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 369

SCHEME 11.13 A concept diagram illustrating a convergent flow synthesis incorporating
flow coils, microfluidic chips, scavengers, and immobilized reagents in cartridges using five
individual starting inputs.

11.4. FLOW SYNTHESIS OF CHEMICAL BUILDING BLOCKS

Appropriate chemical building blocks form the necessary starting points for all
chemical synthesis programmes. They can be simple structures or specially tailored
for a particular functionality. Their availability and cost ultimately determine their
usage; consequently, more automated ways of preparing these materials is important.
The following sections highlight some of the flow chemistry methods that can be
employed to generate specific classes of useful building blocks.

11.4.1. Butane-2, 3-Diacetal-Protected Diols
Various 1,2-diacetals and specifically butane-2,3-diacetals (BDAs) have been used
extensively in natural product syntheses to effect selective vicinal diol and a -hydroxy
acid protection, diastereoselective, and facially selective processes. They have also
been used to prepare a variety of chiral building blocks [31] for use in the syntheses of
natural products, such as ( þ )-aspicillin [32] and bengazole A [33]. Useful key
members of the BDA building block series have been assembled by flow chemistry
methods in higher yields and higher reproducibility than the corresponding batch
process employing minimal manual workup when immobilized reagent cartridges are
used to purify the reaction stream exiting from the flow reactor [34]. The BDA-
protected tartrate

85 , for example, was obtained frommixing a stream of dimethyl-

L -tartrate derivative and trimethyl orthoformate with a second stream containing

butane-2,3-dione together with a catalytic amount of CSA and heated at 90 Cfor
47min in a flow coil (Scheme 11.14). Premixing

84

and trimethyl orthoformate
resulted in formation of an intermediate orthoester that can be observed using
the ReactIR

84

flow cell. This premixing is thought to be an important requirement
for diol activation, thus allowing the reaction to proceed. The product was purified