ASPECTS OF ORGANIC SYNTHESIS STRATEGY / RETROSYNTHESIS OR

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1 ASPECTS F GAIC SYTESIS STATEGY / ETSYTESIS P P' C C ( )- -kainic acid P P' PhS Cl S C Me P 97SL75 P' P C tbu P P' 9JC6968 TBS EtS C tbu EtS TBS C C tbu 98P&A59 Course outline: rganic Synthesis what is it all about? etrosynthesis terminology Guidelines reactions strategic disconnections strategic bonds functional groups transformations selectivity routes Total synthesis here's one somebody else prepared earlier Journal abbreviations: AC Accounts of Chemical esearch; Ang Angewandte Chemie International Edition; CC Journal of the Chemical Society, Chemical Communications or Chem. Commun.; CEJ Chemistry A European Journal; CL Chemistry Letters; hemical eviews; JACS Journal of the AmericanChemicalSociety;JC Journalof rganic Chemistry;PI Journalof the Chemical Society, Perkin Transactions ; P&A Pure and Applied Chemistry; Syn Synthesis; SL Synlett; T Tetrahedron; TA Tetrahedron Asymmetry; TL Tetrahedron Letters. Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00

2 GAIC SYTESIS GAIC SYTESIS TTAL SYTESIS METDLGY ATUAL PDUCTS STUCTUE DETEMIATI PAMACEUTICALS IDUSTIAL BILGICALLY ELEVAT UMBE F STEPS YIELDS CTL / SELECTIVITY PUIFICATI CST STATEGY (verall plan) etrosynthesis Key transformations Methodology CMPEESI (Knowledge) eading / remembering Mechanism Stereoelectronics Conformation TACTICS (nuts and bolts) eagents / conditions Protecting groups Selectivity Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00

3 ETSYTESIS ITDUCTI TEMILGY etrosynthesis - the sequential simplification of a compound to a recognisable starting material a necessary evil (briefly all about simplification discussed sect 7b) draw compound in simplest form C L-allose represents reverse of a chemical reaction always indicate transformation synthon-an idealised unit to aid visualisation / identification of transformation it is T an intermediate protecting groups functional group interconversion self explanatory Bn hydrolysis C Bn or C S Bn C Pummerer Bn Ac PhS or PhS PhS or PhSCl disconnection-breaking a bond to simplify structure indicate bond being broken and transformation to achieve this protection of carbonyl also addition of extra functionality to aid simplification (sect aii) Bn LG Bn Payne rearrangement Bn synthons must have corresponding synthetic equivalent or reagent Bn many rearrangements don't cause simplification BUT aid it at a later stage strategic transformation-reliable method to introduce stereochemistry Bn C SAE epeat process iterative transformations can be good strategic bond-certain bonds readily lend themselves to simplification (sect b) Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00

4 Bn TTAL SYTESIS f course, retrosynthetic analysis is useless unless it can be achieved in the laboratory Payne sets up out of rearrangement stereocentres gives epoxide Ti(iPr), ()-DIPT, tbu 9%; >95%ee Bn PhS, a, /tbu Bn Pummerer reaction (via thionium species) gives protected aldehyde thiol opens epoxide and drives equilibrium Bn Ac Ac, Bn. PCl Me Me. mcpba Bn K C 9% DIBAL 00% excellent selectivity Bn Bn Bn C C. Ph P=CC. ab stereo-divergent-synthesis allows the preparation of a number of isomers from a common intermediate-very useful S.A.E. ()-DIPT L-allose. mcpba. Ac,. DIBAL. Deprotect Bn Bn. PhS, a, /tbu. protection used by Sharpless and Masumune to synthesize 8 natural hexoses (90T5) What have we learnt? the need for synthesis the concept of retrosynthesis the terminology of retrosynthesis how to make sugar Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00

5 ETSYTESIS: GUIDELIES 5 6 swainsonine 5 6 D-mannose ow do we plan such a synthesis? The following set of guidelines give a simple starting point Ultimately practise is the only way to learn Work through total syntheses in the literature Guideline : Knowledge of reactions TBS intermediate towards fluvirucin B 97JACS00? Each possible reaction produces a different intermediate, which in turn results in a different retrosynthetic analysis. Could use: Julia olefination (sulfone & carbonyl) (phosphorane & carbonyl) ing closing metathesis (two alkenes) McMurry reaction (two carbonys) Peterson (silane & carbonyl) Knowledge of mechanism / stereoelectronics etc allows you to devise new solutions to problems and thats where the real fun lies. Be imaginative and creative (SVL) vinylogous Mannich Guideline : Simplicity Ideally each step should reduce the molecular complexity cleaving fused / spiro rings simplifies structure C-C PCl, DMF TIPS C intermediate towards ()-croomine 96JACS99 divide molecule into simple fragments C- protection steps TIPS (C ) Br Me P C Me Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 5 C-C TIPS-Tf, DCM PLEASE TE: I ALL TE ETSYTESES I TIS CUSE I AVE IGED PTECTIG GUPS AD JUST SW TE KEY STEPS Br P C Me vinylogous Mannich

