1976 1195Cyclization of (+)- and (-)-S-(2-Methylprop-l -enyl)-L-cysteineS-OxidesBy John F. Carson and Robert E. Lundin, Western Regional Research Laboratory, Agricultural ResearchService, U.S. Department of Agriculture, Berkeley, California 9471 0, U.S.A.S-(2-Methylprop-l -enyl)-L-cysteine ( 5 ) has been oxidized to two sulphoxides (7a), oru25 +128", and (7b).aD25 -84.3" (in H,O). Cyclization in base was stereospecific. The (+)-sulphoxide (7a) yielded the axialsulphoxide, (1 S,3R)-5,5-dimethyltetrahydro-l,4-thiazine-3-carboxylic acid S-oxide (9). and the (-)-sulphoxide(7b) yielded the corresponding equatorial (1 R ) sulphoxide (1 0). This establishes the absolute configurations ofthe acyclic sulphoxides (7a and b) as R and S, respectively, at sulphur. Reduction of the cyclic sulphoxides tothe corresponding cyclic sulphide, and reoxidation of this compound gave exclusively the equatorial sulphoxide(1 0): suggesting a large steric effect of the axial methyl group.Assignments of ring conformations and sulphoxideconfigurations are based on spectroscopic evidence.IN continuation of studies on the base-induced cycliz-ation of (@-substituted viny1)cysteine S-oxides, we haveinvestigated the cyclizat ion of S-( 2-met hylprop-l-eny1)-cysteine SS-dioxide (6) and of the corresponding dia-stereoisomeric S-oxides (?a and b) to the cyclic sulphone(8) and cyclic sulphoxides (9) and (10). The products(9) and (10) were reduced to the cyclic sulphide (11) andthis was re-oxidized to sulphoxide.The stereospecificity of these cyclizations and of theoxidation of the cyclic sulphide to sulphoxide was inH0-I( 3 )case yielded both cyclic sulphoxides (2) and (3), andwas completely non-stereospecific the proportions of (2)and (3) obtained were independent of the configurationof the original sulphoxide. This may be a consequenceof a sulphoxide-sulphenate rearrangement .2 Reductionof the product (2) to sulphide and re-oxidation yieldedcompound (2) quantitatively. However, the sulphidecorresponding to (3) on oxidation yielded a 1 : 1 mixtureof (3) and the corresponding equatorial sulphoxide.S-( p-Methylally1)-L-cysteine (4) was prepared from L-cysteine and 3-chloro-2-methylpropene and then isomer-ized to S-(2-methylprop-l-enyl)-~-cysteine (5).Oxid-ation of compound (5) with a large excess of hydrogenperoxide in acetic acid produced the sulphone (6), andoxidation with hydrogen peroxide in water yielded amixture of diastereoisomeric sulphoxides which wasseparated by fractional crystallization into (7a),+l28", and (7b),Treatment of the sulphone (6) with ammonium hydrox-ide yielded the expected cyclic sulphone (8). The iso-meric product with an inverted chair conformation wasnot formed. This would have involved unfavourableMe,C02H 1,3-interactions. Cyclization of the sulphox-ides (7a and b) could not be achieved in ammoniumhydroxide at room temperature (conditions effective in-84.3' (in H,O).contrast to our previous results with S-(prop-1-eny1)-Thus reaction of the sulphoxides (1) with base in each1 J.F. Carson and L. M. Boggs, J . Oyg. Chevn., 1966,31,2862;2 R. Tang and K. Mislow, J . Amev. Chenz. SOL, 1970,92,2100.and S-(but-l-enyl)-L-cysteine '-Oxides (la and b).l J. F. Carson, R. E. Lndin, and L. M. Boggs, ibid., 1969, 84, 19661196 J.C.S. Perkin Iprevious reactions), but reaction was effected by heatingin sodium