Molybdenum-Catalyzed Asymmetric Allylic Alkylation

Transcription

1 Molybdenum-Catalyzed Asymmetric Allylic Alkylation X MoL n u u * Tommy Bui 9/14/04

2 Asymmetric Allylic Alkylation from a Synthetic Viewpoint X X M u u * and/or u form a C-C bond with the creation of a new stereogenic center use readily accessible starting materials allow to an opportunity to perform dynamic kinetic transformation can be performed catalytically be able to predict the stereochemical outcome igh regio-and enantioselectivity is achievable. a Typranavir (phase II clinical trials) a therapeutic agent used to combat IV b c S 2 advanced intermediate (rck)

3 Allylic Alkylation from a istorical Viewpoint = n-butyl a 2 C 3, C 2 Cl 2 PdCl 2 Cl Pd 1 2 Cl Pd 2 2 ac(c 2 ) 2 3 P (3 equiv) 2 C 2 C C 2 C % isolated yield Trost, B. M. et al. J. Am. Chem. Soc. 1973, 95, 292 Tsuji. J et al. J. Am. Chem. Soc. 1965, 84, 3275 (Addition of malonate u to cyclooctadiene activated by PdCl 2 ) Cl Pd 2 ac(c 2 ) 2 T 3 P (3 equiv), rt, 2h (-) sparteine/pd (4/1) 2 C C 2 66% isolated yield [a] = (20% optical yield) Trost, B. M. et al. J. Am. Chem. Soc. 1973, 95, 8200

4 egioselective Issue in tal-catalyzed Allylic Alkylation Ac ac(c 2 ) 2 Pd(P 3 ) 4, T, rt 2 C C 2 C 2 C %, 1/2 = 50/50 Keinan, E. et al. J.Chem. Soc. Chem. Comnun 1984, 648 Ac ac(c 2 ) 2 Mo (bpy)(c) 4, toluene reflux 2 C C C 2 C 2 bpy: 75%, 1/2 = 95/5 Trost, B.M. et al. J. Am. Chem. Soc. 1982, 104, 5543 Ac ac(c 2 ) 2 [h(c) 2 Cl] 2,T, rt 2 C C 2 C 2 C %, 1/2 = 97/3 Martin, S.. et al. J. Am. Chem. Soc. 2004, 6, 1321

5 General chanism Linear X ML ML u k 1 u k k S k 3 ML k 4 k 2 u u Branched substrate X X ML ML k k S k 3 u k 1 u chiral racemic X ML ML k 4 k 2 u u

6 Molybdenum-Catalyzed Asymmetric Allylic Alkylation C 2 ac 2 (C 2 ) C C 2 2 C C 2 (EtC) 3 Mo(C) 3 (10 mol%) Ligand (15 mol%), T 4 5 entry 1 T, 0 C time, h yield 4/5 ee% 1 2 reflux /1 99 rt / reflux / reflux /1 97 C 2 entry 1 T, 0 C time, h yield 4/5 ee% 1 2 reflux /1 92 rt / thienyl reflux / reflux / pyridyl 5 reflux / pyridyl 6 reflux / thienyl Trost, B.M. et al. J. Am. Chem. Soc. 1998, 120, 1104 (S,S) 4

7 Linear versus Branched : chanistic Implication C 2 ac 2 (C 2 ) C C 2 2 C C 2 (EtC) 3 Mo(C) 3 (10 mol%) Ligand (15 mol%), T 4 5 entry 1 T, 0 C time, h yield 4/5 ee% linear SM branched SM reflux /1 99 rt /1 99 reflux /1 92 rt /1 97 Whether p-allyl molybdenum complexation or the subsequent nucleophilic attack determines the stereochemical outcome of the product. Mo? Mo Trost, B.M. et al. J. Am. Chem. Soc. 1998, 120, 1104

8 Branched Substrates: Solvent Effects on Enantioselectivity C 2 ac(c 2 ) 2 (1.5 equiv) (C 7 8 )Mo(C) 3 (10 mol%) 2 C C 2 C 2 C (15 mol%), o C solvent 2 3 entry Solvent T, 0 C 2/3 ee% 1 2 T 48 25/1 87 Toluene 60 46/ C 48 23/1 83 C 2 (S) isomer is the fast-reacting enantiomer, 98% ee and 35/1 branched/linear selectivity during the first half of the reaction according to chiral PLC traces and independent synthesis of 1 control experiment: C 2 as above 2 C ughes, D.L.(rck). J. rg. Chem. 2002, 67, 2762 C 2 2 C 1 1 C /3 = 35/1, 97% ee eactions of 1 in T (circles) and in toluene (squares) (S,S) 4

9 Branched Substrates: Matched and Mismatched Cases Matched case ()-ent. 1 C 2 obtained by kinetic resolution ac(c 2 ) 2 (1.5 equiv) (C 7 8 )Mo(C) 3 (10 mol%) (,) 4 (15 mol%), 48 o C T 2 C C 2 (S) 2 3 2/3 = 55/1, > 99% ee C 2 C 2 Mismatched case C 2 same rxn conditions (S,S) 4 2 C C 2 C 2 C 2 ()-ent. 1 () 2 3 2/3 = 12/1, 70% ee modest stereochemical memory effect (,) 4 (S,S) 4 ughes, D.L.(rck). J. rg. Chem. 2002, 67, 2762

