Explorations on the total synthesis of (±)-isoschizogamine using an intramolecular 1,4-dipolar cycloaddition strategy

Abstract


Introduction
The schizozyganes represent a small group of hexacyclic indoline alkaloids 1 that were obtained from the twigs of the East African monotypic shrub Schizozygia caffaeoides. 2,3In addition to the major alkaloid schizozygine (1), 4 a pair of minor alkaloids were isolated 5 and their structures were established as isoschizogaline (2) and isoschizogamine (3) on the basis of extensive NMR studies. 3It was postulated that the skeleton of the schizozyganes could be biogenetically derived from the Aspidosperma alkaloid family, and indeed both groups of alkaloids are found in the same plant species. 6A proposed biosynthesis of the schizozyganes from the Aspidosperma alkaloids and further conversion to the isoschizozyganes was initially proposed by Hájíček 7 and this is shown in Scheme 1.An acid catalyzed rearrangement of the aspidosperma skeleton (4)  results in the ring-opened schizozygane skeleton 6 via intermediate 5.Alternatively, oxidation of 5 would lead to a transient iminium ion intermediate 7. Attack of the indoline nitrogen on the iminium carbon of 7 would first produce the aziridinium intermediate 8, which might then be opened reductively to give 9 and this would be followed by ring closure to provide the isoschizozygane core skeleton 10.To test this hypothesis, Hájíček and Trojánek carried out a successful biomimetic synthesis of (±)-strempeliopine based on this proposal. 7Rearrangement of pentacycle 11 in AcOH with cupric sulfate provided indoline 12 and a subsequent N-formylation gave intermediate 13 in 40% yield as shown in Scheme 2. Oxidative cyclization was accomplished by ozonolysis in acidic methanol followed by treatment with H2O2 to furnish (±)-strempeliopine (14) in 49% yield.

Scheme 2
Heathcock and Hubbs were the first to describe a concise synthesis of the biogenetically related alkaloid (±)-isoschizogamine (3). 8In their synthesis, the key step to forming the aminal functionality was realized through the attack of an aniline nitrogen onto a transient iminium ion embedded in a 6-6-5 fused ring system 9 (Scheme 3).Thus, the Michael addition of imine 15 with 16 gave an intermediate which, upon heating, underwent cyclization with concomitant loss of acetone and carbon dioxide providing a mixture of diasteromeric lactams 17.Dehydration of 17 gave 18.The aromatic nitro group and the lactam carbonyl group in 18 were reduced to 19, which was then subjected to acidic conditions.The resulting hemiaminal was subsequently oxidized to give (±)-isoschizogamine (3).
More recently, Magomedov presented an alternative strategy to the cyclopenta[b]quinoline core using a formal hetero Diels-Alder reaction to reach a densely functionalized tetrahydroquinoline derivative as an advanced intermediate to the targeted alkaloid.10a In a followup approach from his laboratory, an acylamidine intermediate was subjected to acidic conditions, which resulted in an interesting intramolecular cyclization reaction.10b Although his synthetic investigations did not result in a total synthesis of isoschizogamine, Magomedov did point out 10b that the synthesis of a key intermediate obtained in his investigations (vide infra) might be useful for an eventual synthesis of this alkaloid using a route previously developed by our group.

Scheme 3
In an earlier report, 11 we had outlined a new strategy for the synthesis of the isoschizozygane alkaloid core based on the intramolecular 1,4-cycloaddition of a crossconjugated heteroaromatic betaine 12 across a tethered π-bond 13 as illustrated in Scheme 4. We assumed that the hexacyclic skeleton of isoschizogamine (3) could be formed from a compound of type 20 by a sequence of enamide protonation, acyl-iminium ion cyclization and lactamization.Enamide 20 may be generated by extrusion of COS from cycloadduct 21 followed by reduction of both the nitro and keto groups and a subsequent dehydration.

Scheme 4
Although several intermolecular 1,4-dipolar cycloadditions have been described in the literature, 14 applications of the intramolecular type are still rare but have significant synthetic potential. 13In order to test the feasibility of the retrosynthetic strategy outlined in Scheme 4, our initial efforts were focused on model substrates.

