Enantioselective Protonations

Transcription

1 Enantioselective Protonations Marc Timo Gieseler Group Seminar AK Kalesse 1

2 verview Introduction Enantioselective Protonation of Cyclic Substrates Enantioselective Protonation of Acyclic Substrates Group Seminar AK Kalesse 2

3 Important Aspects in Achieving Enantioselective Protonations Simple idea: Selective protonation of a tertiary carbanion with a chiral proton source generates tertiary stereocenters Enantioselective protonations are neccessarily kinetic processes, under thermodynamic control a racememate would be formed pka of proton donor and product need to be finely tuned to prevent racemization before product isolation Typical proton donors are relatively weak acids to make sure they react with the proton acceptor in a more controlled fashion In most cases it is important to generate stereodefined proton acceptors (for example pure E- or Z- enolates) Accessing the reactive proton acceptor is the most important facet, many strategies have been explored (conjugate addition, addition to ketenes ) B. Stoltz et al. Nat. Chem. 2009, 1, Group Seminar AK Kalesse 3

4 Important Aspects in Achieving Enantioselective Protonations Enolate has two enantiotopic faces Proton transfer from a chiral, nonracemic proton source will kinetically favor (R) or (S) Difficult to discriminate between diastereomeric transitions states Proton donors often have chelating sites -Protonation leads to enols which: are transformed to Ketones (racemic) act as undesired proton source Products sometimes tend to racemize C. Fehr Angew. Chem. Int. Ed 1996, 35, Group Seminar AK Kalesse 4

5 Yamamoto s Enantioselective Protonation of Simple Cyclic Enolates Simple cyclic ketones can be protonated with high selectivities using chiral imide 4 Protonation takes place via transition state A A H. Yamamoto et al. Angew. Chem. Int. Ed. 1994, 33, Group Seminar AK Kalesse 5

6 Yamamoto s Enantioselective Protonation of Simple Cyclic Enolates Synthesis of chiral imide 4: C 2 H C 2 H C 2 H Xylene, 17h, reflux 86% C 2 H NH 4 H,H 2,10h,110 C 93% NH C 2 H Kemp's triacid 290 euro/g(aldrich) 8 9 Ph Ph Ph Ph Ph Ph SCl 2 (neat) reflux, 3h, 99% NH C 2 Cl H 2 N H Et 3 N,CH 2 Cl 2, 99% HN H SCl 2 92% NHN H. Yamamoto et al. Angew. Chem. Int. Ed. 1994, 33, D. Kemp et al. J. rg. Chem. 1981, 46, J. Rebek et al. J. Am. Chem. Soc. 1989, 111, Group Seminar AK Kalesse 6

7 Kim s Protonation of Tetralone Derivatives Asymmetric protonation of tetralone derivatives with high ee and excellent yields β-hydroxy-ether moiety coordinates to lithium-ion Transition state A (re) is favored because of stronger π-πinteraction Kim et al. J. rg. Chem. 2004, 69, Group Seminar AK Kalesse 7

8 Kim s Protonation of Tetralone Derivatives TMS 17 Ph MeLi,(R,R)-16 Et 2,CH 2 Cl 2, -78 C Ph 18 79%,87%ee Substrate scope shows high yields and selectivities for tetralone and indanone derivatives TMS MeLi,(R,R)-16 Et 2,CH 2 Cl 2, -78 C Cyclohexanone derived enolate lacks the aryl substituent and therefore shows poor enantiomeric excess (no π-π-interaction possible) %,79%ee TMS MeLi,(R,R)-17 Et 2,CH 2 Cl 2, -78 C yieldnd,3%ee Kim et al. J. rg. Chem. 2004, 69, Group Seminar AK Kalesse 8

9 Fehr s Tandem Grignard Reaction-Enantioselective Protonation Me n-buli Li Me MgCl M Enantioselective Protonation H Al 2 3 H ,E/Z=9:1 26 (S)-(-)- -Damascone H 26 H 26 60%,58%ee 60%,70%ee N NH Ph 27 H N Ph 28 Pioneering work in the field of enantioselective protonation of acyclic substrates Chiral proton sources 27 and 28 can be easily accessed from ephedrin Reaction is very sensitive concerning the counterion Improve the yield by starting from a ketene?. MgCl Mg 28 H yieldnd,16%ee Mg MeLi then 28 H 75%,70%ee C. Fehr et al. J. Am. Chem. Soc. 1988, 110, Group Seminar AK Kalesse 9

10 Deng s Tandem Asymmetric Conjugate Addition- Protonation Cinchona alkaloid derivatives catalyse tandem asymmetric conjugate addition/protonation Catalyst has two functions: Activation of the Michael acceptor Serving as chiral Brönstedt acid for the selective protonation Acyclic Michael donors show bad diastereoselectivity with (32a-c) L. Deng et al. J. Am. Chem. Soc. 2006, 128, Group Seminar AK Kalesse 10

