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Sat Sep 30, 2017, 08:39 AM

A Beautiful Review Article on the Total Synthesis of Vancomycin.

Recently in this space, I mused on the biosynthetic origins of very complex natural products from the natural (by which I mean "genetically coded" ) amino acids.

A wonderful place to consider the interface of RNA catalysis and enzyme catalysis.

My post by the way, contains a statement that is wrong, this one:

We see some very complex natural products of extreme importance to humanity, the total synthesis of which remains even in these times synthetically inaccessible. Examples include the core of taxanes, an important class of cancer drugs, as well as many complex antibiotics like for instance, vancomycin, which clearly involves tyrosine and phenylalanine origins...

I certainly knew better about both taxanes and vancomycins, but somehow wrote this statement anyway. Perhaps I meant to say "industrially synthetically accessible." I can't say. I wrote that post apparently late at night, several weeks ago.


The lab scale synthesis of these kinds of molecules, including Vancomycin, is a part of a very beautiful scientific discipline, "natural product synthesis," for which many Nobel Prizes have been awarded.

I have just alluded to one reason for doing these kinds of syntheses, which is that they are beautiful, works of art, works of high art. The other reason is more practical. By understanding how to manipulate the features of molecules of this complexity, one can make analogues which may be better suited for reasons of pharmacokinetics, toxicology, and (very importantly) bioavailability, bioavailability being the property of delivering a drug to the cellular or biochemical pathologically active regions.

The total synthesis of Vancomycin has been reviewed in a very nice article in the current issue of Chemical Reviews, this one:

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

One of the authors is Dale Bolger, who received his Ph.D. from one of the great synthetic chemists of all time, E.J. Corey. (I have had two friends who worked in Corey's lab, both reported he was personally a bit of an ass, but irrespective of that, he is one of the greatest American scientists of all time.)

Bolger is one of the world's great synthetic chemists (now at the Scripps Institute) worked himself on Vancomycin syntheses, and reviews the great work of other labs.

Bolger's text reiterates the practical raison d’ętre for syntheses of this type, in the text of the introductory paragraphs of the review:

An important development in the field of glycopeptide antibiotics occurred in the late 1990s when three groups independently achieved the total synthesis of vancomycin. Given the sheer structural complexity of the natural product, this series of synthetic accomplishments was remarkable and at the frontier of the field of organic synthesis at that time. With reports of the rapid increase in resistant bacterial strains by health officials, this effort was driven not only by the challenge of developing an effective route to the complex natural product but also to pave the way for biological interrogation of previously inaccessible synthetic analogues. Herein, we review only work completing total syntheses of members of the vancomycin-related glycopeptide antibiotics, their aglycons, and synthetic analogues. Work on their semisynthetic modifications(1, 2) and methodological studies are not reviewed as they have been covered elsewhere.

The glycopeptide antibiotics are currently among the leading members of the clinically important natural products discovered through the isolation of bacterial metabolites. They possess a broad spectrum of antibacterial activity against Gram-positive pathogens with manageable side effects. Since their clinical introduction, the glycopeptide antibiotics vancomycin (1) and teicoplanin (6) have become the drugs of “last resort” when resistant bacterial infections are encountered (Figure 1). With the emergence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin (1) has been widely used in the clinic as the “go to” treatment.(3, 4) Originally restricted to hospitals, today more than 60% of both ICU (intensive care unit) and community acquired S. aureus infections are MRSA(5, 6) and were responsible for nearly 12 000 deaths in the United States in 2011 alone.(7) Moreover, infectious diseases (e.g., influenza and pneumonia), complicated by additional bacterial infections often requiring treatment with vancomycin, are ranked among the leading causes of death in the United States. The glycopeptide antibiotics are also recommended for use with patients allergic to β-lactam antibiotics and those undergoing cancer chemotherapy or ongoing dialysis therapy.(8) Consequently, the importance and clinical use of vancomycin continues to steadily increase since its introduction 60 years ago.(9) As vancomycin-resistant bacteria have been observed in the clinic in both enterococci (VRE, 1987)(10) and S. aureus (VRSA, 2002)(11-17) and as the prevalence of antibiotic-resistant pathogens has increased, discovery of the next-generation durable antibiotics capable of addressing such bacterial infections has become an increasely urgent problem.(18)

Since the establishment of the structures of glycopeptide antibiotics, extensive synthetic efforts have been made through both semisynthetic and total synthesis means. These studies have laid the foundation for ongoing structure–function studies of the antibiotics, aiding in the definition of their mechanism(s) of action. They have also elucidated unanticipated new roles for added non-naturally occurring functionality that have led to the discovery of improved or rationally designed glycopeptide antibiotics.