carbonate solution. The (+)-isomer (7a)yielded the axial sulphoxide (9), ~,25 +3", and the (-)-sulphoxide (7b) the equatorial isomer (lo), 0,,25 - 19.5"(H,O). The optical purity of these isomers was greaterthan 95, as determined by integration of the methylproton resonances in the n.m.r. spectra. The cyclizationy H2CH2 =CMe CH,*S CH2 - C - CO,H( 4 1IHwhich was determined by n.m.r.Oxidation of (11) witheither hydrogen peroxide or sodium periodate yielded theequatorial sulphoxide (10) as the sole product. Thepreference for equatorial over axial sulphoxide in thiscase is also shown by the relative difficulty of cyclizationof the isomeric acyclic sulphoxides. The (+)-isomerrequired more drastic conditions for cyclization than theK O B ~ y 2 - Me2 C=CH*S*CH2--C-C02HI MeZSO( 5 ) H(5) H202 E- Sulphone ( 6 )bsol; AcoHis therefore stereospecific. Apparently no sulphoxide-sulphenate rearrangement occurs and the formation ofan inverted chair conformer would be sterically dis-favoured.Since the absolute configurations of the sulphoxidegroups in the cyclic compounds are known (see later),the absolute configurations of the original amino-acidS-oxides are also known, if we assume that completeinversion in each case does not occur.The (-)-S-oxide(7b) is therefore S at sulphur and the (+)-isomer (7a) isR. By analogy, (+)-trans-S-(prop-l-eny1)-L-cysteine S-oxide, which occurs naturally in the onion (Allium ce@)and undergoes quantitative cyclization to cycloalliin (2 ;R = Me) has the same configuration at sulphur (R) as(7a). These two (+)-substituted cysteine S-oxides havethe same configuration as (+)-S-methyl-L-cysteine S-oxide, the exact structure of which is known by X-rayanalysis .4Reduction of the sulphoxide (9) or (10) with hydriodicacid yielded the cyclic sulphide (11) , the conformation of* We are indebted to K. J. Palmer for these calculations.Theyare based on cycloalliin (2) as a model and assume no change inbond angles and distances.A. I. Virtanen and C. G. Spare, Suomen Kern. (B), 1961, 34,72; 1962, 35, 28.R. Hine and D. Rogers, Chem. and Ind., 1966, 1428; R.Hine, Acta Cryst., 1962,15, 636.(-)-compound, and although the axial isomer was con-figurationally pure, the yield was substantially less thanthat of equatorial isomer obtained from the (-)-sulphoxide.An indication of steric hindrance in the axial sulphox-ide (9) may be obtained from calculations of the distancesbetween methyl hydrogen atoms and oxygen. Incycloalliin (2; R = Me), the distance from sulphoxideoxygen to the 5-axial hydrogen atom is 2.668 A (fromX-ray analysis 5). In the sulphoxide (9), the closestapproach of axial methyl hydrogen atom to axialsulphoxide oxygen is calculated to be 1.23 A (H and 0eclipsed) and the maximum distance is 1.64 A (two Hatoms gauche to 0):The preference for axial sulphoxide in thian S-oxideshas been related to a van der Waals attraction betweenaxial hydrogen in the 3- or 5-position and axial oxygen.6Allinger et aZ.7 have calculated that an axial sulphoxideis more stable than its equatorial isomer in thian S-oxides by 0.37 kcal mol-l.Recently Zefirov * and Friezeand Evans Q have suggested that this preference,6 K. J. Palmer and K. S. Lee, Acta Cryst., 1966, 20, 790.6 C. R. Johnson and D. McCants, jun., J . Amer. Chem. SOC.,1965,87,1109; J. C. Martin and J. J. Uebel, ibid., 1964, 86, 2936.7 