Accredited Programme Title:- GSK Chemistry Continuing ... · of HMPA to lithium bases. Oxidation...

April 2012 version

Accredited Programme Title:- GSK Chemistry Continuing Education Programme: Pathway A Module Specification Form

Unit/Module Title Synthetic Chemistry Module 1

Code GSK/Chem 1

Date of initial approval event

Proposed Level HE Level 4 / NQF Level 7

Proposed General Credit Value

10 credits

Brief Rationale The modular Synthetic Chemistry Course comprises three modules, each consisting of six lecture/tutorial days spread out over one year. The aim is to reaffirm and build on previously gained knowledge of organic synthesis and mechanistic reactivity, thereby creating a solid base of the fundamentals of current synthetic methods.

Description of Learner (target audience)

The module provides a continuing framework of learning for new staff entering the company, primarily recent Chemistry graduates. However it is also suitable for those who have more industrial experience, but who wish to refresh and build on their knowledge and appreciation of synthetic chemistry. This group may include staff who initially joined the company without a first degree, but who have achieved an equivalent qualification by part time study.

Learning Hours 100

Learning Outcomes On completion of each of the sessions of this module, participants should be able to demonstrate knowledge and understanding of each of the topics, with application to their ongoing work and to recent advances as published in the current literature. The learning outcomes for each session are captured as follows:- Carbonyl and Enolate Chemistry

Demonstrate a thorough knowledge and understanding of the classical reactions of the carbonyl group and the enol/enolate functionality (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Show an appreciation of the stereochemical consequences of reactions at a carbonyl centre, and the factors influencing these (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Relate this material to other sessions in Module 1, particularly those covering Retrosynthesis and Oxidation/Reduction (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Oxidation and Reduction

Demonstrate a thorough knowledge and understanding of the classical and modern methods of metal and non-metal mediated oxidation reactions (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Demonstrate a thorough knowledge and understanding of reduction chemistry (concentrating on reductions of carbonyl groups and carbon-carbon multiple bonds) (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Identify and select appropriate oxidation or reduction methods to effect requisite synthetic chemistry transformations towards target molecules (A1, A4, B1b, B1e, B1h, B2j, Cm, Cn,

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Co, Cq, Cs, Ct). Reaction Selectivity: Protecting Groups

Demonstrate knowledge and understanding of the properties and stabilities of commonly used protecting groups (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Identify and select the most appropriate protecting group(s) to enable the completion of a given synthetic sequence (A4, B1a, B1c, B1d, B1f, B1g, Cn, Co).

Demonstrate an awareness of the use of protecting groups in recently published syntheses, including the development of novel protecting groups when required (A2, A4, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Recognise the potential of novel or unusual protecting groups for in-house applications (A1, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

Retrosynthesis

Demonstrate confidence in the use of the techniques and terminology of retrosynthesis, e.g. disconnections, synthons, umpolung (A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Apply retrosynthetic analysis to deduce appropriate reagents for the synthesis of target molecules (A2, B1a, B1c, B1d, B1f, B1g, Cn, Co).

Critically assess the results of such an analysis, and propose, with reasoning, the preferred route of choice (A1, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

Catalytic Organometallic Chemistry: Palladium

Demonstrate a thorough understanding of the principles underlying catalytic organopalladium chemistry (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Show a sound understanding of the mechanisms of commonly used palladium mediated coupling reactions (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Appreciate the breadth of reactions that organopalladium chemistry offers the synthetic organic chemist, and recognise the continuous advances in this area (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Identify the potential for the use of palladium catalysed reactions in ongoing programmes of work, as appropriate (A1, A4, B1b, B1e, B1h, B2j, Cn, Co, Cq, Cs, Ct).

Green Chemistry

Demonstrate an understanding of the basic principles of green chemistry (A2, A7, B1b, B1e, B1h, Cm, Cn, Co, Cq).

Show an understanding of the importance of being green in a chemical environment (A2, B1a, B1c, B1d, B1f).

Be able to identify examples of greener alternatives to well known standard chemicals (reagents/solvents etc.) (A2, A4, B1b, B1e, B1h, B2j, Cm).

Identify the potential to use ‘greener’ processes in ongoing programmes where appropriate (A1, A4, B1b, B1h, B2j, Cn, Co, Cq, Cs, Ct).

Indicative Unit content

The subject matter is of relevance to both research and development chemists and includes: Carbonyl and Enolate Chemistry Oxidation and Reduction Reaction Selectivity: Protecting Groups Retrosynthesis Catalytic Organometallic Chemistry: Palladium Green Chemistry

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Assessment specification

At the end of this module, the participant will be required to write a report of 2500 words maximum (minimum 2000 words), including chemical structures where appropriate. This report will exemplify how the material covered in at least two sessions from Module 1 have been (or may be) applied to an ongoing GSK research programme. Cross referencing to recently published literature and/or internal/external lectures would also be required. The participant’s supervisor will provide written justification regarding their assessment of the final report. The supervisor’s line manager will review, discuss with the supervisor, and ultimately ratify the

recommendations of the participant’s supervisor. Clear guidelines and training where appropriate, will be provided to the both the supervisor and the supervisor’s line manager on how to assess the report. This will be directly related to the Learning Outcomes described above. The external examiner will have access to:

The participant’s worked solutions to tutorial questions

The participant’s report

The supervisor’s and supervisor’s line manager’s assessment summaries

Any additional examples where the knowledge acquired has been applied in the workplace.

