Practical synthesis of pharmaceutically relevant molecules enriched in sp3 character

Article abstract of DOI:10.1039/c7cc08670a

The expedient synthesis of compounds enriched in sp³ character is key goal in modern drug discovery. Herein, we report how a single pot Suzuki-Miyaura-hydrogenation can be used to furnish lead and fragment-like products in good to excellent yields. The approach has been successfully applied in formats amenable to parallel synthesis, in an asymmetric sense, and in the preparation of molecules with annotated biological activity.

Full text of DOI:10.1039/c7cc08670a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Practical synthesis of pharmaceutically relevant
molecules enriched in sp3 character†
Peter S. Campbell,a Craig Jamieson, *a Iain Simpsonb and Allan J. B. Watson
Cite this: Chem. Commun., 2018,
54, 46
a
Received 10th November 2017,
Accepted 27th November 2017
DOI: 10.1039/c7cc08670a
rsc.li/chemcomm
The expedient synthesis of compounds enriched in sp3 character is
key goal in modern drug discovery. Herein, we report how a single
pot Suzuki–Miyaura-hydrogenation can be used to furnish lead and
fragment-like products in good to excellent yields. The approach
has been successfully applied in formats amenable to parallel
synthesis, in an asymmetric sense, and in the preparation of mole-
cules with annotated biological activity.
An increasingly important consideration in modern medicinal
chemistry is control of physicochemical properties with the
aspi-ration of improving overall quality of candidate drugs.1 In
relation to this high-level objective, there has been significant
focus on an increased degree of saturation (i.e. fewer aromatic
rings) in compound design as this has been linked to increased
probability of improved physical properties, such as high solu-
bility.2 Greater sp3 character bestows three-dimensionality,
which allows molecules to sample a wider area of chemical
space and potentially achieve superior selectivity.2,3 In addition,
a higher degree of saturation is believed to impart an increased
likelihood of clinical success.3 The overarching design princi-
ples discussed above become apparent when considering mole-
cules emerging from medicinal chemistry laboratories which
have fewer aromatic rings and are frequently typified by C-aryl
linked saturated heterocycles represented generally by 1 (Fig. 1).
These efforts have furnished a range of compounds of this general
chemotype, and are associated with broad biological activity, as
illustrated by the exemplar compounds (2–4) shown in Fig. 1(a).4
Accordingly, efficient methods for the synthesis of molecules
from this emerging chemotype are currently being actively pursued,
and typically involve a metal-catalysed cross-coupling reaction of an
organometallic reagent (boron, zinc, tin or magnesium)5–8 with a
suitable aryl halide derivative to form the sp2–sp3 bond indicated
Fig. 1 (a) Biologically active molecules exemplifying the motif of interest
with key sp2–sp3 bond indicated. (b) Proposed current study.
in Fig. 1. Despite these efforts, some of the currently available
methods suffer from a number of drawbacks. For example, alkyl-
boron reagents are prone to protodeboronation and b-hydride
elimination.9 Additionally, secondary alkylboron reagents have a
propensity to isomerize during cross coupling, often resulting in
inseparable mixtures of products.9 Taken as a whole, these issues
often preclude the application of many of the current methods to
synthesize target molecules in a high throughput fashion.
Since our aim was to furnish biologically relevant frameworks
with emphasis on 3D character in a manner which was amen-
able to a medicinal chemistry setting, an important objective at
the outset of our study was that the methodology was sufficiently
robust to be applicable diverse range of templates. Currently,
there is no general consensus on the optimal catalyst/ligand
combinations that should be utilized in these transformations,
with cross-coupling protocols often requiring a significant
degree of optimisation. Another practical consideration in a
a Department of Pure and Applied Chemistry, University of Strathclyde,
295 Cathedral Street, Glasgow, G1 1XL, UK. E-mail: craig.jamieson@strath.ac.uk
b Medicinal Chemistry, Oncology IMED Biotech Unit, AstraZeneca, Darwin Building,
Unit 310 Cambridge Science Park, Cambridge, CB10 4EW, UK
† Electronic supplementary information (ESI) available: Full experimental procedures
and spectral data for all compounds. See DOI: 10.1039/c7cc08670a
46 | Chem. Commun., 2018, 54, 46--49
This journal is ©The Royal Society of Chemistry 2018

View Article Online
Communication
ChemComm
Table 1 Optimization with respect to catalyst loading and additive
medicinal chemistry setting is the ability to synthesize target
compounds in a high-throughput manner, meaning that ideally
the chemistry selected should be sufficiently robust to be amen-
able to array format, which may preclude application of more
sensitive reagent and catalyst systems.
