Efficient and highly enantioselective formation of the all-carbon quaternary stereocentre of lyngbyatoxin A

Abstract

Indole 25, an advanced intermediate in a projected enantioselective total synthesis of lyngbyatoxin A 1, was prepared from allylic alcohol 11 in 9 steps and >95% ee, key transformations being the enantiospecific rearrangement of vinyl epoxide 14 and the Hemetsberger-Knittel reaction of azide 24.

Semipinacol Rearrangement in Natural Product Synthesis

“…Lyngbyatoxin A is one of the causative agents of a severe contact dermatitis commonly known as “swimmers’ itch”. Tanner and co-workers prepared its core structure 334 using a semipinacol rearrangement of the chiral vinyl epoxide 332 (Scheme ) . Regioselective ring-opening at the benzylic position and 1,2-migration of the vinyl group created the crucial quaternary carbon center and gave the aldehyde 333 in 52% yield.…”

Organocatalytic, Chemoselective, and Stereospecific House–Meinwald Rearrangement of Trisubstituted Epoxides

“…3 Since epoxidation is one of the most important reactions in organic synthesis and can be performed with an outstanding level of enantioselectivity, 4 the epoxidation–rearrangement sequence describes a powerful tool for the construction of α-chiral quaternary carbonyls. In particular, quaternary carbaldehydes are versatile building blocks in organic synthesis and many groups have used the sequence of ‘ asymmetric epoxidation – House–Meinwald rearrangement ’ to form quaternary carbaldehydes, e.g., in the total synthesis of cuparene, 5 lyngbyatoxin A, 6 and furanoterpene. 7 However, the House–Meinwald rearrangement of trisubstituted epoxides to α-quaternary carbaldehydes remains challenging in terms of chemoselectivity for the alkyl shift versus hydrogen shift.…”

Synthesis of indole derivatives as prevalent moieties present in selected alkaloids

“… 365 Lyngbyatoxin A (442) is an effective tumor promoter 366 and similar to other indolactam alkaloids, applies its biological properties via the activation of the protein kinase C (PKC). In 2006, Tanner and Vital demonstrated 367 that indole 441, an advanced intermediate for the asymmetric total synthesis of lyngbyatoxin A (442), was synthesized from allylic alcohol 439 in nine steps and with a high ee (>95% ee). The effective and very asymmetric construction of the all-carbon quaternary stereocentre of lyngbyatoxin A (442) started with the allylic alcohol 439 (prepared from p -aminoacetophenone 438 in four steps), which after eight steps gave azide 440.…”

“…The latter is appropriately functionalized so as to permit its transformation into lyngbyatoxin A: the C-3 indolic position is essentially nucleophilic, and the bromine at C-4 gives an appropriate handle for insertion of the amino group; moreover, the TBDMS-masked alcohol scaffold permits the formation of the linalyl appendage ( Scheme 62 ). 367 …”