An Efficient Approach to Aspidosperma Alkaloids via [4 + 2] Cycloadditions of Aminosiloxydienes:  Stereocontrolled Total Synthesis of (±)-Tabersonine. Gram-Scale Catalytic Asymmetric Syntheses of (+)-Tabersonine and (+)-16-Methoxytabersonine. Asymmetric Syntheses of (+)-Aspidospermidine and (−)-Quebrachamine

Abstract

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.

Enantioselective Total Synthesis of Cyathin A3.

“…[132][133][134][135][136][137] However, the chloride version of this catalyst gave poor enantioselectivity in the reaction of 105 with 106. The selectivity was improved using the catalyst with a less coordinating SbF 6 -counter ion.…”

Catalytic Asymmetric Synthesis of all‐Carbon Quaternary Stereocenters

“…Although many reactions of this type employ cyclopentadiene as the diene and 2-alkyl acrolein derivatives as the dienophile, several examples involve more intricate dienes or dienophiles. For example, a salen-Cr-catalyzed type I Diels-Alder reaction of siloxydiene carbamate 1 and 2-ethylpropenal (2) to form 3 was the key step in a recent total synthesis of (ϩ)-aspidospermidine (Scheme 2; TBS, tert-butyldimethylsilyl) (10). Other examples of noteworthy enantio-and regioselectivity are found in oxazaborolidine-catalyzed cycloadditions of acyclic dienes with substituted quinones, such as the synthesis of dienedione 5 by using the Lewis acid catalyst 4 (ref.…”

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

“…Among these studies, strategies based on chiral auxiliary are dominant, and catalytic enantioselective method remains as a challenging task. [10][11][12][13] Enantioselective Heck reaction has been well recognized as a powerful method to construct quaternary carbon centers (Fig. 2a).…”

“…The corresponding diastereomeric ligand, L8, gave (S)-1 in 21% ee from (E)-2, and (R)-1 in 64% ee from (Z)-2 (entries 9, 10). Though Z-isomer of chloroformamide 2 showed better selectivities in some cases, the reactions took longer period and the yields were lower than those of the E- 33,34) did not give dramatic improvements (entries 11,12).…”