With these issues in mind, we aimed to develop a robust, one-
pot Suzuki–Miyaura (SM)-hydrogenation protocol10 to enable facile
access to molecules of the general chemotype shown in Fig. 1(b),
employing common laboratory reagents, and avoiding the use of
alkylboron species. From a practical perspective, it was envisaged
that following Suzuki–Miyaura cross coupling, introduction of a
suitable hydrogen source could then enable reduction of the newly
formed olefin 6 in situ, furnishing the desired sp2–sp3 linked
system, 7. Our initial efforts were focused on optimizing the SM
component of the reaction, followed by investigation into the
hydrogenation step; however, it was found that the SM conditions
employed had a significant impact on the extent of hydrogenation.
The most important factor was the choice of phosphine ligand and
the ratio of the two palladium catalysts. Upon initial screening,
excellent SM yields were achieved with minimal optimization.
Attention then turned to the incorporation of an in situ hydro-
Hydrogen
Pd/C (mol%) source
Entry Catalyst (1 mol%)
Ratio 10 : 9a
1
2
3
4
5
6
Pd(dppf)Cl2ÁDCMb
6
6
H2
100 : 0
74 : 26
39 : 61
28 : 72
Pd(dppf)Cl2ÁDCMb
Et3SiH
Et3SiH
Et3SiH
NH4HCO2 80 : 20
NH4HCO2 100 : 0
Pd(dppf)Cl2ÁDCMb 10
PdXPhosG2
PdXPhosG2
PdXPhosG2
10
10
12
Determined by 1H NMR. Using K2CO3 as a base.
a
b
genation protocol using a Pd/C co-catalyst system as use of the SM developing a protocol which allowed all reactants to be present
catalyst system alone was not competent in promoting hydrogena- from the reaction outset in order to elevate the practicality of the
tion. Our investigation commenced with evacuation of the vessel process. Under the standard conditions, addition of ammonium
and subsequent addition of a hydrogen source following the formate at the beginning of the reaction posed two problems:
initial cross-coupling. This was accomplished using hydrogen protodehalogenation of the aryl halide, and reduction (followed
gas, with a 6 : 1 ratio of the two catalysts. Through variation of by protodeboronation) of the vinyl boronate ester, both of which
the palladium catalyst to the monodentate PdXPhosG2, and inhibited the SM reaction. To circumvent these issues, we took
slightly increasing the Pd/C loading, the full one-pot process inspiration from the work of Buchwald et al.11 by employing a
could be achieved with under transfer hydrogenation (Table 1, wax capsule to physically separate the incompatible reagents.
entry 6), thus rendering the transformation amenable to array By encapsulating ammonium formate in a degradable vessel,
chemistry (vide infra).
the rate at which the capsule melted, and thus the release of
Having identified optimal conditions, we next sought to ammonium formate into the system, could be controlled by careful
explore the general applicability of this nascent procedure. In tuning of the reaction temperature. Accordingly, the adapted
the first instance, the scope was examined with respect to the method was successfully applied to a series of substrates
aryl halide coupling partner, using the vinyl-piperidine derived (11a, 11d, 11m and 11r), as indicated in Scheme 1.
system (8) as the boronate ester species (Scheme 1). Methyl
Following on from this initial successful demonstration of
4-bromobenzoate coupled in excellent yield. Electron-neutral, the utility of the process, we sought to apply the conditions
electron-rich, and electron-poor aryl halides were all well toler- developed to a broader range of substrates (Scheme 2). Variation
ated, with ortho, meta, and para substitution patterns examined. of both coupling partners enabled highly efficient access to a raft
The reaction manifold was also compatible with heterocyclic of different substrates, many of which are significantly enriched
substrates which are highly attractive templates from a medic- in sp3 character.