10 Possible Explanation for Solvent Effects on Selectivity Since both carbonate enantiomers give the same major alkylated product when the same catalyst enantiomer is used, diastereomeric equilibration must take place along the reaction path. If K S and K are fast relative to k1,k2,k3, and k4, then enantioselectivity is under Curtin-ammett control. Thus, the concentration of II and II-epi diastereomers is not important. Experimentally, the two carbonate enantiomers do not give the same ee and branched/linear ratio. This suggests that the rate of equilibration of II and II-epi must be competitive with the nucleophilic displacement steps. ughes, D.L.(rck). J. rg. Chem. 1998, 120, 1104 (S,S) 5

11 Efforts towards Understanding Molybdenum-Ligand Interactions C 2 ac(c 2 ) 2 (2 equiv) 2 C C 2 (C 7 8 )Mo(C) 3 (10 mol%) Ligand (15 mol%), o C T 2 3 (or S) C 2 C 2 Table 1: chelating effects Table 1: steric effects entry ligand yield (%) 2/3 ee% entry ligand yield (%) 2/3 ee% 1 (S,S) 1a 95 35/1 97 () 5 (,) /1 98 (S) / trace / / /1 24 Trost, B.M. and ughes, D.L.(rck) Angew. Chem. Int. Ed. 2002, 41, /1 99

12 Variation in the Chiral Backbone of Ligands C 2 ac(c 2 ) 2 (2 equiv) 2 C C 2 (C 7 8 )Mo(C) 3 (10 mol%) Ligand (15 mol%), o C T entry ligand 2 3 (S) yield (%) 2/3 ee% C 2 C 2 1 (,) 1b 93 13/1 96 (S) /1 94 two fold increase in rate / / /1 90 Trost, B.M. and ughes, D.L.(rck) Angew. Chem. Int. Ed. 2002, 41, 1929

13 The ole of the Secondary Amide itrogens C 2 ac(c 2 ) 2 (2 equiv) 2 C C 2 (C 7 8 )Mo(C) 3 (10 mol%) Ligand (15 mol%), o C T 2 3 C 2 C 2 1a 95% yield 2/3 = 35/1 97% ee fold less active than 1a poor enantioselecitivity 13 no observable reaction Amide nitrogens is crucial for achieving catalytic activity Trost, B.M. and ughes, D.L.(rck) Angew. Chem. Int. Ed. 2002, 41, 1929

14 Attempt to identify the Catalytically Active Species 10 (C 7 8 )Mo(C) 3 (1 equiv) T-d 8, rt, 1.5 h 11 Mo(C) 4 15 M Amide nitrogens: 133 ppm, 123 ppm 118 ppm, 119 ppm (free ligand) Pyridine nitrogen: 273 ppm 304 ppm (free ligand) 11 2 equiv Mo(C) 4 T Mo(C) 6 C 2 10 C 2 C d Mo b C c a 12 a situ generated Amide : 130 ppm, 175 ppm 118 ppm, 119 ppm (free ligand) Pyridine : 263 ppm 304 ppm (free ligand) a C d Mo b C c a isolated 12 ac(c 2 ) 2 ac(c 2 ) 2 Mo(C) 6 2 C no reaction C 2 82% yield, > 95% ee isolated 12 C (1 atm) ac(c 2 ) 2 2 C C 2 80% yield, > 95% ee Trost, B.M.; ughes, D.L. (rck) J. Am. Chem. Soc. 1998, 124, 1656 A C source is needed for achieving catalytic activity.

15 Solution and Solid State Studies of the eactive Intermediate C 2 11 situ generated Mo(C) 4 or or 1- T-d 8, ac(c 2 ) 2 (1 equiv) C 2 3- as above C 2 2- as above C d Mo b C c a 12 a Amide : 130 ppm, 175 ppm 118 ppm, 119 ppm (free ligand) Pyridine : 263 ppm 304 ppm (free ligand) ther structures: A B Trost, B.M.; ughes, D.L. (rck) J. Am. Chem. Soc. 2002, 124, ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

16 Possible Pathways for P-allyl Intermediates to Interconvert chanistic possibilities: 1. Mo*1S2S isomer recrystallizes preferentially and u attacks Mo*12 isomer with inversion. 2. Mo*1S2S and Mo*12 are in rapid equilibrium, and Mo*12 is the more reactive intermediate and reacts by inversion (selectivity is under Curtin-ammett control). 3. Mo*1S2S isomer in solution and crystal and the nucleophilic addition occurs with retention of configuration. Trost, B.M.; ughes, D.L. (rck) J. Am. Chem. Soc. 2002, 124, ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

