Asymmetric Nucleophilic Catalysis

Transcription

1 Asymmetric ucleophilic Catalysis Chiral catalyst X 2 Chiral catalyst X = alkyl, X Vedejs, E.; Daugulis,. J. Am. Chem. Soc. 2003, 125, Shaw, S. A.; Aleman,.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,

2 ucleophilic Catalysis: The Basics eactions Catalyzed by ucleophiles Addition of alcohols to ketenes: C Catalyst Acylation of alcohols to anhydrides: Catalyst earrangement of -acylated enolates: Catalyst

3 ucleophilic Catalysis: The Basics Acylation of Alcohols Uncatalyzed Slow Catalyzed Fast DMA Much stronger acylating agent Fu, G. C. Acc. Chem. es. 2000, 33,

4 ucleophilic Catalysis: The Basics Steglich earrangement X 5-acyloxyoxazole x =, DMA X This can also be done with pyridine as the catalyst, but it takes 24 hrs at 100 o C versus a few minutes at room temp. X ofle, G.; Steglich, W.; Vorbruggen,. Angew Chem., Int. Ed. Engl. 1978, 17, 569

5 Kinetic esolutions: Theory Kinetic resolutions are the best way for getting extremely enantioenriched compounds, usually utilizing an enzyme to preferentially react away one enantiomer of the substrate, leaving behind the other enantiomer of the substrate. ln[(1-c)(1-ee)] s = = ln[(1-c)(1+ee)] s = selectivity c = conversion c = 1 k fast-reacting enantiomer k slow-reacting enantiomer A + B ee = %ee of recovered substrate A 0 + B 0 A 0 = initial amt. of fast-reacting enantiomer B 0 = intial amt. of slow-reacting enantiomer A = amt. of fast-reacting time T B = amt. of slow-reacting time T % ee %ee of unreacted substrate % Conversion s = 3 s = 5 s = 10 s = 25 s = 100 Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294 Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator

6 Kinetic esolutions: Theory t. 2 What about the other half of what you have? What is the %ee of the product at a given percent conversion with a known value of s? ln(1-c*(1+ee)) s = = ln(1-c*(1-ee)) s = selectivity c = conversion ee = %ee of product c = 1 k fast-reacting enantiomer k slow-reacting enantiomer A + B A 0 + B 0 A 0 = initial amt. of fast-reacting enantiomer B 0 = intial amt. of slow-reacting enantiomer A = amt. of fast-reacting time T B = amt. of slow-reacting time T % ee %ee of product % Conversion s = 3 s = 5 s = 10 s = 25 s = 100 Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294 Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator

7 L Enantioselective Acylations with Chiral osphines: Early Work with on-enzymes entry substrate catalyst anhydride %ee 5 (conv.) S + 1b 1b 1b 1b 1a 5-10 mol% catalyst C 2 Cl a 6b 6a L Ac 2 Ac 2 Ac 2 Ac 2 Ac 2 S + 9 (40) 11 (60) 65 (66) 42 (80) 52 (10) L 5 1 S selectivity (s) 1a n=0 1b n= meso substrates 2 (C 2 )n C()tBu 3 6a 4 6a 6b 6a Ac 2 Ac 2 Bz 2 Bz 2 Bz 2 3-ClBz 2 50 (40) 27 (22) 22 (31) 68 (84) 58 (70) 81 (25) perdeuterated Ac 2 give monoacetate without loss of deuterium: no ketene mechanism operative This was the largest s value for a non-enzyme at the time chiral phosphines: a, = 6b, = Et Vedejs, E.; Daugulis,.; Diver, T. S. J. rg. Chem. 1996, 61,

8 Enantioselective Acylations with Chiral osphines: An Improved Catalyst A selectivity of is good, but can it be improved? Yes! ew catalysts: etrosyntheses of catalysts: 1 2 Ar S 2 Ar 2 3 Tf Li Vedejs, E.; Daugulis,. J. Am. Chem. Soc. 2003, 125, 4166

9 Enolate Alkylations Using Lactate Triflates Li Tf Et 55 o C Et 2 C Tf Favored Li C 2 Et Tf Li Disfavored due to lone-pair repulsion LA 52% : 1 d.r. ow do you access the minor diastereomer? Use a cryptand-like ester Li Tf 55 o C Toluene Li Tf LA 30-40% 1 : 6-10 d.r.

