Enantioselective Total Synthesis of Cannogenol-3-O-α-l-rhamnoside via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

Abstract

A concise and scalable enantioselective total synthesis of the natural cardenolides cannogenol and cannogenol-3-O-α-L-rhamnoside has been achieved in 19 linear steps. The synthesis features a Cu(II)-catalyzed enantioselective and diastereoselective Michael reaction/tandem aldol cyclization and a one-pot reduction/transposition, which resulted in a rapid (6 linear steps) assembly of a functionalized intermediate containing C19 oxygenation that could be elabo-rated to cardenolide cannogenol. In addition, a strategy for achieving regio- and stereoselective glycosylation at the C3 position of synthetic cannogenol was developed and applied to the preparation of cannogenol-3-O-α-L-rhamnoside.

Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation

“…We first undertook model studies to test the requisite diastereo-induction at C9 and C10 imposed by the C11 stereocenter (Scheme 2B). 28a,29 The Cu(OTf) 2 -catalyzed Michael reaction of β−ketoester 13 and C11 oxygenated enone 14 proceeded with high levels of stereocontrol, yielding steroid 16 (44 % yield over 2-steps, >20:1 dr). As discussed previously, 27, 28a the reaction likely proceeds via an open transition state 15 through a stepwise mechanism.…”

Regioselective single pot C3-glycosylation of strophanthidol using methylboronic acid as a transient protecting group

“…6 and 10 , Scheme 1) are typically observed. 30,34 To circumvent this, strategies requiring C19 protection, glycosylation and following deprotection have been developed. 34,35 However, these strategies require careful selection of the C19 protecting group as the competitive decomposition of the butenolide moiety can be observed upon deprotection.…”

“…30,34 To circumvent this, strategies requiring C19 protection, glycosylation and following deprotection have been developed. 34,35 However, these strategies require careful selection of the C19 protecting group as the competitive decomposition of the butenolide moiety can be observed upon deprotection. 34 Altogether a more efficient strategy for the direct introduction of the sugar moiety at the C3-position of these molecules is highly desired.…”

“…34,35 However, these strategies require careful selection of the C19 protecting group as the competitive decomposition of the butenolide moiety can be observed upon deprotection. 34 Altogether a more efficient strategy for the direct introduction of the sugar moiety at the C3-position of these molecules is highly desired. To streamline the synthesis of glycosylated strophanthidol ( 4a ) analogs as well as other C3-glycosylated cardiotonic steroids possessing C3/C5/C19 hydroxylation pattern, we set out to develop a direct single pot method that is based on the use of boronic acid esters as the traceless protecting group.…”

“…The in situ formation of the boronic acid ester 16 was followed by the addition of the glycosyl donor and promoter that provided glycoside 17 , and the subsequent aqueous work up was used to cleave the boronic acid ester and provide the C11 glycosylated product 18 in a single operation. Having long-term interests in improving the synthesis of cardiotonic steroids 34,41–45 and building on these prior studies, we surmised that this strategy might be particularly useful for the glycosylation of steroids 1 – 4a , and, in particular, strophanthidol ( 4a ). This molecule possesses hydroxyl group at the C3, C5, C14 and C19 positions, and the boronic acid protection could result in two isomeric products protected either at the C3 and C5 positions (exemplified by compound 19 ) or at the C5 and C19 positions (exemplified by compound 20 ).…”