Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD)

Article abstract of DOI:10.1039/c5ob02461g

This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(iii) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.

Full text of DOI:10.1039/c5ob02461g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: D. rees, D.
Norton, N. Palmer and T. Peakman, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB02461G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 14
View Article Online
DOI: 10.1039/C5OB02461G
Journal Name
ARTICLE
Design and synthesis of dihydroisoquinolones for fragment-based
drug discovery (FBDD)
Received 00th January 20xx,
Accepted 00th January 20xx
Nick Palmer, Torren M Peakman, David Norton, David C Rees*
This study describes general synthesis aspects of fragments for FBDD, as illustrated by the
dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms
(N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for
fragment-to-lead elaboration.
DOI: 10.1039/x0xx00000x
www.rsc.org/
elaboration of low affinity (µM/mM) fragments into high affinity
(nM) leads using precisely controlled synthetic growth points
Introduction
(vectors) from predefined positions
.
Fragment-Based Drug Discovery
Table 1. Aspirational properties of many Astex fragments
.
FBDD is well-established within many Pharma, biotech and
academic institutions as a technology for generating new chemical
matter for drug discovery.1 Over 20 compounds derived from
fragment-based drug discovery (FBDD) are being evaluated in
clinical trials2 and the BRAF kinase inhibitor, vemurafenib (Zelboraf)
is a launched drug for late stage melanoma.3
Property
Guideline
Molecular
recognition
Diverse, usually polar groups for binding to a protein (a
single pharmacophore). An aspiration is to express any
given binding pharmacophore in a variety of chemotypes.
Synthetic
vectors
Multiple synthetically accessible positions for fragment
growth in 3 dimensions to form new binding interactions.
Organic chemistry is one of the enabling sciences required for FBDD
and has been critical for the successful development of this field
during the last decade. However, as FBDD has developed it has
Physicoꢀ
chemical
properties
Molecular weight: ~140ꢀ230;
Nonꢀhydrogen atoms: 10ꢀ16;
Lipophilicity (clogP): ~0.0 to 2.0;
Properties commensurate with biophysical screening at
high concentrations, e.g., aqueous solubility (preferably
≥5mM in 5% DMSO, or other screening coꢀsolvents);
stability (>24h in solution); avoid compounds/functional
groups known to be associated with high reactivity,
aggregation in solution, or false positives.7 NB: aromatic Cꢀ
H bonds may assist NMR screening.
unearthed
a pressing need to design and synthesise more
fragments and to develop new synthetic methodology to convert
fragments into leads. The successful prosecution of FBDD projects
often requires new organic synthesis methodology which, not
surprisingly, is frequently time-critical. This is increasingly an issue
as more difficult protein drug discovery targets are screened. There
are two areas in particular that need synthetic methodology
research: 1) the design and synthesis of new fragments and 2) the
Synthetic
tractability
Typically, ~50ꢀ100mg and ≤4 steps from commercially
available reagents
Shape
Variety of 2ꢀ and 3ꢀdimensional shapes for each scaffold
and pharmacophore;
Number of freely rotatable bonds: 0ꢀ3;
Number of chiral centres: 0ꢀ1, sometimes 2
Compared to drugs or high throughput screening (HTS) compounds,
fragments are small, simple molecules. A key advantage of
screening low MW fragments (in comparison with higher MW,
HTS-like compounds) is the improved hit rate resulting from
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
Journal Name
screening such small compounds. Fragments are designed to campaign. Furthermore, compounds 2 and 3 are attractive as
form efficient binding interactions with protein targets but, due to fragments in their own right due to:
their small size, the typical binding affinity of a fragment is only mM
or µM. Table 14 summarises guidelines indicating some of the
•
low MW (177, 204 respectively) and low cLogP (0.32,
1.3 respectively)
chemical properties that we use today as part of the selection
process for adding new fragments into the Astex screening library.
These guidelines have evolved significantly compared to earlier
descriptions of fragments as a result of 10 years of screening
fragments by X-ray crystallography and other biophysical
•
•
•
sufficient aqueous solubility (>5mM) for screening
polar H-bonding groups (amide + alcohol/amine)
numerous positions available for synthetic
elaboration (fragment-to-lead stage)
techniques.5
There are many other publications describing
fragment library design6 and there are fragments with properties
outside those listed in Table 1 that have been used to generate
useful leads, so this is still an emerging area.
Thus, we selected the dihydroisoquinolones 2 and 3 as
prototype examples to develop an FBDD-friendly synthetic
methodology. The synthesis of fragment 2 has been reported
previously using Rh(III) catalysed C-H bond activation
methodology (Figure 2).9
To grow fragments into leads requires the incorporation of
additional binding groups to interact with the protein target.
For this, it is desirable to rapidly elaborate the fragment in any
Figure 2: Previously published synthesis of dihydro-
direction with either polar or non-polar groups, ideally with isoquinolones utilising Rh(III) catalytic C-H activation.9, 10c
regio- and stereo-control utilising synthetic methodology that
has been worked out in advance. These requirements place big
demands on synthetic methodology and represent an
opportunity to significantly improve FBDD.
Selection of dihydroisoquinolones as fragments
Dihydroisoquinolone (1, Figure 1) is a simple, small molecule
(MW = 147, cLogP = 1.0) and contains a strong hydrogen-
bonding motif in the form of the cis-amide. Low complexity8
plus a polar binding motif are important factors to increase the
probability of a fragment being a screening hit. The related
fragments 2 and 3 are examples of compounds that could be
made after 1 is identified as a fragment hit from a screening
This synthesis uses readily available starting materials;
proceeds at room temperature with no requirement to
exclude air; is amenable to >100mg scale and frequently the
two regioisomers (a and b) can be separated by
chromatography. Whilst both of these regioisomers meet
many of the guidelines in Table 1 we prefer fragments not to
have distally separated polar binding groups hence we prefer
isomer (a) for FBDD. The methodology in Figure 2 utilises
catalytic rhodium C-H bond activation and has been developed
in several subsequent publications10. The mechanism is
thought to involve metal coordination to the nitrogen moiety
which directs cyclometalation to the ortho C-H bond. Alkene
insertion occurs via coordination to the metal and the acyl
protecting group acts as an internal oxidant. This methodology
has also been reported with alkynes leading to isoquinolones
Figure 1: Dihydroisoquinolones with attractive fragment-like
properties. ‡
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 14
Journal Name
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
and
extended
to
substituted
alkenes
(for
Results and discussion
dihydroisoquinolones).9-10,
The versatility of the
11
methodology is further illustrated with other publications that
describe, for related systems, chiral induction at the
asymmetric carbon utilising an engineered metalloenzyme10d,
Use of substituted alkenes to give polar functionality for
protein binding and/or further synthetic elaboration (Table 2)
10e 12
or controlling the ratio of the two regioisomers by
modulating the steric properties of the Rh(III) catalyst10b
Compound
4
is readily available following literature
.
procedures10c and was used to explore reactions with mono
substituted alkenes. The alkenes selected were chosen to
expand those previously described in the literature and allow
introduction of new (protected) functional groups useful for
subsequent transformations or protein binding interactions.
Extending the dihydroisoquinolone methodology for FBDD
Despite the modern synthetic methodology of Figure 2 and the
attractive fragment properties, we perceived some additional
requirements from an FBDD perspective. Firstly, many drugs
contain amino groups or heterocyclic aromatic rings.
Fortunately, some methodology for incorporating heteroatoms
into compounds related to 2 is known10a, 10b and we sought to
Table 2 Reaction with functionalised alkenes
apply
this
methodology
to
the
functionalised
dihydroisoquinolone fragments. Secondly, our FBDD projects
are frequently challenged by having to work out methodology
to access synthetic growth points or vectors in 3D space. One
fragment may bind to different protein targets, requiring
different synthetic vectors in each case, as deduced by
examining the protein-fragment X-ray crystal structure. An
attraction of the dihydroisoquinolone fragment template is the
numerous positions available for synthetic elaboration during
the fragment-to-lead stage; these are shown in Figure 3 as
blue arrows. The Rh(III) methodology has already been shown
Alkene
Product a
Product b
Isolated
yield %
Regio-
selectivity
(ratio a:b
estimated
by NMR)
59
>20:1
1:1
a+b: 93
O
NH
H
N
O
6a:42
6b:42
1:1
to permit several of these growth points into Fragment 2.9-10,
O
6a
10c-e
63
74
>20:1
>20:1
Figure 3: Schematic representation of synthetic elaboration of
fragment 1. Growth positions are shown as blue arrows and the
incorporation of aromatic heteroatoms and polar binding groups
are indicated.
Reaction with N,N-dimethyl allylamine gives a single regioisomeric
product, 3 (59% after 24h, note long time required possibly due to
the basic amine coordinating to the catalyst). This is the first
example that we are aware of where an amino substituted alkene is
used in this procedure. Compound 3 is interesting as a fragment
itself, HAC = 15, MW = 204, clogP = 1.3, measured solubility ≥ 5
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
Journal Name
mM, (Figure 1).
This led us to explore this alkene in more We selected aromatic bromides and esters for incorporation into
functionalised systems (see Tables 3, 4).
the hydroxamates to probe the methodology for fragment-to-lead
elaboration (table 3). Note that compounds 13-16 are not designed
to be fragments themselves. Rather, their synthesis builds
confidence that if fragment 3 binds to a protein with an interaction
that shows opportunity for elaboration via the meta or para
positions, synthetic methodology is already established to follow-up
rapidly.
