Protective-group-free strategies

The nitration step was the ultimate test of our decision to pursue a protecting group-free strategy. We were very pleased to find that the desired nitroarene... 

Fanands, R, Mendoza, A., Arto, T., Temelli, B., Rodriguez, R (2012). Scalable total synthesis of (—)-berkelic acid by using a protecting-group-free strategy. Angewandte Chemie International Edition, 51, 4930-4933. 

Gu, Z. and Zakarian, A. (2010) Concise total synthesis of sintokamides A, B, and E by a unified protecting-group-free strategy. Angeiv. Chem. Int. Ed., 49, 9702-9705. 

The spiraled architecture of welwitindolinone A isonitrile 196 has inspired the development of a variety of strategies for its construction. A beautifully simple protecting group-free synthesis of (-F)-welwitindolinone A has been achieved by Baran and coworkers [115-117]. As depicted in Scheme 48, the key step for installation of the aU-carbon quaternary center at oxindole C3 involved fluoro-hydroxylation of (—)-fischerindole 1 194 via treatment with aqueous Xep2. The desired natural product, 196, was obtained as a single diastereomer in 44% yield. The origin of the asymmetry at oxindole C3 can be traced back to enantiopure carvone oxide. 

R.W. (2006) Synthesis, 21, 3531These papers contain very convincing recent examples of protecting-group-free synthesis and demonstrate the advantages of this strategy. 

A typical synthesis of complex organic molecules involves multiple reaction steps with intermediate purification of the intermediates. Such synthetic routes require a lot of labor-intensive manipulations and generate a lot of waste (e.g., solvents). With the atom-efficient biosynthetic pathways in cells as a model, several approaches have been developed in order to facilitate synthetic chemistry, such as protecting group-free syntheses [46], one-pot syntheses [47], cascade reactions [48], and multicomponent reactions [49]. More recently, synthetic chemists have been attracted by flow chemistry since it allows to combine all these processes in a single streamlined continuous process (i.e., multistep one-flow synthesis) [50]. Several strategies have been developed. 

This reductive Heck reaction has become a useful tool in cyclization reactions for complex molecule synthesis. In his protecting group free synthesis of ambiguine H (119), Baran successfully applied this strategy. Slow addition of Herrmann s catalyst 91 to substrate 117 provided intermediate 118 in a reliable 65% yield. This chemistry proved both robust and scalable, providing gram quantities of 118. 

The PIA chemistry presented in this chapter represents only a minor portion of the extensive work directed at synthesizing these complex targets. To find examples that encompass either atom-economical processes or protecting-group-free transformations was a challenging task, due in part to the nitrogen-rich nature of these natural products. In all cases, the development of new strategies/chemistry was necessary, without which the... 

Dave and co-workers have reported a successful synthesis of 2,2,4,4-tetranitroadamantane (117) which uses the mono-protected diketone (113) as a key intermediate. In this synthesis (113) is converted to the oxime (114) and then treated with ammonium nitrate and nitric acid in methylene chloride to yield the em-dinitro derivative (115). This nitration-oxidation step also removes the acetal-protecting group to leave the second ketone group free. Formation of the oxime (116) from ketone (115), followed by a similar nitration-oxidation with nitric acid and ammonium nitrate, yields 2,2,4,4-tetranitroadamantane (117). In this synthesis the protection strategy enables each carbonyl group to be treated separately and thus prevents the problem of internal nitroso dimer formation. 

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