Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via Rhodium-Catalyzed Asymmetric Hydrogenation of β-Difluorophosphonomethyl α-(Acylamino)acrylates

Abstract

A novel and facile synthetic strategy for α,α-difluorinated phosphonate mimetics of phosphoserine/phosphothreonine utilizing rhodium-catalyzed asymmetric hydrogenation was developed. The dehydrogenated substrate β-difluorophosphonomethyl α-(acylamino)acrylates were first prepared from protected serine/threonine followed by asymmetric hydrogenation using the rhodium-DuPhos catalytic system to generate the chiral center(s). These important phosphonate building blocks were successfully incorporated into phosphatase-resistant peptides, which displayed similar inhibition to the 14-3-3 ζ protein as the parent pSer/pThr peptides.

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

“…For example, Chen and co‐workers recently reported a Cu‐mediated cross‐coupling of BrZnCF 2 P(O)(OEt) 2 with 2‐amino‐3‐halogenoacrylates in the synthesis of CF 2 ‐phosphonate mimetics of phosphoserine 68 and phosphothreonine 69 (Scheme 26). [125] In another instance, Kennedy and co‐workers used this reaction to prepare potent and orally active naphthalene‐based PTP1B inhibitors [126] …”

Phosphorus-containing amino acids with a P–C bond in the side chain or a P–O, P–S or P–N bond: from synthesis to applications

“…The synthesis of CF 2 -substituted pSer and pThr mimics reported in 2018 by Chen et al illustrates recent progress in this area. 79 The key step of this synthesis is the substitution of the iodine and bromine a,b-dehydroamino esters 250 and 255, using the diuorophosphonate copper/zinc reagent 251, to afford the unsaturated intermediates 252 and 256 with 85% and 70% yields, respectively. These were subjected to asymmetric hydrogenation catalyzed by a rhodium/DuPhos complex and deprotected using TFA or HCl (9 N).…”

PermaPhosSer: autonomous synthesis of functional, permanently phosphorylated proteins

“…Because the electronegative F-atoms of F2-nhpSer (i) can be H-bond acceptors like the pSer -oxygen and (ii) lower the phosphonate pKa2 from in the 7 to 8 range to near 5.5 so that its charge at physiological pH is ~ -2 (like pSer), it is generally considered a better analog than nhpSer. In fact, reviews give the impression that nhpSer is not a useful mimic for these reasons 5,23 , yet the effectiveness of both has been established in the few studies in which they were incorporated into synthetic peptides 12,[24][25][26][27] and into proteins via semi-synthetic methods such as expressed protein ligation (EPL) [28][29][30][31] . For example, proteins Histone 2A 30 and AANAT 28 with nhpSer (but not Asp/Glu) installed at their N-termini by EPL were able to pull down 14-3-3, a pSer/pThr specific binding protein, from cellular extracts.…”