The silyl protected allyl alcohol and Boc protected allyl amine
gave the cyclised products 5a,b and 6a,b respectively as 1:1
mixtures of regioisomers in good yields. These protected
hydroxyl and amino substituted analogues can be deprotected
to provide groups capable of forming new polar binding
interactions and/or synthetic growth vectors.
Benzyl
substituted acrylamide gives a single regioisomer, 7a (63%). Modest to good yields and a single regioisomer are observed for 13,
This is the first example that we are aware of using an amide in 14, 16. The meta-bromo substituted analogue 10 gave a small
this transformation (but note that 7a has been synthesised amount of product corresponding to cyclisation onto the position
previously by a different route13 and is commercially available ortho to the bromine. This product was not isolated in a pure form,
in milligram quantities). If this growth vector is required, the but 1H NMR of a mixed fraction was consistent with this isomer (see
formation of a single regioisomer is an advantage. Acrolein supporting information).
diethylacetal gives a single regioisomer, 8a (74%) and again the
There is some precedent for using the para-methyl ester
protected aldehyde can provide a handle for a range of
substituted hydroxamate, 1110c,
but the meta-methyl ester
14
subsequent transformations.
substituted hydroxamate, 12 has not been reported previously.
Table 3. Ar-substituted hydroxamates plus N,N-dimethyl
allylamine
In our hands preliminary attempts to cyclise with ortho Br or OMe
substituted hydroxamates were unsuccessful perhaps due to
unfavourable steric interactions between the ortho substituent and
the hydroxamate carbonyl (data not shown). An ortho iodide
substituent on a closely related system has been reported15 but
this remains an area requiring additional research.
Application of methodology to heteroaromatic analogues
(Table 4 and Scheme 1)
Hydroxamate
Product
Isolated
yield %
O
NH
54
53
N
Incorporating heteroatoms into aromatic rings of fragments is
highly desirable in order to: modulate physicochemical properties
(cLogP, solubility etc); probe fragment binding interactions; increase
opportunities for fragment-to-lead synthetic elaboration, and to
subtly alter the growth vectors. Hence, we turned investigated
three heterocycles commonly found in biologically active leads and
drugs: thiophenes, thiazoles and pyridines.
Br
13
84
56
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 14
View Article Online
DOI: 10.1039/C5OB02461G
Journal Name
ARTICLE
Table 4. Thiophene analogues
N,N-dimethyl allyl amine reacted with both the substituted and
unsubstituted thiophenes to give 19a and 22a (31, 30% yields
unoptimised). Compound 19a can be considered as a fragment
itself (HAC = 14, MW = 210, clogP = 1.1) and since aromatic
sulphurs are known to form binding interactions with carbonyls
they provide an additional protein binding possibility. Reaction of
the thiophene hydroxamates 17 and 18 with the TBDMS protected
allyl alcohol gives 20a,b and 23a,b respectively and Boc protected
allyl amine gives 21a,b and 24a,b in good yields and with a similar
isomer ratio.
Hydrox
-amate
Isolated
yield %
Regio
Selectivity
(ratio a:b)
Product
a
Product b
R = H
R = H
31
8:1*
1:2
Scheme 1
a
b
:24
:55
a
b
:27
:52
R = H
1:2
>20:1
1:1
30
R= Br
R = Br
a
+
b
:52
Scheme 1 extends the method to thiazoles. The chloro thiazole
hydroxamate, 25 was prepared using the standard conditions and
treatment with TBDMS protected allyl alcohol generated the two
expected isomers 26a and 26b in a 1:4 ratio. Removal of the silyl
group produced a mixture of regioisomers that could be separated
into 27a and 27b, albeit in low yield (4% and 42% respectively)
(Scheme 1). Unoptimised attempts to use N,N-dimethyl allyl amine
failed in this reaction. The TBDMS-protected alkene also reacted
with the unsubstituted thiazole 28, although the unoptimised yield
of 29a,b was low (16%) and regioisomer b is the major product.
a
b
:25
:29
1:1
R = Br
* isomer ratio determined by LCMS, minor isomer not isolated.
There are a few reports of the Rh(III) methodology being applied to
thiophenes11 and pyridines16 (compound 17 has been used with a
vinyl ester11) but from a fragment perspective the scope of the
methodology is limited and we are not aware of thiazoles being
used previously.
Based upon literature precedent this methodology was known to be
less suitable for pyridyl analogues due to the lower reactivity of
these electron deficient systems and formation of regioisomer
mixtures. This has been overcome to some extent by the use of a
The thiophenes in Table 4 are derivatised with the same (protected)
polar groups used above: amines, alcohols and amides. The
aromatic bromo substituents provide potential synthetic growth
points for the fragment-to-lead stage.
pyridine N-oxide to increase the reactivity of the pyridine ring10a
.
Compound 30 (Scheme 1), synthesised following standard
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
Journal Name
procedures, was treated with N,N-dimethyl allylamine to give a
mixture of isomers and 31 was isolated by preparative HPLC but the
(unoptimised) yield is only 8% and as previously noted, higher
catalyst loading was used. Our results indicate that this
methodology is not yet ideal for heterocycles and given their
importance in drug discovery this is another area that would benefit
from additional research.
•
•
Synthetic methodology that is not exemplified for water
soluble compounds (we require low lipophilicity, Table 1).
Requirement for multiple, synthetically accessible
fragment growth positions (Figure 3) and methodology
that allows regio- and stereo- selective fragment growth
in the presence of polar functionality.
Some of the chemistry methodology challenges for FBDD are similar
to other drug discovery techniques including HTS, e.g. the desire to
incorporate polar side chains and heteroatoms into lead
molecules17. Others, such as the small size and lipophilicity of
fragments; the requirement for synthetic vectors in multiple
directions; and the drive to use X-ray crystallography to design
bespoke synthetic targets, are more evident in FBDD laboratories.
We see a pressing need for even more synthetic organic chemists to
engage with these challenges.
Conclusions
The emergence of FBDD has created new demands for organic
synthesis. Despite the apparent simplicity of fragment-like
compounds they present significant and growing challenges, e.g.,
methodology to design and synthesise new fragments and
methodology to grow fragments into high affinity chemical leads via
synthetic growth points (vectors) according to the particular
fragment-protein binding interactions. These two aspects are
frequently rate limiting in FBDD.
Experimental
General Experimental
All reactions were carried out without exclusion of air or moisture
unless otherwise stated. Commercial solvents and reagents were
used without further purification. Reactions were monitored by
HPLC-MS on an Agilent 1200 series instrument, coupled with an
Agilent 1200 MWD SL UV detector and Agilent 6140 single
quadrupole mass detector. Normal phase flash chromatography
was performed using a Biotage Isolera and silica SNAP cartridges.
Petrol refers to petroleum ether (b.p. 40-60°C). Reverse phase
chromatography was performed using a Biotage SP4 and Biotage
C18 Ultra cartridges with an acetonitrile in water gradient, without
use of modifiers. Preparative HPLC was performed on an Agilent
1260 instrument, using Waters prep columns (Atlantis prep T3 OBD
5µm 100x19mm, Sunfire prep C18 OBD 5µm 100x19mm or XBridge
C18 5µm OBD 100x19mm). HRMS (ESI) spectra were recorded on
an Agilent 6550 QTOF instrument.
This study identified the dihydroisoquinolones, 1-3 as having
attractive fragment-like chemical properties (see Table 1).
A
published method to synthesise compound
2 utilising Rh(III)
10c
catalysed C-H bond activation9,
has been extended to increase
the utility of this template for fragment-based drug discovery. We
have focused on:
•
Adding polar side chains capable of exploring new binding
interactions with proteins (tertiary amines and protected
amines, alcohols and amides)
•
•
Incorporating S and N heteroatoms into the aromatic ring
to modulate logP, solubility, synthetic growth vectors etc.
Adding functional groups that can be used as synthetic
points for fragment growth during fragment-to-lead
optimisation (aromatic bromides and esters)
1H, 13C, 13C-Dept, COSY, HSQC and HMBC NMR spectra were
recorded using Bruker 400 MHz or 500MHz spectrometers (CDCl3 or
d6-DMSO as solvent). Chemical shifts for 1H and 13C NMR spectra
are reported as δ in units of parts per million (ppm) downfield from
SiMe4 (δ 0.0) using the chemical shifts of the residual solvent peaks.
These results illustrate frequently encountered synthetic organic
chemistry challenges that we face in FBDD including:
•
Synthetic methodology that is not exemplified in the
presence of heterocyclic aromatics and polar functional
groups e.g. amines.
