2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: Synthesis and strategies for functionalisation

Article abstract of DOI:10.1039/c3cc46450d

2-Sulfonyl-oxetanes have been prepared, affording non-planar structures with desirable physicochemical properties for fragment based drug discovery. The oxetane motif was formed by an intramolecular C-C bond formation. The fragments were further functionalised via organometallic intermediates at the intact oxetane and aromatic rings. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc46450d

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2-(Aryl-sulfonyl)oxetanes as designer
3-dimensional fragments for fragment screening:
synthesis and strategies for functionalisation†
Kate F. Morgan,a Ian A. Hollingsworthb and James A. Bull*a
Cite this: Chem. Commun., 2014,
50, 5203
Received 23rd August 2013,
Accepted 24th October 2013
DOI: 10.1039/c3cc46450d
www.rsc.org/chemcomm
2-Sulfonyl-oxetanes have been prepared, affording non-planar struc- which can result in improved physicochemical and biochemical
tures with desirable physicochemical properties for fragment based drug properties relative to the parent molecule.12 Enhanced solubility,
discovery. The oxetane motif was formed by an intramolecular C–C reduced lipophilicity, reduced hERG liability as well as improved
bond formation. The fragments were further functionalised via organo- metabolic stability were observed as potential beneficial effects.
metallic intermediates at the intact oxetane and aromatic rings.
The oxetane motif is also found in several biologically active
natural products, such as oxetanocin, taxol and mitrophorone.13
Fragment based drug discovery (FBDD) is now a well-established As a result, oxetanes have recently received significant interest
approach in the development of new drugs and lead compounds.1 in medicinal chemistry.14
Fragments provide desirable starting points for discovery chemistry
We are interested in the preparation of novel non-planar frag-
that allow increases in MW and lipophilicity during the optimisation ments, with desirable properties, which contain biologically important
of potency and selectivity,2,3 whilst remaining in drug-like chemical motifs, and access new areas of chemical space.15 Consequently we
space.4 The design of fragment libraries is a crucial element to the designed 2-sulfonyl oxetanes (Fig. 1), as non-planar fragments to
success of screening. Although desirable criteria for properties of comply with the rule-of-3, modified for the number of hydrogen bond
fragments can vary by biological target, guidelines for ‘fragment space’ acceptors (HBA).16 We envisaged that these small and functional
proposed by Astex are widely cited (Rule-of-3: MW o 300, clog P r 3, group rich molecules, with the potential to make interesting inter-
number of H-bond donors–acceptors r3).5 It has recently been actions, would be desirable fragments for screening in drug discovery
suggested that the incorporation of more H-bond acceptors, up to or chemical biology programmes. In addition they would allow the
6, is advantageous in affording additional binding elements and structure to be ‘grown’ or ‘linked’ in several directions for optimisa-
further points for derivatisation during optimisation.6 Fragment tion, were they to be a hit. Here we report the synthesis of sulfonyl
screening samples a larger portion of available chemical space and oxetanes as well as their further functionalization.
as such FBDD is also a promising approach for complex and
The synthesis of oxetanes remains a challenge. Methods for the
challenging targets such as protein–protein interactions.7 Fragment synthesis of oxetanes are mostly limited to two general approaches:
libraries dominated by sp2 rich molecules have been less successful in photochemical Paterno–Bu¨chi [2+2] reactions of carbonyl com-
`
generating hits for these targets, suggesting more ‘3-dimensional’ pounds with alkenes,17 or intramolecular Williamson etherification
fragments are likely to be required.8 Indeed, more sp3-rich molecules (Fig. 2).11,18 Recently epoxide ring opening/ring closing has
and aliphatic heterocycles can offer improved levels of success been exploited as a facile route to the activated intermediate
through development, relative to highly aromatic compounds.9,10
Oxetanes have recently been highlighted as desirable low mole-
cular weight motifs for drug discovery.11 Carreira, Rogers-Evans,
Mu¨ller, and coworkers have shown an oxetane motif can act as an
isosteric, polar replacement for a gem-dimethyl group or a carbonyl,
a Department of Chemistry Imperial College London, South Kensington,
London SW7 2AZ, UK. E-mail: j.bull@imperial.ac.uk; Tel: +44 (0)207 594 5811
b AstraZeneca Mereside, Alderley Park, Cheshire, SK10 4TG, UK
† Electronic supplementary information (ESI) available: Additional details of
reaction optimisation, calculated molecular properties, experimental, character-
ization data and NMR spectra (1H and 13C) for all novel compounds. See DOI:
10.1039/c3cc46450d
Fig. 1 Sulfonyl-oxetane targets. MW = molecular weight; c log P = calcu-
lated log P (lipophilicity);‡ HAC = heavy atom count (number of non-H
atoms); HBD/A = number of hydrogen bond donors–acceptors.
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Table 1 Lithiation of sulfonyl oxetane 1a and reaction with electrophiles
Entry Electrophile (E+) Conditionsa
Yield (%)
Oxetane
1
2
MeI
MeI
A
B
93
71
5
6
Fig. 2 Approaches to 2-substituted oxetanes.
that undergoes etherification.19 Substituted oxetanes have also
been generated from exo-methylene oxetanes.20 However, these
approaches are unsuitable for our targets, particularly due to the
instability of the often required a-sulfonyl oxy-anion intermediate.21
