Metal-dependant stereoselectivity in the Pauson-Khand cyclization of N -propargyl- γ -amino vinyl sulfones

An efficient enantioselective route to N -propargyl- γ -amino vinyl sulfones has been developed, and their Pauson-Khand cyclization has been investigated. The stereoselectivity of the reaction depends both on the structure of the substrate and on the nature of the metal-carbonyl promoter


Introduction
The intramolecular version of the Pauson-Khand (PK) reaction, 1 a metal-mediated [2+2+1] formal cycloaddition of an alkyne, an alkene and carbon monoxide to give a 2-cyclopentenone unit, has been widely utilized in the direct construction of carbo-and heterobicyclic systems, often with high degrees of stereocontrol. 2 While the presence of electron-deficient substituents in the alkene moiety leads in most instances to low yields and/or to the formation of conjugated 1,3-dienes, 3 Carretero and co-workers have demonstrated that 1-phenylsulfonyl-3-oxygenated enynes are excellent substrates for the reaction. 4Moreover, contrary to the standard selectivity of allyl substituted enynes in PK cyclizations, in which the allylic substituent is located preferentially in the less hindered exo face of the bicyclic product, 1,5 the intramolecular PK reaction of several γ-alkoxy vinyl sulfones takes place with high endo selectivities.
In the context of our long-standing interest in the synthetic applications of scalemic 2-(1aminoalkyl)oxiranes, 6 we have recently developed a general, high-yielding and enantioselective route to γ-amino vinyl sulfones. 7In spite of their high biomedical relevance as key components of potent and selective cysteine protease inhibitors, 8 practically nothing is known about the chemistry of these compounds.We decided therefore to investigate the PK cyclization of Npropargyl-γ-amino vinyl sulfones, paying special attention to the stereochemical outcome of the H Scheme 1. i) NaH, propargyl bromide, THF, ∆ (66% yield); ii) TFA, CH 2 Cl 2 , rt; iii) propargyl bromide, K 2 CO 3 , DMF, rt (60% yield from 1a).
Both 4c and 4d were then submitted to the same synthetic sequence that had allowed the efficient preparation of 2b from 4b: N-propargylation, oxirane ring-opening with thiophenol, oxidation to the hydroxysulfone stage and carbodiimide-mediated dehydration, 7 to provide the target enynes 2c and 2d (Scheme 6).
Conditions A: In situ formation of the alkyne-dicobalt hexacarbonyl complex by treatment of the enyne with a slight excess of dicobalt octacarbonyl in toluene, followed by mild (60ºC) thermal decomposition. 25onditions B: In situ formation of the alkyne-dicobalt hexacarbonyl complex by treatment of the enyne with a slight excess of dicobalt octacarbonyl in toluene, followed by tertiary amine N-oxide (7.7 molar equivs.)oxidative decomposition. 26onditions C: Molybdenum hexacarbonyl-promoted cycloaddition, according to the procedure of Jeong et al. (1.2 molar equivs.Mo(CO) 6 , 5 molar equivs.DMSO, toluene, 100ºC). 20he results obtained in the Pauson-Khand cyclization of enynes 2b-d are summarized in Table 1. a See text, b After chromatographic purification.
The behaviour of substrate 2b was investigated on the first place (entries 1-4 in Table 1).When the reaction was performed under thermal, Co-promoted conditions A, a 65:35 mixture (separable by column chromatography) of two diastereomeric Pauson-Khand adducts 12b and 13b was obtained in a global 41% yield (entry 1).A careful NMR spectroscopic analysis of the two compounds readily established that the major one 12b had both the side alkyl chain and the phenylsulfonyl group in the exo (or convex) face of the 3-azabicyciclo[3.3.0]oct-5-ene-7-oneframework, while the minor component 13b had the opposite stereochemistry at C 2 (alkyl chain in the endo or concave face).Diagnostic signals for the stereochemical assignment were the different chemical shifts for H 2 (3.71When the cyclization was initiated by tertiary amine N-oxide decomposition of the intermediate alkyne-dicobalt hexacarbonyl complex (conditions B, entries 2 and 3 in Table 1), the exo,exo adduct 12b was the sole compound isolated, albeit in low yield.Interestingly enough, when molybdenum hexacarbonyl (conditions C, entry 4 in Table 1) the endo,exo adduct 13b was the predominant one (1:4 exo,exo/endo,exo mixture, 70% global yield).This contrasts the results of Adrio and Carretero, which pointed towards a high exo-selectivity for molybdenum-promoted Pauson-Khand intramolecular cycloadditions. 23 similar behaviour was observed for the methyl-substituted enyne 2c (entries 5-7 in Table 1).In this case, the cobalt-mediated cycloaddition was very inefficient, either under thermal (entry 5) or N-oxide-mediated conditions (entry 6); on the other hand, the molybdenumpromoted reaction again resulted in the predominant formation of the endo,exo isomer 13c, in good global yield (entry 7). 27The stereochemistry of the adducts 12c and 13c was also established by NMR spectroscopy, and is consistent with the following observations: chemical shifts of the H 2 (3.63 ppm for 12c, 4.37 ppm for 13c) and of the H 8 (3.87 ppm for 12c, 3.84 ppm for 13c) protons, and NOE enhancements (12c: NOE between H 2 and H 8 , and between the CH 3 group and H 1 ; 13c: NOE between the CH 3 and H 8 ).
When we performed the cyclization of the phenyl-substituted enyne 2d, we found that under conditions C (entry 10), a single product was obtained in good yield.The diagnostic J H1,H2 value of 8.8 Hz (indicative of a trans stereochemistry), together with the observation of NOE between H 2 and H 8 , established the stereochemistry of this compound as exo,exo (12d).The cobalt-mediated, thermal reaction (conditions A, entry 8) afforded a 58:42 mixture of the same compound with a diastereisomer 14d in 46% global yield.The stereochemistry of 14d was tentatively assigned as exo,endo, according to the 8.8 Hz value of the coupling constant between H 1 and H 2 , and to the lack of NOE between H 2 and H 8 .Also consistent with this assignment is the fact that the chemical shift values for H 8 in the two isomers were no longer similar (4.00 ppm for 12d and 3.20 ppm for 14d).The formation of 14d could be possibly due to intermediate πallyl-Co complexes. 28n summary, we have shown that N-propargyl-γ-amino vinyl sulfones, readily available in highly enantiopure fashion, are good substrates for the intramolecular Pauson-Khand reaction.The stereochemical outcome of this metal-promoted cyclization appears to be controlled not only by the substrate structure, but also by the metal carbonyl used in the reaction.While at present the mechanism and the stereochemical outcome of the standard, cobalt-mediated Pauson-Khand reactions are reasonably well understood, 29 our results suggest that further work in the area of molybdenum-promoted cyclocarbonylation of enynes is needed.

