Ring-Expansion Approach to Medium-Sized Lactams and Analysis of Their Medicinal Lead-Like Properties

Article abstract of DOI:10.1002/chem.201605615

Medium-sized rings are widely considered to be under-represented in biological screening libraries for lead identification in medicinal chemistry. To help address this, a library of medium-sized lactams has been generated by using a simple, scalable and versatile ring-expansion protocol. Analysis of the library by using open-access computational tool LLAMA suggested that these lactams and their derivatives have highly promising physicochemical and 3D spatial properties and thus have much potential in drug discovery.

Full text of DOI:10.1002/chem.201605615

A Journal of
Accepted Article
Title: Ring expansion approach to medium-sized lactams and analysis
of their medicinal lead-like properties
Authors: Laetitia G Baud, Morgan Ann Manning, Helen L Arkless,
Thomas C Stephens, and William Paul Unsworth
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.201605615
Link to VoR: http://dx.doi.org/10.1002/chem.201605615
Supported by

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Ring expansion approach to medium-sized lactams and analysis
of their medicinal lead-like properties
Laetitia G. Baud, Morgan A. Manning, Helen L. Arkless, Thomas C. Stephens and William P.
[
a]
Unsworth*
Abstract: Medium-sized rings are widely considered to be under-
represented in biological screening libraries for lead identification in
medicinal chemistry. To help address this, a library of medium-sized
lactams has been generated using a simple, scalable and versatile
ring expansion protocol. Analysis of the library using open access
computational tool LLAMA suggests that these lactams and their
derivatives have highly promising physicochemical and 3D spatial
properties and thus have much potential in drug discovery.
(compared to smaller ring cyclisations) meaning that unwanted
intermolecular reactions and/or transannular reactions often out-
compete the desired cyclisation. The most common method
used to circumvent these problems is to perform the cyclisation
[12]
at high-dilution, to minimise intermolecular collisions, but such
processes can be highly sensitive to changes in the substrate
and are impractical on large scale. Various innovative
macrocyclisation strategies have emerged in which high-dilution
[
13]
can be avoided,
but there remains a pressing need for the
development of new reliable, practical and scalable methods for
the synthesis of medicinally important larger ring compounds.
The expansion of smaller ring systems is an attractive
alternative for the construction of larger ring compounds, most
Introduction
Five- and six-membered rings are ubiquitous in medicinal
chemistry, with a least one of these rings being present in most
notably because the difficult end-to-end cyclisation step that
[14,15]
blights traditional approaches can be completely avoided.
In
[
1]
marketed pharmaceuticals. However, in recent years, there
has been significant rise in interest in the medicinal
2
015, our group reported one such approach, that enables the
insertion of amino acid and hydroxy acid derived 3- or 4-atom
fragments into cyclic β-keto esters via telescoped
acylation/ring expansion sequence to form lactams and lactones
a
[
2]
applications of larger ring compounds; various methods to
generate libraries of such compounds for bioassay have been
developed, with medium-sized (8–11 membered rings) and
a
[16]
(
1 + 2 → 4, Scheme 1). A notable feature of this method is
[
3,4]
macrocyclic scaffolds (12+) both having been examined.
that the cyclic β-keto ester motif present in the starting material
is replicated in the ring-enlarged product, hence Successive
Ring Expansion (SuRE) reactions can be performed (e.g. 4 →
Larger ring scaffolds generally have sufficiently well-defined
conformations to bind to target receptors without major entropic
[5]
penalties, but are more flexible than their smaller ring
analogues and hence able to change their conformation to
facilitate binding if needed. They have also been shown to
exhibit improved bioavailability, enhanced cell permeability and
greater metabolic stability compared to related linear analogues
5
); repeating the same C-acylation/ring expansion sequence
with different amino/hydroxy acid fragments on the product
means that rings of any size are potentially accessible.
[6]
in various studies. An array of bioactive natural products are
[
7,8]
also known based on medium-sized rings and macrocycles,
including macrocyclic examples that have been developed for
[
2b,c]
use as drugs in the clinic.
Despite these favourable characteristics, medium-sized
and macrocyclic ring systems have historically been under-
[
2]
explored in medicinal chemistry. Both compound classes are
widely considered to be under-represented in most drug
[
3c]
screening libraries
and very few larger ring pharmaceuticals
[9]
produced by chemical synthesis have made it to market.
