Pot Economy in the Total Synthesis of Estradiol Methyl Ether by Using an Organocatalyst

Abstract

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot‐economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction can be carried out in the last one‐pot sequence.

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…[45] In 2017, the same group also reported an enantioselective synthesis of estradiol methyl ether 175 (Scheme 19). [46] The key step of this reaction is to assemble the intermediate 171, which was achieved through a domino reaction of 169 and 4methoxycinnamaldehyde (170) catalyzed by 13. Further transformations of 171 afforded the aldehyde 174, which was finally converted to the desired product via a multistep synthetic maneuver (Scheme 19).…”

“…Further transformations of 171 afforded the aldehyde 174 , which was finally converted to the desired product via a multistep synthetic maneuver (Scheme 19). [46] …”

“…Further transformations of 171 afforded the aldehyde 174, which was finally converted to the desired product via a multistep synthetic maneuver (Scheme 19). [46] In 2016, the same group developed an improved one-pot asymmetric synthesis of (S)-baclofen hydrochloride (178, Scheme 20). [47] They demonstrated that the condensation of 4-chlorobenzaldehyde (176) and acetaldehyde ( 12) could be achieved by using DBU as the catalyst and careful evaporation procedures to give the desired condensation product trans-4-chlorocinnamaldehyde (177) in a good yield (not isolated).…”

Revealing the Similarities of α,β‐Unsaturated Iminiums and Acylazoliums in Organocatalysis

“…Reaction with cyclic 1,3-diketone derivatives Thec ascade reactions proceeding via 1 or 2 can also be applied for the desymmetrization of cyclic 1,3-diones.H ayashi and co-workers employed the cyclic 1,3-diketones 67 having an itro group in the reaction of enals with the secondary amine catalyst 54 for the highly selective synthesis of the functionalized aldehyde 68 bearing five contiguous stereocentres (Scheme 15). [63] Ther eaction is initiated by as elective Michael addition onto the catalytically generated 1 followed by an intramolecular aldol reaction to deliver the expected product. Similar was the case in NHC catalysis using the same nucleophile,and 2-bromoenals for the generation of 2.Biju and co-workers disclosed afacile synthesis of tricyclic b-lactones 69 possessing five contiguous stereocentres,where the reaction proceeds in aM ichael-aldol-b-lactonization cascade.…”

Organocatalytic Asymmetric Cascade Reactions Based on Gamma‐Nitro Carbonyl Compound

“…The designed γ ‐nitroketones 65 were used as starting materials in the procedure of total synthesis of estradiol methyl ether via a domino the Michael‐aldol reaction by Hayashi's group in 2017 (Scheme ) . The best reaction condition was α ‐ α ‐L‐diphenylprolinol silyl ether catalyst Cat.…”