Modular Enantioselective Synthesis of 8-Aza-prostaglandin E₁

Abstract

We report herein for the first time the enantioselective synthesis of 8-aza-PGE1. The synthesis used the cross olefin metathesis reaction to connect the 5-vinyl-γ-lactam subunit, prepared from (R)-malic acid via the Ley's sulfone-based α-amidalkylation protocol (dr = 6.8:1), with the chiral pre-ω-chain. The latter was synthesized in high enantioselectivity from (E)-2-octenol by the Sharpless asymmetric epoxidation and the titanocene-mediated epoxide opening. This modular approach is quite concise and flexible, and requires only eight steps from commercially available reagents.

Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones

“…The desired key intermediates aldehyde (12), iodo alkene (11) and epoxy (10) were also made following the same reported protocol except that TBDPS rather than TBS was used for improved reaction monitoring using TLC. The epoxy (10) was then stereospecifically converted into allyl alcohol (17) in a single step, by using titanocene dichloride and Zn powder ( Wang et al, 2013 ; Katsuki and Sharpless, 1980 ). The final product, stereospecific (4 S, 10 R )-avenolide ( 13 ) was then produced by ring-closing metathesis of molecule 19 , treating the dialkene with Grubb’s second-generation catalyst ( Sheddan and Mulzer, 2006 ).…”

“…10 was then stereospecifically converted into allyl alcohol 17 in a single step, by using titanocene dichloride and Zn powder. 22,23 The final product, stereospecific (4S, 10R)avenolide (13) was then produced by ring-closing metathesis of 19 treating the dialkene with Grubb's second-generation catalyst. 24…”

Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones

“…10 was then stereospecifically converted into allyl alcohol 17 in a single step, by using titanocene dichloride and Zn powder. 22,23 The final product, stereospecific (4 S , 10 R )-avenolide, 13 was then produced by ring-closing metathesis of 19 treating the dialkene with Grubb’s second-generation catalyst. 24 The final yield of avenolide was 14 mg total from 15 g of starting material.…”

“…(R)-8-((2S,3S)-3-(Hydroxymethyl)oxiran-2-yl)-3-((4-methoxybenzyl)oxy)-3-methyloctan-4-one ( 17 ): Following the protocol from the reported literature 22 anhydrous ZnCl 2 (2 mL, 1 M in Et 2 O, 2 mmol) and zinc powder (350 mg, 6.72 mmol) were added to a red solution of Cp 2 TiCl 2 (1.26 g, 5.05 mmol) in anhydrous THF (15 mL). The solution was stirred for 1h at room temperature until it turned green.…”

Efficient asymmetric syntheses of alkaloids and medicinally relevant molecules based on heterocyclic chiral building blocks

“…Taking advantages of the chemistry of malimide 1 (10 in Scheme 2), a modular strategy has been developed for the first enantioselective synthesis of 8-aza-PGE 1 (7) (Scheme 1) [12].…”