Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

NHC-catalyzed/titanium(IV)-mediated highly diastereo- and enantioselective dimerization of enals.

An NHC-catalyzed, diastereo- and enantioselective dimerization of enals has been developed. The use of Ti(Oi-Pr)(4) is a key element for the reactivity and selectivity of this process. The cyclopentenes are obtained with high levels of diastereo- and enantioselectivity and their synthetic utility is demonstrated by functionalization of the product alkene.

Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to gamma-lactams.

Enzymes are a continuing source of inspiration for the design of new chemical reactions that proceed with efficiency, high selectivity and minimal waste. In many biochemical processes, different catalytic species, such as Lewis acids and bases, are involved in precisely orchestrated interactions to activate reactants simultaneously or sequentially. This type of 'cooperative catalysis', in which two or more catalytic cycles operate concurrently to achieve one overall transformation, has great potential in enhancing known reactivity and driving the development of new chemical reactions with high value. In this disclosure, a cooperative N-heterocyclic carbene/Lewis acid catalytic system promotes the addition of homoenolate equivalents to hydrazones, generating highly substituted gamma-lactams in moderate to good yields and with high levels of diastereo- and enantioselectivity.

Cooperative N-heterocyclic carbene/Lewis acid catalysis for highly stereoselective annulation reactions with homoenolates.

A new approach that takes advantage of N-heterocyclic carbene/Lewis acid cooperative catalysis provides access to cis-1,3,4-trisubstituted cyclopentenes from enals and chalcone derivatives with high levels of diastereoselectivity and enantioselectivity. The presence of Ti(OiPr)(4) as the Lewis acid allows for efficient substrate preorganization, which translates into high levels of diastereoselectivity. Additionally, we demonstrate the possibility of controlling the absolute stereochemistry of NHC-catalyzed reactions by employing a catalytic amount of a chiral Lewis acid as the unique source of optically active promoter.

A stereoselective approach to nucleosides and 4'-thioanalogues from acyclic precursors.

D- and L-nucleosides and analogues thereof, including the 4'-thionucleoside series, are one of the most important biological and pharmaceutically active classes of compounds. A novel approach to their synthesis from chiral acyclic thioaminal, bearing the nucleobase, is described.

Stereoselective quaternary center construction via atom-transfer radical cyclization using silicon tethers on acyclic precursors.

A novel strategy for the stereoselective construction of all-carbon quaternary centers on acyclic molecules using a two-step tandem process is reported. The first step involves an intramolecular and stereoselective atom transfer radical cyclization reaction from an allyl or vinyl subunit attached on a silyloxy, serving as a tether, to a tertiary radical alpha to an ester. A subsequent mild acidic elimination leads stereoselectively to a quaternary center bearing an allyl or a vinyl in high yield.

Synthesis of tertiary and quaternary stereogenic centers: a diastereoselective tandem reaction sequence combining Mukaiyama and free radical-based allylation.

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a free radical-based allyl transfer reaction for the elaboration of functionalized tertiary and quaternary centers. The appropriate choice of alcohol-protecting group on the starting alpha-methyl-beta-hydroxyaldehyde and the nature of the Lewis acid used in the Mukaiyama reaction provided access to 3,4-anti and 3,4-syn aldolization products, precursors of the free-radical allylation reaction. After migration or exchange of the Lewis acid, the allyl transfer reaction with allyltributylstannane is then performed by taking advantage of the endocyclic effect, leading to the 2,3-anti relative stereochemistry. Importantly, (13)C NMR studies of the chelated intermediates are also reported and provide additional support for the endocyclic effect. In some cases, the remarkable reactivity of the aluminum-based Lewis acids allowed the use of allyltrimethylsilane, an interesting reagent from an ecological standpoint. The isolation of a key intermediate is also indicative of an atom transfer mechanism when the silicon-based reagent is employed.