Diastereoselective Synthesis of the Aminocyclitol Core of Jogyamycin via an Allene Aziridination Strategy.

Oxidative allene amination provides rapid access to densely functionalized amine-containing stereotriads through highly reactive bicyclic methyleneaziridine intermediates. This strategy has been demonstrated as a viable approach for the construction of the densely functionalized aminocyclitol core of jogyamycin, a natural product with potent antiprotozoal activity. Importantly, the flexibility of oxidative allene amination will enable the syntheses of modified aminocyclitol analogues of the jogyamycin core.

Aminodiols via stereocontrolled oxidation of methyleneaziridines.

A highly diastereoselective Ru-catalyzed oxidation/reduction sequence of bicyclic methyleneaziridines provides a facile route to complex 1-amino-2,3-diol motifs. The relative anti stereochemistry between the amine and the vicinal alcohol are proposed to result from 1,3-bischelation in the transition state by the C1 and C3 heteroatoms.

Tunable, chemoselective amination via silver catalysis.

Organic N-containing compounds, including amines, are essential components of many biologically and pharmaceutically important molecules. One strategy for introducing nitrogen into substrates with multiple reactive bonds is to insert a monovalent N fragment (nitrene or nitrenoid) into a C-H bond or add it directly to a C═C bond. However, it has been challenging to develop well-defined catalysts capable of promoting predictable and chemoselective aminations solely through reagent control. Herein, we report remarkable chemoselective aminations that employ a single metal (Ag) and a single ligand (phenanthroline) to promote either aziridination or C-H insertion by manipulating the coordination geometry of the active catalysts.

Chemoselective allene aziridination via Ag(I) catalysis.

Allene aziridination generates useful bicyclic methylene aziridine scaffolds that can be flexibly transformed into a range of stereochemically complex and densely functionalized amine-containing stereotriads. The scope of this chemistry has been limited by the poor chemoselectivity that often results when typical dinuclear Rh(II) catalysts are employed with homoallenic carbamates. Herein, Ag(I) catalysts that significantly improve the scope and yield of bicyclic methylene aziridines that can be prepared via allene aziridination are described.

Beyond benzyl grignards: facile generation of benzyl carbanions from styrenes.

Benzylic functionalization is a convenient approach towards the conversion of readily available aromatic hydrocarbon feedstocks into more useful molecules. However, the formation of carbanionic benzyl species from benzyl halides or similar precursors is far from trivial. An alternative approach is the direct reaction of a styrene with a suitable coupling partner, but these reactions often involve the use of precious-metal transition-metal catalysts. Herein, we report the facile and convenient generation of reactive benzyl anionic species from styrenes. A Cu(I)-catalyzed Markovnikov hydroboration of the styrenic double bond by using a bulky pinacol borane source is followed by treatment with KOtBu to facilitate a sterically induced cleavage of the C-B bond to produce a benzylic carbanion. Quenching this intermediate with a variety of electrophiles, including CO(2), CS(2), isocyanates, and isothiocyanates, promotes C-C bond formation at the benzylic carbon atom. The utility of this methodology was demonstrated in a three-step, two-pot synthesis of the nonsteroidal anti-inflammatory drug (±)-flurbiprofen.

Synthesis of 1,3-diaminated stereotriads via rearrangement of 1,4-diazaspiro[2.2]pentanes.

The synthesis of 1,3-diaminated stereotriads via the bis-aziridination of allenes is reported. The reactive 1,4-diazaspiro[2.2]pentane intermediates undergo a mild Brønsted acid-promoted rearrangement to yield 1,3-diaminated ketones in good yields with excellent stereocontrol. Directed reduction of the ketone can be achieved to yield a C-N/C-O/C-N stereotriad in high dr. The ability to transfer the axial chirality of the substrates to the products allows for the facile preparation of enantioenriched stereotriads from allenes in two simple steps.

1,4-Diazaspiro[2.2]pentanes as a flexible platform for the synthesis of diamine-bearing stereotriads.

Nitrogen-containing stereotriads occur in a number of biologically active compounds, but general and flexible methods to access these compounds are limited mainly to the manipulation of chiral olefins. An alternative approach is to employ a highly chemo-, regio-, and stereocontrolled allene oxidation that can install a new carbon-heteroatom bond at each of the three original allene carbons. In this paper, an intramolecular/intermolecular allene bis-aziridination is described that offers the potential to serve as a key step for the construction of stereotriads containing vicinal diaminated motifs. The resultant 1,4-diazaspiro[2.2]pentane (DASP) scaffolds contain two electronically differentiated aziridines that undergo highly regioselective ring openings at C1 with a variety of heteroatom nucleophiles to give chiral N,N-aminals. Alternatively, the same DASP intermediate can be induced to undergo a double ring-opening reaction at both C1 and C3 to yield vicinal diaminated products corresponding to formal ring opening at C3. The chirality of a propargyl alcohol is easily transferred to the DASP with good fidelity, providing a new paradigm for the construction of enantioenriched nitrogen-containing stereotriads.

α,ß-Unsaturated imines via Ru-catalyzed coupling of allylic alcohols and amines.

A convenient synthesis of α,ß-unsaturated imines requiring only an allylic alcohol, an amine and a Ru catalyst has been developed. The use of large excesses of oxidant and the purification of sensitive intermediates can be avoided.

Synthesis of propargylic and allenic carbamates via the C-H amination of alkynes.

Propargylic amines are important intermediates for the synthesis of nitrogen-containing heterocycles. The insertion of a nitrene into a propargylic C-H bond has not been explored, despite the attention directed toward the Rh-catalyzed amination of other types of C-H bonds. In this communication, the conversion of a series of homopropargylic carbamates to propargylic carbamates and aminated allenes is described.