Chiral Auxiliaries • Previously on Advanced Synthesis..... • Discussed the need for stereoselective synthesis • Looked at the use of resolution, the chiral pool and substrate control • But 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 Substrate Substrate Auxiliary

formation of single do chemistry enantiomer

Substrate Auxiliary Substrate remove auxiliary

Substrate Auxiliary R R R

• 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 Evans' Oxazolidinones Alkylations • Enolate chemistry very important (Strategy in Synthesis 2nd year) • One of the commonest means of forming C–C bonds is via enolate alkylation • If a chiral centre present can get a diastereoselective reaction preferred • metal fixes M O O conformation by O chelation O M O N O O O N O N H

• auxiliary readily prepared from amino acids Bottom face blocked

O O O O O 1. NaHMDS R R R N O 2. CH2=CHCH2Br N O 1. KOH OH

diastereoisomer enantiomer Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 1 • 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

O O Bu2BO O OH O O Bu2BOSO2CF3, N O iPr2NEt N O RCHO R N O

• auxiliary determines absolute stereochemistry • bulky substituent adopts • Lewis acidic boron activates psuedo-equatorial position • thermodynamic carbonyl by co-ordination and enolate arranges 6-membered transition state

Bu Bu Bu O O O O O O R B R B R B + H Bu H Bu H Bu H N H N H N i-Pr i-Pr i-Pr O O O O O O

• aldehyde approaches • C–O dipoles oppose from least hindered work-up face (due to auxiliary)

OH O O OH O R R N O H H N º i-Pr O O

• There are a number of useful ways of removing the oxazolidinone unit

R CO2H

LiOH, MeOH, E O O H2O R R CH OH N O LiAlH4 2

E E

PhCH2OLi O R OCH2Ph E

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 2 Chiral Sulfoxides • Chiral sulfoxides have been shown to induce good diastereoselectivities • Remember 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

M O O O O R–M S S pTol pTol

R–

• reductive • approach from least cleavage sterically hindered side (away from toluene group)

O O Raney–Nickel pTolS(O)

• Sulfoxide 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 Tol O O OH S O R S DIBAL-H Tol R H O O • hydride approaches from opposite side to S bulky toluene group Tol R Ln Zn DIBAL-H O O O OH ZnCl2 S S Tol R Tol R • conformation controlled H by chelation Auxiliary Removal

O OH OH Li / NH3 S Tol C7H15 C7H15

• reduce sulfoxide

H OH O OH KOH O 1. LiAlH4 O S 2. Me3OBF4 S C8H17 Tol C8H17 Tol C8H17

• cation formation

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 3 Miscellaneous Reactions and Auxiliaries Diels–Alder Reaction • A number of auxiliaries have been utilised for this extremely useful reaction • The following was derived from camphor (a readily available chiral material)

O

Cl NH N O NaH S O S O

O • acylation O (SC last year) • chiral auxiliary can be recovered and used again EtAlCl2, • Lewis acid activates enone - 78 ˚C, 1 hr

CH2OH LiAlH4 + NH N O S O S O O O

• The second example show the versatility of oxazolidinone auxiliaries

• Lewis acid activates enone O O • Controls conformation by chelation Ph Ph O O N ZrCl4 + N Ph O Ph O • think about regiochemistry Radical Reactions and endo / exo selectivity • Recently it has been found that radical reactions can occur with excellent diastereoselectivity • The first example utilises a camphor derivative • readily coverted to amino acid O O NOBn NHOBn N Bu3SnH, Et3B N + SO SO2 2 I

• top face blocked by oxygen

Et3B + O2 O O NOBn N S Et• + H–SnBu3 Bu3Sn + O I

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 4 • The donor / acceptor properties can be readily reversed to give chiral radicals

O O I initiator N N SnBu3 S O S O O O

What have we learnt? • Chiral auxiliaries are, in essence, a form of substrate control • They are temporarily attached, allowing diastereoselective reactions • On removal they can produce the equivalent of an enantioselective reaction • Two disadvantages: need point of attachment (limits structures) • Need a stoichiometric amount of the auxiliary

Next lecture a further improvement in stereoselective synthesis......

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 5