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Carbonyl chemistry 1. General properties a) Order of thermodynamic stability b) Order of acidity c) Tendency to enolize d) !-Dicarbonyl compounds 2.

Alkylation of carbonyl compounds with alkyl halides a) disconnect bond between " and ! Cs b) simple carbonyls + LDA gives enolates i) cannot use LDA with aldehydes (aldol) or acyl halides/anhydrides (ketenes)! Use esters, then reduce, or use enamines or hydrazones ii) for unsymmetrical ketones, regiochemistry issues a) LDA deprotonates least hindered position (99:1 for 2-methylcyclohexanone, 2pentanone) kinetic isomer b) Weaker, slower base (NaH, Et3N) or in presence of proton source (e.g., excess ketone) gives more substituted enolate thermodynamic conditions (78:22 for 2methylcyclohexanone) c) conjugate reduction of ",!-unsaturated ketone gives exclusively a single enolate!!! d) regioselectivity not an issue for esters or nitriles iii) stereochemistry issues a) Can make E or Z enolates, but Z predominates usually b) matters for enantioselective chemistry iv) alkyl halides must be fairly reactive: allylic or benzylic bromides, 1 alkyl iodides c) can use !-dicarbonyls + NaOEt i) enolates of !-dicarbonyls are good nuc/ not-so-good base ii) stable at higher temperatures iii) will react with 1 or 2 alkyl bromides or chlorides (note esp. when ! carbon is branched) iv) decarboxylate after alkylation by Krapcho method v) can turn simple carbonyl into !-dicarbonyl by Claisen reaction with (EtO)2CO a) CO2Et group attaches at RCH2 group first, CH3 group second, but not at R2CH group d) simple carbonyls + NaOEt gives polyalkylation (generally not desired) e) enantioselective alkylation i) most widely used method is Evans chiral oxazolidinones ii) make Z(O) enolate, attack from face opposite chiral auxiliary iii) invert enolate and alkylating agent to get one or the other enantiomer from same chiral auxiliary iv) other chiral auxiliaries are used, e.g. ephedrine (Myers) 3. Conjugate addition reactions a) Michael reactions i) any ",!-unsaturated carbonyl will participate as electrophile ii) !-dicarbonyls participate with catalytic amount of base iii) preformed enolates also participate iv) retron of course is 1,5-dicarbonyl b) any carbonyl can be disconnected in !-position conjugate addition i) disconnects into nucleophile and ",!-unsaturated carbonyl ii) because ",!-unsaturated carbonyl is nucleophilic at carbonyl C and ! C, care must be chosen in nucleophile iii) Grignard reagent and catalytic Cu(I) works sometimes iv) 2 RLi + CuBr # R2CuLi (organocuprate) often works well v) so-called higher order cuprates made from 2 RLi and CuCN vi) immediate product of conjugate addition is a Cu enolate, which can be alkylated with alkyl halide vii) all work best with ",!-unsaturated ketones, not so well for esters viii)Cu chemistry can be capricious and very substrate-dependent 4. Aldol reactions a) defined as carbonyl enolate attacking aldehyde or ketone to give !-hydroxy carbonyl

b) under thermodynamic conditions (NaOEt or acidic conditions) i) requires ketones or aldehydes as nucleophiles ii) aldol product usually dehydrates under reaction conditions to give ",!-unsaturated aldehydes or ketones (thermodynamic mixture of isomers) iii) homo aldol reaction (one ketone or aldehyde as both nuc and elec) gives clean reaction iv) mixed aldol reaction works under these conditions only when one component is more reactive electrophile and cannot be nucleophile(ketone + PhCHO or CH2O) v) more substituted side of ketone reacts selectively under these conditions c) under kinetic conditions (LDA) i) requires ketones, esters, or nitriles as nucleophiles ii) reaction stops at aldol stage (Li chelation) iii) mixed aldol reaction works because enolate is preformed and H+ transfer is slow compared to aldol reaction iv) stereoselective! goes through 6-membered TS with aldehyde R group in pseudoequatorial position
O Li O R H RZ RE X O Li O H R RZ RE X ! X RZ RE O OH R

v) most enolates are Z, so most aldol products have syn stereochemistry vi) when Cy2BCl and Et3N is used to make B enolate, enolate is E, so 1,2-anti aldols are obtained d) retron is !-hydroxy carbonyl or ",!-unsaturated carbonyl i) latter is also retron for Wittig reaction, which is usually a better route anyway e) diastereoselectivity in aldol reaction i) when X is chiral auxiliary, aldol reaction is carried out enantioselectively a) Li enolates give tricoordinate intermediates aldehyde approach controlled by auxiliary
O Li O O O R H RZ RE not N i-Pr O Li O O O N H RZ R RE i-Pr O Li O O O R H RZ RE N ! i-Pr O O N RZ i-Pr RE O OH R

b) Bu2B enolates of same compound give dicoordinate intermediates that lead to opposite aldol stereochemistry!
RZ O Bu2B O i-Pr N H O R RE not O O Bu2B O i-Pr R H N O RZ RE O O Bu2B O i-Pr N H O RZ R RE O ! O O N RZ i-Pr RE O OH R

c) extensively used in synthesis of polypropionate natural products (see below) ii) "-stereocenter on aldehyde a) Cram (Felkin) selectivity RL syn to aldehyde H gives syn relationship of two new stereocenters
O H RS RL H Nu H RS RL HO Nu H ! RL RS OH Nu When Nu = Z enolate: RL RS RZ OH O X

b) with a Z enolate as nucleophile, get syn,syn stereoselectivity; with an E enolate, get anti,syn c) an alkoxy group always goes in RS position to chelate counterion with O chelation

control (1) this model works with ketones, too!


