Mass spectrometric-based investigation of differentially protected azatryptophan derivatives using Orbitrap mass spectrometry: Differentiation of positional isomers under protonation and alkali-cationization conditions.

RATIONALE: Differentiation and structural characterization of positional isomers of differentially protected azatryptophan derivatives using electrospray ionization high-resolution tandem mass spectrometry (ESI-HRMS/MS) is important from the perspective of drug discovery research. Also, these derivatives can be used as building blocks for the synthesis of various biologically active compounds and have attracted significant attention in the field of modern drug discovery, especially peptide-based drugs, protein folding and protein-protein interactions because of their interesting spectral properties. METHODS: ESI-HRMS/MS in positive ionization mode was used to differentiate and characterize positional isomers of protected azatryptophan derivatives. RESULTS: ESI-HRMS/MS of [M + H]+ and [M + Na]+ ions of positional isomers of differentially protected azatryptophan derivatives display distinct fragmentation patterns. The MS/MS of [M + H]+ ion of isomer 1 showed an additional ion at m/z 358.0846 ([M + H-Boc-C14 H10 -HF]+ ) which was not present for 4. The fragment ion at m/z 332.0857 was observed for 1 and not for 4 which would be formed by the expulsion of butyloxycarbonyl (Boc) and fluorenylmethyloxycarbonyl (Fmoc) groups. Moreover, the ions 422.0812 and 378.0912 are found to be relatively more abundant for isomer 4 which could be probably attributed to the formation of stable ions. Similarly, other positional isomers exhibited distinct fragmentation from one another. CONCLUSIONS: The present study demonstrates that ESI-HRMS/MS can be used for differentiation and structural characterization of positional isomers of protected azatryptophan derivatives. The MS/MS of [M + H]+ and [M + Na]+ ions of these positional isomers displayed differences in their fragmentation behaviour. The impact of different substitutions at different positions (1 and 6) of protected azatryptophan derivatives (1-6) on their fragmentation behaviour was also investigated in detail. Also, the nitrogen atom at different positions in the pyrrolopyridine ring led to different fragmentation patterns.

Synthesis of Differentially Protected Azatryptophan Analogs via Pd2(dba)3/XPhos Catalyzed Negishi Coupling of N-Ts Azaindole Halides with Zinc Derivative from Fmoc-Protected tert-Butyl (R)-2-Amino-3-iodopropanoate.

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Negishi coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for the coupling of 1 with the zinc derivative of 2 to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate derivatives 3 in 69-91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and tBu, can be easily removed selectively.

Palladium-catalyzed dehydrogenative ß'-arylation of ß-keto esters under aerobic conditions: interplay of metal and Brønsted acids.

The Brønsted aids: The first dehydrogenative arylation of ß-keto esters with arenes under ambient aerobic conditions is described. Under a Pd(II)/Brønsted acid co-catalytic system, regioselective arylations with alkoxylated arenes and phenols were achieved in good yields, even in gram-scale conditions.

Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

Organocatalytic enantioselective domino Michael-aldol condensation of 5-oxoalkanal and alpha,beta-unsaturated aldehydes. Efficient assembly of densely functionalized cyclohexenes.

Organocatalytic Michael reaction of glutaraldehyde and 3-arylpropenal followed by the subsequent intramolecular aldol condensation provided 2-arylcyclohex-3-ene-1,3-dicarbaldehydes. Reactions with the 5-oxohexanal variant afforded the highly functionalized cyclohexenedicarbaldehydes in high diastereoselectivity and high enantioselectivity (>99% ee). Structure of the adduct 3j was confirmed unambiguously by X-ray analysis.

Enantioselective organocatalytic Michael-Wittig-Michael-Michael reaction: dichotomous construction of pentasubstituted cyclopentanecarbaldehydes and pentasubstituted cyclohexanecarbaldehydes.

Michael addition of carbethoxymethylenetriphenylphosphorane (a Wittig reagent) to nitroalkenes, followed by a reaction with ethyl formylformate and cinnamaldehydes, or formaldehyde and cinnamaldehydes, provided the respective pentasubstituted cyclopentanecarbaldehydes bearing a quaternary carbon center and pentasubstituted cyclohexanecarbaldehydes having five contiguous stereocenters with excellent enantioselectivities (up to >99% ee).

Organocatalytic enantioselective cascade Michael-Michael-Wittig reactions of phosphorus ylides: one-pot synthesis of the all-cis trisubstituted cyclohexenecarboxylates via the [1 + 2 + 3] annulation.

The stereoselective synthesis of all-cis 5-nitro-4,6-diphenylcyclohex-1-enecarboxylic ester has been achieved by an organocatalytic asymmetric Michael-Michael-Wittig cascade reaction of phosphorus ylides, nitroolefins, and alpha,beta-unsaturated aldehydes with excellent enantioselectivities (up to >99% ee).