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