a-direct-early-stage-guanidinylation-protocol-for-synthesis-complex

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

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important ...

Utah Valley University

[reaction: see text] A remote alkoxy substituent strongly stabilizes one particular conformer of an eight-membered ring oxocarbenium ion by a through-space electrostatic effect. X-ray crystallographic analysis of a crystalline derivative proves that kinetically controlled nucleophilic substitution favors the 1,4-trans product. Nucleophilic substitution of the corresponding alkyl-substituted acetate, however, is unselective. A computational model has been developed and experimentally validated to predict the low-energy conformers of C3-, C4-, or C5-alkyl- or alkoxy-substituted eight-membered ring oxocarbenium ions.

Using nucleophilic substitution reactions to understand how a remote alkyl or alkoxy substituent influences the conformation of eight-membered ring oxocarbenium ions.

Nucleophilic substitution reactions of monosubstituted tetrahydropyran acetals give opposite selectivities when a remote alkyl or alkoxy substituent is present at C-4. Coupled with earlier computational reports on the intermediates of glycosylation reactions, these results are consistent with the preference for the oxocarbenium ion intermediate derived from alkoxy-substituted tetrahydropyran acetals to occupy a pseudoaxial conformation. Theoretical, spectroscopic, and X-ray crystallographic evidence of this conformational preference in an analogous and more stable dioxocarbenium ion are provided. This contrasteric preference for an axial orientation of an alkoxy substituent likely derives from the electronically favored pseudoaxial orientation of remote electronegative substituents in neutral six-membered rings possessing electron-deficient carbon atoms.

Structural evidence that alkoxy substituents adopt electronically preferred pseudoaxial orientations in six-membered ring dioxocarbenium ions.

We report a simple, efficient, and stereoselective Mukaiyama aldol approach to install the key hydroxymethyl moiety into the benzazocane framework of FR900482. Synthetic investigations revealed that the reaction is highly dependent upon the electronics of the aromatic ring. This approach enabled the economical introduction of a [13C] label to study the biosynthesis of these structurally and biogenetically related natural products. Epimerization of the initially formed beta-hydroxy ketone may enable access to mitomycin C or FR900482 biosynthetic congeners.

Synthetic and biosynthetic studies on FR900482 and mitomycin C: an efficient and stereoselective hydroxymethylation of an advanced benzazocane intermediate.

Beyond the identification of 3-amino-5-hydroxybenzoic acid (AHBA) and D-glucosamine as biosynthetic precursors to mitomycin C (5) and FR900482 (6), little is known about the pathway Nature uses to prepare these antitumor antibiotics. To gain some insight into their biosynthesis, amino acids 1 and 2 as well as C-2 N-acetylated derivatives 3 and 4 were prepared. Preparation of these putative biosynthetic intermediates and N-acetylcysteamine thioester analogues 28 and 29 should enable confirmation of their involvement in FR900482 and mitomycin C biosynthesis.

Synthesis of potential early-stage intermediates in the biosynthesis of FR900482 and mitomycin C.

The first total synthesis of the potent and selective human blood coagulation factor XIa inhibitor clavatadine A (1) is described. Direct, early-stage guanidinylation enabled rapid, convergent access to an immediate clavatadine A precursor. Concomitant lactone hydrolysis and guanidine deprotection with aqueous acid cleanly provided clavatadine A (1) in only four steps (longest linear sequence, 41-43% overall yield).

Article	Year
Using nucleophilic substitution reactions to understand how a remote alkyl or alkoxy substituent influences the conformation of eight-membered ring oxocarbenium ions. Organic letters\| PubMed ID: 15575674	2004
Structural evidence that alkoxy substituents adopt electronically preferred pseudoaxial orientations in six-membered ring dioxocarbenium ions. Journal of the American Chemical Society\| PubMed ID: 15826161	2005
Synthetic and biosynthetic studies on FR900482 and mitomycin C: an efficient and stereoselective hydroxymethylation of an advanced benzazocane intermediate. Organic letters\| PubMed ID: 18047354	2007
Synthesis of potential early-stage intermediates in the biosynthesis of FR900482 and mitomycin C. Organic letters\| PubMed ID: 19161340	2009
Total synthesis of clavatadine A. Journal of natural products\| PubMed ID: 25517413	2015
Correction to Total synthesis of clavatadine A. Journal of natural products\| PubMed ID: 25654443	2015

Stephen Chamberland

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