Total synthesis of clavaminol A, C and H

Abstract

The first total synthesis of clavaminol A and C, (2R,3S)-2-amino-3-alkanols from the Mediterranean ascidian Clavelina phlegraea has been achieved in 29% overall yield. The key step involved a palladium(II)-catalysed directed Overman rearrangement to create the C-N bond and install the erythro configuration while a one-pot, tributyltin hydride-mediated reduction allowed simultaneous formation of the methyl side-chain and N-acetyl group. Similarly, the first total synthesis of clavaminol H was completed in 48% overall yield using an approach that also provided the cytotoxic des-acetyl analogue.

Preparation of anti-Vicinal Amino Alcohols: Asymmetric Synthesis of d-erythro-Sphinganine, (+)-Spisulosine, and d-ribo-Phytosphingosine

“…21 p -Benzoquinone was also added to the directed rearrangement reaction because previous studies have shown that this prevents the side reaction that forms the [1,3]-product via a Pd(0)-catalyzed process. 13−17 Analysis of the 1 H NMR spectrum of the crude material from this reaction showed the presence of the erythro- and threo -allylic trichloroacetamides in a 28:1 diastereomeric ratio, respectively. Purification by column chromatography allowed the isolation of major erythro -diastereomer 12 in 78% yield from allylic alcohol 10 .…”

“…13 Since then, we have shown that the products of this process can be transformed into various natural products, including β-hydroxy-α-amino acids, 14 the alkaloids α-conhydrine 15 and (+)-monanchorin 16 as well as several members of the clavaminol family. 17 In our continuing studies of how the stereogenic centers within a molecule can influence the outcome of rearrangement reactions, we were interested in investigating the use of directed Overman rearrangements for the general preparation of sphingoid-type bases. We now report the synthesis of d - erythro -sphinganine ( 2 ) and the antitumor agent (+)-spisulosine ( 4 ) 7,11 using a MOM ether-directed Pd(II)-catalyzed Overman rearrangement to create the key anti -vicinal amino-alcohol moiety.…”

General synthetic strategy for clavaminols A, C and H

“…The first total synthesis of clavaminol A, C and H was achieved by Andrew Sutherland et al, 30 starting from (R)-glycidol with an overall yield of 29% and confirmed absolute configuration as (2R,3S). An improved four step synthesis of long-chain anti-2-amino-3-alkanols was achieved by Huang and co-workers.…”

“…1,2 A thorough investigation of the chemical constituents of the Mediterranean ascidian Clavelina phlegraea led to the isolation of clavaminols A-N which are new marine sphingoid-type compounds. 3,4 The structures of these molecules are generally related to the widely distributed amphiphilic sphingosine related long chain amino alcohols, [5][6][7] the central structural element of sphingolipids; their carbon chain varies from C 12 to C 30 and few of them have also polyunsaturated variants. [8][9][10][11][12] Their structures were established by thorough analysis of spectroscopic data and chemical conversion.…”

One-Pot Multi-Reaction Processes: Synthesis of Natural Products and Drug-Like Scaffolds

“…8,9 Mechanistic studies with a range of substrates in non-coordinating solvents showed the MOM ether to be the most effective directing group, with both oxygen at- On optimization of this process, we used the anti-vicinal amino alcohols in efficient preparations of a range of natural products, including β-hydroxy and γ-hydroxy α-amino acids, 10 the alkaloid (+)-monanchorin, 11 and amino alcohols such as clavaminol H and D-erythro-sphinganine. 12,13 However, in completing some of these routes, we were spending more effort in optimizing trivial steps rather than the key transformations. 14 A good example of this was our synthesis of the alkaloid α-conhydrine (5; Scheme 3).…”