A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.

Computation-guided asymmetric total syntheses of resveratrol dimers

Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (−)-malibatol A, (−)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (−)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.

The Application of C-H bond Functionalization in Total Syntheses of Indole Natural Products

The direct functionalization of unactivated C–H bonds is a rapidly growing field in organic chemistry in recent years because of its indisputable advantages in bond forming reactions in terms of...

Total Syntheses of Seven Stemoamide-Type Stemona Alkaloids

Six Stemona alkaloids were synthesized racemically by using stemoamide, obtained via cascade cyclization or our reported transannular cyclization of parvistemoamide, as the common intermediate. Thioamides facilitated the separation of isosaxorumamide...

The Efficient Synthesis of Azasugars from Pentoses

<p>Azasugars [e.g., 1-deoxy-aza-xylopyranose (1) Figure 1] are structural analogues of sugars [e.g., α-D-xylopyranose (2)] where the ring oxygen is substituted by a nitrogen atom. The resemblance of azasugars to their carbohydrate counterparts gives them various biological properties, such as the inhibition of glycosidase and glycosyltransferase enzymes, and as such, these compounds have been in clinical trials for the treatment of AIDS, diabetes,and cancer. Synthetic routes to azasugars have often involved the use of protecting groups, and therefore have generally reduced efficiency by requiring additional steps to apply or remove protecting groups or requiring adjustment of stereochemistry during the synthesis. This thesis presents the first example of a synthesis of four sterochemically different piperidine triols through a four-step methodology minimising the use of protecting groups starting from pentoses. The synthesis of D-xylose derived (3R,4r,5S)-piperidine triol was previously obtained in 40% yield over five steps, but was afforded in 45% overall yield over four steps using the methodology described within this thesis. Next, D-ribose derived (3R,4s,5S)-piperidine triol was obtained in 40% overall yield over four steps, which afforded a vast improvement on the previous most efficient synthetic route obtaining the azasugar in 24% yield over four steps. This four-step three-pot methodology has thus allowed for the synthesis of these piperidine triols in overall yields ranging from 4-69%, surpassing previous total syntheses in efficiency and improving overall atom economy. To further probe the applicability of the methodology, N-alkyl analogues (such as butyl-, phenylethyl-, and hydroxyethyl-analogues) of all four different piperidine triols were synthesised in comparable or greater overall yields compared to literature reports without any required adaptation to the original procedure. Included in these N-alkyl analogues are seven novel azasugars which were obtained in overall yields ranging from 6-35%.</p>

The Efficient Synthesis of Azasugars from Pentoses

<p>Azasugars [e.g., 1-deoxy-aza-xylopyranose (1) Figure 1] are structural analogues of sugars [e.g., α-D-xylopyranose (2)] where the ring oxygen is substituted by a nitrogen atom. The resemblance of azasugars to their carbohydrate counterparts gives them various biological properties, such as the inhibition of glycosidase and glycosyltransferase enzymes, and as such, these compounds have been in clinical trials for the treatment of AIDS, diabetes,and cancer. Synthetic routes to azasugars have often involved the use of protecting groups, and therefore have generally reduced efficiency by requiring additional steps to apply or remove protecting groups or requiring adjustment of stereochemistry during the synthesis. This thesis presents the first example of a synthesis of four sterochemically different piperidine triols through a four-step methodology minimising the use of protecting groups starting from pentoses. The synthesis of D-xylose derived (3R,4r,5S)-piperidine triol was previously obtained in 40% yield over five steps, but was afforded in 45% overall yield over four steps using the methodology described within this thesis. Next, D-ribose derived (3R,4s,5S)-piperidine triol was obtained in 40% overall yield over four steps, which afforded a vast improvement on the previous most efficient synthetic route obtaining the azasugar in 24% yield over four steps. This four-step three-pot methodology has thus allowed for the synthesis of these piperidine triols in overall yields ranging from 4-69%, surpassing previous total syntheses in efficiency and improving overall atom economy. To further probe the applicability of the methodology, N-alkyl analogues (such as butyl-, phenylethyl-, and hydroxyethyl-analogues) of all four different piperidine triols were synthesised in comparable or greater overall yields compared to literature reports without any required adaptation to the original procedure. Included in these N-alkyl analogues are seven novel azasugars which were obtained in overall yields ranging from 6-35%.</p>