Organocatalysis, the use of chiral small-molecule organic compounds as activators for asymmetric reactions has found many recent successes in the literature. The use of proline, in particular, has been an example of an effective asymmetric catalyst. The discovery of general hydrogen-bonding chiral catalysis, a subset of organocatalysis has also been an exciting development in the field. The use of metal and complex chiral ligand environments still remain as the most common and successful strategy for asymmetric catalysis, but the organocatalytic advances do show the attractiveness of more simple approaches. The use of chiral Brønsted acids as catalysts has found, for the most part, only recent success. Conventional thinking was when a Brønsted acid protonated a substrate, to impart activation, the remaining chiral conjugate base would not associate closely enough to the substrate for good asymmetric induction to occur (Figure 1). This belief turned out to be incorrect as a number of selective systems have now been developed and further research is ongoing.
Additions to imines: Catalytic asymmetric additions of nucleophiles to imines have been a popular research direction for a number of academic groups, as the resulting chiral amines are highly desired products of value. The formation of C-C bonds through the addition of carbon nucleophiles in reactions such as imine aldol, aza-Henry, Staudinger, Strecker, and the addition of organometallics, for instance, have all provided for successful catalytic asymmetric reactions.
As a new approach to imine chemistry we envisioned the catalytic addition of nitrogen nucleophiles. This approach appeared to be somewhat analogous to recent conjugate additions of amides to enones (aza-Michael-type reactions, Figure 2) so we had a good inclination that this could be a successful catalytic reaction. The chemical literature shows that the addition of heteroatom nucleophiles to imines has relatively limited examples, with apparently few, if any, catalytic instances.
Figure 1: Chiral Acid-Catalysis. . . . . . . . . . Figure 2: Imine Amidation.
Addition of heteroatom nucleophiles to imines: The addition of amines and other nucleophiles from heteroatoms (N, O, P and S) to imines is not as prevalent in the literature as one would assume. Activated systems that did not require the use of a catalyst comprised many of the examples. Perhaps the earliest examples of such a transformation was the combination of benzaldehyde and two mole equivalents of urea to give a geminal diamide by Hugo Schiff in 1869. This strategy (directly from the aldehyde) is restricted as it can only provide two identical amides (geminal) in the addition. For the most part, the literature contains examples where amines add to doubly activated imines. An example of a case where an inactivated imine is reactive is the synthesis of a MacMillan imidazolidinone, where an alkyl amide adds in an intramolecular fashion to an imine using FeCl¬3. The most common groups bonded to the imine nitrogen were: formyl, acetyl, esters (carbamates) and sulfonyl groups. These reactions also required electron-withdrawing substituents off of the imine carbon (doubly activated) and these groups were most commonly: CX3, CHX2, or CH2X, and CO¬2¬R. With these activated substrates a variety of amines, oxygen nucleophiles, and sulfur nucleophiles could be added without a catalyst. Perhaps one study by Niceas Schamp contained the most examples of this addition. For the most part, the literature contains only limited studies on this topic. Generally, the apparent limitation on the imine caused many of the studies to be very specific for a particular activated substrate. Our laboratory is the first to exploit these types of catalytic asymmetric additions and this proposal details new results where we have now successfully added nitrogen, oxygen and phosphorus based nucleophiles in a highly enantioselective fashion to imines. The oxygen chemistry leads directly to valuable N,O hemiaminal products that could find potential synthetic utility (Figure 3).
Scheme 1: Preliminary Catalytic Asymmetric Alcohol Additions to Imines.
Figure 3: Select Natural Product with Chiral Hemiaminal Core Structures.
Acid Catalysis: The use of acids to catalyze the addition of nitrogen nucleophiles to imines is known but was not generally used in these types of additions. The use of protic acids that contained water (aqueous acids) cause hydrolysis of the imine substrate and this may be a possible reason that acids were not used. The use of anhydrous acids can provide activation without the unwanted hydrolysis of the starting material. To the best of our knowledge, no general study using acid-catalysis or metal-catalysis for this reaction was undertaken. The use of chiral acids or chiral metal-based catalysts in this process could provide enantioselective reactions that were not explored previously.
Applications: Previous methods in the literature to synthesize 1,1-bis-carbamates of this type have normally been made via Curtius or Hoffman-type rearrangements of protected amino acid derivatives. Incorporation of these geminal amides into a peptide chain results in the so-called retro-inverso peptides that Goodman popularized. Another method that has been reported for the synthesis of this type of aminal product is a benzotriazole-mediated approach by Katritzky. We believe our process to synthesize chiral protected N,N-aminals represents very new chemistry that could find synthetic applications. We would also like to use our chiral products from our N, O, or S based additions to enable us to set further stereochemistry.
Friedel-Crafts Additions of N-heterocycles to imines: Considerable success has been found thus far in the chiral phosphoric acid-catalyzed asymmetric addition of a variety of C-based nucleophiles to imines. Relatively soon after the initial reports by Akiyama and Terada a series of papers describing various chiral phosphoric acid-catalyzed methods were soon reported. Recently, Deng reported the first organocatalytic addition of indole to imines catalyzed by modified Cinchona alkaloid-based catalysts. Shortly thereafter S. You reported the analogous reaction catalyzed by chiral phosphoric acids. We have developed a competing chiral phosphoric acid-catalyzed process whereby substituted indoles and pyrroles can be added to imines with excellent yield, broad substrate scope, and with high enantioselectivity using imines that are more synthetically useful. The only other report showing the organocatalytic addition of other electron rich heterocycles to imines is the addition of a single furan by Terada.
Aziridine Chemistry: Aziridines, three-membered ring nitrogen-heterocycles, are attractive targets for methodological development due, in part, to their potential as chiral synthons via ring-opening strategies. Most strategies that utilize aziridines begin from chiral precursors that are used in their formation. A more attractive strategy for their use is the ring-opening of achiral meso-aziridines using chiral catalyst activation or the kinetic resolution of a racemic aziridine via catalytic ring-opening. All catalytic asymmetric ring-opening methods are, to our knowledge, are metal-based. Jacobsen was first to show that these reactions were possible using chiral Chromium based catalysts in the ring-opening with TMS-N¬3. Shibasaki later found that catalysts derived from lanthanides provide excellent enantioselectivity for this desymmetrization strategy with both TMS-CN and TMS-N3 as nucleophiles. Shibasaki, as an effort to demonstrate the synthetic potential of this process, synthesized Tamiflu using the desymmetrization as a key step. New Reactivity: We have found that chiral phosphoric acids can catalyze the ring-opening of meso-aziridines with excellent enantioselectivity and in high yield using TMS-N3 as the nucleophile (Table 1). Such a reaction provides a procedure whereby synthetically important, chiral 1,2-diamine analogues can be readily formed. While excellent 1,2-dihydroxylation methods are well known, the analogous diamination methods are not well known, so this approach to 1,2-diamines could find synthetic application.
Table 1: Brønsted Acid-Catalyzed Ring-Opening Desymmetrization of meso-Aziridines.