Various factors have contributed to this outcome, but in view of
the importance of chemical synthesis at various stages of the
drug discovery process, the well-established difficulties
associated with their synthesis are undoubtedly a significant
Scheme 1. Successive Ring Expansion (SuRE).
[
10,11]
contributor.
Traditional end-to-end cyclisation approaches
are typically hampered by unfavourable enthalpic factors (e.g.
ring/torsional strain) and less favourable entropic factors
Our previous publication on the SuRE method was mainly
focused on the synthesis of macrocyclic lactams, but in selected
cases, we also found that this ring expansion method was
suitable for the synthesis of medium-sized lactams. The method
is exemplified by the conversion of 6-membered ring β-keto
ester 1a into 10-membered ring lactam 6a; an initial
[
a]
L. G. Baud, M. A. Manning, H. L. Arkless, T. C. Stephens and Dr. W.
P. Unsworth
University of York
York, YO24 4PP (UK)
E-mail: william.unsworth@york.ac.uk
MgCl
2
/pyridine mediated C-acylation reaction with acid chloride
2a is followed by Fmoc cleavage under standard conditions,
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
promoting spontaneous ring expansion via the mechanism
shown (Scheme 1). In total, the syntheses of seven medium-
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Chemistry - A European Journal
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sized products (6a–6g) using this method have been reported to
[
16]
date (Scheme 2).
Figure 1. Substrates 1a–g and 2a–h
Scheme 2. Synthesis of 9–11-membered ring lactams 6a–6g. For full
reactions details see reference 16.
In principle, the ring expansion should be reversible (although
we have never observed either of intermediates 4 or 5 in any of
our previous reactions) and given this, we were particularly
pleased to find that the formation of medium ring products 6a–
6g worked so well; medium-sized rings often experience
destabilizing transannular interactions, and the fact they can be
formed from 5–7-membered rings under thermodynamic control
is important. The research described herein details our efforts to
build upon these findings and use this method to generate a
library of 8–12 membered ring products with diverse structural,
physicochemical and 3D-spatial properties. To demonstrate the
usefulness and value of the products, the ‘lead-likeness’ and 3D
spatial properties of the molecular scaffolds formed were
analysed using the open access computational resource LLAMA
[17,18]
(
Lead-Likeness and Molecular Analysis).
Results and Discussion
To enable the preparation of the medium-ring library described
herein, a range of functionalised β-keto esters 1a–g and
protected amino acid chlorides 2a–2h were each required, with
all of these compounds being either commercially available or
readily synthesised by known procedures (detailed in the
Supporting Information). Figure 1 shows all of the starting
materials used, while Scheme 3 outlines the ring-expanded
[
19]
Scheme 3. Synthesis of 6h–6zd. i) Dicarbonyl 1 (1 equiv.), MgCl
and pyridine (6 equiv.) pre-mixed for 30 min in CH Cl (7 mL/mmol of 1) before
adding acid chloride 2 (1.5–3 equiv.) in CH Cl
for 1–2 h at RT; ii) piperidine (10 equiv.), CH Cl
2
(2 equiv.)
product library formed (6h–6zd), grouped by ring size.
2
2
2
2
(3 mL/mmol of 1) and stirring
2
(10 mL/mmol), RT, 1–2 h.
2
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A
range of 8–12 membered ring products 6h–6zd were
terms of their molecular weight (200–350) and lipophilicity (−1 to
+3), with these results included in the Supporting Information.
More realistically, it was considered that compounds 6a–zd
could serve as valuable precursors for more medicinally useful
compounds following additional synthetic steps. This notion was
exemplified using 11-membered ring compound 6u. First, β-keto
ester 6u was converted into ketone 9u via hydrolysis and
decarboxylation in one-pot under standard basic conditions in
high yield. Ketone 9 was then shown to undergo facile reductive
amination, affording amines 10a and 10b, which in turn could be
sulfonylated or acylated, generating compounds 11 and 12
respectively. Functionalisation on the amide nitrogen was also
demonstrated, with compound 13 being formed from secondary
amide 12 in good yield (Scheme 5).
generated using this method, providing a library of 30 medium
ring compounds when compounds 6a–g are included.
Noteworthy examples include the use of benzannulated and
cyclic ether-containing β-keto esters for the first time and a much
wider range of branched α- and β-amino acids than those used
[
16]
in our earlier work.
The isolated yields of the ring expanded
products following column chromatography range from 12–84%,
with around 60% yield for the two-step sequence being typical.