N. L.Allinger, J. A. Hirsh, M. A. Miller, and I. J. Tymanski,J . Amer. Chem. Sac., 1969, 91, 337.8 N. S. Zefirov, Tetrahedron Letters, 1976, 1087.9 D. M. Frieze and S. A. Evans, J. Org. Chem., 1976,40, 29601976 1197particularly in lJ4-oxathian S-oxides, may be due in partto electrostatic interactions. The reversal of axial toequatorial sulphoxide preference for S-oxides of thiansor 1,4-0xathians with axial substituents other thanhydrogen in the 3-position has been demonstrated. tRing conformations and sulphoxide configurationswere established by i.r. and n.m.r. The cyclic sulphone(8) showed J2,3 12.5 and 2.6 Hz, establishing a trans-diaxial relation between protons on C-2 and -3. Sul-phoxide configurations in (9) and (10) were establishedas follows.1.r. stretching frequencies of equatorialsulphoxides are generally higher than those of axialisorners.l0 The isomers (10) and (9) have sulphoxidebands at 1040-1050 and 1025-1030 cm-l, respec-tively. According to the t syrt-axial ' rule, a proton 1,3-disposed and syn-axial with respect to an axial sulphoxideis more deshielded than a proton in the same positionwith respect to an equatorial sulphoxide.ll The sul-phoxide (10) has its H-3 n.m.r. signal at 6 3.89 and (9)has the corresponding signal at 6 4.50 (both in D20).The (+)-isomer (9) is therefore axial by this rule.Lambert and Keske 12 have established a correlationbetween the magnitude of gem-coupling constants forprotons vicinal to a sulphoxide and the configuration ofthe latter.Values are 1.5-2.0 Hz larger in absolutevalue for an axial sulphoxide than for the equatorialisomer. This rule and the syn-axial rule have beenshown to be valid in the cycloalliin series.1 The (+)-sulphoxide (9) has bsol;JZ,J 14 and 1J6,61 15 Hz (in D,O-NaOD). The (-)-isomer (10) has IJ2.21 11.5 and JJ6.6111.8 Hz under the same conditions. This also confirmsthat the (+)-sulphoxide is axial although the difference(2.5-3.2 Hz) is larger than usually observed.The cyclic sulphoxides showed substantial long-rangecouplings between H-2(e) and H-6(e). The isomer (10)also exhibited long-range coupling of 0.75 Hz betweenthe axial methyl protons and H-6(a). The greaterbreadth of the upfield methyl proton resonances andadditional splittings in the lines for H-6(a) suggestedsuch a coupling and this was confirmed by irradiation atboth sites.EXPERIMENTAL1.r.spectra were obtained for KBr pellets with a Perkin-Elmer 237 spectrophotometer. lH N.m.r. spectra wereobtained a t 100 MHz with a Varian HR-100 spectrometer,equipped with an internal field-frequency lock. Forreference compounds, TMS (tetramethylsilane), TSP (sodium/3-trimethyl~ilyl~H,propionate) , DSS (sodium Strimethyl-t An axial methoxy-group 1,3 with respect to sulphur in a 1,4-oxathian directed oxidation to the equatorial sulphoxide ; withan equatorial methoxy-group the axial S-oxide was formed (seeK. W. Buck, A. B. Foster, A. R. Perry, and J. M. Webber, Chem.Comm., 1965, 433; A. B. Foster, Q. H. Hasan, D. R. Hawkins,and J.M. Webber, ibid., 1968, 1084). Perbenzoic acid oxidises2-thia-5a-androstan-17p-01 oxide (with a p angular methyl groupaxial and 1,3 to sulphur) to give an S8y0 yield of equatorial sul-phoxide (see B. P. Sollman, R. Nagarajan, and R. M. Dodson,ibid., 1967, 652). gem-Dimethyl groups in the 3-position ofthian direct oxidation to the equatorial position