11 Deng s Tandem Asymmetric Conjugate Addition- Protonation Michael donor and acceptor are simultaneously activated and oriented by a network of hydrogen bonding interactions Catalyst subsequently effects the protonation of the enol in a stereselective manner L. Deng et al. J. Am. Chem. Soc. 2006, 128, Group Seminar AK Kalesse 11

12 Deng s Tandem Asymmetric Conjugate Addition- Protonation in the Formal Synthesis of (-)-Manzacidin L. Deng et al. J. Am. Chem. Soc. 2006, 128, Y. hfune J. Am. Chem. Soc. 2000, 122, Group Seminar AK Kalesse 12

13 Rovis Synthesis of α-chloroesters by NHC Induced Enantioselective Protonation Ph Cl Cl 52 H H 10 equiv 10mol%54,KH(1equiv),18-crown6(0.5equiv) 1.2 equiv. 2,6-dibromo-4-methylphenol toluene,19h,rt Ph Ph Cl 53 79%,93%ee N F 54 BF 4 - N F N F F F Substrate Scope: Me Ph Ph Ph Cl 55 Cl 56 Cl 57 76%,90%ee 73%,85%ee 68%,89%ee Ph Ph Me Ph Cl 58 Cl 59 Cl 60 65%,93%ee 65%,89%ee 75%,84%ee Ph Ph Bn Ph Cl 61 Cl 62 Cl 63 74%,90%ee 71%,88%ee 71%,84%ee Treatment of α,α-dichloroaldehydes with enantiopure triazolium catalyst 54 leads to α-chloroesters with high ee Reaction shows a very broad substrate scope T. Rovis et al. J. Am. Chem. Soc. 2006, 127, Group Seminar AK Kalesse 13

14 Rovis Synthesis of α-chloroesters by NHC Induced Enantioselective Protonation Proposed reactionpath starts with additon of the NHC to the aldehyde Elimination of HCl generates a zwitterionic enolate that is stereoselectively protonated and hydrolysed to the ester Authors further demonstrated the synthetic application of the so derived α-chloro esters T. Rovis et al. J. Am. Chem. Soc. 2006, 127, Group Seminar AK Kalesse 14

15 Rh-Catalyzed Tandem 1,4-Addition/Enantioselective Protonation Enantioselective synthesis of α-amino esters by a conjugate addition/protonation strategy Phenol derivatives as proton sources provide the best enantioselectivity ther proton sources, such as water or carboxylic acids gave lower yields and/or selectivities 2.2 equiv. of chiral ligand relative to metal gave optimal results J.-P. Genet, S. Darses et al. Angew. Chem. Int. Ed. 2004, 43, Group Seminar AK Kalesse 15

16 Rh-Catalyzed Tandem 1,4-Addition/Enantioselective Protonation After transmetallation with trifluoroborate (I-II) and complexation of dehydroaminoester alkyl-rh species IV is formed β-hydride elimination gives Rh-hydride species V complexed to imidoester Hydride transfer to imidoester generates amido-rh complex VI J.-P. Genet, S. Darses et al. J. Am. Chem. Soc. 2008, 130, Group Seminar AK Kalesse 16

17 Enantioselective Intramolecular Protonation of Aldehyde Derived Enolates Rare example of asymmetric protonation of an aldehyde derived enolate %,95%de 66%,90%de 58%,90%de 44%,90%de Enolate formation by conjugate addition of CuH to Michael acceptor Intramolecular stereocelective protonation by free alcohol 76%,85%de 66%,95%de 81%,90%de Substrates easily accessible by vinylogous Mukaiyama aldol reaction M. Kalesse et al. Angew. Chem. Int. Ed. 2010, 49, Group Seminar AK Kalesse 17

18 Stereoselective Intramolecular Protonation of Aldehyde Derived Enolates bserved stereochemistry consistent with six membered transition state Bulky substituents adopt equatorial postitions Directing effect of γ-stereocenter is less pronounced M. Kalesse et al. Angew. Chem. Int. Ed. 2010, 49, Group Seminar AK Kalesse 18

19 Synthesis of a-amino Acid Derivatives by an Intermolecular Stetter Reaction Synthesis of α-amino acid derivatives by an intermolecular Stetter reaction followed by an intramolecular enolate protonation (see next slide) F. Glorius et al. Angew. Chem. Int. Ed. 2011, 50, Group Seminar AK Kalesse 19

20 Synthesis of a-amino Acid Derivatives by an Intermolecular Stetter Reaction Reaction between aldehyde and NHC leads to Breslow intermediate Benzyl group in A shields the top face of the Breslow intermediate C bears a new but transient stereocenter Stereoinformation is relayed to α- stereocenter by intramolecular protonation F. Glorius et al. Angew. Chem. Int. Ed. 2011, 50, Group Seminar AK Kalesse 20

21 Thanks for your attention Group Seminar AK Kalesse 21

22 Mechanism for the hydrolysis of nitriles Group Seminar AK Kalesse 22