Substituent and solvent effects in the 1,3-dipolar cycloadditions for synthesis of anti-influenza agent peramivir and its analog

Influenza remains a health problem to humans. Peramivir is a FDA approved anti-influenza drug targeting the virus neuraminidase. The (3 + 2) cycloaddition reaction of 2-ethylbutanenitrile oxide with the cyclopentene dipolarophile derived from Vince lactam is a key step in the conventional synthesis of peramivir. Our study showed that conducting the (3 + 2) cycloaddition reactions with either aliphatic or aromatic nitrile oxide in hexane solution provided high percentage of the desired regioisomer, and the N-substituent having electron-withdrawing property is also beneficial to the regioselectivity. This study also demonstrated an alternative synthetic pathway of (−)-peramivir and the analog having a phenyl group in place of the 3-pentyl moiety.Tetrahedron. 2019, 75, 4458–4470.

Site-Selective Functionalization of Flagellin by Steric Self-Protection: A Strategy To Facilitate Flagellin as a Self-Adjuvanting Carrier in Conjugate Vaccine

Flagellin (FliC) can act as a carrier protein in the preparation of conjugate vaccines to elicit a T‐cell‐dependent immune response and as an intrinsic adjuvant to activate the toll‐like receptor 5 (TLR5) to enhance vaccine potency. To enable the use of FliC as a self‐adjuvanting carrier, an effective method for site‐selective modification (SSM) of pertinent amino‐acid residues in the D2 and D3 domains of FliC is explored without excessive modification of the D0 and D1 domains, which are responsible for activating and binding with TLR5. In highly concentrated Na2SO4 solution, FliC monomers form flagellar filaments, in which the D0 and D1 domains are situated inside the tubular structure. Thus, the lysine residues (K219, K224, K324, and K331) in the D2 and D3 domains of flagellin are selectively modified by a diazo‐transfer reaction with imidazole‐1‐sulfonyl azide. The sites with azido modification are confirmed by MALDI‐TOF‐MS, ESI‐TOF‐MS, and LC–MS/MS analyses along with label‐free quantitation. The azido‐modified filament dissolves to give FliC monomers, which can conjugate with alkyne‐hinged saccharides by the click reaction. Transmission electron microscopy imaging, dynamic light scattering measurements, and the secreted embryonic alkaline phosphatase reporter assay indicate that the modified FliC monomers retain the ability either to bind with TLR5 or to reassemble into filaments. Overall, this study establishes a feasible method for the SSM of FliC by steric self‐protection of the D0 and D1 domains. ChemBioChem., 2018, 19, 805–814

Synthesis of (+)-Antroquinonol and Analogues by Using Enantioselective Michael Reactions of Benzoquinone Monoketals

(+)-Antroquinonol is an anticancer agent that was first isolated from the rare mushroom Antrodia cinnamomea, which is indigenous to Taiwan. In this study, (+)-antroquinonol is synthesized from benzoquinone monoketals by using an enantioselective Michael reaction as the strategic step followed by an alkylation, reduction, hydrolysis of a ketal, and inversion of configuration sequence of reactions. Because the enantioselective Michael reaction to the electron-rich 2,3,4,4-tetramethoxycyclohexa-2,5-dien-1-one was problematic, the reaction was facilitated by introducing an electron-withdrawing chloro group to replace the methoxy substituent at the C-2 position. Upon treatment with K2CO3 in MeOH in the final step, the chloro substituent was then replaced by the methoxy group concurrently with the inversion of configuration at C-6 to afford (+)-antroquinonol in a one-pot operation. This modular type of synthetic method can also be applied to efficient total syntheses of other antroquinonol analogues that contain the 4-hydroxycyclohex-2-enone core by starting from their corresponding benzoquinone monoketals. Eur. J. Org. Chem. 2016, 3809–3816

Total Synthesis of Anti-Influenza Agents Zanamivir and Zanaphosphor via Asymmetric Aza-Henry Reaction

The potent anti-influenza agents, zanamivir and its phosphonate congener, are synthesized by using a nitro group as the latent amino group at C4 for asymmetric aza-Henry reaction with a chiral sulfinylimine, which is derived from inexpensive d-glucono-δ-lactone to establish the essential nitrogen-containing substituent at C5. This method provides an efficient way to construct the densely substituted dihydropyran core of zanamivir and zanaphosphor without using the hazardous azide reagent. Org. Lett., 2016, 18, 4400–4403

Diels–Alder reactions of an elusive 1,3-butadiene bearing 2-carboxy and 4-alkoxy substituents

