Synthetic strategy route

Scheme 63 illustrates another synthetic route leading to the penam ring system (78JA4597). lis sequence contains some interesting points of synthetic strategy which are discussed in... 

Literature reports on synthetic methods for the construction of the pyrimidinone core were very limited. Most of the synthetic strategies toward the densely functionalized core fell into two methodologies, which start from the same amidoxime 13 (Scheme 6.3). Route A is a three-step sequence that involves hydrogenation of 13 to prepare amidine 14. Claisen condensation of commercially available a-benzyloxy acetate and methyl tert-butyl oxalate provides the dihydroxyfumarate... 

The synthesis of carbonyl colorants uses a wide diversity of chemical methods, in which each individual product essentially has its own characteristic route. This is in complete contrast to the synthesis of azo dyes and pigments (Chapter 3) where a common reaction sequence is universally used. The subject is too vast to attempt to be comprehensive in a text of this type. The following section, therefore, presents an overview of some of the fundamental synthetic strategies which may be used to prepare some of the more important types of carbonyl colorants. 

The reaction of lactam 79 with 4-fluorophenylboroxine and 1 equiv. (with respect to boron) of water in the presence of Rh(acac)(C2H4)2/( )-BINAP afforded 63% yield and 97% ee of (U)-80, a precursor to (-)-paroxetine (Scheme 37).113 This route offered a better synthetic strategy than the reaction carried out under usual reaction conditions. 

Solution-based synthetic strategies for one-dimessional nano-structures by Wang and Li (2006). Recent progress in the solution-based routes to prepare onedimensional nano-structures are reviewed. The role of crystal structure in the determination of the growth behaviour of the nano-crystals is underlined. 

Any study of colloidal crystals requires the preparation of monodisperse colloidal particles that are uniform in size, shape, composition, and surface properties. Monodisperse spherical colloids of various sizes, composition, and surface properties have been prepared via numerous synthetic strategies [67]. However, the direct preparation of crystal phases from spherical particles usually leads to a rather limited set of close-packed structures (hexagonal close packed, face-centered cubic, or body-centered cubic structures). Relatively few studies exist on the preparation of monodisperse nonspherical colloids. In general, direct synthetic methods are restricted to particles with simple shapes such as rods, spheroids, or plates [68]. An alternative route for the preparation of uniform particles with a more complex structure might consist of the formation of discrete uniform aggregates of self-organized spherical particles. The use of colloidal clusters with a given number of particles, with controlled shape and dimension, could lead to colloidal crystals with unusual symmetries [69]. 

All major synthetic routes to mesoporous silica involve use of a template to achieve mesoporosity. The templates that are most commonly used are surfactants or block copolymers. Below we describe the synthetic strategies for mesoporous silica MCM-41 and SBA-15" , which are representative of this class of materials. 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

The ready accessibility of 1,2-dioximes (glyoximes) and the ease with which they are dehydrated has ensured that this is the most common route to furazans. The starting materials are usually prepared by oximation of the appropriately substituted 1,2-diketone or, more often, by a-nitrosation of an alkyl ketone followed by oximation of the resulting 1,2-dione monooxime (Scheme 16). 1,2-Dioximes can also be prepared by reduction of furoxans (Section 4.05.5.2.4) and, in cases where the furoxan is more readily available than the furazan, for example, by nitrile oxide dimerization, this furoxan-> glyoxime-> furazan sequence represents a viable synthetic strategy for symmetrically substituted derivatives. 

Figure 7. Divergent synthetic strategy to obtain polynuclear metal complexes of dendrimer shape. - ° Each deprotected compound of the dive ent synthetic approach can be used as a core in convergent synthetic processes. Some of these routes starting from a tetranuclear core are illustrated in Figure 8.

Different synthetic routes have been used to prepare these carbenes (Scheme 8.6). The most common procedure is the deprotonation of the conjugate acid. In early experiments, sodium or potassium hydride, in the presence of catalytic amounts of either f-BuOK or the DMSO anion were used. ° Then, Herrmann et al. showed that the deprotonation occurs much more quickly in liquid ammonia as solvent (homogeneous phase), and many carbenes of type IV have been prepared following this procedure. In 1993, Kuhn and Kratz" developed a new and versatile approach to the alkyl-substituted N-heterocyclic carbenes IV. This original synthetic strategy relied on the reduction of imidazol-2(3//)-thiones with potassium in boiling tetrahydrofuran (THF). Lastly, Enders et al." reported in 1995 that the 1,2,4-triazol-5-ylidene (Vila) could be obtained in quantitative yield from the corresponding 5-methoxy-l,3,4-triphenyl-4,5-dihydro-l//-l,2,4-triazole by thermal elimination (80 °C) of methanol in vacuo (0.1 mbar). 

Overall, the chiral auxiliary approach to sitagliptin using (S)-PGA to install the amino group via diastereoselective hydrogenation resulted in a reduction of three chemical steps in the overall synthesis. This new synthetic approach essenhally followed the same convergent strategy (Route A on Scheme 5.8), but represented a big improvement over our previous route. The convergent approach made sense since the triazole heterocycle was a valuable intermediate that required an elaborate preparation with a modest yield of 26%. 

Having thus demonstrated the feasibility of two solid-phase routes affording 3,5-disubstituted 1,5-benzothiazepin-4-ones 2A-D (Scheme 2) or of the molecular type 30 (Scheme 4), we now attempted to further generalize the scope of the synthetic strategy. Interchanging Fmoc-cysteine 10 for Fmoc-penicillamine 31 and Fmoc-homocysteine 32 should potentially provide access to 2,2-dimethyl-l,5-benzothiazepin-4-ones 2b and 1,6-ben-zothiazocin-5-ones (3), respectively. Gratifyingly, both routes could be enabled almost without any additional chemistry optimization work (see Scheme 5). 

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