Chemical Transformation Problem Statements
Problem 1: Asymmetric Hydrogenation
Asymmetric hydrogenation of C=C and C=Het is a powerful strategy in synthesis.
Whilst the asymmetric hydrogenation of isolated acyclic C=Het bonds is largely a solved
problem, the reduction of simple C=C and unsaturated heterocycles remains a key
challenge.1
In the case of C=C the asymmetric variant is reliant on the presence of key functional
groups for success. The use of chiral phosphine ligands co-ordinated to rhodium to
reduce unsaturated amino-acrylates is well precedented, although the scope of the
reaction can be extended using bulkier ligands or amino-phosphine based systems. The
asymmetric reduction of heterocycles often requires the use of high pressure to achieve
successful reaction with variable ee.
Expanding the range of substrates and methodologies in the asymmetric reduction of
C=C and heterocycles would provide a key tool to the synthetic chemist.
Exemplification of Problem
The enantiomerically pure saturated heterocycles shown above are found in GSK
development compounds but represent a real challenge for synthesis, requiring multiple
steps and/or classical resolution. These fragments (and many more) could be prepared by
asymmetric hydrogenation of the corresponding unsaturated heterocycles, thus avoiding
the need for stoichiometric resolving agents and offering yields over the inherent 50%
limit for resolution.
Expected Output of Research
The identification and development of suitable catalyst systems which would enable the
scalable reduction of unsaturated heterocycles and simple olefins. Renewable solvents
should be considered as media for these reactions, and they should demonstrate improved
‘green’ metrics versus the transformation they are replacing. A view towards broader
application industrialization and economics should also be provided.
1
X. Zhang et al., Acc Chem Res., 2007, 40, 1278 and H. Shimizu et al., Acc. Chem. Res., 2007, 40, 1385.
Problem 2: Remote C-H oxidative transformations
The seminal book written by Corey and Cheng twenty years ago taught us how to
disconnect a complex molecule to simpler starting materials using retrosynthetic analysis.
Although remote C-H functionalization was mentioned in this monograph it was an
underdeveloped area. Catalytic C-H functionalization is now revolutionizing the way of
thinking in organic synthesis with a growing number of reviews in the literature. 2 The
introduction of hydroxyl and amino groups through remote C-H functionalization is
expected to be game-changing in terms of how retrosynthetic analysis is perceived and
such methodologies should enable shorter routes to complex molecules.
Exemplification of Problem
Many transition metals have been screened in the oxidation of C-H bonds with
manganese and iron–based catalysts emerging as the most successful. However, the
ligands required to impart the desired reactivity to the active systems, are often too
complex/expensive to enable widespread use of these methods.3 Recently Du Bois
improved the ruthenium system originally reported by Tenaglia and, using pyridine-based
ligands, good conversions and high regioselectivity are observed in the oxidation of
remote C-H bonds in aliphatic systems.4 However, further work is needed to understand
and tune the activity of these systems so that better predictive models for regio- and
chemo-selectivity are generated and with less product over-oxidation. Catalytic C-H
amination via insertion of a metal nitrene species is another exciting area of research.
Intramolecular and intermolecular variants are exemplified by the work of Breslow5 and
Du Bois.6 Expanding the scope and utility of catalytic methodologies to synthesize
amines is a key part of GSK’s sustainability strategy.
See Reference 4
(a) “Selective functionalization of C-H bonds” in Chem Rev., 2010, 575-1211; (b) Newhouse, T.; Baran,
P. S. Angew. Chem. Int. Ed. 2011, 50, 3362. (c) Ishihara, Y.; Baran, P. S. Synlett, 2010, 1733.
3
(a) Costas et al. Angew Chem Int Ed 2009, 48, 5720. (b) C. White et al., Science, 2010, 327, 566.
4
McNeil, E.; Du Bois, J. J. Am Chem Soc. 2010, 132, 10202.
