THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 365

was achievedwith CSA, followed by an immobilized carbonateworkup to quench and
scavenge unwanted acidic residues to give 82 . Oxidation of the primary alcohol in 82
was realized in two steps: TPAP oxidation to the aldehyde and then amodified Pinnick
oxidation using an immobilized reagent combination incorporating immobilized
chlorite to furnish the acid. Although selective deprotection to access

required
aqueous tetrabutylammonium fluoride (TBAF), no further purification protocol was
necessary. Finally, successful Yamaguchi macrolactonization using immobilized
DMAP followed by a catch-and-release protocol gave the macrocycle epothilone
C(

83

56 ), which was conveniently converted to the natural product epothilone A 57 via a

final oxidation using dimethyldioxirane (DMDO).
This synthesis constitutes a record for the use of immobilized systems in
complex molecule assembly, effecting no less than 29 overall steps where the longest
linear sequence was 17 steps from available starting materials in 55% overall yield.

11.3. FLOW CHEMICAL SYNTHESIS

As can be seen from the previous discussion, the use of immobilized reagents,
catalysts, and scavenging techniques provide viable and practical alternative tools to
linear substrate-bound synthesis. Furthermore, thesemethods can incorporatemany
of the advantages of conventional solution-phase chemistry, such as real-time
reaction monitoring, convergency, and rapid sequence optimization. The approach
is highly amenable to multistep telescoped processes, parallel array preparation,
batch splitting methods, and reaction scale-up. However, the real value of immobi-
lized reagents in chemical processing is certainly in the area of flow chemistry.
Flow-based synthesis is emerging as a powerful technology platform that is steadily
gaining acceptance in the modern laboratory for multistep processes and scale-up
operations [21].
As a technique, flow chemistry replaces traditional glassware practices con-
ducted in batch mode with continuously flowing systems integrating connective
tubing, preloaded columns, and cartridges containing immobilized reagents, cata-
lysts, and scavengers (Figure 11.1a and b). Additionally, by building precision

FIGURE 11.1 (a) A column packed with an immobilized copper(I) reagent as used in the
Bestmann-Ohira synthesis of triazoles (shown later); (b) column containing two regions of
different inorganic scavengers; (c) a mesofluidic static mixing chip.