Stereodivergent synthesis of 2-oxo-oligopyrrolidines by an iterative coupling strategy.

Natural linear polyamines play diverse roles in physiological processes by interacting with receptors at the cellular level. Herein, we describe the stereodivergent synthesis of oligopyrrolidines, which are conformationally constrained polyamines. We synthesized dimeric and trimeric 2-oxo-oligopyrrolidines using an iterative coupling strategy. The key to our success is an iridium-catalyzed trans/cis-selective nucleophilic addition and subsequent threo/erythro-stereoselective reduction. The synthesized pyrrolidines show varying cytotoxicities against a human cancer cell line depending on the number of rings and their stereochemistry.

Identification of madangamine A as a novel lysosomotropic agent to inhibit autophagy.

Madangamines are marine natural products isolated from Xestospongia ingens, and madangamine A-E with a different D-ring structure have been reported. We have reported that madangamine A has strong anti-proliferative activity against various human cancer cell lines. In this study, to clarify the anti-proliferative activity of madangamine A, we searched for molecular target of the madangamine A in human cells. Treatment with madangamine A increased the levels of LC3-II and p62, autophagy-related proteins, concomitant with growth inhibition. Moreover, madangamine A resulted in lysosome enlargement and increase in lysosomal pH, which are same phenomena observed in chloroquine-treated cells. These results suggest that madangamine A is a novel lysosome inhibitor, and the anti-proliferative activity of madangamine A is due to the inhibition of lysosome function.

Seven-Step Synthesis of All-Nitrogenated Sugar Derivatives Using Sequential Overman Rearrangements.

All-nitrogenated sugars (ANSs), in which all hydroxy groups in a carbohydrate are replaced with amino groups, are anticipated to be privileged structures with useful biological activities. However, ANS synthesis has been challenging due to the difficulty in the installation of multi-amino groups. We report herein the development of a concise synthetic route to peracetylated ANSs in seven steps from commercially available monosaccharides. The key to success is the use of the sequential Overman rearrangement, which enables formal simultaneous substitution of four or five hydroxy groups in monosaccharides with amino groups. A variety of ANSs are available through the same reaction sequence starting from different initial monosaccharides by chirality transfer of secondary alcohols. Transformations of the resulting peracetylated ANSs such as glycosylation and deacetylation are also demonstrated. Biological studies reveal that ANS-modified cholesterol show cytotoxicity against human cancer cell lines, whereas each ANS and cholesterol have no cytotoxicity.

Practical synthesis of the C-ring precursor of paclitaxel from 3-methoxytoluene.

The practical synthesis of the C-ring precursor of paclitaxel starting from 3-methoxytoluene is described. Lipase-catalyzed kinetic resolution of a substituted cyclohexane-1,2-diol, derived from 3-methoxytoluene in three steps, successfully afforded a desired enantiomer with >99% ee, which was transformed to a cyclohexenone. 1,4-Addition of a vinyl metal species, followed by Mukaiyama aldol reaction with formalin in the presence of a Lewis acid provided the known C-ring precursor of paclitaxel in a 10 g scale.

Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by SmI2-Mediated Cyclization.

A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described. SmI2-mediated reductive cyclization of an allylic benzoate possessing an aldehyde function, synthesized from tri-O-acetyl-d-glucal and 1,3-cyclohexanedione, smoothly afforded the highly strained 6-8-6 tricarbocyclic structure in 66% yield.

Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis.

A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-d-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.

Crystal structure of (±)-(4RS,5RS,7SR)-4-[(1RS,2RS,3RS,6RS)-3-benzo-yloxy-2-(2-hy-droxy-ethyl)-6-meth-oxy-meth-oxy-2-methyl-cyclo-hex-yl]-8,10,10-trimethyl-2-oxo-1,3-dioxa-spiro-[4.5]dec-8-en-7-yl benzoate benzene monosolvate.

In the title compound, C36H44O10·C6H6, the dioxolane ring adopts an envelope conformation with the C atom bonded to the H atom as the flap, while the cyclo-hexene and cyclo-hexane rings are in half-chair and chair conformations, respectively. In the crystal, a pair of O-H⋯O hydrogen bonds with an R 2 (2)(26) graph-set motif connect the benzoate mol-ecules into an inversion dimer. The dimers are linked by a weak C-H⋯O inter-action into a tape structure along [01-1]. The benzene mol-ecule links the tapes through C-H⋯O and C-H⋯π inter-actions, forming a sheet parallel to (100).

Total synthesis of (-)-stevastelin B.

The total synthesis and an unambiguous structure confirmation of stevastelin B 1, a novel 15-membered cyclic depsipeptide, are described; the fatty acid moiety in 1, prepared stereoselectively from L-quebrachitol was converted into the amino carboxylic acid, whose macrolactamization by Shioiri's procedure effectively constructed the cyclic structure of 1.