B lactam synthesis – diabanmomisopelirosipoda
T1 - May phospholipid synthesis by a site of action of β-lactam antibiotics in Staphylococcus aureus?
T o t a l Synthesis of @-Lactam A n t i b i o t i c s B
This inaugural Woodward Wednesdays post will discuss the subject of Woodward's 1965 chemistry Nobel Prize lecture - work culminating in the synthesis of (+)-cephalosporin C. It was difficult to choose a synthesis to open the series with, as a lot of Woodward's papers are, quite rightly, considered classics and have been dissected elsewhere. Woodward's synthesis of strychnine, for example, crops up in a of , has a and is discussed at length in Nicolaou's Classics in Total Synthesis (Chapter 2) as well as T. Hud's Way of Synthesis (pages 803-808) and probably many other places besides; I'm not sure I can add much there that hasn't already been said! Woodward's reserpine synthesis, one of my top five syntheses of all time, is (unfortunately?) also covered in a similarly comprehensive fashion. Strangely, the cephalosporin synthesis remains much less well known, despite containing some excellent chemistry and a few 'Woodwardian' steps.
Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of -Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).
Acyl and sulfonyl isocyanates in .beta.-lactam synthesis
Unfortunately, as creative and original as the preceding sequence was, it had provided only compounds epimeric to those required to complete the synthesis. Thus, three steps (mesylation, displacement with azide and reduction using aluminium amalgam) were therefore required to convert, with inversion, the hydroxyl to the amine required for the β-lactam formation. Cyclisation was achieved with a little Lewis acid assistance, in the form of triisobutylaluminium.
The four-membered ring appears to be the smallest cyclic system that is capable of accommodating the amide function as a constituent. Such four-membered cyclic amides are commonly referred to as beta-lactams. The reluctance with which beta-lactams are formed using conventional methods of lactam synthesis has necessitated unique approaches to the problem. After 1943, interest in beta-lactams was stimulated by the importance of natural penicillins. Although there are at present several useful approaches to the beta-lactam ring systems, the synthesis of beta-lactams by a single general method is not possible. In principle, the synthesis of the beta-lactam ring might be accomplished by the formation of one, two, three, or all four bonds of the ring during the cyclization step. Of these four possibilities, only the last has been realized.
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Finally, with end in sight, the final ring was installed by a clever sequence beginning with 1,4-addition of the lactam nitrogen to the unsaturated dialdehyde shown below (which was made in three steps from tartaric acid). Don't forget that the small ring size in β-lactams minimises the resonance structure responsible for normal amide reactivity (i.e. through oxygen) so they are nucleophilic (and, incidentally, protonate) at nitrogen. Simultaneous cleavage of the acetonide and Boc groups with TFA also formed the second ring of the natural product by condensation of the thiol onto the nearby aldehyde in a cool one pot cascade. Finally, the known sidechain fragment was coupled on with DCC and its free acid was then protected as the 2,2,2-trichloroethyl ester by coupling with trichloroethanol, again using DCC. At this point, containing 9 chloride atoms, I imagine that the mass spec of this compound was pretty interesting. The enal was then reduced to the allyl alcohol using borane in THF, and this was then acetylated using acetic anhydride in pyridine. Further standing in pyridine for 3 days effected isomerisation of the double bond into conjugation with the nearby ester. Finally removal of all three protecting groups using zinc dust in 90% acetic acid gave the natural product which was 'identical with natural material in paper chromatographic behavior, and in antibacterial activity against Neisseria catarrhalis, Alcaligenes faecalis, Staphylococcus aureus, and Bacillus subtilis'. A great synthesis, conducted without NMR, or apparently even TLC!
The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 /. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.
beta lactam antibiotics and other cell wall synthesis
β-lactam antibiotic - Wikipedia
Thermodynamically controlled synthesis of b-lactam antibiotics. Equilibrium concentration and side-chain properties
Staudinger Synthesis - Organic Chemistry Portal
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The subsequent cycloaddition delivers the β-lactam: ..
A new .beta.-lactam synthesis
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