Diethylanilineborane:  A Practical, Safe, and Consistent-Quality Borane Source for the Large-Scale Enantioselective Reduction of a Ketone Intermediate in the Synthesis of (R,R)-Formoterol

Abstract

The development of a process for the use of N,N-diethylanilineborane (DEANB) as a borane source for the enantioselective preparation of a key intermediate in the synthesis of (R,R)formoterol L-tartrate, bromohydrin 2, from ketone 3 on kilogram scale is described. DEANB was found to be a more practical, safer, and higher-quality reagent when compared to other more conventional borane sources: borane-THF and borane-DMS.

Facile Access to Optically Active Ferrocenyl Derivatives with Direct Substitution of the Hydroxy Group Catalyzed by Indium Tribromide

“…Although detailed mechanistic investigations have not yet been presented, and there is no clear evidence that a free carbocation is formed in these reactions, we reasoned that the chiral cationic intermediate, formed by treatment of α‐ferrocenyl carbinol with a catalytic amount of indium salt, could be used in substitution reactions with a variety of different nucleophiles (Scheme ). Encouragingly, in the preliminary experiment, we observed the desired reaction when ferrocenyl alcohol 4 , obtained in 86 % ee by the aminoindanol/BH 3 reduction14 of ketone 1 , was treated with MeOH ( 7a , 2 equiv. )15 in the presence of different indium salts and reaction solvents (Table 1).…”

Drugs for Treating Respiratory System Diseases

“…Diastereo-and enantioselective syntheses of formoterol have been reported [61][62][63][64][65][66][67]. The starting point for them is enantioselective reduction of bromo ketone (23.1.34) to enantiomerically pure (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (23.1.40), which was achieved in different ways, such as cis-l-amino-2-indanol catalyzed borane reduction [61,62], or using Rh-PEGBsDPEN catalyst prepared in situ by mixing η5-pentamethy lcyclopentadienylrhodium dimer ([RhCl2(Cp*)] 2 ) and polyethylene glycol derivative of N-((1S,2S)-2-amino-1,2-diphenylethyl)-4-hydroxybenzenesulfonamide (PEGBsDPEN) [63].…”

A Perspective on Synthetic and Solid-Form Enablement of Inhalation Candidates

“…Selected Gilead phosphate dual prodrug compounds used in ana lysis [107][108][109][110]. Most fragments could be accessed either commercially or through literature procedures [29,30].…”

“…The b 2 headgroup 37 was prepared by an eight-step sequence, as shown in FiguRe 16. While this is a long linear sequence, the first six steps to the TBS-protected bromohydrin (35) are reasonably well precedented [30,33] and should be amenable to scale-up. The remaining two steps are similar to those used in the synthesis of the LABAs discussed earlier, and good yields were obtained for both steps.…”