1 Stereoselective reactions of the carbonyl group • We have seen many examples of substrate control in nucleophilic addition to the carbonyl group (Felkin-Ahn & chelation control) • If molecule does not contain a stereogenic centre then we can use a chiral auxiliary • The chiral auxiliary can be removed at a later stage L Me L Me O MeMgBr Me Mg O O Me Ph –78°C Me Ph O Me O OH O O O Me H H Me H Me Me 98% de Me • Opposite diastereoisomer can be obtained from reduction of the ketone • Note: there is lower diastereoselectivity in the second addition as the nucleophile, ...‘H–’ is smaller Me Me O O KBH(i-OPr) Me Ph 3 Me Ph O OH O O Me Me Me Me H 90% de Advanced organic 2 Chiral auxiliary in synthesis Me Me O Me RMgBr Me O Me Ph HO OH Me Ph –78°C OH LiAlH4 O O O Me Me Me Me Me O3 –78°C O Me O Me (–)-frontalin 100% ee • The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalin Advanced organic 3 Sulfoxides as chiral auxiliaries hydride directed lithium can to si face chelate 2 oxygens O HO H O Tol O Raney Ni HO H S Li S R R LiAlH4 Tol R Me H AlH3 80% de O O S R Tol R i-Bu DIBAL Tol O i-Bu HO H O S Al Raney Ni HO H O S H R R Me H Al Tol i-Bu i-Bu 70% de oxygens are not dipoles directed in directly tethered opposing directions • Underrated chiral auxiliary - easily introduced, performs many reactions & can be readily removed • One auxiliary can give either enantiomer of product • Selectivity dependent on whether reagent can chelate two groups Advanced organic 4 Chiral reagents • Clearly, chiral reagents are preferable to chiral auxiliaries in that they function independent of the substrate’s chirality or on prochiral substrates • A large number have been developed for the reduction of carbonyls • Most involve the addition of a chiral element to one of our standard reagents Me H O Me H O B + B + Me L S Me R R Me Me (+)-α-pinene 9-BBN•THF alpine borane® proceeds via boat- like transition state can be reused Me H OH + B Me L S O R R Me H RL Me Me Me RS O H OH alpine borane® selectivity governed (CH ) Me (CH ) Me by 1,3-diaxial 2 4 2 4 interactions small group as linear 86% ee Advanced organic 5 Chiral reagents II • Alpine-borane is very good for reactive carbonyls (aldehydes, conjugated ketones etc) • It is less efficient with other ketones so a more Lewis acidic variant has been developed • Addition of the chloride makes the boron more electrophilic • Transition state similar to previous slide Me H O BCl H OH Me Me + Me Me Me Me 2 (+)-Ipc2BCl 98% ee • And here is another... O H OH + Me Me Me B Me Me Me H Me Me >99% ee Advanced organic 6 Binol derivative of LiAlH4 1. (S)-BINAL–H O H OMOM 2. MOM–Cl Me Me SnBu3 SnBu3 93% ee O OEt Al O H Li (R)-BINAL–H • Reducing reagent based on BINOL and lithium aluminium hydride • Selectivity is thought to arise from a 6-membered transition state (surprise!!) • Largest substituent (RL) adopts the pseudo-equatorial position and the small substituent (RS) is axial to minimise 1,3-diaxial interactions O RS Al Li O O H O Et RL Advanced organic 7 Chiral reagents: allylation O Ti Ti O Ph O Ph H OH Cl MgBr H H Ph H O H Ph O H Ph Ph Ph O O Ph Ph O O Me Me 95% ee Me Me • Stereoselective reactions other than reduction can be performed with chiral reagents • In the above reaction the standard Grignard reagent is reacted with the titanium complex to give the chiral allylating reagent • Note: the chirality is derived from tartaric acid (again) Advanced organic 8 Chiral allyl boron reagents L L L L RZ B B H2O2 OH O O L O NaOH + E B R RZ R R R L R RZ RE RE RZ RE • Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols • Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron • This activates carbonyl as it is more electrophilic and weakens B–C bond, making the reagent more nucleophilic • Funnily enough, reaction proceeds by a 6-membered transition state H L H L H R H H OH B B L vs L RE RE RE O O OH R H R R RZ RE RZ RZ RZ E-alkene gives anti product Z-alkene gives syn product disfavoured • Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain) • Therefore alkene geometry controls the relative stereochemistry (like aldol rct) Advanced organic 9 Chiral allyl boron reagents II Me OH B O + Et Me Me Et H Me Me 2 92% ee crotyl group orientated away from Me Me pinene methyl groups Me H H H OH B Me Et H O Me Me Et Me Me substituent pseudo- equatorial • Reagent is synthesized from pinene in two steps • Gives excellent selectivity but can be