Author Archive

Highly scalable and step-economical synthesis of a spongistatin 1 fragment for anti-cancer therapeutics

Spongistatin 1 is a highly cytotoxic natural product derived from a marine sponge.  In addition to its exquisite biological activity against human cancer cell lines, the structural complexity of spongistatin 1 has captured the imagination of several organic chemistry groups.

A number of total syntheses of the spongistatins exist, but more recently, simplified analogs of the natural products have been tested for anti-cancer activity.

In order to further probe the biological efficacy of simplified spongistatin analogs– or indeed, fragments– researchers at Columbia University have developed new methodology for the synthesis of the A-B fragment 3 and its merger to the C-D spiroketal fragment 3.

In their most recent Chemical Science Edge article, the Leighton research group have described a synthetic blueprint that could enable the synthesis and testing of a library of ‘C-D spiroketal-modified’ analogs of spongistatin 1.  Towards this overarching goal, Samuel Reznik was able to synthesise 34.5 g of fragment 3 in around 60 days; an achievement that demonstrates both the ‘scalability and step-economy’ of this synthetic route.

The Leighton group hope to apply this route to the synthesis of a series of C-D analogs and also hope to develop a complementary synthesis of the E-F fragment to further explore the anti-cancer therapeutic potential of spongistatin 1 derivatives.

For more, read this HOT Chem Sci Edge article in full:

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts
Samuel K. Reznik and James L. Leighton
Chem. Sci., 2013, 4, 1497-1501
DOI: 10.1039/C3SC22186E

Alice Williamson is a guest web-writer for Chemical Science.  She is currently a postdoc for the OSDDMalaria Project in Dr. Matthew H Todd’s group at the University of Sydney.

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)

Studies reveal a stepwise Diels–Alder in the shortest synthesis of strychnine

Researchers from the University of California have used computational studies to uncover the mechanism of a key step in their synthesis of a powerful toxin.

Last year, Christopher Vanderwal’s group published a very elegant and efficient approach to strychnine (1), resulting in the shortest synthesis of this alkaloid to date. An intramolecular Diels–Alder reaction of a Zinke aldehyde (3) provided tetracyclic intermediate (2) as a single diastereoisomer.

Computational modelling, performed in collaboration with K. Houk’s group, provided evidence that stepwise anionic cycloadditions were operational as opposed to a concerted Diels–Alder reaction.

The presence of a potassium base was found to be essential for the stepwise Michael/Mannich cascade to occur. The potassium cation is thought to organise the aldehyde into the appropriate conformation for the initial Michael reaction to occur. Additionally, the formation of a stable potassium enolate is thought to be the driving force for the Mannich reaction. Subtle changes in the reaction conditions therefore influence the preference for the formation of 6 over cycloreversion to form 4.

The researchers are hopeful that these interesting findings will enable the application of related Diels–Alder reactions to a wider range of substrates.

Read Vanderwal’s Chemical Science Edge 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)

Pushing bonds to break

Researchers from Wuhan University and the Lanzhou Institute of Chemical Physics have described a sulfur-promoted cleavage of aryl–iodo bonds by a Pd(ll) species.

Aiwen Lei and co-workers showed that treatment of thioimido substrates (1) with a catalytic amount of a “pincer” Pd(ll) complex (2) at 80 ˚C could form thiazoles (3) in excellent yield.

In Nature, sulfur plays an important role in tuning the electronic properties of metals found in proteins. In analogy to the role of cysteine (a sulfur-containing amino acid), the incorporation of a donating sulfur ligand in the starting material (1) is thought to promote reaction of the Pd(ll) centre with the aryl-iodo bond. The reaction is thought to proceed via formation of complex A, whose structure has been confirmed by single crystal analysis.

Further investigations into the mechanism of this reaction are ongoing, but the researchers are hopeful that this work will enable new opportunities for the use of Pd(ll)–Pd(lV) chemistry, a powerful yet under-investigated catalysis mode.

Find out more by downloading Lei’s Edge article today.

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)

Copper-catalysed asymmetric allylic alkylation

Computation experiments by researchers from the University of Geneva have illuminated their understanding of chemistry they previously reported and, importantly, have led to an improvement of the original methodology.

Alexandre Alexakis’  group developed a copper-catalysed asymmetric allylic alkylation, which transforms a racemic starting material into an enantioenriched product.

asymmetric allylic alkylation

Computational modelling led to a revision of the original mechanistic explanation for the reaction outcome. The researchers propose that each enantiomer of the starting material undergoes divergent reactivity, where (R)-1 reacts through anti-SN2’ oxidative addition whilst its antipode (S)-1 reacts through anti-SN2. The regiodivergent oxidative addition leads to the formation of a common Cu(III) intermediate 2, which undergoes rapid reductive elimination to give the product (R)-3.

Reaction

This work clearly demonstrates the importance of acertaining mechanistic insight in order to improve the practical application of organic chemistry.

Download Alexakis’ Edge article 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)

Cascading construction of contiguous chiral centres

Researchers from the University of Reading have designed an organocatalysed cascade reaction for the construction of nitrocyclohexanes 4.

This elegant domino reaction enables the union of two achiral reagents to generate products containing up to five contiguous stereocentres in excellent levels of enantio- and diastereoselectivity.

thiourea catalysed construction of nitrocyclohexanes

André Cobb’s group employed a thiourea catalyst 3 to initiate a Michael-Michael cascade reaction between nitro-esters 1 and nitro-styrenes 2. The catalyst is thought to first coordinate to the nitro-ester prior to intramolecular deprotonation at the α-position to generate a nitronate. Synchronous coordination with nitrostyrene enables the first stereoselective Michael addition to generate a second nitronate primed for cyclisation onto the conjugated ester.

This cascade process demonstrates the power of organocatalysis for the asymmetric assembly of complex molecular architecture from simple starting materials.

Read more – download Cobb’s Edge article.

Researcher’s perspective:
The asymmetric synthesis of densely functionalised molecules with up to five contiguous stereocentres in one pot has been a difficult task until now. Our simple new cascade reaction has achieved just this with the synthesis of complex nitrocyclohexanes in excellent stereocontrol. This methodology has then been successfully employed in the synthesis of an alpha-lycorane derivative which is of potential medicinal interest.    
Sundaram Rajkumar, from the Cobb group
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)