Multiplicities are given as:
s (singlet); brs (broad singlet); d
(doublet); t (triplet); q (quartet); dd (doublets of doublet); td (triplet
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 14
Journal Name
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
of doublet); m (multiplets) etc. Coupling constants are reported as J in an ice bath then pivaloyl chloride (1.79 mL, 14.59 mmol, 1 equiv.)
values in Hz. 13C chemical shifts were measured using direct 13C was added dropwise. The resulting mixture was allowed to warm
NMR or via 2D HSQC and HMBC spectra.
to room temperature and stirred for 2 hours. The reaction was
diluted with DCM, transferred to a separating funnel and washed
Preparation of N-pivaloyloxy amide starting materials. General with water then brine. The organic layer was dried over MgSO4,
Procedure A:
filtered and evaporated under reduced pressure. The crude
Step 1: To a suspension of the carboxylic acid (20 mmol, 1.0
eq.) in dry CH2Cl2 (20 mL) at room temperature under a
nitrogen atmosphere was added a catalytic amount of dry
DMF (4 drops). Oxalyl chloride (15 mL, 30 mmol, 1.5 eq., 2M
soln in DCM) was added dropwise over about 20 minutes with
care as effervescence occurs. The reaction was allowed to stir
at room temperature until completion which was judged to be
when no further effervescence could be seen and in some
cases, the solution became homogeneous. The solvent was
then removed under reduced pressure to afford the
corresponding crude acid chloride.
material was purified by flash chromatography using a gradient of
0-30% ethyl acetate in petrol as eluent. The product was obtained
as a white solid (2.4 g, 74% yield). δ H (400 MHz, Chloroform-d) 9.43
(1 H, s), 7.89 – 7.72 (2 H, m), 7.62 – 7.50 (1 H, m), 7.50 – 7.38 (2 H,
m), 1.35 (9 H, s). δ (101 MHz, Chloroform-d) 177.17, 166.92,
C
132.81, 131.08, 128.93, 127.61, 38.61, 27.17.
(4-Bromophenyl)formamido 2,2-dimethylpropanoate
(9)11
Synthesised according to general procedure A, step 2 on a 20 mmol
scale, starting with commercially available acid chloride. The crude
material was purified by flash chromatography using a gradient of
0-20% ethyl acetate in petrol as eluent. The product was obtained
as a white solid (4.8 g, 80% yield). δ H (400 MHz, DMSO-d6) 12.37 (1
H, s), 7.75 (4 H, s), 1.28 (9 H, s).
Step 2: Hydroxylamine hydrochloride (1.39 g, 20 mmol, 1 eq.)
was added to a biphasic mixture of K2CO3 (5.52 g, 20 mmol, 2.0
eq.) in a 2:1 mixture of EtOAc (40 mL) and H2O (20 mL). The
resulting solution was cooled to 0°C followed by dropwise
addition of the crude acid chloride dissolved in a minimum
amount of EtOAc. The flask containing the acid chloride was
then rinsed with additional EtOAc. The reaction was allowed
to warm to room temperature which in most cases resulted in
formation of a thick white suspension of the hydroxamic acid.
The reaction was stirred for 4h to allow complete conversion
of the acid chloride to hydroxamic acid then pivaloyl chloride
(2.46 ml, 20 mmol) was added dropwise. The reaction can be
monitored by TLC and HPLC and also the thick white
precipitate dissolves as the reaction proceeds and the
hydroxamic acid is consumed. Further pivaloyl chloride can be
added if required. The phases were separated and the
16
(3-Bromophenyl)formamido 2,2-dimethylpropanoate (10)11,
Synthesised according to general procedure A, step 2 on a 20 mmol
scale, starting with commercially available acid chloride. The crude
material was purified by flash chromatography using a gradient of
0-30% ethyl acetate in petrol as eluent then recrystallised from
Et2O/petrol. The product was obtained as a white solid (2.4 g, 40%
yield). δ H (400 MHz, DMSO-d6) 12.41 (1 H, brs), 7.97 (1 H, t, J 1.9),
7.82 (2 H, dd, J 7.9, 1.9), 7.50 (1 H, t, J 7.9), 1.29 (9 H, s).
Methyl 4-{[(2,2-dimethylpropanoyl)oxy]carbamoyl}benzoate
(11) Synthesised according to general procedure A on a 20 mmol
scale, starting with commercially available carboxylic acid. The
crude material was purified by flash chromatography using a
gradient of 0-30% ethyl acetate in petrol as eluent. The product was
obtained as a white solid (2.837 g, 50% yield over 3 steps). δ H (400
MHz, DMSO-d6) 12.47 (1 H, brs), 8.18 – 8.02 (2 H, m), 8.02 – 7.87 (2
aqueous phase was extracted twice with EtOAc.
The
combined organic layers were dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude products were
purified by flash column chromatography using an appropriate
solvent mixture of petrol/EtOAc as eluent.
H, m), 3.89 (3 H, s), 1.29 (9 H, s). δ (101 MHz, DMSO-d6) 175.51,
C
165.49, 163.60, 135.15, 132.61, 129.36, 127.71, 52.39, 37.78, 26.76.
HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H17NO5 280.1185;
found: 279.1122 δ = 3.57 ppm.
Phenylformamido 2,2-dimethylpropanoate (4)18
amine (2.03 ml, 14.59 mmol, 1 equiv.) was added to a suspension of
N-hydroxybenzamide (2.0 g, 14.59 mmol, equiv.) in
Triethyl
1
dichloromethane (30 mL). The reaction mixture was cooled to 0oC
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
Methyl 3-{[(2,2-dimethylpropanoyl)oxy]carbamoyl}benzoate
Journal Name
(2-Chloro-1,3-thiazol-5-yl)formamido 2,2-dimethylpropanoate
(12)11 Synthesised according to general procedure A on a 20 mmol (25) Synthesised according to general procedure A on a 12 mmol
scale, starting with commercially available carboxylic acid. The scale, starting with commercially available carboxylic acid. The
crude material was purified by flash chromatography using a crude material was purified by flash chromatography using a
gradient of 0-30% ethyl acetate in petrol as eluent. The product was gradient of 0-50% ethyl acetate in petrol as eluent. The product
1
obtained as a white solid (1.477 g, 26% yield over 3 steps). H NMR obtained is an off white solid (1.818 g, 57% yield over 3 steps). δ
H
(400 MHz, DMSO-d6) δ 12.49 (1 H, brs), 8.42 (1 H, t, J 1.6), 8.16 (1 H, (400 MHz, DMSO-d6) 12.69 (1 H, brs), 8.21 (1 H, s), 1.27 (9 H, s). δ C
dt, J 7.9, 1.6), 8.08 (1 H, dt, J 7.9, 1.6), 7.69 (1 H, t, J 7.9), 3.90 (3 H, (101 MHz, DMSO-d6) 175.36, 157.11, 154.70, 142.98, 133.24, 37.80,
s), 1.29 (9 H, s). 13C NMR (101 MHz, DMSO-d6) δ 175.57, 165.48, 26.67. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C9H11ClN2O3S
163.53, 132.54, 131.90, 131.64, 130.04, 129.33, 127.92, 52.37, 263.0252; found: 263.0261. δ = 3.42 ppm.
37.78, 26.76. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H17NO5
(1,3-Thiazol-5-yl)formamido 2,2-dimethylpropanoate (28)
280.1185; found: 280.1197. δ = 4.28 ppm.
Synthesised according to general procedure A, step 2 on a 15.5
(Thiophen-2-yl)formamido 2,2-dimethylpropanoate
(17) mmol scale, starting with commercially available acid chloride. The
Triethyl amine (0.972 ml, 6.99 mmol, 1 equiv.) was added to a crude material was purified by flash chromatography using a
suspension of N-hydroxythiophene-2-carboxamide (1.0 g, 6.99 gradient of 0-100% ethyl acetate in petrol as eluent. The product
mmol, 1 equiv.) in THF (10 mL). The reaction mixture was cooled to obtained is a yellow oil (0.502 g, 14% yield). δ (400 MHz, DMSO-
H
0oC in an ice bath then pivaloyl chloride (0.86 mL, 6.99 mmol, 1 d6) 9.75 (1 H, brs), 9.20 (1 H, d, J 0.7), 8.32 (1 H, d, J 0.7), 1.25 (9 H,
equiv.) was added dropwise. The resulting mixture was allowed to s). δ C (101 MHz, DMSO-d6) 175.51, 158.92, 157.47, 143.90, 132.64,
warm to room temperature and stirred for 2 hours. The reaction 37.82, 26.90. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C9H12N2O3S
was diluted with EtOAc, transferred to a separating funnel and 229.0641; found: 228.0578. δ = 4.37 ppm.
washed with water then brine. The organic layer was dried over
(2-Bromopyridin-4-yl)formamido 2,2-dimethylpropanoate (30)
MgSO4, filtered and evaporated under reduced pressure. The crude
Synthesised according to general procedure A on a 20 mmol scale,
material was purified by flash chromatography using a gradient of
starting with commercially available carboxylic acid. The crude
0-30% ethyl acetate in petrol as eluent. The product was obtained
material was purified by flash chromatography using a gradient of
as an off-white solid (1.22 g, 77% yield). δ (400 MHz, DMSO-d6)
H
0-20% ethyl acetate in petrol as eluent. The product was obtained
12.25 (1 H, brs), 7.88 (1 H, dd, J 5.0, 1.2), 7.74 (1 H, dd, J 3.7, 1.2),
as an off-white solid (2.21 g, 36% yield over 3 steps). δ H (400 MHz,
7.20 (1 H, dd, J 5.0, 3.7), 1.28 (9 H, s). δ (101 MHz, DMSO-d6)
C
DMSO-d6) 12.75 (1 H, brs), 8.60 (1 H, dd, J 5.1, 0.8), 7.94 (1 H, brs),
175.67, 159.83, 134.95, 131.96, 129.38, 128.12, 37.75, 26.75. HRMS
7.76 (1 H, dd, J 5.1, 1.5), 1.29 (9 H, s). δ (101 MHz, DMSO-d6)
C
(ESI-QTOF): m/z [M+H]⁺ Calcd for C10H13NO3S 228.0689; found:
175.24, 161.05, 151.53, 141.87, 141.20, 125.48, 120.96, 37.81,
228.0692. δ = 1.32 ppm.
