Nucleosides and nucleotides. 192. Toward the total synthesis of cyclic ADP-carbocyclic-ribose. Formation of the intramolecular pyrophosphate linkage by a conformation-restriction strategy in a syn-form using a halogen substitution at the 8-position of the adenine ring.
The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N6-trichloroacetyl-2',3'-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5'-5"-diol derivatives 18. When 18 was treated with POCl3 in PO(OEt)3, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5',5"-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.
Sumita
Y
Y
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Shirato
M
M
Ueno
Y
Y
Matsuda
A
A
Shuto
S
S
D000225:Adenine / Q000737:chemistry*; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D036563:Cyclic ADP-Ribose; D011756:Diphosphates / Q000737:chemistry; D006219:Halogens / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy
D011756:Diphosphates; D006219:Halogens; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D000225:Adenine