Learning support/indicative reading and resources

Lecture notes and tutorial questions are normally made available in advance of each session. Further study of the subject is encouraged and this will improve the participant’s skills in efficient and effective literature retrieval and extraction of information.

For most sessions, a relevant textbook is recommended and references to recent literature are provided by the lecturer.

All participants have access to internet facilities which, through GSK’s electronic journal subscriptions, allows access to a huge volume of worldwide chemistry literature.

All participants are encouraged to discuss session topics/tutorial problems with their line managers, other participants/chemists or mentors.

The participant is entitled to support from their supervisor in the preparation of the report amounting to annotation and review of two drafts. The supervisor can provide advice and input into formatting and direction, but is not permitted to add technical content.

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Synthetic Chemistry Module 1 Assessment Form Candidate Identification Number:……………………………………...…................................................ Supervisor:…………………………………………………………………………………………………….. Assessment Criteria Fail Poor knowledge and understanding of the topics covered in the module despite the supervisor providing considerable support on module content and its implications during the preparation of the report. The organisation of the report was poor, failing to support logical technical arguments and concepts. Pass Good appreciation and understanding of the topics covered in module. Useful suggestions of how the knowledge could be applied. Has integrated knowledge from two or more lectures and included cross-referencing to published work. The organisation of the report was of a very good standard, with the diagrams and structures supporting clear technical arguments and concepts.

Supervisor’s evidence Please give examples of where the report provides the relevant evidence of achievement (refer to evaluation guidelines for Module 1) Tutorial problems Tutorial problems from all sessions completed satisfactorily YES/NO Report Report prepared with sufficient independence Logic flow Overall clarity Technically accurate

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Referencing Evidence of further study (reading, lectures, etc) Context/application of chemistry concepts into GSK work Appropriate breadth, depth and integration of Module 1 topics

Recommendation: Pass or Fail Please outline any particular areas of strength or, if fail, which of the above were not of the required standard.

Signed: (Supervisor) Date:

Comments from Supervisor’s Line Manager

Signed: Date:

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Evaluation Guidelines for Synthetic Chemistry Module 1 Carbonyl and Enolate Chemistry

Recognises the key role played by the carbonyl group as an electrophile in organic synthesis. Is aware of the various models proposed to explain the stereochemistry of addition to carbonyl groups – Cram, Felkin-Ahn, Cornforth.

Can identify the 3 ways in which enantioselective 1,2-addition to carbonyl groups can be achieved – chiral auxiliary, chiral reagent, chiral catalyst – and can exemplify.

Demonstrates knowledge of enolate formation from a range of carbonyl compounds; is able to rationalise the relative ease of formation of such enolates (pKa of ketones, aldehydes, esters, acids, amides, malonate).

Understands the importance of enolate geometry in determining the stereochemical outcome of reactions and is aware of how the choice of reagent and / or solvent can lead to selective trans or cis enolate formation – e.g. use of different boron enolates, addition of HMPA to lithium bases.

Oxidation and Reduction

Recognises and can exemplify the importance of oxidation for the introduction (and subsequent modification) of functionality in organic synthesis.

Able to identify a number of both 1 and 2 electron oxidants and provide examples of their utility.

Demonstrates knowledge of catalytic oxidation processes and can identify the advantages which such processes offer.

Can exemplify the utility of a number of reducing agents, including correctly identifying the ‘type’ – nucleophilic hydride, electrophilic, metal, non-metal.

Recognises the key role played by asymmetric reduction reactions in organic synthesis and can exemplify with reagents based on aluminium, ruthenium and boron.

Reaction Selectivity: Protecting Group Chemistry

Understands the need for protecting groups in modern synthetic organic chemistry.

Is able to identify various strategies involved in selecting protecting groups (acid, base, hydrogen, palladium labile); recognises examples of incompatibility.

Recognises which functional groups routinely require protection during complex multistep syntheses and can provide examples.

Can provide the properties of an ideal protecting group, including examples of where these requirements are met.

Can describe and differentiate between uniform, orthogonal and graded deprotection strategies.

Can identify opportunities for chemoselective synthesis without the need for protecting groups.

Retrosynythesis

Understands the value of retrosynthetic analysis in planning for success in complex, multistep organic synthesis.

Can demonstrate the principles of retrosynthetic analysis on a suitable example – identifying the key elements of carbon skeleton construction, introduction of functionality and the setting up of stereochemistry.

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Is able to explain ‘linear’ and ‘convergent’ synthesis and recognises the advantages of the latter.

Can integrate knowledge of protecting group chemistry into retrosynthetic analysis.

Able to identify a range of group disconnections including ‘one group’ and ‘two group’ disconnections, the ‘umpolung’ concept and the value which radical disconnections bring to organic synthesis.

Catalytic Organometallic Chemistry: Palladium

Demonstrates an understanding of how the 2 common oxidation states of palladium provide access to a wide range of (often complementary) synthetic transformations. Is able to identify typical Pd(0) and Pd(II) catalysts.

Able to identify the organopalladium reaction mechanism types – ligand substitution,

oxidative addition / reductive elimination, migratory insertion / -hydride elimination, nucleophilic attack and transmetalation.

Can recognise the different types of coupling reaction (Suzuki, Stille, Negishi, Sonagashira, Heck, Buchwald-Hartwig); able to supply examples of substrates, catalysts and products.