26.69. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C11H13BrN2O3
(4-Bromothiophen-2-yl)formamido 2,2-dimethylpropanoate 301.0182; found: 301.0194. δ = 3.99 ppm.
(18) Synthesised according to general procedure A, step 2 on a 9.66
Synthesis of 3,4 Dihydroisoquinolones.
mmol scale, starting with commercially available acid chloride. The
crude material was purified by flash chromatography using a
General Procedure B: Without any particular precautions to
gradient of 0-30% ethyl acetate in petrol as eluent. The product was
exclude oxygen or moisture, the pivaloyl-protected hydroxamic acid
obtained as an off-white solid (1.5 g, 50% yield). δ (400 MHz,
H
(1 equiv.), [Cp*RhCl2] 2 (1 mol%) and CsOAc (2 equiv.) were weighed
DMSO-d6) 12.43 (1 H, brs), 8.03 (1 H, d, J 1.5), 7.72 (1 H, d, J 1.5),
into a 5 mL CEM microwave tube equipped with a stirrer bar.
1.28 (9 H, s). δ C (101 MHz, DMSO) 176.03, 158.91, 136.76, 131.55,
MeOH (0.2 M) was then added followed immediately by the alkene
130.27, 109.61, 38.29, 27.22. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd
(1.1 equiv.). The reaction was stirred at room temperature for 16
hours or if necessary, heated up to 65oC in the CEM microwave for
for C10H12BrNO3S 305.9794; found: 305.9802. δ = 2.61 ppm.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 14
Journal Name
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
between 2-7 hours. The reaction was diluted with EtOAc washed 5.45. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C₁₆H₂₅NO₂Si 292.1728;
with Na2CO3 sat. aq. then brine. The combined organic layers were found 292.1736. δ = 2.53 ppm.
dried over MgSO4, filtered and evaporated under reduced pressure.
4-{[(Tert-butyldimethylsilyl)oxy]methyl}-1,2,3,4-
The crude products were purified by flash column chromatography
tetrahydroisoquinolin-1-one (5b) See above.
δ
(400 MHz,
H
on a Biotage using an appropriate solvent mixture of petrol/EtOAc
or EtOAc/MeOH as eluent.
Chloroform-d) 8.08 (1 H, dd, J 7.6, 1.5), 7.47 (1 H, td, J 7.6, 1.5), 7.38
(1 H, td, J 7.6, 1.5), 7.27 – 7.21 (1 H, m), 5.96 (1 H, brs), 3.75 (1 H,
dd, J 13.6, 10.0), 3.70 - 3.66 (2 H, m), 3.66 (1 H, dd, J 10.0, 5.4), 3.08
3-[(Dimethylamino)methyl]-1,2,3,4-tetrahydroisoquinolin-1-
one (3) Synthesised following general procedure B. The reaction – 2.97 (1 H, m), 0.89 (9 H, s), 0.03 (3 H, s), 0.03 (3 H, s). δ (101
C
was carried out at room temperature and the crude material was MHz, CDCl3) 165.74, 137.25, 132.26, 128.69, 128.14, 127.77,
purified by flash column chromatography using a gradient of 0-10% 127.53, 63.58, 40.61, 40.78, 25.83, 18.27, -5.45. HRMS (ESI-QTOF):
MeOH in EtOAc. The desired compound was obtained as a brown m/z [M+H]⁺ Calcd for C₁₆H₂₅NO₂Si 292.1728; found 292.1736. δ =
solid in 59% yield (55 mg) from phenylformamido 2,2- 2.62 ppm.
dimethylpropanoate (4) (0.45 mmol, 100 mg, 1 equiv.). δ (400
H
Tert-butyl
N-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-
MHz, DMSO-d6) 7.88 – 7.81 (1 H, m), 7.48 (1 H, td, J 7.5, 1.5), 7.41 (1
H, brs), 7.37 – 7.32 (1 H, m), 7.32 – 7.28 (1 H, m), 3.72 (1 H, dtdd, J
9.0, 7.1, 4.8, 2.1), 3.01 (1 H, dd, J 15.8, 4.8), 2.79 (1 H, dd, J 15.8,
9.0), 2.35 (1 H, dd, J 12.0, 7.1), 2.27 (1 H, dd, J 12.0, 7.1), 2.18 (s,
yl)methyl]carbamate (6a) Synthesised following general procedure
B. The reaction was carried out at room temperature and the crude
material was purified by flash column chromatography using a
gradient of 0-50% EtOAc in petrol. The desired compound was
6H). δ (101 MHz, DMSO-d6) 164.60, 138.50, 132.37, 129.04,
C
obtained as
a white solid in 42% yield (53 mg) from
128.24, 127.38, 127.13, 63.28, 48.24, 45.98, 31.90. HRMS (ESI-
phenylformamido 2,2-dimethylpropanoate (4) (0.45 mmol, 100 mg,
QTOF): m/z [M+H]⁺ Calcd for
205.1349. δ = 6.82 ppm.
C12H16N2O 205.1335; found:
1 equiv.). δ (400 MHz, DMSO-d6) 7.82 (1 H, dd, J 7.5, 1.5), 7.80 –
H
7.75 (1 H, m), 7.47 (1 H, td, J 7.5, 1.5), 7.33 (1 H, td, J 7.5, 1.2), 7.28
(1 H, d, J 7.5), 6.96 (1 H, t, J 5.9), 3.66 – 3.47 (1 H, m), 3.12 – 2.98 (2
3-{[(Tert-butyldimethylsilyl)oxy]methyl}-1,2,3,4-
tetrahydroisoquinolin-1-one (5a) Synthesised following general H, m), 2.97 (1 H, dd, J 16.0, 5.2), 2.76 (1 H, dd, J 16.0, 8.2), 1.38 (9 H,
procedure B. The reaction was carried out at room temperature s). δ C (101 MHz, DMSO-d6) 164.02, 155.62, 137.52, 131.65, 128.53,
and the crude material was purified by flash column 127.79, 126.60, 126.44, 77.86, 50.16, 43.34, 30.34, 27.94. HRMS
chromatography using a gradient of 0-50% EtOAc in petrol. The (ESI-QTOF): m/z [M+H]⁺ Calcd for C15H20N2O3 277.1547; found:
desired compound was obtained as a 1:1 mixture of regioisomers 277.1558. δ = 3.97 ppm.
(5a and 5b) that were inseparable by column chromatography. The
Tert-butyl
N-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-
mixture was a white solid, 93% combined yield (123 mg) from
phenylformamido 2,2-dimethylpropanoate (4) (0.45 mmol, 100 mg,
1 equiv.). Partial separation of the regioisomers was possible by
reverse phase chromatography, eluting 45-65 % MeCN in water to
give isomer 5a (18mg) plus 5b (16 mg) in pure form with a mixed
yl)methyl]carbamate (6b) Synthesis and purification described for
6a. Compound 6b was obtained as a white solid in 42% yield (54
mg) from phenylformamido 2,2-dimethylpropanoate (4) (0.45
mmol, 100 mg, 1 equiv.). δ (400 MHz, DMSO-d6) 7.85 (1 H, dd, J
H
7.6, 1.5), 7.74 (1 H, d, J 4.4), 7.49 (1 H, td, J 7.6, 1.5), 7.37 (1 H, td, J
7.6, 1.3), 7.27 (1 H, d, J 7.6), 7.03 (1 H, t, J 5.4), 3.48 (1 H, dd, J 12.7,
4.4), 3.31 - 3.23 (1 H, m), 3.15 – 3.05 (2 H, m), 3.03 - 2.94 (1 H, m),
fraction (60mg). δ (400 MHz, Chloroform-d) 8.08 (1 H, dd, J 7.6,
H
1.5), 7.44 (1 H, td, J 7.6, 1.5), 7.39 – 7.30 (1 H, m), 7.22 – 7.16 (1 H,
m), 6.25 (1 H, brs), 3.87 – 3.78 (1 H, m), 3.74 (1 H, dd, J 10.0, 1.0),
3.60 (1 H, dd, J 10.0, 8.4), 2.93 – 2.77 (2 H, m), 0.90 (9 H, s), 0.08 (3
1.37 (9 H, s). δ (101 MHz, DMSO-d6) 163.80, 155.46, 140.29,
C
131.48, 128.61, 126.91, 126.81, 127.36, 77.61, 40.67, 42.22, 36.89,
28.00. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C15H20N2O3
277.1547; found: 277.155. δ = 1.08 ppm.
H, s), 0.07 (3 H, s). δ (101 MHz, CDCl3) 165.74, 137.25, 132.26,
C
128.69, 128.14, 127.46, 127.08, 65.66, 52.68, 30.27, 25.83, 18.27, -
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
N-Benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
Journal Name
7.1), 2.16 (6 H, s). δ (101 MHz, DMSO-d6) 163.22, 140.42, 130.29,
C
(7a) Synthesised following general procedure B. The reaction was 129.50, 128.88, 128.33, 125.44, 62.44, 47.51, 45.25, 30.78. HRMS
carried out at room temperature and the crude material was (ESI-QTOF): m/z [M+H]⁺ Calcd for C12H15BrN2O 283.0441; found:
purified by flash column chromatography using a gradient of 0-50% 283.0448. δ = 2.47 ppm.