as established bylow-temperature n.m.r. analysis (J. B. Lambert, D. S. Bailey,and C. E. Mixan, J. org. Chem., 1972, 37, 377).silylpropane-l-sulphonate), and ButOD (6 1.23) were used.Specific rotations were measured with a Bendix automaticpolarimeter (series 1100) with a cell of 2 cm path-length.Paper chromatography was performed with Whatman No. 1paper; the solvent system BuOH-AcOH-H,O refers tothe mixture with 63 : 10 : 27 proportions, respectively, andcoll-lut-H,O refers to collidine-lutidine (3 : 1) saturatedwith water.S-( P-MethyZaZZyZ) -L-cysteine (4) .-L-Cysteine hydrochloridehydrate (30 g, 0.171 mol) was suspended in ethanol (1 200ml) and stirred under nitrogen in an ice-bath.Sodium(14 g, 0.609 equiv.) was added in small pieces and when thereaction was complete 3-chloro-2-methylpropene (31 g, 0.34mol) was added dropwise with stirring over 3 h. Themixture was stirred overnight a t room temperature andthen concentrated in zlacuo to a pasty solid. This was dis-solved in water (200 ml) and passed through a column of(1 000 cm3) of Dowex 50 resin (H+). The resin was washedwith water (5 1) and developed with 2.5~-ammoniumhydroxide (3.6 1).Concentration of the eluate in vmuoand crystallization from water yielded crude amino-acid(26.1 g, 87). Recrystallization from water gave platy ormicaceous crystals of S- (/3-methyZaZZyZ) -L-cysteine (4) ,-10.8" (c 2 in H,O) and 3-5.2" (G 2.5 in 2.5~-HC1), m.p.189-194' (decomp.) R p (w.r.t. alanine) 5.26 (BuOH-AcOH-H,O) and 2.12 (coll-lut-H,O); v,, 1 575 s (CO,-),1 480s, 1 410s, 1 335m, 1 300m, 1 200w, 1 125w, and 1 035wcm-1; SpaOD in D,O; ref. TMS) 1.82 (3 H, t, CH,), 2.55-y-H,), and 4.94 (2 H, s, vinylic) (Found: C, 47.85; H,7.4; N, 8.05. C,H,,NO,S requires C, 47.95; H, 7.5; N,S-( 2-MethyZprop-l-enyZ) -L-cysteine (5) .-A solution of S-( p-methylally1)cysteine (23 g, 0.131 mol) in dimethyl sulphox-ide (1 200 ml) containing potassium t-butoxide (23 g, 0.205mol) under argon was stirred for 8 h a t 10 "C and overnightat room temperature.The solution was poured into ice-water (3 1) and the resulting turbid solution was passedthrough a column (600 cm3) of Dowex 50 resin (H+) . Thecolumn was washed with water (4 1) and the amino-acideluted with 2.5~-ammonium hydroxide (3 1). Evaporationin vawo and crystallization of the residue from water (250ml) yielded the crude product (11.5 g). The mother liquorwas concentrated to 30 ml ; addition of ethanol (60 ml) thenyielded an additional 4.7 g (total yield 70). Recrystalliz-ation from water yielded pure S-(2-methyZ~rop-l-enyZ)-~-cysteine (5), OL=z5 +26.5' (c 1.5 in H,O), m.p. 179-180'(decomp.), RF (w.r.t.alanine) 5.45 (BuOH-AcOH-H,O) ;vmx. 1575-1 625s (C0,-), 1500s, 1425s, 1390s, 13455,1 290m, 1 265w, 1 19Ow, 1 170w, 1 129w, and 1 050wcm-1;G(D,O-NaOD; ref. TSP) 1.77 (6 H, d, 2 CH,), 2.63-3.17(2 H, dq, P-H,), 3.33-3.46 (1 H, dd, a-H), and 5.71 (1 H, s,7-H) (Found: C, 47.9; H, 7.55; N, 8.05. C,H,,N02Srequires C, 47.95; H, 7.5; N, 8.0).S-( 2-MethyZpro@ l-enyZ)-~-cysteine SS-Dioxide (6) .