1 Stereoselective synthesis: chiral auxiliaries

Chiral auxiliaries

couple to form new chiral compound substrate + substrate (achiral) chiral (achiral) chiral auxiliary auxiliary

product overall diastereoselective chiral reaction reaction auxiliary resolve other diastereoisomer product cleave chiral product (chiral) auxiliary + chiral chiral auxiliary auxiliary

• Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction • Add chiral unit to substrate to control stereoselective reaction • Can act as a built in resolving agent (if reaction not diastereoselective) • Problems - need point of attachment ...... adds additional steps ...... cleavage conditions must not damage product! 123.702 Organic Chemistry 2 Chiral auxiliary and addition to 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

123.702 Organic Chemistry 3 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 • Aggregation pheromone of the Southern Pine Beetle - the most destructive beetle to pine forests in southeastern united states 123.702 Organic Chemistry 4 Stereoselective synthesis: chiral reagents

Chiral reagents

chiral reagent substrate interacts with (achiral) achiral substrate reaction product substrate + (chiral) + (achiral) chiral dead reagent reagent chiral reagent chiral complex

• Chiral reagent - stereochemistry initially resides on the reagent • Advantages - No coupling / cleavage steps required ...... Often override substrate control ...... Can be far milder than chiral auxiliaries • Disadvantages - Need a stoichiometric quantity (not atom economic) ...... Frequently expensive ...... Problematic work-ups

123.702 Organic Chemistry 5 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 123.702 Organic Chemistry 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 123.702 Organic Chemistry 7 Chiral reagent in total synthesis

Cl Me H Ipc O B H OH BCl O Me H Ph Cl Cl Me Me Me Me 2 Cl (+)-Ipc2BCl ≥99% e.e. 1 recrystallisation

ArOH, PPh3 EtO2C N N CO2Et

CF3 CF3

i. MeNH2, H2O, 130°C ii. HCl O H O H Me N Cl H•HCl

R-(–)-fluoxetine Prozac

• (+)-Ipc2BCl is a more reactive, Lewis acidic version of Alpine-borane • Might want to revise the Mitsunobu reaction (step 2) • M. Srebnik, P.V. Ramachandran & H.C. Brown, J. Org. Chem., 1988, 53, 2916 123.702 Organic Chemistry 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) 123.702 Organic Chemistry 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 123.702 Organic Chemistry 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

123.702 Organic Chemistry 11 Chiral reagent in total synthesis

Ar OBn O OBn OH N Me DCM, 0°C BnO2C + Si BnO2C O H O N Cl 80% Me Me 95% d.e. Me Me Me Ar

Cl H Ar H H Si N Me Me O N OH R R H H Ar H

• Silicon reagent developed by J. Leighton • Used in the synthesis of (+)-SCH 351448, a reagent for the activation of low-density lipoprotein receptor (LDLR) promoter (no I don't know what it means either!) • Sergei Bolshakov & James L. Leighton, Org. Lett., 2005, 7, 3809

OH O O O OH

Me CO2H Me Me O O Me Me NaO2C Me OH O O O HO

(+)-SCH 351448 123.702 Organic Chemistry 12 Stereoselective synthesis: chiral catalysis

substrate (achiral) substrate (achiral) chiral catalyst

chiral catalyst

product (chiral) chiral catalyst

product (chiral)

• Chiral catalysis - ideally a reagent that accelerates a reaction (without being destroyed) in a chiral environment thus permitting one chiral molecule to generate millions of new chiral molecules...

123.702 Organic Chemistry 13 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

123.702 Organic Chemistry 14 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

123.702 Organic Chemistry 15 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 123.702 Organic Chemistry 16 Lewis acid catalysed allylation / crotylation

(R)-BINAP, AgOTf OH Ph O E Ph R SSnnBBuu33 THF, —20°C P + Me SnBu3 Ph P Ph H MReZ Ph Me Ph E:Z 95:5 56% 70%de 94%ee E:Z 2:98 72% 70%de 91%ee E:Z 53:47 45% 70%de 94%ee

• Chiral Lewis acids can be used to activate carbonyl group with impressive results • Allylation works very well with high e.e. • Problem with crotylation - often hard to control d.e. • Reason is that the reaction proceeds via an open transition state

P disfavoured P Ag Ag O P OH O P OH H Me Me H Ph Ph Ph H Ph H Me Me

SnBu3 SnBu3

123.702 Organic Chemistry 17 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 99/1 123.702 Organic Chemistry 18 Lewis acid organocatalysis

OTBS cat (10mol%), O OH O toluene, –78°C Me Me + Me O N N Ph OH Ph H OH Me H Me Me O 88% 87% d.e. 98% e.e.

H R O R • Intermolecular hydrogen bond acts as a O Lewis acid and activates carbonyl H O O • Intramolecular hydrogen bond organises H catalyst H • Catalyst derived from simple nature product, O tartaric acid Me H intramolecular • Clean, green and effective H-bond H Ph

O NMe2 bulk blocks attack t-BuMe Si from one face 2

123.702 Organic Chemistry 19 Catalysis in total synthesis

H i. HBCy Me Me O 2 Me H ii. Et2Zn, (+)- Me HO DAIB (1mol%) N Et H Zn H iii. NH4Cl O H Me O H 75% Zn 92%e.e. Et addition to (CH2)10 catalytic Si-face asymmetric carbonyl addition hydroxyl-directed Et2Zn, ClCH2I Simmons Smith reaction (substrate control) 91% O H HO Me i. (COCl) , DMSO; then Et N H 2 3 H ii. Li, NH3(l), –78°C

82%

(R)-muscone

• (R)-Muscone is the primary contributor to the odour of musk, a glandular secretion of the musk deer. • A racemic, synthetic version is used in perfumes. • Wolfgang Oppolzer and Rumen N. Radinov, J. Am. Chem. Soc., 1993, 115, 1593 123.702 Organic Chemistry