Resolution of aryl-H-phosphinates applied in the synthesis of P-stereogenic compounds including a Brønsted acid NMR solvating agent

Abstract

A library of racemic H-phosphinates incorporating a variety of alkoxy groups or substituted aryl groups was prepared. Starting with a resolving agent screening, an efficient enantioseparation method was developed and...

Enantioseparation of P-Stereogenic 1-Adamantyl Arylthiophosphonates and Their Stereospecific Transformation to 1-Adamantyl Aryl-H-phosphinates

“…However, the crystals were a non-centrosymmetric twin, and the ( S ) absolute configuration of the P -stereogenic center was established during the measurement ( Figure 1 ). In this manner, the (−) sign of optical rotation could be linked to an ( S ) absolute P -configuration for ( S )-1-adamantyl phenylphosphonothioic acid (( S )- 2a ), whose correlation was postulated in our previous paper [ 25 ] on the basis of the literature analogy [ 21 ]. The absolute configurations of the ( S )-1-adamantyl (4-methoxyphenyl)phosphonothioic acid (( S )- 2b ) and ( S )-1-adamantyl (4-trifluoromethyphenyl)phosphonothioic acid (( S )- 2c ) could not be verified by XRD measurements, but an ( S ) absolute configuration was assigned to the (−) sign of optical rotation on the basis of structural similarity with compound ( S )- 2a .…”

“…The 1-adamantyl aryl- H -phosphinates ( 1 ) were synthesized according to a literature procedure [ 24 ]. In our previous paper [ 25 ], the synthesis of 1-adamantyl phenylthiophosphonic acid ( 2a ) was reported by reacting 1-adamantyl phenyl- H -phosphinate ( 1a ) with elemental sulfur at room temperature in the presence of triethylamine. However, it was found that the reaction is faster, and the purification is more efficient, when the H -phosphinates ( 1 ) are refluxed in THF with elemental sulfur without any base, and the crude thiophosphonate ( 2 ) is purified as a diethylamine salt ( 2 ꞏEt 2 NH), which is followed by an acidic liberation step [ 46 ].…”

“…Considering the preparation of chiral H -phosphinates, separation of the covalent diastereomers of menthyl H -phosphinates or optical resolutions using either chiral HPLC or resolving agents are the most frequently used methods [ 17 , 18 , 21 , 22 , 23 , 24 , 25 ]. As H -phosphinates usually lack acidic or basic functional groups, enantioseparation via diasteromeric complex formation applying neutral resolving agents is the method of choice [ 25 ]. On the other hand, phosphothionates can be regarded as acidic derivatives of H -phosphinates that can be separated into their enantiomers using chiral bases [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

“…Our recent research interest involved the preparation of optically active P -stereogenic >P(O)H intermediates, such as secondary phosphine oxides and H -phosphinates [ 25 , 43 ]. Our previous paper described the direct enantioseparation of chiral H -phosphinates ( 1 ), but the scope of that method was limited towards H -phosphinates ( 1 ) bearing a substituted aryl moiety [ 25 ].…”

“…Our recent research interest involved the preparation of optically active P -stereogenic >P(O)H intermediates, such as secondary phosphine oxides and H -phosphinates [ 25 , 43 ]. Our previous paper described the direct enantioseparation of chiral H -phosphinates ( 1 ), but the scope of that method was limited towards H -phosphinates ( 1 ) bearing a substituted aryl moiety [ 25 ]. Thus, the current aim of our work was to develop a complementary optical resolution strategy for such compounds ( 1 ) using the corresponding arylthiophosphonates ( 2 ) as key intermediates.…”