A reactive diene, ethyl 2-methylene-4-(pent-3-oxy)but-2-enoate, bearing electron-withdrawing carboxy and electron-donating pentoxy substituents is prepared and trapped in situ by a variety of dienophiles to form [4+2] cycloaddition products. Diels–Alder reaction of this diene with fumarate esters gives multiply substituted cyclohexenes that are useful for building the scaffold of oseltamivir. Tetrahedron Letters 2016, 57, 4293–4296

A short synthesis of (±)-antroquinonol in an unusual scaffold of 4-hydroxy-2-cyclohexenone

Antroquinonol, which was first isolated from a mushroom, Antrodia cinnamomea, found in Taiwan, is an anticancer compound with a unique core structure of 4-hydroxy-2,3-dimethoxycyclohex-2-enone carrying methyl, farnesyl and hydroxyl substituents in the 4,5-cis-5,6-trans configuration. A short synthesis of (±)-antroquinonol is accomplished in seven steps from 2,3,4-trimethoxyphenol, which is oxidized in methanol to a highly electron-rich substrate of 2,3,4,4-tetramethoxycyclohexadienone and then a Michael reaction with dimethylcuprate is performed as the key step, followed by alkylation, reduction and epimerization to incorporate the required substituents at three contiguous stereocenters. Org. Biomol. Chem. 2015, 13, 5510–5519.

A short synthetic pathway via three-component coupling reaction to tamiphosphor possessing anti-influenza activity

Three-component coupling reaction of (pent-3-oxy)acetaldehyde, (Z)-N-(2-nitrovinyl)acetamide, and tetraethyl 1,1-diylbis(phosphonate) is performed in a one-pot operation, followed by reduction of the nitro group and hydrolysis of the phosphonate ester, to afford 8.7% overall yield of tamiphosphor as a potent neuraminidase inhibitor with IC50 and EC50 values of 2.5 and 31.5 nM against wild-type H1N1 influenza virus. The tamiphosphor (5R)-epimer is a less active anti-influenza agent with IC50 and EC50 values of 39 and 117 nM. Tetrahedron 2015, 71, 266–270.

Synthesis and Bioactivity of β-(1→4)-Linked Oligomannoses and Partially Acetylated Derivatives

The synthesis of β-(1→4) linked hexa- to octamannoses and their partially acetylated derivatives was efficiently carried out by assembly of appropriate oligomeric fragments using β-selective glucosylation, followed by gluco to manno epimerization at a late stage of the synthetic pathway. In the course of this study, we also observed that 2-O-acetylated oligomannoses coexisted in equilibrium with the 3-O-acetylated isomers due to intramolecular migration of the acetyl group. Bioactivity of the synthetic oligomannoses and partially acetylated derivatives was investigated in order to identify the possible smallest oligomer for induction of cytokines as that shown in the polysaccharides extracted from Dendrobium huoshanense.
J. Org. Chem. 2012, 78, 6390–6411.

Microflow Synthesis of Saccharide Nucleoside Diphosphate with Cross-coupling Reactions of Monophosphate Components

The advantageous features of a split-and-recombination (SAR) microreactor for organic synthesis of labile bioactive compounds are demonstrated with rapid and efficient cross-coupling reactions of two monophosphate components to form a saccharide–nucleoside diphosphate. With this SAR microreactor, 85 % conversion of a cross-coupling reaction (GlcNAc monophosphate reacting with UMP-morpholidate) to the diphosphate (acetylated UDP-GlcNAc) was achieved in 10 s, which is much less than a reaction period two days for 80 % conversion with a conventional batch reactor; the duration of reaction is decreased >105 fold. An abbreviated period and satisfactory output is expected to be realized when several SAR microreactors are applied in parallel. Chem. Eng. J.2012, 198–199, 33–37.

Flash Synthesis of Carbohydrate Derivatives in Chaotic Microreactors

An efficient and rapid synthesis of carbohydrate derivatives was accomplished using a chaotic microreactor. The reactor shaped as split-and-recombine (SAR) structure which combines mixing mechanisms of both multi-lamination (diffusion) and chaotic advection to enhance mixing and reaction. Using two steps reaction process in SAR-microreactors, the carbohydrate derivatives, aldo-naphthimidazoles were generated by linkage of naphthalenediamine with mono-, di- or trialdoses in less than 10 s with satisfactory yield. Chem. Eng. J. 2011, 174, 421–424.