Demonstrates awareness of a variety of catalysts and reaction conditions and is able to identify why the range is key to the success of organopalladium chemistry.

Is familiar with the preparation and use of metallated alkenes including vinylsilanes, vinylstannanes and can provide examples of their synthetic utility.

Familiar with and can provide examples of -allylpalladium chemistry, including the use of heteroatoms as nucleophiles.

Shows an understanding of the use of non-aryl-aryl cross coupling reactions for the modification of alkenes at the sp2 centre and can identify the commonly used variants - Suzuki, Stille, Heck.

Is familiar with the order of complexation of alkenes with Pd(II) in terms both of substitution and electron rich/poor and can identify and exemplify, in a general sense, reactions of Pd(II) alkene complexes with 3 types of nucleophiles (oxygen, nitrogen and carbon).

Is able to identify Pd(0) catalysed insertion processes (CO, alkene) and exemplify one of these (carbonylation, Heck reaction).

Green Chemistry

Recognises the key role green chemistry has in protecting our environment (e.g. cost of waste – environmentally and monetarily, environmental disasters etc.).

Demonstrates an awareness of the key principles in green chemistry: waste prevention, maximising the incorporation of starting materials in chemical synthesis, generation of non-hazardous substances, chemical products designed so as to be non-toxic, use of catalysts, minimisation of energy demands in chemical syntheses, use of increasingly renewable raw materials etc.

Appreciates the key aims and order of preference when designing greener chemical processes (replacement of hazardous materials, reduction of chemical usage, recycling, benign disposal).

Has an understanding of new green technologies such as the use of enzymes, catalysis, flow chemistry, SC CO2, aqueous systems.

Understands and can calculate fundamental green chemistry metrics (yield, effective mass yield [EMY], E Factor, Atom Economy [AE], Mass Intensity [MI], Carbon Efficiency [CE], Reaction Mass Efficiency [RME]) and appreciates their relative merits.

Is aware of renewable sources of chemicals.

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Has an appreciation of environmental chemistry legislation (REACh, Substance classification, RoHS).

Can show examples of the application of green chemistry approaches to pharmaceutical chemistry, manufacturing, pharmaceuticals in the environment (toxicity, bioaccumulation, persistence).

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Unit/Module Title Synthetic Chemistry 2

Code GSK/Chem 2




15 credits

Brief Rationale The aim of Module 2 is to build on the foundations of Module 1, with a continuing emphasis on mechanism-based teaching of current synthetic methodology. Furthermore, references to examples from the recent chemical literature are a key component of the teaching material. This module provides a continuation of the learning framework for new staff entering the company. It is also suitable for those who have previous industrial experience (obtained e.g. within another organisation), or those who wish to refresh and increase their knowledge of modern synthetic chemistry. Whilst Module 1 provides the participant with the knowledge and confidence to discuss chemistry in a range of settings, participation in this more advanced module will provide a greater depth of understanding of the more specialised topic areas covered, particularly their application to pharmaceutical research and development. As before, further independent study of each subject is encouraged, and this will continue to improve the attendee’s skills in efficient and effective literature retrieval and extraction.


The module provides a continuing framework of learning for new staff entering the company, primarily Chemistry graduates. However it is also suitable for those who have more industrial experience, but who wish to refresh and build on their knowledge and appreciation of synthetic chemistry. This group may include both staff with doctorates and staff who initially joined the company without a first degree.

Learning Hours 150

Learning Outcomes On completion of each of the sessions of this module, participants should be able to demonstrate knowledge and understanding of each of the topics, with application to their ongoing work and to recent advances as published in the current literature. The learning outcomes for each session are captured as follows:- Aromatic Chemistry

Demonstrate a thorough understanding of the principles of aromaticity, the classical reactions of aromatic molecules, and their importance in synthetic organic chemistry (A2,

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B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Understand the mechanisms and synthetic applications of catalytic carbon-carbon bond forming reactions onto aromatic systems (e.g. Heck, Stille, Suzuki etc), applying knowledge gained in other sessions of the modules (A2, B1a, B1c, B1d, B1f, B1g).

Understand the mechanisms and synthetic applications of modern methods used to react amines, alcohols, etc with aromatic systems (e.g. Buchwald-Hartwig chemistry) (A2, B1a, B1c, B1d, B1f, B1g).

Select appropriate reactions/methods to achieve the synthesis of selected targets, as appropriate (A1, A4, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

Reactions of Heterocycles

Demonstrate an understanding of the fundamental reactivities of the heterocyclic systems discussed, including 5- and 6-membered monocyclic heterocycles, quinolines, isoquinolines and indoles (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Apply this understanding to the design of synthetic routes to key compounds (A1, B1a, B1c, B1d, B1e, B1f, B1g, B1h, B2j, Cm, Cn, Co, Cq).

Relate the properties of heterocycles with more than one heteroatom to the parent systems, understanding the similarities and differences in reactivities (B1a, B1c, B1d, B1f, B1g).

