1. Voituriez Arnaud A. B. Charette Group 04/04/2006 Enantioselective Additions of Organolithiums Derivatives to Carbonyls Literature meeting

2. Content Introduction Classes of chiral reagents General features in enantioselective additions of organolithiums to carbonyls 3-Aminopyrrolidine Lithium Amide: opening of a black box The industrial synthesis of Efavirenz

3. Enantioselective Additions of Organolithiums to Carbonyls Since it is known that organolithium reagents and ligands lithiated in situ form mixed anionic aggregates, the understanding of the nature of these aggregates provides a way to design chiral reagents… Nucleophilic addition to carbonyl carbon using organometallic reagents (R 2 Zn, RMgX or RLi) is a central reaction in organic synthesis allowing the formation of C-C bonds. When a chiral ligand is used, optically active alcohol is obtained: Only few examples of asymmetric alkylation reactions using RLi reagent have been reported.

4. Classes of Chiral Reagents These structures share probably a common chelating pattern Li cation in a five membered metallacycle Tight experimental conditions (T<-100°C, solvent mixtures) 1. 2. 3.

5. Chiral Diamines and O-alkylated Ligands 1.

6. Aminoalcoholates Ligands 2.

7. Aminoalcoholates Ligands 2.

8. Lithium Amides Ligands 3.

9. Better Understanding of the System… McGarrity 1 : « Rapid injection NMR » : n-BuLi additions to PhCHO at –85°C Dimeric n-BuLi was found to be 10 times more reactive than the tetrameric species. Reactivity of Li 4 (n-Bu) 2 (OBu) 2 = Reactivity of (n-BuLi) 2 Why the addition of the « chiral L*n-BuLi » instead of the n-BuLi ? 1 JACS 1985, 107, 1810.

10. Better Understanding of the System… 1 See, for example enolate alkylations JACS 1999, 121, 6213. Effect of ligand and solvent ? Coordinating solvents (THF) and/or ligands (TMEDA) de-aggregate organolithiums and hence give rise to higher reactivities than the oligomers 1 Is a catalytic procedure possible? Because of high reactivity of non-modified organolithiums towards aldehydes, catalytic procedures seem to be hardly possible… Temperature ? A maximum of –78°C is necessary…

11. Better Understanding of the System… Optimized conditions: Ethereal solvents, low temperatures, protic ligands Central role of mixed chiral organolithium aggregates in nucleophilic alkylation Subject of intensive research…

12. Mixed Complex: Li-1 / n-Bu[ 6 Li] Hilmersson and Davidsson Chem. Eur. J. 1999, 5, 1348.

13. Mixed Complex: Li-Amide / n-Bu[ 6 Li] Hilmersson T 2002, 58, 4717. The mixed lithium amide/n-BuLi B aggregate alkylates faster than the pure n-BuLi oligomers A AB

14. 3-Aminopyrrolidine Lithium Amide Tetrahedron: Asymmetry 1997, 8, 1519-1523. J. Am. Chem. Soc. 1997, 119, 10042-10048. J. Org. Chem. 1998, 63, 8266-8275. J. Am. Chem. Soc. 2002, 124, 15267-15279. Pierre Duhamel, Jacques Maddaluno et al. J. Organomet. Chem. 1997, 549, 81-88. J. Org. Chem. 2000, 65, 8899-8907. DFT studies, with C. Fressigné, C. Giessner-Prettre and B. Silvi: J. Org. Chem. 2001, 66, 6476-6479. Tetrahedron 2002, 58, 4707-4716. J. Org. Chem. 2003, 68, 1290-1294. Organometallics 2003, 22, 4090-4097. J. Org. Chem. 2005, 70, 7816-7828. Tetrahedron 2005, 61, 3325-3334. 3-AP Enantioselective addition to aldehydes NMR studies Pure Appl. Chem. 2006, 78, 321-331.

15. 3-Aminopyrrolidine Lithium Amide Why are the (R 1,R 2 ) groups important? Enantioselective addition: Synthesis: TA 1997, 8, 1519.

16. 3-Aminopyrrolidine Lithium Amide o-TolCHO R = H: 49% ee R = Ph: 73% ee Norbornyl-like bridged structure Extremely simple spectra Dimeric lithium amide The amides A and B adopt drastically different structures in solution: JACS 1997, 119, 10042. A B

17. H7H7 H6H6 H2H2 H 2’, H 5’ H7H7 H6H6 H2H2 H 2’ H2H2 H5H5 H 5’ H5H5 (-40°C) (25°C) (-40°C) (-70°C)

18. Proposed Models for Tolualdehyde Docking 1. Coordination between the metal cation and the carbonyl oxygen 2. Transfer to the butyl anion onto the carbonyl

19. 3-Aminopyrrolidines Li-Amides as Chiral Ligands for RLi Derivatives

20. Presence of a Second Asymmetric Center on the 3-AP JOC 1998, 63, 8266. JACS 2002, 124, 15267.

21. Presence of a Second Asymmetric Center on the 3-AP

22. 6 Li spectrum of [ 6 Li]-3c In THF-d 8 at –78°C 6 Li spectrum of [ 15 N, 6 Li]-3c 15 N spectrum of [ 15 N, 6 Li]-3c Quintet : Two 6 Li (I=1); 1 J = 8.0 Hz Empirical rule: 1 J ( 13 C/ 6 Li) = 17/n 13 C spectrum of [ 6 Li]-3c Doublet : One 15 N (I=1/2); 1 J = 1.3 Hz

23. A Useless Chiral Center? (3S,8S) and (3R,8S) 3-AP Lithium amide leading to (S)-1-phenylethanol

24. Theoretical Consideration Crucial piece of information, not available from spectroscopy: The approach and docking of the aldehyde on the mixed aggregates. Oxygen-Lithium coordination. Tendency for the nucleophile to follow a Burgi-Dunitz type trajectory JOC 2000, 65, 8899.

