methods and design in organic synthesisdiposit.ub.edu/dspace/bitstream/2445/134177/12/8. dreaming...

methodsanddesigninorganicsynthesis

2018-19Master Course

PereRomea

inOrganicChemistry

8.Dreamingthefuture

BladerunnerRidleyScott,1982

I'veseenthingsyoupeoplewouldn'tbelieve.

AttackshipsonfireofftheshoulderofOrion.

IwatchedC-beamsglitterinthedarkneartheTannhäuserGate.

Allthosemomentswillbelostintime,liketearsinrain.

Timetodie.

Tearsintherain,byRoyBatty

BladeRunner

The Dream: Ideal Synthesis

Hendrickson,J.B.JACS1975,97,5784;Wender,P.A.Nature2009,460,197&Nat.Prod.Rep.2014,319,433Baran,P.S.JOC2010,75,4657

Chapter1

Anidealsynthesisisgenerallyregardedasoneinwhichthetargetmoleculeispreparedfrom

readilyavailable,inexpensivestartingmaterialsinonesimple,safe,environmentalacceptable,

andresourceeffectiveoperationthatproceedsquicklyinaquantitativeyield

Key Concepts

POTECONOMYChapter1,2&7

ATOMECONOMY

STEPECONOMY

REDOXECONOMY

CHEMOSELECTIVITY

REGIOSELECTIVITY

STEREOSELECTIVITY

ProtectingGroupFreeSynthesis

New chemo, regio, and stereoselective methodsare required for

the strategic design of a synthetic route to avoid situations where selectivity is a problem

ScalabilityPracticalSynthesis

Baran,P.S.Nat.Prod.Rep.2014,31,419Allred,T.K.CR2017,117,11994

Green Chemistry

Anastas,P.T.ACR2002,35,686Lipshutz,B.H.JOC2017,82,2806

Greenchemistryisanongoingattempttoaddresstheproblemsthat

chemicalsandchemicalprocessescansometimescause

12Principles1. WastePrevention2. AtomEconomy3. LessHazardousChemicalSynthesis4. DesigningSaferChemicals5. SaferSolvents&Auxiliaries6. DesignforEnergyEfficiency7. UseofRenewableFeedstocks8. ReduceDerivatives9. Catalysis10. DesignforDegradation11. RealTimePollutionPrevention12. SaferChemistryforAccidentPrevention

Synthetic Metrics

Sheldon,R.A.GreenChem.2007,9,1273;Li,C.-J.PNAS2008,105,13197Andraos,J.OPRD2009,13,161;Lipshutz,B.H.ACIE2013,52,10952

%ideality=numberofconstructionrxs+numberofstrategicredoxrxs

totalnumberofstepsx100

Baran,P.S.JOC2010,75,4657[ForarecentanalysisonMolecularComplexity,seeEastgate,M.D.OBC2015,13,7164]

%yield=quantityofproductisolated

theoreticalquantityofproductx100

%atomeconomy=weightofthedesiredproduct

weightofallproductx100

E(nvironmental)Factor=massofwaste

massofproduct

Perspectives on Synthesis

TARGETORIENTEDSYNTHESIS

DIVERSITYORIENTEDSYNTHESISDOS was conceived as a novel conceptual alternate to combinatorial chemistry,

useful for identifying new targets and for understanding biological functions.It does not rely upon retrosynthetic analysis

It includes the development of efficient pathways to a large amount of skeletal and stereochemical diverse small molecules

Schreiber,S.L.Science2000,287,1964;Nature2009,457,153Arya,P.ACIE2001,40,339

LEADORIENTEDSYNTHESIS

Churcher,I.ACIE2012,51,1114

LOS intends to deliver molecules with specific molecular properties with utility in the drug discovery and optimization process.

It pays attention to the physicochemical and FG properties of the target,while also maintaining the synthetic efficiency to allow their cost effective utilization

Perspectives on Synthesis

FUNCTIONORIENTEDSYNTHESISFOS as a strategy to achieve function by design and with synthetic economy.

FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired

functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion

Wender,P.A.ACR2007,41,40;2015,48,752Sheng,C.CR2019,119,4181

BIOLOGICALORIENTEDSYNTHESISThe key criterion to generate hypotheses for the design and synthesis of focused compound

libraries in BIOS is the biological relevance. As scaffolds of natural products can be considered as privileged structures chosen in evolution, their structures can be viewed as good starting points for compound collection development

Antonchick,A.P.;Waldmann,H.ACR2014,47,1296

Dreaming the Future

CATALYSIS

STEREOCONTROLLEDMETHODS

C–HACTIVATION

LATE-STATEFUNCTIONALIZATION

PHOTOCHEMISTRYLookbeyondwhatyousee