10 Continued Synthesis of osphine Catalysts SCl 2 CCl 4 reflux S ucl ai 4 C, CCl 4, 2, 60% S 2 Li TF S 3 Li BuLi Li S 3 Li B 3 TF 85% B 3 36:1 d.r. B 3 yrrolidene

11 Acylation of Alcohols Using enyl Catalyst 1 2 Toluene, r.t Anhydride 1 2 elative rate s t-bu 1 24 t-bu 0.1( 40 o ) 67 1-naphthyl t-bu t-bu i-r i-r naphthyl 24 7 i-r c-c i-r i-r 0.1 1

12 Syntheses of ther osphine Catalysts S 2 2 Ar= 3,5-2 C Ar= 3,5-t-Bu 2 C 6 3 ArLi TF Ar S 3 Li BuLi Ar Ar B 3 TF 85% B 3 Ar 2 = 43:1 3 = 91:1 B 3 Ar yrrolidene Ar

13 Evaluation of 2 -B Anhydride 1 2 Solvent s t-bu Toluene 8.1 i-bu 2-naphthyl Toluene 14 i-bu i-r eptane 14 i-bu i-bu eptane 12

14 Evaluation of t-bu 2 -B t-bu 1 2 t-bu Anhydride 1 2 Solvent/Temp s t-bu tol/t 10 i-r i-r hept/t 20 i-r i-r hept/ 40 C 99 (117) i-r 2-naphthyl tol/t 17 i-r n-bu hept/t 18 i-r n-bu hept/ 40 C 55 (60) i-r 2,4,6-3 C 6 2 tol/t 15 i-r 2,4,6-3 C 6 2 tol/ 40 C 220 (328) i-r 2,4,6-3 C 6 2 tol/ 40 C 390

15 Summary of Acylations Using B Catalysts osphabicylooctane catalysts can be effectively used for a number of kinetic resolutions of benzylic alcohols. Separation of enantiomers of these catalysts is not exceptionally difficult, done through use of lactate esters and recrystallizations Enantioselectivities are exceptional, with values of s = 380 Selectivites high enough to warrant correction for %ee of catalyst Synthesis is quite air-sensitive at parts, yields of the alkylations are low, and the catalyst must be stored as the borane complex, due to interconversion of diastereomers at phosporus The full paper only covered the use of a few catalysts Will this replace using enzymes for kinetic resolutions? ot yet, I think

16 Chiral ucleophilic yridine Catalysts: Background 2 DMA Two mirror plane 2 ne mirror plane 2 ML n o mirror planes a "planar-chiral" DMA 2 * Substitution with a chiral group will also make a chiral DMA Greg Fu was the first person to use these types of catalysts for catalytic enantioselective work Vedejs' Catalyst Fu's Catalysts: CAr 3 Ac Fe C 2 TES 2 Fe

17 Acylations Catalyzed by lanar-chiral DMA Analogs racemic + 2 mol% cat Et 3 solvent, rt Ac Fe entry solvent % conv. after 1 h selectivity entry solvent % conv. after 1 h selectivity DMF C 3 C C 2 Cl 2 acetone TF EtAc toluene Et 2 t-amyl alcohol catalyst Desymmetrizations: meso 1% cat, Ac 2 Et 3, 0 C t-amyl alcohol Ac 99% ee 91% Ac Ac 1% cat, Ac 2 Et 3, 0 C t-amyl alcohol racemic 98% ee 43% uble, J. C.; Tweddell, J.; Fu, G. C. J. rg. Chem. 1998, 63, % ee 39%

18 Synthesis of a ew Chiral ucleophilic Catalyst 3 CC LA 3 CC 2 TA, M 63% 3 CC Br 2, K 2 C 3 Br t-buli Li 3 CC Ac 2 58% C 3 Ac C 3 Ac 1. in toluene 2. a 3. epeat C 2 S 3 C 3 Ac Ab initio geometry of acyl pyridinium Groziak, M..; lcher, L. M. eterocycles, 1987, 26, 2905.

19 Comparison of yridine Catalyst and t-bu 2 -B Catalyst C 2 ' 1 mol % ()-DMA catalyst or 10 mol % B, t-amyl alcohol, 0 o C, 12h C 2' catalyst % yield % ee DMA Bn B Bn DMA Bn Bn B allyl DMA allyl Bn B ibu DMA ibu Bn B DMA Bn B 96 20

20 Substrate Scope for the Chiral ucleophilic yridine Catalyzed Steglich earrangement 10 mol% (S)-DMA TF, 23 o C, 24h C2 2 C C 2 CCl 3 1 mol% (S)-DMA Et 2, 23 o C 20 mol% (S)-DMA C 2 Cl 2, 40 o C 83% yield 90% ee 92% yield 92% ee 92% yield 86% ee C 2 CCl 3 7% yield 80% ee 10 mol% (S)-DMA t-amyl alcohol, 40 o C C 2 C 2 93% yield 86% ee

21 Summary of Vedejs ucleophilic Asymmetric Catalysts Four new asymmetric nucleophilic catalysts have been synthesized and evaluated by the Vedejs group Catalysts are straightforward to make in moderate yields t-bu 2 -B and the chiral pyridine catalyst both show high enantioselectivities when catalyzing a Steglich rearrangement B catalysts have exceptional s values for kinetic resolutions of benzylic alcohols, and, based on Fu s research, Vedejs chiral pyridine catalyst could also work well in this reaction