Further Studies toward the Stereocontrolled Synthesis of Silicon-Containing Peptide Mimics

Abstract

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.

Silylated Pyrrolidines as Catalysts for Asymmetric Michael Additions of Aldehydes to Nitroolefins

“…and further investigated independently by the groups of O’Brien and Coldham 12. Their optimized procedure was employed here for the preparation of silylated N ‐Boc‐pyrrolidines 1 a – d (Scheme ) 13. In accordance with the literature, products 1 a and 1 b were obtained with high enantioselectivities in good yields 12.…”

Structure‐Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

“…[21] The latter was explored, as it offers a safe and convenient method to access βamino acid derived substrates without the use of either toxic/ explosive diazomethane or pressurized hydrogen. [22] Central intermediate 6 (Scheme 1) was synthesized by reduction of 4-(trifluoromethyl)phenylacetic acid with LiAlH 4 and subsequent oxidation using 2-iodoxybenzoic acid (IBX) [23] to give 2-(4-(trifluoromethyl)phenyl)acetaldehyde, which was condensed with (S)-(À )-2-methyl-2-propanesulfinamide using catalytic pyridinium p-toluenesulfonate (PPTS) [24] to give the corresponding N-tert-butanesulfinyl imine 4 in 57 % yield over two steps. Next, diastereoselective addition of dimethyl malonate (DMM) to neat 4 in presence of NaI [22a] produced 5 in moderate yield.…”

“…Since a substituent in the meta-position of the phenylacetamide appeared to be favored, we directed our attention at exploring substituents in this position. Replacement of the electron withdrawing chloro by the similarly sized electron donating methyl (19) maintained potency, whereas larger metasubstituents, including the electron withdrawing, hydrophobic trifluoromethyl (20), the more polar, electron donating methoxy (21), and the planar naphthyl (22), benzothiophene (23) and indole (24) led to decreased potency, suggesting that increased steric bulk is generally disfavored, whereas electron donating or withdrawing properties seem less important.…”

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…Application of this methodology allowed the stereocontrolled synthesis of a series of silicon-containing peptide mimics, including a potential inhibitor of the human neutrophil elastase as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide [58,59].…”