Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression. In this study, we examined the antitumor effect of M-COPA on NSCLC cells with TKI resistance. As a result, M-COPA effectively downregulated cell surface EGFR and its downstream signals, and finally exerted in vivo antitumor effect in NSCLC cells harboring secondary (T790M/del19) and tertiary (C797S/T790M/del19) mutated EGFR, which exhibit acquired resistance to first- and third generation EGFR-TKIs, respectively. M-COPA also downregulated MET expression potentially involved in the acquired resistance to EGFR-TKIs via bypassing the EGFR pathway blockade. These results provide the first evidence that targeting the Golgi apparatus might be a promising therapeutic strategy to overcome the vicious cycle of TKI resistance in EGFR-mutated NSCLC cells via downregulating cell surface RTK expression.

Synthesis and Structure-Activity Relationship Study of 5a-Carbasugar Analogues of SL0101.

The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay.

Total synthesis of 6-deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 cancer cell line.

A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.

Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin.

A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective S(N)2' substitution, and selective conversion of a C-Si to C-I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20-C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.

Synthesis of SL0101 carbasugar analogues: carbasugars via Pd-catalyzed cyclitolization and post-cyclitolization transformations.

A general approach to the stereoselective synthesis of 5a-carbasugars has been developed. The route mimics our palladium-catalyzed glycosylation/postglycosylation approach to carbohydrates in that it also utilizes a highly regio- and stereospecific palladium-catalyzed allylation and postglycosylation reaction sequence for the installation of either D- or L-cyclitols. This cyclitolization/postcyclitolization sequence was used for the enantioselective synthesis of a cyclitol analogue of SL0101, its D-sugar enantiomer, as well as several acetylation pattern analogues.

De novo asymmetric synthesis of an alpha-6-deoxyaltropyranoside as well as its 2-/3-deoxy and 2,3-dideoxy congeners.

A highly divergent de novo asymmetric synthesis of benzyl alpha-6-deoxyaltropyranoside, benzyl alpha-ascarylopyranoside, benzyl alpha-amicetopyranoside, and benzyl alpha-digitoxopyranoside has been achieved via a common pyranone intermediate. The routes rely upon a palladium(0)-catalyzed glycosylation reaction and corresponding post-glycosylation transformations. The control of the absolute and relative stereochemical configuration came from a Noyori reduction of 2-acylfuran and subsequent diastereoselective introduction of other stereogenic centers.

Synthesis of carbasugar C-1 phosphates via Pd-catalyzed cyclopropanol ring opening.

The stereoselective syntheses of 2,3-dideoxy-4-oxo-5a-carba-alpha- d-rhamnopyanose 1-phosphate, 2,3-dideoxy-5a-carba-alpha- d-rhamnopyranose 1-phosphate, 5a-carba-alpha- d-rhamnopyranose 1-phosphate, 5a-carba-beta- d-digitoxopyranose 1-phosphate, and 5a-carba-alpha- l-rhamnopyranose 1-phosphate have been achieved from d-quinic acid. The routes rely upon a Simmons-Smith cyclopropanation and diastereospecific ring opening of cyclopropanol under Pd/C hydrogenation condition to set up the alpha-methyl ketone. A sequence of diastereoselective reduction, dihydroxylation, and/or Myers' reductive 1,3-rearrangement were used to install the desired stereochemistry.

De novo asymmetric syntheses of SL0101 and its analogues via a palladium-catalyzed glycosylation.

The enantioselective syntheses of naturally occurring kaempferol glycoside SL0101 (1a) and its analogues 1b-e, as well as their enantiomers, have been achieved in 7-10 steps. The routes rely upon a diastereoselective palladium-catalyzed glycosylation, ketone reduction, and dihydroxylation to introduce the rhamno-stereochemistry. The asymmetry of the sugar moiety of these kaempferol glycosides was derived from Noyori reduction of an acylfuran. An acetyl group shift from an axial (C-2) to equatorial position (C-3) under basic conditions was also described. [reaction: see text]

Polyprenylated phloroglucinol derivatives from Hypericum erectum.

Three polyprenylated phloroglucinol derivatives, namely erectquione A, B, and C, were isolated from Hypericum erectum. Their structures were established using extensive spectral methods.