Phosphorous and Sulphur

Demonstrate an understanding of the principle features that distinguish phosphorous and sulphur-based reagents from others in organic synthesis (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Show familiarity with a number of synthetically useful reactions of organophosphorous and organosulphur reagents (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Recognise the key properties that influence the outcome of reactions of these reagents, and hence gain an ability to predict the outcome of reactions (including stereochemistry), or choose the most appropriate reagent for a given transformation (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Boron and Silicon

Understand the principle features that distinguish boron and silicon-based reagents from others in organic synthesis (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Show familiarity with a number of synthetically useful reactions of organoboron and organosilicon reagents (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Recognise the key properties that influence the outcome of reactions of these reagents, and hence gain an ability to predict the outcome of reactions (including stereochemistry), or choose the most appropriate reagent for a given transformation (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Rearrangements

Explain the mechanisms of polar rearrangements, in particular as exemplified by key well-known named reactions (e.g. Curtius, Beckmann, Pummerer rearrangements) (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Appreciate the factors influencing the stereochemical outcome of these rearrangements, and apply to the design of synthetic schemes, as appropriate (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Physical Organic Chemistry

Recognise that physical organic chemistry concepts underpin all reactions (A2, A7, B1c, B1d, B1f, B1g, Cm, Cn, Co).

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Appreciate that an understanding of physical chemistry parameters is essential for planning any new/novel reactions (A2, B1c, B1d, B1f, B1g, Cm, Cn).

Appreciate the factors influencing the kinetics and/or thermodynamics of a given reaction (A7, B1c, B1d, B1f, B1g, Cm, Cn).

Understand (and where appropriate be able to calculate) key physical parameters such as pKa and equilibrium constants (A7, B1c, B1d, B1f, B1g, Cm, Cn, Co).


The subject matter is of relevance to both research and development chemists and includes:

Aromatic Chemistry Reactions of Heterocycles Phosphorous and sulphur Boron and silicon Rearrangements Physical Organic Chemistry

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Successful completion of the module will require the participant to pass all aspects of the assessment process. These comprise completed tutorial problems, a written report and a viva voce examination. The participant will be required to write a report of 2500 words maximum (minimum 2000 words), including chemical structures where appropriate. This report will exemplify how the material covered in at least two sessions from Module 2 has been (or may be) applied to an ongoing GSK research programme. Cross referencing to recently published literature and/or internal/external lectures would also be required. The viva voce examination will be conducted by two selected senior/experienced members of staff, who are also likely to have an active involvement with our recruitment of PhD/Post-Doc qualified chemists, and thus a good appreciation of the level of knowledge and understanding we wish to assess. To initiate the detailed science-driven discussion, the participant will be asked to discuss a particular topic of their own choosing (using visual aids, as required). Through detailed scientific questioning, the assessor will seek to establish that the participant has appropriate knowledge and understanding at Masters level. The participant will be expected to defend their position during detailed chemistry questioning. Furthermore, the assessor will seek to establish understanding of a range of material covered in other sessions of Module 2. The focus will be on a high quality issues-led discussion and debate, rather than a pre-set list of questions to be covered. This is an established practice at GSK. The assessors will write a formal report, indicating whether the participant has successfully passed the module. Clear guidelines and training where appropriate, will be provided to the assessors on how to conduct the viva voce examination, and the expected level of knowledge and understanding that the participant is required to demonstrate in order to pass the module. This will clearly be directly related to the Learning Outcomes described above. The external examiner will have access to:



The participant’s visual aids for viva voce examination

Assessors’ report






All participants are encouraged to discuss session topics/tutorial

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problems with their line managers, other participants/chemists or mentors.


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Synthetic Chemistry Module 2 Assessment Form Candidate Identification Number:…………………………..…………………...……............................... Assessors:…………………………………………………………………………………………………...… Assessment Criteria Fail Poor knowledge and understanding of the topics covered in the module (see evaluation guidelines). In the report and/or viva voce discussion, the participant failed to demonstrate adequate breadth and/or depth of the material. Pass Topics selected have been clearly identified and are well exemplified. Participant has a good understanding and appreciation of the chemistry discussed and can clearly demonstrate how this has been relevant to a GSK research effort. Information from a minimum of two topics has been incorporated. There is clear evidence of further study around the topics. The organisation of the report and the visual aids for the viva voce examination were of a very good standard, with the diagrams and structures supporting clear technical arguments and concepts

Assessors’ evidence Please give examples of where the report and viva voce examination provide the relevant evidence of achievement (refer to evaluation guidelines for Module 2) Tutorial problems Tutorial problems from all sessions completed satisfactorily YES/NO Report Logic flow Overall clarity Technically accurate

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Referencing Evidence of further study (reading, lectures, etc) Context/application of chemistry concepts into GSK work Appropriate breadth, depth and integration of Module 2 topics Viva voce examination Please indicate the evidence as it relates to those topics chosen by the participant and also those additional topics that have been discussed. Technical Engaged in detailed scientific discussion Generated and prioritised suggestions/ideas Used nomenclature and vocabulary accurately Showed breadth of knowledge and evidence of further study (within research department or wider literature)

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Behavioural Fluidity of discussion Clarity of logic Enthusiasm for material Independence/ability to defend position/ideas or to constructively disagree

Recommendation: Pass or Fail Please outline any particular areas of strength or, if fail, which of the above were not of the required standard.

Signed: (Assessor 1) Date: (Assessor 2)

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Evaluation Guidelines for Synthetic Chemistry Module 2 Aromatic Chemistry

Understands the theory of aromaticity and is familiar with the special properties which this imparts on aromatic compounds.

Is familiar with electrophilic aromatic substitution, including the mechanism, the different substituents which can be introduced, the directing and activating / deactivating effects of existing substituents on further substitution.

Understands the synthetic value of directed metalation of aromatic compounds and can provide examples of directing groups.

Demonstrates awareness of nucleophilic aromatic substitution, including the severe limitations of the reaction, and of aromatic Sn1 reactions.

