Synthesis and stereoselective addition reactions of 2-( S -phenyl- N -tosylsulfoximinoyl)cycloalk-2-enones

(±)-2-( S -Phenyl- N -tosylsulfoximinoyl)cyclohex-2-enone and the homologue 2-( S -phenyl- N - tosylsulfoximinoyl)cyclohept-2-enone (as both the racemate and the R S -isomer) have been synthesised in two steps from respectively racemic 2-( S -phenyl- N -tosylsulfoximinoyl)methane and δ -valerolactone, and 2-( S -phenyl- N -tosylsulfoximinoyl)methane (racemate and S S -isomer) and ε -caprolactone. Highly


Introduction
Asymmetric synthesis enabled by sulfoximines continues to attract substantial research effort. 1 Our own research in the area of sulfoximine chemistry was initiated over ten years ago when we began to investigate asymmetric intramolecular Diels-Alder (AIMDA) reactions of trienes and dienynes substituted on the dienophile with various sulfoximine residues.The reactivity of these systems could be fine-tuned by varying the sulfonyl residue on the sulfoximine nitrogen atom; the most reactive AIMDA substrates underwent cycloadditions which were more rapid than those of the analogues possessing arylsulfones as the dienophile-activating groups, and some of these transformations showed enhanced stereoselectivity. 2 Most recently we showed that highly substituted diastereomeric dienynes possessing alkynylsulfoximine dienophiles and containing an additional stereocentre in the chain linking diene and dienophile showed matched and mismatched cycloaddition behaviour resulting from cooperative or competing directing effects of the sulfur and carbon stereocentres. 3 This chemistry was applied to the synthesis of the CD-ring fragment of vitamin D 3 , and the sulfoximine-containing substrates showed improved cycloaddition selectivity in comparison with the reactions of a sulfone-containing analogue. 4An overview of this synthetic methodology is provided in Scheme 1.We became interested in exploring further the utility of the sulfoximine residue in addition reactions.It occurred to us that enhanced reactivity might be attainable by positioning an additional electron-withdrawing group such as a carbonyl function on the sulfoximine-bearing carbon atom.Given the substantial precedent in sulfoxide chemistry 5 we elected to look at addition reactions of 2-(S-aryl-N-arylsulfonylsulfoximinoyl)cycloalk-2-enones; this paper presents the results of this investigation. 6

Synthesis of 2-(S-aryl-N-arylsulfonylsulfoximinoyl)cycloalk-2-enones
The 2-[S-aryl-N-(arylsulfonyl)sulfoximinoyl]cycloalk-2-enones required for this study were accessed straightforwardly via an intramolecular aldol condensation route.Thus, (±)-2-(Sphenyl-N-tosylsulfoximinoyl)-2-cyclohexenone 2 was made by first treating δ-valerolactone with the lithio-anion of (±)-(S-phenyl-N-tosylsulfoximinoyl)methane; 7 low-temperature proton quench provided the adduct as a 1:3:8 mixture of the acylic hydroxyketone 1 and two diastereomeric ketols 3 in excellent yield after chromatographic purification.Treatment of this mixture with Dess-Martin periodinane gave the desired enone 2 in virtually quantitative yield, without the need for chromatography.Compound 2 was found to undergo rapid decomposition in the presence of silica gel, and slowly decomposed on standing at ambient temperature to give an unidentified mixture; it was stable over several months when stored under an inert atmosphere at -4°C.The higher homologue 2-(S-phenyl-N-tosylsulfoximinoyl)cyclohept-2-enone 5 was similarly synthesised as the racemate and the R S -enantiomer, starting from ε-caprolactone and respectively (±)-(S-phenyl-N-tosylsulfoximinoyl)methane and the optically pure S S -sulfoximine.Key differences in the synthesis of the higher homologue were that (i) the initial lithiosulfoximine addition reaction gave as expected only the acyclic hydroxyketone 4, and (ii) Dess-Martin periodinane-mediated oxidation of 4 gave the corresponding aldehyde as the crude product, from which enone 5 was formed during careful silica gel chromatography.Attempts to make the five-membered analogue of 2 and 5 met with failure.Although treatment of γbutyrolactone with the lithio-anion of racemic (S-phenyl-N-tosylsulfoximinoyl)methane gave in moderate yield a mixture of the expected ketol lower homologue of 3 and the corresponding enol ether dehydration product, this mixture resisted all efforts to convert it into the cyclopentenone derivative.The syntheses of 2 and 5 are shown in Scheme 2.

