Total Asymmetric Synthesis of a New 9,12-Anhydroerythronolide Aglycone

Abstract

Two novel, potentially antimicrobial erythronolide aglycon analogs ((À)-9 and (À)-30, respectively), which incorporate a large number of contiguous stereogenic centers, have been prepared by multistep synthesis from simple chirons. The chemistry presented demonstrates the power of the so-called −naked sugars of the second generation× approach. As for the sporeamicins, our macrolides are 9,12-anhydroerythronolides, yet presenting a higher degree of complexity due to additional functional groups.

Macrolactonizations in the Total Synthesis of Natural Products

“…To date, the Yamaguchi protocol and variations have been used in more than 200 synthetic applications, including eight-membered lactones; , nine-membered halicholactone , and a nine-membered intermediate to laurencin; 10-membered didemninlactone, decarestricine, mueggelone, , hebarumin, and ascidiatrienolide; epothilones A, B, D, E, and F and congeners; ,− macrolactin A; erythronolides and analogues; ,,,,,− oleandolide; ,,, lankanolide; deoxytedanolide; mycinolide; brefeldin; − mycotycin; roxaticin; ,, colletol; , colletallol; clado...…”

Direct Entry to Erythronolides via a Cyclic Bis[Allene]

“…The strategy presented herein focuses on substances that can be called upon to react along differing pathways . The longest linear sequence to 12 is 11 steps, and compounds 13 – 22 were prepared from this intermediate in three or fewer steps; this compares well to previous work in the area. , Compound 12 is a processable intermediate that integrates the routes to targets that occupy underexplored erythromycinoid structure space, including valuable desmethyl, cyclic, and other functionalized variants. Taken together, the convergent assembly of 5 , 6 , and 9 , the conversion of 10 to 11 , and the reactions summarized in Schemes – suggest a realistic route by which to effect extensive and expeditious changes to the macrolide scaffold represented by erythromycin.…”

“…Nevertheless, de novo synthesis represents a means by which to gain unrestricted access to erythromycinoid structure space. Only recently has total synthesis produced a new erythromycinoid antibiotic candidate, namely, a desmethyl analogue that is thought to have the potential to address resistance . The motif redundancy in erythromycin at C4–C6 and C10–C12 led us to consider allenic functionality in these regions ( IV ).…”

“…In brief, prior studies suggest the following: (a) portions of the glycans, especially the amino sugar, are critical, and both the hydrophilic character of the β-face and the hydrophobic character of the α-face of the macrolide contribute to binding (center structure); (b) C9 amine or oxime functionality suppresses unwanted side effects ( V ); , (c) C9–C11 or C11–C12 heteroannulation can improve binding and appears to represent opportunities to overcome resistance ( VI , VII ); (d) C6–C9 heterocyclization leads to interesting (albeit nonantibiotic) activity ( VIII ); and (e) retention of the C6 and C12 heteroatom connectivity is desirable, and ether formation at C6 may improve the antibiotic activity and suppress other activity ( V , IX ) . C3 ketone derivatives ( X ) and alterations to the hydrophobic face of the macrocycle (e.g., at C4, C8, and C10; XI and XII ) may overcome resistance. , Hence, modification of the C3–C6 and C9–C12 regions offers opportunities to improve drug properties and avoid bacterial resistance.…”

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; ,…”