In recent years, our search for new nitrogen transfer reactions has concentrated on aziridine chemistry. This Account highlights our efforts toward the synthesis and functionalization of aziridines. In the course of our research, we have investigated the electrochemical aziridination of olefins, the acid-catalyzed ring opening of aziridines, and the development of transition metal mediated nitrogen allylation, arylation, and alkenylation of unprotected aziridines. Our studies have also involved the synthesis of aziridine-based enamine intermediates and their stereoselective transformations into heterocyclic compounds.

An efficient method for the asymmetric gold(I)-catalyzed preparation of medium sized rings has been developed. The method provides 7-to 9-membered rings in excellent yield. High enantioselectivities can be achieved for 7-and 8-membered ring products employing chiral gold(I) complexes. The results provide insight into the mechanism, showing the fluxional nature of gold(I)-stabilized vinyl carbenoid intermediates.The construction of medium sized rings is an important and challenging goal in organic synthesis. 1 Transition metal catalyzed cycloisomerization and cycloaddition reactions are powerful methods to access these ring systems. 2 However, only a few of these methods are applicable to the enantioselective synthesis of medium-sized rings. 3 Although cyclization with rhodium carbenes generated from diazo-precursors has provided some limited success, dimerization can be a significant problem. 4 On the other hand, dimerization of the propargyl ester derived gold(I)-carbenoid is absent in the gold(I)-catalyzed asymmetric olefin cyclopropanation reaction (eq 1). 5a Moreover, the reactions of propargyl esters represent a rare class of gold-catalyzed carbon-carbon bond forming transformations that work efficiently in an intermolecular sense. 5-7 Given this unique reactivity, we hypothesized that the goldcatalyzed olefin cyclopropanation reaction might provide an opportunity for the enantioselective preparation of medium-sized ring compounds, 5,6a despite the fact that enantioselective gold(I)-catalyzed enyne cycloisomerization reactions remain rare. 8(1)We were pleased to find that triphenylphosphinegold(I)-catalyzed the cycloisomerization of propargyl ester 3 to cycloheptene 4 in quantitative yield (eq 2). 9,10 A similar result was fdtoste@berkeley.edu. obtained for the formation of 8-membered ring 6 from propargyl ester 5. The gold-catalyzed intramolecular cyclopropanation reaction also allowed for the synthesis of a 9-membered ring, albeit in diminished yields. 11 Surprisingly, reaction of propargyl ester 1 provided 6-membered ring product 2 in only 10% yield. 12 Moreover, reaction of 3 or 5 in the presence of styrene only resulted in the intramolecular 7-or 8-membered ring products (4 and 6 respectively); no intermolecular cyclopropanation was observed. NIH Public Access(2)On the basis of these results we turned our attention towards the development of a catalytic enantioselective intramolecular cyclopropanation. To this end, we first examined the catalyst system developed for the intermolecular enantioselective cyclopropanation reaction (eq 1); however, we were disappointed to find that under these conditions cyclooctene 10 was formed with very low enantiomeric excess (Table 1, entry 1). Further experiments found that the BINAP family of ligands was optimal with xylyl-BINAP giving the highest enantioselectivity (entries 2-4). In contrast to the intermolecular reaction in which pivaloate esters were required to achieve high enantioselectivity, acetate ester 9 afforded the cyclopropane with noticeably bett...

A comparative investigation into palladium-catalyzed allylic amination of unsubstituted aziridines and secondary amines has been carried out. The use of NH aziridines as nucleophiles favors formation of valuable branched products in the case of aliphatic allyl acetates. The regioselectivity of this reaction is opposite to that observed when other amines are used as nucleophiles. Our study provides evidence for the palladium-catalyzed isomerization of the branched (kinetic) product formed with common secondary amines into the thermodynamic (linear) product. In contrast, the branched allyl products obtained from unsubstituted aziridines do not undergo the isomerization process. Crossover experiments indicate that the isomerization of branched allylamines is bimolecular and is catalyzed by Pd(0). The reaction has significant solvent effect, giving the highest branched-to-linear ratios in THF. This finding can be explained by invoking the intermediacy of sigma-complexes, which is consistent with NMR data. The apparent stability of branched allyl aziridines towards palladium-catalyzed isomerization is attributed to a combination of factors that stem from a higher degree of s-character of the aziridine nitrogen compared to other amines. The reaction allows for regio- and enantioselective incorporation of aziridine rings into appropriately functionalized building blocks. The resulting methodology addresses an important issue of forming quaternary carbon centers next to nitrogen. The new insights into the mechanism of palladium-catalyzed allylic amination obtained in this study should facilitate synthesis of complex heterocycles, design of new ligands to control branched-to-linear ratio, as well as absolute stereochemistry of allylamines.