Results and Discussion
The synthesis of 5a-aza-acenaphthylen-5-one 26 commenced from the easily available thiolactam 23 (Scheme 5).Generation of the bright yellow isolable betaine 24 was accomplished by the reaction of 23 with carbon suboxide 15 at 25 o C for 5 h.Heating a sample of 24 at 120 o C for 3 h in toluene afforded 26 as a single diastereoisomer in 66% yield as a pale yellow solid whose formation is easily accounted for by extrusion of COS 16 from the originally formed cycloadduct 25 followed by a hydrogen shift.The preferred stereoselectivity is associated with fewer nonbonded interactions in the transition state for the cycloaddition process.Catalytic reduction of the nitro functionality (H 2 , Pd/C) in 26 to the corresponding amino group was followed by enamide reduction using LAH.The transient enamine 27 was treated with acid to furnish a 3:2-mixture of diastereomeric aminals 28 and 29.The formation of the two observed diastereomers can be explained by protonation of the two diastereotopic faces of the double bond in the initially formed enamine 27. 8 Treatment of either isolated isomer with acetic acid resulted in an equilibrated 1:6-mixture of 28 and 29 with the major diastereomer possessing the correct core skeleton of the isoschizozygane family of alkaloids.

Scheme 5
The above result establishes that the intramolecular 1,4-dipolar cycloaddition of a crossconjugated heteroaromatic betaine intermediate (i.e.24) can be used as a method to prepare the core skeleton of the isoschizogamine family of alkaloids.Our next task was to synthesize the precursor δ-lactam 30 needed for the generation and cycloaddition of the required betaine intermediate 22 so as to to eventually furnish compond 32 as indicated in Scheme 6.

Scheme 6
After inspection of the structural features of δ-lactam 30, we decided to make use of an aza-Claisen rearrangement 17 strategy related to that previously described by Zhou and Magomedov.10b Our efforts to synthesize the required N-acetyl aziridine intermediate 39 are outlined in Scheme 7. Toward this goal, alkyne 33 was readily synthesized by treating the anion derived from methyl diethylphosphonoacetate with but-3-ynyl-4-methylbenzenesulfonate.A subsequent Sonogashira arylation 18 using 1-bromo-4,5-dimethoxy-2-nitrobenzene with Cl2Pd(PPh3)2 and CuI as the catalyst provided the expected coupled product 34.Reduction 19 of the triple bond present in 34 furnished alkene 35 as a 9:1-mixture of Z/E isomers.The ,unsaturated ester 39 needed for the aza-Claisen rearrangement was obtained through a Horner-Wadsworth-Emmons olefination 20 between phosphonate 35 and the aziridinyl aldehyde 36 21 and was acquired as an inseparable mixture of E/Z isomers (11:1) about the newly created A number of acidic conditions were attempted for the deprotection of the trityl group in 37, and finally the conditions of TFA, Et3SiH, 0 o C were observed to give the best results. 22After detritylation the NH-aziridine was obtained primarily as the Z-isomer 38.N-Acetylation of 38 (Ac2O, Et3N, CH2Cl2) gave aziridine 39.
The critical aza-Claisen rearrangement of aziridine 39 under the Somfai conditions 17 (LHMDS, THF, -78 C to 0 C) did occur, but only in 10% yield.We had assumed that the release of the aziridine ring-strain would facilitate formation of the seven-membered ring in tetrahydro-1H-azepine 40.Apparently, the low yield is due to a much higher activation energy for this reaction as compared to those reported by Somfai. 17The higher activation energy might be due to disruption of conjugation of the ,-unsaturated ester in the transition state.We speculated that heating enolate 39a would overcome the energy barrier for the rearrangement, which occurs by a boat-like transition state.Indeed, after 39 was deprotonated (LHMDS, PhMe, -78 C) and then heated at 80 C, the starting aziridine had disappeared and the rearranged product 40 was produced in somewhat better yield (30%).Further attempts to improve the yield 40 by varying the solvent, reaction time and temperature were unsuccessful.
At this stage of our studies we decided to push ahead and determine whether tetrahydro-1H-azepine 40 could be converted into the desired δ-lactam precursor 30 that is ultimately needed for the  In summary, an efficient approach to the core skeleton of the isoschizozygane family of alkaloids was accomplished by an intramolecular 1,4-dipolar cycloaddition reaction of a crossconjugated heteroaromatic betaine intermediate.Application of this strategy to a total synthesis of (±)-isoschizogamine is underway and the required substituted piperidin-2-one needed for the eventual 1,4-dipolar cycloaddition step has been prepared using an aza-Claisen rearrangement.