3, 25°C)
δ /ppm: 7.12 (br s, 1H), 4.03 (br s, 1H), 3.55-3.37 (m, 4H), 2.34 (s, 2H),
1.79-1.60 (m, 4H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ /ppm: 176.8,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
Eur. J 2017, 23, 9262–9265.
D. B. Li, M. Rogers-Evans, E. M. Carreira, Org. Lett. 2013, 15, 4766–
4769.
■ Keywords: Heterocycles • Spirocycles • Fragment-based Drug
Discovery • Diversity-Oriented Synthesis • Cycloadditions
[41]
[42]
[43]
P. B. Brady, E. M. Carreira, Org. Lett. 2015, 17, 3350–3353.
G. Wuitschik, M. Rogers-evans, A. Buckl, M. Bernasconi, M. Märki,
T. Godel, H. Fischer, B. Wagner, I. Parrilla, F. Schuler, et al., Angew.
Chemie - Int. Ed. 2008, 47, 4512–4515.
E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257–8322.
D. B. Li, M. Rogers-evans, E. M. Carreira, Org. Lett. 2011, 13, 6134–
6136.
Y. Wang, J. W. Bode, J. Am. Chem. Soc 2019, 141, 9739–9745.
S. D. Griggs, N. Thompson, D. T. Tape, M. Fabre, P. A. Clarke, Org.
Biomol. Chem. 2018, 16, 6663–6674.
S. Castellano, D. Kuck, M. Viviano, J. Yoo, L. Fabian, P. Conti, L.
Tamborini, A. Pinto, L. Medina-franco, G. Sbardella, J. Med. Chem.
2011, 54, 7663–7677.
[1]
[2]
P. Ertl, S. Jelfs, J. Mühlbacher, A. Schuffenhauer, P. Selzer, J. Med.
Chem. 2006, 49, 4568–4573.
W. R. Pitt, D. M. Parry, B. G. Perry, C. R. Groom, J. Med. Chem. 2009,
52, 2952–2963.
[44]
[45]
[3]
[4]
R. Macarron, Drug Discov. Today 2006, 11, 277–279.
R. Macarron, M. N. Banks, D. Bojanic, D. J. Burns, D. A. Cirovic, T.
Garyantes, D. V. S. Green, R. P. Hertzberg, W. P. Janzen, J. W.
Paslay, et al., Nature 2011, 10, 188–195.
[46]
[47]
[5]
P. F. Chan, D. J. Holmes, D. J. Payne, Drug Discov. Today Ther.
Strateg. 2004, 1, 519–527.
[48]
[49]
[6]
[7]
[8]
S. L. Schreiber, Science 2000, 287, 1964–1969.
D. Lee, J. K. Sello, S. L. Schreiber, Org. Lett. 2000, 2, 709–712.
D. C. Rees, M. Congreve, C. W. Murray, R. Carr, Nat. Rev. Drug
Discov. 2004, 3, 660–672.
R. Ramesh, K. De, S. Chandrasekaran, Tetrahedron 2007, 63,
10534–10542.
[50]
[51]
[52]
N. Jarwal, P. P. Thankachan, J. Mol. Model. 2015, 21, 87.
P. N. Collier, Tetrahedron Lett. 2009, 50, 3909–3911.
D. Goyard, B. Konya, A. S. Chajistamatiou, E. D. Chrysina, J. Leroy,
S. Balzarin, M. Tournier, D. Tousch, P. Petit, C. Duret, et al., Eur. J.
Med. Chem. 2016, 108, 444–454.
C. Brullo, R. Ricciarelli, J. Prickaerts, O. Arancio, M. Massa, C. Rotolo,
A. Romussi, C. Rebosio, B. Marengo, M. Adelaide, et al., Eur. J. Med.
Chem. 2016, 124, 82–102.
[9]
[10]
W. P. Jencks, Proc. Natl. Acad. Sci. 1981, 78, 4046–4050.
D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke, H. Jhoti, Nat.
Rev. Drug Discov. 2016, 15, 605–619.
[11]
[12]
D. A. Erlanson, R. S. McDowell, T. O’Brien, J. Med. Chem. 2004, 47,
3463–3482.
P. D. Leeson, B. Springthorpe, Nat. Rev. Drug Discov. 2007, 6, 881–
90.
[53]
[13]
[14]
A. Ciulli, C. Abell, Curr. Opin. Biotechnol. 2007, 18, 489–496.
C. W. Murray, D. C. Rees, Angew. Chemie - Int. Ed. 2016, 55, 488–
492.
[54]
[55]
Y. Pan, C. Guo, H. Tu, C. Tsai, W. Cheng, ACS Comb. Sci. 2013, 15,
425–434.
