The synthesis of 1,2,3,6,6a,7-hexahydro-7-methyl-5-imino-1 H - pyrrolo[1,2-c ]imidazolo[5,4-b ]indole

N -3-(1-Methylindol-3-yl)propan-N -(2,2,2-trichloroethoxysulfonyl)guanidine was synthesized from 3-formyl-1-methylindole in six steps and subjected to conditions intended to convert the side-chain into a 2-iminotetrahydropyrimidine-containing product, of relevance to a possible synthesis of the aplicyanins. An alternative reaction course was observed, resulting in the formation of a new tetracyclic system.


Introduction
Recently, a new family of five antitumor agents, the aplicyanins, 1, was isolated from an Antarctic ascidian Aplidium cyaneum, 1 for example aplicyanin A has R 1 =R 2 =R 3 =H, aplicyanin B has R 1 =Ac, R 2 =R 3 =H, and the most complex, aplicyanin F has R 1 =Ac, R 2 =OMe, R 3 =Br.Following our studies on the synthesis of a variety of heterocyclic marine natural products 2 and derivatives 3 we were attracted to the synthesis of such structures and describe here our initial model study aimed at constructing a 4-(indol-3-yl)tetrahydropyrimidine.Our plan was to construct the reduced pyrimidine unit, following the recent work by Du Bois et al. 4 However, an unexpected cyclization took place involving the indole unit and there was formed a fused tetracyclic structure, 2, an example of a previously unknown heterocyclic system.DuBois demonstrated the use of trichloroethoxysulfonamides in intermolecular benzylic C-H insertion reactions, 4b and further that trichloroethoxysulfonyl (Tces)-protected ureas and guanidines can be used for intramolecular insertions into benzylic and tertiary positions.4c The example which was of most relevance for our proposed synthesis is shown in Scheme 1 wherein a five-membered reduced imidazole 4 was constructed from precursor 3. Our thesis was that a comparable insertion into the indolylic position of a compound 5 would lead to 6 (Scheme 2).

Results and Discussion
The construction of the cyclization precursor 5 began with 3-formyl-1-methylindole, 7, which was brought into a Wittig reaction with commercially available 8, giving the unsaturated aldehyde 9. 5 Catalytic reduction of compound 9 saturated the double bond and also converted the aldehyde into an alcohol, producing the N-methyl homotryptophol 10 6 (Scheme 3).

Scheme 3
Conversion of the alcoholic function into a primary amine was achieved in three steps, the last two in one pot.The alcohol was converted efficiently into a mesylate 11, and the nitrogen introduced by displacement using the anion of diformamide, hydrolysis then liberating the Nmethyl homotryptamine, 12, in an overall 92% yield for the last two steps (Scheme 4).

Scheme 4
Finally, the Tces-protected guanidine unit in 5 was constructed by reaction of the primary amine with the isothiourea 13, again following the work of Du Bois 4c (Scheme 5).We were now ready to attempt the side-chain cyclization hoping for the formation of the tetrahydropyrimidine, 6.Exposure of 5 to the conditions described by Du Bois produced, in 25% yield, a product that we deduce has structure 2 (Scheme 6).Initially, we were surprised to observe the presence of three CH 2 groups in the product, instead of the two expected for a tetrahydropyrimidine derivative.Thus, in addition to the benzene ring signals, there were signals for the (CH 2 ) 3 unit, but there was no indole α-proton signal in the 1 H NMR spectrum, but instead a singlet signal at 5.34 was observed for H-6a (see Scheme 7 and Table 1).A detailed HMBC and NOESY study revealed correlations (Scheme 7) that support the proposed structure 2. The H-6a shows HMBC long distance correlations (C1, C5, N-Me, C7a, and C11a), as well as NOE signals (H1, H6, and N-Me) with at least one atom of each ring, which was very useful for the assignment of the structure and stereochemistry of 2. In particular, the NOE effect between H6a and one of the protons on C1 established the cis-relationship shown in 2. Deprotection of 2 gave the corresponding N-hydrogen guanidine 14.

Mechanism of the cyclization
We have considered several mechanisms whereby the tetracycle 2 might be formed.One possibility, summarized in Scheme 8, is that the rhodium catalyst is not involved and that the conversion is initiated by activation of nitrogen by PhIOAc + then electrophilic attack at the indole β position.We discounted this possibility on the grounds that when compound 5 was exposed to PhI(OAc) 2 and MgO without the rhodium catalyst, a very complex mixture was obtained, in which the tetracycle 2 could not be detected.We speculate that the rhodium-catalyzed oxidative cyclization of an indol-3-ylmethanol carbamate 7 (Scheme 9, 15 → 16), which was postulated to involve nucleophilic attack of the indole on the nitrogen of a rhodium-nitrene complex, is a partial precedent for the present conversion.

Scheme 9
The analogy is not exact, as in the present case the nitrene nitrogen becomes attached to C2 of the indole.However, it is possible that a similar mechanism could operate, perhaps by initial direct attack at indole C3 (→ 18), followed by migration (or equilibration) to C2 (Scheme 10, 18 → 19).A variant on this would involve attack of the indole on the metal, followed by reductive elimination.Such processes may be related to the palladium-and rhodium-catalyzed direct intermolecular arylations of indoles, which proceed via electrophilic metallation and involve C2/C3 equilibration. 8,9inally, the mechanism could involve a nitrene formed from the primary amino group engaging in a cycloaddition with the indole double bond forming an aziridine 20.Intramolecular nucleophilic ring opening, as indicated in Scheme 11 would complete the process.This step would have to involve considerable S N 1 character in the breaking of the C-N bond, to allow formation of the observed stereochemical outcome.Multiplicity of the carbons was assigned with DEPT and gHSQC experiments, although the usual abbreviations according to off-resonance decoupling are used: (s) singlet, (d) doublet, (t) triplet, and (q) quartet.The same abbreviations are used for the multiplicity of signals in H-NMR and also: (m) multiplet, (bs) broad singlet, (bt) broad triplet.Spectra were referenced to appropriate residual solvent peaks (d 6 -DMSO, or CDCl 3 ).IR spectra were obtained on a Thermo Nicolet FT-IR spectrometer.HRMS were performed on a Bruker Autoflex high-resolution mass spectrometer by Unidad de Espectrometría de Masas (Universidad de Santiago de Compostela) and by Servei d'Espectrometria de Masses (Universitat de Barcelona).Microwave-assisted reactions were carried out in a CEM Discover microwave apparatus.An automatic syringe pump was used as specified for controlled addition of some reactants.Reversed phase analytical HPLC was performed on a Waters Alliance separation module 2695 using a Waters Xterra MS C 18 column (150 x 4.6 mm, 5 µm) and a Waters 996 PDA detector at 254 nm.