Elegant syntheses

A more recent development in quinone chemistry has been the tandem reaction sequence. In seeking elegant syntheses of complex molecules, careful orchestration of transformations has become essential. The use of the Thiele-Winter reaction in tandem with arylation gives good yields of pharmacologically interesting heterocycles, such as (62), from 2,5-dihydroxy-l,4-ben2oquinone [615-94-1] and pyridines, where R = H or CH (60). 

The most important connective transforms in retrosynthetic analysis are the family of C=C cleavage transforms, including one-step (e.g. ozonolytic) or two-step (e.g. OSO4 followed by Pb(OAc)4) (Chart 25). There are many elegant syntheses of challenging molecules which depend on such processes. Two examples will provide an idea of the underlying retrosynthetic approach. 

When the Woodward-Eschenmoser synthesis began, it was known from the work of Bernhauer et al.5 that cobyric acid (4), a naturally occurring substance, could be converted directly into vitamin B12. Thus, the synthetic problem was reduced to the preparation of cobyric acid, a molecule whose seventh side chain terminates in a carboxylic acid group and is different from the other side chains. Two strategically distinct and elegant syntheses of the cobyric acid molecule evolved from the combined efforts of the Woodward and Eschenmoser groups and both will be presented. Although there is naturally some overlap, the two variants differ principally in the way in which the corrin nucleus is assembled. 

Two very short and elegant syntheses of the antiparasitic agent parvaquone 125 and the insecticide 124 isolated from Scrophulariaceae were developed using the dry-state absorption protocol [72,73] (Scheme 53). 

Hirsutine (58), the pseudo isomer of corynantheidine and dihydrocory-nantheine, has been elegantly synthesized by Wenkert and his collaborators (161). The reaction of keto diester290 with Meerwein s reagent, followed by hydrogenation, resulted in pseudo-type diester 321, which on reduction and methylation gave ( )-hirsutine (161). 

Demethoxycarbonyldihydrogambirtannine (71) was synthesized several times (189-191) before its isolation as a natural product from Ochrosia lifuana Guill. as well as Ochrosia miana H.Bn. ex Guill. (65). In the last decade, ( )-71 was elegantly synthesized by Wilcock and Winterfeldt (792) from an appropriately substituted cyclohexadienyltetrahydronorharmane derivative 349 via the Cope rearrangement, cyclization, reduction, and acid-treatment sequence. 

Electrochemistry offers a new and promising alternative for the generation of masked iminium ions. This approach is illustrated by the elegant syntheses of hygrine and hygroline (Scheme 22) (168). 

Several elegant syntheses of anthra-cyclinone aglycons are based on the ability to intercept the intermediate radical cation (76) formed from the oxidation of aromatic ethers (75) and (79) in situ with alkanols [9, 44, 45]. Inter- and intramolecular capture can occur. As illustrated in Scheme 19, the methodology leads to the facile construction of substituted quinone mono- and bisketals. 

The most spectacular examples of the wide applicability of this method are the elegant syntheses of strained cubane- and homocubanecarboxylic acid derivatives,52 which have partially been reviewed (Houben-Weyl, Vol. 4/4, pp 94-119). 

The assigned absolute configuration is supported by two elegant syntheses [63,64]. 

Synthetic applications of these photocycloadditions to aromatic compounds are sometimes hampered by low chemical yields and poor selectivity in the photoreactions. However, a number of elegant syntheses of tricyclic sesquiterpenes have been hased on intramolecular 1,3-phutocycloadditions ie.g. 3. SI), and these represent a completely new approach to the preparation of such systems. 

A great deal of literature attention has been devoted to polymers in this section as thermally stable polymers (B-80MI11101). While some very elegant syntheses have been conducted, the resulting polymers have been, for the most part, quite intractable materials not conducive to extensive screening for a variety of applications. Thus, aside from their bulk thermal performance, little else besides the conditions of synthesis is known about most of the polymers shown. Three notable exceptions about which considerable characterization and product information are available are poly(imides), poly(benzimidazoles) and poly(quinoxalines), and a short discussion is included concerning properties and applications of these polymers. 

W. S. Johnson and co-workers have produced several elegant syntheses of estrone. One of the shortest and most stereospecific follows ... 

Many of the most elegant syntheses of complex natural products are based on mechanistic speculation, as illustrated by the following postulated entry to stiychnine-based alkaloids. Thus, it was reasoned that treatment of the indole 1 with methyl chloroformate and a non-nucleophilic base followed by acid catalysed rearrangement would lead to the tetracycle 2. In practice, the first step worked well when Hiinig s base was used, but the second step, the acid catalysed rearrangement, failed to give 2. The only product, isolated in good yield, was the carbazole 3. 

Dehydrorotenone 1 can be readily transformed into rotenone 2 by reduction of the chromone to the chromanol followed by Oppenauer oxidation. Two elegant syntheses of dehydrorotenone 1 used DCC as a key reagent as follows (i) treatment of derrisic acid 3 with DCC/EtjN followed by reaction of the intermediate thus obtained with sodium propanoate in ethanol gave 1. (ii) Condensation of tubaic acid 4 with the pyrrolidine enamine derived from 5 in the presence of DCC also gave 1. 

