Enantioselective Synthesis of Enantioselective Synthesis of Biphenols from 1,4-Biphenols from 1,4-

Diketones by Traceless Diketones by Traceless Central-to-axial Chirality Central-to-axial Chirality

ExchangeExchange

Research By: F Guo, LC Konokol, and RJ Thomson; Northwestern University

Summary by: Sonja Gamby; UMCP

Some termsSome 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

Common molecule exhibiting Common molecule exhibiting axial chirality - BINOLaxial 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.

OH

HO

OH

HO

(R)-1,1'-Bi-2-Napthol

(S)-1,1'-Bi-2-Napthol

Derivatives of BINOL: Why Derivatives of BINOL: Why

and How?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

OH

HO

R

R

R=H,Br,Cl

Electrophilic aromatic substitutions in conjunction with protection of the hydroxyl moieties are a quick route to a vast library of derivatives

…Some derivatives

OH

HO

Ph

Ph

O

O

Br

Br

O

O

Zr

L

L

Br

Br

Kelly et al.Diels-Alder reactions of naphthoquinone derivatives

Kobayashi et al.Mannich Reaction involving silyl enolates

HO

N

Ar H

OSiMe3

R

R

R

HO

HN

ArR R

O

R

O

O O

BO O

PhPh

HO

Ph

OH

Ph

I.

II.

BINAP for use in asymmetric BINAP for use in asymmetric catalysiscatalysis

… 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

PPh2

Ph2P

2,2'-bis(diphenylphosphino)-2,2'-bis(diphenylphosphino)-

1,1'-binaphthyl1,1'-binaphthyl• Synthesis from BINOL

OH

OH

(Ph)3PBr2

320 C

Br

Br

Mg

Ph2POClP

P

O

O

(R) or (S)HSiCl3

Et3NBINAP (R or S)

Asymmetric Hydrogenation (Noyori et al.)

…in the Isomerization of allylic amines

..to reduce B-keto esters

Limited routes to axially chiral biphenyls

I.Direct asymmetric Coupling Fusion of two naphthol rings using transition metals

II. Atropselective transformation of preformed biaryls

OH

HO

OH

OH

Cu, Va, Zr..

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

Spectroscopic Confirmation

Scope of Methodology

O

MeO OMe

O

MeO OMeAr

O

MeO OMeAr

O

OMe

OMeArH

H ArOMe

OH

ArMeO HO

a bc+ ArZnCl

a= 1. [RhCl(((R) - BINAP)]2 2.TMSCl (3 equiv.), THF, -10 Cb = LDA, then; CuCl2 / THFc = BF3OEt2 / PhMe / 110 C

NHAc

OMe

MeO

MeO

CO2Me

OMe

MeO

MeO

OAc

O

O

O

O

(-)allocolchicine (-)steganacin

Some Natural Products

Acknowledgements

• Dr. Davis

• Ben Roembke