Experimental Section
General Procedures.Melting points were determined in an open capillary tube and are uncorrected.Optical rotations were measured at room temperature (23 °C); concentrations are given in g 100 ml -1 . Infrared spectra were recorded in a Fourier transform mode, using the NaCl film technique.Unless otherwise stated, NMR spectra were recorded in CDCl 3 solution.Chemical shifts are given in ppm and referenced to TMS or CHCl 3 .Carbon multiplicities were established by DEPT experiments.Elemental analyses were performed by the "Servicios Xerais de Apoio á Investigación, Universidade da Coruña".MS spectra were performed at the "Servei de Espectrometria de Masses de la Universitat de Barcelona", using chemical ionization (CI) with ammonia or methane, electrospray ionization (ESI) or fast atom bombardment (FAB) techniques.Exact mass measurements (HRMS) were performed by the "Unidad de Espectrometría de Masas de la Universidad de Santiago de Compostela".Reactions were generally run in flame-or oven-dried glassware under a N 2 atmosphere, with solvents dried by routine procedures.Commercially available reagents were used as received.
After filtration through Celite ® , the organic phase was dried over anhydrous magnesium sulfate.Evaporation of the solvent under vacuum afforded 2.4 g (75% yield) of (2S,3S)-3-azido-1,2butanediol 5c as a colorless oil, that was used for the next step without further purification.
[α] D 23  Method C: with Mo(CO) 6 .To a solution of Mo(CO) 6 (32 mg, 0.12 mmol) and of enyne 2b-d (0.10 mmol) in anhydrous toluene (5 ml), at room temperature and under argon atmosphere, DMSO (36 µλ, 0.50 mmol) was added in one portion.The resulting solution was heated to reflux until complete disappearance of the starting enyne (TLC monitoring).After cooling to room temperature, the reaction mixture was filtered through Celite ® , and washed with toluene.The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel, hexanes-ethyl acetate mixtures as eluents).

Table 1 .
Pauson-Khand cyclization of enynes 2b-d ppm in 12b and 4.39 ppm in 13b), the presence of NOE between H 2 and H 8 in the case of 12b, and a 4.2 Hz coupling constant between H 1 and H 2 (indicative of a cis relationship) in 13b.Moreover, both compounds had very similar chemical shift values for H 8 (3.84-3.85ppm);seeFigure1for the numbering of compounds 12-14.

with Co 2 (CO) 8 and activation with amine N-oxides.
To a solution of Co 2 (CO) 8 (43 mg, 0.12 mmol) in anhydrous toluene (2 ml), at room temperature and under argon atmosphere, a solution of enyne 2b-d (0.10 mmol) in dry toluene (2 ml) was added dropwise.The resulting redcolored solution was stirred at room temperature for 30 min, and the amine N-oxide (0.78 mmol) was added in one portion.Stirring was maintained until complete disappearance of the dicobalt-enyne complex (TLC monitoring), and the reaction mixture was filtered through Celite ® , and washed with toluene.The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel, hexanes-ethyl acetate mixtures as eluent).