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 aminoacrylates 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 and ee’s are variable.
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
HO2C
NH2
H
N
R
N
H
H
N
R
Y
N
R3
R2
R1
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 and industrialization 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 functionalisation was mentioned in this monograph it was an
underdeveloped area. Catalytic C-H functionalisation is now revolutionizing the way of
thinking in organic synthesis with a growing number of reviews in the literature.2
Exemplification of Problem
Manganese and iron–based catalysts have been used with both molecular oxygen and
hydrogen peroxide to oxidize a range of systems, including remote C-H bonds.3
However, the activity of these systems is difficult to tune with significant problems of
over-oxidation and chemoselectivity. Further work is needed to provide better predictive
models for reactivity and chemoselectivity.4 In addition, new methodologies are needed
to expand the scope and utility of the area.
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
synthesise amines is a key part of GSKs sustainability strategy.
Expected Output of Research
The identification and development of suitable catalysts which would enable the scalable
and predictable oxidative transformation of remote C-H bonds. The functionalisation 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. A view towards broader application and industrialization should also be
provided. If oxygen or hydrogen peroxide is used, safe use in a Pharmaceutical
environment should be considered.
“Selelective functionalisation of C-H bonds” in Chem Rev., 2010, 575-1211
B. L. Feringa et al., J. Am. Chem. Soc., 2005, 127, 7990 and C. White et al., Science, 2007, 318, 783
4
C. White et al., Science, 2010, 327, 566.
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 and J. Am. Chem. Soc., 2004, 126, 15378.
2
3
Problem 3: Green Oxidations (in Air, e.g.)
Oxidations, as a broad class of reactions, can be some of the most powerful reactions
used in organic chemistry. Unfortunately, they are often plagued by high molecular
weight oxidants and 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.
One such approach centers around the use of catalysts (both metal and non-metal) in the
presence of molecular oxygen or air.17 Several “green” advantages to this approach
include, the use of a cheap and atom economical oxidant, the use of catalytic amounts of
metals or co-oxidants and minimization of toxic waste streams (filtration and recycling of
metal catalyst). An important consideration with the use of oxygen as a stoichiometric,
terminal oxidant is flammability. Use in water or with nitrogen dilution should be
strongly considered. Alternatively, engineering solutions may be possible. A range of
approaches have emerged including the use of palladium catalysis, hypervalent iodine
(HVI) compounds, Pt/Bi on carbon, etc.
Exemplification of Problem8,9
R2
R1
Pd cat., O2
HOAc
OAc
R2
R1
K2CO3
MeOH
OAc
OH
R1
R2
OH
O
OH
PhI(OAc)2, TEMPO, KNO2
O2, 80 oC
R
R
Expected Output of Research




7
The identification and development of suitable catalyst systems which enable
scaleable oxidations.
Use of molecular oxygen as the terminal oxidant (or some comparable, low MW,
safe, low impact oxidant) in non-halogenated solvents.
Flammability of reactions systems should be considered. Thus oxidations in
water are preferred or oxidations with the use of dilute oxygen (dilution with
nitrogen, e.g.) or ones which incorporate an engineering solution.
A view towards broader application and industrialization should also be provided.
Mallat, T.; Baiker, A. Chem Rev. 2004, 104, 3037.
Wang, A.; Jiang, H.; Chen, H. J. Am Chem. Soc. 2009, 131, 3846.
9
Herrerias, C.; Zhang, T.; Li, C-J. Tetrahedron Lett. 2006, 47, 13.
8
Problem-4: Amide Bond Reduction Without Hydride Reagents
Amide reduction can be a preferred approach to amine synthesis as a way of eliminating
the need to make or handle alkylating agents associated with N-alkylation strategies.
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 piperidone to
the corresponding piperidine using LiAlH4.10 While LiAlH4 has a favorable hydride
density,1 aluminum waste disposal (aluminum hydroxide salts) is an issue for highvolume products.
Ar
Ar
CO2Me
N
O
R
OH
N
R
Hydrogen gas is the ideal reducing agent as the only by-product is water. While there has
been progress in area of metal-catalyzed reduction of amides using hydrogen gas,11
current methods require high temperatures and pressures. Pressures of these magnitudes
are not routinely available in a typical pharmaceutical manufacturing plant.
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.
10
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.
11
Problem-5: Greener Mitsunobu Alternatives
The Mitsunobu reaction is a powerful way to substitute alcohols with a range of
competent nucleophiles and in the case of secondary alcohols, with high stereospecificity.
The reaction has also been applied intramolecularly in the synthesis of lactones, lactams
and macrocycles. For a comprehensive and contemporary review of the Mitsunobu
reaction, see Swamy, et al.12. The primary drawback of this reaction from an
environmental perspective is the stiochometric requirement for azodicarboxylates and
trialkyl- or triarylphosphines which negatively impact overall atom economy.1 Further,
purification issues often arise from stoichiometric by-products that are derived from the
use of these reagents.
Exemplification of Problem
The overall conversion in the Mitsunobu reaction is a substitution reaction accompanied
by a redox reaction (mediated by trialkyl- or triarylphosphines and azodicarboxylates).
The power of the Mitsunobu reaction lies with the sterochemical fidelity with which
secondary alcohols can be substituted. Further benefits include predictability, scope of
competent nucleophiles and moderate operating temperature.
A number of approaches11 have been taken to improve isolation issues including
modifications to azocarboxylates and phosphines which alter solubility (e.g.
acid/base/water). Further, derivatives of these reagents have been attached to solid
supports. While these approaches may facilitate isolation on small scale, they still
present significant drawbacks (particularly solid supported reagents) in terms of
environmental impact and atom economy. Step improvements have also been made with
improving atom economy be combination of redox partners within a single reagent. 13
Expected Output of Research
Ideally catalytic methods would be developed that achieve the overall net transformation
observed with the classical Mitsunobu reaction. The new method(s) would eliminate the
need for phosphines, azodicarbolxylates or other stoichiometric reagents that lead to
isolation issues, poor atom economy or poor Mass Intensity. 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.
12
13
Swamy, K.; Kumar, N.; Balaraman, E.; Kumar, K. Chem. Rev. 2009, 109, 2551.
Tsunoda, T.; Nagino, C.; Oguri, M.; Ito, S. Tetrahedron Lett. 1996, 37, 2459.
Problem-6: 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 quantites of Bronstead 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. More recently, allyic carbonates
have been used, for example, in iridium-catalyzed amination reactions.14 Even more
promising is the use of iridium15, palladium16 or platinum17 catalysis for the direct
conversion of allylic alcohols.
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.
14
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.
16
Nishikata, T.; Lipshutz, B. Organic Lett. 2009, 11, 2377.
17
Ohshima, T.; Miyamoto, Y.; Ipposhi, J.; Nakahara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem. Soc.
2009, 131, 14317.
15
Problem 7: 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 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 (Scheme 1).18
Scheme 1. Phosphoramidite based solid phase oligonucleotide synthesis
18
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.19
The phase of synthetic process is another consideration. The solid phase synthesis is
currently employed in all practical oligonucleotide syntheses. While 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.20,21
Expected Output of Research
Development of a synthetic process which uses significantly less volume 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.
19
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
21
Donga R. A.; Hassler M.; Chan T-H.; Damha M. J., Nucleosides, Nucleotides nucleic Acids, 2007, 26,
1287
20