6 recognition pattern the necessary structural motif required to be able to apply a disconnection Guideline : Strategic Bonds a. C-X Bonds The simplest disconnection to spot Very reliable " C Br so which bonds do we consider first ' ' C C C PMB 9% ee C- Pd(0) % L, -5 C PMB Ac 96JACS697 PMB Ph P C Et L = PPh Ph P proceeds via π-allyl species interconversion of Pd between enantiotopic faces rapid compared to nucleophilic attack ligand differentiates both faces so Pd resides on one preferentially amine approaches from opposite face reductive amination Swainsonine 87T08 both rings made by C reductive hydrogenation reductive amination 5 6 swainsonine 5 6 D-mannose protection C- steps Bn C C protection Bn 5 5. Pd / black, Bn, Ac. hemi-acetal is protected aldehyde C Pd / C, C sugar provides all the stereocentres guideline b Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 6

7 Swinholide A C X disconnections frequently offer a good starting point Me esterification Me Ar TBS Me C- Me Me swinholide A 95T Me Yamaguchi macrolactonisation,,6-cl C 6 CCl, Et, DMAP Me C- TBS Me tbu tbu Si Me Ar Yamaguchi esterification,,6-cl C 6 CCl, Et, DMAP two halves are identical except protecting groups convergent synthesis guidelines & 5f Ar Me TBS Me C tbu tbu Si TBS Me C Me Me. ArC. TBAF. C use of common precursors greatly simplifies synthesis (cf. hexoses) What have we learnt? opefully that we all need to keep reading / learning C X bond disconnection is readily achieved C X bond disconnection easily spotted Most helpful in cyclic sturctures Also reliable means of combining molecules Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 7

8 b. Bonds Alkenes are wonderful They are readily functionalised in a myriad of ways There are a large number of reliable ways of generating them ' ' or PhS ' etc divide molecule in half convergent C Julia eaction indanomycin 8JC50 Julia eaction. nbuli, TF, MPA then BzCl. a / g 5% C Me PhS C SEM Diels-Alder and IMDA very useful (guideline 6) C-C bonds, rings, and stereocentres predictably set up. SEM-pyrrole / BuLi. PhS-succinimide, PBu. mcpba C S Et C P C Et C P intramolecular Diels-Alder Et C PPh (complete stereoselectivity) IMDA guideline a P' P Et C P()(Et) Wadsworth-Emmons In Ley's original synthesis tetrahydropyran ring formed from sugar A later synthesis by icolaou (85JC0) formed TP via chemistry Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 8

9 C Me Br PBr C Me MgBr C Me bromide more successful than Julie reaction in their hands often add alkene to aid simplification (see below & guideline aii) guideline a C-C C P P' Ph P P' P C P C two fragments made from same precursor elegant use of material P P Sometimes hard concept to grasp BUT simplification can be aided by the addition of functionality (see guideline aii) Fluvirucin B 97JACS00 CM P P P P P P F. Pd / C. adding functionality allows the use of CM (guideline b) good use of guideline a CM TBS C C sugar molecule divided into three fragments for convergency (guideline & 5f) Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 9

10 Many other methods for the formation of alkenes Asymmetric CM 98JACS970 McMurry reaction 98CEJ567 Cl Ph C Et Peterson olefination 00Ang77 C Tebbe reagent Takeda thioacetals What have we learnt? a versatile bond to make Easy to introduce stereoselectively ften useful to add a double bond to allow further disconnection Large molecules can be readily formed with only a few basic reactions Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00 0

11 c. Adjacent to Functional Groups Bonds adjacent to functional groups are readily disconnected via a huge variety of transformations Examples include carbonyl additions (& the aldol), sufones, Stille couplings, dithianes etc i) alcohols ' ' ' ' P Bn guideline a F-ing (C8-C) of Altohyrtin A 97T8667 C protection. g(ac)., ab. protection stereochemistry set up by Sharpless asymmetric epoxidation C regiocontrolled epoxide opening Bz Bn. S.A.E.. Ti(Pr), PhC Bn B Brown Crotylation guideline c use chiral borane to set up stereochemistry Alcohol functionality invaluable as there are many ways to control stereochemistry eductions (BIAP, CBS), allylation (Brown, oush), aldol (Evan's, boron) etc ii) aldol reaction The aldol reaction has proved to be invaluable in the synthesis of natural products ' ' ' ' Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00

12 A-B spirocycle of altohyrtin A 96TL858 & 97TL8 P Grignard addition 9 B alcohol oxidised 5 P Bn P' Bn all aldols proceeded with excellent selectivity guideline ci ( )-IpcBCl P P ketalisation 9 5 TES aldol ozonolysis TES 5 Brown allylation guideline a C. ppts. []. C MgBr guideline b Bn P Petasis reagent aldol asymmetric boron enolate Cp TiMe ( )-IpcBCl P' aldol TES TES TES P' 5 Bn TES 5 5 P ( )-IpcBCl P Bn iii) sp couplings ' X Y ' Examples include the eck (9C07;9Ang79), Stille (9Syn80), Suzuki (8AC87) or sp-sp couplings Sonogashi (75TL67) Gareth owlands (g.rowlands@sussex.ac.uk) Ar0, etrosynthesis 00