5
R. Breslow et al., J. Am. Chem. Soc., 1983, 105, 6728.
6
J. Du Bois et al., J. Am. Chem. Soc., 2001, 123, 6935, J. Am. Chem. Soc., 2004, 126, 15378 and Zalatan,
D. S.; Du Bois, J. Top Curr Chem. 2010, 292, 347.
2
Expected Output of Research
Research in this area should identify and develop suitable catalysts which will enable the
scalable and predictable oxidative transformation of remote C-H bonds.
The
functionalization of C-H bonds to introduce halogen, oxygen and nitrogen can be
considered as a formal oxidation process. Renewable solvents should be considered as
media for these reactions, and they should demonstrate improved ‘green’ metrics versus
the transformation they are replacing. If oxygen or hydrogen peroxide is used, safe use in
a Pharmaceutical environment should be considered. A view towards broader application
and industrialization should also be provided.
Problem 3: Green Oxidations
Oxidations, as a broad class of reactions, can be some of the most powerful reactions
used in organic chemistry. Traditional oxidations are often plagued by high molecular
weight oxidants and/or requirements for large excesses of toxic metals which lead to
negative environmental impacts if used on scale. Recent work using sub-stoichiometric
amounts of metal catalysts in concert with environmentally friendlier oxidizing reagents
has led the way towards greener approaches to oxidations.
Exemplification of Problem,
Air or oxygen are attractive green and sustainable oxidants7 although with some safety
concerns. These could be addressed via the use of water or other green non-flammable
solvents or perhaps engineering solutions such as nitrogen dilution and flow techniques.
The efficient mass transfer of gaseous reagents into a continuous process stream however
remains a challenge. Examples or recent advances include the use of palladium in alkene
dihydroxylation8 and copper complexes in primary alcohol oxidation.9 Another approach
has been the development of organocatalysts such as iminium salts in the (asymmetric)
epoxidation of alkenes10 as well as combinations of metal and organocatalysts (e.g.
CAN/TEMPO).11
Reference 8
Reference 11
7
Mallat, T.; Baiker, A. Chem Rev. 2004, 104, 3037.
Wang, A.; Jiang, H.; Chen, H. J. Am Chem. Soc. 2009, 131, 3846.
9
“Large scale oxidations in the pharmaceutical industry” Chaudhuri et al. Inorg. Chem., 2008, 47, 8943.
8
10
Rassias, G. et al. Adv. Synth. Catal. 2008, 350, 1867-1874; Eur. J. Org. Chem. 2006, 803-813.
11
Sridharan, V. and Menendez, J. C. Chem. Rev., 2010, 110, 3805–3849.
Reference 9
Expected Output of Research
Research in this area should establish oxidation reactions in pharmaceutical syntheses
through the use of a cheap, safe and atom economical oxidant and catalytic amounts of
metals and/or organic mediators. Engineering solutions such flow techniques should
enable aerial oxidations to be performed in a safe and efficient manner. A view towards
broader application and industrialization should also be provided.
Problem-4: C-H cross coupling reactions
Cross coupling reactions are among the most frequent transformations in the
pharmaceutical industry. Yet the prerequisite for the presence of activating groups in
both coupling partners (boronates, halogens, stannanes, triflates, zincates etc.) renders the
entire process poor from atom economy and waste management perspectives.
Recent advances in the field of catalysis have allowed the use of at least one nonactivated coupling partner to become the standard in this process.
Exemplification of Problem
At the forefront of this research is the coupling of non-activated components, namely the
coupling of two (hetero)aryl C-H bonds into a C-C bond. In principle this is an oxidative
process and several oxidants have been used although air and oxygen gas constitute the
most attractive class due to their green and sustainable credentials. Aerial oxidative cross
coupling reactions of non-activated substrates have been achieved via the use of a
directing group in one of the reaction partners.12 Regioselective coupling through
electronic and/or catalyst control instead of non-removable or difficult to remove
directing groups (e.g. 2-pyridyl, CO2H, oxime, etc.) remains a desirable objective.
Expected Output of Research
Research in this area should identify and develop suitable catalysts which will enable
efficient cross-coupling of non-activated components. Renewable solvents should be
considered as media for these reactions and safe use in a pharmaceutical environment
should be considered if air or oxygen is used an oxidant. A view towards broader
application and industrialization should also be provided.
