The Intramolecular Asymmetric Pauson−Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins:  Synthesis of UT-15 (Treprostinil)

Abstract

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase

“…The title compound was synthesized by the method described previously (Moriarty et al, 2004). To a solution of ( R )-(−)-epichlorohydrin (5.08 mL, 64.9 mmol) in 10 mL THF was added copper iodide (1.2 g, 6.3 mmol) and cooled to 0°C.…”

Asymmetric Enynylation of N‐Sulfonyl Aldimines Catalyzed by Zn‐BINOL Complexes

“…Adducts 4 are versatile synthetic intermediates and can be readily transformed into functionalized amine derivatives that are otherwise difficult to access. For instance, treatment of adduct 4pb with Co 2 (CO) 8 at 80 °C underwent a Pauson–Khand cycloaddition reaction to give polycyclic product 5 in 58 % yield (Scheme ) 10. Compound 5 was crystallized from CH 2 Cl 2 and hexane, and its absolute configuration was determined to be (4 R ,9a S ) from single‐crystal X‐ray diffraction analysis (Figure 1).…”

Diastereoselective Pauson‐Khand Reaction using Chiral Pool Techniques (Chiral Substrates)

“…18 Optically pure enyne amino acid derivatives 64, which were easily prepared by an alkenylboronic acid-mediated Mannich-type reaction, were successfully used for intramolecular PK reactions with a variety of catalytic systems. Optimal results featuring yields up to 82% were obtained using 10 mol% Co 2 (CO) 8 21 This work provided the first demonstration of the synthetic utility and reliability of the asymmetric PK cyclization route for the synthesis and subsequent manufacture of complex drug compounds on a multikilogram scale. The key step in the synthesis involves efficient stereoselection via the PK cyclization of benzoenyne 73 under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group and is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone product (Scheme 4.19).…”