EtOAc in petrol. The desired compound was obtained as a white
Methyl
3-[(dimethylamino)methyl]-1-oxo-1,2,3,4-
solid in 63% yield (40 mg) from phenylformamido 2,2-
tetrahydroisoquinoline-6-carboxylate (14) Synthesised following
general procedure B. The reaction was carried out at room
temperature and the crude material was purified by flash column
chromatography using a gradient of 0-10% MeOH in EtOAc. The
desired compound was obtained as a brown solid in 84% yield (100
dimethylpropanoate (4) (0.225 mmol, 50 mg, 1 equiv.). δ (500
H
MHz, , DMSO-d6) 8.50 (1 H, t, J 6.0), 7.98 (1 H, d, J 4.1), 7.83 (1 H,
dd, J 7.6, 1.5), 7.47 (1 H, td, J 7.6, 1.5), 7.35 (1 H, t, J 7.6), 7.27 (1 H,
d, J 7.6), 7.25 – 7.15 (3 H, m), 7.09 – 6.98 (2 H, m), 4.32 – 4.12 (3 H,
m), 3.29 (1 H, dd, J 16.0, 6.3), 3.16 (1 H, dd, J 16.0, 4.4). δ (126
C
mg)
from
methyl
4-{[(2,2-
MHz, DMSO-d6) 170.70, 164.21, 139.12, 136.63, 131.57, 129.01,
127.92, 127.42, 126.67, 126.63, 126.59, 126.46, 52.69, 41.89, 30.98.
HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C17H16N2O2 281.1285;
found: 281.1298. δ = 4.62 ppm.
dimethylpropanoyl)oxy]carbamoyl}benzoate (11) (0.45 mmol, 125
mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 7.96 (1 H, dd, J 7.9, 0.7), 7.93
– 7.86 (2 H, m), 7.72 – 7.61 (1 H, m), 3.87 (3 H, s), 3.74 (1 H, dtdd, J
8.5, 7.2, 4.9, 2.3), 3.10 (1 H, dd, J 16.0, 4.9), 2.86 (1 H, dd, J 16.0,
3-(Diethoxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-one (8a) 8.5), 2.34 (1 H, dd, J 12.1, 7.2), 2.26 (1 H, dd, J 12.1, 7.2), 2.16 (6 H,
Synthesised following general procedure B. The reaction was s). δ (101 MHz, DMSO-d6) 165.63,163.06, 138.37, 132.89, 132.22,
C
carried out at room temperature and the crude material was 128.44, 127.12, 127.10, 62.49, 52.08, 47.45, 45.25, 30.86. HRMS
purified by flash column chromatography using a gradient of 0-50% (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H18N2O3 263.1390; found:
EtOAc in petrol. The desired compound was obtained as a yellow 263.1412. δ = 8.36 ppm.
solid in 71% yield (40 mg) from phenylformamido 2,2-
7-Bromo-3-[(dimethylamino)methyl]-1,2,3,4-
dimethylpropanoate (4) (0.225 mmol, 50 mg, 1 equiv.). δ (500
H
tetrahydroisoquinolin-1-one (15) Synthesised following general
MHz, DMSO-d6) 7.83 (1 H, dd, J 7.6, 1.4), 7.65 – 7.603 (1 H, m), 7.46
procedure B. The reaction was carried out at room temperature
(1 H, td, J 7.6, 1.5), 7.32 (1 H, td, J 7.6, 1.3), 7.31 (1 H, d, J 7.6), 4.32
and the crude material was purified by flash column
(1 H, d, J 6.3), 3.69 – 3.53 (3 H, m), 3.46 (2 H, dq, J 9.6, 6.9), 3.04 (1
chromatography using a gradient of 0-10% MeOH in EtOAc. The
H, dd, J 16.2, 5.7), 2.93 (1 H, dd, J 16.2, 6.9), 1.15 – 1.03 (6 H, m). δ C
desired compound was obtained as a brown solid in 53% yield (68
(126 MHz, DMSO-d6) 164.02, 137.58, 132.06, 131.71, 127.13,
mg) from (3-bromophenyl)formamido 2,2-dimethylpropanoate (10)
126.58, 102.44, 62.53, 51.89, 27.93, 14.98. HRMS (ESI-QTOF): m/z
(0.45 mmol, 135 mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 7.91 (1 H, d,
[M+H]⁺ Calcd for 250.1438; found: 250.1454. δ = 6.40 ppm.
J 2.2), 7.66 (1 H, dd, J 8.0, 2.2), 7.64 (1 H, br s), 7.30 (1 H, d, J 8.0),
6-Bromo-3-[(dimethylamino)methyl]-1,2,3,4-
3.78 – 3.63 (1 H, m), 2.99 (1 H, dd, J 16.0, 4.9), 2.76 (1 H, dd, J 16.0,
tetrahydroisoquinolin-1-one (13) Synthesised following general 8.5), 2.32 (1 H, dd, J 12.1, 7.1), 2.25 (1 H, dd, J 12.1, 7.2), 2.16 (6 H,
procedure B. The reaction was carried out at room temperature s). δ C (101 MHz, DMSO-d6) 162.63, 137.28, 134.23, 131.05, 130.13,
and the crude material was purified by flash column 129.06, 119.46, 62.43, 47.41, 45.26, 30.42. HRMS (ESI-QTOF): m/z
chromatography using a gradient of 0-10% MeOH in EtOAc. The [M+H]⁺ Calcd for C12H15BrN2O 283.0441; found: 283.0444. δ = 1.06
desired compound was obtained as a brown solid in 54% yield (70 ppm.
mg) from (4-bromophenyl)formamido 2,2-dimethylpropanoate (9)
Methyl
3-[(dimethylamino)methyl]-1-oxo-1,2,3,4-
(0.45 mmol, 135 mg, 1 equiv.). δ (400 MHz, DMSO-d6) 7.75 (1 H,
H
tetrahydroisoquinoline-7-carboxylate (16) Synthesised following
general procedure B. The reaction was carried out at room
temperature and the crude material was purified by flash column
chromatography using a gradient of 0-10% MeOH in EtOAc. The
d, J 8.2), 7.58 (1 H, d, J 2.0), 7.55 (1 H, br s), 7.53 (1 H, dd, J 8.2, 2.0),
3.71 (1 H, dtdd, J 8.7, 7.1, 4.9, 2.2), 3.02 (1 H, dd, J 16.0, 4.9), 2.79 (1
H, dd, J 16.0, 8.7), 2.33 (1 H, dd, J 12.1, 7.1), 2.25 (1 H, dd, J 12.1,
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 11 of 14
Journal Name
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
desired compound was obtained as a brown solid in 56% yield (67 143.19,130.26, 130.89, 127.48, 64.05, 52.71, 25.41, 25.49, 17.83, -
mg) from methyl 3-{[(2,2- 5.75. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H23NO2SSi
dimethylpropanoyl)oxy]carbamoyl}benzoate (12) (0.45 mmol, 125 298.1292; found: 298.1299. δ = 2.35 ppm.
mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 8.41 (1 H, d, J 1.9), 8.03 (1 H,
4-{[Tert-butyldimethylsilyl)oxy]methyl}-4H,5H,6H,7H-
dd, J 7.9, 1.9), 7.65 (1 H, br s), 7.53 – 7.43 (1 H, m), 3.87 (3 H, s),
3.75 (1 H, dtdd, J 8.5, 7.1, 4.9, 2.3), 3.10 (1 H, dd, J 16.3, 4.9), 2.88 (1
H, dd, J 16.3, 8.5), 2.34 (1 H, dd, J 12.1, 7.1), 2.26 (1 H, dd, J 12.1,
thieno[2,3-c]pyridin-7-one (20b) Synthesis and purification
described for 20a Compound 20b was obtained as a white solid in
55% yield (148 mg) from (thiophen-2-yl)formamido 2,2-
7.1), 2.16 (6 H, s). δ (101 MHz, DMSO-d6) 165.58, 163.31, 143.34,
C
dimethylpropanoate (17) (0.9 mmol, 204 mg, 1 equiv.). δ (400
H
131.90, 129.31, 128.43, 128.22, 127.46, 62.49, 51.94, 47.33, 45.27,
31.11. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H18N2O3 263.139;
found: 263.1409. δ = 7.22 ppm.
MHz, DMSO-d6) 7.76 (1 H, d, J 5.0), 7.62 (1 H, br s), 7.14 (1 H, dd, J
5.0, 0.4), 3.73 (1 H, dd, J 10.0, 5.4), 3.63 (1 H, dd, J 10.0, 8.5), 3.52 (1
H, ddd, J 12.6, 5.4, 1.9), 3.39 (1 H, ddd, J 12.7, 5.4, 3.4), 3.07 (1 H,
5-[(Dimethylamino)methyl]-4H,5H,6H,7H-thieno[2,3-c]pyridin- dq, J 8.5, 5.4), 0.86 (9 H, s), 0.03 (6 H, s). δ (101 MHz, DMSO-d6)
C
7-one (19a) Synthesised following general procedure B. The 161.35, 145.25, 131.57, 130.59, 126.99, 62.56, 41.76, 37.05, 25.52,
reaction was carried out at room temperature overnight then 17.83, -5.78. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H23NO2SSi
additional catalyst was added and the reaction heated to 50oC for 3 298.1292; found: 298.1296. δ = 1.34 ppm.
hours.