H. Shih, C. Guo, K. Lo, M. Huang, W. Cheng, J. Comb. Chem. 2009,
11, 281–287.
H. Shih, W. Cheng, Tetrahedron Lett. 2008, 49, 1008–1011.
C. J. A. Ribeiro, S. P. Kumar, R. Moreira, M. M. M. Santos,
Tetrahedron Lett. 2012, 53, 281–284.
R. Sakly, H. Edziri, M. Askri, M. Knorr, K. Louven, C. Strohmann, M.
Mastouri, J. Heterocycl. Chem. 2017, 54, 3554–3564.
E. A. Litinas, Konstantinos E. Nicolaides, Demetrios N. Varella, J.
Heterocycl. Chem. 1990, 27, 769–774.
D. Nicolaides, Demetrios N. Fylaktakidou, Konstantina C. Litinas,
Konstantinos E. Hadjipavlou‐Litina, J. Heterocycl. Chem. 1996, 33,
967–971.
M. Mancera, I. Roff, J. A. Galbis, Tetrahedron 1995, 51, 6349–6362.
H. Zheng, R. Mcdonald, D. G. Hall, Chem. A Eur. J. 2010, 16, 5454–
5460.
J. H. Bateson, R. Southgate, J. W. Tyler, S. C. M. Fell, J. Chem. Soc.,
Perkin Trans. 1, 1986, 973–981.
M. P. Sibi, Z. Ma, C. P. Jasperse, J. Am. Chem. Soc 2004, 126, 718–
719.
A.-H. Li, H. Dong, T. Zhang, (Spirocyclylamido)Aminothiophene
Compounds and Their Preparation, Pharmaceutical Compositions,
and Hyperproliferative Activity for Treatment of Tumors and Cancers,
2006, US 20060063791 A1.
N. Anand, B. A. Shah, M. Kapoor, R. Parshad, R. L. Sharma, M. S.
Hundal, A. P. S. Pannu, P. V Bharatam, S. C. Taneja, J. Org. Chem.
2011, 76, 5999–6006.
C. Lucatelli, F. Viton, Y. Gimbert, A. E. Greene, J. Org. Chem. 2002,
67, 9468–9470.
C. E. Song, S. W. Lee, J. Roh, S. Lee, W. Lee, Tetrahedron:
Asymmetry 1998, 9, 983–992.
N. Boechat, M. de L. G. Ferreira, M. M. Bastos, A. L. S. Camilo, S. M.
S. V Wardell, J. L. Wardell, E. R. T. Tiekink, J Chem Crystallogr 2010,
40, 1137–1141.
M. Congreve, R. Carr, C. Murray, H. Jhoti, Drug Disocvery Today
2003, 8, 876–877.
T. Rui-ren, Y. Zi-er, L. Yi-ming, J. Cent. South Univ. Technol. 2005,
12, 693–698.
B. Peschke, M. Ankersen, B. Sehested, T. Kruse, N. Langeland, J.
Lau, K. Madsen, H. Petersen, H. Thogersen, B. Watson, Eur. J. Med.
Chem 1999, 34, 363–380.
M. S. Ashwood, A. W. Gibson, P. G. Houghton, G. R. Humphrey, D.
C. Roberts, S. H. B. Wright, J. Chem. Soc., Perkin Trans. 1, 1995, 6,
641–644.
[15]
R. J. Spandl, G. L. Thomas, M. Diaz-Gavilan, K. M. G. O’Connell, D.
R. Spring, in Link. Strateg. Solid-Phase Org. Synth. (Ed.: P. Scott),
Wiley, 2009, pp. 241–262.
[56]
[57]
[16]
[17]
[18]
W. R. J. D. Galloway, D. R. Spring, Expert Opin. drug Discov. 2009,
4, 467–472.
R. J. Spandl, H. Rudyk, D. R. Spring, Chem. Commun. 2008, 3001–
3003.
N. Mateu, S. L. Kidd, T. Osberger, H. L. Stewart, S. Bartlett, W. R. J.
D. Galloway, A. J. P. North, H. F. Sore, D. R. Spring, in Chem. Biol.
Synth. Enabling Approaches Underst. Biol. (Eds.: N.J. Westwood, A.
Nelson), The Royal Society Of Chemistry, 2018, pp. 8–44.
W. R. J. D. Galloway, D. R. Spring, Divers. Oriented Synth. 2013, 1,
21–28.
B. M. Ibbeson, L. Laraia, E. Alza, C. J. O. Connor, Y. S. Tan, H. M. L.
Davies, G. Mckenzie, A. R. Venkitaraman, D. R. Spring, Nat.
