Guideline 5: Tactical Bonds

Transcription

1 Guideline 5: Tactical Bonds f the molecule contains more than one functional group and hence there is a choice of which bonds to disconnect, how do you decide? Practice, but here are a few rough guidelines a) emove or protect reactive functionality as early as possible reduces chemoselectivity issues b) n polycyclic systems cleave rings normally easier to spot disconnections in acyclic systems c) f a ring is present, think about cycloadditions often proceed with excellent regio- and stereocontrol d) Bicyclic systems, think about intramolecular cycloadditions e) (normally) Conserve (don't disconnect) aromatic rings and isolated functional groups f) Divide the molecule in the middle (be convergent) opefully the previous examples (and the following) illustrate such principles (±)-Porantherine 74JAC6516 guideline 4aii; further functionality aids disconnections Mannich reaction guideline 3cii aldehyde condensation FG 1. ab 4 2. Cl 2 (), pyr guideline 3cii pta guideline 3a C Cl Me guideline 3a C elegant as it is made from a symmetrical molecule (which greatly aids starting material preparation and carbonyl protecting group manipulations Mannich reaction 22

2 one isomer due to complimentary anomeric effects 2 C Julia coupling kadiac Acid 98P3907 C-glycosidation guideline 3b guideline 3c much milder variant of the Julia reaction spiroketalisation guideline 3a C 2 Bn not just a protecting group functions as a chiral auxiliary FG simple Me Me C=C vinyl anion coupling convergency P P P FG hetero Diels-Alder 3 sections so convergent spiroketalisation P "one-pot" two bond process due to anomeric effect selectively protects anti diols TB Me P() 2 BDA-a selective protecting group C Ac TBDP C Ac Bn 2 Me Ac Me selective protection Bn Ar Ac Ac P Me P 23

3 guideline 3a & 3c spiroketalisation "one-pot" two bond process 2 C C P C convergent What have we learnt? plitting a molecule into fragments (convergency) is good Cleaving rings simplifies structure rapidly Use any symmetry inherent within a molecule 24

4 Guideline 6: Transformations Transformations can be used to bring about the rapid simplification of a molecule ften use other guidelines to set up the recognition pattern for certain transformations Most common examples are the Diels-Alder reaction, harpless asymmetric epoxidation and sigmatropic rearrangements (Claisen, oxy-cope, ene reactions) The recognition pattern for these is given below: Diels-Alder heteroatoms can be a part of the ring FG Diels-Alder indicator is the end of two π-systems 6 atoms apart igmatropic rearrangement rearrangement X X CP 263,114 ( ) 2 ( ) 5 C 2 fascinating molecule problems inculde an anti-bredt bridgehead alkene the incorporation of an acetal, an anhydride and a lactone T going to deal with the synthesis (icolaou and Danishefsky) nterested in the use of Transformation strategies for the core guideline 3cii Tandem oxy-cope Dieckman cyclisation 98JAC10784 oxy-cope P Dieckman Cyclisation P C 2 Me anion accelerated oxy-cope P C 2 Me Dieckman guideline 3ci Grignard C 2 Me 25

5 ntramolecular Diels-Alder 99Ang1669,1676 ' guideline 3a & 5b C ' C 2 not only cleaving rings to simplify but removing sensitive acetal P P 6 ring with double bond is crying out for a Diels-Alder reaction (but check stereochem of substituents first) MDA C P MDA P P see reference P P xy-cope 99JAC890 oxy-cope TE TE oxy-cope rearrangement, 95% TE 1,5-diene, think sigmatropic rearrangement "one-pot" 46%! Me 2 C TE Tf 2 x C [Pd(P 3 ) 4 ], Et 3, C TE prepared from Diels-Alder reaction palladium carbonylation 26

6 reland-claisen rearrangement reland-claisen 91CC1641 Mukaiyama macrolactonisation 76CL C-C 1. LDA, TMCl Ar C- Cl Ar C 2 enolate formation provides required double bond reductive desulfonylation conjugate addition 1.a / g 2. K FG TB C- Ar 2 C 2 Me 1. a Ar 2 C 2 Me TM Ar TM Ar proceeds via boat-like T as geometry constrained by 9-ring What have we learnt? Can base synthesis around one simplifying transformation tarting materials often easy to prepare igmatropic rearrangements hard to spot BUT very powerful n the hierarchy of organic reactions Diels-Alder near the pinnacle in terms of usefulness 27

7 ETYTE F ( )-TEE A B C simplify structure by removing substituents D C-C guideline 3a C- removing C-ring 96Ang904 C- guideline 3a D-ring FG adds alkene to give the recognisable Diels-Alder disconnection Diels-Alder forms 2 bonds and sets up 4 (out of 7) of the stereocentres in stenine guideline 3a C- cleaves A-ring C- C 2 (C 2 ) 4 C-C Diels-Alder C 2 C B P (C 2 ) 4 C- guideline 6 C P (C 2 ) 4 ssues to be addressed: egiochemistry of the Diels-Alder reaction Enantioselectivity of the Diels-Alder reaction nstallation of the nitrogen Diels-Alder sets up 4 out of 7 stereocentres, must control last 3 Answers: ntramolecular Diels-Alder with a chiral auxiliary 1 of 3 stereocentres will be directly transcribed to form cis junction between A and B-rings emaining 2 centres will be induced by bowl-like shape of molecule ketone sufficient functionality to prepare rest of molecule MDA all skeletal carbons contained in fragment MDA B C 2 * (C 2 ) 4 (C 2 ) 4 * TE: breaking C-C bonds sometimes highly advantageous strategy for synthesis amide activates dienophile amide also chiral auxiliary 28