12
S. L. Buchwald et al. Org. Lett. 2008, 10, 2207.
Problem-5: Greener OH Activation Methods
Due to the poor leaving group ability of hydroxide ion, methods for alcohol displacement
typically require pre-activation in the form of halide or sulfonate ester derivatives or
alternatively the use of, in some cases, stoichiometric quantities of Brønstead or Lewis
acids (with the net displacement of water). Thus an atom-efficient method for the direct
displacement of alcohols with a range of nucleophiles is desirable.
Exemplification of Problem
Alkyl, allylic or benzylic halides and sulfonate esters often pose significant handling and
purification issues due, in part, to their potential genotoxicity. Furthermore, sulfonate
esters are not atom economical. Alternatively, strong Brønsted or Lewis acids have been
used for alcohol displacements. These methods are, at times, limited by substrate
sensitivities, functional group incompatibilities or selectivity issues. The use of
stoichiometric Lewis acids naturally leads to significant waste.
It is well known that allylic acetates have been used extensively in Pd-catalyzed
substitution reactions with a variety of nucleophiles. Recently, allyic carbonates have
been used, for example, in iridium-catalyzed amination reactions.13 Even more
promising is the use of iridium14, palladium15 or platinum16 catalysis for the direct
conversion of allylic alcohols; and the development of the hydrogen auto-transfer
approach to substitution of primary and secondary alcohols.17 More recently a method
based on gold nanoparticles has been developed by Kobayashi.18 In this the alcohol is
initially oxidized to aldehyde and condensed with an amine to give an aminal which can
be reacted further. The method is tolerant of most functional groups and substitution
patterns on both substrates and uses oxygen as the oxidant.
13
Pouy, M.; Stanley, L.; Hartwig, J. J. Am. Chem. Soc. 2009, 131, 11312.
Defieber, C.; Ariger, M. Moriel, P.; Carreira, E. Angew. Chem. Int. Ed. 2007, 46, 3139.
15
Nishikata, T.; Lipshutz, B. Organic Lett. 2009, 11, 2377.
16
Ohshima, T.; Miyamoto, Y.; Ipposhi, J.; Nakahara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem. Soc.
2009, 131, 14317.
17
(a) Dobereiner, G. E. ; Crabtree, R. H., Chem. Rev. 2010, 110, 681-703, (b) Guillena, G.; Ramón, D. J.;
Yus, M. Chem. Rev. 2010, 110, 1611-1641.
18
Kobayashi et al. J. Am. Chem. Soc. 2011, 133, 18550–18553
14
Expected Output of Research
Ideally, methods could be developed which involve catalytic activation of alcohols which
would enable displacement by a range of competent nucleophiles. In the case of
secondary alcohol substrates, stereochemical integrity (either retention or inversion)
would be preserved. The additional challenge would be expansion of scope to include a
broad range of alcohol substrates. Renewable solvents should be considered as media for
these reactions, and they should demonstrate improved ‘green’ metrics versus the
transformation they are replacing.
A view towards broader application and
industrialization should also be provided.
Problem 6: An efficient synthesis of oligonucleotides
Synthetic oligonucleotides have become a new class of therapeutic agents in recent years.
Currently oligonucleotides are synthesized by the phosphoramidite-based solid phase
synthesis. Although this process provides high quality oligonucleotides at quantities
required for clinical development, it requires excess reagents and extremely large volume
of solvents, hence it is not considered to be sustainable, and not suitable for the large
scale commercial production.