Can provide details of the formation of aryl metals and of the different metals which can be employed. Is aware of the synthetic utility of such species and can provide examples. Understands how directed ortho-metalation has made a significant additional contribution to the utility of this reaction type.

Is aware of methodologies for aromatic nucleophilic and electrophilic amination.

Can correctly identify the products of Birch reduction and is aware of the factors which influence reactivity and regioselectivity.

Reactions of Heterocycles

Is familiar with the presence of heterocycles in commercial drug molecules and can provide examples.

Can correctly identify a number of nitrogen, oxygen, sulphur and mixed heterocycles.

Understands the electronic configuration in various nitrogen heterocycles and can use this to predict basicity (or lack of).

Able to identify and rationalise the electrophilic and nucleophilic reactivity of heterocycles, including favoured positions for the reactions.

Recognises the importance of tautomerism in the reactivity of heterocycles.

Is able to provide examples where the metalation of heterocycles extends their synthetic

utility, including examples of both ring and -benzylic metalation. Phosphorus and Sulphur

Understands the benefits which the lower electronegativity of phosphorus and sulphur (cf oxygen and nitrogen), the longer bonds formed to carbon and the multiple valencies and coordination states bring to organic synthesis and can exemplify.

Can identify methods for the formation of organophosphorus reagents – reduction of P(V) to P(III) and vice versa, ligand exchange on phosphorus with examples.

Is able to exemplify substitution (Mitsunobu) and halogenation (PX5, PX3, POX3 etc) reactions.

Demonstrates knowledge of the use of phosphorus reagents in olefination reactions – Wittig, Emmons-Horner and Wadsworth-Emmons – and can identify the phosphorus species involved in each.

Can provide details of phosphorus mediated alkene synthesis, including the Wittig reaction and similar variants. Understands the key role played by phosphorus in these reactions and the way in which reaction conditions can influence formation of cis or trans alkene isomers.

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Understands how sulphur can behave as both an electrophile and a nucleophile in different reactions and can provide examples of each.

Can provide details of the Julia olefination reactions (Marc or Sylvestre or both) and of Corey’s reagent(s).

Is aware of the use of sulphoxides as chiral auxiliaries and can provide an example.

Demonstrates knowledge of the use of dithianes for carbonyl ‘umpolung’, including dithiane formation and deprotection procedures.

Boron and Silicon

Understands the ways in which the electronic configuration of boron, as an element and in compounds, governs organoboron chemistry – Lewis acidity, acceptance of lone pairs from reaction partners.

Is able to identify a number of boron based reducing agents and provide details of their relative reactivity / selectivity, including the use of chiral boron reagents for asymmetric reduction – to include hydride reagents and hydroboration.

Demonstrates knowledge of the use of allylboranes and vinylboranes in organic synthesis.

Is familiar with the key role which boronic acids play in the formation of C-C bonds and can exemplify.

Understands how the longer Si-X bond lengths (cf C-X), the increased electropositivity of silicon (cf carbon) and the availability of d-orbitals for penta- and hexa- valency are responsible for the useful synthetic properties of silicon reagents.

Can provide details of the use of silanes as reducing agents – hydrosilylation, including an asymmetric example.

Is familiar with the role of silyl enol ethers as stable enolate equivalents, including how these can be generated.

Demonstrates knowledge of how the ability of silicon to stabilise a -positive charge makes vinylsilanes, arylsilanes and allylsilanes useful synthetic tools and can provide examples of their use.

Recognises that silicon can also stabilise an -negative charge and can provide examples of the use of silicon stabilised anions.

Is familiar with the Peterson olefination reaction and how different conditions for the elimination step can provide different olefin isomers.

Rearrangements

Demonstrates knowledge of nucleophilic rearrangements involving an electron deficient carbon terminus, including details of the different migrating groups – alkyl, hydride, carbanion and carbene and can identify 2 named examples with mechanisms (e.g. Wagner-Meerwein, Pinacol, Favorskii, Wolff, Arndt-Eistert).

Provides details of nucleophilic rearrangements to a heteroatom terminus and can identify examples involving nitrogen (e.g. Beckmann, Curtius, Schmidt, Hoffmann) and oxygen (Baeyer-Villager).

Is aware of acid catalysed rearrangements around aromatic rings and side chains and can provide 1 example.

Recognises that electrophilic rearrangements are much less common than their nucleophilic counterparts and that the migration origin for the former is a heteroatom

capable of stabilising a negative charge at the -position.

Can provide information on polar sigmatropic rearrangements, specifically either the 3,3 variant (Fischer indole) or 5,5 variant (benzidine).

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Physical Organic Chemistry

Understand the concepts and equations associated with the kinetic and thermodynamic control of reactions (kinetics, equilibrium).

Understand the differences that occur in certain reactions depending on whether they are carried out under kinetic or thermodynamic control.

Know the approximate pKa values of common functional groups.

Be able to make an appropriate choice of base for a reaction based on knowledge of the pKa of the material being deprotonated.

Understand the concepts of solubility and distribution.

Awareness of the effects different solvents can have on reaction outcome and why.

Is able to give an example of how a reaction mechanism might be elucidated (e.g. isotope effects).

Understand reaction rates and key related concepts (e.g. Curtin-Hammett principle, Hammond’s postulate).

Demonstrate an understanding of the concept of catalysis and effect on rates of reaction.