Diphosphate Formation Using Cyanuric Chloride or Triisopropylbenzenesulfonyl Chloride as the Activating Agents

By using cyanuric chloride or 2,4,6-triisopropylbenzenesulfonyl chloride (TIPSCl) as the condensing agents and magnesium bromide as the promoter, the phosphate cross-coupling reactions are effectively carried out to give lipid–saccharide and pyrrolidine–guanosine diphosphates. Under optimized conditions, the TIPSCl-facilitated cross-coupling reactions complete in a short reaction time (~ 5 h) without complication of possible self-coupling reactions. Tetrahedron Lett. 2011, 52, 2232–2234.

Tagging Saccharides for Signal Enhancement in Mass Spectrometric Analysis

Oligo- and polysaccharides are less sensitive in MS analysis partly due to their neutral and hydrophilic nature to cause low ionization efficiency. In this study, four types of oligosaccharides including aldoses, aminoaldoses, alduronic acids and α-keto acids were modified by appropriate tags at the reducing termini to improve their ionization efficiency. Bradykinin (BK), a vasoactive nonapeptide (RPPGFSPFR) containing two arginine and two phenylalanine residues turned out to be an excellent MS signal enhancer for maltoheptaose, GlcNAc oligomers and oligogalacturonic acids. Interestingly, concurrent condensation and lactonization of a2,8-linked tetrasialic acid (SA4) was carried out with an arginine linked phenylenediamine (H2N)2Ph-R(OMe) to obtain a quinoxalinone derivative, which showed >200-fold enhancement over unmodified SA4 in the MALDI–TOFMS analysis. J. Mass Spectr. 2011, 46, 247–255.

Regioselective Synthesis of Di-C-glycosylflavones Possessing Anti-inflammation Activities.

A series of 6,8-di-C-glycosylflavones bearing identical or distinct glycosyl moieties are synthesized and shown to exhibit anti-inflammation activity. Three methods are utilized to synthesize a variety of 6,8-di-C-glycosylflavones bearing identical or distinct glycosyl moieties. Some C-glycosylation compounds are found to have better anti-inflammation activities than the parent flavones. Among them, 6,8-di-C-glucosylapigenin (known as vicenin-2) shows inhibition of TNF-α expression and NO production with IC50 values of 6.8 and 5.2 mM, respectively. Org. Biol. Chem. 2010, 8, 4451–4462.

Direct Amidation of Aldoses and Decarboxylative Amidation of α-Keto Acids: An Efficient Conjugation Method for Unprotected Carbohydrate Molecules

Using iodine as an appropriate oxidant, unprotected and unmodified aldoses undergo oxidative amidation with a variety of functionalized amines, α-amino esters, and peptides, whereas KDO, sialic acid and other α-keto acids proceed with oxidative decarboxylation followed by in situ amidation. Glycoside bond and many other functional groups are inert under such mild reaction conditions. This reaction protocol for direct ligation of carbohydrate molecules looks promising in development of a general and efficient synthesis of glycoconjugates. J. Org. Chem.2009, 74, 1549-1556.

Using Molecular Iodine in Direct Oxidative Condensation of Aldoses with Diamines: An Improved Synthesis of Aldo-benzimidazoles and Aldo-naphthimidazoles for Carbohydrate Analysis

A practical method is developed for conversion of unprotected and unmodified aldoses to aldo-benzimidazoles and aldo-naphthimidazoles. Using iodine as an oxidant or promoter in acetic acid solution, a series of mono-, di- and trialdoses, including those containing carboxyl and acetamido groups, undergo an oxidative condensation reaction with o -phenylenediamine or 2,3-naphthalenediamine at room temperature to give the aldo-benzimidazole and aldo-naphthimidazole products in high yields. No cleavage of the glycosidic bond occurs under such mild reaction conditions. The composition analysis of saccharides is realized by the HPLC analysis of the fluorescent naphthimidazole derivatives. J. Org. Chem.2008, 73, 3848-3853.

Stereoselective Synthesis of δ -Lactones from 5-Oxoalkanals via One-Pot Sequential Acetalization, Tishchenko Reaction, and Lactonization by Cooperative Catalysis of Samarium Ion and Mercaptan

By the synergistic catalysis of samarium ion and mercaptan, a series of 5-oxoalkanals was converted to (substituted) δ -lactones in efficient and stereoselective manners. This one-pot procedure comprises a sequence of acetalization, Tishchenko reaction and lactonization. The deliberative use of mercaptan, by comparison with alcohol, is advantageous to facilitate the catalytic cycle. Such samarium ion/mercaptan cocatalyzed reactions show the feature of remote control, which is applicable to the asymmetric synthesis of optically active δ -lactones. J. Org. Chem. 2001, 66, 8573–8584.