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Asymmetric Synthesis Additions to carbonyl compounds.

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Presentation on theme: "Asymmetric Synthesis Additions to carbonyl compounds."— Presentation transcript:

1 Asymmetric Synthesis Additions to carbonyl compounds

2 Outline Addition of non-chiral nucleophiles to chiral aldehydes or ketones Addition of non-chiral nucleophiles to chiral aldehydes or ketones Crams ruleCrams rule Felkin-Anh modelFelkin-Anh model Chelation controlChelation control Chiral auxiliaries Chiral auxiliaries Chiral acetalsChiral acetals Chiral reagentsChiral reagents Chiral catalysts Chiral catalysts Chiral amplificationChiral amplification

3 Achiral Nu + prochiral C=O

4 Addition to Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828. CramKarabatsos

5 Addition to RSMLNud.e.% HHHHMeMeMeHHHHHHHMeEtMeMeMeMeMePhPhPhPhPhPhPhMeMgIMeMgIEtMgBrPhMgBrMeMgIEtMgIPhMgI334350>60667583 Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

6 Faulty Assumptions Ground state and reactive conformation are wrong. Ground state and reactive conformation are wrong. Ground state and reactive conformation (TS) cannot be assumed to be the same. Ground state and reactive conformation (TS) cannot be assumed to be the same. The directing influence of substituents does not only derive from their steric effects. Electronic interactions are crucial. The directing influence of substituents does not only derive from their steric effects. Electronic interactions are crucial. The C=O group assumes pyramidal state early, therefore Cram model is unfavourable. The C=O group assumes pyramidal state early, therefore Cram model is unfavourable.

7 Felkin-Anh Model

8 Nucleophile Approach Anh, Bürgi-Dunitz

9 Chelation Control J Amer Chem Soc 1990, 112, 6130.

10 Examples RSLY:Nu(solvent)d.e.% PhPhPhPhPhPhPhMeMeMeHMeMeMeMeMeMeMeMeMeHMePhPhPhPhPhPhPhPhPh C 7 H 15 HOHOHOHOHOMeOMeOMeOHOMeOMEMOH MeLi(Et 2 O) Me 2 Mg(Et 2 O) MeMgBr(Et 2 O) MeMgBr(THF MeLi(Et 2 O) MeMgBr(Et 2 O) MeMgBr(THF) Ph 2 Mg(Et 2 O) Ph 2 Mg(THF) C 4 H 9 MgBr(THF) PhLi(Et 2 O) 84665080343484748610046

11 Chiral auxiliaries Attached to the carbonyl compound Attached to the carbonyl compound Attached to the nucleophile Attached to the nucleophile Chiral acetals and -ketoaldehydes Chiral acetals and -ketoaldehydes Sulfoxides Sulfoxides Organometallics Organometallics Allylboranes, -silanes, -stannanes Allylboranes, -silanes, -stannanes

12 Auxiliary attached to carbonyl Tetrah Lett 1991, 32, 2919

13 1,3-Oxathianes

14 Transition state model

15 Auxiliary attached to nucleophile J C S Perkin I 1981, 1278

16 Organometallic: Chiral ligand Tetrah Lett 1986, 27, 5711

17 Allylic nucleophiles Alternative route to aldol-type products Alternative route to aldol-type products Two new chiral centres introduced Two new chiral centres introduced Complication: reaction at C-1 Complication: reaction at C-1 Achiral reactants: syn and anti racemates Achiral reactants: syn and anti racemates Chiral reactants: in principle one major stereoisomer Chiral reactants: in principle one major stereoisomer

18 Chiral boron reagents

19 Examples (1) Ranti:syn e.e. % n-C 9 H 19 > 99:188 TBSOCH 2 CH 2 > 97:385 tBu 95:573 n-C 7 H 15 CH=CH> 99:174

20 Examples (2) Ranti:syn e.e. % n-C 9 H 19 3:9786 TBSOCH 2 CH 2 > 3:9772 tBu> 1:9970 n-C 7 H 15 CH=CH 3:9762

21 Examples (3) R e.e. % n-C 4 H 9 95 Ph90 tBu98 C 6 H 11 99 Chen, Eur J Org Chem 2005, 1665-1668

22 Transition state

23 Selectivity: E anti

24 Double asymmetric synthesis

25 Iterative Asymmetric Synthesis J Amer Chem Soc 1990, 112, 6348

26 Diisopinocampheylborane

27 Addition to aldehydes R e.e. %Yield % Me9374 Et8671 iPr9086 nBu8772 tBu8388 Ph9681

28 Other allylic boranes High diastereoselectivity and enantioselectivity High diastereoselectivity and enantioselectivity Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivityReagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity Consistent and predictable Consistent and predictable Also with -chiral aldehydes Also with -chiral aldehydes Diamine-based ligands Diamine-based ligands

29 Allylsilanes and Allylstannanes Promoted by Lewis acids Promoted by Lewis acids High diastereoselectivity High diastereoselectivity Cram controlledCram controlled Chelation controlledChelation controlled

30 Chiral Catalysts Organozinc catalysts Organozinc catalysts Chiral amplification Chiral amplification

31 Chiral ligand as catalyst Organometallic reagent must be relatively unreactive towards C=O unless combined with the catalyst – ligand acceleration. Organometallic reagent must be relatively unreactive towards C=O unless combined with the catalyst – ligand acceleration. Catalyst must have suitable 3D structure to provide high e.e. Catalyst must have suitable 3D structure to provide high e.e.

32 Dialkylzinc addition to aldehydes RNu e.e., % PhMe 91 PhEt 99 PhBu 98 p-Cl-PhEt 93 p-MeO-PhEt 93 2-FurylC 5 H 11 >95 (E)-C 6 H 5 -CH=CHEt 96 (E)-Bu 3 SnCH=CHC 5 H 11 85 PhCH 2 CH 2 Et 90 J Amer Chem Soc 1986, 108, 6071

33 Transition state model

34 Aminothiocyanate derivatives R Yield, % e.e., % Ph9896 p-Cl-Ph9795 o-MeO-Ph9690 p-MeO-Ph9591 2-Naphthyl9593 C 6 H 13 8275 Tetrahedron Letters 2005, 46(15), 2695-2696

35 Transition state? Tetrahedron Letters 2005, 46, 2695-2696

36 Chiral amplification High catalyst optical purity is not needed! High catalyst optical purity is not needed! J Amer Chem Soc 1989, 111, 4028

37 Why amplification? (50%)

38 Summary Addition of non-chiral nucleophiles to chiral aldehydes or ketones Addition of non-chiral nucleophiles to chiral aldehydes or ketones Crams ruleCrams rule Felkin-Anh modelFelkin-Anh model Chelation controlChelation control Chiral auxiliaries Chiral auxiliaries Chiral acetalsChiral acetals Chiral reagentsChiral reagents Chiral catalysts Chiral catalysts Chiral amplificationChiral amplification

39 Questions ?


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