Enantioselective Synthesis of Biphenols from 1,4-Diketones by Traceless Central-to-axial Chirality Exchange

1. Enantioselective Synthesis of Biphenols from 1,4-Diketones by Traceless Central-to-axial Chirality Exchange Research By: F Guo, LC Konokol, and RJ Thomson; Northwestern University Summary by: Sonja Gamby; UMCP

2. Some terms “Axial Chirality” Axial chirality results from a hindered axis of rotation as opposed to a chiral center “Traceless” Denotes transition from sp3 to sp2 and the exchange between typical “central” chirality and axial chirality

3. Common molecule exhibiting axial chirality - BINOL • The original synthesis of BINOL was reported by Pummerer et al. in 1926. • Original syntheses involved oxidative coupling of the two naphthol units induced by FeCl3. • There are two methods for the preparation of chiral binaphthol ligands: (a) through coupling reactions of substituted naphthol units and (b) through regioselective modification of the binaphthol scaffold.

4. Derivatives of BINOL: Why and How? • Subject to racemization in acidic or basic media • Limited control over electronics and sterics of metal center • Useful in a variety of transformations Electrophilic aromatic substitutions in conjunction with protection of the hydroxyl moieties are a quick route to a vast library of derivatives

5. …Some derivatives Kelly et al. Diels-Alder reactions of naphthoquinone derivatives I. Kobayashi et al. Mannich Reaction involving silyl enolates II.

6. BINAP for use in asymmetric catalysis … To discover high-performance asymmetric catalysts, developing an excellent chiral ligand is crucial. Attracted by its molecular beauty [Chemica Scripta 1985, 25, 83], we initiated the synthesis of BINAP (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) [J. Am. Chem. Soc. 1980, 102, 1932] in 1974 at Nagoya with the help of H. Takaya, my respected long-term collaborator. BINAP was a new fully aromatic, axially dissymmetric C2 chiral diphosphine that would exert strong steric and electronic influences on transition metal complexes. Its properties could be fine-tuned by substitutions on the aromatic rings. … Ryoji Noyori, Nobel Lecture, December 8, 2001

7. 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl • Synthesis from BINOL

8. Asymmetric Hydrogenation (Noyori et al.) …in the Isomerization of allylic amines ..to reduce B-keto esters

9. Limited routes to axially chiral biphenyls • Direct asymmetric Coupling • Fusion of two naphthol rings using transition metals • II. Atropselective transformation of preformed biaryls

10. Is there a better way??.... Yes!

11. Spectroscopic Confirmation

12. Scope of Methodology

13. Some Natural Products (-)allocolchicine (-)steganacin

14. Acknowledgements • Dr. Davis • Ben Roembke