Chiral Auxiliaries. attach auxiliary Substrate Substrate Auxiliary

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1 Chiral Auxiliaries Previously on Advanced ynthesis... Discussed the need for stereoselective synthesis Looked at the use of resolution, the chiral pool and substrate control t there are some potential problems with those methods What if the substrate does not contain an appropriate stereocentre? What if the target does not contain a readily exploited stereocentre? attach auxiliary ubstrate ubstrate Auxiliary formation of single enantiomer do chemistry ubstrate remove auxiliary ubstrate Auxiliary ubstrate Auxiliary A form of substrate control in which a temporary asymmetric unit is attached At worst it is a built in resolving agent At best they are stereodirecting groups resulting in single enantiomers Criteria for Chiral Auxiliaries cheap and readily available easily attached induce stereochemistry (surprise) chemically inert easily removed vans' xazolidinones Alkylations nolate chemistry very important (trategy in ynthesis 2nd year) ne of the commonest means of forming C C bonds is via enolate alkylation f a chiral centre present can get a diastereoselective reaction metal fixes conformation by chelation M M preferred auxiliary readily prepared from amino acids ottom face blocked 1. amd 2. C 2 =CC 2 r 1. K diastereoisomer enantiomer Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced ynthesis 1

2 The aldol reaction is an extremely valuable means of introducing stereochemistry Used extensively in the synthesis of polypropionate natural products Frequently used to control two new stereocentres geometry of enolate determines syn or anti aldol 2 2 CF 3, ipr 2 t 2 C bulky substituent adopts psuedo-equatorial position thermodynamic enolate auxiliary determines absolute stereochemistry Lewis acidic boron activates carbonyl by co-ordination and arranges 6-membered transition state aldehyde approaches from least hindered face (due to auxiliary) C dipoles oppose work-up There are a number of useful ways of removing the oxazolidinone unit C 2 Li, Me, 2 LiAl 4 C 2 PhC 2 Li C 2 Ph Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced ynthesis 2

3 Chiral ulfoxides Chiral sulfoxides have been shown to induce good diastereoselectivities emember last years course they have many useful transformations This combination has led to their use as chiral auxiliaries metal used to fix conformation by chelation p M p M reductive cleavage approach from least sterically hindered side (away from toluene group) aney ickel p() ulfoxide can be used to control reduction of ketones Depending on reaction conditions either diastereoisomer can be produced with complete control preferred conformation has dipoles opposed DAL- DAL- ZnCl 2 conformation controlled by chelation L n Zn hydride approaches from opposite side to bulky toluene group Auxiliary emoval C 7 15 Li / 3 C 7 15 reduce sulfoxide C LiAl 4 2. Me 3 F 4 K C 8 17 C 8 17 cation formation Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced ynthesis 3

4 Miscellaneous eactions and Auxiliaries Diels Alder eaction A number of auxiliaries have been utilised for this extremely useful reaction The following was derived from camphor (a readily available chiral material) Cl a chiral auxiliary can be recovered and used again acylation (C last year) Lewis acid activates enone talcl 2, - 78 C, 1 hr C 2 LiAl 4 The second example show the versatility of oxazolidinone auxiliaries Lewis acid activates enone Controls conformation by chelation Ph Ph ZrCl 4 Ph Ph think about regiochemistry adical eactions and endo / exo selectivity ecently it has been found that radical reactions can occur with excellent diastereoselectivity The first example utilises a camphor derivative readily coverted to amino acid n n 3 n, t top face blocked by oxygen t 3 2 t n 3 3 n n Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced ynthesis 4

5 The donor / acceptor properties can be readily reversed to give chiral radicals initiator n 3 What have we learnt? Chiral auxiliaries are, in essence, a form of substrate control They are temporarily attached, allowing diastereoselective reactions n removal they can produce the equivalent of an enantioselective reaction Two disadvantages: need point of attachment (limits structures) eed a stoichiometric amount of the auxiliary ext lecture a further improvement in stereoselective synthesis... Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, Advanced ynthesis 5