Diastereoselective Reductive Amination of Aryl Trifluoromethyl Ketones and α‐Amino Esters

Abstract

The optimization of new drug entities depends on the manipulation of the potency, selectivity, adsorption, and metabolic properties of lead structures. One of the most commonly employed strategies for accomplishing these objectives involves the incorporation of fluorinated moieties into drug candidates, which often has a profound influence on their in vivo performance.[1] As such, there has been intense interest in the stereoselective inclusion of fluorinated fragments into small organic molecules.[2] One particularly important functionality employed in these endeavors is the bulky and highly electron withdrawing trifluoromethyl group, which is capable of dramatically perturbing the electronic properties of neighboring atoms. Given the ubiquitous nature of a-amino acids in biologically active compounds, it is not surprising that there have been a number of reports describing the stereoselective incorporation of the trifluoromethyl group into simple amino acids, as well as more complex polypeptides. [3] In this way, Zanda and co-workers have shown that 2,2,2-trifluoroethylamines can act as a nonbasic amide surrogate, and have made use of this strategy in the development of novel peptidomimetics. [3a-e] This approach has also recently been employed in the development of potent and selective cathepsin K inhibitors for the treatment of osteoporosis, where the planar amide functionality of the parent compound A has been replaced with a stereogenic 2,2,2-trifluoroethyl moiety (Scheme 1).[4] Amidation of the S,S isomer B of these novel a-amino acids affords particularly potent cathepsin K inhibitors, but it is likely that future applications would benefit from stereoselective access to either isomer of this intriguing class of compounds.While a number of methods for preparing the corresponding b-amino alcohols C from 1,3-oxazolines D have been described in the literature (Scheme 1), [4,5] these approaches have a number of drawbacks. Initial reports involved condensation of trifluoroacetadehyde hemiacetals and b-amino alcohols to afford approximately 1.5:1 mixtures of diastereomeric oxazolines (Scheme 1, R 4 = H).[5b] Chromatographic separation of the diastereomers, followed by stereoselective addition of an organolithium species then afforded the desired amino alcohols with excellent levels of diastereoselectivity. Recent reports from our research describe alternative protocols which avoid the need for the separation of the diastereomeric oxazolines; [4b, 5a, 6] however, these methodologies still require the use of expensive trifluoroacetaldehyde hemiacetals, are limited to substrates containing functionality which is compatible with organolithium reagents, and require oxidation of the amino alcohols to the amino acids. Mikami and co-workers have shown that 1,3-oxazolines derived from readily available trifluoroacetophenones can be converted into the same types of amino alcohols by selective reduction (Scheme 1, R 4 = Ar); [5c] however, this approach again relies on the chromatographic separation of mixtures of dias...

Enantioselective Synthesis of α‐Trifluoromethyl Arylmethylamines by Ruthenium‐Catalyzed Transfer Hydrogenation Reaction

“…More recently, Benaglia’s group proposed the enantioselective Lewis base‐organocatalyzed hydrosilylation of not only aryl but also alkyl ketimines by means of trichlorosilane in up to 98% ee 12. Diastereoselective reductive aminations were also reported exploiting either simple amino acids13 or N ‐ tert ‐butanesulfinamide14 as chiral auxiliaries to get high dr values. In addition, N ‐benzyl trifluoromethyl ketimines were catalytically isomerized into α‐trifluoromethyl amines with the aid of chiral bases 15.…”