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1 Stereoselective synthesis: chiral auxiliaries Chiral auxiliaries substrate (achiral) + couple to form new chiral compound chiral auxiliary overall reaction product (chiral) + substrate (achiral) chiral auxiliary product diastereoselective reaction cleave chiral auxiliary chiral auxiliary chiral auxiliary resolve other diastereoisomer product chiral 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 Me Me Me O Ph O O L L Mg O O Me MeMgBr –78°C Me H Me Me O OH H Me Me H Me O Ph O 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 Me Me O Ph O O Me KBH(i-OPr)3 O Me Me Ph O OH Me H 90% de 123.702 Organic Chemistry 3 Chiral auxiliary in synthesis Me Me O Me Me Ph O O RMgBr –78°C Me O Ph O Me Me OH LiAlH4 HO Me OH 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 substrate (achiral) + chiral reagent interacts with achiral substrate chiral reagent substrate (achiral) reaction product (chiral) chiral reagent + dead 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 B + Me O Me H O B + RL Me Me 9-BBN•THF (+)-α-pinene RS Me alpine borane® proceeds via boatlike transition state can be reused Me H OH Me + RL B O RS Me Me H Me O alpine borane® (CH2)4Me small group as linear Me RS H OH (CH2)4Me 86% ee RL selectivity governed by 1,3-diaxial interactions 123.702 Organic Chemistry 6 Binol derivative of LiAlH4 1. (S)-BINAL–H 2. MOM–Cl O Me H OMOM Me SnBu3 O O SnBu3 93% ee OEt Al H Li (R)-BINAL–H • Reducing reagent based on BINOL and lithium aluminium hydride • Selectivity is thought toL arise from a 6-membered transition state (surprise!!) (R ) adopts the pseudo-equatorial position and the small • Largest substituent S substituent (R ) is axial to minimise 1,3-diaxial interactions O O Al O H RS Li Et RL O 123.702 Organic Chemistry 7 Chiral reagent in total synthesis Cl Me H O B BCl Cl Me Me Me H Me 2 Ipc O Ph H OH Cl Me 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 H•HCl Cl 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 RZ O + L R O RE B L B O RZ R L L L OH H2O2 NaOH B R 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 R RE H B O RZ disfavoured H L H L vs RE R RZ B O H OH H L RE R RZ OH R RZ RE E-alkene gives anti product Z-alkene gives syn product • 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 O B + Me Et Me Me H Et Me 92% ee 2 crotyl group orientated away from pinene methyl groups Me Me Me H H H Et Me H B Me Me O Et Me OH Me substituent pseudoequatorial • 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 Me RE B Me Me RZ O i-PrO2C RE O i-PrO2C 2 attacks on si face of RCHO B RZ Ts attacks on si face of RCHO tartaric acid derivative N Ph RE B N Ts Ph attacks on re face of RCHO • 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 BnO2C O Me N + H OBn OH DCM, 0°C BnO2C Si Me Me 80% 95% d.e. Cl N O Me Me Ar Cl H Me H Si N O R Ar H Ar Me H N Me H R OH 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 Me O Me Me NaO2C OH CO2H Me Me O 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%) BH3•THF MeO H OH 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 N Ph Ph B O Me CBS catalyst proline derivative H BH3 Ph N Ph H3B B O Me active catalyst 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 catalyst turnover H Ph N BH3•THF Ph Ph N H3B B O Me B O Me Ph O H OH RL RS RL Ph coordination of aldehyde activates aldehyde and places it close to the borane Ph O Ph RS N B Me H B O H O Ph RS H N B Me H B O H RS H RL RL chair-like transition state largest substituent is pseudo-equatorial 123.702 Organic Chemistry 15 Catalytic enantioselective nucleophilic addition O O H + C5H11 Zn C5H11 Me H OH (–)-DAIB (2%) O Me C5H11 >95% ee NMe2 OH Me (–)-DAIB Me Me Me Me Me C5H11 N Me O Zn C H 5 11 Zn C H 5 11 Me Me Me Me Me N C5H11 O Zn Ar vs. O Zn C5H11 C4H9 H Me Me Me C5H11 O Zn H O Zn N Me C5H11 C4H9 Ar 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 O + Ph RE SnBu SnBu33 SnBu3 Me Ph Me RZ H Ph P Ph OH (R)-BINAP, AgOTf THF, —20°C P Ph Ph Me E:Z 95:5 E:Z 2:98 E:Z 53:47 56% 70%de 94%ee 72% 70%de 91%ee 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 O P disfavoured Ag H Ph P Me H OH Ph O Ag Me Ph Me SnBu3 P OH H H Ph Me SnBu3 123.702 Organic Chemistry 17 Catalytic chiral Lewis base mediated allylation O + R RE Lewis base catalyst (LB) SiCl3 RE R H H H OH RZ RE R RZ LB Cl Si LB O Cl Cl 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 H H N O P N N Me RE = Me 86% ee anti/syn 99/1 N O 5 () N P N H Ph Me N Ph Me H Me RZ = Me 95% ee syn/anti >19/1 H RE = Me 98% ee anti/syn >99/1 O RZ = Me 98% ee syn/anti 40/60 Me RE = Me 86% ee anti/syn 97/3 N N O O RZ = Me 84% ee syn/anti 99/1 123.702 Organic Chemistry 18 Lewis acid organocatalysis OTBS Me Me N Me H cat (10mol%), toluene, –78°C O + Ph O Me H OH N O Ph Me Me 88% 87% d.e. 98% e.e. R O R O • Intermolecular hydrogen bond acts as a • • • OH O H Lewis acid and activates carbonyl Intramolecular hydrogen bond organises catalyst Catalyst derived from simple nature product, tartaric acid Clean, green and effective OH O H H O H O Me intramolecular H-bond bulk blocks attack from one face H H Ph O NMe2 t-BuMe2Si 123.702 Organic Chemistry 19 Catalysis in total synthesis H O H i. HBCy2 ii. Et2Zn, (+)DAIB (1mol%) iii. NH4Cl 75% 92%e.e. Me Me Me Me Me N Et O Zn O Zn Et addition to Si-face H H H H (CH2)10 hydroxyl-directed Simmons Smith reaction (substrate control) Et2Zn, ClCH2I HO i. (COCl)2, DMSO; then Et3N ii. Li, NH3(l), –78°C catalytic asymmetric carbonyl addition 91% O Me H HO H H 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