Total Synthesis Without Protecting Groups: Pyrrolidines and Cyclic Carbamates

A protecting group free synthesis of 2,3-cis substituted hydroxypyrrolidines is reported. Two novel reaction methodologies allow for the stereoselective formation of cyclic carbamates from olefinic amines, and the formation of primary amines via a Vasella/reductive amination reaction, both performed in aqueous media

De Novo Synthesis of Aceric Acid and an Aceric Acid Building Block

The de novo synthesis of an aceric acid thioglycoside building block and the total synthesis of the plant carbohydrate aceric acid are described via a highly convergent strategy. Aldol reaction of acetaldehyde and a protected tartaric acid derivative provided the open chain carbohydrate. Subsequent acid treatment yielded the aceric acid thioglycoside in 35% total yield over five steps. Oxidative cleavage of the thioketal in the open chain carbohydrate and basic hydrolysis of the methyl ester furnished fully deprotected aceric acid in 31% yield over six steps

De Novo Synthesis of Aceric Acid and an Aceric Acid Building Block

The de novo synthesis of an aceric acid thioglycoside building block and the total synthesis of the plant carbohydrate aceric acid are described via a highly convergent strategy. Aldol reaction of acetaldehyde and a protected tartaric acid derivative provided the open chain carbohydrate. Subsequent acid treatment yielded the aceric acid thioglycoside in 35% total yield over five steps. Oxidative cleavage of the thioketal in the open chain carbohydrate and basic hydrolysis of the methyl ester furnished fully deprotected aceric acid in 31% yield over six steps

De Novo Synthesis of Aceric Acid and an Aceric Acid Building Block

The de novo synthesis of an aceric acid thioglycoside building block and the total synthesis of the plant carbohydrate aceric acid are described via a highly convergent strategy. Aldol reaction of acetaldehyde and a protected tartaric acid derivative provided the open chain carbohydrate. Subsequent acid treatment yielded the aceric acid thioglycoside in 35% total yield over five steps. Oxidative cleavage of the thioketal in the open chain carbohydrate and basic hydrolysis of the methyl ester furnished fully deprotected aceric acid in 31% yield over six steps

Total Synthesis of Aigialomycin D Using a Ramberg−Bäcklund/RCM Strategy

The bioactive resorcylic acid lactone aigialomycin D (1) has been synthesized by a novel combination of ring-closing metathesis (RCM) and Ramberg−Bäcklund reactions. This synthetic strategy enables the C1′−C2′ alkene to be masked as a sulfone during formation of the macrocycle by ring closing metathesis at the C7′−C8′ olefin, thus avoiding competing formation of a cyclohexene. A subsequent Ramberg−Bäcklund reaction efficiently produces the C1′−C2′ E-alkene. This combined RCM/Ramberg−Bäcklund reaction strategy should be widely applicable to the synthesis of macrocyclic dienes

Applications and Limitations of the I₂‑Mediated Carbamate Annulation for the Synthesis of Piperidines: Five- versus Six-Membered Ring Formation

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis

Protecting-Group-Free Synthesis of Amines: Synthesis of Primary Amines from Aldehydes via Reductive Amination

New methodology for the protecting-group-free synthesis of primary amines is presented. By optimizing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals, primary amines were selectively prepared with no or minimal formation of the usual secondary and tertiary amine byproduct. The methodology was performed on a range of functionalized aldehyde substrates, including in situ formed aldehydes from a Vasella reaction. These reductive amination conditions provide a valuable synthetic tool for the selective production of primary amines in fewer steps, in good yields, and without the use of protecting groups

The Rapid and Facile Synthesis of Oxyamine Linkers for the Preparation of Hydrolytically Stable Glycoconjugates

The synthesis of a number of <i>N</i>-glycosyl-<i>N</i>-alkyl-methoxyamine bifunctional linkers is described. The linkers contain an <i>N</i>-methoxyamine functional group for conjugation to carbohydrates and a terminal group, such as an amine, azide, thiol, or carboxylic acid, for conjugation to the probe of choice. The strategy for the linker synthesis is rapid (3–4 steps) and efficient (51–96% overall yield), and many of the linkers can be synthesized using a three-step one-pot strategy. Moreover, the linkers can be conjugated to glycans in excellent yield and they show excellent stability toward hydrolytic cleavage

Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that recognizes trehalose dimycolate (TDM), and trehalose dibehenate (TDB) and related trehalose diesters, and thus represents a promising target for the development of vaccine adjuvants based on the trehalose glycolipid scaffold. To this end, we report on the synthesis of a series of long-chain α-branched, β-modified trehalose monoesters and diesters to explore how glycolipid structure affects signaling through Mincle. Key steps in our synthetic strategy include a Fráter-Seebach α-alkylation to install the C₂₀ aliphatic lipid on a malic acid derivative, and the formation of a β,γ-epoxide as an intermediate from which modifications to the β-position of the lipid can be made. Biological evaluation of the derivatives using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing mMincle or hMincle revealed that the hMincle agonist activity of all diesters was superior to that of the current lead trehalose glycolipid adjuvant TDB, while the activity of several monoesters was similar to that of their diester counterparts for mMincle, but all showed reduced hMincle agonist activity. Taken together, diesters <b>2d</b>–<b>g</b> are thus potent Mincle agonists and promising vaccine adjuvants

The Use of a Mannitol-Derived Fused Oxacycle as a Combinatorial Scaffold

An efficient and high-yielding solid-phase synthesis of a small library of compounds containing a cis-fused pyranofuran structural motive is descibed. With use of the cheap and readily available d-(+)-mannitol, a highly functionalized sugar template was synthesized and immobilized on a solid support via an olefinic linker. Modification of this two-point molecular scaffold and subsequent ring-closing metathesis/cleavage gave access to a series of functionalized conformationally constrained fused oxacycles