Concise, Asymmetric, Stereocontrolled Total Synthesis of Stephacidins A, B and Notoamide B

Abstract

Concise asymmetric total syntheses of the fungal metabolites (−)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B are described. Key features of these total syntheses include (1) a facile synthesis of (R)-allyl proline methyl ester, (2) a revised route toward the pyranoindole ring system, (3) a novel cross-metathesis strategy for the introduction of important functional groups, and (4) an S N 2′ cyclization to form the [2.2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates.

Stereoselective Synthesis of Quaternary Proline Analogues

“…Interestingly, Williams et al reported that treatment of the lactone 6 (R = allyl) with Na in methanol, followed by the addition of acetyl chloride to the solution and heating to reflux, readily removes the trichloroacetaldehyde auxiliary. [27] In this manner, (R)-allylproline methyl ester hydrochloride salt was prepared on a 20 g scale and was used as a building block for the total synthesis of the fungal metabolites (-)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B. Besides this, the (trichloromethyl)oxazolidinones could also be readily transformed into amides by nucleophilic ring-opening with amines.…”

“…In particular, enantiomerically pure α-allylproline has shown plentiful applications in the synthesis of type II [29] and type VI [30] β-turn [31] mimetics, spirolactams [25,32] as conformationally restricted pseudopeptides, biologically active natural products, [21,27,33] and peptidomimetics. [24,34] As well as alkylation reactions, additions to carbonyl groups of aldehydes [17,35] and ketones, [17] Michael additions, [17] and acylation reactions [17,32b] have also been reported (Scheme 3).…”

Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

“…via cations or radicals or anions. For example, S N 2' cyclizations of diketopiperazine (DKP) enolates were used by Williams' group in their approaches to both brevianamide B (I) [16,17] and stephacidin A (IV) [18][19][20][21][22], whereas Sarpong et al used an intramolecular enolate amidation [23]. Myers' [24] and Trost's [25,26] groups used radical cyclizations to construct the diazabicyclo[2.2.2]octane skeleton, whereas Simpkins' group developed both cationic [27][28][29] and radical [30,31] cyclization cascades to malbrancheamide B (V) and stephacidin A (IV), respectively.…”

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

“…Treatment of compound 57 with a palladium catalyst resulted in the formation of coupling product 59 through intermediate 58. 11 An early contribution for the synthesis of a pyrrole-containing natural product by using an intramolecular C-H arylation strategy. rhazinilam was achieved.…”