1 Can the Computer do the retrosynthetic analysis for me? - - PDF document

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1 Can the Computer do the retrosynthetic analysis for me? - - PDF document

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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

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Designing Organic Syntheses Syntheseplanung

Starting 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 Retrosynthesis

WODCA; logic-oriented programme; Gasteiger, Erlangen

Computer-generated Retrosynthesis

WODCA; logic-oriented programme; Gasteiger, Erlangen

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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

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Computer-generated Retrosynthesis

SYNGEN: http://syngen2.chem.brandeis.edu/syngen.html

Computer-generated Retrosynthesis

SYNGEN: 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 there are 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

Cl Cl Cl Cl Cl Cln Cln

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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!”

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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 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.

Corey-Bakshi-Shibata Reduction Itsuno-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