Most of the examples showed in Scheme 3 proceeded as
expected, with no obvious side product formation and with
little/no changes to the standard reaction conditions being
required. However, it is also instructive to highlight two rare
exceptions that did not proceed as expected, to illustrate ways
which the reaction course can deviate (Scheme 4). For example,
when β-keto ester 1c was reacted with acid chloride 2h using
the standard protocol, imine condensation product 7 was formed
as the major product, with the expected product 6o isolated as a
[
20]
minor side product only. The reaction of β-keto ester 1h with
acid chloride 2a also proceeded unexpectedly; in this example, it
appears that the acylation/ring expansion sequence proceeded
in the usual way, but that piperidine used to cleave the Fmoc
protecting group condensed with the product ketone to form
[
21]
enamine 8. It is likely that both of these side reactions could
be avoided following optimisation of the reaction conditions (e.g.
by using aqueous conditions during the ring expansion step);
additional optimisation experiments such as these are planned
and will be reported in due course.
Scheme 5. Chemical elaboration of compound 6u
A major strength of LLAMA is its ability to create and enumerate
virtual libraries of compounds for analysis. To do this, a new
virtual library of 30 compounds 9a–zd was created, based on
the hydrolysis/decarboxylation of the original synthetic library (i.e.
Scheme 4. Rare examples of side product formation
compounds 6a–zd in which CO Et has been replaced with H,
2
see Supporting Information for a table of these structures). We
then used LLAMA to enumerate these 30 compounds via five
distinct reactions modes (reductive amination, sulfonamide
formation, secondary amide alkylation/arylation and amide
formation) based on the synthetic reactions that were
successfully demonstrated on compound 9u. More specific
details of these five reactions, as well as the structures of the set
of 40 reagents used to enumerate the compounds, are included
in the Supporting Information.
With a library of 30 compounds (6a–zd) in-hand, attention turned
to analysing their molecular properties, in particular with respect
to their potential to act as lead compounds in medicinal
[
22]
chemistry. This analysis was done using online open-access
[
17]
[18]
tool LLAMA.
LLAMA assesses the lead-likeness of small
molecule scaffolds based on their molecular weight, predicted
lipophilicity, heavy atom count, number of aromatic rings and
functional group makeup. In addition, LLAMA is able assess the
predicted 3D spatial properties of the compounds using the
Upon performing a single enumeration, a virtual library of
[
23,24]
principal moments of inertia (PMI) method,
provides an indication on their novelty.
and also
402 compounds was generated, comprising compounds that can
[
25]
theoretically be synthesised in a single synthetic step from any
of compounds 9a–zd. Some of the data generated is shown in
Compounds 6a–zd are unlikely to be medicinally relevant
in their own right, as they all contain a metabolically labile β-keto
ester motif. Nonetheless, the majority of compounds 6a–zd were
at least calculated to have favourable lead-likeness properties in
Figure 2 as a plot of molecular weight against calculated
[26]
AlogP;
of the 402 compounds in this virtual library, 283
(
70.4%) fall within ‘lead-like’ chemical space (defined as having
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Chemistry - A European Journal
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a molecular weight of 200–350 and AlogP of −1 to +3) and
almost all are within traditional Lipiniski rule-of-five space. As an
additional point of analysis, all of the compounds in the library
are assigned a numerical ‘lead-likeness penalty’; this is a
parameter specific to LLAMA in which compounds considered to
have the best ‘lead-like’ properties are given a value of 0 (shown
in green), and larger numbers (shown in orange/red) represent
increasing deviation from defined ideal parameters for medicinal
[
17]
lead compounds. Encouragingly, 200 of the 402 compounds in
this library have a lead-likeness penalty of 0, with an average
lead-likeness penalty for the whole data set of just 1.30.
Figure 3. PMI plot for a virtual library generated from compounds 9a–zd with
one enumeration. The blue + denotes the average PMI coordinates.
By allowing LLAMA to perform two consecutive enumerations,
an even larger virtual library can be generated; using the same
compound set described above, a virtual library of 3546
compounds was generated and analysed, with plots of these
data included in the Supplementary Information. In this data set,
diverse 3D spatial properties were again observed (I1 = 0.381,
I2 = 0.825), but the average lead-likeness penalty was higher
(
3.16). This is not particularly surprising, given that after two
enumerations, the molecular weight, heavy atom count and
number of aromatic rings will inevitably be higher than for the
Figure 2. Plot of molecular weight against calculated AlogP for a virtual library
generated from compounds 9a–zd with one enumeration.
singly enumerated library. Indeed, after enumerating
compound twice, it is reasonable to expect that it will be less
lead-like’ and ideally will start becoming more ‘drug-like’, and to
a
Information on the spatial properties of the compounds in the
virtual library is also obtained from LLAMA using the PMI
‘
this end, it is noteworthy that the majority of this 3546 compound
library fall within Lipinski rule-of-five space. Thus, the medium-
sized lactam scaffolds generated appear to have significant
potential as medicinal lead compounds. The predictive power of
the data generated using LLAMA should be useful in directing
future chemical synthesis and bioassay studies towards
compounds with the most promising lead-likeness and 3D
spatial properties.
