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 381

alkyl isocyanoacetate containing an electron-withdrawing ethyl ester moiety in a
microfluidic chip as the initial reactor. The prior mixing before the introduction of the
immobilized base was important to ensure high yields. Furthermore, NMR studies of
the reaction showed that formation of an adduct occurs exclusively via the methylene
unit, which is in contrast to the batch process [46]. The reactive intermediate then
cyclizes in the presence of polymer-immobilized BEMP at 50 C. The product output
stream was finally purified using a benzylamine resin to furnish the 4,5-disubstituted
oxazole derivatives

. Sulfonates (from the corresponding tosyl substituent) could
also be prepared (nine examples, 81-94%), as well as phosphonates (three examples,
84-85%), by using a similar synthesis strategy. The immobilized BEMP column could
be regenerated using solution-phase BEMP in hexane or NaOMe/ t -BuOK in MeOH.

127

11.5. MULTISTEP FLOW SYNTHESIS OF NATURAL
PRODUCTS AND PHARMACEUTICAL COMPOUNDS

The first application of a flow process for the multistep synthesis of a natural product
was achieved in 2006 for (

)-oxomaritidine using a combination of scavengers
and reagents to effect product formation at all individual steps [47]. In this work,
microfluidic pumping systems were used to direct material through various packed
columns, containing immobilized reagents, catalysts, scavengers, or catch-and-
release agents. The route involved seven separate synthetic steps linked to a
continuous flow sequence. No column chromatography or aqueous workups were
required at any stage and the automated sequence employed readily available starting
materials to produce ( in less than a day (Scheme 11.42), which

compares extremely well with the four day batch process of this natural product.
The first step of the oxomaritidine synthesis involved passage of the bromide
4-(2-bromoethyl)phenol

)-oxomaritidine 7

128 through a packed column containing an azide exchange

resin to give was then coupled directly

with a second column containing an immobilized phosphine, furnishing a corre-
sponding trapped aza-Wittig intermediate. In a separate but convergent channel, the
aldehyde coupling partner

129 . The output stream containing azide 129

was prepared. Here, a prepacked column of tetra- N -
alkylammonium perruthenate (PSP) was used to oxidize 3,4-dimethoxybenzyl
alcohol

131

and the product stream was then passed through the column containing
the immobilized aza-Wittig intermediate, thus producing the desired imine

130

132 . The

exiting THF solution of imine was then subjected to continuous flow hydro-

genation using the Thales H-Cube flow hydrogenator, containing a cartridge of 10%
palladium on carbon as a catalyst. The product of this reaction

132

was then collected
and the THF solvent removed using a Vapourtec V-10 solvent evaporator. After being
redissolved in dichloromethane, the secondary amine

133

was passed into a micro-
fluidic reaction chip that combined an additional stream of trifluoroacetic anhydride
(TFAA) in dichloromethane, resulting in trifluoroacetylation of the amine to give the
amide

133

134

. After a short scavenging process whereby a silica gel-immobilized
primary amine removed any excess TFAA or residual trifluoroacetic acid (TFA),
the product was then directed into a column containing immobilized (ditrifluoroa-
cetoxyiodo)benzene, which performed the oxidative coupling, generating a seven-