Designing Organic Syntheses
Starting material Syntheseplanung
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 17 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 - DDT Cl
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 5 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
BF3 OEt2, -78oC, 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 19 Schmidt glycosydation
20