Enantioselective Synthesis of Herbarumin III by Using a Chelation‐Controlled Reduction

Abstract

The total synthesis of herbarumin III (1) was achieved via an alkynide ion addition onto a chiral aldehyde and LiAlH 4 /LiI reduction as key steps (Scheme 2).Introduction. -Natural lactones with a medium ring size between eight to eleven [1] are attracting the attention of several groups because of their significant biological importance, but their syntheses are challenging. The phytotoxic lactone herbarumin III (1) was isolated by Mata and co-workers from the fermentation broth and mycelium of the fungus Phoma herbarum along with herbarumin I (2) and II (3) [2]. The structure of 1 was elucidated by spectroscopic methods combined with molecular modeling. Herbarumin III showed significant phytotoxic effects when tested against seedlings of A. hypochondriacus [3]. The herbarumin macrolides 1 -3 interact with bovine-brain calmodulin and inhibited the activation of the calmodulin-dependent enzyme camp phosphodiesterase. Considering its structure and selective biological profile, herbarumin III has attracted a great deal of interest among synthetic organic chemists. Consequently, the synthesis of 1 has been reported by various research groups [4]. Herein, we report a protocol for the synthesis of herbarumin III based on an alkynide ion addition onto a chiral aldehyde and reagent-controlled synthesis.

A simple formal stereoselective synthesis of Herbarumin III

“…The pure syn-isomer was separated and it was reacted with K2CO3 in MeOH to furnish the syn-epoxy alcohol 8. The diastereoselective preparation of an iodocarbonate and its conversion into a 1,3-syn epoxy alcohol has not been applied earlier in the synthesis of Herbarumin III [2][3][4][5][6][7][8][9]. The hydroxyl group of the alcohol 8 was protected as TBS-ether by treatment of the former with TBSCl using imidazole to form the TBS-protected epoxide 9.…”

“…These compounds also interacted with bovine brain calmodulin dependent enzyme cMAP phosphodiesterase. Due to interesting structural pattern and important biological properties, Herbarumin III (1) has recently become the synthetic target of the organic chemists [2][3][4][5][6][7][8][9]. In continuation of our work [10][11][12] on stereoselective synthesis of natural products we have developed a simple formal synthesis of the compound, which we would like to mention here.…”

Nonanolides of Natural Origin: Structure, Synthesis, and Biological Activity

“…Selective protection as TBS ether at the allylic position and subsequent deprotection of the PMB group afforded a primary alcohol, which was oxidized to the corresponding acid 338 by a two-step process. Finally, lactonization applying Yamaguchi's protocol and subsequent removal of the silyl protecting group yielded the herbarumin III (42) [187].…”

Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

“…To date, the Yamaguchi protocol and variations have been used in more than 340 synthetic applications, including eight-membered lactones − such as topsentolide A1 and solandelactone E; − nine-membered halicholactone , and a nine-membered intermediate to laurencin; 10-membered lactones such as didemninlactone, aigialomycin, aspergillides, − aspinolides, , and decarestricine; − exiguolide; , cytotoxic macrolide FD-891; , the bacterial DNA primase inhibitor Sch642305; , iriomoteolide; lituarines B and C; neopeltolide; ,− chloriolide; , oxopolyene macrolide RK-397; , milbemycin; mueggelone; − herbarumin; herbarumin III; , ascidiatrienolide; epothilones A, B, D, E, and F and congeners; ,− lasonolide; macrolactin A; microcarpalide; , erythronolides and analogues; ,,,,,− ,− leiodolide; oleandolide; ,…”

“…280,281 cytotoxic macrolide FD-891; 2 8 2 , 2 8 3 the bacterial DNA primase inhibitor Sch642305;245,284 iriomoteolide; 285 lituarines B and C; 286 neopeltolide; 68,287−291 chloriolide;292,293 oxopolyene macrolide RK-397; 294,295 milbemycin; 296 mueggelone; 297−299 herbarumin;300 herbarumin III;301,302 ascidiatrienolide;303 epothilones A, B, D, E, and F and congeners;228,304−335 lasonolide; 336 macrolactin A; 337 microcarpalide;338,339 erythronolides and analogues;55,61,147,148,170,270−274,340−346 leiodolide; 347 oleandolide;67,229,340,348 lankanolide; 60 deoxytedanolide; 77 tedanolide; 78,349 mycinolide; 350 brefeldin; 351−357 mycolactone 358 and mycolactone core; 359 mycotycin; 360 norhalichondrin; 361 palmerolide A; 362,363 roxaticin; 215,364−366 colletol; 367,368 colletallol; 221 cladospolides A−D; 369−378 patulolides; 251,252,379−383 stagonolide; 384 various insect pheromones; 142,385 antiobiotic A26771B; 386 spiruchostatin; 387 formamicin; 388 formamicinone; 389 callipeltoside; 234,390−392 borrelidin;83,393,394 dictyostatin; 395−402 rutamycin; 232 spongistatins; 75,76,403−410 lepicidin; 240 halichondrin;411,412 jasmine ketolactone; 413 haterumalide;249,414 ent-haterumalide methyl ester; 415 myxovirescine;416 grahami-mycin;417,418 auriside; 419−422 bryostatins; 230,423−427 apicularen; 74,428,429 leiodermatolide;66,430 madumycin; 431 mycacolide;432 hydroxybutanoic acid, hydroxylenic acid, dihydropyrans (up to a 72-membered macrocycle), and quinine oligomers;433−437 pamamycin 607; 438−440 phorboxazole; 254 recifeiolide; 441 amphidinolides; 216,247,442−449 cineromycin; 450 phorbaside A; 451 tartrolon B; 452,453 spinosyn A; Mukaiyama, Keck, and Palomo protocols failed; 490 apoptolidinone; 70−72491−495 conglobatin;…”