Stille tandem

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

On the other hand, if only specific GC detectors, e.g. the electron capture, nitrogen-phosphorus or flame photometric detectors, are tested, the argument of lack of GC method sensitivity is not acceptable. In most cases mass spectrometric detectors provide the sensitivity and selectivity needed. Unfortunately, tandem mass spectrometry (MS/MS) or MS" detectors for GC are still not widely used in official laboratories, and therefore these techniques are not always accepted for enforcement methods. 

More recently, liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) have been evaluated as possible alternative methods for carfentrazone-ethyl compounds in crop matrices. The LC/MS methods allow the chemical derivatization step for the acid metabolites to be avoided, reducing the analysis time. These new methods provide excellent sensitivity and method recovery for carfentrazone-ethyl. However, the final sample extracts, after being cleaned up extensively using three SPE cartridges, still exhibited ionization suppression due to the matrix background for the acid metabolites. Acceptable method recoveries (70-120%) of carfentrazone-ethyl metabolites have not yet been obtained. 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Murakami generated 3-tributylstannylindoles in situ (but also isolable) using 3-bromoindole 174, allylic acetates and carbonates, and hexamethylditin [179]. A typical procedure is illustrated for the synthesis of 175. The corresponding 5-bromo analog is allylated to the extent of 59%. 3-Stannylindoles couple smoothly in tandem fashion with 2,3-dibromo-5,6-dimethylbenzoquinone under Stille conditions [180]. 

While the early days of LC-NMR and LC-NMR-MS were plagued by the poor sensitivity of the NMR spectrometer, the recent probe design advances have provided a means to potentially overcome this hurdle. As reported in the literature, it is possible to get both ID and 2D homo-nuclear and heteronuclear correlation data on sub micrograms of materials in quite complex mixtures utilizing cryogenic flow-probes in tandem with SPE peak trappings [98]. While these technologies are still in their infancy, they have the potential to revolutionize LC-NMR as a structure elucidation technique. 

There are still rather few fundamental studies of the mass spectrometry of organotin compounds, but the fragmentation pathways of organotin compounds have been further elucidated by means of tandem mass spectrometry.51,52... 

Scheme 28 explains the stereochemical outcome from the tandem radical cyclization in the presence of the [Yb(Ph-pybox)(OTf)3] (pybox = 2,6-bis(2-oxazolin-2-yl)pyridine). The ytterbium complex 107 is shown in an octahedral geometry (with one triflate still bound to the metal) where re-face cyclization is favored due to the steric interactions of the substrate and the ligand s phenyl groups. The 6-endo cyclization takes place via a chair-like transition state to yield a tertiary radical 108 followed by a ring flip and... 

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