The Chiral Pool and Resolution Strategies

• n Stereocentres in a molecules means there are up to 2^n stereoisomers- bad when large amounts of stereocentres • Poor stereocontrol in synthesis is inelegant and wasteful • Absolute and relative structure determination by synthesis • Each enantiomer of a chiral molecule frequently has a different biological activity - react with receptors differently • Pharmaceutical companies required to develop chiral drugs as single enantiomers

• Carvone • penicillamine • Thalidomide • Aspartame

• Commonly available enantiopure molecules which are often naturally-occurring are often referred to as the chiral pool

• Amino acids • Sugars • Terpenes • Hydroxy acids

• Often used for synthetic endeavours that build up complex natural products form simple chiral pool building blocks

• Potentially cheap • Good availability • Sustainability • Academic challenge

• Structural restrictions - sometimes starting material is not suited to the product • Single enantiomer availability - amino acids only available in s form until recently • Low yield

• alpha-amino acids are useful for medicinal as contain N • Historically only (S)-alpha-amino acids were readily available from nature in large amounts via hydrolysis of proteins • Both enantiomers now available from bacterial fermentation processes- (R)-enantiomers are more expensive

• A range or pyranose carbohydrates from nature • Exist as an equilibrium between open chain and closed ring form - hexose <–>pyranose form • Ideal for consideration in polyoxygenated contexts • Cost and availability is directly related to natural abundance • Diastereomers

• Very highly oxygenated • Need to remove some hydroxyl groups as not useful • But can make bio OH for fuel by chopping up

• Na/glucose co-transported SGLT2 is mainly expressed in the kidneys which is responsible for 90% glucose reabsorption in humans • SGLT1 inhibitors work by blocking the reabsorption of glucose in the kidneys preventing the build up of glucose in blood - allowing elimination in urine- good for diabetes • Drug candidate AP1 was developed as an inhibitor of SGLT1

• Start with pyranose and Bn groups protecting free OH except on anomeric carbon • TEMPO/bleach, NaHCO3 used to oxidise anomeric OH to =O • Br-R-Et, n-BuLi added to anomeric carbon at Br, reducing =O to OH • Adds selectively to top face creating new stereocentre- controlled • BF3.OEt2/ i-Pr3SiH used to reduce out OH group • H2, Pd/C used to deprotect OHs

• Generates two molecules for every one D-mannitol • Selectively protect terminal Hydroxyl group to form a bis-keta, using MeO-R-OMe • Then oxidise remaining OH to =O and cleave across C-C bond using NaIO3 and NaHCO3- periodate cleavage

• Synthesis of a wide range of complex natural products • With its aldehyde and protected diol fragments employed as handles to introduce functional groups and control stereoselectivity

• Offer a wide range of commercial hydrocarbon-rich building blocks • Terpene have a large level of structural variety • Often both enantiomers are available • Cost per unit mass or volume can be very low • Most widely available are those from turpentine

• Monocyclic • 6-membered ring • Isopropyl group at bottom

• From (+)-limonene - cheaper monoterpene acts as chiral building block for carvone • Add NOCl • Add Base • Add H3O+ • Produces (-)-carvone

• It can be more efficient to do resolution by selective crystallisation of diastereomeric salts • When its easier to make a racemic compound then separate into enantiomers

• Diastereomeric salts like diastereomers, have different physical properties including melting points and solubility

• No - have identical physical properties

• React a racemic mix of acids with an enantiopure molecule • Enantiomers of starting product will be converted to diastereomers which can then be separated • Can then transfer back to original enantiomers to obtain in pure form

• Selective crystallisation • Chiral chromatography 3.

• Separate a mixture of compounds by chromatography on a chiral (non-racemic) column

• Add mix of diastereomers (S,S) and (R,S) to a column with an achiral stationary phase e.g. SiO2 (Silica) • Diastereomers have different affinity for stationary phase and flow through column at different rates resulting in separation- elute separately