1,4-Diazaspiro[2.2]pentanes as a Flexible Platform for the Synthesis of Diamine-Bearing Stereotriads

Abstract

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.

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

“…We previously leveraged the unusual strain (~42 kcal/mol) in methyleneaziridine 1a to achieve a formal [3+1] reaction to furnish methyleneazetidine 1d upon exposure to rhodium-supported carbene 1b ( Fig. 2a) [55][56][57][58][59][60][61][62] . Mechanistic studies support initial formation of the aziridinium ylide 1c, which subsequently undergoes a highly asynchronous, concerted [2,3]-Stevens rearrangement to form 1d 63 .…”

Stereocontrolled Synthesis of 1,3‐Diamino‐2‐ols by Aminohydroxylation of Bicyclic Methylene‐Aziridines

“…The successful implementation of this second‐generation synthesis required achieving a stereo‐ and regioselective aminohydroxylation to form an N,O‐aminal intermediate capable of stereoselective rearrangement to 1,3‐diaminoketone 2a . As our previous reports on the reactivity of methylene‐aziridines demonstrated that the concavity of this unusual fused heterocycle can promote highly diastereoselective reactions of the exocyclic olefin, this strategy warranted further investigation 2c…”

Synthesis and applications of methyleneaziridines

“…Treatment of bicyclic MAs 189 with N-aminophthalimide in the presence of PhIO gave diazaspiro [2.2]pentane (DASP) 80 products 190 with complete facial selectivity (Scheme 54). 81 It's worth noting that the ability to electronically differentiate between the two aziridine rings of the DASPs enabled regioselective ring opening at the terminal carbon of either aziridine depending on the reaction conditions. Mostly, the addition of nucleophiles to the DASP typically favored ring-opening at C1 position to give N,N-aminal products 194 (Scheme 55).…”