17 Deterium-Labeling Experiments 96/4 er 96/4 er 1. In reaction [1] about 3% of trans-4-d corresponds well with the 4% enantiomer present in the SM. This means that little or no scrambling of the deuterium occurs in the reaction. 2. In reaction [2], about 7% nontransposed product indicates that no more than 3% of the reaction can occur with scrambling of the label since the SM has 96/4 er. and reacts by inversion (selectivity is under Curtin-ammett control). ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

18 Stoichiometric reactions: 1 M Studies of p-allyl Molybdenum Complexes C 2 C 2 or or C 2 [Mo] ligand 10 T-d8, rt [1] 2 C D 1-D (S) 96/4 er as above 95% in solution major diastereomer ac(c 2 ) 2 2 C C 2 D cis-4-d () [2] 2 C D 2-D () 96/4 er as above > 95% in solution major diastereomer ac(c 2 ) 2 2 C C 2 D trans-4-d () [3] 10 The results of experiments 1 & 2 confirm that the reaction proceeds by retention-retention pathway. ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

19 chanistic Pathways for the ormation of Cis-4-D and Trans-4-D Products 2 C D 2 C D 1-D (S) path c inv path d inv 2-D () path a ret path b ret Mo D 5 (observed) ret 2 C? C 2 D inv Mo D 6 not observed cis-4-d () Mo 8 D? Mo D 7 (observed) inv 2 C C 2 ret D trans-4-d () ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

20 Linear Chiral Allylic Substrates Catalytic reaction: 96/4 er Less than 2% of oxidative addition occurred with inverted stereochemistry Stoichiometric reaction: C 2 D 2-D () 96/4 er ac(c 2 C C 2 [Mo] ligand 10 2 ) 2 T-d8, rt D trans-4-d () Again, the reaction proceeds by a double retention pathway. 10 ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

21 The X-ray Structure of the Protio Complex vs its Solution Structure Competition experiments: 77.5%ee mismatched case (memory effect) 2 C D 2-D () path b ret Mo D 96%ee 6 minor If 12 was the minor isomer and required equilibration to the major isomer (7) before undergoing nucleophilic addition, then both the 3- substituted and unsubstituted products should exhibit a memory effect and have similar, low ee. If 12 is the major complex (7) and requires no equilibration, then a high ee should result. Mo D 7 major distereosomer Mo(C) 3 (S,S) ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379

22 Proposed chanism for Product ormation The ligand binds to Mo in a tridentate fashion C is imperative for the reaction to take place Allyl substrates react with overall retention of configuration S,S catalyst gives product with configuration Independent synthesis of 16 which has activity the same as that of Mo(C) 4 a complex 16 C 2 2 C C 2 quantitative yield ughes, D.L. (rck) Pro. at. Acad. Sci. 2004, 101, 5379 Trost, B.M.; ughes, D.L. (rck) J. Am. Chem. Soc. 2002, 124, 12656

23 Application of Molybdenum-Catalyzed Asymmetric Allylic Alkylation 2 1. MgCl - 50 C C 2 C ac 2 (C 2 ) 2 (EtC) 3 Mo(C) 3 (10 mol%) 2 C C 2 kg scale 2. Cl toluene 85% 1 (15 mol%), T % yield, 97% ee, 19/1 branched/linear eating (EtC) 3 Mo(C) 3 can generate ethylene and C, thus raising a safety issue. Palucki, M.(rck). J. rg. Chem. 2002, 67, 5008

24 Searching for Different Molybdenum Precatalysts (S,S) equiv Mo(C) cm C LnMo(C) cm cm cm cm -1 2 C ac 2 (C 2 ) 2 [Mo] (10 mol%) 2 C C 2 1 (15 mol%), toluene 2 3 Palucki, M.(rck). Adv. Synth. Catal. 2001, 343, 46

25 Molybdenum-Catalyzed Asymmetric Allylic Alkylation in Large Scale Synthesis 2 C ac 2 (C 2 ) 2 Mo (C) 6 (10 mol%) 2 C C aq a, 90 o C 2 C 1 (15 mol%), toluene 2. 2 Cl, heat Kg scale 84-91% yield, 96-97% ee, 95/5 branched/linear 90%, MgCl 2 K C 2 Cl 2 95% C 2 Cl 2 S % 94 Kg scale Palucki, M.(rck). J. rg. Chem. 2002, 67, 5008

26 Completion of the Synthesis 2 [(C)4]Cu]P6, 75 o C 1,2 dichloroethane 1 (exo) 2 (endo) 1/2 = 83/17, 98% yield 1/2 = 83/ kg scale aac, Ac 105 o C 15 h? one pot operation 5 a, DM 60 o C 30 min 16/1 trans/cis 86-94% 56% overall yield starting from 3-fluorobenzaldehyde. Palucki, M.(rck). J. rg. Chem. 2002, 67, 5008

27 Summary Molybdenum-catalyzed allylic alkylation is a general reaction. Ligands and solvents can greatly influence both regio-and enantioselectivity The reaction proceeds by a retention-retention pathway. Modest stereochemical memory effect is observed in the case of chiral racemic substrates. Labeling, solution, and solid state studies have shed light on the identity of the catalytically active species. The reaction has great potential for synthetic application.