Chiral Catalysis Chiral (stoichiometric) reagents are a very important class of compound but... eed a stoichiometric quantity of the chiral component Unless it is cheap or recoverable this is not very efficient The investigation of chiral catalysis has become one of the most important in modern synthetic chemistry Chiral Catalyst Substrate Substrate Chiral Catalyst Substrate The beauty of chiral catalysis is that one molecule of chiral compound can produce millions of molecules of enantioenriched product eduction Alkenes A classic asymmetric transformation is the reduction of alkenes It is now a highly viable (and valuable) commercial process Many of the best known use h (rhodium) or u (ruthenium) catalysts in association with chiral phosphine ligands Some examples of ligands are below... P 2 P 2 P 2 P 2 ()-BIAP (,)-DIP (S,S)--DuPS P P chelating group And their use... 2, BIAP-u (II), C 2 Cl 2 note that both examples require a chelating group on the substrate 94 % e.e. It is a very important means of producing amino acids C 2 Me Ac 2, [(DuPS)h(CD)] + X, Me chelating group CD = 1,5-cyclooctadiene C 2 Me Ac > 99 % e.e. Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 1
eduction of non-co-ordinating substrates is considerably more taxing u and h give very poor results on the whole A few examples exist represents substituted cyclopentadienyl ring similar to ferrocene (inorganic lectures possibly?) Cl 2 Ti 2 2, Bui, -75 C * 95 % e.e. Me 3 mol% cat., 2 50 bar Me BAF 98 % e.e. P Ir tbu CD (again) BAF = tetrakis{3,5-trifluoromethyl}phenyl borate Carbonyl groups Majority of work has been carried out on substrates with a second chelating functional group emember previous years lectures: eduction can, at a very simple level be thought of as the addition of (nucleophilic addition) like ial 4, ab 4 and DIBA The catalysts in todays lectures may progress by a different mechanism but overall it is still nucleophilic addition of n X 2, ()-BIAP-u(II) X = - 2, -, -C 2, C 2, etc. n X Importance of chelation is highlighted by... u(()-biap) 2, 2 (100 atm) 92 % e.e. u(()-biap) 2, 2 (100 atm) < 1 % product Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 2
nce again reduction of simple, isolated carbonyls is more of a challenge A number of strategies have successfully achieved this desired transformation The use of iridium Ir based systems for transfer hydrogenation is one Ar [IrCl(CD)] 2 -ligand, K, 2-Pr, 80 C Ar * different mechanism - related to the Meerwein-Ponndorf-Verley reduction Corey Bakshi Shibata (CBS) eduction Probably one of the most versatile and successful catalytic reducing systems Corey introduced the use of oxazoborolidines to catalyse the borohydride mediated reduction of carbonyl compounds educes most ketones with few structural restrictions catalytic + B3 TF B Me stoichiometric reductant Mechanism interaction of amine and borane activates hydride source increase ewis acidity of endo boron S B Me endo boron co-ordinates carbonyl both activates carbonyl and spatially arranges it B B 3 Me S Me B B 2 S Me B 2 B S chair-like 6-membered transition state (again) large substituent organised away from oxazaborolidine - psuedo-equatorial Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 3
xidation o discussion of asymmetric catalysis would be complete without mention of Sharpless Asymmetric Epoxidation (S.A.E.) This was the first general, effective asymmetric catalyst must have allylic alcohol 2 1 3 catalytic metal and ligand Et 2 C C 2 Et -(+)-DET -(+)-diethyl tartrate Ti(iPr) 4, C 2 Cl 2, 4 Å sieves, -20 C or Et 2 C Mechanism C 2 Et D-(-)-DET D-(-)-diethyl tartrate stoichiometric oxidatant 1 2 3 70-90 % > 90 % e.e. tbu tbu internal delivery Ti(iPr) 4 TBP oxidises titanium TBP rapid ligand exchange tbu Ti activation of peroxide Ti tbu tbu Ti Preco-ordination of allylic alcohol, titanium and tartrate required Sense (direction) of asymmetric induction highly predictable "" D-( )-DET unnatural isomer 2 1 3 alcohol always placed in bottom right corner "" -(+)-DET natural isomer Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 4
Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 5
Catalytic Dihydroxylation Any alkene can be dihydroxylated by osmium tetroxide s 4 The Upjohn conditions use -methyl-morpholine -oxide M as stoichiometric oxidant so that only a catalytic amount of the expensive and highly toxic osmium is required MEM s 4 (cat.), M MEM TP TP mechanism breifly mentioned in my 2nd year lectures s 4 + igand Attacks from the least hindered face It always proceeds via syn addition s Mechanism (controversial) stoichiometric s concerted [3+2]-like mechanism results in syn addition s s s VI s 4 catalytic as regenerated s VIII s 2 Sharpless Asymmetric Dihydroxylation The use of enantiomerically pure ligands has led to an asymmetric variant being developed eaction is reasonably general ot as reliable as the S.A.E. The most commonly used ligands are... Et Et Et Et Me Me Me Me α = (DQ) 2 PA β = (DQD) 2 PA Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 6
Proposed Catalytic Cycle s osmium glycolate ester Primary cycle (high ee) 2 s M MM s hydrolysis must occur before oxidation of osmium or low ee 2 Secondary cycle (low ee) s Sharpless has developed a system that prevents the secondary cycle from occurring Use of K 3 Fe(C) 6 -K 2 C 3 as the oxidant in a biphasic mixture of tbu- 2 results in the oxidant remaining in the aqueous layer and thus regeneration of the active osmium species can only occur after hydrolysis of the osmium glycolate ester Mnemonic to Predict which igand to Use β-face largest substituent in south-west corner S M α-face Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 7
A related process has also been developed by Sharpless, asymmetric aminohydroxylation C 2 Me + Bn Cla K 2 s 2 () 4, (DQ) 2 PA, Pr / 2 Cbz ends up furthest from EWG Bn C 2 Me 94 % e.e. as proved very useful in the semi-synthesis of taxol, a potent anti-carcinogen Ac Ac Bz What have we learnt? That asymmetric catalysis is the most efficient means of introducing a stereocentre A number of asymmetric reductions can be achieved A number of asymmetric epoxidations or dihydroxylations can be achieved Many other transformations can be achieved by catalysis (see next week) Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 8