aspidospermidine and quebrachamine

Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.

Topics: Alkaloids; Aspidosperma; Chemistry Techniques, Synthetic; Cyclization; Indole Alkaloids; Quinolines; Stereoisomerism

The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (-)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (-)-quebrachamine, are reported herein.

Topics: Alkylation; Allyl Compounds; Catalysis; Indole Alkaloids; Indoles; Molecular Structure; Palladium; Pyridines; Quinolines; Stereoisomerism

The preparation of tricyclic amines from acyclic precursors is described using a cascade of tandem reactions involving condensation of an aldehyde with a primary amine, cyclization (with displacement of a halide), and then in situ deprotonation or decarboxylation to give an azomethine ylide or nitrone followed by intramolecular dipolar cycloaddition. The methodology is straightforward, and the aldehyde precursors are prepared easily and quickly in high yield using nitrile alkylations followed by DIBAL-H reduction. The relative ease of reaction of various substrates with different tether lengths between the aldehyde and the halide or dipolarophile has been studied. Several primary amines including simple amino acids such as glycine, alanine, and phenylalanine and derivatives such as glycine ethyl ester and also hydroxylamine have been investigated. High yields are obtained in the formation of different tricyclic ring sizes; the dipolar cycloaddition necessarily creates a five-membered ring, and we have investigated the formation of five- and six-membered rings for the other two new ring sizes. In all cases, yields are high (except when using glycine when the tether to the terminal alkene dipolarophile leads to a six-membered ring), and most efficient is the formation of the tricyclic product in which all five-membered rings are formed. Examples with an alkyne as the dipolarophile were also successful. In all the reactions studied, the products are formed with complete regioselectivity and remarkably with complete stereoselectivity. The key step involves the formation of three new rings and potentially up to four new stereocenters in a single transformation. The power of the chemistry was demonstrated by the synthesis of the core ring systems of the alkaloids (+/-)-scandine and (+/-)-myrioneurinol and the total syntheses of the alkaloids (+/-)-aspidospermine, (+/-)-quebrachamine, and (+/-)-aspidospermidine.

Topics: Aldehydes; Alkaloids; Amines; Cyclization; Heterocyclic Compounds, 3-Ring; Indole Alkaloids; Quinolines; Stereoisomerism

Topics: Cyclization; Indole Alkaloids; Quinolines

[reaction: see text] A formal synthesis of the Aspidosperma alkaloids aspidospermidine, aspidospermine, and quebrachamine is reported through an efficient preparation of Stork's penultimate intermediate. The key step of the sequence involved an intramolecular [3 + 2] cycloaddition of the 2-azapentadienyllithium 21 formed in situ from the corresponding imine 1, which after N-alkylation of the resulting cycloadduct provided 2 in excellent yield. The synthesis represents a new disconnection of the classical tricyclic ketone used for appendage of the requisite indole.

Topics: Aspidosperma; Catalysis; Cyclization; Indole Alkaloids; Lithium; Molecular Structure; Quinolines

Described is a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids, one that is readily adapted to the asymmetric synthesis of these compounds. The strategy is demonstrated by the total synthesis of (+/-)-tabersonine (rac-1), proceeding through a 12-step sequence. The basis for this approach was provided by a highly regio- and stereoselective [4 + 2] cycloaddition of 2-ethylacrolein with 1-amino-3-siloxydiene developed in our laboratory. Subsequent elaboration of the initial adduct into the hexahydroquinoline DE ring system was accomplished efficiently by a ring-closing olefin metathesis reaction. A novel ortho nitrophenylation of an enol silyl ether with (o-nitrophenyl)phenyliodonium fluoride was developed to achieve an efficient, regioselective introduction of the requisite indole moiety. The final high-yielding conversion of the ABDE tetracycle into pentacyclic target rac-1 relied on intramolecular indole alkylation and regioselective C-carbomethoxylation. Our approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members of the Aspidosperma family of indole alkaloids. The versatility of the synthetic strategy was illustrated through the asymmetric syntheses of the following Aspidosperma alkaloids: (+)-aspidospermidine, (-)-quebrachamine, (-)-dehydroquebrachamine, (+)-tabersonine, and (+)-16-methoxytabersonine. Of these, (+)-tabersonine and (+)-16-methoxytabersonine were synthesized in greater than 1-g quantities and in enantiomerically enriched form ( approximately 95% ee). The pivotal asymmetry-introducing step was a catalyzed enantioselective Diels-Alder reaction, which proceeded to afford the cycloadducts in up to 95% ee. Significantly, the synthetic sequence was easy to execute and required only four purifications over the 12-step synthetic route.

Topics: Alkaloids; Aspidosperma; Indole Alkaloids; Indoles; Quinolines; Stereoisomerism