Designing Organic Syntheses Syntheseplanung Starting material Target molecule 1
Can the Computer do the retrosynthetic analysis for me? Computer-generated Retrosynthesis Programme LHASA (http://lhasa.harvard.edu): E.J. Corey Based on known reactions; interactive search for the best route. 2
Computer-generated Retrosynthesis Programme LHASA (http://lhasa.harvard.edu) Based on known reactions; interactive search for the best route. Computer-generated Retrosynthesis Programme LHASA (http://lhasa.harvard.edu) Based on known reactions; interactive search for the best route. 3
Computer-generated Retrosynthesis WODCA; logic-oriented programme; Gasteiger, Erlangen Computer-generated Retrosynthesis WODCA; logic-oriented programme; Gasteiger, Erlangen 4
Computer-generated Retrosynthesis SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html Claim: SynGen generates only the shortest and most efficient syntheses. SynGen generates the syntheses without user intervention, freeing it from user bias and allowing it to explore all possibilities. All the generated syntheses have commercially-available starting materials. Free Mac Version for Download; no Windows Version available Computer-generated Retrosynthesis SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html 5
Computer-generated Retrosynthesis SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html Computer-generated Retrosynthesis SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html 6
Functional Group Interconversions Functional group interconversions (FGIs) Change carbon oxidation level 7
Functional group interconversions (FGIs) Same carbon oxidation level Amines ! 8
Amines ! Removal of functional groups – Hydrocarbon synthesis 9
Disconnections Strategic disconnection approach 10
Strategic structure approach 11
Strategic structure approach C-C Bond Formation 12
No functional group present One group disconnection based on normal carbonyl reactivity 13
One group disconnection based on normal carbonyl reactivity One group disconnection based on normal carbonyl reactivity 14
Two group disconnection based on normal carbonyl reactivity 15
Retrosynthesis with classic carbonyl reactions - overview 16
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d) Two-group Disconnections: “Unlogical” disconnections, “unnatural” reactivity patterns Synthetic strategies for 1,2-difunctionalysed compounds Synthon required 18
Use of 1,2-difunctionalysed starting materials Difunctionalisation of alkenes and epoxide opening 19
α - Functionalisation of carbonyl compounds α - Functionalisation of carbonyl compounds 20
α - Functionalisation of carbonyl compounds Radical coupling Pinacol reaction 21
Acyloin condensation Umpolung strategies CN - 22
Dithioacetals 23
Nitroalkanes Imidoyl 24
Alkyne Synthetic strategies for 1,4-difunctionalysed compounds Commercially available starting materials Acyl equivalent + Michael acceptor Acyl anion synthons 25
Homoenolate + electrophilic carbonyl resonance 26
Additional Umpolung strategies 27
Enolate + α -functionalised carbonyl compound Enolate + α,β -unsaturated nitro compound (Michael type acceptors) 28
Enolate + α,β -unsaturated nitro compound (Michael type acceptors) Epoxide based transformations 29
Epoxide based transformations Epoxide based transformations 30
Functional group addition 31
Reconnection strategies for 1,6-difunctionalysed compounds Ozonolysis of cycloalkenes Baeyer-Villiger rearrangement 32
Beckmann rearrangement 33
Synthesis of carbocyclic compounds Diels-Alder disconnections 34
Synthesis of carbocyclic compounds Cyclisation reactions Synthesis of carbocyclic compounds Other methods of carbocycle synthesis 35
Synthesis of heterocyclic compounds Synthesis of oxiranes, thiirans and azirans 36
Synthesis of oxiranes, thiirans and azirans Synthesis of oxiranes, thiirans and azirans 37
Synthesis of furans Paal-Knoor Synthesis of furans Feist-Benary Addition to alkyne 38
Thiophen Pyrrol: Paal-Knorr: Knorr 39
Hantzsch Fischer-Indole 40
Hantzsch pyridine Quinolines (Deutsch: Chinoline!) Quinoline Isoquinoline Skraupsch synthesis 41
