Stereoselective Synthesis

Transcription

1 Stereoselective Synthesis Dr Michel Perkins, Fliners University Reference Texts: Stereochemistry of orgnic compouns Ernest L. Eliel New York : Wiley & Sons, c1994. Chpter 12 on stereoselective synthesis y Lewis N. Mner. Stoichiometric Asymetric Synthesis y Mrk Rizzcs n Michel Perkins, Sheffiel Acemic Press 2000

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8 Terminology Chirl Centre: oler term, tht for cron correspons to the symmetric cron of vn't off (1874) Distereomers often contin two or more centres with 4 ifferent groups, ut this is not necessrily the cse. eg. the two istereoisomers elow re neither chirl nor contin chirl centres Cl trns Cl c Cl cis Cl

9 Terminology Cl Cl Cl Cl trns cis A Better term to use is Stereogenic centre : (stereocentre) ny centre where interchnge of two ligns (groups toms etc) les to stereoisomer

10 Introuction of Stereogenic Centres Introuction of new stereocentre into trget molecule is normlly chieve y one of two funmentlly istinct processes: either through ition to one or other stereoheterotopic (enntiotopic or istereotopic) fces of oule on e ition e

11 Introuction of Stereogenic Centres less commonly y selective moifiction or replcement of stereoheterotopic (enntiotopic or istereotopic) ligns e sustitution ition e

12 Introuction of Stereogenic Centres nother importnt group of processes is se on the sustitution of groups or ligns in meso sustrtes e e enntiomers (provie,,, e not chirl)

13 Terminology Enntioselectivity: one of two enntiomers is forme preferentilly. There my e n enntioselective step or n overll enntioselective conversion over severl steps. The egree of selectivity is inicte s enntiomeric excess (% ee) Enntiomeric # moles mjor enntiomer # moles minor enntiomer excess (% ee) = X 100 # moles of oth isomers Distereoselectivity: one of two or more istereomers is forme preferentilly. The egree of istereoselectivity is given s % s, the percentge of certin istereomer in mixture of two or more istereomers Shoul not use the term e s often more thn two isomers cn e prouce in rection

14 Terminology stereospecific use when the configurtion of the prouct is relte to tht of the rectnt n the rection is mechnisticlly constrine to procee in steroechemiclly efine mnner lso ifferent isomer of strting mteril gives ifferent prouct eg. C 3 3 C Br 2 Br C 3 Br C 3 trns - 2-utene meso only

15 stereospecific eg. 3 C Terminology C 3 C 3 Br 2 Br Br + Br C 3 Br cis - 2-utene C 3 (±) rcemte C 3 vi C 3 C 3 Br + C 3 C 3 Br Br Br C 3 C 3 C 3 Br C 3

16 stereoselective Terminology use to escrie the stereochemicl outcome of rection when it is possile for more thn one isomer to e forme, ut one is forme in excess Methyls shiel top fce B 3.S(C 3 ) 2 } 2 B or } 2 B only prouct not oserve B 2 ) 2 B B Tht the Boron n re e from the sme sie is stereospecific!

17 Stereoselective Synthesis stereochemicl outcome is etermine y ifferences in free energy ssocite with istereomeric trnsition sttes (ΔΔG ± ) eg. for SM => Pro A or Pro B!!G =!G A!G B!G A!G B E A SM B

18 Stereoselective Synthesis Three clsses of istereoselective rections stereochemiclly controlle synthesis of chirl istereomeric compouns introuction of new stereogenic centres into chirl sustrtes coupling of two compouns t prostereogenic centres with formtion of two new stereocenters

19 Distereoselective Synthesis Synthesis of Achirl Distereomers for exmple reuction of t-butyl cyclohexnone presence or lck of plne of symmetry hs no ering (provie the other rectnt is chirl) O O ren + O

20 Distereoselective Synthesis Introuction of new stereogenic centres into chirl molecules iverse clss of istereoselective rection configurtion of new stereocenters re estlishe in reltive reltionship to preexisting stereocenters rcemic sustrtes rect with chirl regents to give the sme reltive reltionship

21 Distereoselective Synthesis Introuction of new chirl centres into chirl molecules (cont) O Rcemte O ~ 90 : 10 O O O O

22 Distereoselective Synthesis formtion of two stereogenic centres eg the lol n Michel rection O R R 1. LDA OLi R O O O O O R R OLi O O O O

23 Enntioselective Synthesis generlly the sustrtes re chirl n stereoselectivity in the formtion of new stereogenic centres will require regents tht re chirl potentil for ctlyse rections! O Et 2 Zn N(C 3 ) 2 8 Mole% O (95 % ee) O potentil useful lterntive is where rcemte is resolve into its iniviul enntiomers, which re then utilise in the synthesis, either y recycling or use of complimentry sequence enntioselective synthesis epen on the vliility of enntiomericlly pure compouns from iologicl sources