[
23,24]
method,
with a PMI plot of the same compound set
[
26,27]
depicted in Figure 3.
The lowest energy conformation and
normalised principal moments of inertia ratios (I1 and I2) of the
compounds are displayed on a triangular plot, with the three
vertices corresponding to rod, disc, and spherical-shaped
molecules. A trend that is typically seen when PMI analysis is
performed on medicinally-oriented compound collections is a
tendency for multiple data points to be found close to the ‘rod-
disc’ axis, which corresponds to an abundance of relatively flat
[
28]
molecules.
What is clearly evident from this plot is that the
compounds in this library have unusually diverse 3D spatial
properties. With average PMI coordinates well away from the
rod-disc axis (denoted by the blue + on the plot) of I1 = 0.404, I2
Conclusions
The ring expansion protocol described herein has been
validated for the synthesis of a broad range of medium-sized
ring lactams. A library of 30 such compounds (8–12-membered
rings) was produced using the method and their lead-likeness
properties were analysed using LLAMA. An enumerated virtual
library was generated based on validated synthetic
transformations, suggesting that the compounds have highly
promising lead-like characteristics. Furthermore, 3D shape
analysis, performed using the PMI method, also suggests that
=
0.859 the virtual library can certainly be said to possess much
higher levels of 3D character than is typically found in high
[
29]
throughput screening libraries. Arguably of more importance is
the spread of the data points; the distribution of 3D spatial
properties means that wide areas of chemical space can be
probed, which is particularly pleasing giving that all of the
compounds derive from medium-ring scaffolds produced by the
same synthetic method.
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Chemistry - A European Journal
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the compounds occupy diverse regions of chemical space,
further increasing the likelihood that this method will generate
novel medicinal lead compounds.
[1]
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M. Driggers, S. P. Hale, J. Lee, N. K. Terrett, Nat. Rev. Drug Discov.
This research demonstrates the value of ring expansion
reactions for the synthesis of medicinally relevant medium-ring
scaffolds. We hope that improving access to a compound class
considered to be underrepresented in screening libraries will
help to address this current shortfall. In future work, biological
screening of the compounds generated in this research program
will be performed, as well as on their derivatives, and any useful
results will be revealed in due course.
2
008, 7, 608; (c) E. Marsault, M. L. Peterson, J. Med. Chem. 2011, 54,
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Chem. Sci. 2015, 6, 30.
[3]
For examples focussed principally on medium-sized rings, see: (a) K. R.
Romines, K. D. Watenpaugh, P. K. Tomich, W. J. Howe, J. K. Morris, K.
D. Lovasz, A. M. Mulichak, B. C. Finze, J. C. Lynn, M.-M. Horng, F. J.
Schwende, M. J. Ruwart, G. L. Zipp, K.-T. Chong, L. A. Dolak, L. N.
Toth, G. M. Howard, B. D. Rush, K. F. Wilkinson, P. L. Possert, R. J.
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A. Bauer, T. A. Wenderski, D. S. Tan, Nat. Chem. Bio. 2013, 9, 21.
For examples focussed principally on macrocycles, see: (a) F. Leon, D.
G. Rivera, L. A. Wessjohann, J. Org. Chem. 2008, 73, 1762; (b) A. R.
Kelly, J. Wei, S. Kesavan, J. C. Marié, N. Windmon, D. W. Young, L. A.
Marcaurelle, Org. Lett. 2009, 11, 2257; (c) A. Isidro-Llobet, T. Murillo, P.
Bello, A. Cilibrizzi, J. T. Hodgkinson, W. R. J. D. Galloway, A. Bender,
M. Welch, D. R. Spring, Proc. Natl. Acad. Sci. 2011, 108, 6793; (d) K.
M. G. O’Connell, H. S. Beckmann, L. Laraia, H. T. Horsley, A.
Bender, A. R. Venkitaraman, D. R. Spring, Org. Biomol. Chem. 2012,
Experimental Section
A representative example of the typical ring expansion protocol is
provided below for the formation of compound 6u. Full experimental
procedures, characterisation data and NMR spectra for all of the other
compounds described in this manuscript can be found in the Supporting
Information.
