Studies towards the Construction of Quaternary Indolizidines by [ 2 , 3 ]-Sigmatropic Rearrangement Cocatalyzed by Ionic Liquid

Uma abordagem enantiosseletiva eficiente para a preparação de centros quaternários a partir da prolina 5 foi desenvolvida através do rearranjo [2,3]-sigmatrópico de Stevens, co-catalisado por líquido iônico. O rearranjo sigmatrópico foi estereoespecífico porque as migrações-[2,3] foram restritas à mesma face e a estereosseletividade surgiu na etapa preliminar da N-alquilação em 8. O método mostrou melhores rendimentos do que os descritos na literatura. O uso de hexafluorofostato de 1-butil-3-metilimidazólio mostrou uma melhora nos rendimentos do rearranjo de Stevens devido a possível estabilização e/ou ativação das espécies zuiteriônicas em solução, pelo líquido iônico. Diversas indolizidinas foram sintetizadas a partir do derivado (S)-5 da prolina quaternária.


Introduction
Chirality in molecules plays an enormous role in areas ranging from medicine to material science.However, after great developments in synthetic organic chemistry, there are still few methodologies that allow the stereoselective construction of predetermined moieties in some classes of compounds.In this context, particular attention in efficient synthetic routes for novel chemotypes is already pursued when stereoselectivity is required.As part of our efforts in the field of biologically relevant N-moieties, we turned our attention toward an alternative synthetic route for indolizidines, figured out through key intermediate (S)-5, as depicted in Figure 1.Quaternary proline derivatives are important amino acids due to the pharmacological applicability of natural peptides is greatly limited by profound factors such as lack of selectivity for a specific receptor, enzymatic instability, or low bioavailability. 1 Most vital physiological processes by the construction of several peptides and proteins are therefore targets for potential medical applications across the full spectrum of human disease. 2 A number of strategies devised for the synthesis of α-substituted proline derivatives involve the α-functionalization of L-proline itself.Most often, the assembly of the fully substituted stereocenter is accomplished by electrophilic alkylation of L-proline enolate equivalents. 3The asymmetric construction of molecules with quaternary carbon stereocenters, that is, carbon centers with four different non-hydrogen substituents, represents a very challenging and dynamic area in organic synthesis.Chirality transfer from carbon to carbon via sigmatropic rearrangements is a well-established approach in asymmetric synthesis. 4However, the classic methodologies are being substituted more and more by catalytic and modern processes.Thus, we figured out to explore N→C chirality transfer under [2,3]-shift of proline derivative ammonium ylides stereogenic at nitrogen.

