Chiral Catalyst II. Palladium Catalysed Allylic Displacement ( -allyl complexes) 1. L n Pd(0) 2. Nuc

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1 Chiral Catalyst II ast lecture we looked at asymmetric catalysis for oxidation and reduction Many other organic transformations, this has led to much investigation Today we will look at some others... Palladium Catalysed Allylic Displacement ( -allyl complexes) 1. n (0) 2. = Ac (most common), C 2, halide, epoxide (any good leaving group) = soft carbanions (malonates / enolates),,, S nucleophiles, -M = frequently phosphorus ligand A very useful means of froming C C bonds (and others for that matter) Trost's group has extensively studied the asymmetric variant But lets start with the basics... complexes to alkene chanism (0) n oxidative addition σ-bonded complex and π-allyl species in equilibrium n1 (0) if necessary n (0) (II) (0) regenerated (0) n electron deficient π-allyl species is electrophile Alkene palladium co-ordination is weak thus allowing the palladium to insert into more substrate A number of factors control the stereochemistry... Palladium attacks from opposite face to leaving group C 2 C 2 C 2 ( 3 P) 4 (cat), TF, 2 C C 2 C 2 Ac C 2 approaches from opposite face ( 3 P) 4 (cat), TF, 2 C 2 Ac soft nucleophiles attack ligand from opposite face to 2 C C 2 C 2 C 2 C 2 Ac 2 Ac C 2 Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 1

2 The nature of the nucelophile also controls stereochemistry Soft nucleophiles (enolates, soft carbanions) attack ligand ard nucleophiles (Mg,, organometallics) attack metal first C 2 2 Ac anti to attack at ligand Soft nucleophile C 2 n C 2 ard nucleophile C 2 2 Ac attack at metal C 2 2 syn to reductive elimination C 2 et retension the result of two inversions if attack at ligand et inversion if second step is attack at metal egiochemistry Again controlled by nature of nucelophile If attack at ligand, nucleophile normally adds to least hindered end If attack at metal, nucleophile normally adds to most hindered end Soft nucleophile S 2 Ac ard nucleophile S S S S It should be noted that this is a simplification and other effects including electronics of the allyl system and the nature of the ligands on palladium have a profound effect Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 2

3 Use in Synthesis (0), ats C 2 net retension so double inversion alkoxide formed by complexation acts as base to form nucleophile Ts 2 S S 2 2 S S 2 (0), TF Asymmetric -Allyl Alkylations There are a number of conceivable asymmetric allylic alkylations We will limit ourselves to just two Formation of a stereocentre on the incoming nucleophile Vs And differentiation of the ends of a meso π-allyl system Vs Both suffer the same basic problem leophile attacks from opposite face of allyl complex to the palladium so is removed from the source of steric chirality nucleophile and chirality separated Again there are a number of possible solutions of which we will cover two The use of big ligands to overcome separation The use of secondary interactions to guide the incoming nucleophile Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 3

4 The Use of Bulky igands The idea is to force the bulk of the ligand close to the π-allyl complex The use of large ring sizes forces the substituents on the phosphorus closer to where nucelophile attacks P 2 2 P Cl 2 Ac 86 % e.e. approach so bulk out the way The same catalyst can also be used for the alkylation of meso π-allyl systems The C 2 symmetry of the ligand results in only one enantiomer being formed Ac C 2 P 2 2 P C 2 Cl 2 C C % e.e. Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 4

5 An alternative strategy utilises secondary interactions ydrogen bonding between the ligand and the enolate guides the approach of the enolate 1. a, TF 2. Cl(η 3 -allyl) / Ac ()(C 2 ) 2 81 % e.e. Fe P 2 P 2 The proposed transition state is -bonding delivers enolate largest group away from ligand stereochemistry controlled by chirality of chain and axial chirality of ferrocene Fe 2 P P 2 A very similar catalyst has been used for the desymmetrisation of meso allyl complexes Ac C 2 1. a, TF 2. Cl(η 3 -allyl) / C 2 2 C C 2 Fe P 2 90 % e.e. P 2 nce again hydrogen-bonding controls the attack of the nucelophile P Fe P Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 5

6 Chiral ewis Acid Catalysis Diels Alder [42] Cycloaddition C 2 thermally allowed C 2 You met the Diels Alder eaction last year Thermally allowed [42]-cycloaddition It is (normally) the interaction of the M of diene and the UM of the dienophile.a. UM UM M E E A M E > E A Co-ordination of a ewis acid (A) with the dienophile lowers the energy of the UM The smaller E is the lower the activation energy eaction is considerably more rapid and proceeds at a lower temperature UM lowered as a result of "spreading" the electrons over a larger number of atoms A A The use of ewis acids has many advantageous properties in Diels Alder reactions By reducing both the temperature the reaction proceeds at and the reaction time, yields are frequently increased and decomposition reduced Selectivity is increased The normal endo selectivity is increased by aiding secondary orbital interactions The bulk of the ewis acid often increases syn : anti selectivity The regioselectivity is also improved And... k (uncat.) dative bond effectively adds temporary chiral auxiliary k (uncat.) < k (A) A k (A) As long as rate of reaction of co-ordinated dienophile is greater than the background reaction (uncat.) then there can be good induction of chiral information from the ewis acid to the product Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 6

7 C toluene, - 78 C C monodentate so conformational freedom and poor induction coordination adds temparary chiral auxiliary AlCl 2 72 % e.e. free rotation results in poor induction Use of an achiral oxazolidinone auxiliary allows the formation of a bidentate complex This results in a more rigid transition state and better asymmetric induction coordination makes dienophile chiral bidentate remember that geometry is conserved in the DA TiCl 2 ligand cannot rotate 94 % e.e. An intramolecular variant is possible S S TiCl 2 S S 95 % e.e. ne of the most versatile class of chiral ligand has been the bis(oxazolines) derived from amino acid (chiral pool lct1) tbu tbu Cu(Tf) 2, C 2 Cl 2 blocked tbu Cu 97 % e.e. tbu favoured bidentate Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 7

8 Catalytic Asymmetric Mukaiyama Aldol eaction The Diels Alder reaction is not the only reaction that can be catalysed by ewis acids Any reaction that proceeds via nucleophilic attack on a carbonyl or enone system can be catalysed by the lowering of the UM The aldol reaction below is a good example important that this is bidentate Bn TMS SEt Cu 2 2 SbF 6 Catalytic Asymmetric Michael eaction Bn SEt % e.e. Shibasaki has developed a catalysed that contains a ewis acid which activates enones within a chiral environment by co-ordination The catalyst also contains a Brønsted base to form the nucleophile Et ()-SB * a a * a a * Et 91 % e.e. Et Brønsted base ()-SB = a a a a ewis acid What have we learnt? A number of C C bond forming reactions can be performed by asymmetric catalysis Addition to carbonyl systems can be facilitated by ewis acids There are many, many more catalytic asymmetric reactions If you are interested see chapter 12, Classics in Total Synthesis by KCicolaou & EJSorensen, or Asymmetric Catalysts in rganic Synthesis by oyori or Tye, J. Chem. Soc., Perkin Trans , 275 Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced Synthesis 8