Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2H-furo[3,2-b]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells

Abstract

Two series of novel chiral hexahydro-2H-furo [3,2b]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected D-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC 50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.

Rapid Access to Divergent Fused Polycycles Via One‐Pot A3 Coupling and Intramolecular Diels‐Alder Reaction

“…The double bond in this bicyclic substructure has been reported to be amenable to ring‐opening metathesis [14] . Following this report, compound (±)‐ 24 a was successfully subjected to ring opening metathesis catalyzed by the Grubbs‐II catalyst to form a poly‐functionalized bicyclic hexahydro‐2H‐furo[2,3‐c]pyrrole (±)‐ 46 (Figure 3) in 61 % isolated yield, which is an analogue of PDE1 inhibitors [15] . In addition, TiCl 4 was used to successfully cleave the oxa‐bridge in compound (±)‐ 4 a to form a functionalized derivative (±)‐ 47 of hexahydro‐1H‐isoindole in 75 % yield (Figure 3), which is a known scaffold with biological relevance [16] …”

“…[14] Following this report, compound (�)-24 a was successfully subjected to ring opening metathesis catalyzed by the Grubbs-II catalyst to form a poly-functionalized bicyclic hexahydro-2H-furo [2,3-c]pyrrole (�)-46 (Figure 3) in 61 % isolated yield, which is an analogue of PDE1 inhibitors. [15] In addition, TiCl 4 was used to successfully cleave the oxa-bridge in compound (�)-4 a to form a functionalized derivative (�)-47 Table 3. Substrate scope of amine in the one-pot synthesis.…”

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids

“…Vinpocetine has multiple cellular targets, with its initial identified target being phosphodiesterase 1 (PDE1), a member of the phosphodiesterase enzyme superfamily that catalyzes the degradation of cGMP or cAMP [ 9 , 10 , 11 , 12 , 13 ]. PDE1 is categorized into three subtypes based on different gene coding: PDE1A, PDE1B, and PDE1C.…”