25. Solvent Effect on the Mixed Aggregates 6 Li spectra of 3b T 2005, 61, 3325. Progressive addition of THF-d 8 in DEE-d 10 1 2

26. Aldehyde Docking

27. Fressigné, C.; Giessner-Prettre, C. in progress

28. Structure Effects 80 % ee (R) Rate = 1 80 % ee (R) Rate = 1 46 % ee (R) Rate = 0.3 71% ee (R) Rate > 1

29. Enantioselective Hydroxyvinylation with Lithioethenes Synlett 2005, 10, 1555.

30. The Bingo Question: What is the particularity of this molecule?

31. The Industrial Synthesis of Efavirenz Efavirenz (Merck) Anti-AIDS drug, a non-nucleoside reverse transcriptase inhibitor for a variety of HIV-1 mutant strains. Used worldwide for the treatment of AIDS. Enantioselective lithium acetylide addition yielding an efavirenz precursor Nice illustration of interplay between asymmetric synthesis, NMR studies, X-ray structures and computational chemistry. Grabowski, E. J. J. Chirality 2005, 17, 249.

32. The Story Begins with L-738,372. Huffman JOC 1995, 60, 1590. L-738,372 Enantioselective acetylide addition to an imine: PG = smaller group: lower ee T = -40°C or 0°C: lower ee At this point, the medicinal chemists were asked to focus their attention on what became efavirenz…

33. Optimization of the Key Step The amine is quite acidic, so they decided to protect it: Ephedrine alkoxides are the best chiral amino alcohols. Thompson TL 1995, 49, 8937.

34. The Effect of the Temperature This is known that the Li-aggregates change with temperature, but is there any variations on the ee? Subsequent experiments showed that the reaction exhibits a nonlinear effect: 50% ee chiral alkoxide yields 77% ee of product, suggesting chiral mixed aggregate… (30 min) Necessity of « aging » the alkynylation mixture at 0°C. This « aging » effect implicates an unusually slow aggregate exchange

35. NMR Studies to Define the Nature of the Aggregation States Cubic tetramer during the high- Temperature equilibration. Ratio Ephedrine-Li / Acetylide-Li: 1 / 1 Thompson, Collum JACS 1998, 120, 2028.

36. Proposed Mechanism This simple model predicts the observed enantioselectivity for the reaction.

37. Importance of the Stoichiometry To complete the reaction, 2 moles of acetylide and 2 moles of ephedrine are needed! 122 At 1/1/1 ratio, alkynylation proceed rapidly, but only up to 50% conversion at -78°C. When warmed to 0°C, 90% conversion in 5 h, with 70% ee in the last 40% conversion! So, what is the rather unreactive species formed after 50% conversion? Infrared spectroscopic studies: Further addition on ketone at –78°C : IR detects CO and NH bands of ketone No C-H signal of protonated acetylene After 50 % conversion: Substrate coexists with rather unreactive species, which does not alkynylate the CO or deprotonate the NH of the substrate!

38. 3:1 alkoxide-acetylide aggregate Unreactive After 50% conversion, the product alkoxide is now present in the new cubic tetramer that is formed. Importance of the Stoichiometry Reactive 2/2 aggregate Reactive Reactive 3/1 aggregate (X-ray) Unreactive Semiempirical (MNDO) computational method

39. What is the Structure of the Tetramer After the Addition? Tetramer that has no symmetry With 15 N-ephedrine two 6 Li of the product became doublet With 15 N-ketone, no change in the product spectrum. Xu, Collum JACS 2000, 122, 11212.

40. Proposed Reaction Pathways Xu, Collum JACS 2000, 122, 11212.

41. The Manufacturing Process 4 steps, 76 % overall Pierce JOC 1998, 63, 8536.

42. The Manufacturing Process : the Key Step 60 min The chiral additive is easily recycled from the aqueous layer by basification with NaOH and Toluene extraction (>99% purity, 98% yield)

43. The Manufacturing Process : Completion of the Synthesis AcOH, recristalisation Tol / Heptane 7 steps, 76 % overall from chloroaniline Over 50 000 Kg have been prepared.

44. Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides: Direct Enantioselective Alkynylation of the Unprotected Ketoaniline Tan ACIEE 1999, 38, 711.

45. Conclusion The enantioselective addition of organolithium derivatives to carbonyls is one of the fundamental reactions in organic chemistry The in-depth study of the chiral entity involved in an enantioselective reaction can provide essential information regarding the exact mechanism of asymmetry tranfer, and opening little by little « the black box ». We have always to keep in mind that one day our ligands can be used in a 50 000 Kg scale (mine too, if it is possible...)…