Birschler-Napieralski Pictet-Spengler Oxazole Isoxazole 42
Thiazole Pyrazole 1,4-Dioxane 43
Assessment of Syntheses and Strategies The assessment of a synthesis depends on the aim of the synthesis. • shortest synthesis (time required) • cheapest synthesis (material needed) • a new synthesis (to get a patent) • environmental benign synthesis (minimize waste) • synthesis without toxic risk (no toxic reagents and intermediates) • reliable synthesis (no risk of failure) • ……… Assessment of a chemical reaction • High chemical yield • Good chemo-, regio- and stereochemistry • Catalytic reagents, not stoichiometric • Minimal energy input; efficient energy intake and perfect control of reaction (microwave, irradiation, microreactor) • Use of renewable resources (natural products) • No use of mutagenic and teratogenic compounds; consideration of oeco- and human toxcicity of all chemicals involved 1
Assessment of a chemical reaction The ideal synthesis is, • safe • simple • 100 % yield • one step • resource efficient • environmentally acceptable • uses available, if possible renewable, starting materials Assessment of a chemical compound The assessment of a chemical compound depends on its use, but there are also general considerations particular important large scale commodities • No oeco- or human toxicity • Distribution and persistence in the environment should be limited • Complete degradation and mineralization possible • Lifetime of the compound adjusted to its use • Highly effective in its properties; minimal amount needed to perform the desired task • Not mutagenic, teratogenic or carcinogenic 2
Assessment of a chemical compound The ideal chemical compound (material, drug, dye, polymer etc.) is • safe and non-toxic • cheap • shows high performance during its life cycle • then completely degrades to minerals • can be recycled to safe energy and material resources´ • does not accumulate in the environment • … Assessment of a chemical compound Materials and compounds that later turned out not to be good: Cl Cl - DDT Cl Cl Cl - Asbestos - PCB Cln Cln 3
Assessment of a synthesis Number of steps as indicator “The ideal synthesis creates a complex molecule .. in a sequence of only construction reactions involving no intermediary refunctionalizations, leading directly to the target, not only its skeleton but also its correctly placed functionality.” Hendrickson , J. Am. Chem. Soc. 1975, 97, 5784 Generation of complexity - Complexity generating reactions, e.g. cycloaddition yielding tricycles - Late increase of complexity in the synthesis is advantageous Linear vs convergent strategies - Higher overall yield achievable by convergent strategies Risk of failure -Unknown or hypothetical key step increases risk of failure - Good syntheses has at least on safe alternative - Change in sequence of steps increases flexibility “ Get the most done in the fewest steps and the highest yield!” 4
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Protecting groups for alcohols Silyl ether Silyl ether 6
Silyl ether Silyl ether 7
Carbonate Carbonate Ester 8
Ether Photolabile protecting groups 9
Orthogonal protecting groups Key steps of the synthesis Weinreb Amide 10
Corey-Bakshi-Shibata Reduction Itsuno-Corey Reduction Practical enantioselective reduction of ketones using oxazaborolidine catalyst generated in situ from chiral lactam alcohol and borane Y. Kawanami, S. Murao, T. Ohga, N. Kobayashi, Tetrahedron , 2003 , 59 , 8411-8414. An Efficient and Catalytically Enantioselective Route to ( S )-(-)-Phenyloxirane E. J. Corey, S. Shibata, R. K. Bakshi, J. Org, Chem. , 1988 , 53 , 2861-2863. 11
Alder Ene Reaction 12
Asymmetric allylic alkylation BF 3 OEt 2 , -78 o C, 94% 13
Homologous Aldol addition 14
Dess Martin Periodinane Corey Fuchs 15
Cyclopropane synthesis Radical chlorination of cyclopropane 16
Corey-Fuchs reaction 17
Metathese Takai Olefination Stille Coupling reaction 18
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Schmidt glycosydation 20
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