8 YTE F ( )-TEE TP 1. BuLi Cl (C 2) 4 PMB 2. + (C 2 ) 4 PMB 1. wern 2. 2()P PMB(C 2 ) 4 stabilised orner-wadsworth-emmons installs chiral auxiliary complete control of geometry dithiane protects carbonyl also allows it to act as nucleophile (umpolung) Lewis acid activates dienophile 1. Me 2 AlCl Curtius rearrangement installs nitrogen deprotect dithiane C 2 Me 1. () 2 P 3 C 2 1. Ag 3, C 2. LiEt 3. Et 3 i, Pd / C 4. acl 2 (C 2 ) 4 PMB PMB(C 2 ) 4 PMB(C 2 ) 4 * steps 2-4 removes auxiliary 29

9 YTE F TEE thermodynamic enolate TM via epoxide 1. TMCl, Et 3, 50 C 1. mcpba C 2 Me C 2 Me C 2 Me (C 2 ) 4 PMB (C 2 ) 4 PMB (C 2 ) 4 PMB MDA gives 4 stereocentres & all skeletal carbons oxidises electron-rich alkene oxidative cleavage , 2 aminol formation 2 C 4 4 C 2 Me (C 2 ) 4 PMB C 2 Me (C 2 ) 4 PMB C 2 Me (C 2 ) 4 PMB transdiaxial ring-opening acid approaches from bottom face, opposite to iodonium species installs Me C 2 Me (C 2 ) 4 PMB 1. CA, C(Me) 3, Me 2. Bu 3 nc 2 C=C 2, AB 3. LDA, Me Me C 2 Me (C 2 ) 4 PMB stereocentre from MDA transcribes new centre both additions occur from convex face last 2 stereocentres controlled by molecular shape 30

10 YTE F TEE reduce aminol via imminium ion Me C 2 Me (C 2 ) 4 PMB 1. Et 3 i, BF 3.Et 2 C 2 Me (C 2 ) 4 oxidative cleavage dithiolane formation 1. s 4(cat), a 4 2. (C 2 ) 2, BF 3.Et 2 deprotection C 2 Me reduces dithiolane 1. aney ickel 2. Ms-Cl 3. a C 2 Me (C 2 ) 4 1. TM 2. eat What have we learnt? MDA powerful means of installing stereochemistry Chiral auxiliaries useful way of making enantiopure compounds Cleaving C-C bonds often useful Cascades efficient way of setting up complex structures (A & D ring) Many ways to control stereochemistry emoving carbons can be hard (3 steps) ( )-stenine 31

11 Guideline 7: electivity f you are anything like myself, having planned your first retrosynthesis, you will then bin it for one of two reasons: i) Functional group / protecting group incompatibility ii) o means of stereocontrol This is the problem of selectivity 7a. tereoselectivity ubstrate Control largest group perpendicular to carbonyl attack along Bürgi-Dunitz angle ' Br " Li-C 2 Cl smallest group opposite oxygen Br ' " C 2 Cl Felkin-Anh model oxygens eclipse due to chelation nucleophile attacks along Bürgi-Dunitz angle passed smallest group ' attack favoured with trajectory close to smallest group C 2 Cl " Br 93TL3173 TB Bn TB Bn MgBr Me Mg (C 2 ) 2 TB Cram-Chelation control Bn C8-C15 fragment of monesin 80JAC2117 Chiral Auxiliaries At worst chiral auxiliaries are built in resolving agents. At best they are stereodirecting groups that ultimately lead to single enantiomers. thermodynamic enolate i-pr 1. Bu 2 BTf, i-pr 2 Et 2. C dipoles align anti Bu B Bu i-pr remove auxiliary 81JAC2127, 90JAC5290 Me 32

12 eagent Control To overcome problem of auxiliary addition / removal compatibility EAGET CTL has been developed. Achiral substrate reacts with chiral reagent to give optically pure product. C 8 17 C 2 Me Al C 8 17 C 2 Me Asymmetric chiral catalysis C 8 17 beetle pheromone 84JAC6709, 6717 Arguably one of the biggest / most important areas in organic chemistry; the use of sub-stoichiometric quantities of a reagent to generate enantiopure compounds. Used for a vast range of different reactions. ipr, Bu 3 n, Mg 2, Ligand ipr 91 % e.e. 96JAC9200 M X What have we learnt? There are five basic ways of controlling stereochemistry All have their place in synthesis still Most atom economical are substrate control and chiral catalysis 33