A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products

Summary

Here, we present a protocol for direct, early stage guanidinylation that enables rapid total synthesis of aminoguanidine-containing small organic molecules. An advanced synthetic intermediate used in the synthesis of a blood coagulation factor XIa inhibitor was prepared using this protocol.

Abstract

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important structural element found in many complex natural products and pharmaceuticals. Owing to the continual discovery of new guanidine-containing natural products and designed small molecules, rapid and efficient guanidinylation methods are of keen interest to synthetic and medicinal organic chemists. Because the nucleophilicity and basicity of guanidines can affect subsequent chemical transformations, traditional, indirect guanidinylation is typically pursued. Indirect methods commonly employ multiple protection steps involving a latent amine precursor, such as an azide, phthalimide, or carbamate. By circumventing these circuitous methods and employing a direct guanidinylation reaction early in the synthetic sequence, it was possible to forge the linear terminal guanidine containing backbone of clavatadine A to realize a short and streamlined synthesis of this potent factor XIa inhibitor. In practice, guanidine hydrochloride is elaborated with a carefully constructed protecting array that is optimized to survive the synthetic steps to come. In the preparation of clavatadine A, direct guanidinylation of a commercially available diamine eliminated two unnecessary steps from its synthesis. Coupled with the wide variety of known guanidine protecting groups, direct guanidinylation evinces a succinct and efficient practicality inherent to methods that find a home in a synthetic chemist's toolbox.

Introduction

The objective of this video is to show how using a direct and early guanidinylation method to make a terminal guanidine structure is more practical, rapid, and efficient than traditional guanidinylation methods in organic synthesis. The guanidine functional group, found on the amino acid arginine, is a key structural element in many complex natural products and pharmaceuticals. The discovery and design of new guanidine containing natural products and small molecules establish the need for a more efficient guanidinylation method. The commonly used circuitous approach features the introduction of a latent guanidine precursor that is unmasked at a late stage in the synth....

Protocol

Caution: Please consult and heed Safety Data Sheets (SDS) for each chemical prior to use. A few of the chemicals used in this synthesis are corrosive, toxic, carcinogenic, or otherwise harmful. Consequently, take every precaution to avoid inhalation, ingestion, or skin contact with these chemicals. Please wear appropriate Personal Protective Equipment (PPE) correctly. Proper PPE includes wrap-around safety goggles, nitrile gloves or more chemically resistant gloves, a lab coat, long pants that cover the tops of the shoes, closed-toe shoes. Use a working fume hood with the sash at the lowest possible height, in tandem with additional relevant engineering controls, to m....

Results

Direct guanidinylation of a commercially available α,ω-diamine, followed by reaction with triphosgene, afforded the reactive isocyanate 8 as the linear portion of clavatadine A (Figure 1b). Yields of this two-step reaction sequence are invariably high, 95% or greater. Guanidinylation reagent 6 was prepared exactly as described by Goodman.^11,24

When isocyanate .......

Discussion

Initial efforts to prepare clavatadine A enlisted a traditional, indirect approach to guanidinylation from a suitable amine precursor, which in this case was a terminal azide. Central to this effort was the union of the two halves of the molecule to construct the carbamate moiety. Unfortunately, all attempts to realize an azide reduction in anticipation of a planned late-stage guanidinylation were unsuccessful.^25,26 These setbacks inspired the pursuit of compound 7, which could be prepared in .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Chloroform-d	Sigma-Aldrich	612200-100G	99.8% D, 0.05% v/v tetramethylsilane; Caution: toxic
Dimethylsulfoxide-d6		185965-50G	99.9% D, 1% v/v tetramethylsilane
sodium thiosulfate pentahydrate	Sigma-Aldrich	S8503-2.5KG
sodium sulfate, anhydrous	Sigma-Aldrich	238597-2.5KG
silica gel	Fisher Scientific	S825-25	Merck, Grade 60, 230-400 mesh
washed sea sand	Sigma-Aldrich	274739-5KG
hexane	Sigma-Aldrich	178918-20L	Caution: flammable
ethyl acetate	Sigma-Aldrich	319902-4L
methylene chloride	Sigma-Aldrich	D65100-4L
sodium chloride	Sigma-Aldrich	S9888-10KG
sodium bicarbonate	Sigma-Aldrich	S6014-2.5KG
acetic acid	Sigma-Aldrich	695092-2.5L
hydrochloric acid	Sigma-Aldrich	258248-2.5L	Caution: Corrosive
bromine	Sigma-Aldrich	470864-50G	>99.99% trace metals basis; Caution: Corrosive, causes severe burns
hydrobromic acid	Sigma-Aldrich	244260-500ML	48% aqueous; Caution: Corrosive
2,5-dimethoxyphenylacetic acid	ChemImpex	26909
chloroform	Sigma-Aldrich	132950-4L	Caution: Toxic
tetrahydrofuran	Sigma-Aldrich	360589-4x4L	Caution: highly flammable
N,N-diisopropylethylamine	Sigma-Aldrich	D125806-500ML	Caution: Corrosive
triethylamine	Sigma-Aldrich	T0886-1L	Caution: Corrosive
3 Angstrom molecular sieves	Sigma-Aldrich	208574-1KG
calcium hydride	Sigma-Aldrich	213268-100G	Caution: Corrosive, reacts violently with water
ammonium molybdate	Sigma-Aldrich	431346-50G
phosphomolybdic acid	Sigma-Aldrich	221856-100G
cerium(IV) sulfate	Sigma-Aldrich	359009-25G
1-butanol	Sigma-Aldrich	537993-1L
1,4-butanediamine	Sigma-Aldrich	D13208-100G	Caution: Corrosive / warm in hot water bath to melt prior to use
triphosgene	VWR	200015-064	Caution: Highly Toxic
methanol	Sigma-Aldrich	646377-4X4L
sodium acetate	Sigma-Aldrich	241245-100G
Dimethylsulfoxide-d6	Sigma-Aldrich	570672-50G	Anhydrous, 99.9% D
sodium hydroxide	Sigma-Aldrich	221465-500G	Caution: Corrosive
guanidine hydrochloride	Sigma-Aldrich	G4505-25G	Caution: Toxic, Corrosive
di-tert-butyl dicarbonate	VWR	200002-018%	Caution: Toxic / may warm in hot water bath to melt prior to use
trifluoromethanesulfonic anhydride	Fisher Scientific	50-206-771	98%, anhydrous; Caution: toxic, corrosive, extremely moisture sensitive