Natural product synthesis transmetallation

Alkyl substituted a-lithiodihydrofurans 599-602 and a-lithiodihydropyrans 603-606 have been used for natural product synthesis. They are prepared by deprotonation of the corresponding DHF or DHP derivatives with f-BuLi in THF at —78 to 0 °C. Lithiated DHP 606 has been prepared by tin-lithium transmetallation starting from the hemiacetal 607, by successive transformation into the sulfone 608907 and the stannane 60 9908 (Scheme 163). 

Heterocyclic aromatic boronic acids, in particular pyridinyl, pyrrolyl, indolyl, thienyl, and furyl derivatives, are popular cross-coupling intermediates in natural product synthesis and medicinal chemistry. The synthesis of heterocyclic boronic acids has been reviewed recently [222], and will not be discussed in detail here. In general, these compounds can be synthesized using methods similar to those described in the above section for arylboronic acids. Of particular note, all three isomers of pyridineboronic acid have been described, including the pinacol ester of the unstable and hitherto elusive 2-substituted isomer, which is notorious for its tendency to pro-todeboronate [223]. Improvements and variants of the established methods for synthesizing heterocyclic boronic acids have been constantly reported [13, 182]. For example, a Hg-to-B transmetallation procedure was recently employed to synthesize a highly functionalized indolylboronic acid (entry 19, Table 1.3) [187]. 

This reaction is far-reaching, because a wide variety of air- and thermally stable organoboron reagents are commercially available or easily synthesized, and it has indeed found extensive use in natural product synthesis. The Suzuki reaction allows the introduction of alkenes, alkynes and arenes in C-C coupling processes, the hydroboration of alkenes and alkynes being very well known. It is the addition of a base in the medium of the Suzuki reaction that leads to the transformation of a borane BR3 into a boronate BR3(OH) that is the active species for transmetallation towards Pd ... 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

Total synthesis has benefited from key DoM reactions. The sequence 48 —> 49 —> 50 —> 51 (Scheme 12) en route to the natural product ochratoxin A (52) takes multiple advantage of anion chemistry (53) ortho-metalation of the powerful OCONEtj group (step 1), anionic Fries rearrangement (step 2), in-between DoM and chain-extension by Li-Mg transmetalation (step 3) [12]. 

The Ziegler-modified Ullmann reaction was used for the total synthesis of pyrrolophenanthridinium alkaloid tortuosine by L.A. Flippin and co-workers. First, A/-Boc-5-methoxyindoline was lithiated at C7 with s-BuLi in the presence of TMEDA, and then it was transmetallated to the corresponding organocopper species that smoothly underwent the Ullmann reaction with a 3-iodoaryl imine. The resulting biaryl product was treated with anhydrous HCI in chloroform, which promoted the cyclization followed by dehydration to give the natural product. 

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

At first this new technique of adding metallated Schiff bases appeared problematical for the possible synthesis of natural products, because during its application to methylketones, such as jS-ionone, it could be expected that the proton active -COCH3 system would undergo a transmetallation or transanionization with the metallated Schiff base. Fortunately, this was not the case as was shown by model experiments with acetone, acetophenone, and cyclohexanone. 

Since the discovery of Pd-catalyzed carbonylation of aryl, vinyl, and benzyl halides by Heck in 1974, this reaction has been used for the synthesis of ester, amide, acid, and acid anhydride. We can nse enol triflate, aryl Iriflate, aniUne derivatives, and vinyl silane as the pseudo aryl or vinyl halide. This reaction has now been further extended for the synthesis of aldehyde and ketone by combination with transmetalation. These reactions have widely been used in organic syntheses, especially the syntheses of biologically active substances in the field of fine chemistry and the syntheses of natural products. 

This year has also seen approaches towards components of the anticancer natural product taxol from carbohydrate starting materials. Paquette and Bmley have used the 5-deoxy-5-iodo-ribofuranoside 61 as starting material for synthesis of 63, a precursor to the C ring of taxol. The carbohydrate-derived vinyl iodide 62 is transmetallated and the resulting vinyllithium reacts with terpenone 64 to afford 63 (Scheme 12). ... 

Several natural products total syntheses used the hydrozirconation-transmetal-lation strategy for the constmction of a structurally elaborated carbon framework such as the preparation of polyene segment in (+)-curacin A and in the manumy-cin family [17]. An interesting diastereoselective transmetallation reaction of functionalized Zr to Zn was also recently reported in the synthesis of fostriedne 18 [18] and an enantioseletive transformation of functionalized Zr to Zn followed by reaction with an aldehyde was also reported at a late stage of the total synthesis of (+)-halichlorine 19 (Scheme 12.15) [19]. 

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