Amen...
http://www.coronene.com/blog/?p=1017
Sunday, October 11, 2009
Wednesday, October 7, 2009
Cancer doesn't like sugar chemistry
I shuddered when I saw the sugary graphical abstract for Danishefsky's recent JOC Note, "A Practical Total Synthesis of Globo-H for Use in Anticancer Vaccines." (doi: 10.1021/jo901682p) And then a moment later, I realized... anticancer vaccines?! Where the hell have I been? Apparently, this glycosphingolipid compound Globo-H is an antigen that was isolated in 1983 from a breast cancer cell line, and is now known to also be over-expressed on the surface of other types of cancer cells (prostate, ovary, lung, colon, and small cell lung cancers). Administration with alpha-galactosylceramide induces antibodies against globo-H and SSEA3 (the pentasaccharide precursor of globo-H). If I understand correctly, it's the equivalent of administering a dead or partial or similar virus in order to trigger the formation of antibodies. The pentavalent vaccine also contains other antigens that are overexpressed on cancer cells (prostate and breast). A search for "globo-h" on pubs.acs.org alone produces 118 hits, encompassing syntheses, development, and animal studies.
There have been other syntheses, including that of Schmidt, Boons, Wong, Seeberger (2002 and 2007), and Huang referenced in Danishefsky's paper, and an earlier synthesis of his as well which was too low-yielding. The ABC trisaccharide that will be incorporated later was synthesized according to the previously reported Cp2Zr(OTf)2-mediated coupling. The starting material was synthesized via α-epoxidation followed by glycosylation to produce the DE disaccharide shown below; coupling of this molecule with the thiofucosyl donor (with fucose being a hexose deoxy sugar) selectively produced the α-trisaccharide. The conditions screened that produced the highest yield, 80%, were Cp2Zr(OTf)2 with 5:1 toluene:THF and 2,6-di-t-butylpyridine(hindered base) in the dark over 72 hours, but the conditions the authors moved forward with produced an impressive 78% yield in only 4 hours:
That's not so scary - silver triflate draws the chlorine away from TolSCl, which pulls -STol in after the alcohol displaces it. The next step involved a (to me) funky iodine reagent, I(coll)2ClO4 to promote iodosulfonimidation of the now DEF glycol. The sulfonamide blocks any attack from the bottom face of the ring, forcing the nucleophile in the next step to attack from the top to form the β-isomer. Treatment of the crude intermediate with lithium ethanethiolate leads to the complete DEF donor in 75%, ready for coupling with the ABC acceptor.
There have been other syntheses, including that of Schmidt, Boons, Wong, Seeberger (2002 and 2007), and Huang referenced in Danishefsky's paper, and an earlier synthesis of his as well which was too low-yielding. The ABC trisaccharide that will be incorporated later was synthesized according to the previously reported Cp2Zr(OTf)2-mediated coupling. The starting material was synthesized via α-epoxidation followed by glycosylation to produce the DE disaccharide shown below; coupling of this molecule with the thiofucosyl donor (with fucose being a hexose deoxy sugar) selectively produced the α-trisaccharide. The conditions screened that produced the highest yield, 80%, were Cp2Zr(OTf)2 with 5:1 toluene:THF and 2,6-di-t-butylpyridine(hindered base) in the dark over 72 hours, but the conditions the authors moved forward with produced an impressive 78% yield in only 4 hours:
The last coupling proceeds without fuss in 72% yield after treatment with methyl triflate. Deprotection of TIPS with TBAF and Bn with sodium reducing conditions followed by global peracetylation leads to the target hexasaccharide:
The last steps to append this molecule to the carrier protein KLH (keyhole limpet hemocyanin) were previously published by Danishefsky and co-workers, as was to covalently link the molecule to an amide (doi: 10.3987/COM-08-S(D)82). I'll add those as soon as Heterocycles loads on my work laptop tomorrow.
Saturday, October 3, 2009
Uranium = C-H Activation
Uranium is the 92nd element, and the last naturally occurring element, in the periodic table. I've always held an intense disdain for it since my final project in junior Inorganic Chemistry was to elucidate the energy levels and their symmetry of UO2. F AND d orbitals? Seriously? No one else had to deal with f orbitals. I know it was a test because I was a straight A student and he wanted to see if I was as brilliant as I seemed... nope. It was an awful presentation, and a classmate was nice enough to bring me home on her red, brand new Vespa to cheer me up. (Bitch.) Anyway, what I didn't know at the time was that organouranium compounds, and organoactinides on the whole, are actually freaking awesome. Uranium complexes can catalyze oligomerization, dimerization, hydrosilation and hydroamination of terminal alkynes, hydrogenation of arenes, polymerization of olefins, and coupling of isonitriles with terminal alkynes, all extensively reviewed in Coordination Chemistry Reviews in 2006 (doi:10.1016/j.ccr.2005.12.007). It's a really interesting review, even if you just check out the schemes. Another published last year on organouranium and organothorium specifically is also worth checking out (doi 10.1039/b614969n).
What caught my eye was a paper that just came out in Early View in ACIE by the Diaconescu group at UCLA, in which examined the reaction of a dibenzyl uranium complex with multiple equivalents of methylimidazole. They found that instead of merely coordinating, as one would expect such a heterocycle to do with a transition metal, the metal center inserted itself into the C2 position's C-H bond on two separate methylimidazole molecules; a third equivalent coordinates via the lone pair. By using deuterated benzene as the solvent, they were able to observe that two equivalents of toluene are also formed, confirming the C-H insertion steps. Mechanistically, uranium doesn't proceed through oxidative addition or reductive elimination steps like the transition metals; rather, it goes through a sigma-bond metathesis type 4-center transition state. The C-H insertion positions are highlighted in red.
That's not all - after the imidazoles are bonded to uranium, crazy sh#t happens. Two of the imidazoles couple, which prepares one for ring-opening, then migratory insertion to create a crazy structure that I wouldn't believe if they weren't supported by crystal structures. It's not surprising that it requires a lot of heat and a lot of time to accomplish.
What caught my eye was a paper that just came out in Early View in ACIE by the Diaconescu group at UCLA, in which examined the reaction of a dibenzyl uranium complex with multiple equivalents of methylimidazole. They found that instead of merely coordinating, as one would expect such a heterocycle to do with a transition metal, the metal center inserted itself into the C2 position's C-H bond on two separate methylimidazole molecules; a third equivalent coordinates via the lone pair. By using deuterated benzene as the solvent, they were able to observe that two equivalents of toluene are also formed, confirming the C-H insertion steps. Mechanistically, uranium doesn't proceed through oxidative addition or reductive elimination steps like the transition metals; rather, it goes through a sigma-bond metathesis type 4-center transition state. The C-H insertion positions are highlighted in red.
The intermediates in brackets were not able to be isolated in this case, but when 1-methylbenzimidazole was used instead of 1-methylimidazole, the reaction stopped at the first intermediate directly after the imidazole coupling, and they were able to isolate and confirm the structure of the complex. Here are the crystal structures of the reaction with 1-methylimidazole to compare with the products (with 50% and 35% ellipsoids, respectively).
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