Conjugate (1,4-) addition

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1 1 Conjugate (1,4-) addition uc R 1 R 2 uc R 1 R 2 uc R 1 E R 2 E ucleophilic 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 ubstrate control - initial addition to the least hindered face of enone reagent uc electrophile uc E R R R yield% x%de econd addition normally occurs from opposite face rganic Chemistry

2 2 ubstrate control in total synthesis i t-bu + I C 5 11 TB i. t-buli ii. CuI, P 3 iii. MPA 78 TB TB C 5 11 iv. 3 ncl v. I C 2 C 2 i. Pyr F(F) x ii. hydrolysis C 2 C % TB C 5 11 prostaglandin E 2 TB 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. uzuki, A. Yanagisawa & R. oyori, J. Am. Chem. oc. 1988, 110, rganic Chemistry

3 3 Diastereoselective conjugate additions ppolzer's camphor sultam EtMgCl trans conformation disfavoured chelation restricts rotation Mg Et Cl Mg Cl Et cis conformation favoured Et Li 90% de Et Mg Et Et Mg Cl Cl 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 rganic Chemistry

4 4 Chiral auxiliary to control two stereocentres 1. BuMgCl 2. I Bu Mg L L I 95% de Bu electrophile approaches from bottom face Li + Bu 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 nce again the sultam chiral auxiliary controls the face of addition (of ) rganic Chemistry

5 5 Alternative chiral auxiliaries I aldol-like reaction & acid catalysed elimination 1. LDA 2. R 1 C 3. CF 3 C 2 R 1 R 2 Li R 1 R2 Li 2 R 1 C % ee R 2 3 R 1 R 2 2 R 1 R 2 Li hydrolysis A second chiral auxiliary is the oxazoline (5-membered ring) of yers 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 rganic Chemistry

6 6 Chiral auxiliary and radical conjugate addition R 1 Yb(Tf) 3 (1eq), R 2 X (5eq), Bu 3 n (2eq), Et 3 B, 2, 3h, 78 C R 2 R % 76-96%de R 1 =, R 2 =i-pr, Et, c-ex etc L n Yb R 2 R 1 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 & 2 as radical initiator allows the use of low temperatures rganic Chemistry

7 7 ulfoxide-based chiral auxiliary (& total synthesis) ZnBr 2 MgBr L L Zn Ar Raney i ulfoxide 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 ulfoxide substituent blocks the bottom face & is readily removed imple 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.. Posner, T. P. Kogan,. R. aines, L. L. Frye, Tetrahedron Lett. 1984, 25, 2627 ( )-podorhizon 95% ee nuc Ar 2 CCl Ar rganic Chemistry

8 8 Chiral auxiliaries and total synthesis C 2 Et + Br LiBr Et 3 72% 92%de C 2 Et i. Cl ii. Li 59% 2 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 ubhash P. Chavan, Pallavi harma, Rasapalli ivappa, Mohan M. Bhadbhade, Rajesh G. Gonnade and Uttam R. Kalkote, J. rg. Chem. 2003, 68, rganic Chemistry

9 9 Enantioselective catalytic conjugate addition Et 2 Zn, Cu(Tf) 2 (2%), lig. (4%), tol, 3h, 30 C Et 94% >98% ee P 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 Et 2 Zn, Cu(Tf) 2 (2%), lig. (4%), tol, 3h, 30 C Et 75% 10% ee rganic Chemistry

10 10 Enantioselective radical conjugate addition + I i. Et 3 B, 2 ii. MgX 2 90% 97%ee ot 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 ibi rganic Chemistry

11 11 rganocatalysis + Bn Bn Bn cat. (10%), neat, rt, 165h C 2 Bn 2 C C 2 Bn 86% 99% ee C 2 C 2 Bn C 2 Bn C 2 Bn C 2 Bn ew 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 rganic Chemistry

12 12 rganocatalysts II X + R 2 Bn Cl R 2 X 68-90% 84-92% ee R 2 X X X Ar 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 rganic Chemistry

13 13 rganocatalysts III + TM R Possible to introduce two stereogenic centres with good diastereoselectivity and enantioselectivity An interesting reaction is the tetter 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) Bn Cl cat. (20%) DCM / 2 20 to 70 C, 11 30h R 77% syn:anti = 1-31: % ee cat. (20%) KMD (20%) 25 C, 24h C 2 Et C 2 Et 80% 97% ee BF rganic Chemistry

14 14 chanism of tetter reaction C 2 Et Ar C 2 Et Ar base C 2 Et Ar Ar 2 base Ar Et base Ar Et The tetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies and the reaction is thus biomimetic rganic Chemistry

15 15 rganocatalytic bifunctional catalysis CF 3 F 3 C Et 2 C C 2 Et 2 + Et 2 C C 2 Et 2 toluene, rt, 24h 86% 93% ee CF 3 CF 3 F 3 C F 3 C C 2 Et Et Et C 2 Et 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 rganic Chemistry

16 16 rganocatalysis and total synthesis Br Boc + Bn t-bu i. cat (20mol%) ii. ab 4 78% 90%ee Br Boc Br ( )-flustramine B Boc R Boc R Br Br Beautiful example of enantioselective conjugate addition in total synthesis From the synthesis of a marine alkaloid from the Bryozoa, Flustra foliacea by Joel F. Austin, ung-gon Kim, Christopher J. inz, Wen-Jing Xiao, and David W. C. MacMillan, PA 2004, 101, rganic Chemistry