The crude material was purified by flash column
Tert-butyl
N-({7-oxo-4H,5H,6H,7H-thieno[2,3-c]pyridin-5-
chromatography using a gradient of 0-10% MeOH in EtOAc. The
desired compound was obtained as a brown oil in 31% yield (30 mg)
from (thiophen-2-yl)formamido 2,2-dimethylpropanoate (17) (0.45
mmol, 102 mg, 1 equiv.). Note: Minor isomer not isolated. Ratio
yl}methyl)carbamate (21a) Synthesised following general
procedure B. The reaction was carried out at room temperature
and the crude material was purified by flash column
chromatography using a gradient of 0-30% EtOAc in petrol. The
desired compound was obtained as an off-white solid in 27% yield
(35 mg) from (thiophen-2-yl)formamido 2,2-dimethylpropanoate
(17) (0.45 mmol, 102 mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 7.76 (1
H, d, J 4.9), 7.56 (1 H, br s), 7.04 (1 H, d, J 4.9), 6.97 (1 H, t, J 5.7),
3.75 – 3.55 (1 H, m), 3.15 – 3.15 (2 H, m), 2.91 (1 H, dd, J 16.4, 5.6),
estimated by LC-MS. δ (400 MHz, DMSO-d6) 7.76 (1 H, d, J 4.9),
H
7.16 (1 H, br s), 7.06 (1 H, d, J 4.9), 3.80 (1 H, dtdd, J 9.2, 7.2, 5.5,
1.8), 2.95 (1 H, dd, J 16.3, 5.5), 2.69 (1 H, dd, J 16.3, 9.2), 2.37 (1 H,
dd, J 12.0, 7.2), 2.30 (1 H, dd, J 12.0, 7.2), 2.17 (6 H, s). δ C (101 MHz,
DMSO-d6) 161.38, 143.99, 130.97, 130.55, 127.43, 62.32, 49.35,
45.22, 27.55. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C10H14N2OS
211.0900; found: 211.0913. δ = 6.16 ppm.
2.68 (1 H, dd, J 16.4, 8.8), 1.38 (9 H, s). δ (101 MHz, DMSO-d6)
C
161.38, 155.52, 143.39, 130.94, 130.08, 127.51, 77.84, 51.78, 43.13,
27.92, 26.76. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C13H18N2O3S
5-{[(Tert-butyldimethylsilyl)oxy]methyl}-4H,5H,6H,7H-
thieno[2,3-c]pyridin-7-one (20a) Synthesised following general 283.1111; found: 283.1114. δ = 1.06 ppm.
procedure B. The reaction was carried out at room temperature
Tert-butyl
N-({7-oxo-4H,5H,6H,7H-thieno[2,3-c]pyridin-4-
overnight then additional catalyst was added and the reaction
heated to 50oC for 3 hours. The crude material was purified by
flash column chromatography using a gradient of 0-30% EtOAc in
petrol. The desired compound was obtained as a colourless oil in
24% yield (65 mg) from (thiophen-2-yl)formamido 2,2-
yl}methyl)carbamate (21b) Synthesise and purification described
for 21a. Compound 21b was obtained as a glassy yellow solid in
52% yield (66 mg) from (thiophen-2-yl)formamido 2,2-
dimethylpropanoate (17) (0.45 mmol, 102 mg, 1 equiv.). δ (400
H
MHz, DMSO-d6) 7.77 (1 H, d, J 5.0), 7.61 (1 H, d, J 3.0), 7.09 (1 H, d, J
5.0), 7.04 (1 H, t, J 6.8), 3.47 (1 H, dd, J 12.5, 3.6), 3.31 – 3.16 (2 H,
dimethylpropanoate (17) (0.9 mmol, 204 mg, 1 equiv.). δ (400
H
MHz, DMSO-d6) 7.75 (1 H, d, J 4.9), 7.50 (1 H, d, J 2.3), 7.06 (1 H, d, J
4.9), 3.72 – 3.64 (1 H, m), 3.62 (1 H, dd, J 10.0, 4.8), 3.53 (1 H, dd, J
10.0, 7.2), 2.98 (1 H, dd, J 16.6, 6.1), 2.84 (1 H, dd, J 16.6, 6.6), 0.84
(9 H, s), 0.02 (3 H, s), 0.01 (3 H, s). δ C (101 MHz, DMSO-d6) 161.39,
m), 3.15 – 2.98 (2 H, m), 1.38 (9 H, s). δ (101 MHz, DMSO-d6)
C
161.50, 155.71, 146.37, 131.35, 130.77, 126.54, 77.76, 42.91, 41.26,
34.83, 27.96. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C13H18N2O3S
283.1111; found: 283.1112. δ = 0.35 ppm.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
3-Bromo-5-[(dimethylamino)methyl]-4H,5H,6H,7H-thieno[2,3-
Journal Name
general procedure B. The reaction was carried out at room
c]pyridin-7-one (22a) Synthesised following general procedure B. temperature and the crude material was purified by flash column
The reaction was carried out at room temperature and the crude chromatography using a gradient of 0-30% EtOAc in petrol. The
material was purified by flash column chromatography using a desired compound was obtained as a glassy off white solid in 25%
gradient of 0-10% MeOH in EtOAc. The desired compound was yield (42 mg) from (4-bromothiophen-2-yl)formamido 2,2-
obtained as
a brown solid in 30% yield (40 mg) from (4- dimethylpropanoate (0.45 mmol, 137 mg, 1 equiv.). δ (400 MHz,
H
bromothiophen-2-yl)formamido 2,2-dimethylpropanoate (18) (0.45 Chloroform-d) 7.48 (1 H, s), 6.22 (1 H, br s), 4.91 (1 H, br s), 3.99 (1
mmol, 137 mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 7.98 (1 H, s), 7.45 H, br s), 3.47 – 3.34 (1 H, m), 3.28 (1 H, dt, J 14.2, 7.0), 2.90 (1 H, dd,
(1 H, br s), 3.86 (1 H, dtdd, J 8.8, 7.1, 5.7, 1.9), 2.85 (1 H, dd, J 16.5, J 16.5, 5.6), 2.67 (1 H, dd, J 16.5, 10.0), 1.46 (9 H, s). δ (101 MHz,
C
5.7), 2.63 (1 H, dd, J 16.5, 8.8), 2.41 – 2.28 (2 H, m), 2.17 (6 H, s). δ C CDCl3) 128.50, 52.92, 44.45, 27.48, 28.31. δ (101 MHz, CDCl3)
C
(101 MHz, DMSO-d6) 160.15, 142.42, 131.07, 128.42, 109.82, 62.15, 162.13, 142.78, 131.18, 128.72, 110.72, 53.20, 44.67, 28.51, 27.69.
49.16, 45.25, 26.97. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for Sidechain NCO not determined. OC(Me)3 under chloroform
C10H13BrN2OS 289.0005; found: 289.0009. δ = 1.38 ppm.
resonances. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C13H17BrN2O3S
361.0216; found: 361.0214. δ = 0.55 ppm.
3-Bromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-
4H,5H,6H,7H-thieno[2,3-c]pyridin-7-one
(23a)
Synthesised
Tert-butyl
N-({3-bromo-7-oxo-4H,5H,6H,7H-thieno[2,3-
following general procedure B. The reaction was carried out at c]pyridin-4-yl}methyl)carbamate (24b) Synthesis and purification
room temperature and the crude material was purified by flash described for 24a. Compound 24b was obtained as a glassy off
column chromatography using a gradient of 0-30% EtOAc in petrol. white solid in 29% yield (48 mg) from (4-bromothiophen-2-
The regioisomers were inseparable by column chromatography and yl)formamido 2,2-dimethylpropanoate (18) (0.45 mmol, 137 mg, 1
were obtained as an approximately 1:2 mixture of a:b as judged by equiv.). δ (400 MHz, DMSO-d6) 7.96 (1 H, s), 7.75 (1 H, d, J 4.5),
H
1H NMR. The mixture was a white solid in 52% combined yield (88 7.08 (1 H, br s), 3.55 (1 H, dd, J 13.0, 3.4), 3.41 (1 H, dd, J 13.0, 4.7),
mg)
from
(4-bromothiophen-2-yl)formamido
2,2- 3.08 – 2.92 (3 H, m), 1.38 (9 H, s). δ (101 MHz, DMSO) 160.14,
C
dimethylpropanoate (18) (0.45 mmol, 137 mg, 1 equiv.). δ (400 155.56, 144.37, 132.28, 128.60, 109.72, 77.71, 41.82, 34.06, 30.63,
H
MHz, DMSO-d6) 7.96 (1 H, s), 7.77 (1 H, d, J 2.9), 3.82 – 3.68 (1 H, 28.21. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C13H17BrN2O3S
m), 3.65 – 3.48 (2 H, m), 2.89 (1 H, dd, J 16.8, 6.6), 2.79 (1 H, dd, J 361.0216; found: 361.0211. δ = 1.38 ppm.
