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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