SYNTHESIS OF ACID-LABILE GEMINAL BIS- AND TRISPHOSPHONIC ACIDS¹

The McKenna reaction – avoiding side reactions in phosphonate deprotection

“…BTMS is known for its chemoselectivity and cleaves phosphonate esters, without affecting carboxyester groups. However, the formation of phosphonic acids in the solvolysis step of the Mc Kenna reaction could lead to the cleavage of acid-labile groups [52,53]. In order to prevent this reaction, the solvolysis step commonly is performed in buffered solutions [53].…”

Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics

“…Similarly, a sodium salt of an acid-labile trisphosphonic acid 38 could be prepared with minimal P–C scission by carbonate-buffered hydrolysis of in situ formed silyl ester (Scheme 19) [43]. …”

“…In particular, in the case of aminotrisphosphonate ester 1a all standard synthetic routes to phosphonic acids (A–C) via acidic hydrolysis of phosphonate esters lead to the elimination of one phosphonyl group and the formation of bisphosphonic acid 39 . Even with Me 3 SiBr/H 2 O, transsilylation and solvolysis under mild conditions afforded only the dephosphonylated product (Scheme 20) [43]. …”

Synthesis of phosphoantigens and chiral trisphosphonates

“…To conclude, a family of phosphoantigens has been synthesized containing non- Substitution at the α-position of the trisphosphonate motif has been reported and includes halogens, aryl groups, amines, and alkyl groups. [56][57][58][59] The trisphosphonates were first reported by Gross through conjugate addition of a hydrogen phosphonate to the quinone methide 86 forming the phenol 87. 60 Further extension of this class involved formation of the methane trisphosphonate from the tetra isopropyl bisphosphonate ester by treatment with base, a chlorophosphite, and oxidation.…”

“…Pivalate esters have been used in pharmaceutical drugs to mask hydroxyl groups 45. With the pivalate-protected hydroxyl compound(57) showing γδ T-cell stimulation, synthesis of a phosphonic acid derivative with a protected hydroxyl group would allow for a second point of comparison.Starting with dimethyl homoprenyl phosphonate 33, allylic oxidation provided the gamma hydroxy phosphonate 52. Standard protection was accomplished using pivaloyl chloride and pyridine to incorporate the pivalate ester.…”