16.8, 5.5), 0.82 (9 H, s), 0.00 (6 H, s). δ (101 MHz, DMSO) -5.10,
C
6-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-chloro-
17.78, 25.52, 26.15, 52.92, 64.84, 109.76, 128.97, 131.00, 141.64,
4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridin-4-one (26a) Synthesised
160.04. HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C14H22BrNO2SSi
following general procedure B. The reaction was carried out at
376.0397; found: 376.0391. δ = 1.60 ppm.
room temperature and the crude material was purified by flash
3-Bromo-4-{[(tert-butyldimethylsilyl)oxy]methyl}-
4H,5H,6H,7H-thieno[2,3-c]pyridin-7-one (23b)
column chromatography using a gradient of 0-30% EtOAc in petrol.
the The regioisomers were inseparable by column chromatography and
See
experimental information for 23a. δ (400 MHz, DMSO-d6) 7.99 (1 were obtained as an approximately 1:4 mixture of a:b as judged by
H
H, s), 7.80 (1 H, d, J 3.8), 3.60 – 3.48 (4 H, m), 2.95 (1 H, ddt, J 9.7, 1H NMR. The mixture was a white solid 36% yield (54 mg) from (2-
5.3, 2.7), 0.87 (9 H, s), 0.05 (3 H, s), 0.03 (3 H, s). δ (101 MHz, chloro-1,3-thiazol-5-yl)formamido 2,2-dimethylpropanoate (25)
C
DMSO) 159.87, 142.60, 132.68, 129.19, 61.34, 41.32, 37.17, 26.26, (0.45 mmol, 118 mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 7.92 (1 H, d,
17.78, -4.97, -5.06,. C-Br not determined. HRMS (ESI-QTOF): m/z J 2.8), 3.81 – 3.71 (1 H, m), 3.67 – 3.58 (2 H, m), 3.13 (1 H, dd, J 17.1,
[M+H]⁺ Calcd for C14H22BrNO2SSi 376.0397; found: 376.0391. δ = 7.1), 2.95 (1 H, dd, J 17.1, 5.4), 0.81 (9 H, s), 0.00 (6 H, s).
1.60 ppm.
7-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-chloro-4H,5H,6H,7H-
Tert-butyl
N-({3-bromo-7-oxo-4H,5H,6H,7H-thieno[2,3- [1,3]thiazolo[5,4-c]pyridin-4-one (26b) Major regioisomer. δ (400
H
c]pyridin-5-yl}methyl)carbamate (24a) Synthesised following MHz, DMSO-d6) 7.97 (1 H, br s), 3.85 (1 H, dd, J 10.2, 4.4), 3.81 –
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 13 of 14
Journal Name
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
3.74 (1 H, m), 3.66 – 3.55 (1 H, m), 3.47 (1 H, ddd, J 12.9, 5.9, 3.2),
7-{[(Tert-butyldimethylsilyl)oxy]methyl}-4H,5H,6H,7H-
3.21 (1 H, dtd, J 7.9, 5.9, 4.4), 0.84 (9 H, s), 0.03 (3 H, s), 0.01 (3 H, [1,3]thiazolo[5,4-c]pyridin-4-one (29b) Procedure described for
s).
29a. δ H (400 MHz, DMSO-d6) 9.25 (1 H, s), 7.85 (1 H, br s), 3.90 (1 H,
dd, J 10.1, 4.3), 3.73 (1 H, dd, J 10.1, 8.7), 3.64 – 3.57 (1 H, m), 3.49
(1 H, ddd, J 12.8, 5.6, 3.2), 3.28 – 3.22 (1 H, m), 0.85 (9 H, s), 0.04 (3
H, s), 0.02 (3 H, s). δ C (101 MHz, DMSO-d6) 160.94, 159.47, 157.80,
126.41, 61.84, 41.57, 38.02, 25.47, 17.81, -5.76.
2-Chloro-6-(hydroxymethyl)-4H,5H,6H,7H-[1,3]thiazolo[5,4-
c]pyridin-4-one (27a) TBAF (0.243 ml, 0.243 mmol, 1.5 eq) was
added to the regioisomeric mixture of silyl ethers 26a and b in THF.
The reaction was stirred at room temperature for 1h then
concentrated and purified by preparative HPLC to give the
7-Bromo-3-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-2,6-
separated regioisomers. Regioisomer 27a was obtained as a white naphthyridin-1-one (31) Synthesised following general procedure
solid 1.5 mg, 4% yield. δ H (400 MHz, DMSO-d6) 7.89 (1 H, br s), 4.98 B. The reaction mixture was heated to 65oC for 4 hours then
(1 H, m), 3.72 (1 H, dtdd, J 7.5, 6.5, 5.2, 2.4), 3.52 – 3.37 (2 H, m), worked up and the crude material was purified by flash column
3.06 (1 H, dd, J 17.1, 6.5), 2.94 (1 H, dd, J 17.1, 7.5). δ (101 MHz, chromatography using a gradient of 0-30% EtOAc in petrol to give a
C
DMSO-d6) 159.83, 157.00, 154.06, 127.25, 62.66, 52.56, 26.68. mixture of regioisomers. The major component was isolated by
HRMS (ESI-QTOF): m/z [M+H]⁺ Calcd for C7H7ClN2O2S 218.9990; preparative HPLC to give the structure indicated as a white solid in
found: 218.999. δ = 0.00 ppm.
8% yield (10 mg) from (2-bromopyridin-4-yl)formamido 2,2-
dimethylpropanoate (27) (0.45 mmol, 135 mg, 1 equiv.). δ (400
H
2-Chloro-7-(hydroxymethyl)-4H,5H,6H,7H-[1,3]thiazolo[5,4-
MHz, DMSO-d6) 8.46 (1 H, d, J 0.7), 8.12 – 7.99 (1 H, m), 7.81 (1 H, d,
J 0.7), 3.83 – 3.70 (1 H, m), 3.04 (1 H, dd, J 16.1, 5.0), 2.79 (1 H, dd, J
16.1, 8.1), 2.32 (1 H, dd, J 12.2, 6.8), 2.26 (1 H, dd, J 12.2, 7.5), 2.16
c]pyridin-4-one (27b) This regiosiomer was obtained as a white
solid 15 mg, 42% yield. δ (400 MHz, DMSO-d6) 7.95 (1 H, br s),
H
4.97 (1 H, t, J 4.6), 3.69 (1 H, dd, J 9.4, 5.2), 3.64 – 3.45 (3 H, m),
(6 H, s). δ (101 MHz, DMSO) 161.16, 150.36, 139.56, 138.67,
C
3.21 – 3.07 (1 H, m).
δ
(101 MHz, DMSO-d6) 159.82, 158.72,
C
132.11, 124.10, 62.26, 47.56, 45.32, 27.32. HRMS (ESI-QTOF): m/z
[M+H]⁺ Calcd for C₁₁H₁₄BrN₃O 284.0393; found 284.0394. δ = 0.23
ppm.
154.03, 128.63, 60.01, 41.47, 38.34. HRMS (ESI-QTOF): m/z [M+H]⁺
Calcd for C7H7ClN2O2S 218.9990; found 218.9992. δ = 0.91 ppm.
6-{[(Tert-butyldimethylsilyl)oxy]methyl}-4H,5H,6H,7H-
[1,3]thiazolo[5,4-c]pyridin-4-one (29a) Synthesised following
general procedure B. The reaction was carried out at room
temperature and the crude material was purified by flash column
chromatography using a gradient of 0-30% EtOAc in petrol. The
regioisomers were not separable by column chromatography and
were obtained as an approximately 1:2 mixture of a:b as judged by
1H NMR. The mixture was a white solid in 16% yield (22 mg) from
(1,3-thiazol-5-yl)formamido 2,2-dimethylpropanoate (0.45 mmol,
102 mg, 1 equiv.). δ H (400 MHz, DMSO-d6) 9.22 (1 H, s), 7.77 (1 H,
d, J 2.7), 3.81 – 3.72 (1 H, m), 3.67 – 3.53 (2 H, m), 3.17 (1 H, dd, J
Acknowledgements
The authors warmly thank our Astex colleagues, Stuart
Whibley and Nicola Wilsher for providing the HRMS data.
Notes and references
‡cLogP is calculated from Daylight version 4.93
http://www.daylight.com/products/toolkit.html.
Solubility measurements were carried out by 1H quantitative NMR
at 500MHz using the QUANTAS approach19. Aliquots of fragments
(100mM in DMSO-d6) were diluted x20 with buffer (40mM
phosphate, 100mM TRIS, 15% D2O, pH=7.1) to afford samples with
nominal concentrations of 5mM. A 2.5mM sample of p-
16.9, 6.8), 3.03 (1 H, dd, J 16.9, 5.8), 0.81 (9 H, s), -0.00 (6 H, s). δ
C
hydroxybenzoic acid, prepared by dilution of a 50mM stock in
DMSO-d6 x20 with buffer was used as the qNMR standard.
(101 MHz, DMSO) 158.19, 157.76, 124.64, 51.95, 64.49, 26.57,
25.47, 17.78, -5.76. C=O not determined. HRMS (ESI-QTOF): m/z
[M+H]⁺ Calcd for C₁₃H₂₂N₂O₂SSi 299.1244; found 299.1247. δ = 1.02
ppm.
1. (a) Erlanson, D., Introduction to Fragment-Based Drug
Discovery. In Fragment-Based Drug Discovery and X-Ray
Crystallography, Davies, T. G.; Hyvönen, M., Eds. Springer Berlin
Heidelberg: 2012; Vol. 317, pp 1-32; (b) Hubbard, R. E.; Murray, J.
B., Chapter twenty - Experiences in Fragment-Based Lead Discovery.
