Studies in the FR901483 tricyclic skeleton synthesis and a new approach to the perhydropyrrolo[2,1-i ]indole ring system

Palladium-and radical-mediated cyclizations from N -(2-bromoprop-2-enyl)-1- azaspiro[4.5]decanes were studied, leading to the formation of azatricyclic derivatives embodying 7,10a-methanopyrrolo[1,2-a ]azocine or a pyrrolo[2,3-i ]indole framework depending on the reaction conditions


Introduction
The immunosuppressant FR901483 (Scheme 1) was isolated by a Fujisawa group in 1996, 1,2 who determined the structure by X-ray crystallography and the absolute configuration was eventually assigned when Snider achieved the enantiocontrolled total synthesis in 1999. 3From a structural point of view, the most conspicuous feature of FR901483 is an azatricyclic ring system consisting of the combined morphan and indolizine nuclei sharing the piperidine ring.
4][5][6][7][8] Four of them (Snider, 3 Sorensen, 4 Ciufolini, 5 and Brummond 6 ) achieved the enantioselective synthesis of the natural enantiomer, while Funk's 7 and Fukuyama's 8 syntheses were developed in the racemic series.In all reported routes, a functionalized 1-azaspiro [4.5]decan-8-one was used as an intermediate to build the azatricyclic core of the target, using an aldol process whose regioselectivity is sensitive to the substitution pattern and reaction conditions.
With the aim of approaching the FR901483 framework 10 through a regioselective ring closure from an azaspiro [4.5]decan-8-one, we decided to prepare the azaspiranic enone 1 with the idea of forming the bridge either on the carbonyl α' position, the double bond acting as a blocking group (path a) or on the double bond, after reduction of the enone group, (path b) (Scheme 1).In the former case we would explore our Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates 11 as the methodology for the synthesis of the target nitrogen heterocycle using an enone as the substrate.Path b, on the other hand, would lead to a reversed regioselectivity, enabling us to study the feasibility of a radical cyclization either through a direct 6-endo or 5-exo process followed by a rearrangement of the initially-formed homoallyl radical, via a reversible 3-exo-trig cyclization, to give the corresponding six-membered ring.

Results and Discussion
To access the tricyclic skeleton of FR901483 through the proposed methodology we required a cyclization precursor embodying the 1-azaspiro [4.5]dec-6-en-8-one framework (i.e. 1).Although we have recently described an approach to obtain compounds of this type in their enantiopure form, 13 for this study we prepared compound 1 in its racemic form.Our protocol to assemble this azabicyclic system was inspired by Kawahara and Nagumo's procedure 14 for preparing spirolactams from proline derivatives, based on the alkylation of a proline derivative followed by some functional group interconversion steps and a final aldol cyclization step.
The synthesis (Scheme 2) starts with the alkylation of the L-proline derivative 2 with 4bromo-1-butene using 1.15 eq of LDA to afford racemic 3 (64%). 15The synthetic sequence 3 ∏ 6 involves conversion of ester 3 to aldehyde 5 through a reduction-oxidation process, followed by Wacker oxidation of the terminal alkene to give the keto aldehyde 6. Aldol condensation and succesive elimination process in the ketol intermediate gave cyclohexenone 1, in accordance with the recently reported protocol. 13RKAT USA, Inc.
Removal of the Boc group and alkylation of the secondary amine with 2,3-dibromopropene provided the aminotethered ketone vinyl halide 7, which was submitted to the Pd promoted cyclization in presence of KOPh 11c (Scheme 3).Treatment of vinyl halide 7 with 0.2 equiv of Pd(PPh 3 ) 4 and 2.5 equiv of KOPh in refluxing THF gave a mixture of tricyclic enone 8 (21% yield) and tricyclic ketone 9 (12%).It became clear from this result that the use of a base to form the enolate does not allow the regiocontrol in the cyclization step, since the vinylpalladium intermediate species reacted with both the enolate and enone double bonds. 16In the latter case the reaction evolved through a Heck reductive process.The two compounds formed were separated and their structure elucidated by 2D NMR spectra (see Table 1 Although this ring-forming reaction led to the azatricyclic compound 8 and constitutes a novel approach to the heterocyclic system found in FR901483, the low regioselectivity (2 to 1) together with the poor yield in the synthesis of the bridged azatricyclic compound, via the intramolecular palladium-catalyzed enolate-driven cross coupling between the vinyl halide and the enone, induced us to discard this approach.Thus we turned our attention to Path b using the same azaspiranic intermediate 1.
As we mentioned before, we were curious to see if a radical process from vinyl bromide 11 through a homoallyl-cyclopropylmethyl radical could be an entry to the FR901483 framework.Reduction of enone 1 with NaBH 4 /CeCl 3 stereoselectively gave the allylic alcohol 10, which after deprotection and alkylation with 2,3-dibromopropene provided the radical precursor 11.Subjection of the vinyl bromide 11 to standard tin hydride conditions promoted only the 5-exo radical cyclization to give 12, no bridged product E being observed (Scheme 4).
The course of the reaction may be influenced by steric factors.Indeed, the vinyl radical initially formed from the conformationally mobile 11 could lead to two conformationally different homoallyl radicals (A and B), but only homoallyl radical B could evolve to afford the cyclopropylmethyl radical (B ∏ C process) required for the formation of the six-membered ring intermediate D, from which E could be obtained.
Considering that the only conformation detected for compound 12 was that corresponding to a trans-diequatorial conformational relationship between the hydroxyl group and the nitrogen atom, as suggested by the NMR experiments (Table 1), we assumed the same conformation for its radical precursor A. This may suggest that one of the reasons for the non-formation of compound E is the inaccessibility of the correct chair conformation B in the first radical formed.In turn, the lack of reactivity in the homoallyl radical A to the corresponding rearranged radical is due to steric reasons, as the conformation depicted in Scheme 4 shows, and to the fact that a conformational change to B is not available in the time-scale of the radical processes.

Scheme 4
Table 1 shows the NMR data of the three azatricyclic compounds reported here.Comparison of the NMR values of protons and carbons in the C(3)-C(5)-C(10a) domain reveals significant differences (Table 1).Most notably, the spirane carbon C-10a of the bridged compound 8 resonates at δ 58.3, whereas that of fused compounds 9 and 12 appears at δ 71.6.
The relative configuration of 12 was inferred from the pattern of the two methine proton coupling constants of the stereogenic carbons at C-6a and C-8.
In summary, although the attempts to introduce a regioselective formation of the FR901483 azatricyclic framework have not been very fruitful, the easy formation of the tricyclic system of perhydropyrrolo[2,1-i]indole 17 could be useful in the development of new synthetic routes to cylindricine 18 and lepadiformine alkaloids 19 embodying the related azatricyclic framework of perhydropyrrolo[2,1-j]quinoline.

Experimental Section
General Procedures. 1 H and 13 C NMR spectra were recorded in CDCl 3 solution.Chemical shifts are reported as δ values (ppm) relative to internal Me 4 Si.Infrared spectra were recorded on a Nicolet 205 FT-IR spectrophotometer.TLC was performed on SiO 2 (silica gel 60 F 254 , Merck) or on Al 2 O 3 (aluminium oxide 60 F254, Merck).The spots were located by UV light, a 1% KMnO 4 aqueous solution or a 1.5% K 2 PtCl 6 aqueous solution.Unless otherwise noted chromatography refers to flash chromatography and was achieved on SiO 2 (silica gel 60, SDS, 230-400 mesh).All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents and under anhydrous conditions.Drying of the organic extracts during the work-up of reactions was performed over anhydrous Na 2 SO 4 .