Exemplification of Problem
The current phosphoramidite method had become the “method of choice” to synthesize
oligonucleotide since late 1990’s as a group from ISIS pharmaceuticals established the
automated process. Since then, numerous modifications/improvements have been made
to make this process more efficient, as a result, it becomes the standard method for the
oligonucleotide synthesis.19
Phosphoramidite based solid phase oligonucleotide synthesis
19
Capaldi, Daniel C.; Scozzari, Anthony N., Antisense Drug Technology (2nd Edition) (2008), 401-434
Besides the phosphoramidite method, on the other hand, there are numerous reports
utilizing different modes of coupling methods, such as H-phosphonate approach,
phosphate trimester approach, and phosphotriester approach. Because the majority of the
focus has been devoted to phosphoramidite chemistry for the past decade, these
alternative approaches are still underdeveloped.20
The phase of synthetic process is another consideration. The solid phase synthesis is
currently employed in all practical oligonucleotide syntheses. Whilst the solid phase
synthesis has clear advantages over solution phase syntheses, such as easy removal of
excess reagents, it normally requires large excess reagents/solvents to achieve high
chemical conversion. Other media have been explored (ionic liquid, solution phase,
PEG, Fluorous), but all approaches are still considered to be primitive.21, 22
Expected Output of Research
Development of a synthetic process which uses significantly fewer volumes of solvents
than the current solid phase synthesis. Demonstration of the process which enables
production of 15-20-mer oligonucleotides with comparable quality to the current state of
the solid phase synthesis. Ideally, the new process would be capable of scaling up to >10
kg scale.
20
C. B. Reese, Org. Biomol. Chem., 2005, 3, 3851
Bonora G. M.; Rossin R.; Zaramella S.; Cole D. L.; Eleuteri A.; Ravikumar V. T., Org. Process Res.
Dev., 2000, 4, 225
22
Donga R. A.; Hassler M.; Chan T-H.; Damha M. J., Nucleosides, Nucleotides nucleic Acids, 2007, 26,
1287
21
Problem 7: Hydride-free Reduction of Amides
Amide reduction can be a preferred approach to amine synthesis. Common methods for
reduction of amide bonds, however, involve the use of metal hydrides (LiAlH4, DIBAL,
RedAl, etc.), diborane, Et3SiH or polymethylhydrosiloxane (PMHS). Many of these
methods can lead to product isolation issues (slow filtrations, product occlusion, etc.) and
waste disposal problems (e.g. aluminum waste).
Exemplification of Problem
One of the steps in the synthesis of Paroxetine involves the reduction of a piperidinedione
to the corresponding piperidine using LiAlH4.23 While LiAlH4 has a favorable hydride
density, aluminum waste disposal (aluminum hydroxide salts) is an issue for high-volume
products.
Hydrogen gas is the ideal reducing agent as the only by-product is water. Whilst there
has been progress in area of metal-catalyzed reduction of amides using hydrogen gas,24
current methods require high temperatures and pressures (e.g. 160 °C, 100 bar H2).
Pressures of these magnitudes are not routinely available in a typical pharmaceutical
manufacturing plant and many functional groups are not compatible with the reaction
conditions.
Expected Output of Research
Identification and development of suitable catalysts which would enable direct amide
bond reduction with the use of hydrogen gas or another atom-economical reducing agent
under relatively mild temperatures and pressures. Renewable solvents should be
considered as media for these reactions, and they should demonstrate improved ‘green’
metrics versus the transformation they are replacing. A view towards broader application
and industrialization should also be provided. If hydrogen is used, low pressures are
preferred to minimize installation costs. Electrochemical methods may be considered.
23
Yu, M.; Lantos, I.; Peng, Z-Q.; Yu, J.; and Cacchio, T. Tetrahedron Lett. 2000, 5647.
(a) Magro, A.; Eastham, G.; Cole-Hamilton, D. Chem. Commun. 2007, 3154. (b) Hirosawa, C.; Wakasa,
N.; Fuchikami, T. Tetrahedron Lett. 1996, 6749. (c) Beamson, G.; Adam J. Papworth, A. J.; Philipps, C.;
Smith A. M.; Whyman, R. Journal of Catalysis, 2011, 278, 228–238.
24
Problem 8: Deoxyhalogenation
After decades of advances, classical heterocyclic chemistry is still critical to the success
of drug discovery. One of the most common ways of functionalising heterocycles for
subsequent SNAr substitution or cross-couplings remains deoxyhalogenation.
