Author Archive

Asymmetric Allylic Alkylation for the Introduction of Chiral Fluoroalkyl Groups

Researchers from the University of Geneva have developed a transition-metal-free method for the asymmetric installation of  fluoroalkyl groups.

Reaction Scheme

The Alexakis group found that the use of N-heterocyclic carbenes (2) in conjunction with Grignard reagents, enabled the highly selective synthesis of γ-functionalised products (3) from readily accessible starting materials (1). The reaction was initially performed in the presence of copper(l) salts, which afforded the desired products although regioselectivity and ee were suppressed.

A range of alkyl groups (R) could be introduced in moderate yields and very good levels of enantioselectivity (84–95%) from the corresponding Grignard reagent. Similarly, the reaction was tolerant of different aryl substituents (Ar). Exchanging the aryl component with cyclic alkyl groups did not affect the ee, however, the introduction of less bulky aliphatic groups caused enantioselectivity to plummet.

The demonstrated importance of fluoroalkyl groups in medicinal chemistry necessitates the development of new methods for the introduction of this important functional group. Alexander Alexakis and his group have developed the first asymmetric allylic alkylation reaction for the synthesis of quaternary centres containing fluoroalkyl groups; a method that may be of particular benefit to the pharmaceutical industry.

Read this HOT Chem Comm article today (free to access until the 13th of December 2012):

Formation of chiral fluoroalkyl products through copper-free enantioselective allylic alkylation catalyzed by an NHC ligand
David Grassi , Hailing Li and Alexandre Alexakis
Chem. Commun., 2012, 48, 11404-11406

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

Selective formation of (Z)-enynes via Zirconium catalysed alkyne dimerisation

Researchers from the University of British Columbia have developed a ‘head to head’ dimerisation of alkynes to provide (Z)-enynes in high yields.

The conjugated enyne products are important, both as intermediates for organic synthesis and in optoelectronics – a type of electronics that detect, source and control light. Therefore, new methods for the selective synthesis of these compounds are in demand.

Platel and Schafer have overcome regioselectivity problems often associated with alkene dimerisation.  The researchers used a readily accessible Zirconium catalyst (2) in conjunction with aniline as co-catalytic proton source.

A number of alkynes (1) were successfully dimerised to provide (Z)-enynes (3) in mostly high yields. The reaction is tolerant of a number of differentially substituted aryl compounds and also some alkyl rings.

The exclusive formation of (Z)-enynes was at odds with previously established mechanistic pathways for metal-catalysed alkyne dimerisation and led the researchers to further probe the mechanism. Complex 4 was isolated when a stoichiometric amount of aniline and complex 2 were mixed, leading the researchers to consider the validity of 4 as a catalytic intermediate. When 4 was mixed with alkyne (1) under the reaction conditions, complete conversion to (Z)-enyne (3) was observed. This result suggests that the unusual dimeric imido-bridged species is a viable intermediate in the reaction pathway.

This method represents an interesting development in catalytic and regioselective C­–C bond formation.

Read the ‘HOT’ Chem Comm article today:

Zirconium catalyzed alkyne dimerization for selective Z-enyne synthesis
Rachel H. Platel and Laurel L. Schafer
Chem. Commun., 2012, 48, 10609-10611
DOI: 10.1039/C2CC35913H

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

A new catalyst for asymmetric aziridination

Aziridines are used extensively as intermediates for organic synthesis. The strained three-membered heterocycles reveal amino groups on ring-opening and therefore provide access to a variety of useful products. Enantioselective methods for forming aziridine rings are highly desirable because enantiopure amino-compounds represent important targets for both natural product synthesis and in the discovery of novel therapeutics.

Researchers from Kyushu University in Japan have reported a newly designed Ru(CO)salen complex (4), which acts as an efficient catalyst for asymmetric aziridination of alkenes.

Reaction of olefinic substrates (1) with 2-(trimethylsilyl)ethanesulfonyl (SES) protected azide (2) in the presence of the Ru(CO)salen complex 4 afforded enantioenriched aziridine products. 4 efficiently decomposes azides under ambient conditions and also catalyses asymmetric aziridination.