Cuprate addition reactions of 2-(S-aryl-N-arylsulfonylsulfoximinoyl)cycloalk-2-enones
Initial studies focused on the addition of organocuprates to 2 and 5. Exposure of the lower homologue 2 to lithium dimethylcuprate 8 gave in 71% isolated yield a 27:6:4:3 mixture of methyl addition products, the ratios being measured by 1 H nmr analysis of the crude mixture.Difficulties in separating this mixture precluded further study.A similar reaction carried out on the racemic cycloheptenone substrate 5 was likewise unselective, with four components 6a-d being formed in a 10:8:4:3 ratio.The major component 6a crystallised as a single enantiomer, and the structure was assigned by X-ray crystallographic analysis. 1H Nmr spectroscopic analysis of 6a showed a H2-H3 coupling constant of 8 Hz consistent with the 2,3-anti-relationship, and the same H2-H3 coupling constant of 8 Hz allowed assignment of the other possible 2,3-antistructure to 6c.Later studies (see below) enabled the unequivocal structural assignment of the major 2,3-syn compound 6b, and therefore that of the minor isomer 6d, both of which showed 0 Hz H2-H3 coupling constants.Thus, Me 2 CuLi treatment of 5 exhibited 72:28 facial selectivity for methyl addition to the enone C-C double bond; both pairs of products were formed as ca.56:44 2,3-anti:2,3-syn mixtures.
Next, reactions of racemic cycloheptenone 5 with n-Bu 2 CuLi were carried out, which gave similar product ratios.However, use of the sterically more demanding reagent bromomagnesium bis(isopropenyl)cuprate gave only two products, in a 5:2 ratio.Both of these were assigned 2,3anti-stereochemistry on the basis of the H2-H3 nmr coupling constants, and the major compound was assigned structure 7a following X-ray crystallographic analysis, implying that the minor product had structure 7b; 7a has the same C β -S relative stereochemistry as the major product 6a from the Me 2 CuLi addition reaction of 5.The exclusive formation of anti-2,3-disubstituted cycloheptanones 7a and 7c may be attributed to the greater steric bulk of the isopropenyl moiety, which destabilises the 2,3-syn isomer.Finally, treatment of (±)-5 or (R S )-5 with chloromagnesium diisopropylcuprate gave a single product 8, whose structure was again assigned by X-ray crystallography.This product was further elaborated by SmI 2 -mediated 9 reductive desulfoximinoylation, which yielded (-)-(S)-3-isopropylcycloheptanone 9 in good yield.The cuprate addition reactions of 5 are summarised in Scheme 3. The X-ray structures of (±)-6a, (±)-7a and (+)-8 are shown in Figure 1.

Discussion of stereochemistry
All of the cuprate addition reactions of the seven-membered substrate had shown the same sense of 1,3-asymmetric induction from sulfoximine sulfur to the β-carbon of the enone.Although the observed selectivities were modest for the addition of straight-chain alkyl groups and a branched alkenyl group, a more hindered reagent possessing a branched alkyl group had enabled the realisation of complete selectivity.We rationalise this tendency in terms of delivery of the carbon nucleophile to the enone having a preferred conformation in which the C=O and S=O bonds are oriented in a mutually anti sense so as to minimise dipole-dipole repulsion; addition takes place syn with respect to the sulfoximine phenyl group, anti with respect to the bulkier NTs group.

