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. (10%) NaOH Ph H Et S Et O Et S Et Ph Br Ph Ph Ph Ph Ph 92% ee Et S Et O 85% de (trans)

• As we have seen with many stereoselective reactions, small organic molecules are now finding considerable use as enantioselective catalysts • Above is a simple example of epoxide formation • The reaction proceeds by SN2 displacement of the bromide by the sulfide and subsequent deprotonation to give the reactive ylide • Nucleophilic attack & cyclisation give the epoxide and regenerate the sulfide catalyst

Advanced organic 17 Organocatalysts II

H H NH HN

N H N OTf P(O)Ph2 Boc HN N R NO + 2 NO2 cat. (10%) Ar Ar H R 90% ee 90% de

O O H Boc N N R Ar H

• Acts as a ‘chiral proton’ • Protonation of the imine forms a highly electrophilic species • Aza-Henry reaction can then proceed to give the new amine

Advanced organic 18 Bifunctional organocatalysts

CF3

S

F3C N N H H P(O)Ph2 P(O)Ph2 N HN N Me Me R NO 2 + NO2 cat. (10%) Ar Ar H DCM, rt R 76% ee

CF3 CF3 S S H F3C N N F3C N N H H H H H N Me Me O MOe N O O N H Me N NDpp R R H H Ar

• Thio(urea) acts as a Lewis acid to activate & position the nitro substrate • Pendent amine functionality deprotonates the nitro α-C–H and presumably an electrostatic interaction shields the bottom face of the nitro enolate Advanced organic