Synthesis of 2,6‐Dioxo‐1,2,3,4,5,6‐hexahydroindoles by Acid‐ Catalyzed Cyclization of Acetal‐Protected (2,4‐Dioxocyclohex‐1‐yl)acetamides and their Transformation into 5,8,9,10‐Tetrahydro‐6H‐indolo[2,1‐a]isoquinolin‐9‐ones

Abstract

Acetal-protected (2,4-dioxocyclohex-1-yl)-acetic acids were prepared by allylation of dilithiated 1,3-cyclohexane-1,3-diones, protection of the carbonyl groups and oxidation of the alkene moiety. Their reaction with amines afforded the corresponding amides which were transformed, by acid-catalyzed cyclization, into various 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles. The reaction of the latter with triflic acid resulted in the formation of novel 5,8,9,10-tetrahy-Keywords: alkaloids; amides; C À C bond formation; cyclization; nitrogen heterocycles IntroductionErythrina alkaloids occur in various tropical and subtropical plants [1] and show a wide range of interesting biological properties.[2] This includes, for example, curare-like, hypotensive, sedative, anticonvulsive, and CNS-depressive activity.[3] Erythrina alkaloids have been prepared, for example, using photochemical [2 + 2] cycloadditions or Diels-Alder reactions as the key steps.[4] An important strategy for the synthesis of Erythrina alkaloids relies on the acid-catalyzed domino reaction of (2-oxocyclohex-1-yl)acetic amides. [4][5][6] This transformation proceeds by acid-catalyzed cyclization of the amide to give an N-(2-arylethyl)-2-oxo-1,2,3,4,5,6-hexahydroindole which is transformed in situ into the Erythrina-type spirocyclic product by a Pictet-Spengler reaction. For example, spirocycle I has been directly prepared from the amide II under various conditions (use of acids or Lewis acids) (Scheme 1). Despite its utility, the preparative scope of this reaction is very narrow and its success strongly depends on the structure of the substrate (substitution pattern of the aryl group, length of the linker between the aryl group and the nitrogen atom, etc.). This is a severe limitation because the synthesis of specific target molecules heavily relies on functional group transformations of the spiro compounds obtained by the domino process. FULL PAPERSTo address this problem, we planned to prepare the unknown Erythrina derivative III, which contains an additional carbonyl group, from the corresponding amide IV (Scheme 1). The carbonyl group of III was expected to be a useful tool for the synthesis of Erythrina-type natural products and their non-natural analogues. It was planned to prepare the required starting material IV from (2,4-dioxocyclohex-1-yl)acetic acid which, therefore, represents an important key intermediate of the present study.Recently, we have reported [7] preliminary results related to the synthesis of (2,4-dioxocyclohex-1-yl)acetic amides, such as IV. Their cyclization, in the presence of catalytic amounts of para-toluenesulfonic acid (PTSA), resulted in the formation of 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles rather than the expected Erythrina-type spiro compounds. Herein, we report a full account of the preparative scope of this methodology which provides, to the best of our knowledge, the as yet most general approach to 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles.

Short Total Synthesis of (±)‐γ‐Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

“…[7,8] Lycorane alkaloids have also been shown to displaysignificant antiproliferative activity in variousc ancerc ell lines including melanoma, multiple melanoma, leukemia, carcinoma, lymphoma, glioblastoma and non-small-celll ung cancer ( Figure 1). [7,8] Due to their potent and wide ranging activities and their associated structural complexity,t hey have accordingly attracted significant efforts towards their syntheses, [9][10][11][12][13][14][15] including radicalc yclisation,a minocyclization, intramolecular addition reactions and several metal-catalyzed amidation reactions amongsto thers. [9][10][11][12][13][14][15][16] Despite the structural diversity of both classes of compound and the wide array of synthetic methods used in their syntheses,m anyh ave focused on the synthesis of the dihydroindolenone core 11, due to its ready elaboration to either of the core structures of erythrina (1-3)o r lycoranealkaloids (4-10)( Figure 2).…”

“…[7,8] Due to their potent and wide ranging activities and their associated structural complexity,t hey have accordingly attracted significant efforts towards their syntheses, [9][10][11][12][13][14][15] including radicalc yclisation,a minocyclization, intramolecular addition reactions and several metal-catalyzed amidation reactions amongsto thers. [9][10][11][12][13][14][15][16] Despite the structural diversity of both classes of compound and the wide array of synthetic methods used in their syntheses,m anyh ave focused on the synthesis of the dihydroindolenone core 11, due to its ready elaboration to either of the core structures of erythrina (1-3)o r lycoranealkaloids (4-10)( Figure 2). [10,16,17] As ar esult of the structuralc omplexitiesa nd potent biological activitiesa ssociated with each class of compound, we were interested in the development of new methodology to access molecules relatedt ot he bicyclic core 11 as ar oute to both classes of compound.…”

“…[9][10][11][12][13][14][15][16] Despite the structural diversity of both classes of compound and the wide array of synthetic methods used in their syntheses,m anyh ave focused on the synthesis of the dihydroindolenone core 11, due to its ready elaboration to either of the core structures of erythrina (1-3)o r lycoranealkaloids (4-10)( Figure 2). [10,16,17] As ar esult of the structuralc omplexitiesa nd potent biological activitiesa ssociated with each class of compound, we were interested in the development of new methodology to access molecules relatedt ot he bicyclic core 11 as ar oute to both classes of compound. [18,19] We were also cognizant of the need to develop aflexible route, which would facilitatet he synthesis of ar ange of analogues for biological testing.…”

Strategies Based on Aryllithium and N‐Acyliminium Ion Cyclizations for the Stereocontrolled Synthesis of Alkaloids and Related Systems

“…This approach involves the formation of a five-membered ring through Parham cyclization of the imide 62 to form the hydroxylactam 63, which is reduced with Et 3 SiH in the presence of TFA. [38] Tertiary bicyclic N-acyliminium intermediates have also been successfully used in intramolecular α-amidoalkylation reactions, leading to erythrinanes such as 67 (Scheme 20) in a straightforward route with use either of protic (PTSA, 2 mol-%) [39] or Lewis [AlMe 3 /In(OTf) 3 ] acids. [40] The construction of the erythrinane skeleton has also been achieved through a sequence that involves a tandem Parham cyclization/intermolecular α-amidoalkylation with allylsilane in the presence of TiCl 4 to afford the pyrroloisoquinoline 68 (Scheme 21), which could be carried forward to the erythrinane 70 by a stereoselective conjugate addition followed by an RCM reaction.…”