Stereoselective reactions of the carbonyl group

Transcription

1 1 Stereoselective reactions of the carbonyl group We have seen many examples of substrate control in nucleophilic addition to the carbonyl group (Felkin-Ahn & chelation control) If molecule does not contain a stereogenic centre then we can use a chiral auxiliary The chiral auxiliary can be removed at a later stage Mgr 78 C L L Mg 98% de pposite diastereoisomer can be obtained from reduction of the ketone ote: there is lower diastereoselectivity in the second addition as the nucleophile,... is smaller K(i-Pr) 3 90% de

2 2 Chiral auxiliary in synthesis Mgr 78 C LiAl C ( )-frontalin 100% ee The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalin

3 3 Sulfoxides as chiral auxiliaries lithium can chelate 2 oxygens hydride directed to si face LiAl 4 Tol S Li Al 3 S Tol 80% de aney i S Tol DIAL Tol S Al i-u Al i-u i-u i-u S Tol 70% de aney i oxygens are not directly tethered dipoles directed in opposing directions Underrated chiral auxiliary - easily introduced, performs many reactions & can be readily removed ne auxiliary can give either enantiomer of product Selectivity dependent on whether reagent can chelate two groups

4 4 Chiral reagents Clearly, chiral reagents are preferable to chiral auxiliaries in that they function independent of the substrate s chirality or on prochiral substrates A large number have been developed for the reduction of carbonyls Most involve the addition of a chiral element to one of our standard reagents can be reused (+)-α-pinene + 9- TF alpine borane + L S proceeds via boatlike transition state + L S S L (C 2 ) 4 small group as linear alpine borane (C 2 ) 4 86% ee selectivity governed by 1,3-diaxial interactions

5 5 Chiral reagents II Alpine-borane is very good for reactive carbonyls (aldehydes, conjugated ketones etc) It is less efficient with other ketones so a more Lewis acidic variant has been developed Addition of the chloride makes the boron more electrophilic Transition state similar to previous slide Cl + 2 (+)-Ipc 2 Cl 98% ee And here is another... + >99% ee

6 6 inol derivative of LiAl4 Snu 3 1. (S)-IAL 2. MM Cl MM Snu 3 93% ee Al ()-IAL Li educing reagent based on IL and lithium aluminium hydride Selectivity is thought to arise from a 6-membered transition state (surprise!!) Largest substituent ( L ) adopts the pseudo-equatorial position and the small substituent ( S ) is axial to minimise 1,3-diaxial interactions Al S Li L

7 7 Chiral reagents: allylation Cl Ti Mgr Ti 95% ee Stereoselective reactions other than reduction can be performed with chiral reagents In the above reaction the standard Grignard reagent is reacted with the titanium complex to give the chiral allylating reagent ote: the chirality is derived from tartaric acid (again)

8 8 Chiral allyl boron reagents + L L Z E L L Z E L L Z E 2 2 a Z E Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols eaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron This activates carbonyl as it is more electrophilic and weakens C bond, making the reagent more nucleophilic Funnily enough, reaction proceeds by a 6-membered transition state E Z L disfavoured L vs E Z L L Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain) Therefore alkene geometry controls the relative stereochemistry (like aldol rct) E Z Z E E-alkene gives anti product Z-alkene gives syn product

9 9 Chiral allyl boron reagents II % ee crotyl group orientated away from pinene methyl groups substituent pseudoequatorial eagent is synthesized from pinene in two steps Gives excellent selectivity but can be hard to handle (make prior to reaction) emember pinene controls absolute configuration Geometry of alkene controls relative stereochemistry

10 10 ther boron reagents Z 2 attacks on si face of C E i-pr 2 C i-pr 2 C Z attacks on si face of C tartaric acid derivative E Ts Ts Z E attacks on re face of C A number of alternative boron reagents have been developed for the synthesis of homoallylic alcohols These either give improved enantiomeric excess, diastereoselectivity or ease of handling / practicality Ultimately, chiral reagents are wasteful - they need at least one mole of reagent for each mole of substrate End by looking at chiral catalysts

