Pd-mediated Cycloisomerization Research Articles

Metal-mediated alkynediol cycloisomerization: first and second generation formal total syntheses of didemniserinolipid B

A formal total synthesis of didemniserinolipid B was developed by employing a regioselective metal-mediated 6-endo-dig alkynol-cycloisomerization reaction. Two routes for the synthesis of key Burke's intermediate have been developed. Our initial approach involved the introduction of a C17-alkynol followed by Pd-mediated cycloisomerization and then coupling with the serinol unit prior to the introduction of an α,β-unsaturated ester unit through selective oxidation of 1°-OH followed by a two-carbon Wittig homologation. Alternatively, the second generation strategy featuring the serinol coupling with the C17-alkynol followed by alkyne addition to the epoxide and subsequent Au-mediated cycloisomerization of an acetonide protected alkynediol unit has been executed. This approach has avoided several late stage protection–deprotection events.

The influence of electronic factors on Pd-mediated cycloisomerization: a systematic investigation of competitive 6- exo-dig versus 7- endo-dig cyclizations of sugar alkynols

Pd-mediated cycloisomerization of 3- C-propargyl- ribo- and allofuranose derivatives was investigated in detail to understand the influence of electronic factors on the regioselectivity (6- exo- vs 7- endo) of alkynol cycloisomerization leading either to a six- or seven-membered ring. In general, the 6- exo-dig mode of cyclization is facile and is independent of electronic factors. With some of the alkynols, a regioselective (7- endo?) hydration of the alkyne unit was observed and this has been attributed to the participation of C(3)–OH. When the C(3)–OH was protected as its benzyl ether, cycloisomerization of these alkynols occurred exclusively in a 6- exo-dig mode resulting in the corresponding [3.2.1]-bicyclic ketals. Additional control experiments conducted were in support of the participation of C(3)–OH in regioselective alkyne hydration.

The influence of electronic factors on palladium-mediated cycloisomerization: a systematic investigation of competitive 5-exo-dig versus 6-endo-dig cyclizations of sugar alkynols

Pd-mediated cycloisomerization of 3-C-alkynyl-allo- and ribofuranose derivatives was investigated in detail to understand the influence of electronic factors on the regioselectivity in ring closure reaction. The reactions in general are influenced by the electronic nature of the substituent on the alkyne unit. A preference for endo-dig cyclization over exo-dig is noted, if the alkynyl substituent is not sufficiently electron withdrawing.

Steric control in Pd-mediated cycloisomerization of sugar alkynols: documentation of a rare allylic epimerization

Pd-mediated cycloisomerization of C3-alkynylated glucofuranosyl derivatives revealed a dominance of steric factors over electronic factors. However, the intermediate glycals were epimerized prior to the ketalization and afforded the more stable cis-fused bicyclic ketals.

Cyclic α-amino acids by Pd-mediated cycloisomerization and coupling reactions

Stereoselective syntheses of cyclic α-amino acids are described. The α-carbon of the amino acid is incorporated into a five- or six-membered vicinal dimethylenecycloalkane or conjugated methylenecycloalkene. Palladium-catalysis was used for cycloisomerization of intermediate enynes and intramolecular Heck type cyclizations of bromodienes. A stereoselective elimination from a homoallylic Pd-intermediate is described. Enantiomerically pure substrates for the cyclization reactions were available by stepwise alkylations of the chiral auxiliary ( R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with bromo-alkenes and -alkynes.