Synthesis of 10-Aza-9-oxakalkitoxin by N–O Bond Formation

Abstract

We describe a formal synthesis of 10-aza-9-oxakalkitoxin, the hydroxalog of the cytotoxic marine natural product kalkitoxin, that features Mukaiyama Markovnikov silyl peroxidation of a terminal alkene and N–O bond formation as the central enabling steps.

Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer

“…To our knowledge, there is only one actual small-molecule pharmaceutical containing the trisubstituted hydroxylamine moiety: the tetracycline, Sarecycline . To access novel chemical space accessible to trisubstituted hydroxylamines, we have developed synthetic strategies for their assembly by direct N–O bond formation. − Using this method, we conducted a matched molecular pair (MMP) analysis to assess the early absorption, distribution, metabolism, and excretion (ADME) parameters of trisubstituted hydroxylamines and found them to exhibit unique properties that include similarities in lipophilicity to morpholine units . This suggested that trisubstituted hydroxylamines could serve as a novel bioisosteric modification of nitrogen heterocycles, which have received little attention in bioisosteric design compared to carbocycles, − but which are present in roughly 60% of unique small-molecule drugs .…”

The N,N,O-Trisubstituted Hydroxylamine Isostere and Its Influence on Lipophilicity and Related Parameters

“…Motivated by these results, we developed , synthetic methods to access the trisubstituted hydroxyl­amine moiety by N–O bond formation from 1°, 2°, and 3° alcohols and 2° amines, thereby providing concise, convergent approaches to this isostere . We now report a matched molecular pair (MMP) , analysis of the effect of N,N,O -trisubstituted hydroxyl­amine incorporation on lipophilicity using scaffolds present in small molecules, ranging from the pre-clinical to FDA-approved status, and reveal that in most cases the N,N,O -trisubstituted hydroxyl­amine moiety decreases lipophilicity in carbon–carbon bond replacements to a degree similar to that obtained by tertiary amine incorporation.…”

“…41 Accordingly, 2-tetralone (21) was reduced in 74% yield to the alcohol (25) and coupled with valeric acid in 75% yield to give ester (26). Partial reduction and in situ acetylation afforded a 60% yield of the α-acetoxyacetal (27), which gave the desired ether (28) in 79% yield on reduction with BF 3 •OEt 2 and Et 3 SiH. Hydroxylamine (31) was prepared by conversion of 5-pentanol (29) to the MTHP monoperoxyacetal (30) in 59% yield, followed by treatment with a 1,2,3,4-tetrahydroisoquinoline-derived magnesium salt in 81% yield.…”

Recent Advances in the Synthesis of Di- and Trisubstituted Hydroxylamines

“…Compatible functional groups included internal alkenes ( 172 ), internal alkynes ( 173 ), aryl halides ( 174 ), complex carbohydrates ( 175 ), azides ( 178 ), or basic nitrogen heterocycles ( 179 ), all of which generally gave excellent yields (up to 98%) ( Scheme 18 A). Importantly, the reaction was also applicable in total synthesis as demonstrated by 10-aza-9-oxakalkitoxin ( 182 ), a hydroxylamine analog (hydroxalog) of the marine natural product kalkitoxin, that was synthesized in 16 steps using direct N-O bond formation as a key step [ 91 ], representing a marked improvement to Crich’s original 25 step synthesis of this molecule ( Scheme 18 B) [ 92 ].…”