Sunkyu Han

Concise total synthesis and stereochemical revision of all (-)-trigonoliimines.

The concise and enantioselective total syntheses of (-)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (-)-trigonoliimines A, B, and C.

Asymmetric Catalysis at a Distance: Catalytic, Site-Selective Phosphorylation of Teicoplanin

We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A2-2. Two of the catalysts are based on a design that capitalizes on a catalyst-substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a DXaa-DXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 Å, based on the X-ray crystal structure of teicoplanin A2-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself.

Synthesis and anticancer activity of all known (-)-agelastatin alkaloids.

The full details of our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure-activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 μM). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose-dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy, we have determined that neither alkaloid affects tubulin dynamics within cells.

Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

A full account of our concise and enantioselective total syntheses of all known (-)-trigonoliimine alkaloids is described. Our retrobiosynthetic analysis of these natural products enabled identification of a single bistryptamine precursor as a precursor to all known trigonoliimines through a sequence of transformations involving asymmetric oxidation and reorganization. Our enantioselective syntheses of these alkaloids enabled the revision of the absolute stereochemistry of (-)-trigonoliimines A, B, and C. We report that trigonoliimines A, B, C and structurally related compounds showed weak anticancer activities against HeLa and U-937 cells.

X-ray Crystal Structure of Teicoplanin A2-2 Bound to a Catalytic Peptide Sequence via the Carrier Protein Strategy

We report the X-ray crystal structure of a site-selective peptide catalyst moiety and teicoplanin A2-2 complex. The expressed protein ligation technique was used to couple T4 lysozyme (T4L) and a synthetic peptide catalyst responsible for the selective phosphorylation of the N-acetylglucosamine sugar in a teicoplanin A2-2 derivative. The T4L-Pmh-dPro-Aib-dAla-dAla construct was crystallized in the presence of teicoplanin A2-2. The resulting 2.3 Å resolution protein–peptide–teicoplanin complex crystal structure revealed that the nucleophilic nitrogen of N-methylimidazole in the Pmh residue is in closer proximity (7.6 Å) to the N-acetylglucosamine than the two other sugar rings present in teicoplanin (9.3 and 20.3 Å, respectively). This molecular arrangement is consistent with the observed selectivity afforded by the peptide-based catalyst when it is applied to a site-selective phosphorylation reaction involving a teicoplanin A2-2 derivative.

An Accelerated Intermolecular Rauhut–Currier Reaction Enables the Total Synthesis of (−)-Flueggenine C

The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C is completed via an accelerated intermolecular Rauhut-Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (-)-flueggenine C.

Tunable Grating Couplers for Broadband Operation Using Thermo-Optic Effect in Silicon

We demonstrate a tunable grating coupler for broadband operation using an impurity-doped thermo-optic heater fabricated by complementary metal-oxide-semiconductor-compatible processes. As a thermo-optic heater, a p-n diode is employed to have a p-type region inside of an in-coupling grating connected with outside p+/n+ contacts and is heated directly by a current flow through the grating. Applying a forward-bias voltage of 7 V, we shift the central wavelength of the grating coupler from 1525 to 1574 nm with a coupling efficiency of close to -4 dB. Considering a 1-dB bandwidth at each central wavelength, we extend the operational bandwidth to nearly 90 nm. A thermal tuning efficiency of 0.23 nm/mW and transient responses of 32/22 μs for heating/cooling times are obtained.

Biomimetic total synthesis of (±)-berkeleyamide D

We describe the total synthesis of (±)-berkeleyamide D using a biosynthetically inspired strategy. The spirocyclic core of berkeleyamide D was constructed via sequential epoxidations and a late-stage base-mediated cyclization of a biosynthetically relevant precursor. Our synthetic solution might be applicable to access other fungal natural products of this family.

Six-Step Total Synthesis of Azaspirene

The total synthesis of (±)-azaspirene (1) was achieved in a total of six steps from commercially available materials. Keys to the conciseness of our synthetic approach were the effective γ-lactam formation from linear precursor 36 and successful tandem epoxidations of γ-lactam 34 to afford α,β-epoxy-γ-hydroxy-γ-lactam intermediate 14. While our streamlined synthesis of azaspirene (1) sought inspiration from its biogenetic hypothesis, experimentally observed chemical reactivity of biosynthetically relevant precursors conversely provides insights to the biological origin of this natural product.

Tunable grating coupler based on thermo-optic effect in silicon

We demonstrate an efficient tunable grating coupler using thermo-optic heater in silicon. Tuning of the central wavelength from 1537nm to 1573nm is achieved with an increased 1 dB-bandwidth up to 59nm.