Commun. 2014, 5, 1–8.
[58]
[59]
[60]
[19]
[20]
[61]
[62]
[63]
[64]
[65]
[21]
[22]
[23]
[24]
[25]
W. R. J. D. Galloway, A. Bender, M. Welch, D. R. Spring, Chem.
Commun. 2009, 2446.
C. J. O’ Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev.
2012, 41, 4444–56.
N. Mateu, S. L. Kidd, L. Kalash, H. F. Sore, A. Madin, D. R. Spring,
Chem. Eur. J 2018, 24, 13681–13687.
A. W. Hung, A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A.
Clemons, D. W. Young, Proc. Natl. Acad. Sci. 2011, 108, 6799–6804.
D. G. Twigg, N. Kondo, S. L. Mitchell, W. R. J. D. Galloway, H. F.
Sore, A. Madin, D. R. Spring, Angew. Chemie - Int. Ed. 2016, 55,
12479–12483.
[66]
[67]
[68]
[69]
[26]
[27]
[28]
[29]
[30]
A. Sveiczer, A. J. P. North, N. Mateu, S. L. Kidd, H. F. Sore, D. R.
Spring, Org. Lett. 2019, 3–7.
T. A. Alanine, W. R. J. D. Galloway, T. M. Mcguire, D. R. Spring,
European J. Org. Chem. 2014, 5767–5776.
M. S. Frei, M. K. Bilyard, T. A. Alanine, W. R. J. D. Galloway, J. E.
Stokes, D. R. Spring, Bioorg. Med. Chem. 2015, 23, 2666–2679.
T. A. Alanine, W. R. J. D. Galloway, S. Bartlett, J. J. Ciardiello, T. M.
Mcguire, D. R. Spring, Org. Biomol. Chem. 2015, 14, 1031–1038.
Y. Zheng, C. M. Tice, S. B. Singh, Bioorg. Med. Chem. Lett. 2014, 24,
3673–3682.
[70]
[71]
[72]
[31]
[32]
[33]
Y. Zheng, C. M. Tice, Expert Opin. Drug Discov. 2016, 11, 831–834.
C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514–5533.
G. Müller, T. Berkenbosch, J. C. J. Benningshof, D. Stumpfe, Chem.
– A Eur. J. 2017, 23, 703–710.
[73]
[74]
[75]
[34]
[35]
R. Rios, Chem Soc Rev 2012, 41, 1060–1074.
A. Ding, M. Meazza, H. Guo, J. W. Yang, R. Rios, Chem Soc Rev
2018, 47, 5946–5996.
C. C. Lynch, A. Konradi, R. A. Galemmo, JR, A. D. Presley,
Aminopyridine Compounds and Methods for the Preparation and Use
Thereof, 2018, WO2018209132 (A1).
B. A. Chalyk, M. V Butko, O. O. Yanshyna, K. S. Gavrilenko, T. V.
Druzhenko, P. K. Mykhailiuk, Chem. Eur. J 2017, 23, 16782–16786.
[36]
[37]
K. P. Melnykov, A. N. Artemenko, B. O. Ivanenko, Y. M. Sokolenko,
P. S. Nosik, E. N. Ostapchuk, O. O. Grygorenko, D. M. Volochnyuk,
S. V Ryabukhin, ACS Omega 2019, 4, 7498–7515.
J. A. Burkhard, C. Gu, H. Knust, E. M. Carreira, Org. Lett. 2012, 14,
66–69.
[38]
[39]
K. Geoghegan, W. Bode, Org. Lett. 2015, 17, 1934–1937.
C. J. A. Ribeiro, J. D. Amaral, C. M. P. Rodrigues, R. Moreira, M. M.
M. Santos, Bioorg. Med. Chem. 2014, 22, 577–584.
S. D. Griggs, N. Thompson, D. T. Tape, M. Fabre, P. A. Clarke, Chem.
[40]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900847
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Heterocyclic spirocycles*
Thomas A. King, Hannah L. Stewart,
Kim T. Mortensen, Andrew J. P. North,
Hannah F. Sore and David R. Spring*
Cycloaddition Strategies for the
Synthesis of Diverse Heterocyclic
Spirocycles for Fragment-Based Drug
Discovery
Heterocyclic spirocycles represent a promising region of chemical space for
fragment-based drug discovery, combining the advantages of heteroatoms and
three-dimensionality. The sterically-crowded quaternary carbon has historically
provided a significant synthetic challenge. This work explores the application of
cycloaddition reactions as a solution in the synthesis of heterocyclic spirocycles.
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