Nucleophilic epoxidation reactions of 2-(S-aryl-N-arylsulfonylsulfoximinoyl)cycloalk-2enones
Our attention was turned next to nucleophilic epoxidation reactions of enones 2 and 5. Following extensive literature precedent, mostly from the work of Jackson and co-workers, 10 we elected to use the t-BuOOLi reagent system.Treatment of 5 with t-BuOOLi generated from n-BuLi and t-BuOOH gave a 5:2 mixture of epoxyketone diastereomers.X-Ray crystallographic analysis of the major isomer allowed its assignment as 10a, which indicated that initial, nucleophilic attack by t-BuOO -had taken place with the sense of asymmetric induction opposite to that found in the organocuprate additions.Interestingly, when the epoxidations were carried out in aqueous media (NaOH-H 2 O 2 ), or under anhydrous conditions with potassium as the counter-cation the transformations were modestly selective in the opposite sense.We explain this varying behaviour in terms of the involvement of a chelating or nonchelating enone substrate.In the reactions containing lithium the enone coordinates to the metal cation in a bidentate fashion such that the ketone C=O and sulfoximine S=O bonds are aligned; nucleophilic attack takes place syn to the sulfoximine phenyl moiety.In aqueous media, or in the presence of the weakly oxaphilic potassium counter-cation such chelation is no longer significant, and the dipole-dipole repulsion effect observed in the organocuprate reactions dominates.Reaction of the lower homologous enone 2 with t-BuOOLi gave a 8:5 mixture of epoxides, with the same stereochemical preference observed in the cycloheptenone reaction with BuOOLi, as evidenced by X-ray analysis of the minor product 11b.The epoxidation reactions of 2 and 5 are summarised in Scheme 4; the X-ray structures of 10a and 11b are depicted in Figure 2.

Cyclopropanation reactions of 2-(S-aryl-N-arylsulfonylsulfoximinoyl)cycloalk-2-enones
The final phase of our study sought to establish a protocol for the cyclopropanation of enones 2 and 5. Reaction of the seven-membered analogue 5 with a large excess of diazomethane gave an unstable pyrazoline 11 as a single isomer, as evidenced by 1 H nmr analysis (500 MHz) of the crude product.The appearance in the spectrum of a pair of highly second-order double doublets assigned to the ex-CH 2 N 2 methylene group strongly suggested that pyrazoline formation had occurred by C-C bond formation at the β-rather than at the α-position of the enone.Irradiation of crude, freshly prepared pyrazoline in dilute acetone solution during 48 h using a 150W lamp with external cooling gave a single bicyclic cyclopropane, shown by X-ray crystallographic analysis to have the structure 13.The precursor pyrazoline was assigned structure 12 on the basis of its 1 H nmr characteristics and the X-ray structure of 13.The sense of asymmetric induction was in accord with that observed in the cuprate addition reactions and in the non-chelationcontrolled nucleophilic epoxidation reactions.An enantiomerically pure sample of (-)-13 was subjected to reductive desulfoximinoylation using SmI 2 in MeOH-THF, providing (-)-17 in 95% yield.Alternatively, ring-opening of racemic 13 using the sodium salt of thiocresol gave a 4:1 mixture of two α-sulfoximine-substituted cycloheptanones, which were further desulfurised with retention of the sulfoximine moiety to give two of the four compounds formed in the lithium dimethylcuprate-mediated reaction of 5, clearly establishing the identity of 6b (Scheme 3).Diazomethane treatment of the lower homologous enone 2 was strikingly different: no pyrazoline was isolated, with the cyclopropane being formed directly in 48% yield on exposure of 2 to diazomethane in THF at -20°C.The methylene insertion product 15 was isolated also, in 33% yield.X-Ray crystallographic analysis confirmed the now expected structure 14 for the simple cyclopropanation product.Finally, reaction of lower homologue 2 with diazoethane 12 gave directly a single product 16 in 51% yield; the exo-nature of the methyl substituent on the cyclopropane moiety was shown by X-ray crystallographic analysis.The cyclopropanation reactions of 2 and 5 are summarised in Scheme 5; the X-ray structures of 13, 14 and 16 are depicted in Figure 3.

