Abstract
A diastereoselective allylation of N-tert-butane sulfinyl α-iminoesters using allylboronic acids is developed to obtain optically active non-proteinogenic α-amino acid precursors in good yields and diastereoselectivities. Gram-scale synthesis, broad tolerance of functional groups, excellent stereodivergence, post-synthetic modifications, and easy removal of the chiral auxiliary are some of the key highlights. The protocol is applicable to various amino acids and short peptides, resulting in the incorporation of these precursors at the N-terminal position.
Highlights
With 60 peptide-based drugs in the market, over 150 in the clinical trial, and another 400 in preclinical development, the peptide-based drug market is having an estimated US$ 25.4 billion of worth as of 2018 (Figure 1).[1]
Over the past few years, the optically pure non-proteinogenic α-amino acids (NPAA) have emerged as alternatives to fill the void that was left by their natural counterparts and spans its noteworthiness over a significant area of biological importance such as intermediates in biosynthesis, post-translationally formed in proteins, and possess a significant role in drug discovery.[2]
Reported a highly regioselective and diastereoselective propargylation of N-sulfinyl-α-iminoester using pinacol allenylboronate and potassium allenyltrifluoroborate which results in an inseparable mixture of both propargylated and allenylated products (Scheme 1b).7k Recently, allylboronic acids have emerged as a powerful alternative to their allylboronate counterpart due to the more Lewis acidic boron atom which results in a more organized transition state leading to greater stereocontrol and diastereo- and enantioselective allylation of different acyclic and cyclic imines and hydrazonoesters were developed.[9]
Summary
With 60 peptide-based drugs in the market, over 150 in the clinical trial, and another 400 in preclinical development, the peptide-based drug market is having an estimated US$ 25.4 billion of worth as of 2018 (Figure 1).[1]. Tin/boronate reagents where the diastereoselectivity is controlled by the chiral auxiliary group attached to the imine nitrogen atom (Scheme 1a).[7] incompatibility of several critical functional groups, geometrical instability of allyl nucleophiles, tedious synthetic efforts, and substoichiometric usage of organometallic reagents allured chemists to look for other alternative reagents. In conjunction with our recent interest in the total synthesis of hapalindole alkaloids, we report a mild, diastereoselective allylation protocol of N-tert-butane sulfinyliminoester using allylboronic. Tedious synthetic efforts geometrical instability of allyl Nu b) In-catalyzed propargylation: (Pyne et al 2016) O
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