11 11 Catalytic enantioselective reduction CS catalyst (10%) 3 TF 93% ee An efficient catalyst for the reduction of ketones is Corey-akshi-Shibata catalyst (CS) This catalyst brings a ketone and borane together in a chiral environment The reagent is prepared from a proline derivative The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and works most effectively if there is a big difference between each of the substituents on the ketone The mechanism is quite elegant... CS catalyst proline derivative 3 3 active catalyst

12 12 chanism of CS reduction interaction of amine & borane activates borane it positions the borane it increases the Lewis acidity of the endo boron catalyst turnover 3 TF 3 L S L S L S L S coordination of aldehyde activates aldehyde and places it close to the borane chair-like transition state largest substituent is pseudo-equatorial

13 13 Catalytic enantioselective nucleophilic addition + C 5 11 Zn C 5 11 ( )-DAI (2%) C 5 11 >95% ee ( )-DAI 2 C 5 11 Zn Zn C 5 11 C 5 11 C 5 11 Zn Ar Zn C 5 11 C 4 9 vs. C 5 11 Zn Zn C 5 11 C Ar 4 9 disfavoured There are now many different methods for catalytic enantioselective reactions ere are just a few examples... Many simple amino alcohols are known to catalyse the addition of dialkylzinc reagents to aldehydes chanism is thought to be bifunctional - one zinc becomes the Lewis acidic centre and activates the aldehyde The second equivalent of the zinc reagent actually attacks the aldehyde nce again a 6-membered ring is involved and 1,3-diaxial interactions govern selectivity

14 14 Catalytic chiral Lewis acid mediated allylation + Snu 3 cat. (5%), DCM, rt, 7h 88% 62% ee n Cl h Cl n cat. derived from amino acid (via the alcohol) A variety of chiral Lewis acids can be used to activate the carbonyl group These can result in fairly spectacular allylation reactions (higher ee than this example) A problem frequently arises with crotylation ften the reactions proceed with poor diastereoselectivity favouring either the syn or anti diastereoisomer regardless of geometry of the starting crotyl reagent This is because the reactions proceed via an open transition state (just to confuse you most actually favour syn! I use this example as the comparisons were easy to find...) cat. (10%), DCM, rt, 72h + Snu 3 E : Z 95 : 5 2 : 98 M anti (ee) : syn (ee) 71 (57) : 29 (8) 63 (60) : 37 (7) Snu 3 open transition state

15 15 Catalytic chiral Lewis base mediated allylation + E Z SiCl 3 Lewis base catalyst (L) E Z E Z L Cl Si L Cl Cl An alternative strategy is the use of Lewis bases to activate the crotyl reagent eaction proceeds via the activation of the nucleophile to generate a hypervalent silicon species This species coordinates with the aldehyde, thus activating the aldehyde and allowing the reaction to proceed by a highly ordered closed transition state As a result good diastereoselectivities are observed and the geometry of nucleophile controls the relative stereochemistry P ( ) 5 P E = 86% ee anti/syn 99/1 Z = 95% ee syn/anti >19/1 E = 98% ee anti/syn >99/1 Z = 98% ee syn/anti 40/60 E = 86% ee anti/syn 97/3 Z = 84% ee syn/anti 99/1

16 16 rganocatalysts r cat. (10%) a S S S 92% ee 85% de (trans) As we have seen with many stereoselective reactions, small organic molecules are now finding considerable use as enantioselective catalysts Above is a simple example of epoxide formation The reaction proceeds by S2 displacement of the bromide by the sulfide and subsequent deprotonation to give the reactive ylide ucleophilic attack & cyclisation give the epoxide and regenerate the sulfide catalyst

17 17 rganocatalysts II Ar oc + 2 Tf cat. (10%) Ar P() 2 90% ee 90% de 2 oc Ar Acts as a chiral proton Protonation of the imine forms a highly electrophilic species Aza-enry reaction can then proceed to give the new amine

18 18 ifunctional organocatalysts CF 3 S 2 + Ar P() 2 F 3 C cat. (10%) DCM, rt P() 2 2 Ar 76% ee CF 3 CF 3 F 3 C S F 3 C S Dpp Ar Thio(urea) acts as a Lewis acid to activate & position the nitro substrate Pendent amine functionality deprotonates the nitro α-c and presumably an electrostatic interaction shields the bottom face of the nitro enolate