-S-( 2-Methylprop-1-eny1)cysteine (6.00 g, 0.0342 rnol) in aceticacid (300 ml) was stirred a t 45 f 3 "C for 6 h while 30hydrogen peroxide (25 ml) was added a t 5 ml h-1. Thelo P. B. D. de la Mare, D. J. Millen, J. G. Tillet, and D. Watson,J. Chem. SOL, 1963,1619; R. Nagarajan, B. H. Chollar, and R. M.Dodson, Chem. Comm., 1967, 650.I1 K. W. Buck, A.B. Foster, W. D. Pardoe, M. H. Quader, andJ. M. Webber, Chem. Comm., 1966, 769; A. B. Foster, J. M. Dux-bury, T. D. Inch, and J. M. Webber, ibid., 1967, 881.la J. B. Lambert and R. G. Keske, J. Org. Chem., 1966, 31,3429.2.92 (2H, dq, P-H,), 3.35-3.47 (lH, dd, a-H), 3.21 (ZH, S,8.0)1198 J.C.S. Perkin Isolution was set aside overnight a t room temperature andconcentrated in vacuo to an oil. Water (100 ml) was addedand the solution was concentrated in zlacuo. The residuecrystallized from water-ethanol (1 : 3) (80 ml) to give theproduct (3.35 g). From the mother liquor an additional1.81 g was obtained (combined yield 72). Recrystalliz-ation from water-ethanol (1 : 4) yielded pure sulphone (6),-0.2" (G 2.5 in H,O), decomp. sharply a t 156-157';vmx.1 650s (CO,-), 1525m, 1400s, 1375s, 1325s, 1300s,1230m, and 1 115s cm-l (sym. SO,); 6(D,O; ref. TSP) 2.04He), 4.15-4.27 (1 H, q, a-H), and 6.31 (1 H, sept, y-H)(Found: C, 40.6; H, 6.45; N, 6.75. C,H,,NSO, requiresC, 40.55; H, 6.3; N, 6.75).( + ) - and ( - ) -S- (2-Methylprop- l-enyl) -L-cysteine S-Oxides(7a and b) .-A solution of S-( 2-methylprop-1-eny1)cysteine(5) (10.0 g, 0.0571 mol) in oxygen-free water (1 1) wascoveredwith argon and stirred a t 10-15 "C while 30 hydrogenperoxide (10 ml) was added a t 1.5 ml h-1. The slightlyturbid solution was then stirred overnight a t room tempera-ture and concentrated in vacuo to an amorphous solid (10.3g ) . Crystallization from water (30 m1)-acetone (56 ml) a t0 OC for 2 days yielded a product (3.09 g), ccD25 +99.3" (inH,O). The residue from the mother liquor from water (15m1)-acetone (80 ml) yielded a second fraction (4.78 g ) ,aD25 - 36.4".With increasing proportions of acetone, athird fraction (1.13 g), aD25 -62.9", and a fourth fraction(1.46 g), ccD25 -20.8", were obtained (total yield 96).The first fraction was recrystallized four times from water-acetone (1 : 2) to yield needles (0.986 g) of the S-oxide (7a),aJD25 +128" (c 2 in H,O), unchanged on recrystallization,decomp. 102-103.5", R p (w.r.t. alanine) 1.81 (BuOH-1337s, 1290m, 1140w, 1 lOOw, 1 060w, and 975-1000s cm-l (S-oxide); 6 (D,O-CF,*CO,D, pH 2; ref.ButOD) 1.99 (3 H, d, CH,), 2.06 (3 H, d, CH,), 3.40-3.47(2 H, 3 lines, B, of AB,, p-H,), 4.36-4.49 (1 H, dd, A ofAB,, a-H), and 6.25 (1 H, sept, y-H) (Found: C, 44.0; H,7.05; N, 7.25.C,H,,NO,S requires C, 43.95; H, 6.85; N,The second and third (laevorotatory) fractions were re-crystallized four times from water-acetone (1 : 6) to giveneedles (0.933 g) of the S-oxide (7b), ccD25 -84.3" (G 2.0 inH,O), decomp. 131-132', RF (w.r.t. alanine) 1.77 (BuOH-AcOH-H,O), vmX. 1 625s (C0,-), 1 550-1 575s, 1 425m,1 375s, 1 265m, 1 21Ow, 1 175w, and 1 000s cm-l (S-oxide) ;6(D,O; ref. ButOD) 2.00 (3 H, d, CH,), 2.06 (3 H, d, CH,),3.24-3.66 (2 H, 7 lines, AB of ABX, P-H,), 4.33-4.45 (1 H,dd, X of ABX, cc-H), and 6.28 (1 H, sept, y-H) (Found: C,44.1; H, 6.95; IS, 7.35).Cyclization of the Sulphone (6) .-A solution of the sulphone(6) (1.56 g) in 2~-ammonium hydroxide (200 ml) was keptat room temperature for 4 days, then concentrated in vacuo.The solid was crystallized from water-ethanol (1 : 2) to givecoarse prisms (1.23 g, 79) of (3R)-5,5-dinzethyltetrahydro-1,4-thiazine-3-carboxylic acid SS-dioxide (8), v,,,.1 620s(C0,-), 1 575s, 1 450w, 1 3853, 1 325m, 1 290 1 220w,1150s, 1130s, 1115s (SO,), 1075m, and 1030w cm-l;6 (D,O; ref. TSP) 3.08 dd, H-2(a), 3.56 dt, H-2(e), 4.01dd, H-3(a) by ABX approximation J z S z 14.1, J 2 . 