Experimental Section
General Procedures. 1 H and 13 C NMR spectra were recorded in CDCl 3 on either Jeol GX-270Q, Bruker WM-250, Bruker AM-500, Bruker DRX-400, Bruker DRX-300 spectrometers, using residual isotopic solvent (CHCl 3 , δ H = 7.26 ppm or CDCl 3 , δ C = 77.0ppm) as an internal reference.Multiplets in some 1 H NMR spectra were assigned with the aid of a recently published practical guide. 93Infrared spectra were recorded as a thin film on either KBr or NaCl plates with Mattson 5000 FTIR or Perkin-Elmer 983G spectrophotometers.Mass spectra were recorded using VG Trio, VG Quattro, VG 707E or VG Autospec Q instruments.Accurate masses were determined using the VG Autospec Q instrument at Imperial College.Elemental combustion analyses were performed in the Imperial College microanalytical laboratory.Melting points were determined using a Mettler FP62 Automatic Melting Point machine, a Büchi Melting Point Unit B-545 or a Stewart Scientific SPM1 melting point apparatus.Optical rotations were measured using a Perkin-Elmer Polarimeter 241.Flash column chromatography refers to chromatography on BDH (230-400 mesh) silica gel or Merck Kieselgel 60 (230-400 mesh) under pressure using hand bellows.Filtration through a short pad of silica gel refers to filtration through BDH (230-400 mesh) silica gel under vacuum suction.HPLC separations were carried out on analytical and semi-preparative scales using Dynamax Macro Si columns.Analytical thin layer chromatography was performed using pre-coated glass-backed plates (Merck Kieselgel 60 F 254 ) and visualised with ultraviolet light and/or iodine, acidic ammonium molybdate (IV), 2,4dinitrophenyhydrazine, p-anisaldehyde or potassium permanganate solutions as appropriate.
Standard solvents were distilled under dried nitrogen: Et 2 O and THF from sodium-benzophenone ketyl, CH 2 Cl 2 from phosphorus pentoxide, MeCN from calcium hydride and toluene from sodium.Petrol refers to petroleum ether bp 40-60 o C which was distilled prior to use; EtOAc was also distilled before use.Freshly distilled refers to bulb-to-bulb distillation using a Kugelrohr apparatus or standard fractional distillation either under nitrogen or under vacuum as appropriate.Diazomethane was generated from Diazald® and distilled using a kit constructed from glass tubing with flame-smoothed joints.Diazoethane was generated from 2-ethylamino-2methyl-N-nitroso-4-pentanone and distilled using an Aldrich Mini Diazald® Apparatus.Other solvents and reagents were obtained from commercial sources and purified where necessary according to standard procedures. 14 (±)-7-Hydroxy-1-(S-phenyl-N-tosylsulfoximinoyl)-2-heptanone (4).To a stirred solution of (±)-S-methyl-S-phenyl-N-tosylsulfoximine (5.00 g, 16.2 mmol, 1.0 equiv) in dry THF (162 ml) at -78 ˚C under nitrogen was added dropwise n-BuLi (6.8 ml of a 2.37 M solution in hexanes, 16.2 mmol, 1.0 equiv).The resulting pale yellow solution was stirred at this temperature for 10 min then freshly distilled ε-caprolactone (1.97 ml, 2.03 g, 17.8 mmol, 1.1 equiv) was added dropwise and the resulting mixture stirred at -78˚C for 5 min.Tlc examination indicated new material and some starting material remaining and after a further 15 min tlc indicated no change.
1 mmol, 1.0 equiv) in dry THF (40 ml) and dry MeOH (20 ml) at -78˚C under nitrogen was added dropwise SmI 2 (44 ml of a 0.1 M solution in hexanes, 4.4 mmol, 4.0 eq).The mixture initially turned pale yellow and when addition of SmI 2 was complete, a blue colour persisted.Tlc examination indicated complete consumption of starting material and the mixture was quenched by the addition of saturated aqueous NH 4 Cl (50 ml) and allowed to warm to rt.The mixture was diluted with saturated aqueous Na 2 S 2 O 3 (50 ml) and extracted with Et 2 O (3 x 75 ml).The combined organic extracts were washed with saturated aqueous Na 2 S 2 O 3 (2 x 50 ml), water (2 x 50 ml) and brine (50 ml) then dried (MgSO 4 ) and the solvents removed by evaporationunder reduced pressure to give a pale yellow semi-solid (436 mg).