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Unit/Module Title Synthetic Chemistry Module 3

Code GSK/Chem 3




15 credits

Brief Rationale The aim of Module 3 is to build on the foundations of Module 1, with a continuing emphasis on mechanism-based teaching of current synthetic methodology. Furthermore, references to examples from the recent chemical literature are a key component of the teaching material. This module provides a continuation of the learning framework for new staff entering the company. It is also suitable for those who have previous industrial experience (obtained e.g. within another organisation), or those who wish to refresh and increase their knowledge of modern synthetic chemistry. Whilst module One provides the participant with the knowledge and confidence to discuss chemistry in a range of settings, participation in this more advanced module will provide a greater depth of understanding of the more specialised topic areas covered, particularly their application to pharmaceutical research and development. As before, further independent study of each subject is encouraged, and this will continue to improve the attendee’s skills in efficient and effective literature retrieval and extraction.


The module provides a continuing framework of learning for new staff entering the company, primarily Chemistry graduates. However it is also suitable for those who have more industrial experience, but who wish to refresh and build on their knowledge and appreciation of synthetic chemistry. This group may include both staff with doctorates and staff who initially joined the company without a first degree.

Learning Hours 150

Learning Outcomes On completion of each of the sessions of this module, participants should be able to demonstrate knowledge and understanding of each of the topics, with application to their ongoing work and to recent advances as published in the current literature. The learning outcomes for each session are captured as follows:- Heterocycle Assembly

Recognise the common reactions involved in heterocycle assembly, and the importance of carbonyl group chemistry to these (applying knowledge gained in Module 1) (A7, B1c, B1d, B1f, B1g, Cm, Cn, Co).

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Appreciate the importance of oxidation/reduction steps in the syntheses of heterocyclic systems (A2, B1c, B1d, B1f, B1g, Cm, Cn, Co).

Demonstrate knowledge of several standard approaches to the synthesis of key nitrogen-containing heterocycles e.g pyridines, quinolines, pyrroles, and apply to the synthesis of selected target molecules, as appropriate (A1, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

Catalytic Organometallic Chemistry: Beyond Palladium

Demonstrate an understanding of the basic principles of organotransition metal chemistry (A7, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Show a sound understanding of the mechanisms of commonly used coupling reactions involving catalysis by transition metals and their complexes above and beyond palladium based systems (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Appreciate the breadth of reactions that organometallic chemistry offers the synthetic organic chemist, and recognise the continuous advances in this area (A2, A4, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Identify the potential for the use of metal catalysed reactions in ongoing programmes of work, as appropriate (A1, A4, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

Reactive Intermediates

Explain the mechanisms of synthetic reactions involving particular “reactive intermediates” specifically, but not limited to, nitrenes and carbenes (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Appreciate the synthetic utility of the reactions of these species, and apply to the synthesis of selected target molecules as appropriate (A1, A4, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq, Cs, Ct).

Demonstrate an understanding of the mechanisms of radical reactions used in modern synthesis, particularly within the context of intramolecular reactions (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Appreciate the synthetic utility of radical reactions, and apply to the synthesis of selected target molecules as appropriate (A1, A4, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq, Cs, Ct).

Pericyclic Reactions

Understand the fundamental theory that underpins pericyclic reactions (FMO theory, Woodward-Hoffmann rules) (A2, A7, B1a, B1c, B1d, B1f, B1g).

Demonstrate an understanding of the key mechanisms underlying synthetically useful cycloaddition reactions (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Also show an understanding of other sigmatropic and electrocyclic reactions, and their outcomes depending on whether under thermal or photochemical conditions (A2, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Apply the acquired knowledge to construct ring systems in a predictable regio-and stereo-controlled manner (B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Asymmetric Synthesis

Recognise, understand and apply the terms used in the description of asymmetric molecules (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Understand the types of methods used in asymmetric synthesis, e.g. use of chiral auxillaries, chiral reagents and chiral catalysts, appreciating the synthetic opportunities provided by each method (A2, A7, B1a, B1c, B1d, B1f, B1g, Cm, Cn, Co, Cq).

Select appropriate reactions/methods to achieve the synthesis of selected targets, as appropriate (A1, A4, B1b, B1e, B1h, B2j, Cm, Cn, Co, Cq, Cs, Ct).

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Biological Chemistry

Demonstrate a thorough knowledge of the key ‘building blocks of life’ (amino acids – proteins, nucleic acids – DNA) (A2, A7, B1a, B1c, B1d, B1f, Cm, Cn, Co, Cq).

Understand principal mechanisms in biological chemical reactions (A2, A7, B1a, B1c, B1d, B1f, Cm, Cn, Co, Cq).

Recognise key pathways and their role in the biosynthesis of complex natural products (A2, A7, B1a, B1c, B1d, B1f, Cm, Cn, Co, Cq).


