Atropo-Diastereoselective Cleavage of Configurationally Unstable Biaryl Lactones with Alkali Metal Activated Primary 1-Arylethylamines

Abstract

The atropo-diastereoselective cleavage of lactone-bridged and thus configurationally unstable biaryls with chiral metal-activated 1-arylethylamines gives axially chiral biaryl amides in good yields and high atropo-diastereomeric ratios of up to 95:5. In this methodology, even the minor not desired rotational isomer can be recycled literally by recyclization back to the configurationally unstable lactone, and renewed stereoselective cleavage. Furthermore, by the use of the corresponding enantiomer of the N-nucleophile, the enantiomeric biaryl product is also attainable from the same lactone precursor (ªatropo-divergenceº). In addition, several methods have been developed to transform the amide function into a methyl or an aminomethylene group. All these options further enlarge the scope and the utility of the method elaborated.

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

“…The second crucial step requires the atroposelective transformation of the axially prostereogenic lactones 33 into configurationally stable biaryl compounds, which can be achieved simply by cleavage of the bridge with chiral O, N, or H nucleophiles (Scheme ) 20. 229, 230 Potassium ( S )‐1‐phenylethylamide (( S )‐ 259 ) and sodium ( R )‐menthoxide (( R )‐ 261 ) were the N and O nucleophiles of choice for the atropodiastereoselective ring opening of 33 b and 33 c , leading to the respective biaryl amides 258 and esters 260 in good yields (70–97 %) and diastereoselectivity (74–90 % de ) 231–233. Almost complete control of the configuration at the biaryl axis was attained in the atropodiastereoselective cleavage of 33 c with the sterically more demanding sodium ( R )‐8‐phenylmenthoxide (( R )‐ 262 ), delivering exclusively the ester ( M , R ) ‐ 263 c in 95 % yield 232…”

The Lactone Concept: An Efficient Pathway to Axially Chiral Natural Products and Useful Reagents

“…The good crystallization properties of the amides furthermore allowed X-ray structure analyses of several of the products to be performed, which established their relative and (given the known centrochirality of the reagent) absolute axial configuration; for an example, see Scheme 2 (cf also Section 4). 40 Other 1-nucleophiles, e.g. the likewise commercially available 1-(1-naphthyl)ethylamine (, M = H) or 2,3,4trimethoxyphenylethylamine (, M = H), which can be easily prepared by stereoselective reductive amination of the corresponding ketone (cf.…”

“…Scheme 27), 41 were also tested and gave comparably good results (dr up to 93:7), again best with potassium as the counter ion (Scheme 3). 33,37,40 The availability of these nucleophiles in both enantiomeric forms again allows one to establish any axial configuration starting from the same lactone precursor .…”

“…of HQW-3-F, can be removed either with or without rupture of the 'new' &,1-bond (Scheme 4), giving rise to 3-F (via the secondary amine 0-F) or, optionally, 0F (via the nitrile 0-F) both without any decrease in stereochemical purity. 40 5LQJ2SHQLQJ 5HDFWLRQV ZLWK 0HWDODWHG 21XFOHRSKLOHV…”

The ‘lactone method’: enantioselective preparation of novel P,N-biaryl ligands and their use in the synthesis of the biarylic alkaloids, ancistrotanzanine B and ancistroealaine A

“…11 As an example, reaction of 6c (R¼Me) with potassium (R)-1-phenylethylamide [(R)-11] gives the amide (M,R)-12c in 85% yield and with 90% de. 17 With the O-nucleophile sodium (1R)-8-phenylmenthoxide [(R)-13c], the ester (M,R)-14c is obtained in 95% yield and with an excellent de of .98%. 18 The atropo-enantioselective CBS-reduction 20 of 6c delivers the diol (M)-16c in 94% yield and with 97% ee.…”