Nuno Maulide

The Redox-Neutral Approach to C-H Functionalization

The direct functionalization of C-H bonds is an attractive strategy in organic synthesis. Although several advances have been made in this area, the selective activation of inert sp(3) C-H bonds remains a daunting challenge. Recently, a new type of sp(3) C-H activation mode through internal hydride transfer has demonstrated the potential to activate remote sp(3) C-H linkages in an atom-economic manner. This Minireview attempts to classify recent advances in this area including the transition to non-activated sp(3) C-H bonds and asymmetric hydride transfers.

Sulfoxide-mediated α-arylation of carbonyl compounds.

A novel sulfoxide-mediated α-arylation of carbonyl compounds is reported. This reaction proceeds under very mild conditions at room temperature and does not require any transition-metal promoter or catalyst.

Gold-Catalyzed Synthesis of Furans and Furanones from Sulfur Ylides

Scheme 1 reveals a notable incidence of 3-carboxy-functionalized polysubstituted furans in the natural product cores, including furofuranone and -pyranone moieties (such as in angelone). Herein we report a simple and flexible gold-catalyzed synthesis of densely functionalized 3-carboxyfuran derivatives that hinges on a key cross-coupling between sulfonium ylides and alkynes. We further disclose an intriguing reactivity switch that allows the synthesis of furanones containing a quaternary center as well as computational data on the mechanism of these transformations. Initial studies focused on the alkynyl sulfonium ylide 1a, readily available by direct ylide transfer to the corresponding ketoester. Exposure of this compound to diverse gold(I) promoters led to sharply contrasting results (see the Supporting Information for details), and it was found that the simple combination of commercially available PPh3AuCl and AgSbF6 led to quantitative conversion into the furofuranone 2a at room temperature within 3 h. We then examined the scope of this simple yet highly effective procedure for the intramolecular preparation of bicyclic furans. Importantly, all the alkynyl sulfonium ylides employed as substrates could be readily accessed by direct ylide transfer in very high yields according to our previously reported procedure. Their stability towards chromatography and recrystallization along with their crystallinity renders them easily handled substrates for subsequent transformations. As shown in Table 1, a variety of bicyclofurans could be readily prepared by simply stirring the ylide precursors in the presence of the gold catalyst at room temperature. Importantly, the preparation of the furopyranone 2 i (Table 1, entry 9) required slightly modified conditions and the use of a different, more electron-poor phosphine, once again suggesting that less facile cyclizations of sulfonium ylides onto alkynes may be favored by the use of more electrondeficient gold(I) species. Various alkyl and aryl moieties were tolerated by the procedure, and furopyrrolones such as 2k could also be prepared by employing an amide-tethered alkyne. All-carbon tethers are also suitable for this transformation (Table 1, entry 12). To the best of our knowledge, this constitutes the first intramolecular synthesis of furans from stabilized sulfonium ylides. We then turned our interest to an intermolecular version of the same reaction. The double stabilization of our sulfonium ylides made some optimization of this process necessary, and some key results obtained are compiled in Scheme 2. The use of tBuXPhos as a ligand was required to obtain synthetically useful yields of product 5 a, particularly with regard to preventing excessive polymerization of phenylacetylene (4a ; Scheme 2a). The very high regioselectivity of this reaction is noteworthy, as only trace amounts of other regioisomers could be detected. Additionally, and in complementary fashion to the recent elegant report by Skyrdstrup et al. employing singly stabilized sulfonium ylides, we Scheme 1. Selected examples of natural products containing a furan core.

Sulfur(IV)-Mediated Transformations: From Ylide Transfer to Metal-Free Arylation of Carbonyl Compounds

The development of a direct ylide transfer to carbonyl derivatives and of a sulfoxide-mediated arylation is presented from a unified perspective. Mechanistic studies (including density functional calculations) support a common reaction pathway and showcase how subtle changes in reactant properties can lead to disparate and seemingly unrelated reaction outcomes.

Electrophilic Rearrangements of Chiral Amides: A Traceless Asymmetric α-Allylation

A one-pot protocol for the asymmetric α-allylation reaction is reported relying on a key efficient asymmetric Claisen rearrangement, triggered by electrophilic activation of chiral pseudoephedrine amides. Subsequent reduction or hydrolysis of the resulting iminium ions provides highly enantioenriched α-allylic aldehydes or carboxylic acids in a traceless manner. Compared to traditional alternatives which make use of strongly basic conditions, the work presented herein displays unprecedented functional group tolerance.

Direct Room‐Temperature Lactonisation of Alcohols and Ethers onto Amides: An “Amide Strategy” for Synthesis

The amide functional group is usually considered as the most robust and resistant of the carboxylic acid derivatives. As taught in standard organic chemistry undergraduate textbooks, the reduced electronegativity of the nitrogen atom in an amide (as compared to oxygen in esters or acids) results in more effective orbital overlap with the adjacent carbonyl, thus markedly reducing its electrophilic character. Therefore, it is not surprising that amide hydrolysis is a difficult transformation, which typically proceeds with notoriously long reaction times (t1/2 of >10 2 years at pH 7 and 25 8C in aqueous solution). Many elegant strategies have been developed to prepare so-called “twisted” amides, for which the aforementioned resonance stabilisation is greatly reduced by carefully designed strain elements and which have carbonyl reactivities akin to ketones. On the other hand, lactones form structural units within a large range of naturally occurring bio ACHTUNGTRENNUNGlogically active compounds, and many methods of lactone preparation have gained relevance over the past few decACHTUNGTRENNUNGades.[4] Nevertheless, the chemical synthesis of lactones of all ring sizes still relies predominantly on ring-closure techACHTUNGTRENNUNGniques starting from w-hydroxycarboxylic acids (seco-acids), esters or their activated derivatives, as evidenced by their prevalent use in the late stages of total synthesis efforts. Interestingly, in these strategies lactonisation is subordinate to two, often sequential, unproductive deprotection steps for both the alcohol and the carboxylic acid moieties prior to the actual lactonisation event, as exemplified by the selected examples shown in Scheme 1 a,b.

Diastereodivergent De-epimerization in Catalytic Asymmetric Allylic Alkylation

Diastereomers made to order: In an unprecedented ligand-controlled process a racemic mixture of four stereoisomers can be converted with high selectivity into each one of the diastereomers of the product, at will (see scheme). The mechanism of this deracemization of epimers, that is, a de-epimerization, was also studied.

Stereoselective intramolecular cyclopropanation through catalytic olefin activation

A novel stereoselective and convergent catalytic method for the cyclopropanation of electron-neutral and -rich olefins by sulfonium ylides is reported which unusually proceeds through olefin activation rather than by metal carbene formation.

Stereoselective Synthesis of Dienyl-Carboxylate Building Blocks: Formal Synthesis of Inthomycin C

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.

Dual nucleophilic/electrophilic capture of in situ generated iminium ethers: towards the synthesis of functionalized amide building blocks.

Rearranging its feathers: The transformation of simple linear amides into a diverse range of branched, functionalized products by conversion to iminium esters is followed by sequential treatment with nucleophiles and electrophiles (see scheme). The method takes advantage of a novel Claisen rearrangement and the use of aromatic substrates greatly facilitates the formation of the intermediate iminium ether.