inal chemistry perspective as they are highly lead-like in terms of
Additional diversity could be achieved when using more
their physicochemical properties.1,2 In another aspect of this functionalized aryl bromide precursors. For example, when
part of the study, we examined whether reducible groups (e.g., ethyl 3-(5-bromo-2-nitrophenyl)acrylate was used, an efficient
nitrobenzene derivatives) or protecting groups labile to hydro- in situ lactamisation took place, with three reductions and
genolysis could be concomitantly transformed using the newly two bond forming steps occurring in one pot, yielding 12q
developed procedure, although this may represent a potential and 12r in excellent overall yield. We have also demonstrated
limitation of the method if these are required to be retained how application of a chiral vinyl bromide substrate can lead to
during subsequent synthetic manipulation.
isolation of a fully reduced, cross-coupled product in high
The results of this work indicated that nitrobenzene deriva- enantio- and diastereomeric purity (12s) and good yield. The
tives could be reduced to the corresponding aniline systems thermodynamically more stable trans-product is presumably
(11b, 11d), while CBz protected amines and benzyl ethers could obtained through a hydritic rather than concerted reduction of
be removed under the reaction conditions, furnishing com- the alkene.12 To illustrate the practicality of this approach in a
pounds 11d and 11h, respectively, providing additional function- medicinal chemistry setting, the chemistry was applied to an
ality for further derivatization. We then focused our attention on array synthesis format. This allows the preparation of multiple
This journal is ©The Royal Society of Chemistry 2018
Chem. Commun., 2018, 54, 46--49 | 47

View Article Online
ChemComm
Communication
Scheme 1 Lead-like molecules exemplifying the motif of interest with
key sp2–sp3 bond indicated.
Scheme 2 Variation of both coupling partners with key sp2–sp3 bond
indicated.
sp3-enriched analogues in parallel from commercial monomers
in a highly efficient manner. We carried out a 4 Â 6 array with a
range of sp2-functionalised organoboron esters and aryl bromides
which enabled the successful preparation of 23 compounds, 22 of
which were obtained in greater than 50% conversion as determined
1
by H NMR (Fig. 2).
To further underline the utility of the developed process we
also examined the synthesis of two bioactive compounds.
Firstly, pridopidine (3, Scheme 3),4c a dopaminergic antagonist,
was efficiently accessed in 3 steps, which considerably improves
upon the previously reported synthesis of 7 steps.4c Pleasingly,
the SM-hydrogenation step could be also be accomplished in
comparable yield through use of the encapsulation approach
described previously. Our second target compound was a
2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic acid (AMPA)
receptor modulator, 15 (Scheme 3).13 Vinyl bromide 14 and
biphenyl boronic acid (13) were coupled to provide the protected
sulfonamide in 71% yield, with subsequent acidolysis of the of
2,4-dimethoxybenzyl (DMB) group providing the desired com-
pound (15) in high yield (Scheme 3).
Fig. 2 24-compound array synthesis.
48 | Chem. Commun., 2018, 54, 46--49
This journal is ©The Royal Society of Chemistry 2018

View Article Online
Communication
ChemComm
3 F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752.
4 (a) R. E. Zelle, A. A. Hancock, S. A. Buckner, F. Z. Basha, K. Tietje,
J. F. DeBernardis and M. D. Meyer, Bioorg. Med. Chem. Lett., 1994,
´
4, 1319; (b) A. P. Truong, G. Toth, G. D. Probst, J. M. Sealy, S. Bowers,
D. W. G. Wone, D. Dressen, R. K. Hom, A. W. Konradi, H. L. Sham,
J. Wu, B. T. Peterson, L. Ruslim, M. P. Bova, D. Kholodenko, R. N.
Motter, F. Bard, P. Santiago, H. Ni, D. Chian, F. Soriano, T. Cole,
E. F. Brigham, K. Wong, W. Zmolek, E. Goldbach, B. Samant, L. Chen,
H. Zhang, D. F. Nakamura, K. P. Quinn, T. A. Yednock and J. M. Sauer,
´
Bioorg. Med. Chem. Lett., 2010, 20, 6231; (c) F. Pettersson, H. Ponten,
N. Waters, S. Waters and C. Sonesson, J. Med. Chem., 2010, 53, 2510.
5 For examples of cross-coupling with alkylboron reagents see:
(a) B. Potter, A. A. Szymaniak, E. K. Edelstein and J. P. Morken,
J. Am. Chem. Soc., 2014, 136, 17918; (b) C. Sun, B. Potter and J. P.
Morken, J. Am. Chem. Soc., 2014, 136, 6534; (c) G. A. Molander and
S. R. Wisniewski, J. Am. Chem. Soc., 2012, 134, 16856; (d) D. N.
Primer, I. Karakaya, J. C. Tellis and G. A. Molander, J. Am. Chem.
