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Designing Organic SynthesesSyntheseplanungStarting material
Target molecule
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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.
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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.
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Computer-generated RetrosynthesisWODCA; logic-oriented programme; Gasteiger, Erlangen
Computer-generated RetrosynthesisWODCA; logic-oriented programme; Gasteiger, Erlangen
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Computer-generated RetrosynthesisSYNGEN: 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 forDownload; no WindowsVersion available
Computer-generated RetrosynthesisSYNGEN: http://syngen2.chem.brandeis.edu/syngen.html
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Computer-generated RetrosynthesisSYNGEN: http://syngen2.chem.brandeis.edu/syngen.html
Computer-generated RetrosynthesisSYNGEN: http://syngen2.chem.brandeis.edu/syngen.html
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Functional Group
Interconversions
Functional group interconversions (FGIs)
Change carbon oxidation level
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Functional group interconversions (FGIs)
Same carbon oxidation level
Amines !
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Amines !
Removal of functional groups – Hydrocarbon synthesis
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Disconnections
Strategic disconnection approach
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Strategic structure approach
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Strategic structure approach
C-C Bond Formation
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No functional group present
One group disconnection based on normal carbonyl reactivity
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One group disconnection based on normal carbonyl reactivity
One group disconnection based on normal carbonyl reactivity
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Two group disconnection based on normal carbonyl reactivity
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Retrosynthesis with classic carbonyl reactions - overview
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d) Two-group Disconnections:“Unlogical” disconnections, “unnatural” reactivity patterns
Synthetic strategies for 1,2-difunctionalysed compounds
Synthon required
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Use of 1,2-difunctionalysed starting materials
Difunctionalisation of alkenes and epoxide opening
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α- Functionalisation of carbonyl compounds
α- Functionalisation of carbonyl compounds
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α- Functionalisation of carbonyl compounds
Radical coupling
Pinacol reaction
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Acyloin condensation
Umpolung strategies
CN-
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Dithioacetals
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Nitroalkanes
Imidoyl
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Alkyne
Synthetic strategies for 1,4-difunctionalysed compounds
Commercially available starting materials
Acyl equivalent + Michael acceptor
Acyl anion synthons
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Homoenolate + electrophilic carbonyl
resonance
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Additional Umpolung strategies
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Enolate + α-functionalised carbonyl compound
Enolate + α,β-unsaturated nitro compound (Michael type acceptors)
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Enolate + α,β-unsaturated nitro compound (Michael type acceptors)
Epoxide based transformations
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Epoxide based transformations
Epoxide based transformations
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Functional group addition
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Reconnection strategies for 1,6-difunctionalysed compounds
Ozonolysis of cycloalkenes
Baeyer-Villiger rearrangement
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Beckmann rearrangement
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Synthesis of carbocyclic compounds
Diels-Alder disconnections
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Synthesis of carbocyclic compounds
Cyclisation reactions
Synthesis of carbocyclic compounds
Other methods of carbocycle synthesis
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Synthesis of heterocyclic compounds
Synthesis of oxiranes, thiirans and azirans
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Synthesis of oxiranes, thiirans and azirans
Synthesis of oxiranes, thiirans and azirans
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Synthesis of furans
Paal-Knoor
Synthesis of furans
Addition to alkyne
Feist-Benary
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Thiophen
Pyrrol:
Paal-Knorr:
Knorr
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Hantzsch
Fischer-Indole
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Hantzsch pyridine
Quinolines (Deutsch: Chinoline!)
Quinoline Isoquinoline
Skraupsch synthesis
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Birschler-Napieralski
Pictet-Spengler
Oxazole
Isoxazole
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Thiazole
Pyrazole
1,4-Dioxane
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Assessment of Syntheses and Strategies
• 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)
• ………
The assessment of a synthesis depends on the aim of the synthesis.
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
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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
• 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
The assessment of a chemical compound depends on its use, but thereare also general considerations particular important large scale commodities
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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:
- DDT
- Asbestos
- PCB
ClCl Cl
Cl
Cl
Cln
Cln
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Assessment of a synthesisNumber of steps as indicator
“The ideal synthesis creates a complex molecule .. in a sequence of only construction reactions involving no intermediary refunctionalizations, leadingdirectly to the target, not only its skeleton but also its correctly placedfunctionality.” 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!”
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Protecting groups for alcohols
Silyl ether
Silyl ether
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Silyl ether
Silyl ether
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Carbonate
Carbonate
Ester
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Ether
Photolabile protecting groups
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Orthogonal protecting groups
Weinreb Amide
Key steps of the synthesis
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Practical enantioselective reduction of ketones using oxazaborolidine catalyst generated in situfrom chiral lactam alcohol and boraneY. Kawanami, S. Murao, T. Ohga, N. Kobayashi, Tetrahedron, 2003, 59, 8411-8414.
An Efficient and Catalytically Enantioselective Route to (S)-(-)-PhenyloxiraneE. J. Corey, S. Shibata, R. K. Bakshi, J. Org, Chem., 1988, 53, 2861-2863.
Corey-Bakshi-Shibata ReductionItsuno-Corey Reduction
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Alder Ene Reaction
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Asymmetric allylic alkylation
BF3 OEt2,-78oC, 94%
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Homologous Aldol addition
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Dess Martin Periodinane
Corey Fuchs
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Cyclopropane synthesis
Radical chlorination of cyclopropane
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Corey-Fuchs reaction
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Metathese
Takai Olefination
Stille Coupling reaction
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Schmidt glycosydation
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