The Chemical Development of LB71350

Abstract

An efficient synthesis of the HIV-1 protease inhibitor LB71350 (1) is described. High diastereoselective epoxidation of the cisallylic carbamate fragment of (5S)-[N-(benzyloxycarbonyl)-amino]-N-[2-methyl-(1R)-[(phenyl)carbonyl]-propyl]-6-phenylhex-(Z)-enamide (16) and one-pot preparation of N-[(1-methylethoxy)carbonyl]-3-(methylsulfonyl)-L-valine (4) are the key features of the synthesis.

Ytterbium Acetate Promoted Asymmetric Reductive Amination: Significantly Enhanced Stereoselectivity

“…Figure provides a working model of the low energy conformers of the cis - and trans -ketimines influencing facial selectivity during the addition of hydrogen to N -α-MBA ketimines. The models are consistent with the major amine diastereomer formed (either S , S or R , R depending on the starting enantiomer of α-MBA) and are in accordance with the well-established concept of allylic 1,3-strain and earlier proposed models. 15c,i Contrary to this model, it has been previously suggested that the reductive amination of an α-keto ester with α-MBA may involve a rotamer (about the nitrogen-benzylic carbon bond) with the phenyl ring of α-MBA coplanar to the ketimine double bond . The idea is appealing because of the well described affinity of π bonds for heterogeneous hydrogenation catalyst surfaces, but examination of the two possible trans -ketimine rotamers (not shown), with a coplanar phenyl group relative to the ketimine double bond, shows one suffering from high allylic 1,3-strain 35 (prominent phenyl group steric crowding with the methyl group attached to the carbonyl carbon of the ketimine) while the other rotamer is less encumbered (1,2-strain from the electron pair of the ketimine nitrogen and one of the ortho hydrogens of the phenyl ring) but leads to the formation of the wrong amine product diastereomer.…”

N-Tfa- and N-Fmoc-(α-aminoacyl)benzotriazoles as Chiral C-Acylating Reagents under Friedel−Crafts Reaction Conditions

“…Chiral N-protected α-amino ketones are useful precursors to many biologically active compounds including chiral α-amino alcohols, pharmaceutically important chiral heterocycles, , and diamines. 1c, Preparations of α-amino aliphatic ketones and α-amino aryl ketones have been thoroughly investigated, but much less attention has been directed toward the synthesis of α-aminoalkyl heterocyclic ketones and to our knowledge, no general method has been reported. Previous syntheses of chiral α-amino ketones utilized N - protected α-amino acids, esters, and amides (i) with organometallic reagents for nucleophilic substitution 6 or (ii) with AlCl 3 for Friedel−Crafts acylations .…”

A one-step base-free synthesis of N-arylamides via modified pivaloyl mixed anhydride mediated amide coupling

“…24–27 In the presence of a base, namely Et 3 N, NMM or N -methylpiperidine, carboxylic acids are first transformed into the corresponding mixed anhydrides using acid chlorides, such as pivaloyl chloride (PivCl) 28–41 or isobutyl chloroformate (IBCF). 42–51 The advantages of PivCl for scale-up include its relatively low cost, wide availability, and nontoxic pivalic acid as a byproduct after aqueous workup. Recently, we questioned whether inexpensive and easy to handle pivaloyl anhydride (Piv 2 O) might be applied for the generation of pivaloyl mixed anhydrides via carboxyl exchange 52–59 to avoid the use of an additional base and enable a more sustainable amine condensation method.…”