[4]
Ethyl
1,5-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-
benzo[c][1]azacycloundecine-6-carboxylate (6u) A mixture of ethyl 5-
oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate 1f (791 mg,
10, 7545; (e) K. V. Lawson, T. E. Rose, P. G. Harran, Tetrahedron,
16
2013, 69, 7683; (f) A. Grossmann, S. Bartlett, M. Janecek, J. T.
Hodgkinson, D. R. Spring, Angew. Chem. Int. Ed. 2014, 53, 13093; (g)
A. P. Treder, J. L. Hickey, M.-C. J. Tremblay, S. Zaretsky, C. C. G.
Scully, J. Mancuso, A. Doucet, A. K. Yudin, E. Marsault, Chem. Eur. J.
3
.40 mmol), MgCl
mmol) in DCM (25 mL) under an argon atmosphere was stirred at RT for
0 mins. Next, a solution of freshly prepared acid chloride 2a (4.78 mmol)
2
(922 mg, 9.68 mmol) and pyridine (1.58 mL, 19.5
3
in DCM (9 mL) was added and the reaction mixture was stirred for 1 h at
rt. The mixture was then diluted with DCM (150 mL) and washed with
2
015, 21, 9249; (h) T. E. Storr, S. J. Cully, M. J. Rawling, W. Lewis, D.
Hamza, G. Jones, R. A. Stockman, Bioorg. Med. Chem. 2015, 23,
621; (i) J.-P. Krieger, G. Ricci, D. Lesuisse, C. Meyer, J. Cossy Chem.
1
1
0% aq. HCl (75 mL). The aqueous layer was extracted with DCM (3 ×
50 mL) and the combined organic extracts were dried over MgSO and
2
4
Eur. J. 2016, 22, 13469; (j) I. B. Seiple, Z. Zhang, P. Jakubec, A.
Langlois-Mercier, P. M. Wright, D. T. Hog, K. Yabu, S. R. Allu, T.
Fukuzaki, P. N. Carlsen, Y. Kitamura, X. Zhou, M. L. Condakes, F. T.
Szczypiński, W. D. Green, A. G. Myers, Nature, 2016, 533, 338; (k) S.
Collins, S. Bartlett, F. Nie, H. F. Sore, D. R Spring, Synthesis 2016,
concentrated in vacuo. The crude material was then re-dissolved in DCM
34 mL) and piperidine (3.36 mL, 34.0 mmol) was added. The resulting
mixture was stirred for 1 h at RT, before the solvent was removed in
vacuo. Purification by column chromatography (SiO 10:1 1:1
hexane:ethyl acetate → pure ethyl acetate) afforded the title compound
(
2
,
→
1457; (l) S. Javed, M. Bodugam, J. Torres, A. Ganguly, P. Hanson,
6
0
1
u (816 mg, 78%) as a white solid; M.p. 162–164 °C (chloroform); R
f
-
1
Chem. Eur. J. 2016, 22, 6755
.20 (1:1 hexane:ethyl acetate); vmax (thin film)/cm 3278, 2938, 1742,
710, 1635, 1530, 1184, 730; δ (400 MHz, CDCl ) 7.27–7.06 (4H, m,
), 3.92 (1H, dd, J =
0.7, 4.6 Hz, CH), 3.89–3.78 (1H, m), 3.56–3.39 (2H, m), 2.79–2.59 (2H,
m), 2.56–2.44 (1H, m), 2.12–2.00 (1H, m), 1.92–1.78 (1H, m), 1.69–1.54
1H, m), 1.36–1.25 (1H, m), 1.21 (3H, t, J = 7.1 Hz, CH ) δ (100 MHz,
CDCl ) 208.6 (C=O, ketone), 171.1 and 169.0 (C=O, amide and ester),
39.2 (C), 137.1 (C), 129.8, 129.6, 126.2, 126.0 (4 CH), 61.5 (OCH ),
6.6 (CH), 41.5, 36.6, 31.3, 28.9, 27.5 (5 CH ), 14.1 (CH ); HRMS
] requires 326.1363.
[
5]
6]
E. Marsault, Macrocycles as templates for diversity generation in drug
discovery, in Diversity Oriented Synthesis: Basics and Applications in
Organic Synthesis, Drug Discovery, and Chemical Biology, ed. A.
