Total Synthesis and Biological Evaluation of Clavatadines C-E.

We described herein the application of a convergent and protecting-group avoidant approach that led to the first total synthesis of the marine natural products clavatadine D (4) and E (5), and the second total synthesis of clavatadine C (3). In each case, a key amide-coupling afforded an immediate precursor of each natural product in a rapid manner from structurally similar western and eastern portions that derived from an ester of l-tyrosine and butane-1,4-diamine, respectively. A deprotection step free of detectable byproducts cleanly provided the remaining known members of the clavatadine family of natural products. Each total synthesis required five steps (longest linear sequence) with overall yields of 30-37%, 26-39%, and 28-50% for clavatadine C (3), D (4), and E (5), respectively. A screen of their potential anticancer activity against the NCI-60 cell line panel revealed cytotoxicity levels up to 38% across a broad spectrum of tumor types. Although clavatadine C (3) was relatively benign, clavatadine D (4) exhibited 20-38% growth inhibition against a wide array of cancer cell types including leukemia, non-small-cell lung, colon, ovarian, and breast. Clavatadine E (5) was active against two types of human brain tumors.

Total Synthesis of Clavatadine B.

The first total synthesis of clavatadine B (2), a natural product found to be a selective human blood coagulation factor XIa inhibitor, is described. A convergent approach that exemplifies the advantages of direct, early stage guanidinylation provided an immediate clavatadine B precursor, which was assembled in an efficient manner using known synthetic precursors of the structurally related natural product clavatadine A (1). Global deprotection cleanly provided clavatadine B in only four steps from a known derivative of homogentisic acid lactone (longest linear sequence, 75% overall yield).

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 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.

Total synthesis of clavatadine A.

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).

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

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.

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

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.

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

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

[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.