Deoxychlorination reactions are perhaps most commonly achieved with phosphorus
oxychloride.1 Phosphorus oxychloride can only be used when the substrate has limited
functionality, and the safe quenching this material is time consuming. Other options have
been reported in the literature for this transformation, most commonly use of Vilsmeirtype reagents prepared from thionyl chloride and DMF or oxalyl chloride and DMF.2 Of
these, thionyl chloride/DMF is preferred since oxalyl chloride/DMF produces carbon
monoxide off-gassing. Unfortunately, replacement of phosphorus oxychloride with
thionyl chloride/DMF for deoxychlorination can give rise to worse impurity profiles and
poorer conversion than the use of phosphorus oxychloride.
Exploration of alternative and greener deoxyhalogenation reagents and specifically the
demonstration of the utility of these reagents on challenging substrates (sensitive
functionality, poor solubility, etc.) would be of much value to the synthetic chemist.
Exemplification of Problem
O
N
Cl
HO
N
R
N
O
N
R
N
OH
R = C, N
The substructures indicated above are common substrates for deoxychlorination, as
represented in the literature as well as in the synthesis of project compounds of interest
within GSK. Deoxyhalogenation of other heterocyclic substrates would also be of
interest to further demonstrate the scope.3 One must be careful to plan the synthesis so as
to avoid having any sensitive functionality present during the deoxychlorination, as well
as to comply with the appropriate safety protocols (and employ care in the quench) if
phosphorus oxychloride is utilized.
Expected Output of Research
Identification and development of suitable deoxyhalogenation systems enabling the
scalable deoxyhalogenation of substrates such as those identified above. The ideal
reagent would be safe and convenient to handle, atom economic, perform at least
comparably to phosphorus oxychloride with regard to conversion and impurity profile,
and be compatible with green solvents. Development of a new reagent system which also
had the benefit of being milder/compatible with sensitive functionality would allow more
flexibility in the design of the synthesis.
1.
2.
3.
S. Broxer et al, Org. Process Res. Dev. 2011, 15, p. 343.; Y. Xu et al, Org. Process Res. Dev. 2007, 11, p.
716.
M. Crespo et al, J. Med. Chem. 1998, 41, p. 4021. M. Prasad et al, Chem. Pharm. Bull. 2007, 55 (4), p. 557.
Phosphorus oxychloride, eROS review.
Problem 9: Seeking Catalytic Cross-coupling Reactions in Water
using Common Base Metal Alternatives to Pd
Proposal
Cross-coupling is arguably one of the more powerful reaction classes in organic
synthesis. They are commonly carried out in organic solvent and can exhibit solventdependent selectivity, reactivity or kinetic affects. There is increasing interest however,
in reducing the carbon footprint of development- and manufacturing-scale processes.
Replacement of organic solvents with water (e.g.) would result in substantial benefit.
Significant progress has been made in this area and a review of coupling reactions
conducted in water with the aid of surfactants has recently appeared.25 Various reactions
include, among others: Suzuki-Miyaura, Heck, Negishi couplings, amination and CH
activiation.
Many of these reactions are carried out with the use of palladium catalysis. While a
powerful metal for catalysis, the use of alternative base metals is also highly desirable.
Some examples of nickel-catalyzed couplings in water have been reported by Bakherad26
and Galland27.
The essesnce of this proposal therefore, is to develop cross-coupling reactions that can be
carried out in water (with or without the use of a surfactant) and a common base metal
catalyst (e.g. Ni, Cu, Fe).
Exemplification of the Proposal
A single Sonogashira type coupling is shown below.2 Other cross-coupling reactions
(e.g. Heck, Suzuki, etc) should also be considered.
Expected Output of the Research
Assess to cross-coupling reactions that can be carried out in water using minimal
surfactant and low-cost, readily available alternatives to Pd (e.g. Ni, Cu, Fe).
25
Lipshutz, B.H.; Ghorai, S. Adrichimica Acta, 2012, 45, 3.
Bakherad, M.; Keivanloo, A.; Mihanparast, S. Syn. Commun. 2010, 40, 179.
27
Galland, J-C; Savignac, M.; Genêt, J-P Tetrahedron Lett. 1999, 40, 2323.
