The de novo asymmetric syntheses of several partially acylated dodecanyl tri- and tetra-rhamnoside natural products (cleistriosides-5 & 6 and cleistetrosides-2 to 7) have been achieved (19 to 24 steps). The divergent route requires the use of three or less protecting groups. The asymmetry was derived via Noyori reduction of an acylfuran. The rhamno-stereochemistry was installed by a diastereoselective palladium-catalyzed glycosylation, ketone reduction and dihydroxylation.
Radiotherapy (RT) is one of the most widely used cancer treatments in the clinical setting, while hypoxia-associated resistance often occurs. Herein, a PEGylated TaOx-based oxygen-carrying nanoplatform was constructed for triple sensitizing tumor radiotherapy. The high-Z element based hollow mesoporous TaOx nanospheres were prepared following the in situ growth of ultrasmall CuS nanocrystals and then packaged with O2-saturated perfluoropentane (PFP). NIR laser-triggered mild hyperthermia would lead to the increase of intratumoral blood flow, together with the release of O2, the radiotherapeutic efficiency would be enhanced. Alternatively, radiant energy would be deposited inside the tumor by the Ta element, therefore triple sensitization of radiotherapy could be achieved. The in vivo studies showed that the as-prepared nanospheres could achieve almost total inhibition of tumor growth without obvious side effects, which provides new possibilities for multisensitizing tumor radiotherapy.
A de novo approach to the formal total synthesis of the macrolide natural product (−)-apicularen A has been achieved in 18 steps from achiral starting materials.Both the absolute and relative stereochemistry of apicularen A were introduced by a Sharpless asymmetric dihydroxylation, a π-allyl-palladium catalyzed reduction, a stereoselective reduction and a base promoted transannulation to install the C-9 stereocenter.Since its isolation and structural determination by Jansen and co-workers, 1 apicularen A has attracted significant interest due to its extremely potent antitumor activity, apicularen A showed remarkable cytotoxicities against nine human cancer lines at quite low concentration (IC 50 ∼ 0.1-3 ng/mL). This activity persisted even with the multi-drug resistant line, KB-VI (IC 50 ∼ 0.4 ng/mL). 1b Recently, the mode of action for the apicularens was demonstrated to occur via the selective inhibition of the mammalian VATPases, 2 which are responsible for regulating the intracellular pH. Interestingly, while apicularen A and B were equipotent inhibitors of VATPases, apicularen A is ∼100 times more toxic to cancer cells. 1b This switch in activity controlled by glycosylation has peaked our interest in the synthesis of both apicularen A and B, as well as other glycosylated potential prodrugs.In addition to its fascinating biological activities, the structural novelty of apicularen A has also attracted the attention of the synthetic community. To date several total syntheses of apicularen A have been completed, 3 along with several formal total syntheses and various efforts to the unique bicyclic ring system. 4 While all of the previous syntheses of the apicularen A derived their asymmetry by a resolution or from the chiral pool, we were interested in a de novo asymmetric approach that would use asymmetric catalysis to install the four stereocenters in apicularen A from achiral starting materials. Herein we describe our successful efforts to implement this strategy for the de novo formal total synthesis of apicularen A.Retrosynthetically, we envisioned apicularen A (1) and apicularen B (2) as being derived from the known macrolide 3 and the amide side chain 4, which have been successfully used by Maier George.ODoherty@mail.wvu.edu. Supporting Information Available: Complete experimental procedures and spectral data for all new compounds can be found in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. for the synthesis of 1 (Scheme 1). 5 In our strategy (Scheme 2), the macrolide 3 could be derived from macrolactone 5, which in turn could be obtained by cross metathesis of styrene 6 and alkene 7 . The homoallylic alcohol stereochemistry in the differentially protected tetraol 7 was planned to be introduced by the diastereoselective introduction of an allyl-group to the benzylidene-protected triol 8. 6 Previously we have been successful at preparing protected 3,5-dihydroxy esters from 2,4-dienoates. 6,7 Thus, we envisioned using this 4-step asy...
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