1 Conjugate (1,4-) addition Nuc O Nuc O Nuc O 1 ∗ ∗ 2 1 2 R R R R R1 ∗ R2 E E • Nucleophilic attack on C=C bond normally requires electron deficient alkene • Know as 1,4-addition or conjugate addition • As enolate formed during reaction - possibility of forming two stereogenic centres • Substrate control - initial addition to the least hindered face of enone HE O Nuc O reagent electHrophile Nuc O R R R yield% x%de • Second addition normally occurs from opposite face 123.702 Organic Chemistry 2 Substrate control in total synthesis O i. t-BuLi O ii. CuI, PPh3 iii. HMPA I C5H11 –78° + O OTBS C5H11 TBSO Si Me Me t-Bu OTBS iv. Ph3SnCl v. I CO2Me O O i. Pyr•HF(HF)x CO2H ii. hydrolysis CO2Me C5H11 78% C5H11 HO TBSO OH OTBS prostaglandin E2 78% 94%de • Prostaglandins are technically hormones with very strong physiological effects • Prostaglandins have been utilised to prevent and treat peptic ulcers, as a vasodilator, to treat pulmmonary hypertension and induce childbirth / abortion • This is a synthesis of prostaglandin E2 (PGE2) by M. Suzuki, A. Yanagisawa & R. Noyori, J. Am. Chem. Soc. 1988, 110, 4718 123.702 Organic Chemistry 3 Diastereoselective conjugate additions Me Me Me Me Me Me Me Me H EtMgCl Et NH N N O O Mg Cl S O S O S trans conformation Mg Cl O O O O disfavoured Et Oppolzer's cis camphor sultam conformation favoured chelation restricts rotation Me Me Me Me Me Me Me Me H H HO Me LiOH Et N NH N Et O Mg Cl O Et O S S O S O Mg Cl O O O O Et 90% de • Possible to use chiral auxiliary to control 1,4-nucleophilic addition • Chelation of amide and sultam oxygens to Mg restricts rotation and favours cis conformation • Addition occurs from most sterically accessible side • Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound via diastereoselective reaction 123.702 Organic Chemistry 4 Chiral auxiliary to control two stereocentres Me Me Me Me Me Me Me Me H Me Me 1. BuMgCl H H 2. MeI N Bu N O N Bu O S Me O S O Mg L S O O O O L I O 95% de electrophile LiOH approaches from bottom face Me Me Me HO Me NH + S O O Bu O • It possible to utilise 1,4-addition to introduce two stereogenic centres • The first addition (BuMgBr) occurs as before to generate an enolate • The enolate can then be trapped by an appropriate electrophile • Once again the sultam chiral auxiliary controls the face of addition (of Me) 123.702 Organic Chemistry 5 Alternative chiral auxiliaries I aldol-like reaction & acid catalysed elimination O Ph O Ph O Ph Me 1. LDA R2–Li 1 N 2. R1CHO R N R1 N R2 H H OMe 3. CF3CO2H OMe Li OMe OH O Ph O Ph R1 H O H O CO H 3 2 Ph OMe 2 1 1 2 R N R N H R R2 R2 NH 2 95-99% ee H OMe H Li OMe hydrolysis • A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers’ • It can be prepared from carboxylic acids (normally in 3 steps) or from condensation of the amino alcohol and a nitrile • As can be seen excellent enantiomeric excesses can be achieved via a highly diastereoselective reaction 123.702 Organic Chemistry 6 Chiral auxiliary and radical conjugate addition 2 O O Yb(OTf)3 (1eq), R –X O O R2 (5eq), Bu3SnH (2eq), 1 1 O N R Et3B, O2, 3h, –78°C O N R Ph 81-94% Ph 76-96%de Ph Ph R1=Me, Ph R2=i-Pr, Et, c-Hex etc Ln Yb O O R2 O N R1 Ph Ph • Radicals once thought to be too reactive to allow diastereoselective reactions • Clearly not true - oxazolidinone auxiliary • Rare-earth Lewis acids give superior results • Use of Et3B & O2 as radical initiator allows the use of low temperatures 123.702 Organic Chemistry 7 Sulfoxide-based chiral auxiliary (& total synthesis) L L O O O O Zn ZnBr S S 2 O O O O S H O MgBr O MeO MeO MeO O Ar Raney Ni nuc O O MeO O O Ar2COCl O MeO H OMe H O Ar O (–)-podorhizon 95% ee • Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but it activates the alkene by addition of an extra electron-withdrawing group • Sulfoxide substituent blocks the bottom face & is readily removed • Simple substrate control instals aryl group on opposite face to substituent • (–)-Podorhizon is a member of the anticancer podophyllotoxin family of compounds • This synthesis is by G. H. Posner, T. P. Kogan, S. R. Haines, L. L. Frye, Tetrahedron