Use of 5,5-(Dimethyl)-i-Pr-PHOX as a Practical Equivalent to t-Bu-PHOX in Asymmetric Catalysis

Abstract

The use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent of t-Bu-PHOX in asymmetric catalysis is reported. This new member of the phosphinooxazoline (PHOX) ligand family behaves similarly in terms of stereoinduction to t-Bu-PHOX with the key advantage of being readily accessible as both enantiomers starting from either (S)- or (R)-valine.

Preparation of phosphines through C–P bond formation

“…The organometallic reagents are mostly Grignard reagents [136–138] or organolithium [139–142] derivatives. Other organometallic reagents such as aluminum [143] or organomercury [26,144] reagents have been used less frequently.…”

“…These sensitive groups have to be protected first to avoid undesired reactions. Despite these limitations this approach is still generally used for the synthesis of simple phosphines [137–138 148–149]. …”

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel–Crafts Alkylations

“…26 Their bis(oxazoline) ligand replaced the tert-butyl substituent at C-4 with an isopropyl group in conjunction with a vicinal gem-dimethyl at the C-5 position and provided better enantioselectivity than the analogous tert-butyl ligand (85% vs 82%). 27 This gem-disubstitution effect 28 was further applied in many other areas of research, 29,30 including chiral auxiliaries, 31−35 phosphinooxazoline (PHOX) ligands, 36,37 and recently by Paquin, 38,39 who explored the gem-disubstituent effect, again with the PHOX type ligands, 40,41 as did Stoltz in a very recent report on an electronically modified PHOX ligand. 42 We have recently exploited this effect in the design of oxazoline-containing N,O ligands 4 and P,N ligands 5 and 6, which were applied with success in the diethylzinc and ethylphenylzinc addition to aldehydes and the asymmetric intermolecular Heck reaction, respectively ( Figure 2).…”

Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

“…Synthesis of ( R )-( p -CF 3 ) 3 - i -PrPHOX Me 2 ( ( R )-L5 ) was initiated with acid chloride 11 19 and the hydrogen chloride salt of ( R )-valine derivative 12 18 (Scheme 3). Intermolecular coupling of acid chloride 11 and amino alcohol 12 in the presence of excess Et 3 N provides amide 13 in 79% yield.…”

“…( R )-L3 and ( R )-L4 , Figure 2) have been constructed as cost-effective alternatives to ( R )- t -BuPHOX ( ( R )-L2 ). 18 We sought to extend this precedent to the synthesis of electronically modified congener ( R )-5,5-dimethyl-( p -CF 3 ) 3 - i -PrPHOX (( R )-( p -CF 3 ) 3 - i -PrPHOX Me 2 , ( R )-L5 , Figure 2) and explore its efficacy as a ligand in palladium-catalyzed enantio-and diastereoselective allylic alkylation reactions.…”