Trifluoroacetic acid-promoted ring contraction in 2,3-di-O-silylated O-galactopyranosides and hemiacetals

A pyranose ring contraction of 2,3-di-O-silylated O-galactopyranosides with retention of aglycone promoted by anhydrous trifluoroacetyc acid (TFA) in CH2Cl2 was demonstrated for the first time. In addition, TFA-promoted pyranose ring contraction of 2,3-bis-O-(triisopropylsilyl)-D-galactopyranose with formation of the corresponding anomeric triols in furanose form was successfully performed. A representative series of β-D-galactopyranosides with Me, Bn, allyl, or 3-(trifluoroacetamido)propyl aglycones has been investigated. TBDPS protective groups were found to be more stable than TIPS groups under conditions of TFA-promoted pyranose ring contraction. An easy access to 2,3-di-O-TBDPS substituted allyl and benzyl galactofuranosides and 2,3-bis-O-(triisopropylsilyl)-β-D-galactofuranose may present an advantage in synthesis of selectively protected monosacharide bilding blocks, useful for the synthesis of biologically important oligosaccharides.

Adventures in 1,3-Selenazole Chemistry

The synthesis of 1,3-selenazoles and related compounds, including 2,4,5-trisubstituted, 2,4-disubstituted, 4,5-disubstituted, 4-substituted 1,3-selenazoles, and parent unsubstituted 1,3-selenazole, is highlighted. Emphasis is also given on 2-benzoyl-1,3-selenazoles which can be functionalized by Knoevenagel reactions or by rearrangements via their corresponding oximes. Syntheses of bis-, tris-, and tetrakis(1,3-selenazoles) are discussed as well. 1,3,4-6H-Selenadiazines are available from selenosemicarbazides and can undergo ring-contraction or deselenation reactions. Most syntheses rely on the application of selenocarboxylic amides, selenourea and related building blocks which are conveniently available by reaction of the corresponding oxygen analogues with P4Se10.1 Introduction2 Selenocarboxylic Amides3 2,4,5-Tri- and 2,4-Disubstituted 1,3-Selenazoles4 Bis(1,3-selenazoles)5 2-Amino-1,3-selenazoles6 2-Unsubstituted 1,3-Selenazoles7 1,3,4-Selenadiazines8 Conclusions

Ring Contraction Reactions of a Non-Benzenoid Aromatic Cation and a Neutral Homoaromatic System into Benzene Derivatives

Aromaticity is one of the most intriguing concepts in organic chemistry. Simple and extended benzenoid aromatic systems have been very well established in undergraduate textbooks, and there are also mentions of non-benzenoid aromatic structures such as cyclopropenium, cyclopentadienide and cycloheptatrienylium (tropylium) ions. However, the structural relationship and the comparison of stabilization energy of such aromatic ions to benzene ring have been rarely studied and remained an underexplored area of advanced organic chemistry research. To contribute some insights into this topic, we focused on the chemical transformation, namely a ring contraction reaction, of the tropylium ion to benzene ring in this work. With an approach combining computational studies with experimental reactions, we also aim to turn this transformation into a synthetically useful tool. Indeed, this work led to the development of a new synthetic protocol, which involved an oxidative ring-contraction of tropylium ion, to formally introduce the phenyl ring onto a range of organic structures. Furthermore, the homoaromatic cycloheptatrienyl precursors of tropylium salts used in these reactions can also be rearranged to valuable benzhydryl or benzyl halides, enriching the synthetic utility of this ring-contraction protocol.

Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

The sugars streptose and dihydrohydroxystreptose (DHHS) are unique to the bacteria Streptomyces griseus and Coxiella burnetii respectively. Streptose forms the central moiety of the antibiotic streptomycin, whilst DHHS is found in the O-antigen of the zoonotic pathogen C. burnetii. Biosynthesis of these sugars has been proposed to follow a similar path to that of TDP-rhamnose, catalysed by the enzymes RmlA/RmlB/RmlC/RmlD. Streptose and DHHS biosynthesis unusually require a ring contraction step that might be performed by the orthologues of RmlC or RmlD. Genome sequencing of S. griseus and C. burnetii proposed the StrM and CBU1838 proteins respectively as RmlC orthologues. Here, we demonstrate through both coupled and direct observation studies that both enzymes can perform the RmlC 3'',5'' double epimerisation activity; and that this activity supports TDP-rhamnose biosynthesis in vivo. We demonstrate that proton exchange is faster at the 3'' position than the 5'' position, in contrast to a previously studied orthologue. We solved the crystal structures of CBU1838 and StrM in complex with TDP and show that they form an active site highly similar to previously characterised enzymes. These results further support the hypothesis that streptose and DHHS are biosynthesised using the TDP pathway and are consistent with the ring contraction step being performed on a double epimerised substrate, most likely by the RmlD paralogue. This work will support the determination of the full pathways for streptose and DHHS biosynthesis.

Photo-mediated ring contraction of saturated heterocycles

Saturated heterocycles are found in numerous therapeutics as well as bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish Type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

Formal Electrophilic Phenylation Reaction with Tropylium Ion

Arylation reaction is an important transformation in synthetic chemistry as aryl building blocks are ubiquitous in valuable organic frameworks. Traditionally, this type of reaction has been carried out either via biaryl coupling reactions or with the use of reactive intermediates such as arynes or aryl radicals. Direct electrophilic arylation reactions have been rarely reported in literature, as the required arenium building blocks are often unstable or inaccessible. To develop a new strategy for such transformation, we herein introduce the development of a formal phenylation reaction, which proceeds via an electrophilic cycloheptatrienylation with tropylium ion, followed by an oxidative ring-contraction.