Chapter 3 by S. Prabhakar and M.R. Tavares summarizes recent advances in the synthesis of Amaryllidaceae alkaloids, an important class of naturally-occurring bases and neutral compounds. The increased activity in the synthesis of these alkaloids over the last decade is undoubtedly due to the fact that certain members of this family possess interesting and useful biological properties. Many elegant syntheses, chiral and otherwise, of structures incorporating many asymmetric centres are reviewed. 

Several elegant syntheses of sphingosine bases — not involving carbohydrate derivatives — have also been reported recently [52-62, 313]. 

The cyclic ylide intermediate 366, as a 1,3-dipole, is generated by intramolecular reaction of Rh-carbene with the ketone in 365, and undergoes cycloaddition with n-bonds to give the adduct 367 [121]. When a-diazocarbonyls have additional unsaturation, domino cyclizations occur to produce polycyclic compounds. The Rh-carbene method offers a powerful tool for the construction of complex polycyclic molecules in short steps, and has been applied to elegant syntheses of a number of complex natural products. 

Elegant syntheses of representative members of this family of alkaloids have been completed. However, in spite of numerous efforts, lycorine (1) has resisted all synthetic approaches. 

The wide range covered by nearly forty contributions ensures a concise overview of the latest developments in the field, w hethcr they be new methods of C-C bond formation or race-mization, asymmetric phase-transfer catalysis or stereoselective metathesis reactions, solid phase reactions or particularly elegant syntheses of challenging natural products. 

Terminal attack occurs with water, methyl iodide, and trimethylchlorosilane, whereas central attack was preferred with alkenyl halides, aldehydes, and ketones at low temperatures under kinetic control [Eq. (5)]. The Et3SiO group is readily removed from 6 by potassium fluoride in isopropanol to give the vinyl ether RCH2CH2COCH=CH2 (61). Some of these reactions have also been used in elegant syntheses of terpenes (99-102). 

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-50], an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [51-53], This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocon-trolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2-pyrrolidinyl)isoxazole which has been found to have nanomolar activity, comparable to (5)-nicotine, against whole rat brain [54]. 

The use of chiral 1-oxa-l,3-butadienes for the stereoselective preparation of carbohydrates has also been investigated by Schmidt et al. [479]. The elegant syntheses of N-acetyl-/J-D-neuraminic acid derivatives are an impressive result of these studies [480]. 

Recently several excellent reviews have appeared which describe various aspects of pheromone synthesis (l- 7). Although many elegant syntheses of pheromones have been published, few of these routes are suitable for producing kilogram quantities. Efficient synthesis of these compounds depends on developing uncomplicated synthetic routes and simple purification procedures. 

On the other hand, Intramolecular versions of the magnesium-ene reaction commonly proceed in high yield, with good regio- and stereoselectivity, and have furnished elegant syntheses of the carbon skeleton of natural products. Oppolzer [32] has classified intramolecular magnesium-ene reactions as type I, in which the enophile becomes linked to the terminal carbon atom of the magnesium-ene unit, or type II, in... 

The dihydropyridines resulting from analogous reactions of /V-acyl- or N-alkoxycarbonylpyridinium salts may be isolated and characterized moreover, they are valuable intermediates in elegant syntheses of alkaloids. What is more, the /V-alkoxycarbonylpyridinium salts may be generated in situ by the reaction of the pyridine with a chloroformate even in the presence of a Grignard reagent [9], An example is a four-step synthesis of ( )-lasubine II (Scheme 5.2), and a procedure is given for the key step [10]. 

Bercaw and co-workers (118) have pursued some elegant syntheses and reactions of permethylated zirconocenes. They have observed the reduction of CO by H2 to methanol when Or)-C5Me5)2Zr(CO)2 (46) is treated with H2. 

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centers continue to be important in both academic and industrial laboratories (Nicolaou et al. 2003, 2006). In particular, catalytic asymmetric multicomponent domino reactions, used in the course total syntheses of natural products and synthetic building blocks, are highly desirable (Nicolaou et al. 2003, 2006 Tietze and Beifuss 1993 Tietze 1996 Tietze and Haunert 2000 Wasilke et al. 2005 Ramon and Yus 2005 Guo and Ma 2006 Pellissier 2006 Pellisier 2006 Tietze... 

A number of elegant syntheses of mixed-metal clusters have been accomplished through the condensation of unsaturated metal complexes with metal donors. For example, condensation of the unsaturated cluster H20s3(CO)io with the alkylidyne see Alkylidyne) complex CpW(CO)2(CR) produces H20s3W(/u.3-CR)(C0)i2. Metal-metal, metal-carbon, or carbon-carbon multiple bonds may serve as the sites for metal fragment condensation. Other examples are shown in equations (80 and (9). 

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