Trabocchi, John Wiley & Sons, Inc, Hoboken, New Jersey, 2013, 253–
H
3
Ar), 6.26 (1H, s, NH), 4.11 (2H, q, J = 7.1 Hz, OCH
2
1
287.
(
3
C
[
For papers describing various physicochemical studies on larger ring
compounds, see references 1–5 and references cited therein, as well
as: (a) T. Rezai, B. Yu, G. L. Millhauser, M. P. Jacobson, R. S. Lokey, J.
Am. Chem. Soc. 2006, 128, 2510; (b) Y.-U. Kwon, T. Kodadek, Chem.
Biol. 2007, 14, 671.
3
1
5
2
2
3
+
(ESI+): Found: found 326.1363. [C17H21NNaO
4
[
7]
8]
For medium-sized ring natural products, see: (a) D. J. Faulkner, Nat.
Prod. Rep. 1984, 1, 251; (b) A. Hussain, S. K. Yousuf, D. Mukherjee,
RSC Adv. 2014, 4, 43241 and references therein.
Acknowledgements
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The authors wish to thank the Leverhulme Trust (for an Early
Career Fellowship, ECF-2015-013, for W. P. U.), the University
of York (M. A. M., H. L. A., W. P. U.), Erasmus+ and the
University of Grenoble Alpes (L. G. B.) and the EPSRC (for a
contribution towards a departmental PhD studentship for T. C.
S.) for funding this research.
2
62; (e) X. Yu, D. Sun Molecules 2013, 18, 6230 (f) T. O. Ronson, R. J.
K. Taylor, I. J. S. Fairlamb, Tetrahedron 2015, 71, 98.
For exceptions of fully synthetic macrocycles approved for clinical use
or in late stage development in oncology, see: J. Mallinson, I. Collins,
Future Med. Chem. 2012, 4, 1409.
[
[
9]
Keywords: Medium-sized rings • Ring Expansion • Lactams •
Lead-oriented synthesis • Amino acids
10] G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201605615
FULL PAPER
[
11] (a) M. Hesse in Ring Enlargement in Organic Chemistry, Wiley-VCH,
Weinheim, 1991; (b) C. J. White, A. K. Yudin, Nature Chem. 2011, 3,
bulky iso-butyl group causes the cyclised intermediate to adopt a
conformation in which the required fragmentation process is less
favourable.
509.
[
[
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[21] Interestingly, in the case of the formation of piperidine adduct 8, this
side reaction could be viewed as an opportunity to introduce additional
functionality; in future work it is planned to examine whether other
amines can operate similarly to furnish ring-expanded enamines of the
form 8 in one-pot. We speculate that the reason side product 8 is
formed in this case, but not in most others, may be a consequence of it
containing a basic nitrogen group; this could have introduced a small
amount of HCl (used in the work-up of the acylation step) into the ring
expansion reaction, which in turn might catalyse imine condensation.
To the best of our knowledge, we have never observed any instances
of piperidine condensation taking place before ring expansion,
suggesting that the Fmoc cleavage and ring expansion steps are
significantly faster than condensation.
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[
[
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To access LLAMA online, see: https://llama.leeds.ac.uk
[26] All of the plots included in this manuscript and its Supporting
Information are completely unaltered from those generated within
LLAMA.
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[
19] In Schemes
2
and 3, compounds 6a–zd are depicted as single
, some of
tautomers and rotamers, but note that in solution in CDCl
3
these products exist as concentration dependent equilibrating mixtures
of tautomers (keto/enol), rotamers and/or diastereoisomers. For specific
details for each compound, see the Supporting Information.
[
20] A tentative explanation for the greater propensity of this substrate to
form an imine rather than undergo ring-expansion is that the relatively
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Chemistry - A European Journal
10.1002/chem.201605615
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Medium-sized rings are under-
Laetitia G. Baud, Morgan A. Manning,
Helen L. Arkless, Thomas C. Stephens
and William P. Unsworth*
represented in biological screening
libraries for lead identification. To
address this, a library of medium-
sized ring lactams was generated
using a ring expansion protocol.
Analysis of the library using open
access computational tool LLAMA
suggests that the medium synthesised
ring lactams and their derivatives have
highly promising physicochemical and
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Ring expansion approach to medium-
sized lactams and analysis of their
medicinal lead-like properties
3D spatial properties and thus have
much potential in drug discovery.
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