3 (aa)12.5, J 2 , 3 (ae) 2.6, and J z , 6 , 2.6 Hz, 3.12 d, H-s(a), 3.29dd, H-6(e), 1.39 (s, CH,), and 1.43 (s, CH,). By ' AB'analysis J 6 , 6 14.7, J,,, 12.5 and 2.6 Hz, establishing the chairconformation as shown (Found: C, 40.8; H, 6.3; N, 6.8.C,H,,NSO, requires C, 40.55; H, 6.3; N, 6.75).(3 H, d, CH,), 2.18 (3 H, d, CH,), 3.55-4.01 (2 H, dq, p-AcOH-H,O); vmX.1 650s (CO,-) 1550-1 575~, 1 395~,7.3).Cyclization of the (-)-S-Oxide (7b).-A solution of the S-oxide (3.0 g, 0.0157mol) in water (500 ml) containing N-sodium hydroxide (10 ml) and sodium carbonate (1.2 g) washeated a t 90 "C for 8 h. The turbid solution was passedthrough a column (175 cm3) of Dowex 50 resin (H-+). Theresin was washed with water (1 1) and developed with 2 ~ -ammonium hydroxide (1 1). Concentration of the eluate todryness and crystallization from ethanol yielded the product(1.90 g, 63). Recrystallization from water-acetone (1 : 4)yielded needles of (1 R, 3R) -5,5-dirnetl~yltetrahydro- 1,4-thiaz-ine-3-carboxylic acid S-oxide (lo), - 19.5" (c 3.3 inH,O), decomp.247-252", RF (w.r.t. alanine) 1.02 (BuOH-AcOH-H,O) ; v, 1 620s (CO,-), 1 460m, 1 380s, 1 325w.1260w, 1230w, 1215w, 1 1 4 5 ~ ~ and 1040-1 050s cm-l(50); 6 (D,O; ref. TSP) 1.37 (3 H, s, CH,), 1.48 (3 H, s,CH,), 2.71 I H, t, H-Z(a), 2.71 l H, d, H-6(a), 3.67 l H,dd, H-B(e), 3.89 l H, dd, H-3(a), and 4.00 l H, dt, H-2(e);6 (D,O-NaOD; ref. TSP) 1.21 (3 H, s, CH,), 1.33 (3 H, s,CH,), 2.44 l H, t, H-2(a), 2.44 l H, d, H-s(a), 3.53 l H,dd, H-6(e), 3.59 l H, dd, H-3(a), and 3.84 l H, dt, H-2(efl ( J 2 . z 11.5 Jqa).*a) 12.2, Jz(c).qa) 2.1, J 6 . 6 11-75, J2(e),6(.e)2.8, Jqa), OH, 0.75 Hz). In base, the resonance of H-3 isselectively shifted upfield by the presence of the adjacentcarboxylate group so that i t no longer overlaps the resonanceof H-2(e).First-order methods could, therefore, be usedto obtain the coupling constants. Coupling between theaxial methyl and 6-axial protons was established by irradi-ation a t 121 Hz (CH,) which eliminated the splitting of theH-6(a) lines and irradiation a t 244 Hz H-6(a) lines whichequalized the intensities of the two methyl signals (Found:C, 43.8; H, 6.83; N, 7.45. C,H,,NO,S requiresc, 43.95;H, 6.85; N, 7.3.)Cyclization of the S-Oxide (7a).-A solution of the S-oxide(7a) (3.753 g, 0.0196 mol) {aID2* indicates 88 (?)-isomer) containing N-sodium hydroxide (12 ml) and sodiumcarbonate (1.6 g) in water (500 ml) was heated and theproduct was isolated with Dowex 50 resin (Hf) as in thereaction with the (-)-isomer.Paper chromatography andlH n.m.r. indicated that the isolated product still containeda large amount of starting material. Accordingly, thereaction with base was repeated and unchanged materialwas removed by addition of sodium 2,4, G-trinitrobenzene-sulphonate (2.5 g, 0.0079 mol) to the cooled solution. Theresulting red solution was stirred overnight a t room temper-ature, acidified with hydrochloric acid, and filtered. Theorange filtrate (ca. 500 ml) was extracted with ethyl acetate(4 x 120 ml). The aqueous phase was concentrated invacuo to dryness, and the residue was dissolved in waterand purified with Dowex 50 resin (H+) as described before.The ammoniacal eluate was taken to dryness and the residuecrystallized from water-acetone (1 : 4; 25 ml) to giveprisms (0.988 g), aD25 +3.1" (G 3.5 in H,O).An additional0.565 g was obtained from the mother liquor (yield 41).Recrystallization from aqueous acetone gave ( +)-( lS,3R)-5,5-dimethyltetrahydro- 1,4-thiazine-3-carboxylic acid S-oxide(9), +3.0" (c 3.7 in H,O), decomp. 