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 370

OH

MeO 2 C

CO 2 Me

OH

90°C, 47 min

84

OMe

NMe 3 IO 4

NH 2

MeO 2 C
MeO 2 C
85 (75%)

O O

CH(OMe) 3 (2.4 equiv) MeOH

100 psi bpr OMe

O

CSA +

O

(0.1 equiv) (1.2 equiv)

SCHEME 11.14 Flow synthesis of BDA-protected tartrate 85 .

using an immobilized benzylamine to scavenge the remaining butanedione and
CSA catalyst. Periodate resin was then employed to perform rapid glycol cleavage
of the remaining tartrate ester 84 to generate volatile by-products that could be

easily removed.
The BDA-protected tartrate

85 was subsequently transformed to the unsatu-

rated system by subjecting it to a strong base in the presence of iodine

(Scheme 11.15). The product stream was purified by scavenging (quenching lithium
salts, removing diisopropylamine using a sulfonic acid resin, and removing residual
iodine using a thiosulfate resin). Finally, a short plug of silica gel was used to remove
inorganic lithium salts.
The corresponding crystalline meso -BDA-protected derivative

87

89

was readily

87

generated from in quantities using the H-Cube Midi system with a Rh/Al 2 O 3

catalyst under recycling conditions (Scheme 11.16).
The preparation of the BDA-protected glyceraldehyde as a building block for

synthesis proved more challenging. It was finally found that premixing mannitol 90 ,
trimethyl orthoformate, and CSA greatly aided solubility such that a flow synthesis
could be achieved (Scheme 11.17). When only a small excess of butadione was used
with gentle warming of the stream to 40 C, an optimum yield was obtained. This
process also reduced the propensity for the formation of the tris -protected by-product.
A final column of benzylamine was used to scavenge excess reagents; however, a

91

OMe

MeO 2 C
MeO 2 C

O O

85

OMe 25°C, 14 min

[NMe 3 ] 2 S 2 O 3 2-

SiO 2 OMe

SO 3 H

MeO 2 C

O

-78°C, LDA THF

O

100 psi bpr MeO 2 C

OMe

87 (65%)

I 2 , -78°C

SCHEME 11.15 Flow synthesis of BDA-protected alkene ( 87 ).

H-Cube TM Midi

OMe

MeO 2 C

MeO 2 C
MeO 2 C

OMe

Rh/Al 2 O 3

O

O

O O

MeO 2 C

OMe

OMe

87 89 (quant)

MeOH, 60 bar, 40°C

SCHEME 11.16 Flow synthesis of meso -BDA-protected derivative 89 .