Scaleable processes for the synthesis of (−)-β-d-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (−)-β-d-2-aminopurine dioxolane (APD)

Abstract

An efficient and scalable synthesis of (−)-DAPD and (−)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved β-selectivity and an isolated yield four fold greater than the original process scale method. Using this new process, (−)-DAPD has been prepared on greater than 20 g scale. In the synthesis of (−)-APD, a key enzyme-catalyzed hydrolysis reaction afforded the water-soluble deprotected α-anomer while leaving the β-anomer completely untouched.

Structure, Synthesis and Inhibition Mechanism of Nucleoside Analogues as HIV‐1 Reverse Transcriptase Inhibitors (NRTIs)

“…Emtricitabine ( 102 ), which contains a fluorine atom at the 5 position of lamivudine ( 83 ), also has HIV‐1 reverse transcriptase inhibitory activity similar to lamivudine ( 83 ; Figure 14). [11] Furthermore, not only apricitabine ( 103 ), in which the positions of the oxygen and sulfur atoms of the (+)‐enantiomer of lamivudine ( 83 ) are interchanged, but also amdoxovir ( 104 ), a 1,3‐dioxolane nucleoside, has been found to show good anti‐HIV‐1 activity [54–58] . These are notable for their effectiveness against viruses that display drug resistant toward lamivudine ( 83 ).…”

“…[33] The scheme is characterized by the use of reagents containing tellurium, which is homologous to selenium. Dimethoxytritylation at the 5' position and acetylation at the 3' position for 5-metyluridine occurs (56) Such an elimination reaction does not occur when dimethyl diselenide is used instead of dimethyl ditelluride as the reagent (Scheme 16), and the adducts of the methyl selenide can be isolated. This sequence of reactions arises because alkyl telluride is highly unstable and reactive, a specific property not possessed by alkylselenide.…”

“…[11] Furthermore, not only apricitabine (103), in which the positions of the oxygen and sulfur atoms of the (+)-enantiomer of lamivudine (83) are interchanged, but also amdoxovir (104), a 1,3-dioxolane nucleoside, has been found to show good anti-HIV-1 activity. [54][55][56][57][58] These are notable for their effectiveness against viruses that display drug resistant toward lamivudine (83). In 2013, emtricitabine (102) was modified to a prodrug by Agarwal to enhance emtricitabine intracellular uptake and anti-HIV-1 activity.…”

Biocatalytic approaches applied to the synthesis of nucleoside prodrugs

“…This compound was subjected to pancreatic porcine lipase (PPL) resolution, obtaining the desired (R)-lactone (2) in 98% ee (Scheme 8). After its chemical reduction and glycosylation, followed by a selective enzyme-catalysed hydrolysis using CALB, the desired β-anomer was obtained (Zhou et al, 2012). From 2-amino-6-chloropurine dioxolane (ACPD, 3, X = Cl, Scheme 8) DAPD and APD were prepared by amination or reduction, respectively.…”

Follow the Silyl Cation: Insights into the Vorbrüggen Reaction

“…The stoichiometry of this process is consistent with HMDS serving as both a Brønsted base and a silylating agent, allowing for the formation of the bis-silylated species 8 after the addition of only 1 equiv of TMSOTf. On the basis of this stoichiometry, HMDS only transfers a single trimethylsilyl group to the substrate 3 . Therefore, in effect, 2.6 equiv of the silylating agent has been added to this reaction, and to write the full kinetic scheme, their fate needs to be fully accounted for.…”