O H RS RL R Nu H RS RL HO Nu R e.g. HO Ph O H Ph H H HO Ph HO H Ph

d) selectivity is often very weak iii) "-stereocenter on enolate


Me Me OBn O Cy2BCl Et3N O BCy2 Me Me OBn RCHO R Cy B O Cy H O Me Me OBn R OH O Me Me OBn

f) Epothilone A (Schinzer et al., Chem. Eur. J. 1999, 5, 2483) i) epothilones have Taxol-like action against cancer (stabilizes tubulin polymers) but have much simpler structure than Taxol ii) disconnection by ring-closing metathesis, lactonization, aldol reaction
O S N O epothilone A O OH O OH S N OH O

OH

OH

a) need key aldol reaction to give syn,anti diastereomer, as expected for Z enolate + aldehyde but against Cram, so need directing group on enolate to override Cram selectivity iii) enantiopure aldol fragment made by chiral auxiliary-controlled aldol reaction a) two aldol disconnections possible
Ph O O O HO Ph Ph O O O

b) less obvious disconnection chosen so that chiral auxiliary can introduce asymmetry c) ketone introduced by ozonolysis iv) aldehyde made by Evans chiral auxiliary-controlled alkylation
O O O Bn N O

v) allylic alcohol
S N OH O OH OH OTBS OTBS

a) Wittig reaction on enantiopure "-oxyketone b) ketone from alkene made enantiopure by Sharpless kinetic resolution c) can also make by asymmetric allylation of aldehyde, which is made by Wittig reaction vi) aldol reaction to assemble ring a) 2,3-syn aldol obtained, as expected from Z enolate and chair TS

b) 3,4-anti stereochemistry obtained, showing that stereocenter in enolate overwhelms very modest Cram selectivity preferred by "-stereocenter of aldehyde c) observed product is best explained by TS in which there is no chelation of the dioxane ring to the enolate
chelation control Me O Li O O H O no chelation control Me O Li O H O O O Li O H O O Me O H ! Me Me O O OH H Li O O H O not observed H ! Me Me O O O O OH Me

d) stereocenter on enolate forces absolute stereoselectivity opposite to preference of aldehyde stereocenter for Cram selectivity get syn,anti selectivity g) Epothilone A (Danishefsky et al., Angew. Chem. 1998, 37, 2675) i) disconnection by Suzuki coupling, lactonization, aldol reaction
O S N O epothilone A O OH O OH S N OH Lactonization t-BuO O O Noyori reduction O Suzuki I O

ii) key aldol was found to proceed with anti-Cram selectivity even with no chiral auxiliary on enolate! Explained by secondary interactions between unsaturated group on aldehyde
HR Me H Me O Li O not R H O Li O

Me H Me

h) Lonomycin (Evans et al., JACS 1990, 112, 866) i) unfold starting material to see polypropionate that can come from aldol reactions ii) look for syn aldol units in chain

OMe O H Me Me O Me

Me

OMe O O O H Me Me

OMe Me O OH O X Me Me Me Me Me Me Me O O OMe OH OH O H

OH

Me

OH

Lonomycin

iii) aldol gives syn product, absolute stereo controlled by auxiliary iv) neighboring group-controlled reduction gives syn,anti,syn tetrad
O O N Me Bn Me Me O O O X Me Me Me O O OH NaBH(OAc)3 H Me Me Me O O O

v) alternative solution to make syn,anti,syn tetrad is to do two aldols, using chiral aux in second step to direct absolute stereochemistry vi) natural preference for syn,syn product (Cram selectivity) overridden by chiral auxiliary
O O N Me Bn Me O O H Me Me Me O O O X Me Me Me Me Me O O OMe O O

i) How does nature make polypropionates? i) uses Claisen condensations followed by stereoselective reductions
Protein-S
11

Protein-S 9 O

Protein-S O
7

Protein-S O
5

Protein-S O
3

Protein-S O
1

Protein-S
13

Protein-S 11 O
13

Protein-S O OH
9

Protein-S O OH OH
7 9

Protein-S O O OH OH
5

Protein-S O
3 5

Protein-S O OH
1 3 5

O OH OH

11 13

7 9

Claisen, reduction O
9 11 7

11 13

O OH OH

7 9

Claisen, reduction Claisen

11 13

O OH OH

7 9

11 13

O OH OH

OH
13 5

O
1 3

OH OH

Claisen, reduction, dehydration, reduction

11 13

Claisen, reduction Claisen, reduction

ester formation

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