Soc., 2015, 137, 2195; (e) S. D. Dreher, S.-E. Lim, D. L. Sandrock and
G. A. Molander, J. Org. Chem., 2009, 74, 3621; ( f ) L. Li, S. Zhao,
A. Joshi-Pangu, M. Diane and M. R. Biscoe, J. Am. Chem. Soc., 2014,
136, 14027.
Scheme 3 Application to synthesis of biologically active compounds.
6 For examples of cross-coupling with alkylzinc reagents see: (a) C. Han
and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 7532; (b) Y. Yang,
K. Niedermann, C. Han and S. L. Buchwald, Org. Lett., 2014, 16, 4638;
(c) A. Joshi-Pangu, M. Ganesh and M. R. Biscoe, Org. Lett., 2011,
13, 1218; (d) K. Moriya and P. Knochel, Org. Lett., 2014, 16, 924;
(e) S. Çalimsiz and M. G. Organ, Chem. Commun., 2011, 47, 5181.
7 For examples of cross-coupling with alkyltin reagents see: (a) L. Li,
C.-Y. Wang, R. Huang and M. R. Biscoe, Nat. Chem., 2013, 5,
607–612; (b) M. Goli, A. He and J. R. Falck, Org. Lett., 2011,
13, 344; (c) A. Herve, A. L. Rodriquez and E. Fouquet, J. Org. Chem.,
2005, 70, 1953.
8 For examples of cross-coupling with alkylmagnesium reagents see:
(a) A. Joshi-Pangu, C.-Y. Wang and M. R. Biscoe, J. Am. Chem. Soc.,
2011, 133, 8478–8481; (b) M. E. Limmert, A. H. Roy and J. F. Hartwig,
J. Org. Chem., 2005, 70, 9364; (c) J. A. Miller, Tetrahedron Lett., 2002,
43, 7111.
In conclusion, a general and versatile method for formal
sp2–sp3 coupling has been developed which is applicable to a
palette of substrates representing frameworks of pharmaceutical
relevance. Computational analysis14 of set shows it has a high
mean fraction sp3 (fsp3) of 0.52, which based on Lovering’s data3
is well above the high watermark for candidate drugs (mean
fsp3 = 0.38 for phase I clinical candidates), with the caveat that
some of the molecules contain protecting groups which may
influence the overall average fsp3. Successful application of the
method in an array format further supports its utility in the
context of pharmaceutical research and development. Work is
currently focused on further extension of the process towards
asymmetry, and will be reported in due course.
9 R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417.
10 For a two-step protocol involving isolation of the alkene intermediate
see: K. D. Hesp, D. P. Fernando, W. Jiao and A. T. Londregan, Org.
Lett., 2014, 16, 413.
11 A. C. Sather, H. G. Lee, J. R. Colombe, A. Zhang and S. L. Buchwald,
Nature, 2015, 524, 208.
Conflicts of interest
There are no conflicts to declare.
12 J. Lopez-Serrano, S. B. Duckett and A. Lledos, J. Am. Chem. Soc.,
2006, 128, 9596.
13 P. L. Ornstein, D. M. Zimmerman, M. B. Arnold, T. J. Bleisch,
B. Cantrel, R. Simon, H. Zarrinmayeh, S. R. Baker, M. Gates,
J. P. Tizzano and D. Bleakman, J. Med. Chem., 2000, 43, 4354.
14 Determined using LLAMA: I. Colomer, C. J. Empson, P. Craven,
Z. Owen, R. G. Doveston, I. Churcher, S. P. Marsden and A. Nelson,
Chem. Commun., 2016, 52, 7209.
Notes and references
1 E. H. Kerns and L. Di, Drug Like Properties: Concepts, Structure,
Design and Methods, Academic Press, Burlington MA, 2008.
2 T. J. Ritchie, S. J. F. Macdonald, R. J. Young and S. D. Pickett, Drug
Discovery Today, 2011, 16, 164.
This journal is ©The Royal Society of Chemistry 2018
Chem. Commun., 2018, 54, 46--49 | 49