- Pentanidium- and Bisguanidinium-Catalyzed Enantioselective Alkylations Using Silylamide as Br?nsted Probase
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Most asymmetric phase transfer reactions are Br?nsted base reactions, and the inorganic bases used greatly influenced the profile of the reaction. Alkoxide salts are able to activate substrates with high pKa values, but background reactions are often unavoidable. On the other hand, carbonate and phosphate salts are milder, but their low basicity limits the scope of their reactions. This presents a difficult situation whereby fragile substrates such as lactone will be hydrolyzed by a stronger base but will not be activated with a weaker one. Thus, a Br?nsted probase strategy is devised, in which a strong base can be generated in situ from silylamide (probase) through the use of fluoride. In this approach, the strong base produced will be transient and not be in excess, thus reducing background and side reactions. We demonstrate this strategy using pentanidinium and bisguanidinium as catalysts; highly enantioselective phase transfer alkylation of several types of substrates including dihydrocoumarin (lactone) can be achieved. We found that the probase also acts as a silylation reagent, generating silyl enol ether or silyl ketene acetal, which are key intermediates in the reaction. We further propose that hypervalent silicates form ion-pairs with pentanidinium and bisguanidinium as intermediates in the reaction, and it is through these ion-pairs that the selective enantiofacial approach of the electrophile is determined.
- Teng, Bo,Chen, Wenchao,Dong, Shen,Kee, Choon Wee,Gandamana, Dhika Aditya,Zong, Lili,Tan, Choon-Hong
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- Enantioselective decarboxylative alkylation reactions: Catalyst development, substrate scope, and mechanistic studies
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α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. Sly as a PHOX: The development of an enantioselective decarboxylative palladium-catalyzed allylic alkylation reaction, utilizing phosphinooxazoline ligands, is described. The catalyst is applied to a range of allyl enol carbonate, silyl enol ether, and allyl β-ketoester substrates to provide alkylated ketone products in excellent yield and good ee (see scheme). The utility of these products is demonstrated by their use in several asymmetric syntheses. Mechanistic studies are reported suggesting an unusual inner-sphere mechanism. Copyright
- Behenna, Douglas C.,Mohr, Justin T.,Sherden, Nathaniel H.,Marinescu, Smaranda C.,Harned, Andrew M.,Tani, Kousuke,Seto, Masaki,Ma, Sandy,Novak, Zoltan,Krout, Michael R.,McFadden, Ryan M.,Roizen, Jennifer L.,Enquist Jr., John A.,White, David E.,Levine, Samantha R.,Petrova, Krastina V.,Iwashita, Akihiko,Virgil, Scott C.,Stoltz, Brian M.
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p. 14199 - 14223
(2012/02/01)
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