hard to handle (make prior to reaction) • Remember pinene controls absolute configuration Geometry of alkene controls relative stereochemistry Advanced organic 10 Other boron reagents RZ Z Me Ts R E B R O E N B R B RE i-PrO2C Ph Me RZ O N Ts Me 2 i-PrO2C Ph attacks on si face of RCHO attacks on si face of RCHO attacks on re face of RCHO tartaric acid derivative • A number of alternative boron reagents have been developed for the synthesis of homoallylic alcohols • These either give improved enantiomeric excess, diastereoselectivity or ease of handling / practicality • Ultimately, chiral reagents are wasteful - they need at least one mole of reagent for each mole of substrate • End by looking at chiral catalysts Advanced organic 11 Catalytic enantioselective reduction OMe O CBS catalyst (10%) MeO H OH BH3•THF MeO MeO 93% ee • An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst (CBS) • This catalyst brings a ketone and borane together in a chiral environment • The reagent is prepared from a proline derivative • The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and works most effectively if there is a big difference between each of the substituents on the ketone • The mechanism is quite elegant... H H Ph Ph BH3 N Ph N Ph B O H3B B O Me Me CBS catalyst active catalyst proline derivative Advanced organic 12 Mechanism of CBS reduction • interaction of amine & borane activates borane • it positions the borane • it increases the Lewis acidity of the endo boron H H Ph Ph catalyst turnover BH3•THF N Ph N Ph B O H3B B O Me Me H OH O RL RS RL RS coordination of Ph Ph aldehyde activates aldehyde and places O Me O Me it close to the borane N B N B Ph H Ph H B B H O RS H O RS H H RL RL chair-like transition state largest substituent is pseudo-equatorial Advanced organic 13 Catalytic enantioselective nucleophilic addition O H OH O (–)-DAIB (2%) O + C5H11 Zn C5H11 H C5H11 Me Me >95% ee NMe2 OH Me (–)-DAIB Me Me Me Me Me Me Me Me Me Me Me N C H N C H N 5 11 5 11 Me Zn Zn O vs. O O Zn C H Ar H 5 11 Me O Me O Me Zn Zn Zn C H 5 11 C5H11 C5H11 C5H11 H Ar C4H9 C4H9 disfavoured • There are now many different methods for catalytic enantioselective reactions • Here are just a few examples... • Many simple amino alcohols are known to catalyse the addition of dialkylzinc reagents to aldehydes • Mechanism is thought to be bifunctional - one zinc becomes the Lewis acidic centre and activates the aldehyde • The second equivalent of the zinc reagent actually attacks the aldehyde • Once again a 6-membered ring is involved and 1,3-diaxial interactions govern selectivity Advanced organic 14 Catalytic chiral Lewis acid mediated allylation O H OH SnBu cat. (5%), DCM, rt, 7h O O + 3 Cl Ph H Ph N Rh N 88% Cl 62% ee Bn Bn cat. derived from amino acid (via the alcohol) • A variety of chiral Lewis acids can be used to activate the carbonyl group • These can result in fairly spectacular allylation reactions (higher ee than this example) • A problem frequently arises with crotylation • Often the reactions proceed with poor diastereoselectivity favouring either the syn or anti diastereoisomer regardless of geometry of the starting crotyl reagent • This is because the reactions proceed via an open transition state • (just to confuse you most actually favour syn! I use this example as the comparisons were easy to find...) M cat. (10%), H OH O O DCM, rt, 72h Me SnBu + 3 Ph Ph H R H Me E : Z anti (ee) : syn (ee) 95 : 5 71 (57) : 29 (8) 2 : 98 63 (60) : 37 (7) SnBu3 open transition state Advanced organic 15 Catalytic chiral Lewis base mediated allylation LB Cl H OH H LB O E Si R SiCl3 Lewis base catalyst (LB) + RE Cl Cl R H R O RZ RE RZ R RZ • An alternative strategy is the use of Lewis bases to activate the crotyl reagent • Reaction proceeds via the activation of the nucleophile to generate a hypervalent silicon species • This species coordinates with the aldehyde, thus activating the aldehyde and allowing the reaction to proceed by a highly ordered closed transition state • As a result good diastereoselectivities are observed and the geometry of nucleophile controls the relative stereochemistry Me Me N N H O O H P ( )5 P Ph N Ph N H N N H Me O N N Me Me H O Me O N E Z RE = Me RZ = Me R = Me R = Me 98% ee 98% ee 86% ee 95% ee RE = Me RZ = Me anti/syn >99/1 syn/anti 40/60 anti/syn 99/1 syn/anti >19/1 86% ee 84% ee anti/syn 97/3 syn/anti 99/1 Advanced organic 16 Organocatalysts O cat.