Here's a figure from the text which particularly appealed to me:

Figure 4. Evans retrosynthetic analysis of vancomycin aglycon.

Organic chemists will recognize that molecule 28 itself, an oxazolidone derived (probably by phosgenation) from (3-chloro-5-nitro-4-fluorophenyl)-β-hydroxyalanine, a early stage precursor in the Evans synthesis it itself a nontrivial synthetic target, owing to its substitution pattern. Early in my career, I had the pleasure of working on BOC and FMOC N protected oxalidones, albeit diones.

Final stages of the Evans synthesis:

Esoteric, but interesting, I think.

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Reply A Beautiful Review Article on the Total Synthesis of Vancomycin. (Original post)
NNadir Sep 2017 OP
eppur_se_muova Sep 2017 #1
NNadir Sep 2017 #2

Response to NNadir (Original post)

Sat Sep 30, 2017, 02:05 PM

1. Piece of cake. ;)

Closest I ever came to anything like that was an Ullmann condensation -- anhydrous PhOK (from, um, elemental potassium in anhydrous PhOH -- lots of fun there), a little Cu(I), a robust aryl chloride, and reflux. (That's refluxing phenol, of course ! Ah, good times.) Not even chiral -- I was making conjugated donors for charge-transfer complex formation.

More seriously, what's the 5:1 indicate ?? My only guess is rotamers, which would raise the obvious question, did they equilibrate under those mild reaction conditions ?

(In better times, I'd have full access through my employer -- can only view the abstract now.)

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Response to eppur_se_muova (Reply #1)

Sat Sep 30, 2017, 03:52 PM

2. From the text:

The final peptide coupling brought together the ABCD tetrapeptide 43 and the acyclic tripeptide 44 and was conducted with EDCI, remarkably without detectable epimerization (Scheme 4). The final macrocyclization of the 16-membered DE ring system was accomplished with a second room temperature SNAr reaction for diaryl ether formation, using CsF (DMSO) and providing selective formation of the natural P atropisomer 45 (5:1 ratio) in high yield (95%).59,60,67 After subsequent reduction of the nitro group to the aniline, the diastereomers could be separated by column chromatography. The appropriately functionalized E ring 46 was formed through a Sandmeyer substitution reaction upon CuCl and CuCl2 treatment of the aniline-derived diazonium tetrafluoroborate salt.72−74 Next, the masked C-terminus N-methylamide was nitrosated with dinitrogen tetraoxide (N2O4) and subsequently hydrolyzed with LiOOH in 68% yield.68 Despite the potential nitrosation at other amide sites, the documented steric effects of such a competitive reaction with amides were defined,68,69 aiding in the designed and implemented selectivity first explored in the total synthesis of the orienticin aglycon.49,50 Allyl ether cleavage followed by hydrogenolysis cleavage of the benzyl ethers, using transfer hydrogenation conditions (Pd/C and 1,4-cyclohexadiene) to avoid dechlorination, afforded 49.75 The final step in the conversion to vancomycin aglycon (50) was achieved by acid-catalyzed N-terminus Boc and asparagine residue Ddm removal (83%).

The atropisomers could be separated chromatographically, which means that they are fairly stable. But note that they were separated before several final synthetic steps.

There are several routes to these ring systems described in the paper. Many of the aryl couplings are Suzuki chemistry which is very popular if I recall correctly - I don't do much organic chemistry these days; only occasionally do I find cause even to comment on it, although, truth be told, the last time I commented on organic chemistry, it happened to involve vancomycin. (I remember going to a Trost lecture many years ago, where he had "the periodic table according to Trost" which featured all of the other elements in the periodic table in the background to a giant palladium. Palladium is, indeed, a great element, for organic people and inorganic people alike.)

PM me if you'd like the full paper.

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