The subject matter is of relevance to both research and development chemists and includes: Heterocyclic Assembly Catalytic Organometallic Chemistry: Beyond Palladium Reactive Intermediates Pericyclic Reactions Asymmetric Synthesis Biological Chemistry


Successful completion of the module will require the participant to pass all aspects of the assessment process. These comprise completed tutorial problems, a written report and a viva voce examination. The participant will be required to write a report of 2500 words maximum (minimum 2000 words), including chemical structures where appropriate. This report will exemplify how the material covered in at least two sessions from Module 3 have been (or may be) applied to an ongoing GSK research programme. Cross referencing to recently published literature and/or internal/external lectures would also be required. The viva voce examination will be conducted by two selected senior/experienced members of staff, who are also likely to have an active involvement with our recruitment of PhD/Post-Doc qualified chemists, and thus a good appreciation of the level of knowledge and understanding we wish to assess. To initiate the detailed science-driven discussion, the participant will be asked to discuss a particular topic of their own choosing (using visual aids, as required). Through detailed scientific questioning, the assessor will seek to establish that the participant has appropriate knowledge and understanding at Masters level. The participant will be expected to defend their position during detailed chemistry questioning. Furthermore, the assessor will seek to establish understanding of a range of material covered in other sessions of Module 3. The focus will be on a high quality issues-led discussion and debate, rather than a pre-set list of questions to be covered. This is an established practice at GSK. The assessors will write a formal report, indicating whether the participant has successfully passed the module. Clear guidelines and training where appropriate, will be provided to the assessors on how to conduct the viva voce examination, and the expected level of knowledge and understanding that the participant is required to demonstrate in order to pass the module. This will clearly be directly related to the Learning Outcomes described above. The external examiner will have access to:

April 2012 version



The participant’s visual aids for viva voce examination

Assessors’ report






All participants are encouraged to discuss session topics/tutorial problems with their line managers, other participants/chemists or mentors.


April 2012 version

Synthetic Chemistry Module 3 Assessment Form Candidate Identification Number:…………………………………..…………...……............................... Assessors:……………………………………………………………………………………………...……… Assessment Criteria Fail Poor knowledge and understanding of the topics covered in the module (see evaluation guidelines). In the report and/or viva voce discussion, the participant failed to demonstrate adequate breadth and/or depth of the material. Pass Topics selected have been clearly identified and are well exemplified. Participant has a good understanding and appreciation of the chemistry discussed and can clearly demonstrate how this has been relevant to a GSK research effort. Information from a minimum of two topics has been incorporated. There is clear evidence of further study around the topics. The organisation of the report and the visual aids for the viva voce examination were of a very good standard, with the diagrams and structures supporting clear technical arguments and concepts

Assessors’ evidence Please give examples of where the report and viva voce examination provide the relevant evidence of achievement (refer to evaluation guidelines for Module 3) Tutorial problems Tutorial problems from all sessions completed satisfactorily YES/NO Report Logic flow Overall clarity Technically accurate

April 2012 version

Referencing Evidence of further study (reading, lectures, etc) Context/application of chemistry concepts into GSK work Appropriate breadth, depth and integration of Module 3 topics Viva voce examination Please indicate the evidence as it relates to those topics chosen by the participant and also those additional topics that have been discussed Technical Engaged in detailed scientific discussion Generated and prioritised suggestions/ideas Used nomenclature and vocabulary accurately Showed breadth of knowledge and evidence of further study (within research department or wider literature)

April 2012 version

Behavioural Fluidity of discussion Clarity of logic Enthusiasm for material Independence/ability to defend position/ideas or to constructively disagree

Recommendation: Pass or Fail Please outline any particular areas of strength or, if fail, which of the above were not of the required standard

Signed: (Assessor 1) Date: (Assessor 2)

April 2012 version

Evaluation Guidelines for Synthetic Chemistry Module 3

Synthesis of Heterocycles

Recognises the key role of ammonia (amines) and carbonyl compounds in the formation of heterocycles and can identify the two key reaction types (imine formation and enamine aldol).

Can identify 3 different synthetic strategies for the synthesis of pyridines (5C+1N), (2C+2C+1C+N) and (2C+2C+2C+N) and is able to exemplify 2 of these strategies.

Is familiar with 2 synthetic strategies for quinolines and 2 for isoquinolines and can provide examples.

Is aware of the common starting material which can provide pyrroles, thiophenes and furans and can exemplify all 3 reaction variants.

Demonstrates awareness of the key role of dicarbonyl compounds in synthetic routes to diazines (pyrazines, pyridazines and pyrimidines) and can exemplify for 2 of these.

Can provide an example of the synthesis of both 1,2-azoles and 1,3-azoles

Is familiar with the Fischer synthesis of indoles and can provide brief details of 2 other strategies for indole ring construction.

Catalytic Organometallic Chemistry: Beyond Palladium

Understands the key disadvantages associated with Pd catalysis (primarily cost, environmental impact) and the need to find alternatives.

Can explain the significance of the 18-electron rule in the role of transition metals in organic synthesis, provide examples of 16-electron ‘exceptions’ and can demonstrate how to count the electrons in a complex.

Recognise that iron is a cheap and environmentally benign catalyst.

Can describe examples of reactions that iron can catalyse (cross-couplings, addition reaction, substitutions, cycloadditions etc.)

Recognise that copper is a cheap alternative to palladium.

Can describe examples of reactions that copper can catalyse (C-Het bond formation, C-C cross couplings etc.)

Recognises metal catalysis is a rapidly developing area with new process being discovered almost daily.

Shows an appreciation of ground-breaking advances in the field and new metals being used (e.g. Ir, Ru, Rh etc.).

Appreciates and can give examples of ‘state-of-the-art’ metal catalysed reactions (e.g. C-H activation leading to functionalisation – arylation, hydroacylation, borolation, atom insertions).

Reactive Intermediates

Can exemplify the generation and synthetic utility of dihalocarbenes in both ring expansion and ring formation reactions.