Results and Discussion
We first explored the Stevens rearrangement 6 of the preformed iminium 8 co-catalyzed by ionic liquid.It was suggested that ionic liquids can activate and stabilize zwiterionic species in solution. 7Thus, iminium 8 was obtained in 75% overall yield from N-benzylproline methyl ester 7, 8 which was alkylated stereoselectively with allyl bromide and fractionally crystallized (Scheme 2).Having prepared iminium 8, the next stage was set to introduce the allyl group α-nitrogen selectively through Stevens rearrangement and the role of co-catalysis by the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate [BMIm] .PF 6 9 studied to give 9, Table 1.In all the examples described, just stereospecific [2,3]-sigmatropic rearrangement was observed in the migration of the allyl group from 8, and no competing [1,2]-sigmatropic rearrangement was detected, although it has been observed in some cases for allyl-substituted ammonium ylides. 10It was previously reported that allyl-migration using K 2 CO 3 afforded 9 in low yield (40%) and good enantioselectivities (entry 1, Table 1). 11Then, using [BMIm] .PF 6 as co-catalyst it was observed the same selectivity, but in a better yield of 50% (Table 1, entry 2).Trying to improve the yields we set out the use of stronger bases in different solvents and co-catalysis by ionic liquid (Table 1).When NaHMDS was employed using THF as solvent an improvement in the yields was achieved as well as higher enantiomeric excesses than K 2 CO 3 (90% ee, Table 1, entry 3).Testing the co-catalysis by [BMIm] .PF 6 showed a significative improvement in the yields and no influence in the selectivities (entries 4, 6, 8-13 and 15) as depicted in Table 1.Product (S)-9 was obtained as the major enantiomer in all the studied cases (Table 1), consistent with the notion that when an prenyl group is added to 7 a [2,3]-shift mechanism is ongoing and would be restricted to the same face of proline derivative, due to the trans arrangement of the benzyl and ester groups.Stereospecificity for exclusive [2,3]-shifts of a prenyl group derivative had previously been reported by West and Glaeske 12 and by Coldham and co-workers, 11 respectively.Then, benzyl group deprotection of 9 using Et 3 SiH/PdCl 2 in CH 2 Cl 2 13 afforded 5 in quantitative yield.To further illustrate the versatility of this methodology, the diallyl derivatives 10 was obtained by allylation of 5, followed by a ring-closing metathesis (5 mol% of Grubbs third generation catalyst, 25 °C, CH 2 Cl 2 ) to afford the indolizidine 11 in excellent yields. 14Reduction of methyl ester employing LiAlH 4 in refluxing THF afforded the alcohol with concomitant olefinic bond reduction in 86% overall yield (Scheme 3).The dehydroxylation to achieve 6 15 was carried out using PBr 3 followed by AIBN and Et 3 SiH treatment (82% in two steps).It was also tested the reduction of the bromide derivative 14 with LiAlH 4 in THF and reflux, but it was observed lower yields (56%) when compared with radical AIBN/Et 3 SiH protocol.The cis-dihydroxylation of 11 using catalytic osmium tetroxide (OsO 4 ) and N-methylmorpholine N-oxide (NMO) in THF:H 2 O afforded the diastereomeric diols 12 and 13 (90%) in a 5:1 dr (Scheme 3).The facial selectivity in the osmylation can be rationalized in terms of the concavity of the indolizidine system, which proceeded through the less hindered face. 16Diols 12 and 13 were unseparated by chromatography, and to prove the absolute configuration of the dihydroxylation step of products 12 and 13, reduction of methyl ester was performed.Thus, reduction of 12 and 13 with alane (AlH 3 ) gave after silica gel purification 1 and 2 in 92% and 95% yield, respectively. 17This route provides enantiomerically pure 1-azabicyclo[4.3.0]nonane.
Further, with an efficient approach to quaternary indolizidine established by Grubbs catalyst, the stage was now set for the indolizidinone moiety.Treatment of (S)-5 and acrylic acid with EDC and HOBt in CH 2 Cl 2 gave 15 in 92% yield (Scheme 4). 18Metathesis reaction of 15 with Grubbs catalyst afforded 4 in 80% (90% ee), as depicted in Scheme 4. The enantiomeric excesses were determined by HPLC to assure that no epimerization was occurred in the process. 19inally, allyl proline 5 can be converted to 16 using NaHMS and 1-bromopronyn in 95% yield. 20In the course of our investigation, the stoichiometric use of Co 2 (CO) 8 for the intramolecular amine oxide promoted Pauson-Khand reaction in the ionic liquid [BMIm] .PF 6 was studied.Pauson-Khand reaction using 16, catalytic amount of Co 2 (CO) 8 (10 mol%), cocatalyzed with [BMIm] .PF 6 under CO atmosphere (1.0 bar) afforded tricyclic enone 3 in 89% yield as a single stereoisomer, as depicted in Scheme 5.The reaction was performed using catalytic amount of cobalt (0) octacarbonyl in THF in the presence of NMO as promoter. 21

Conclusions
In summary, a mild and efficient method for preparation of quaternary centers from proline 5 building block has been developed.The Stevens rearrangement was stereospecific because the [2,3]-migrations was restricted to the same face, and the stereoselectivity arose from the previous N-alkylation step.For the first time, the use of 1-butyl-3-methylimidazolium hexafluorophosphate showed an improvement in the yields of the Stevens rearrangement due to a possible stabilization and/or activatation of zwiterionic species in solution by the ionic liquid.The results described here provide an attractive route to 8a-substituted indolizidines, and the utilization of this approach in the Scheme 3.