240-241", RF(w.r.t. alanine) 1.16 (BuOH-AcOH-H20) lH n.ii1.r. analysisindicated that the solid material isolated was free of the(-)-isomer ; v,,, 1 635s (CO,-), 1 460m, 1 365s, 1 325m,1 235w, 1 210w, 1 135w, 1 080w, and 1 025-1 030s cm-l (S-oxide); 6 (D,O; ref. TSP) 1.54 (3 H, s, CH,), 1.73 (3 H, s,CH,), 3.10 l H, dd, H-2(a), 3.68 l H, dt, H-2(e), 4.51Jz(e),6(e) 2.4 Hz by ABX analysis, 2.75 l H, d, H-6(a), and3.40 l H, dd, H-6(e) (J6,6 15.7 Hz) (the values of J 2 , 31 H, dd, H-3(a) I,,, 15.3, J2.3 (aa) 12-9, J 2 .3 (ea) 2.41976 1199established the chair conformation as shown) ; 6 (D,O-NaOD; ref. TSP) 1.23 (3 H, s, CH,), 1.45 (3 H, s, CH,), 2.42l H, d, H-6(a), 2.66 l H, dd, H-2(a), 3.02 l H, dd, H-6(e), 3.26 l H, dt, H-Z(e), and 4.07 l H, dd, H-3(a) :J2,214.0, Js.6 15.0 Hz; no long-range coupling between the axialmethyl protons and H-6(a) could be resolved; however, theexcessive width of the H-6(a) peaks (2.5 Hz) suggests a smallcoupling of this type (Found: C, 44.1, H, 6.9; N, 7.4.C,H1,NO,S requires C, 43.95; H, 6.85; N, 7.3).Reductiorr of the Cyclic S-Oxide (10) to the Cyclic Sulphide(1 1) .-A4 solution of the S-oxide (1.475 g, 0.007 72 mol) (10)in 48 hydriodic acid (25 ml) was kept in the dark for 3days and then concentrated in vacuo t o a dark solid.Iodine was removed by extraction with ether (5 x 50 ml).The resulting pale yellow solid was dissolved in water (60ml) and passed through a column (50 em3) of Dowex-I resin(acetate).The resin was washed with water (250 ml) andthe eluate concentrated in vucuo to a solid, which wascrystallized from water (10 m1)-acetone (40 ml) t o yield(3R) -5,5-dimethyEtetrahydro-l, 4-thiazine-3-carboxyEic acid(11) (0.955 g, 70), olD25 -65.7' (c 1.7 in H20), sintersat 280-285"; vmnX 1600s (CO,-) 1 460m, 1 390s, 1330w,1270w, 1235w, 1 165w, 1 130w, and 1 0 6 0 ~ cm-1 (noS-oxide absorption) ; 6 (D,O; ref. TSP) 1.53 (3 H, s, CH,), 1.56(3 H, s, CH,), 2.71-2.97 dd, H-2(a), 2.98-3.18 ddd,H-2(e), 3.87-4.02 dd, H-3(a) J 2 , , (aa) 12.3, J 2 , 3 (ae)2.8, J,,, 14.5, J 2 , s 1.6 Hz (ABX analysis), 2.48-2.64dd, H-6(e), and 2.9.4-3.10 dd, H-6(a) ( J 6 . 6 14.8, J 2 . 6 1.6Hz by AB analysis) (Found: C, 47.8; H, 7.45; N, 8.05.C,H1,NO,S requires C, 47.95; H, 7.5; N, 8.0).Oxidation of the Sulphide (11) to the S-Oxide (lo).-Thesulphide (11) (0.435 g, 0.002 48 mol) in water (35 ml) con-taining 30 hydrogen peroxide (0.5 ml) was kept for 20 ha t room temperature and then concentrated to a solid.Crystallization from water (1.5 m1)-acetone (25 ml) yieldedneedles (0.411 g, 87), -18.8' (c 3.5 in H,O), of theS-oxide (10) , identified by i.r. and lH n.m.r. data. Integra-tion of methyl resonances established that the crudeproduct contained over 90 of the (-)-isomer. Oxidationof the sulphide with sodium periodate at 0 "C gave the sameresults.We thank G. Secor for elemental analyses, amp;I. Benson forassistance with n.m.r., and F. Wong for help with i.r.spectroscopy.5/2001 Received, 13th October, 1976
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