STRATEGIES IN SYNTHESIS

Transcription

1 STRATEGIES I SYTESIS Professor T. J. Donohoe MT Lectures: Tuesday at 10 am; Thursday at 9 am (weeks 6-8) DP: Lecture Theatre Monensin Me 7 Et Me Me Me Me Me Me C 2 1 Me Kishi J. Am. Chem. Soc, 1979, 101, 259. A copy of this handout is available at:

2 Strategies in Synthesis Synopsis 1) Introduction to synthesis: why do we want to synthesise molecules- what sort of molecules do we need to make? What aspects of selectivity do we need to exert to accomplish a good synthesis (chemo-, regioand stereoselectivity) 2) Protecting group chemistry is central to any synthetic effort (examples) 3) Retrosynthesis- learning to think backwards (revision from first year). Importance of making C-C bonds and controlling oxidation state. Umpolung 4) Examples of retrosynthesis/synthesis in action. 5) andy hints for retrosynthesis Recommended books: General: rganic Chemistry (Warren et al) rganic Synthesis: The Disconnection Approach (S. Warren) Classics in Total Synthesis Volumes I and II (K. C. icolaou) The Logic of Chemical Synthesis (E. J. Corey) 2

3 1) Why do we want to synthesise complex molecules? Taxol Ac Ac Strychnine Sidenafil Et S 3

4 In order to undertake the synthesis of a complex organic molecule, we need to control the following: 1) Carbon 2) Functional 3) Stereochemistry In order to control 1) and 2) Chemoselectivity CMe Regioselectivity Protecting group strategy 4

5 A) CEMSELECTIVITY Using different tactics we can reduce each of the a) 2, Pd-C. This reagent is sensitive to steric b) a, 3, tbu (1 eq.) electron 3 + 5

6 Q. What would happen if we added >2 eq. of tbu? a, 3? 2 eq.t B u c) ab 4, CeCl 3 (Luche reduction) ab 4 ab 4, CeCl 3 What does CeCl 3 do to sodiumborohydride? ab 4 + Me B + B This process is promoted by Ce(III) 6

7 B) REGISELECTIVITY aet Et Et Et pka ow to influence regioselectivity by LDA LDA Et Et PhC 2 Br Et Dianion LDA= 7

8 C) PRTECTIG GRUPS (are essential to most syntheses) R 3 SiCl Et 3 R 3 SiCl increasing increasing Me 3 SiCl SiCl SiCl There are tactics for protecting the least and the most hindered groups. TBSTf tbu? tbu 8

9 RETRSYTESIS The theory (Corey- obel prize 1) Think about reactions in reverse A B A B X C D 2) Use disconnections to break down molecules S Make sure that your disconnections correspond to known and 3) Synthons: These are simply There are two ways of analysing a single A number shows the position of the charge relative to the 9

10 S You have to decide which synthon is realistic and Remember the concept of UMPLUG is helpful (especially) with carbonyl groups: 1) ormal reactivity of the carbonyl group Ph Ph 10

11 2) Use UMPLUG to reverse the reactivity of the carbonyl group Ph Ph The hard part is choosing a particular disconnection (from several others) in a complex molecule. 4) Sometimes functional group interconversion on the target helps Simple FGI More difficult CEt FGI CEt Ph Ph 11

12 Even stereochemistry can be altered in this way. FGI Some problems: ow would you synthesise the following? (int: think about Diels Alder) CMe CMe CMe Ac CMe CMe CMe CMe Ac 12

13 Synthesis 1) Eletriptan (Pfizer) Migraine S S S The synthesis: C 2 Ph C 2 Ph Cl Br + Cl C 2 Ph LiAl 4 13

14 Mechanism for this step is: To finish the synthesis 14

15 Br S Synthesis 2) Talaromycin B (Schrieber, Tetrahedron Letters, 1983, P4781) 1) Most substituents on each ring are 2) The only axially disposed groups are 3) The AMERIC 15

16 Further disconnections are possible ow only The synthesis in full: 1) Preparation of the starting materials Ac 2 MgBr SCl 2 mech? Cl, Me Me Me + Putting these pieces together: 16

17 Cl S BuLi S 2, Pd Cat. BuLi A A B 3 then 22, a gcl 2 2 And finally, 17

18 Me Me TsCl Me 2 CuLi mechanism

19 Synthesis 3) Estradiol (elvetica Chimica Acta, 1980, 63, 1703) ow the synthesis. then think about relative The other half: 19

20 S I 2 Ag S ac, (Ph 3 ) 4 Pd S Pd S ac S The end-game a then S S Si I S 20

21 And finally, MeLi + quench Synthesis 4) Prostaglandin F 2α (Journal of the American Chemical Society, 1969, P5675) E. J. Corey P= protecting group C 2 Wittig Reaction and protection Reconnect Lactol and change oxidation state Wadsworth Emmons P P 21

22 AD Me P P Me Me Problem: C The synthesis: 22

23 Tl MeC 2 Cl MeC 2 Cl C Cl Why Tl? Me K Me Me Me Me Me Me MCPBA a Me I 2, ac 3 then Ac 2 Me Ac 23

24 mechanism of iodide reduction: BBr 3 PCC Me Ac Ac Ac Me Me P C 5 11 a Ac 24

25 Why do P Me Me P C 5 11 P Reduction of the C= bond ab 4 Ac Ac (i) K 2 C 3 (i) Ts 25

26 DIBAl- Ph 3 P C 2 ow do you make the ylid? Ph 3 P C 2 Why do non-stabilised P P P 26

27 Finally, to complete the synthesis: 3 + Some handy hints for retrosynthesis 1) Make the synthesis Use convergent rather than 2) Use only disconnections corresponding to Ac 3) Disconnect C-X bonds wherever possible (this includes RC S 27

28 4) Disconnect C-C bonds by using nearby functional groups or by Also, it makes more sense to disconnect in the middle Ph Ph 5) Disconnect back to readily recognisable 28

29 Some problems to think about: Disconnect the following and then devise forward syntheses: Me Me 2 Me Cl C Me 29