Early Synthetic Approaches

The initial synthesis of a trifluoromethyl-substituted transition metal compound occurred when trifluoroacetyl manganese pentacar-bonyl was first formed, then thermally decarbonylated as shown in Eqs. (1) and (2) (14-16). 

This indirect, two-step procedure for the synthesis of trifluoromethyl derivatives of transition metals was developed after it had become evident that the reaction of CF3I with metallate ions such as Mn(CO)5 resulted in the formation of the iodide rather than the expected trifluoromethyl derivative, as indicated in Eq. (3) (16). 

Since 1959, a number of other trifluoromethyl transition metal derivatives have been formed from thermal decarbonylations of trifluoroacetyl complexes. Examples of compounds which have been formed by trifluoromethyl migration are listed in Table I. 

Evidence for CO insertions into CF3-metal bonds, a reaction which is presumably the reverse of the methyl migration step, has been sought in several instances (25), but, as yet, no CF3-metal derivative generated in this manner has been isolated. However, upon UV irradiation of CF3Mn(CO)5 held at 17 K, vibrational spectra were obtained that were consistent with the formation of a trifluoroacetyl manganese species. The product was not separated (26). 

Immediately upon their isolation, trifluoromethyl-containing derivatives of (low valent) transition metals were universally found to be much more robust, both thermally and oxidatively, than their methylated counterparts. Many perfluoromethyl complexes, for example, have been found to be unreactive in air whereas the corresponding methyl derivatives are air sensitive. Under anaerobic conditions a number of trifluoromethylated species decompose at temperatures approximately 100°C higher than the analogous methylated compounds. 

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Cox and Owen [42] and Whistler and Campbell [43] provided early synthetic approaches to the 6-thioseptanose system. The latter workers prepared a protected open-chain 6-thio dithioacetal of D-galactose that, upon deprotection at C-1 and S-6, could be cychzed to form the corresponding l,2,3,4,5-penta-0-acetyl-D-galacto-6-thioseptanose 37. From this intermediate, several derivatives, such as both anomers of the thioseptanosyl chloride as well as the methyl thioseptanosides, were synthesized. The methyl thioseptanoside was found to be more prone to hydrolysis than the corresponding sulfur containing pyranoid glycoside. 

Early synthetic approaches to nucleosides with sulfur in the furanose ring were reported by Reist and coworkers [10,15], and Whistler and his group [11,17,120], mainly aiming at synthesizing antibacterial agents [121,122]. 

These natural products have each been synthesized via several routes and by different research groups. To provide an historical perspective, we have selected compounds that were synthesized in different decades, allowing for comparison of early synthetic approaches with modern ones. With your exposure to modern organic... 

Scheme 133 The early synthetic approaches towards unsubstituted hexa-perr-hexabenzocoronene (HBC 1).

The first synthesis of BDT molecule was reported in as early as 1971 [11]. However, the early synthetic approach was rather... 

Estrone (54, Chart 6) contains a full retron for the o-quinonemethide-Diels-Alder transform which can be directly applied to give 55. This situation, in which the Diels-Alder transform is used early in the retrosynthetic analysis, contrasts with the case of ibogamine (above), or, for example, gibberellic acid (section 6.4), and a Diels-Alder pathway is relatively easy to find and to evaluate. As indicated in Chart 6, retrosynthetic conversion of estrone to 55 produces an intermediate which is subject to further rapid simplification. This general synthetic approach has successfully been applied to estrone and various analogs. ... 

The interest in indolocarbazoles began in the early 1950s with the first rational synthetic approaches. Since then, this interest has escalated dramatically as numerous derivatives of indolo[2,3-a]carbazole (1) have been isolated from various natural sources. These derivatives were demonstrated to possess highly potent and diverse biological effects, prompting novel efforts in the area. In particular, derivatives of indolo[2,3-n]pyrrolo[3,4-c]carbazole, such as the alkaloid staurosporine (8), have attracted much attention. 

For more than two decades Woodward s total synthesis1 1 "d of chlorophyll a was in fact the only total synthetic approach to a chlorin. When, in the early eighties, new chlorin-type natural products were isolated from different biological sources, a systematic investigation of selective synthetic approaches leading to chlorins was induced.4... 

In our early designs, we indeed ignored the perfectly plausible regiochemical orientation shown as 3B, which could lead to a disaster. Furthermore, our tunnel vision was enhanced by the fact that all the synthetic approaches reported at the... 

Early work focused on compounds with open-chain carbenes generally synthesized in the coordination sphere of the gold atom, for example, by addition of amines or alcohols to isocyanide ligands in the corresponding gold complexes. Subsequent synthetic approaches have relied on the in situ deprotonation of onium salt precursors by a... 

Since the early contributions of Willstatter and Robinson, several alternative approaches following mainly two routes have been considered for synthesis of anthocyanins.One of the routes includes condensation reactions of 2-hydroxybenzaldehydes with acetophenones, while the other uses transformations of anthocyanidin-related compounds like flavonols, flavanones, and dihydroflavonols to yield flavylium salts. The urge for plausible sequences of biosynthetic significance has sometimes motivated this latter approach. In the period of this review, new synthetically approaches in the field have also predominantly been following the same general routes however, some new features have been shown in synthesis of pyranoanthocyanidins. 

Going back to the synthetic biology discussed in this book, I mentioned also that the construction in the laboratory of the early cell using the bottom-up approach is made difficult by the clouds of contingency, and added that there is instead confidence in a different approach to the minimal cell. This is the semi-synthetic approach seen in the previous chapter, which utilizes extant enzymes and/or genes. 

H-Azepines are more rare than 1H- or 3H-azepines and only a few synthetic approaches have been developed. Of these the two main methods involve the ring expansion of six-membered heterocycles. Early studies revealed that highly substituted 4f/-azepines (269) result from the base-catalyzed ring expansion of 4-(chloromethyl)-l,4-dihydro-pyridines (267 Scheme 37). The reaction was found to be temperature and solvent sensitive, and azepines (268)-(270) have been isolated and characterized. However, later studies (68JCS(C)1675) on cyano derivatives (267 E = CN) show the reaction to be even more... 

Solid-phase peptide synthesis has become widely used for the preparation of peptides built from a-amino acids of varying sizes and complexity, and also in the recent synthetic approaches to peptide libraries. It has been recognized that the use of solid-phase protocols for the synthesis of (3-peptides is likely to make them more attractive lead compounds in drug discovery. Although still at an early stage, work has begun to develop suitable protocols for automated (3-peptide synthesis. 

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