Lett. 1984, 25, 2627 123.702 Organic Chemistry 8 Chiral auxiliaries and total synthesis Ph Me Me Me H N LiBr Ph N CO Et O Ph 2 Et3N O CO Et + 2 Br Ph O 72% 92%de O Me Me Me i. HCl ii. LiOH 59% H NH2 OH HO O O L-CCG-I • L-CCG-I (L-carboxycyclopropylglycine-I) is a conformationally restrained analogue of L-glutamic acid (there are four possible stereoisomers of L-CCG) • L-Glutamic acid is the most abundant excitatory neurotransmitter in our bodies; it is thought to be involved in cognitive functions like learning and memory in the brain and possibly with umami, one of the five basic human tastes • This synthesis is by Subhash P. Chavan, Pallavi Sharma, Rasapalli Sivappa, Mohan M. Bhadbhade, Rajesh G. Gonnade and Uttam R. Kalkote, J. Org. Chem. 2003, 68, 6817 123.702 Organic Chemistry 9 Enantioselective catalytic conjugate addition O O Ph Et2Zn, Cu(OTf)2 (2%), Me lig. (4%), tol, 3h, –30°C O P N O Me Et 94% Ph >98% ee lig. • Much effort has been expended trying to develop enantioselective catalysts for conjugate addition • Whilst many are very successful for certain substrates, few are capable of acting on a wide range of compounds • The system above gives excellent enantioselectivities for cyclohexenone but... no selectivity for cyclopentenone O O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C Et 75% 10% ee 123.702 Organic Chemistry 10 Enantioselective radical conjugate addition O i. Et B, O Me Me O Me 3 2 O O ii. MgX2 + I O N Ph Me O N Ph O O 90% N N 97%ee • Not unsurprisingly, once stereoselective conjugate radical additions with auxiliaries had been developed, the enantioselective catalytic variant rapidly followed • Effectively, this is a chiral Lewis acid catalysed reaction • Most work in this area has been pioneered by Sibi 123.702 Organic Chemistry 11 Organocatalysis Me N CO Bn Bn CO H 2 N 2 BnO C O O O H 2 + cat. (10%), Ph Me BnO OBn Ph O neat, rt, 165h Me 86% 99% ee Me Me N N CO H N 2 N CO2H Me BnO H Me CO2Bn H O H CO2Bn CO2Bn • New small molecule organic catalysts are now achieving remarkable results • Enone is activated by formation of the charged iminium species • The catalyst also blocks one face of the enone allowing selective attack 123.702 Organic Chemistry 12 Organocatalysts II O Me N Me Bn X H NR2 N Me X O H•HCl Me + O H R2N 68-90% 84-92% ee O Me O Me O Me N N N Me Me Me N Me N Me N Me Me Me Me H H NR2 H X Ar X X H H steric hindrance results in predominantly one conformation • A range of reactions can be achieved, including enantioselective Friedel-Crafts • Catalyst ensures that the enone reacts via one conformation • Must use electron rich aromatic substrates 123.702 Organic Chemistry 13 Organocatalysts III O Me N Me O Bn N Me H O H•HCl Me Me + O TMSO O Me R O cat. (20%) DCM / H2O –20 to –70°C, 11–30h R H 77% syn:anti = 1-31:1 84-99% ee • Possible to introduce two stereogenic centres with good diastereoselectivity and enantioselectivity • An interesting reaction is the Stetter reaction - this is the conjugate addition of an acyl group onto an activated alkene and proceeds via Umpolung chemistry (the reversal of polarity of the carbonyl group) OMe O cat. (20%) O KHMDS (20%) Me Me 25°C, 24h N N H CO2Et H O CO2Et O N 80% O BF4 97% ee 123.702 Organic Chemistry 14 Mechanism of Stetter reaction O O Me Ar Me CO Et H 2 N N O O CO Et N 2 O N Ar N Ar N O H base N N Me OH CO2Et N H base Ar2 O O O Ar Ar N N OEt N N OH HO OEt N N O H base O Me Me • The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies and the reaction is thus biomimetic 123.702 Organic Chemistry 15 Organocatalytic bifunctional catalysis CF3 S F3C N N H H EtO C CO Et N 2 2 NO2 Me Me + EtO2C CO2Et NO2 toluene, rt, 24h 86% 93% ee CF3 CF3 S S H F3C N N F3C N N H Me H H N Me H H N Me Me O O H O O O H N O N CO Et H 2 H OEt EtO CO2Et Ph Ph • The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds • The amine both activates the nucleophile and positions it to allow good selectivity 123.702 Organic Chemistry 16 Organocatalysis and total synthesis O Me Me OH N NHBoc Me Bn t-Bu O N NBoc H N Br N + Br N H Me i.