Transition-metal-catalyzed allylic amination has long been an area of intense research. 1 Allylamines have previously been prepared using iridium 2 and rhodium 3 catalysts with high selectivities for the branched products. On the other hand, the use of palladium in this chemistry has been known to produce linear allylamines with few notable exceptions. 4 This phenomenon has been obscure for some time. The goal of this contribution is to shed light on this long-standing problem and to evaluate ways of exercising control over selectivity with palladium catalysts.We recently demonstrated an instructive aberration in palladiumcatalyzed allylic amination: unsubstituted aziridines were found to give preferential formation of branched allylated products. 5 Mechanistic investigations indicate that amines other than aziridines undergo branched/linear (b/l) isomerization to form the thermodynamically more stable linear products. 5,6 It was found that protic acid generated during the reaction is the prerequisite for product isomerization. 5 Palladium coordination to the double bond of the protonated allylamine initiates ionization of the kinetically favored branched product (Figure 1). We consequently sought conditions under which the proton can be scavenged without detrimental effect on catalytic turnover such that the linear product formation can be suppressed.

The first transition metal-catalyzed asymmetric carboalkoxylation reaction of propargyl esters is described. The (R)-MeO-DTBM-BIPHEP(AuCl) 2 -catalyzed reactions allows for the construction of benzopyrans containing quaternary stereocenters with excellent enantioselectivity. Experimental evidence supports a mechanism proceeding via the generation of a stabilized carbocation from an allylic oxonium intermediate, and subsequent trapping by a chiral allylgold(I) spieces.The gold-catalyzed 1,2-rearrangement of propargyl esters has provided the basis for the development of a wide range of transformations. 1,2 These reactions are proposed to proceed through gold-stabilized cationic intermediates (A) that show reactivity analogous to electrophilic transition metal carbenoids. 3 Despite the current interest in reactions involving these intermediates, very few examples of enantioselective transformations have been described. We have recently reported that chiral biarylphosphinegold(I) complexes catalyze the enantioselective cyclopropanation of alkenes with propargyl esters (eq 1). 3c,i We hypothesized that related gold(I) complexes might exert enantioface control on the addition of nucleophiles to prochiral vinylcarbenoid intermediate A.(1)On the basis of reported 2,3-rearrangements of oxonium ylides generated from transition metalstabilized carbenoid intermediates, 4 we envisioned that allyl ethers might serve as nucleophiles towards the electrophilic gold(I)-carbenoid intermediate to generate chiral gold(I)-allyl B. We turned our attention to the gold(I)-catalyzed asymmetric synthesis of 2a. We were pleased to find that the complex employed in our gold(I)-catalyzed enantioselective cyclopropanation reaction afforded 2a in 59% yield and 97% ee (Table 1, entry 3). Moreover, the excellent enantioselectivity was maintained when nitromethane or dichloromethane 6 were employed as solvents; however acetonitrile generally provided higher yields of 2a. 7 As in the enantioselective cyclopropanation reaction, substitution on the phosphine aryl rings is critical to the obtaining the excellent enantioselectivity. For example, the unsubstituted (entry 6) or dimethyl-substituted (R)-MeO-BIPHEP(AuCl) 2 generated the benzopyran with only 30 % and 35% ee, respectively. 8 In contrast, when 3,5-di-tert-butyl MeO-BIPHEP derivatives were employed as ligands, the gold-catalyzed rearrangement proceeded with excellent enantioselectivity (entries 8 and 9). 9Under the optimized reaction conditions, substitution on the aryl ring was well tolerated. Propargyl pivaloate 1 having halogen (Table 2, entries 2 and 3), sterically demanding (entries 4 and 7), phenyl (entry 5), or electron-donating groups (entry 6) on the aromatic ring afforded 2 in good yields and with excellent enantioselectivities. 10,11 Use of substrates with bulkier substituents in the propargyl position decreased the rate of the reaction, however, enantioselectivities remained excellent in all cases (entries 8-10). 12 Of particular note is the reaction of allyl substituted e...