To incorporate the 2-sulfonyl group, we envisaged a strategy
involving C–C bond formation, as opposed to the usual C–O
bond formation (Fig. 2, lower). While this approach is necessi-
tated in ring closure to form cyclobutanes and is known in the
synthesis of azetidines,22 it has not been exploited for oxetane
synthesis. For oxetanes, a comparable mode of cyclisation has
only been observed in intramolecular epoxide opening of lithiated
benzyl ethers, using LDA-KOtBu at À78 1C.23,24
3
4
EtI
A
A
85
91
Allyl bromide
7
5
B
B
8
9
90
The route developed to sulfonyl-oxetanes 1a–d is shown in
Scheme 1. The cyclisation precursors were accessed by alkylation of
ethylene glycol with chloromethyl aryl-sulfide to afford S,O-acetal 3,
using ethylene glycol as solvent to avoid double alkylation. Tosyla-
tion25 followed by oxidation with mCPBA afforded sulfone 4. The
6
86b
a
Conditions A: LiHMDS (1.2 equiv.), electrophile (2 equiv.) THF, À78 1C,
crucial step, the 4-exo-tet cyclisation, was optimised with 4a, 90 min; conditions B: nBuLi (1.3 equiv.), electrophile (2 equiv.) THF, À78 1C,
30 min. b Isolated as a mixture of diastereoisomers, d.r. = 1 : 0.9.
varying reaction temperature, time, base and equivalents, solvent
and concentration.26 Excellent yields were obtained using LiHMDS
focused on the functionalisation of this molecule as a way to access a
(1.1 equiv.) at 0 1C in THF. Under these conditions the reaction
variety of fragment-like, and larger lead-like compounds. Sulfones
was complete in 1 h, with the carbenoid-like organolithium inter-
can facilitate a wide array of transformations and here we envisaged
mediate stable to decomposition. Cyclisation did not occur at lower
they would allow functionalization of the intact oxetane ring by
temperatures and a larger excess of base led to decomposition of
metallation. Capriati and co-workers recently reported an efficient
the product. The route could be readily scaled and the cyclisation
route to 2-substituted phenyloxetanes via 2-lithio-2-phenyloxetane,
was performed on 6.5 mmol affording >1 g of oxetane 1a in 93%
formed by deprotonation with sBuLi, which was reacted with
yield. By this method the synthesis of oxetanes 1b–d, were similarly
electrophiles.27 We envisaged that the sulfonyl oxetane would
successful, modifying the size and electronics of the aromatic,
undergo regioselective deprotonation on the oxetane ring and this
including the incorporation of a pyridine ring.
was examined first. We investigated several bases to successfully
An important part of our design was the ability to ‘grow’ the
perform this deprotonation and identified 2 sets of reaction condi-
fragments by subsequent C–C bond formation in various directions.
tions that were appropriate for different electrophiles.26 The use of
Therefore, having validated the route to the sulfonyl oxetanes we
LiHMDS (1.2 equiv.) at À78 1C in THF afforded clean reactions
with compatible electrophiles (Table 1, conditions A). Under
these conditions methyl, ethyl and allyl groups were introduced
in excellent yield (entries 1, 3 and 4).16
A second set of conditions using nBuLi (Table 1, conditions B)
was more suitable for some electrophiles. These conditions were
successful using methyl iodide and 3-fluorobenzyl bromide
(entries 2 and 5). In addition, these conditions were successful
with iso-butyraldehyde, which was unsuccessful using the amide
base, to give oxetane 9 in high yield (entry 6).
Oxetane 5 was then derivatised at the aryl group by directed
ortho-metallation (Scheme 2). Snieckus has demonstrated
that tBu-aryl sulfones are powerful directing groups for ortho
metallation.28,29 Employing the Snieckus conditions using MeI
successfully afforded ortho-methylated oxetane 10.
Scheme 1 Synthetic route to sulfonyl oxetanes 1a–d via C–C bond
formation. a Reaction scale in parentheses: mmol of 4 employed.
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Finally we examined the cross-coupling of sulfonyl oxetane 1c
from the aryl chloride. The chloride substituent provides an inter-
esting potential binding element and also provides a route to further
derivatisation to access alkyl and aryl derivatives. Fu¨rstner recently
reported an iron-catalysed cross-coupling of Grignard reagents with
aryl chlorides.30 Employing Fu¨rstner’s conditions with 1c afforded
oxetanes 11 and 12 in good yields. Hexylmagnesium bromide and
propylmagnesium chloride were successfully cross-coupled, in the
presence of the acidic a-sulfonyl oxetane proton, and without notice-
able ring opening of the oxetane (Scheme 3, conditions a).
Suzuki cross-couplings of chloride 1c with boronic acids were
also successful using Buchwald’s SPhos ligand with Pd-catalysis
(Scheme 3, b).31 Electron-rich and electron-poor aromatic boronic
acids were successful, affording oxetanes 13–16.
In summary, here we report a new approach to the synthesis of
2-functionalised oxetanes that provides novel fragment-like com-
pounds. The initial fragments can be further elaborated through
lithiation on the oxetane ring itself, by directed ortho-metallation on
the aromatic, as well as by iron and palladium catalysed cross-
couplings of the aryl chloride. We are currently expanding the diversity
of small ring fragments that can be obtained by this approach and
developing enantioselective routes.
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For financial support we gratefully acknowledge the EPSRC
(Career Acceleration Fellowship to J.A.B., EP/J001538/1), Imperial
College London, and AstraZeneca for CASE funding. Thank you to
Prof Alan Armstrong for generous support and advice. We thank
EPSRC National Mass Spectrometry Facility, Swansea.
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