Stille reaction intermolecular

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

Stannaries have become prominent in multifunctional anchoring groups. A polymer-bound tin hydride 41 has been used to hydrostannylate alkynes under the action of palladium-catalysis to give polymer-bound alkenylstannanes 42. These alkenyl stannanes have been employed in intermolecular [45] and intramolecular Stille reactions [46]. Alkenylstannanes can also undergo protonation to give alkenes 44 in a traceless fashion. This linker is therefore multifunctional (Scheme 6.1.12). 

Intermolecular Stille reaction of aryl halides with immobilized stannanes (Scheme 6.1.21) provided the coupling products in good yield [45], In addition, the stanny-... 

In their synthetic studies towards lophotoxin and pukalide, Paterson and coworkers explored both intermolecular and intramolecular Stille coupling reactions [108]. The intermolecular approach between vinyl iodide 107 and furylstannane 108 is more successful, giving adduct 109 in 67% yield. The intramolecular version provides the macro-cyclized 14-membered lactone in only 15% yield. Pattenden reported a related investigation towards the synthesis of lophotoxin and observed comparable inter- and intramolecular reactivity in similar Stille reactions [109]. 

Both intramolecular and intermolecular versions of palladium-free, copper-catalyzed, Stille reactions have been reported. In most of these cases, the Cu(I) is added as a salt in the absence of added ligand. In these cases, CuBr or Cul is typically used as the catalyst with CsF as an additive in DMF or NMP solvent at 60-90 Li and Zhang reported a reusable copper catalyst for the Stille reaction of aryl iodides, bromides, and even activated chlorides based on 10% of cubic Cu O nanoparticles with 20 mol % of P(o-tol), and the combination of KF 2H20 and Bu NBr at 125-130... 

Stille reactions are finding increasing use in natural product synthesis, employing both intermolecular and the more attractive intramolecular reaction mode. The individual coupling that is most frequently used is that between vinyltins and vinyl... 

C.ii.b. Stille Couplings. A polymer-bound tin hydride has been used to hydrostannylate alkynes under palladium catalysis hydrostaimylation to give polymer-bound alkenyl-stannanes.t Alternatively, the latter could be prepared from a polymer-bound tin chloride and an alkenyllithium or -magnesium halide reagent. These alkenylstannanes were employed in intermolecular as well intramolecular Stille reactions. The inter-molecular reactions provided the coupling products in good yields. In addition, the... 

Although only a few examples have been reported, palladium-catalyzed C—O bond formation has proved useful in the synthesis of isocoumarins. Wang and Shen utilized an intramolecular C—O bond formation in tandem with an intermolecular Stille reaction to produce isocoumarin products such as 66 in excellent yields from gem-dibromovinylarene substrates such as 65 (Scheme 24.37) [129], The Stille reaction was postulated to occur first with the E-alkenyl bromide before the intramolecular C—O bond-forming cyclization and ensuing elimination of methyl bromide. Tadd et al. reported a palladium-catalyzed carbonylative isocoumarin synthesis, beginning with the same a-(o-haloaryl) ketone substrates as those used previously in benzofuran synthesis (Scheme 24.30) [130]. 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

Acid chloride 5 is readily available from the known benzylic alcohol 6,4e but intermediate 4 is still rather complex. It was recognized that compound 4 could conceivably be formed in one step from 2-methoxyfuran (9)10 and iodotriflate 10. The latter compound was designed with the expectation that it could be converted to benzyne 8," a highly reactive species that could be intercepted in an intermolecular Diels-Alder reaction with 2-methoxyfuran (9) to give 7. The intermediacy of 7 is expected to be brief, for it should undergo facile conversion to the aromatized isomer 4 either in situ or during workup. 

The exact mechanism has still not been completely worked out. Opinions have been expressed that it is completely intermolecular, completely intramolecular, and partially inter- and intramolecular. " One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, interraolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out sometimes crossover products have been found and sometimes not. As in 11-14, an initial complex (40) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1 1 is required. 

There is some increase in selectivity with functionally substituted carbenes, but it is still not high enough to prevent formation of mixtures. Phenylchlorocarbene gives a relative reactivity ratio of 2.1 1 0.09 in insertion reactions with i-propylbenzene, ethylbenzene, and toluene.212 For cycloalkanes, tertiary positions are about 15 times more reactive than secondary positions toward phenylchlorocarbene.213 Carbethoxycarbene inserts at tertiary C—H bonds about three times as fast as at primary C—H bonds in simple alkanes.214 Owing to low selectivity, intermolecular insertion reactions are seldom useful in syntheses. Intramolecular insertion reactions are of considerably more value. Intramolecular insertion reactions usually occur at the C—H bond that is closest to the carbene and good yields can frequently be achieved. Intramolecular insertion reactions can provide routes to highly strained structures that would be difficult to obtain in other ways. 

Wong reported that stoichiometric amounts of copper(I) chloride alone can promote the intramolecular Stille coupling (equation 138)243. In fact, copper(I)-mediated reaction was cleaner and faster compared with that catalysed by Pd(0) species. Selected examples of intermolecular Stille coupling reactions leading to dienes (Table 25)236a,242b 244, polyenes (Table 26)245 and macrocyclizations (Table 27)246 are given in the respective tables. 

In order to define more precisely the significance of the term favoured, we propose to classify as favoured a reaction whose EM is greater than 0.1 M. This simply means that when such a reaction is run at an initial concentration of 0.1 M, it is favoured over the corresponding intermolecular reaction. The admittedly arbitrary limit of 0.1 M derives from the simple consideration that such a concentration is still acceptable in ordinary preparative work. Accordingly, all but one of the SN2 ring-closure reactions whose pertinent data are plotted in Fig. 27 are classified as favoured processes, since their EM s are greater than 0.1 M. This is consistent with Baldwin s rule that 3- to 1-exo-tet are all favoured processes. 

Although a fair number of examples of the Ti-promoted intermolecular alkyne-alkene coupling reactions are known, those that display high pair selectivity and regioselectivity are still relatively limited. Some representative examples are shown in Scheme 18 51 53>53a... 

It is much more difficult to control the pair-selectivity and regioselectivity of the intermolecular cyclic carbozirconation. The fundamentally dynamic and reversible nature of most of the microsteps in these reactions is primarily responsible for the often capricious nature of these reactions. Nevertheless, considerable progress has been made recently. In particular, the use of (ethylene)zirconocene in place of (l-butene)zirconocene has been shown to provide convenient and selective procedures, as shown in Scheme 39 13,13c,212,226,227 q [lcsc procedures, however, are still not fully satisfactory, especially in terms of regioselectivity, and additional developmental works are desirable. 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

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