Stereoselective Synthesis of Cyclic Guanidines by Directed Diamination of Unactivated Alkenes

Abstract

A method for a directed stereoselective guanidinylation of alkenes is described. The guanidine unit can be delivered as an intact fragment by a hydroxy or carboxy group, usually with a high level of stereocontrol. After the guanidine delivery, the directing group can be cleaved under exceptionally mild conditions, typically by alcoholysis in the presence of acetic acid. Broad functional group tolerance and mild reaction conditions for the cycloguanidilation suggest applications in medicinal chemistry and natural products synthesis.

Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation

“…This method enables efficient delivery of guanidine as an entire unit from free guanidine with a high level of stereocontrol. 6 Herein, we demonstrate the utility of this method with a short, protecting-group-free synthesis of (+)-guadinomic acid ( 1 ).…”

“…Recently, we developed an alternative method for the stereoselective synthesis of cyclic guanidines by directed vicinal diamination of alkenes. This method enables efficient delivery of guanidine as an entire unit from free guanidine with a high level of stereocontrol . Herein, we demonstrate the utility of this method with a short, protecting-group-free synthesis of (+)-guadinomic acid ( 1 ).…”

Short Total Synthesis of [15N5]-Cylindrospermopsins from 15NH4Cl Enables Precise Quantification of Freshwater Cyanobacterial Contamination

“…This was achieved by a two-stage approach described previously. 28 First, free [ 15 N 3 ]-guanidine was attached to the hydroxy group by a carbonyl linker in good yield using 1.2 equiv of 15 N-labeled reagent. Second, electrophilic cycloguanidylation was performed in the presence of N-iodosuccinimide, delivering [ 15 N 5 ]-12 after treatment with 4-methoxybenzenesulfonyl chloride (MbsCl) in 71% yield and 2.5:1 dr favoring the requisite diastereomer.…”

“…Alkyne iii was intended as a precursor to diene ii via a transition-metal-mediated rearrangement. As an essential element of the plan, homoallylic alcohol iv serves as the substrate for a hydroxyl-directed stereoselective delivery of free [ 15 N 3 ]-guanidine that we previously developed for this application …”

“…As an essential element of the plan, homoallylic alcohol iv serves as the substrate for a hydroxyl-directed stereoselective delivery of free [ 15 N 3 ]-guanidine that we previously developed for this application. 28 The success of this plan rests on identifying a suitable substituent Z, which must first activate the diene for addition of guanidine, then facilitate C7 hydroxylation, and eventually be converted to uracil. Although several options can be considered, heterocyclic substituents such as 2,4-dimethoxypyrimid-6-yl appeared to be especially enticing as precursors of uracil.…”