C-H activation enables a concise total synthesis of quinine and analogues with enhanced antimalarial activity

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in vitro and in mice infected with Plasmodium berghei

Charting a course for chemistry

To mark the occasion of Nature Chemistry turning 10 years old, we asked scientists working in different areas of chemistry to tell us what they thought the most exciting, interesting or challenging aspects related to the development of their main field of research will be — here is what they said

Novel applications of functionalised orthoesters : towards the synthesis of various natural products/

For the past years, our laboratory has been interested in the development of a specific class of functionalised orthoester derivatives and their application as annelating reagents. Previous work had demonstrated that these reagents could be used in a two-step procedure to generate interesting spirocyclic ketones. At the onset of our thesis, we devoted our efforts to the study and application of this methodology. This resulted in an improved and more efficient procedure for the spirohexannelation of â-ketoketals. During these initial studies, an intriguing and novel transannular cyclisation was discovered. The reactivity of these spirocycles was also briefly examined, laying the ground for an application to the total synthesis of Agarospirol, Hinesol and á-Vetispirene, three natural products belonging to the Spirovetivane family. The applicability of a CAN-catalysed deprotection of ketals and silyl ethers, in the presence of an enol triflate moiety, was also investigated. The potential of our functionalised orthoesters as annelating agents was then further evaluated in the context of other silyl enolethers. The heteroaromatic derivatives of furan proved to be excellent coupling partners for our functionalised orthoesters, and enabled the efficient preparation of a wide array of butenolides. These butenolides could then be elaborated, by an efficient and highly stereoselective radical-mediated cyclisation, into bicyclic lactones. Alternatively, treatment with base triggered an efficient spirocyclisation, delivering spirocyclic butenolides in good to excellent yields. The corresponding pyrrole derivative was also examinated, and preliminary work hints at the possibility of readily preparing azaspirocycles as well as indolizidine frameworks. Finally, the evaluation of silylated acyloins allowed an entry into the chemistry of cyclobutanones, and a simple procedure for the synthesis of spirocyclic ethers was developed. During these investigations, an unexpected fragmentation was serendipitously discovered upon application of the Beckmann rearrangement. We were able to use this reaction in a new procedure for the synthesis of interestingly substituted tetrahydropyrans.(CHIM 3)--UCL, 200

Synthesis and ring expansions of functionalized spirocyclobutanones.

The first condensations between bis(trimethylsilyloxy)cyclobutene derivatives and functionalized orthoesters are reported. The resulting adducts are readily converted into spirocycloethers, which undergo a variety of -CH2- and -O- insertions with excellent regioselectivity

Cerium(IV) ammonium nitrate catalysed highly chemoselective deprotection of ketals and THP ethers in the presence of enol triflates

The chemoselective, catalytic deprotection of a variety of ketals, THP, and selected silyl ethers can be efficiently performed, in the presence of enol triflates, by the action of cerium(IV) ammonium nitrate (CAN)

2-(Trimethylsilyloxy)furan as a dianion equivalent: a two-step synthesis of functionalized spirocyclic butenolides.

[reaction: see text] The use of 2-(trimethylsilyloxy)furan derivatives as dianion equivalents leads to a general and connective spiroannulation protocol for the efficient preparation of spirocyclic butenolides

Stereoselective synthesis of bicyclic lactones by annelation with functionalized orthoesters.

An efficient two-step annelation of functionalized orthoesters with trimethylsilyloxyfuran derivatives, which delivers suitably decorated bicyclo[3.n.0]lactones in high overall yields and with complete diastereocontrol of up to three contiguous stereocenters, is reported

Reinventing Hydroacylation: A Redox-Neutral Synthesis of Ketones by Coupling of Alkenes and Amides

Herein, we present a new concept for the hydroacylation of alkenes employing amides in a metal-free regime, proceeding by an entirely new mechanism and offering orthogonal reactivity to the conventional, metal-catalysed alternatives. </p

Skeletal rearrangements of bicyclo[2.2.2]lactones: a short and efficient route towards Corey's lactone

The application of a unique tandem radical-initiated, Bronsted acid-catalysed, skeletal rearrangement of bicyclo[2.2.2]-lactones provides a novel route towards Corey&PRIME; s lactone 2. The strategy also features a high-pressure promoted inverse election-demand Diels-Alder (IEDDA) reaction of 3-carbomethoxy-2-pyrone (3-CMP), which proceeds with complete regio- and diastereocontrol. &COPY; 2005 Elsevier Ltd. All rights reserved