Judicious selection of an appropriate azide protecting-group also influenced the design of the catalyst. The researchers chose to include an appropriately located C–F  bond within the ligand in order to improve tolerance of 4 to reacting electrophiles.

Low catalyst loadings enabled the highly enantioselective azirdination of a variety of substrates possessing conjugated or non-conjugated terminal or cyclic olefins.

Find out more – download the communication for free for a limited period.

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

First synthesis of potential sleeping sickness drug lead

Researchers from the University of Oxford have completed the first synthesis of (±)-hydroxyanthecotulide, an antiparasitic molecule that displays a number of other interesting biological activities.

David Hodgson’s group used their previously developed Cr(II)-catalysed allylation reaction to construct the molecule’s carbon skeleton. Alcohol 1 was constructed in a single step and then oxidised to aldehyde 2, which was used crude in an allylation reaction with 3 to give the anti-product (5) in good yields and high levels of diastereoselectivity.

 

The desired enone functionality was revealed by a Meyer-Schuster rearrangement of 5, which proceeded in excellent yield with in situ desilylation occurring under the reaction conditions.

1H and 13C NMR spectra of 6a were then compared with spectra of an authentic sample of (±)-hydroxyanthecotulide. Discrepancies in this spectral data encouraged the researchers to synthesise syn6b, by inversion of the C-4 secondary alcohol.

Gratifyingly, the spectra of syn-(±)-hydroxyanthecotulide (6b) was found to match data for the authentic sample and HPLC analysis provided further evidence to confirm that natural (±)-hydroxyanthecotulide, possesses syn-stereochemistry.

This research enabled the synthesis of both anti– and syn-(±)-hydroxyanthecotulide in 5 and 7 steps respectively, and may provide an attractive synthetic route for access to analogues of this biologically relevant family of molecules.

Download the full communication to find out more >

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

Selective condensations of saccharides

Researchers from Leiden University have developed a new method for the synthesis of βD-rhamnosides (5).

Gijsbert van der Marel’s group showed that C-6 thiophenyl ethers act as stereodirecting groups for condensation reactions of mannosyl donors (1), leading to 1,2-cis products.

They think the reaction proceeds via formation of a bicyclic sulfonium ion (2) that acts as a ‘reservoir’ for a reactive oxocarbenium species (3). Following reaction with an intermolecular nucleophile to form 4, desulfurisation provides the corresponding 1,2-cisD-rhamnoside (5).

The researchers demonstrated the method’s utility for assembling complex oligosaccharides by making tetrasaccharide 6. This tetrasaccharide forms part of the structure of Xanthomonas campestris pathovar campestris, the causative agent of a devastating disease affecting cruciferous crops such as cabbage and broccoli.

To find out more, download the group’s ChemComm communication.

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)

A radical approach towards the stephacidin alkaloids

Researchers from the University of Birmingham have developed a radical cascade process for rapid access to intermediates, which are important for the synthesis of alkaloids related to the stephacidin family.

Stephacidin A (1), along with other structurally related compounds, has been shown to possess activity against a number of tumour cell lines.

The group of Nigel Simpkins have demonstrated an elegant approach to the synthesis of the indoline core 3, present in a number of naturally occurring alkaloids.

Commencing from 4 ­­(available in five steps from tryptophan), a one-pot prenylation and sulfenylation sequence afforded cyclisation precursor 5 in good yield. Treatment of sulfenyl diketopiperazine 5 with Bu­3SnH and ACCN facilitated a double radical cyclisation to provide 6a and 6b. Pleasingly, isomers possessing the correct C6 stereochemistry represented the major products (4.6–3:1 depending on R group), and desired product 1 could be obtained following deprotection of 6a and 6b and subsequent purification.

This work represents an efficient entry into the stephacidin alkaloids and a potentially powerful method for the synthesis of other medicinally relevant analogues.

To read more on Simpkin’s indoline synthesis, download the ChemComm article.

Digg This
Reddit This
Stumble Now!
Share on Facebook
Bookmark this on Delicious
Share on LinkedIn
Bookmark this on Technorati
Post on Twitter
Google Buzz (aka. Google Reader)