Asymmetric Synthesis of Amines

Asymmetric Synthesis of Amines

The Ellman group has developed a practical and general method for the asymmetric synthesis of amines (Figure 1), which are one of the most important functionalities found in drugs. The method is based upon the use of enantiomerically pure tert-butanesulfinamide, which is prepared by catalytic enantioselective methods in two steps in 70-72% overall yield from inexpensive starting materials. The amine synthesis chemistry that we have developed has become very popular due to a number of desirable aspects: (1) Direct condensation of tert-butanesulfinamide with aldehydes and ketones with a wide range of steric and electronic properties proceeds in high yields under mild conditions. In contrast to most imines, N-sulfinyl imines are hydrolytically stable and do not tautomerize to enamines and therefore can easily be manipulated, stored, extracted, or chromatographed. (2) The electronegative N-sulfinyl group enhances the electrophilicity of the imine resulting in very high yields for the addition of a wide range of nucleophiles such as organometallic reagents and enolates. Significantly, side reactions that typically plague nucleophilic additions to imines, such as competitive deprotonation, are minimized. (3) The chiral N-sulfinyl group usually provides high diastereoselectivity. (4) The N-sulfinyl group is readily cleaved from the addition products to provide amine hydrochlorides in very high yields. A wide variety of amine containing compounds have been prepared using this chemistry, including branched amines, dibranched amines, 1,2- and 1,3-amino alcohols, highly substituted beta-amino acids, and of alpha,alpha-disubstituted alpha-amino acids.

Figure 1. Asymmetric synthesis of amines using tert-butanesulfinamide

tert-Butanesulfinamide-based methods are now among the most extensively used methods for the preparation of amine containing compounds. Indeed, academic and industrial laboratories have filed over 300 patents where tert-butanesulfinamide has been employed in wide ranging applications, including the discovery of numerous drug candidates and the large scale production of many candidates for clinical trials. Moreover, due to the very high demand of the reagent, over 40 chemical suppliers now market tert-butanesulfinamide, and a large majority of these suppliers rely on our process for its preparation, including those companies such as Allychem with ton scale production capacity.

We have significantly expanded on the utility of tert-butanesulfinamide chemistry by the deprotonation of N-sulfinyl ketimines to provide metalloenamines, which then add with high diastereoselectivity to electrophiles. Nucleophiles are then added to the imine products to provide rapid access to densely functionalized amine containing compounds. For example, this approach has been developed to provide a highly convergent and stereoselective synthesis of each of the four possible stereoisomeric 1,3-amino alcohols (Figure 2).

Figure 2. Asymmetric synthesis of syn- and anti-1,3-amino alcohols

We have applied tert-butanesulfinamide chemistry to the asymmetric syntheses of a number of natural products and drug candidates (Figure 3). Recently, we completed the 1^st total synthesis of the potential anticancer agent tubulysin D, which has exceptionally potent cell growth inhibitory activity that exceeds the important anticancer agents the epothilones, vinblastine, and taxol by a factor of 20 to 1000-fold. Our synthesis has enabled us to define the essential features of the natural product necessary for biological activity against a series of human and animal cancer cell lines. Moreover, by identifying functionality that surprisingly is not necessary for activity, highly potent cell-growth inhibitors have been developed that are smaller and considerably more stable than tubulysin D.

Figure 3. Natural products and drug candidates synthesized using tert-butanesulfinamide

Asymmetric Catalysis

The vast majority of chiral ligands utilized in enantioselective catalysis rely on chiral carbon centers for stereochemical induction. In contrast, ligands incorporating chirality solely at sulfur have been much less well developed. Sulfinyl imines should serve as versatile donor ligands for enantioselective catalysis due to their ease of synthesis, chirality about sulfur, and the potential for metal coordination through the N, S, and O atoms. We therefore explored several ligand classes (Figure 4), which incorporate the N-sulfinyl imine structure. Cu(I) complexes of 7 provide extremely high enantio- and diasteroselectivities in enantioselective catalytic Diels Alder reactions, and for select substrates, the P,N-ligand 8 provides high enantioselectivities in palladium-catalyzed allylic substitution reactions and iridium-catalyzed hydrogenations of unfunctionalized alkenes. The x-ray crystal structures of several catalysts were determined with metal coordination being observed to the N, S or O atoms depending upon the metal, oxidation state, and ligand structure. In very recent work, we have also developed new classes of sulfinamide-based organocatalysts that promise to be highly effective for catalyzing a range of different asymmetric transformations.

Figure 4. Chiral N-sulfinyl-based ligands for enantioselective catalysis