26
Problem 10: Seeking Catalytic sp2-sp2 Kumada Reactions with Iron
Catalysts as a Replacement for Palladium Catalyzed Suzuki-Miyaura
Cross-Coupling.
Proposal
Cross-coupling is arguably one of the more powerful reaction classes in organic
synthesis. Moreover, the Suzuki-Miyaura is the most scaled cross-coupling technology
in the pharmaceutical industry.28 While a powerful reaction, there are several
inefficiencies built into the palladium catalyzed process that would be resolved by a
direct Kumada coupling approach using iron catalysis. Firstly, The boronic acid
component is typically prepared from a precursor through metallation or halogen-metal
exchange, usually involving an extra step to isolate the intermediate boronic acid,
effectively proceeding through two organometallic intermediates. In contrast, the
Kumada coupling using the initially formed organometallic species directly. Secondly,
compared to iron, palladium is a precious metal of relatively low abundance, high
toxicity, and higher risk to sustainable sourcing (Table).
Cost
Toxicity
Sustainability
Metal
Cost
($/oz)1
Annual Production
(tonnes)
Oral Exposure
limits (ppm)2
Natural
Abundance
(ppm)
Supply Risk
Index3
Pd
690
24
10
0.015
8.5
Fe
0.004
1,200,00,00
1300
56,300
3.5
1
Price on January 12, 2012. 2 Specific Limits for Residues of Metal Catalysts, Accessed May 13, 2012 at:
http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500003586. 3 “British
Geological Survey: Risk List 2011” http://www.bgs.ac.uk/downloads/start.cfm?id=2063 ; Accessed May 13, 2012
There are limited recent examples of this type of coupling.29 The essence of this proposal
is to develop sp2-sp2 cross-coupling reactions that can be carried out with iron catalysts.
Exemplification of the Proposal
A single generic type coupling is shown below.
Expected Output of the Research
Identification of iron based catalysts that can efficiently cross-couple organometallic sp2
carbons with halogen or other sp2 carbon electrophiles.
28
29
Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844.
Problem 11: To Increase the Efficiency of Continuous
Hydrogenations by Monitoring and Minimizing Catalyst Deactivation
and Facilitating Catalyst Regeneration.
Proposal
Catalytic hydrogenations are the most efficient and green type of reduction in that the
reducing agent is inexpensive and readily available, the metal catalyst can be used in
substoichiometric quantities, and there are no stoichiometric byproducts. Continuous
hydrogenations offer the added advantages that (1) high pressures and temperatures can
be achieved safely in low volume flow reactors, (2) the local catalyst loading in the flow
reactor is extremely high yet the overall catalyst loading for an extended period of flow is
very low, and (3) the effluent stream is just product in solvent, ready for isolation or the
next synthetic step without work up. These first two factors provide a very powerful
reducing environment for clean and fast reactions, and the third factor lowers the number
of unit operations in the process. These advantages are predicated upon stable, long
lived catalysts. Thus we are seeking:



Noninvasive analytical methods to observe catalyst deactivation before it affects the
product stream by detecting changes in the properties of the pressurized catalyst bed
during partial catalyst deactivation while the catalyst is still active enough to give
complete conversion.
More robust heterogeneous hydrogenation catalysts or hydrogenation conditions which
are resistant to catalyst poisoning (e.g. from nitrogen compounds, sulfur compounds, or
tars), coking from the dehydrogenation of substrates, or leaching of the metal catalyst.
Well defined and efficient methods for catalyst regeneration within the flow reactor
such that two beds can be used for prolonged periods with alternating reduction and
regeneration cycles.
Exemplification of the Proposal
The continuous hydrogenation of substituted pyridine 1 to trans piperidine 2 proceeds
with greater diastereoselectivity and higher catalyst turnover than the corresponding
batch hydrogenation.30 Piperidine 2 is a component of JAK inhibitor tofacitinib.
Expected Output of the Research
Increased use of more efficient and green continuous hydrogenations.
30
Hawkins, J. M., et al., manuscript in preparation.