Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach

Abstract

We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).

Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse

“…Similar reactions were also conducted in an attempt to make the β-boryl aldehyde by initially converting the α,β-unsaturated aldehyde in situ into the respective imine, followed by catalytic borylation and then workup; however, the product was extremely unstable, and therefore, subsequent Wittig olefination was used to facilitate the generation of a stable and versatile homoallylic boronate ester . Furthermore, starting from the α,β-unsaturated aldehyde, such a process has been utilized in the total syntheses of ( R )-fluoxetine and ( S )-duloxetine …”

“…533 Furthermore, starting from the α,β-unsaturated aldehyde, such a process has been utilized in the total syntheses of (R)-fluoxetine and (S)-duloxetine. 534 A novel copper(I) bifluoride NHC complex showed relatively high activity for the β-borylation of an α,βunsaturated ester (Scheme 65); however, a copper complex with a chiral NHC ligand used in the study showed poor yield and enantioselectivity. 535 Borylations of α,β-unsaturated carbonyls using bulky copper(I) phosphine catalysts and B 2 (OH) 4 have also been reported.…”

Ball mill and microwave assisted synthetic routes to Fluoxetine

“…Data in agreement with the literature. (Calow et al 2014). Aminoketone hydrochloride 3b (105 mg, 0.5 mmol) and NaBH4 (39 mg, 1.0 mmol) were added into a 25 mL stainless steel grinding jar with a 25 mm Ø stainless steel ball.…”

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…133 Several chemical methods, in addition to enzymatic methods utilizing lipases or lyases (section 2.1.4 and 2.1.5), were developed for the synthesis of (S)-duloxetine. 130 However, chemical methods, ranging from Noyori-based asymmetric hydrogenations, 134 enantioselective allylation, 135 boronane-based asymmetric reductions, 136 to asymmetric aldol condensations, 137 mostly give reduced yields and lower e.e. 's compared to the presented biocatalytic reduction.…”