Is familiar with the general chemical structures / features of carbenes and nitrenes, including the alternative representations and the existence of singlet and triplet states. Can identify general reaction types for generation of both carbenes and nitrenes.

Recognises the key role played by bond insertion in the chemistry of carbenes and nitrenes and can provide examples of both intermolecular and intramolecular reactions (e.g Reimer Tieman reaction and 5-membered ring formation).

April 2012 version

Can describe an example of both cyclopropanation and aziridination and is aware of the asymmetric variants of both reactions.

Demonstrates awareness of the role of metals in providing carbenoid (and more recently nitrenoid) species with moderated activity and hence increased selectivity. Is able to identify 2 transition metals which have been used.

Is aware of the utility of stable transition metal carbenoids in promoting metathesis reactions and can provide a general reaction mechanism for such reactions.

Is familiar with the basic processes which drive radical chemistry (atom abstraction, -

scission, rearrangement, radical-radical reactions and additions to -bonds) and the key role which chain reactions play in radical processes.

Is aware of the existence of both ‘nucleophilic’ and ‘electrophilic’ radicals and can demonstrate how molecular orbital considerations can explain these reactivities.

Can exemplify the key role played by radical species in cyclisation reactions, including an example of a tandem radical cyclisation using either acyl or nitrogen centred radicals.

Recognises the utility of 1,5-hydrogen abstraction in the functionalisation of remote carbon atoms and can exemplify with either the Hofmann-Loffler-Freytag or Barton reactions.

Demonstrates awareness of the utility of radical reactions in achieving ring expansion and can show how this works for either 1-carbon or 3-carbon expansions.

Can describe a general example of a ring expansion reaction using an aminyl radical which provides a macrocyclic lactam.

Pericyclic Reactions

Shows and understanding of the molecular theory that underpins pericyclic reactions (e.g. FMO theory, Woodward-Hoffmann rules).

Demonstrates knowledge of the mechanistic nature of most cycloaddition reactions (concerted) and is aware of the 3 methods which can be used to predict thermal vs photochemical conditions and the expected regiocontrol and stereocontrol in cycloadditions.

Recognises that concerted cycloadditions involve suprafacial interactions of molecular orbitals and leads to conservation of stereochemistry whereas antarafacial molecular orbital interactions are characteristic of stepwise cycloadditions where steric interactions are often unfavourable and stereochemical information is lost.

Is able to identify the 5 principal types of cycloadditions (2+1, 2+2, 3+2, 4+2, 6+4) and can provide a general example of each type.

Can exemplify the processes involved in the formation of ketenes and their reaction with olefins to form cyclobutanones.

Is familiar with the formation and use of 1,3-dipoles in cycloadditions and can identify 3 types of 1,3-dipole (ozone, diazoalkanes, nitrones, nitrile oxides, azomethine ylides) and the products which result from their reactions with olefins.

Recognises the key role played by the Diels Alder reaction in organic synthesis. Is familiar with the ‘Kinetic Endo Effect’ and can use this to predict the stereochemistry of a typical DA cycloaddition. Can identify 2 ways of accelerating DA reactions (Lewis acid and pressure).

Recognises other electrocyclic and sigmatropic reactions.

Can explain the differences in structural outcome seen when conducting electrocyclic reactions under thermal or photochemical conditions (e.g. con- and dis-rotatory mechanisms).

Asymmetric Synthesis

April 2012 version

Demonstrates awareness of the 3 ways in which asymmetric synthesis is commonly achieved – starting from the chiral pool, use of chiral auxiliaries and use of chiral reagents, including chiral catalysts.

Can identify common chiral pool molecule classes, including sugars, amino acids and terpenes.

Is familiar with the principles of the Chiron approach, including cases where existing asymmetry is preserved (correlation), partially destroyed, used to induce additional asymmetry in new stereochemical centres (communication).

Provides details of the concept of chiral auxiliaries and can identify the properties of a good chiral auxiliary including – cheap, easily available in both optically active forms, readily attached and removed from the substrate.

Can give examples of reaction types to which the use of chiral auxiliaries has been successfully applied, including 2 specific examples – e.g aldol, Diels-Alder, amino acid synthesis.

Demonstrates knowledge of the use of chiral reagents in asymmetric synthesis including boranes / boronates, chiral bases and application of tartrates in asymmetric epoxidation.

Is aware of developments in asymmetric catalysis and can identify 1 chemical and 1 enzymatic example.

Biological Chemistry

Can name the natural amino acids, recall their structures and abbreviations, and their role as the building blocks of proteins.

Show an understanding of protein structure and methods of synthesis (e.g. Strecker synthesis of AAs, Merrifield - peptides, 1o structure, B-sheets, disulfide bridges, helices etc.).

Know the structure of the nucleic acids and understand how they build up to form DNA.

Show an appreciation of the structural features of DNA (base pairing, double-helix).

Demonstrates a good understanding of the principal mechanisms in biochemical reactions and how they relate to laboratory techniques (e.g. NADPH – hydride reduction, pyridoxal phosphate – reductive amination, acetyl CoA – enol chemistry).

Understands and can work through some of the the key biosynthetic pathways (citric acid cycle, shikimic acid pathway, metabolism).

Be able to give examples of the complex natural products that come about via the aforementioned biosynthetic pathways (e.g. fatty acids, polyketides/lipids, prostaglandins, terpenoids, alkaloids, carbohydrates).

Accredited Programme Title:- GSK Chemistry Continuing ... · of HMPA to lithium bases. Oxidation...

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