In Methods in Enzymology, Lawrence, C. K., Ed. Academic Press:
2011; Vol. Volume 493, pp 509-531; (c) Magee, T. V., Progress in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 13
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 14 of 14
View Article Online
DOI: 10.1039/C5OB02461G
ARTICLE
Journal Name
discovery of small-molecule modulators of protein–protein
interactions via fragment screening. Bioorganic & Medicinal
9. Guimond, N.; Gorelsky, S. I.; Fagnou, K., Rhodium(III)-Catalyzed
Heterocycle Synthesis Using an Internal Oxidant: Improved
Chemistry Letters 2015, 25 (12), 2461-2468; (d) Murray, C. W.; Rees, Reactivity and Mechanistic Studies. Journal of the American
D. C., The rise of fragment-based drug discovery. Nat Chem 2009, 1
(3), 187-192; (e) Zartler, E. R., Fragonomics: The -Omics with Real
Impact. ACS Medicinal Chemistry Letters 2014, 5 (9), 952-953; (f)
Burke, J. P.; Bian, Z.; Shaw, S.; Zhao, B.; Goodwin, C. M.; Belmar, J.;
Browning, C. F.; Vigil, D.; Friberg, A.; Camper, D. V.; Rossanese, O.
W.; Lee, T.; Olejniczak, E. T.; Fesik, S. W., Discovery of Tricyclic
Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods
and Structure-Based Design. Journal of Medicinal Chemistry 2015,
58 (9), 3794-3805.
2. Baker, M., Fragment-based lead discovery grows up. Nat Rev
Drug Discov 2013, 12 (1), 5-7.
3. Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.;
Hirth, P., Vemurafenib: the first drug approved for BRAF-mutant
cancer. Nat Rev Drug Discov 2012, 11 (11), 873-886.
Chemical Society 2011, 133 (16), 6449-6457.
10. (a) Huckins, J. R.; Bercot, E. A.; Thiel, O. R.; Hwang, T.-L.; Bio, M.
M., Rh(III)-Catalyzed C–H Activation and Double Directing Group
Strategy for the Regioselective Synthesis of Naphthyridinones.
Journal of the American Chemical Society 2013, 135 (39), 14492-
14495; (b) Hyster, T. K.; Dalton, D. M.; Rovis, T., Ligand design for
Rh(iii)-catalyzed C-H activation: an unsymmetrical cyclopentadienyl
group enables a regioselective synthesis of dihydroisoquinolones.
Chemical Science 2015, 6 (1), 254-258; (c) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F., Rh(III)-Catalyzed Directed C−H Olefinaꢀon
Using an Oxidizing Directing Group: Mild, Efficient, and Versatile.
Journal of the American Chemical Society 2011, 133 (8), 2350-2353;
(d) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T., Biotinylated Rh(III)
Complexes in Engineered Streptavidin for Accelerated Asymmetric
C–H Activation. Science (New York, N.Y.) 2012, 338 (6106), 500-503;
(e) Ye, B.; Cramer, N., Chiral cyclopentadienyl ligands as
4. Murray, C. W.; Rees, D. C., Opportunity Knocks: Organic
Chemistry for Fragment-Based Drug Discovery (FBDD). Angewandte
Chemie International Edition 2015, published on line Nov 3, 2015.
DOI: 10.1002/anie.201506783
stereocontrolling element in asymmetric C-H functionalization.
Science (New York, N.Y.) 2012, 338 (6106), 504-6.
5. (a) Congreve, M.; Carr, R.; Murray, C.; Jhoti, H., A ‘Rule of Three’ 11. Webb, N. J.; Marsden, S. P.; Raw, S. A., Rhodium(III)-Catalyzed
for fragment-based lead discovery? Drug Discovery Today 2003, 8
C–H Activation/Annulation with Vinyl Esters as an Acetylene
(19), 876-877; (b) Jhoti, H.; Williams, G.; Rees, D. C.; Murray, C. W.,
Equivalent. Organic Letters 2014, 16 (18), 4718-4721.
The 'rule of three' for fragment-based drug discovery: where are we 12. Ye, B.; Cramer, N., Asymmetric Synthesis of Isoindolones by
now? Nat Rev Drug Discov 2013, 12 (8), 644-644.
Chiral Cyclopentadienyl-Rhodium(III)-Catalyzed C H
Functionalizations. Angewandte Chemie International Edition 2014,
53 (30), 7896-7899.
13. Dou, D.; Viwanathan, P.; Li, Y.; He, G.; Alliston, K. R.; Lushington,
G. H.; Brown-Clay, J. D.; Padmanabhan, R.; Groutas, W. C., Design,
Synthesis, and In Vitro Evaluation of Potential West Nile Virus
Protease Inhibitors Based on the 1-Oxo-1,2,3,4-
6. (a) Baurin, N.; Aboul-Ela, F.; Barril, X.; Davis, B.; Drysdale, M.;
Dymock, B.; Finch, H.; Fromont, C.; Richardson, C.; Simmonite, H.;
Hubbard, R. E., Design and Characterization of Libraries of
Molecular Fragments for Use in NMR Screening against Protein
Targets. Journal of Chemical Information and Computer Sciences
2004, 44 (6), 2157-2166; (b) Blomberg, N.; Cosgrove, D.; Kenny, P.;
Kolmodin, K., Design of compound libraries for fragment screening.
tetrahydroisoquinoline and 1-Oxo-1,2-dihydroisoquinoline
J Comput Aided Mol Des 2009, 23 (8), 513-525; (c) Fejzo, J.; Lepre, C. Scaffolds. Journal of Combinatorial Chemistry 2010, 12 (6), 836-843.
A.; Peng, J. W.; Bemis, G. W.; Ajay; Murcko, M. A.; Moore, J. M., The 14. Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S., Rhodium-
SHAPES strategy: an NMR-based approach for lead generation in
drug discovery. Chemistry & Biology 1999, 6 (10), 755-769; (d) Lau,
W.; Withka, J.; Hepworth, D.; Magee, T.; Du, Y.; Bakken, G.; Miller,
M.; Hendsch, Z.; Thanabal, V.; Kolodziej, S.; Xing, L.; Hu, Q.;
Narasimhan, L.; Love, R.; Charlton, M.; Hughes, S.; van Hoorn, W.;
Mills, J., Design of a multi-purpose fragment screening library using
molecular complexity and orthogonal diversity metrics. J Comput
Aided Mol Des 2011, 25 (7), 621-636; (e) Schuffenhauer, A.;
catalyzed C-H functionalization-based approach to eight-membered
lactams. Chemical Science 2015, 6 (4), 2275-2285.
15. Guimond, N.; Gouliaras, C.; Fagnou, K., Rhodium(III)-Catalyzed
Isoquinolone Synthesis: The N−O Bond as a Handle for C−N Bond
Formation and Catalyst Turnover. Journal of the American Chemical
Society 2010, 132 (20), 6908-6909.
16. Presset, M.; Oehlrich, D.; Rombouts, F.; Molander, G. A.,
Complementary Regioselectivity in Rh(III)-Catalyzed Insertions of
Ruedisser, S.; Marzinzik, A.; Jahnke, W.; Selzer, P.; Jacoby, E., Library Potassium Vinyltrifluoroborate via C–H Activation: Preparation and
Design for Fragment Based Screening. Current Topics in Medicinal
Chemistry 2005, 5 (8), 751-762; (f) Morley, A. D.; Pugliese, A.;
Birchall, K.; Bower, J.; Brennan, P.; Brown, N.; Chapman, T.;
Drysdale, M.; Gilbert, I. H.; Hoelder, S.; Jordan, A.; Ley, S. V.;
Merritt, A.; Miller, D.; Swarbrick, M. E.; Wyatt, P. G., Fragment-
based hit identification: thinking in 3D. Drug Discovery Today 2013,
18 (23–24), 1221-1227; (g)
http://www.maggichurchouseevents.co.uk/bmcs/Downloads/Frag
ments%20-%20Mon%201115%20Brennan%20Paul.pdf.
7. Davis, B. J.; Erlanson, D. A., Learning from our mistakes: the
'unknown knowns' in fragment screening. Bioorg. Med. Chem. Lett.
2013, 23 (10), 2844-52.
Use of 4-Trifluoroboratotetrahydroisoquinolones. Organic Letters
2013, 15 (7), 1528-1531.
17. Nadin, A.; Hattotuwagama, C.; Churcher, I., Lead-Oriented
Synthesis: A New Opportunity for Synthetic Chemistry. Angewandte
Chemie International Edition 2012, 51 (5), 1114-1122.
18. Zhang, Z.; Yu, Y.; Liebeskind, L. S., N-Amidation by Copper-
Mediated Cross-Coupling of Organostannanes or Boronic Acids with
O-Acetyl Hydroxamic Acids. Organic Letters 2008, 10 (14), 3005-
3008.
19. Farrant, R. D.; Hollerton, J. C.; Lynn, S. M.; Provera, S.;
Sidebottom, P. J.; Upton, R. J., NMR quantification using an artificial
signal. Magnetic Resonance in Chemistry 2010, 48 (10), 753-762.
8. (a) Hann, M. M.; Leach, A. R.; Harper, G., Molecular Complexity
and Its Impact on the Probability of Finding Leads for Drug
Discovery. Journal of Chemical Information and Computer Sciences
2001, 41 (3), 856-864; (b) Leach, A. R.; Hann, M. M., Molecular
complexity and fragment-based drug discovery: ten years on.
Current Opinion in Chemical Biology 2011, 15 (4), 489-496.
14 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins