Biotransformation Problem Statement - GSK · Web viewWhilst the asymmetric hydrogenation of isolated acyclic C=Het bonds is largely a solved problem, the reduction of simple C=C and

Biotransformation Problem Statement

Chemical Transformation Problem StatementsProblem 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.[footnoteRef:1] [1: X. Zhang et al., Acc Chem Res., 2007, 40, 1278 and H. Shimizu et al., Acc. Chem. Res., 2007, 40, 1385.]

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.

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.[footnoteRef: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. [2: (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.]


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.[footnoteRef: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.[footnoteRef: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 Breslow[footnoteRef:5] and Du Bois.[footnoteRef:6] Expanding the scope and utility of catalytic methodologies to synthesize amines is a key part of GSK’s sustainability strategy. [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.]

See Reference 4


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 oxidants[footnoteRef:7] 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 dihydroxylation[footnoteRef:8] and copper complexes in primary alcohol oxidation.[footnoteRef:9] Another approach has been the development of organocatalysts such as iminium salts in the (asymmetric) epoxidation of alkenes[footnoteRef:10] as well as combinations of metal and organocatalysts (e.g. CAN/TEMPO).[footnoteRef:11] [7: Mallat, T.; Baiker, A. Chem Rev. 2004, 104, 3037.] [8: 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.] [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 8

Reference 11

Reference 9


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 non-activated coupling partner to become the standard in this process.


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.[footnoteRef: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. [12: S. L. Buchwald et al. Org. Lett. 2008, 10, 2207.]


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.

Problem-5: Greener OH Activation MethodsDue 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.[footnoteRef:13] Even more promising is the use of iridium[footnoteRef:14], palladium[footnoteRef:15] or platinum[footnoteRef:16] catalysis for the direct conversion of allylic alcohols; and the development of the hydrogen auto-transfer approach to substitution of primary and secondary alcohols.[footnoteRef:17] More recently a method based on gold nanoparticles has been developed by Kobayashi.[footnoteRef: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.] [14: 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]


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 oligonucleotidesSynthetic 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.


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.[footnoteRef:19] [19: Capaldi, Daniel C.; Scozzari, Anthony N., Antisense Drug Technology (2nd Edition) (2008), 401-434]

Phosphoramidite based solid phase oligonucleotide synthesis

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.[footnoteRef:20] [20: C. B. Reese, Org. Biomol. Chem., 2005, 3, 3851]

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.[footnoteRef:21], [footnoteRef:22] [21: 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]


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.

Problem 7: Hydride-free Reduction of AmidesAmide 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 ProblemOne of the steps in the synthesis of Paroxetine involves the reduction of a piperidinedione to the corresponding piperidine using LiAlH4.[footnoteRef:23] While LiAlH4 has a favorable hydride density, aluminum waste disposal (aluminum hydroxide salts) is an issue for high-volume products. [23: Yu, M.; Lantos, I.; Peng, Z-Q.; Yu, J.; and Cacchio, T. Tetrahedron Lett. 2000, 5647.]

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,[footnoteRef: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. [24: (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.]


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.

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 Vilsmeir-type 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.


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.


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. S. Broxer et al, Org. Process Res. Dev. 2011, 15, p. 343.; Y. Xu et al, Org. Process Res. Dev. 2007, 11, p. 716.

2. M. Crespo et al, J. Med. Chem. 1998, 41, p. 4021. M. Prasad et al, Chem. Pharm. Bull. 2007, 55 (4), p. 557.

3. Phosphorus oxychloride, eROS review.

Problem 9: Seeking Catalytic Cross-coupling Reactions in Water using Common Base Metal Alternatives to PdProposal

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 solvent-dependent 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.[footnoteRef:25] Various reactions include, among others: Suzuki-Miyaura, Heck, Negishi couplings, amination and CH activiation. [25: Lipshutz, B.H.; Ghorai, S. Adrichimica Acta, 2012, 45, 3.]

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 Bakherad[footnoteRef:26] and Galland[footnoteRef:27]. [26: 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.

]

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).

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.[footnoteRef: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). [28: Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.]

Cost

Toxicity

Sustainability

Metal

Cost

($/oz)1

Annual Production (tonnes)

Oral Exposure limits (ppm)2

Natural Abundance(ppm)

Supply Risk Index3

Pd

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24

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0.004

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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.[footnoteRef:29] The essence of this proposal is to develop sp2-sp2 cross-coupling reactions that can be carried out with iron catalysts. [29: Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844.]


A single generic type coupling is shown below.


Identification of iron based catalysts that can efficiently cross-couple organometallic sp2 carbons with halogen or other sp2 carbon electrophiles.

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.


The continuous hydrogenation of substituted pyridine 1 to trans piperidine 2 proceeds with greater diastereoselectivity and higher catalyst turnover than the corresponding batch hydrogenation.[footnoteRef:30] Piperidine 2 is a component of JAK inhibitor tofacitinib. [30: Hawkins, J. M., et al., manuscript in preparation.]


Increased use of more efficient and green continuous hydrogenations.

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Documents

Biotransformation Problem Statement - GSK · Web viewWhilst the asymmetric hydrogenation of isolated acyclic C=Het bonds is largely a solved problem, the reduction of simple C=C and