General procedures
All experiments were carried out under an argon atmosphere except for hydrolysis under acid conditions.Dichloromethane was distilled from CaH 2 , tetrahydrofuran previously treated with CaH 2 and distilled from sodium, methanol was distilled from Mg tunings.The normal extracts consisted of drying over MgSO 4 , filtration and concentration under reduced pressure with a rotatory Vol. 20, No. 5, 2009

Preparation of iodotrimethylsilane (TMSI)
To a mixture of (TMS) 2 (8.86 g, 8.19 mL, 40.0 mmol) and iodine (10.2 g, 40.0 mmol) was heated to 65 o C in a system equipped with a flask coupled to Vigreux column and two condensers, careful due to a high exothermic reaction took place.A homogenous solution was achieved.Then, the mixture was refluxed by 1.5 h.(TMS) 2 was converted quantitatively to TMSI.

Dihydroxylation of 11 followed by ester reduction of 12 and 13
Osmium tetroxide (67.0 μL of a freshly prepared 0.039 mol L -1 solution in t-BuOH) was added to a solution of 11 (0.775 mmol) and N-methylmorpholine N-oxide (0.256 mL, 50%, v/v, in water) in a 9:1 THF-H 2 O solution (9.70 mL) at 0 °C.After 12 h at room temperature, the mixture was treated with Florisil (0.350 g) and NaHSO 3 (0.111 g), stirred for 1 h, filtered, and concentrated.The residue was diluted with EtOAc, and the organic layer was washed with 5% H 3 PO 4 and brine, dried, and concentrated to give an unseparated 5:1 mixture of 8 and 9 in 88% yield.A solution of the isomers 12 and 13 (5:1) (0.502 mmol) in dry THF (6.0 mL) was added a solution of AlH 3 in THF (1.55 mol L -1 , 1.94 mL, 3.01 mmol) 22 at room temperature.After 10 min, the reaction was quenched with saturated aqueous sodium sulfate solution and filtered.The solids were washed with CH 2 Cl 2 (200 mL), dried with Na 2 SO 4 , and evaporated in vacuum.Purification by chromatography afforded compound 1 and 2 in 75 and 15% yields, respectively.
(6R,7S,8aS)-6,7-Dihydroxy-8a-hydroxymethylindolizidine hydrochloride (1)  mp 198-200 o C. [α] D = −8.0(c 1.0, H 2 O).FTIR (KBr) ν max /cm −1 : 3330, 3275, 3230, 3148, 1475.HRMS, ESI(+)-evaporator.The compounds were purified by column chromatography on silica gel (70-230 mesh).The 1 H NMR and 13 C NMR spectra were recorded on a Bruker (400 MHz) spectrometer.Chemical shifts (d) are recorded in ppm with the solvent resonance as the internal standard and coupling constants (J) recorded in Hz.Signals for rotational and/or configuration isomers are denoted inside brackets.The infrared spectra were recorded as films in KBr cells on a Nicolet Nexus 470 (FTIR).Mass spectrometry experiments were performed on a highresolution high accuracy hybrid double quadrupole (Qq) and orthogonal time-of-flight (Tof) mass spectrometer (QTof, Micromass UK).The temperature of the nebulizer was 50 °C.The ESI source and the mass spectrometer were operated in the positive-ion mode.The cone and extractor potential were set to 40 and 10 V, respectively.Optical rotations were measured on a polarimeter Polamat A Carl Zeiss Jena using a quartz cell and a mercury or sodium lamp.The melting points were measured on an Eletrothermal 9100 apparatus.The gas chromatography analyses (FID detector) were performed using a Shimazu equipment.Column chromatography was performed using silica gel Merck 230-400 mesh.TLC analyses were performed with silica gel plates Merck using iodine, KMnO 4 and UV-lamp for visualization.

Preparation of 8
Allyl bromide (60 mmol) was added neat to 7 (6.57g, 30 mmol), and the mixture was stirred for 2 h.Excess allylbromide was removed under reduced pressure, and the brown residue was dissolved in CH