Features of the Synthesis

The split-mix synthesis has several key features that are crucial in the utility of the method in drug discovery or other kinds of applications. 

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In this section, only salient features of the synthesis, physicochemical properties, and reactivity of major derivatives of 2-aminothiazole and 2-imino-4-thiazoline are summarized. Further details on each compound are found in associated references collected in Section VII. The synthetic methods reported in this section exclude heterocydization methods treated in Chapter II but given in specific references found in Section VII. 

An interesting feature of the synthesis is the use of allyl as a two-carbon extension unit. This has been used in the stereospecific synthesis of dicyclohexano-18-crown-6 (see Eq. 3.13) and by Cram for formation of an aldehyde unit (see Eq. 3.55). In the present case, mannitol bis-acetonide was converted into its allyl ether which was ozonized (reductive workup) to afford the bis-ethyleneoxy derivative. The latter two groups were tosylated and the derivative was allowed to react with its precursor to afford the chiral crown. The entire process is shown below in Eq. (3.59). 

The olefin metathesis reaction was also a key feature of the synthesis of epothilone A completed by a group at the Technical University in Braunschweig, Germany (Scheme 13.61). This synthesis employs a series of stereoselective additions to create the correct substituent stereochemistry. Two enantiomerically pure starting materials... 

A new approach to ( )-deserpidine has been published by Wenkert (264) in preliminary form. The characteristic feature of the synthesis is the addition of a nucleophile to a pyridinium salt, followed by acid-induced ring closure. For the preparation of the desired pyridinium salt 532, nicotinaldehyde was condensed with methyl methoxyacetate, and the methyl acrylate derivative 531 was alky-... 

This complex functions as a safer and more convenient source of H2SiCl2. General features of the synthesis are short reaction times, high yields, simple apparatus, and a routine workup that produces very pure product. The major advantage, of course, is the elimination of the need to handle dichlorosilane. A synthesis of SiH2Ph2 from [SiH2Cl2 teeda] is included to show the utility of this new reagent. 

A similar pathway is thought to be involved in the synthesis of chromenes from coumarin (see Section 2.23.6.4.1), whilst the spontaneous dehydration of the alcohol (97) to the ketochromene (98), which occurs during acid hydrolysis, also presumably proceeds through the same type of intermediate. This step is an important feature of the synthesis of siccanochromene A, a fungal metabolite, from orcinol and the aldehyde (96) outlined in Scheme 10. Another point of interest in this route is the use of heteroatom-facilitated metallation to achieve the correct orientation (71T6073). 

A special feature of the synthesis described here is the glass apparatus used to achieve high-dilution reaction conditions (Figure 1).4 This "trident" is simple but effective and can be fabricated quite easily from standard parts. The one shown here is designed to accept an overhead mechanical stirrer. 

An important feature of the synthesis of heteroaromatized derivatives of azoloazines via their dihydro analogues is high regioselectivity when R is not the same as R2 (Scheme 3.88) in comparison with reactions of aminoazoles with (3-diketones with the same R and R2 substituents. 

Convergent assembly using a monofunctionalised AB2FG-type monomeric branching building block. Random monofunctionalisation of dendritic branches on monomeric building blocks is a necessary feature of the synthesis. 

An important feature of the synthesis of substituted benzodiazepines is the stereochemistry of the substituents in the reduced heterocyclic ring. In this context, further studies on the preparation of enantiomeric 3-amino- and 3-methyl-benzodiazepines have been published <95JOC730>, <95T(A)849>, <95ii(4(>)7i7> The asymmetric reduction of the 3,4-double bond in 4-methyl-2,3-benzodiazepines is also reported <95JCS(PI)1423>. 

A new synthesis of ( )-crinane (13) (Scheme 2) may be applicable to Amaryllidaceae alkaloids.5 Key features of the synthesis are the preparation of the acid (10) by Claisen rearrangement of the allylic acetate (9) and intramolecular ene reaction of a protected acylnitroso-enophile (11) to give the cyclic hydroxamic acid (12). 

The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(ll)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1. If). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-configuration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained... 

