First General Approach to Cyclohex-3-ene-1,1-bis(phosphonates) by Diels−Alder Cycloaddition of Tetraethyl Vinylidenebis(phosphonate) to 1,3-Dienes

Abstract

Tetraethyl vinylidenebis(phosphonate) (VBP) reacts smoothly with substituted 1,3-dienes at 90-110 degrees C without solvent to give the corresponding cyclohex-3-ene-1,1-bis(phosphonates) in good yields (60-85%). With nonsymmetrically substituted dienes, mixtures of regioisomers are obtained, the regioisomeric ratio being exclusively controlled by electronic effects. Danishefsky's diene allows tetraethyl 4-oxocyclohex-2-ene-1,1-bis(phosphonate) to be obtained in an 81% overall yield after the acid-catalyzed hydrolysis of the Diels-Alder cycloadduct. With 2,3-dimethoxy-1,3-butadiene, a mixture of regioisomeric dimethoxycyclohexene-1,1-bis(phosphonates) is formed by the VBP-catalyzed isomerization of the normal Diels-Alder cycloadduct. The mixture converges into tetraethyl 3,4-dimethoxycyclohex-2-ene-1,1-bis(phosphonate) at prolonged reaction times.

Organocatalytic Enantioselective Epoxidation of Some Aryl-Substituted Vinylidenebisphosphonate Esters: On the Way to Chiral Anti-Osteoporosis Drugs

“…This situation reflects the problems of dealing synthetically with molecules having a bisphosphonate group which induces (i) a strong electrophilicity on the central C atom and eventually on adjacent moieties; (ii) a significant steric hindrance leading in many cases to limited accessibility and poor reactivity; and (iii) the capacity of strongly binding metal ions, thereby inactivating catalysts in transition metal-catalyzed reactions. A useful synthetic approach allowing the formation of a broad range of BPs is based on vinylidenebisphosphonate precursors (VBPs) as starting materials [15][16][17][18]. The application of a series of enantioselective catalytic reactions based on the use of a variety of nucleophilic reagents towards these precursors opens the way to the possibility of obtaining a wide range of structurally complex BPs, and in principle the opportunity to verify the different behaviors of the synthesized enantiomers.…”

Synthesis of cycloalkenyl geminal bisphosphonates by ring closing metathesis

“…It must be pointed out that isomers 15 and 16 were already obtained through the Diels-Alder reaction of tetraethyl vinylidene bisphosphonate with isoprene [13] but could not be separated, whereas the RCM allows the separate synthesis of both isomers. Therefore, RCM can be considered as a regioselective, alternative synthesis of six-membered cycloalkenyl bisphosphonates.…”

“…These interests led to the development of a number of methods for the synthesis of bisphosphonates, including alkylation of tetraalkyl methylene bisphosphonate [9], nucleophilic addition to vinylidene bisphosphonate esters [10], enolate chemistry [11], pentacovalent organophosphorus chemistry [12], Diels-Alder reactions [13], radical chemistry [14], and palladium catalysis [15].…”

“…These compounds have been scarcely reported: thus, the dialkylation [9a, 17] of methylene bisphosphonates with alkyl ditosylates or dibromides proceeds satisfactorily with selected substrates, but is hampered by the lack of generalization. On the other hand, the Diels-Alder reaction of tetraethyl vinylidene bisphosphonate with 1,3-dienes [13] occurs smoothly but is limited to the preparation of six-membered homologues, and leads to stereomeric mixtures. Finally, the transition metal-catalyzed enyne cyclization only provides fivemembered bisphosphonates [18].…”

Organocatalytic Stereoselective Epoxidation of Aryl-Substituted Vinylidenebisphosphonate Esters: On the Way to Chiral Anti-Osteoporosis Drugs

“…A useful synthetic approach allowing the formation of a broad range of BPs is based on vinylidenebisphosphonate precursors (VBPs) as starting materials [15][16][17][18]. The application of a series of enantioselective catalytic reactions based on the use of a variety of nucleophilic reagents towards these precursors opens the way to the possibility of obtaining a wide range of structurally complex BPs, and in principle the opportunity to verify the different behaviors of the synthesized enantiomers.…”