Synthesis NANA

Carbon-carbon bond lyases, used in the reverse, synthetic direction have also enjoyed significant application in the pharmaceutical industry. For example 7/-acetyl-D-neuraminic acid (NANA), an intermediate in the chemoenzymatic synthesis of the influenza virus sialidase inhibitor zanamavir, may be synthesized using NANA aldolase. 

In nature, NANA arises through condensation of phosphoenolpyruvic acid with A-acetyl-D-mannosamine (NAM) catalysed by the biosynthetic enzyme NANA synthase. Owing to the labile nature of phosphoenolpyruvate, the use of this reaction in the synthesis of NANA has been limited to whole-cell systems where this substance can be generated biosynthetically in situ Most recently, the NANA synthase reaction forms the basis of fermentation processes for total biosynthesis of NANA. ... 

Catabolic enzyme NANA aldolase catalyses cleavage of NANA to form NAM and pyruvic acid, the latter being a more attractive material for a chemoenzymatic process. It has long been known that the reverse reaction may be used for NANA synthesis. However, this approach to a manufacturing process also has complications. 

N-Acetvlneuraminic Acid Aldolase. A new procedure has also been developed for the synthesis of 9-0-acetyl-N-acetylneuraminic acid using the aldolase catalyzed reaction methodology. This compound is an unusual sialic acid found in a number of tumor cells and influenza virus C glycoproteins (4 ). The aldol acceptor, 6-0-acetyl-D-mannosamine was prepared in 70% isolated yield from isopropenyl acetate and N-acetyl-D-mannosamine catalyzed by protease N from Bacillus subtilis (from Amano). The 6-0-acetyl hexose was previously prepared by a complicated chemical procedure (42.) The target molecule was obtained in 90% yield via the condensation of the 6-0-acetyl sugar and pyruvate catalyzed by NANA aldolase (Figure 6). With similar procedures applied to KDO, 2-deoxy-NANA and 2-deoxy-2-fluoro-NANA were prepared from NANA. 

Table X shows results of reactions of 3-cyclohexyl-trans-2,3-epoxypropan-l-ol (8) with NaNs supported on various cation-exchanged Y-type zeolites, silica, and alumina, and with a mixture of MejSiNj and Ti(0 Pr)4 as a control experiment with a homogeneous system. Concerning the use of zeolite-supported NaNa, both the reactivity and regioselectivity in the synthesis of 8a/8b are greatly influenced by the type of cation in the zeolite NaNj on CaY showed the highest reactivity and selectivity (94%). It should be noted that the high performance with NaN3/CaY is superior to that with the homogeneous system of Me3SiN3-Ti(0 Pr)4 (31).

Figure 6-15. Synthesis of sphingolipids. NANA = W-acetylneuraminic acid G/c = glucose Gal = galactose GalNAc = N-acetylgalactosamine PIP = pyridoxal phosphate FA = fatty acyl groups derived from fatty acids = hydrophobic chains of ceramide. The dashed box contains the portion of ceramide derived from serine.

Acyl azides. A one-pot synthesis of RCONj from carboxylic acids is through reaction with PhjP, NCS, and NaNa in acetone. 

Sialic acid (NANA), other amino sugars Glutamine Most cells In the liver, synthesis of oligosaccharide chains on secreted proteins. Most cells, glycoproteins, proteoglycans, and glycolipids. 

Figure 8. Top, synthesis of 9-deoxy-9-fluoro-NANA from 6-deoxy-6-f1uoro-N-acetyl-D-glucosamine (27). (a) Potassium di-tert-butyl-oxaloacetate-MEOH (epimerization), (b) condensation and hydrolysis. Bottom, synthesis of 9-deoxy-9-fluoro-NANA from NANA (27). (a) Benzyl bromide-Ba(OH)o-DMF, (b) AcOH-HoO (70%),...

Scheme 56 Synthesis of 3-(5-tetrazol)d)pyridines 285 from nicotino-nitrUes 284. HN3 = a NaNa, AcOH, m-BuOH b NaNa, ZnBr2, H2O c MeaSiNa, Bu2SnO, dioxane (also microwave assisted) [193]...

The goal of the work on architecture synthesis within the Ascis and Nana projects has been to contribute design methodologies and synthesis techniques which address the design trajectory from real behavior down to the RT-level structural specification of the system. Our view of this synthesis process is illustrated in figure 1. 

Figure 1 Architecture synthesis as viewed within the Ascis and Nana projects. The input from the user is converted to a formal system model which can also be written out in a readable specification format. Different design trajectories must be followed, depending on the characteristics of the application. The figure only shows the two main branches we have addressed. The final high-level performance-driven controller synthesis is similar for both branches. In the next design stages, which have not been addressed by the projects, the detailed synthesis of the data-paths and controllers on the RT and logical levels still has to take place. This is then followed by the physical design stage.

Many of the new solutions and methods reported here have been derived within the scope of Nana, owing to the cross-fertilization between partners of complementary expertise. Chapters 4, 5 and 6 introduce several novel and practically oriented array synthesis approaches that have been stimulated by our experience with the APP and other demonstrators. 

The material in this book is based on work in the context of two research projects, Ascis (Architecture Synthesis for Complex Integrated Systems) and Nana (Novel parallel Algorithms for New real-time Architectures), both sponsored by the Esprit program of Directorate XIII of the European Commission. The chapters are partly based on material presented at the final project workshops, which took place at IMEC in Leuven, Belgium, on the 29th and 30th of April, 1992, marking the completion of three successful years of project cooperation. 

Figure 11.22 Possible pathways for the synthesis of gangliosides. Cer, ceramide Glc, glucose Gal, galactose GalNAc, N-acetylgalactos-amine CMP, cytidine monophosphate NANA, A/-acetylneuraminic add (sialic acid) UDP, uridine diphosphate. Reproduced from Gurr and James (1980) with permission.

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