Synthesis of 3-amino-2,3-dideoxysugars with their applications and total synthesis of pyridone alkaloids

Firstly, a highly stereoselective tandem hydroamination/glycosylation on glycal scaffold has been developed to form 3-amino-2,3-dideoxysugars in a one-pot manner. Based on the developed methodology, broad applications were introduced in glycochemistry. Secondly, a combination of convergent and divergent total synthesis (DTS) approach presented herein sets stage for an iterative introduction of R1 chain among structurally diverse pyridone alkaloids (see scheme). Interestingly, among the six tumor cell lines conducted for cell proliferation, Jurkat T-cells was discovered with potent and apoptotic inhibitory activites. Thirdly, a diverted total synthesis (DTS) approach to the total syntheses of pyridone alkaloids N-deoxymilitarninone A and Torrubiellone Bhas been developed. The common intermediate was first assembled by dual Directed ortho Metalation (DoM) process using MOM as Directed Metalation Groups (DMGs).DOCTOR OF PHILOSOPHY (SPMS

Bimodal Glycosyl Donors Protected by 2-<i>O‑</i>(<i>ortho</i>-Tosylamido)benzyl Group

A glucosyl donor equipped with C2-<i>o</i>-TsNHbenzyl ether was shown to provide both α- and β-glycosides stereoselectivity, by changing the reaction conditions. Namely, β-glycosides were selectively obtained when the trichloroacetimidate was activated by Tf₂NH. On the other hand, activation by TfOH in Et₂O provided α-glycosides as major products. This “single donor” approach was employed to assemble naturally occurring trisaccharide α-d-Glc-(1→2)-α-d-Glc-(1→6)-d-Glc and its anomers

Triflimide-catalyzed allyl–allyl cross-coupling : a metal-free allylic alkylation

A highly efficient metal-free intermolecular C(sp3)–C(sp3) allyl–allyl cross-coupling protocol between allyl acetates and allyltrimethylsilanes, which proceeded smoothly in the presence of catalytic triflimide to form 1,5-dienes with good to excellent regioselectivity, has been developed

Ferrier-Type <i>N</i>‑Glycosylation: Synthesis of <i>N</i>‑Glycosides of Enone Sugars

A mild and efficient protocol for the stereoselective synthesis of <i>N</i>-glycosides of enone sugars has been developed. The reaction proceeds to provide <i>N</i>-glycosides of enone sugars in moderate to good yields with preferential α-anomeric selectivity. Additionally, applications of the <i>N</i>-glycosides of enone sugar derivatives as precursor to assemble some biochemically functional derivatives have also been explored. This includes the use of <i>N</i>-glycosides of enone sugars as reactive dienophile in asymmetric synthesis of bicyclic adduct through Diels–Alder cycloaddition reaction

Design and synthesis of multivalent neoglycoconjugates by click conjugations

A highly stereoselective BF3∙OEt2-promoted tandem hydroamination/glycosylation on glycal scaffolds has been developed to form propargyl 3-tosylamino-2,3-dideoxysugars in a one-pot manner. Subsequent construction of multivalent 3-tosylamino-2,3-dideoxyneoglycoconjugates with potential biochemical applications was presented herein involving click conjugations as the key reaction step. The copper-catalyzed regioselective click reaction was tremendously accelerated with assistance of microwave irradiation.Published versio

Direct and stereoselective synthesis of 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides

The 3-aminoglycosides are ubiquitous in biologically important classes of glycoconjugates and naturally occurring oligosaccharides. Despite the rapid growth in the development of synthetic method of 3-amino glycosides, the current state-of-the art suffers from limited substrate scope, low yields, long reaction times, and anomeric mixtures. This work presents a novel direct method for the synthesis of 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides via α-selective glycosylation and hydroamination of glycal in a one-pot manner. This efficient multicomponent reaction methodology provides ready access to 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides and allows derivatization by variation of each component

A concise route to the highly-functionalized azetidine precursor: the enantioselective synthesis of penaresidin B

An efficient and high-yielding synthesis of penaresidin B is disclosed herein. The concise 8-step synthesis of azetidine aldehyde was devised by incorporating our novel strategy for ready access to 3-amino-2,3-dideoxysugars via regio- and stereoselective tandem hydroamination/glycosylation of glycal as the key step.MOE (Min. of Education, S’pore)Published versio

Collective synthesis of 4-hydroxy-2-pyridone alkaloids and their antiproliferation activities

A collective synthesis of 4-hydroxy-2-pyridone alkaloids—specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C—has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki–Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC50 values of 7.05 μm. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery

Synthesis of (R)-Mellein by a partially reducing iterative polyketide synthase

Mellein and the related 3,4-dihydroisocoumarins are a family of natural products with interesting biological properties. The mechanisms of dihydroisocoumarin biosynthesis remain largely speculative today. Here we report the synthesis of mellein by a partially reducing iterative polyketide synthase (PR-PKS) as a pentaketide product. Remarkably, despite the head-to-tail homology shared with several fungal and bacterial PR-PKSs, the mellein synthase exhibits a distinct keto reduction pattern in the synthesis of the pentaketide. We present evidence to show that the ketoreductase (KR) domain alone is able to recognize and differentiate the polyketide intermediates, which provides a mechanistic explanation for the programmed keto reduction in these PR-PKSs

Insights into the programmed ketoreduction of partially reducing polyketide synthases : stereo- and substrate-specificity of the ketoreductase domain

One of the hallmarks of iterative polyketide synthases (PKSs) is the programming mechanism which is essential for the generation of structurally diverse polyketide products. In partially reducing iterative PKSs (PR-PKSs), the programming mechanism is mainly dictated by the ketoreductase (KR) domain. The KR domain contributes to the programming of PR-PKSs through selective reduction of polyketide intermediates. How the KR domain achieves the selective ketoreduction remains to be fully understood. In this study, we found that the KR domain of the (R)-mellein-synthesizing PR-PKS SACE5532 functions as a B-type KR domain to generate (R)-hydroxyl functionalities. Comparative studies of the KR domains of SACE5532 and NcsB suggested that the two KR domains have distinct substrate preferences towards simple N-acetylcysteamine thioester (SNAC) substrates. We further found that the substrate preference of KRSACE5532 can be switched by swapping several motifs with KRNcsB, and that swapping of the same motifs in the full length SACE5532 resulted in a reprogramming of the PKS. Together, the results advance our understanding of the programming of iterative PR-PKSs by providing new support to the hypothesis that the programmed ketoreduction is accomplished by differential recognition of polyketide intermediates.Accepted versio