The synthetic route used to prepare atenolol is shown in Scheme 8.3 [60]. One of the notable features of the synthesis involved simply stirring a suspension of the methyl or ethyl ester intermediate in aqueous ammonia at ambient temperature whereupon quantitative yields of the primary amides were obtained. 

A synthesis recently reported by Sharpless of MIT and his coworkers appears to be the most promising of those described since 1974 (10). Its advantage lies In the formation of an optically active epoxide In 90 to 95 percent enantiomeric excess. Thus, by avoiding separation of diastereomers, It eliminates a potentially difficult and wasteful feature of the synthesis. 

The synthesis has been evaluated In a number of laboratories, including our own. Modifications may be made over several stages to Improve yields but the basic features of the synthesis recommend It as a convenient and economical route. 

An alternative synthesis, suitable for bulky wingtip groups, was introduced by Mercer et al. [53]. The key feature of the synthesis is the reductive dimerisation of a Schiff base by a base metal (manganese, magnesium or zinc) in the presence of trifluoroacetic acid (see Figure 5.13). 

Vishnev A.A., Himov E.G., Kolbanev l.V. et al. Specific features of the synthesis and the properties of high-temperature superconductor YBa2Cu20, obtained by mechanochemical activation of the initi oxides. Superconductivity Physics, Chemistry, Technology 1990 3 2390-99. 

Oxidation of (5) with freshly sublimed selenium dioxide in refluxing 97% aqueous ethanol gave the aldehyde (6) in 54 % yield. Addition of (6) to 10 molar eq. of the dilithio salt of 3-butyn-2-ol in THF gives the acetylenic triol (7), which is reduced to the triene (8) with excess sodium in liquid ammonia-THF and a trace of ethanol. The final step is oxidation of (8) with activated manganese dioxide (Winlhrop Laboratories, New York City) at 0 in chloroform. An important feature of the synthesis is that the highly reactive 1,4-diene-3,6-dione system is generated in the final step. 

One of the nice features of the synthesis used by Berson and Pedersen to prepare optically active trans-cyclopropane-l,2-d2 is that it involved synthesis of optically active trflns-phenylcyclopropane-2-d as an intermediate. It was thus possible from one synthetic sequence to determine not only the mechanism of stereomutation of the dideuterated cyclopropane but also to find out what effect, if any, a phenyl substituent had on the mechanism. 

Tetrahydrido(i -pentamethylcyclopentadienyl)iridium was synthesized in 1982, and proved to be a useful precursor for several iridium complexes of varied oxidation state.The tetrahydride and its derivatives are among the very few iridium(V) polyhydrides that do not contain phosphine ligands. No alternative preparation of the title complex has been reported. The key feature of the synthesis described here is the oxidation of the iridium(III) intermediate to the iridium(V) product during work-up of the reaction mixture. ... 

Acylating ring opening of ACmethylaziridine is a key feature of the synthesis of dasycarpidone (165) and epidasycarpidone (166) (Scheme 33). The reaction of A-methylaziridine (159) with a-bromobutyryl chloride (160)... 

Allylsilanes, which are accessible by bis-silylation of 1,3-dienes and silylation of allylic substrates, are useful allylation reagents in organic synthesis [99, 100] ( , )-l,8-bis(Trimethylsilyl)octa-2,6-diene 63a, prepared by palladium-catalyzed bis-silylative dimerization of 1,3-butadiene, was successfully applied to the synthesis of dZ-muscone (Scheme 8) [58]. A key feature of the synthesis is regi-oselective reaction with acetaldehyde at the positions y to the silyl groups. 

The remarkable feature of the synthesis of pyrrole from coordinated dinitrogen is that the original N2 compounds 1 are recovered in moderate yield when the metal-containing products [MH4(dppe)2] in the reaction of the pyrrolylimi-do complexes with LiAlH4 are treated with N2 under irradiation. This completes the cyclic reaction pathway for the synthesis of pyrrole from N2 as illustrated in Scheme 7. 

E.A. Vasil eva, et al., Specific features of the synthesis of porous materials based on a magnesium-aluminum spinel. Glass Pltys. and Chem. 29(5), 490-493 (2003). 

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