Enantioselective Route to β-Silyl-δ-keto Esters by Organocatalyzed Regioselective Michael Addition of Methyl Ketones to a (Silylmethylene)malonate and Their Use in Natural Product Synthesis

Abstract

The direct Michael addition of alkyl methyl ketones through the acetyl methyl terminal to diethyl {[dimethyl(phenyl)silyl]methylene}malonate was catalyzed by the (S)-N-(pyrrolidin-2-ylmethyl)pyrrolidine/trifluoroacetic acid combination with high yield and excellent regio-and enantioselectivity. The ketone adducts can easily undergo de-ethoxycarbonylation to give b-silyl-dketo esters with excellent synthetic potential. This has been demonstrated by the synthesis of a suitably substituted b-silyl-d-keto ester as an advanced intermediate for a chiral hydroxylated pyrrolidine natural product, (+)-preussin. Silicon-controlled diastereoselective reduction of the ketone functionality of b-silyl-d-keto esters followed by lactonization of the resulting hydroxy esters gave disubstituted d-valerolactones. Advanced intermediates for the antipodes of natural products, namely (+)-massoialactone and (+)-mevinolin analogue, and natural products, namely (-)-tetrahydrolipstatin and (+)-5-hexadecanolide, have been achieved.

Chemical Constituents from the deep‐sea‐derived Fungus Aureobasidium melanogenum LUO5

“…By comparison of the NMR, MS, and optical rotation data with those reported in the literature, eight known compounds were identified as (3 R ,5 R )‐methyl 3,5‐dihydroxydecanoate ( 7 ), [20,21] massoia lactone ( 8 ), [22] (3 R ,5 R )‐3‐hydroxy‐5‐decanolide ( 9 ), [23] (+)‐2‐oxo‐6‐pentyltetrahydro‐2 H ‐pyran‐4‐yl acetate ( 10 ), [24] 2,3‐dihydroxypropyl (9 Z )‐9‐heptadecenoate ( 11 ), [25] 1‐monolinolein ( 12 ), [26] uridine ( 13 ), [27] and acetyl‐ L ‐tryptophan ( 14 ) [28] …”

“…By comparison of the NMR, MS, and optical rotation data with those reported in the literature, eight known compounds were identified as (3R,5R)-methyl 3,5-dihydroxydecanoate ( 7), [20,21] massoia lactone (8), [22] (3R,5R)-3-hydroxy-5-decanolide (9), [23] (+)-2-oxo-6-pentyltetrahydro-2H-pyran-4-yl acetate (10), [24] 2,3-dihydroxypropyl (9Z)-9-heptadecenoate ( 11), [25] 1monolinolein ( 12), [26] uridine (13), [27] and acetyl-L-tryptophan ( 14). [28] Microglial activation closely related to the pathogenesis of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's and Parkinson's diseases.…”

β‐Silylacrylate as a Multipurpose Reagent in Organic Synthesis

“…The synthesis of densely functionalized pyrrolidinol based bioactive natural products can be accessed from β‐silylacrylates. Ghosh and co‐workers have reported the total synthesis of (+)‐preussin ( 56 ; Scheme 21), [80–82] starting from β‐SA ( E )‐ 1c . Michael addition of dimethyl malonate (DMM) to β‐silylacrylate followed by Krapcho demethoxycarbonylation of the derived triester gave the diester 50a ( Scheme 21).…”