Flexibility in the Partial Reduction of 2,5-Disubstituted Pyrroles:  Application to the Synthesis of DMDP

Abstract

[reaction: see text] The partial reduction of electron-deficient 2,5-disubstituted pyrroles has been developed into a flexible procedure that gives control of relative stereochemistry by variation of the reduction conditions. After the reaction, the pyrroline products were dihydroxylated at C-3,4 to give either the cis or trans isomers; this flexibility means that a variety of polyhydroxylated pyrrolidines can be prepared in a short sequence. Finally, this method was applied to a synthesis of the naturally occurring glycosidase inhibitor DMDP.

Synthesis and Electron Spin Relaxation of Tetracarboxylate Pyrroline Nitroxides

“…Because our target is the trans -isomer, we quench the dianion of 3 with electrophiles, ClCO 2 Me and BrCH 2 CO 2 Me, to provide products 4 and 6 , respectively. In analogy to the reported reaction of the dianion of 3 with an acid, 28 we expect a bulky electrophile such as BrCH 2 CO 2 Me to provide a similar outcome. That is, after the first C–C bond formation, the resulting monoenolate anion reacts, from the least hindered face , with the second molecule of BrCH 2 CO 2 Me, to produce tran s- 6 .…”

“…28,29 Subsequently, the dianion of 3 in THF is generated using the conditions reported for preparation of the cis -2,5-tetrasubstituted pyrroline, which was formed by quenching the dianion with 2,6-di- tert -butylphenol. Because our target is the trans -isomer, we quench the dianion of 3 with electrophiles, ClCO 2 Me and BrCH 2 CO 2 Me, to provide products 4 and 6 , respectively.…”

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…Interestingly, reduction of 98 under the Birch or ammonia-free reaction conditions, followed by protonation, led to opposite stereochemical outcomes, as reported in Scheme 12.23 [39,41]. 1) 1) Reductive protonation in NH 3 was originally reported to afford 7 : 3 mixture of cis and trans isomers; see, however, note 7 of Ref.…”

“…1) 1) Reductive protonation in NH 3 was originally reported to afford 7 : 3 mixture of cis and trans isomers; see, however, note 7 of Ref. [41]. This finding, attributed to the different aggregation states of the dianionic intermediate in the different solvents, found practical applications in the synthesis of diastereoisomeric polyhydroxylated pyrrolidines, en route to the synthesis of the naturally occurring glycosidase inhibitors [41][42][43].…”

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era

“…Subsequent efforts directed at optimization of the reaction resulting in 190 focused on the evaluation of various tertiary amine bases. When the reaction of indole 187 and bromomalonate 188 was conducted with Hunig's base under otherwise identical reaction conditions, exclusive formation of diethylmalonate(191) was observed.…”