Stereoselective Synthesis of Enantiopure AminoCompounds, via Mitsunobu Azidation of(2S,RS)-1-(p-Tolylsulfinyl)butan-2-ol$Pierfrancesco Bravo,*a Giancarlo Cavicchio,*b Marcello Crucianelli,aAndrea Poggiali,a Alessandro Volonterioa and Matteo ZandaaaCentro di Studio sulle Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico,C.N.R., via Mancinelli 7, I-20131 Milano, Italy,bIngegneria Chimica e Materiali, Coppito, Dipartimento di Chimica, Universita di L'Aquila, ViaVetoio, I-67010 Coppito, Italy,Azidation of (2S,RS)-1¡Ó(p-tolysulfinyl)butan-2-ol under Mitsunobu conditions is the key step for a highly stereoselectivepreparation of enantiomerically pure amino compounds via chiral sulfoxide chemistry.The stereocontrolled synthesis and the reactivity of chiralamines are topics of great interest in modern organicchemistry,1 owing to the remarkable biological propertiesconnected with this class of molecule.Our recent atten-tion towards the development of new stereocontrolledapproaches to chiral amines led us to investigate theazidation of uorosubstituted b-sulnyl alcohols underMitsunobu conditions2 as a new tool for preparing enantio-merically pure b-uoro a-amino acids.3 Since, to our knowl-edge, no reports dealing with Mitsunobu-type reactions ofuorine-free b-sulnyl alcohols are extant in the literature, afurther aim of this study was to investigate the compatibilityof the stereogenic sulnyl group with the Mitsunobuconditions, to extend this methodology to the synthesis ofuorine-free chiral amines.In this paper we describethe Mitsunobu azidation of enantiopure (2S,RS)-1-( p-tolyl-sulnyl)butan-2-ol 1, and the transformation of the resultingazide (2R,RS)-2 into several amino compounds (4¡Ó7)(Scheme 1).The starting b-sulnyl alcohol (2S,RS)-1 was stereoselec-tively prepared by reduction with diisobutylaluminiumhydride (DIBAH) of the corresponding (R)-1-( p-tolyl-sulnyl)butan-2-one.4 Transformation of (2S,RS)-1 into theb-sulnyl azide (2R,RS)-2 was accomplished by treatmentwith NaN3¡ÓPPh3¡ÓCBr4 (method A, 76%)5 or, alternatively,with HN3¡ÓPPh3¡ÓDEAD (method B, 57%). As expected thedesired product (2R,RS)-2 was formed with clean inversionof conguration at C-2, as a single diastereoisomer, isolatedin pure form by ash chromatography on silica gel.The b-sulnyl azide (2R,RS)-2 can be considered as aversatile synthetic intermediate.In fact its sulnyl andazide moieties were submitted to several chemoselectiveelaborations, as described in Scheme 1.Oxidation of(2R,RS)-2 to the corresponding b-tosylazide (R)-3 wasachieved by reaction with m-chloroperbenzoic acid(m-CPBA) at 0 8C (96%). Furthermore, the azide functionof (2R,RS)-2 could be reduced to amine by treatment withHS[CH2]3SH¡Ótriethylamine,6 providing the b-sulnyl amine(2R,RS)-4 in almost quantitative yield, without aecting thestereogenic sulnyl centre.The amino group of (2R,RS)-4 was subsequently protectedupon treatment with DCC¡Óbenzoic acid (72%).The sulnylgroup of the resulting N-benzoyl derivative (2R,RS)-5 wasdeoxygenated with NaI¡Ótriuoroacetic anhydride (TFAA),according to the Oae¡ÓDrabowicz protocol,7 which deliveredthe N-benzoyl b-( p-tolylthio)amine (R)-6 in 83% yield.Finally, N-benzoyl sec-butylamine (S)-7 was obtained byreductive desulfenylation of (R)-6, with Raney-Ni in ethanolat 60 8C (94%). Since the enantiomeric compound (R)-7,having [a]20D £¾21.5 (c 1.15, CH2Cl2), has been previouslydescribed in the literature,8 polarimetric analysis of oursample, having [a]20D 24.7 (c 1.12, CH2Cl2), allowedus to conrm both its (S)-conguration, as well as theenantiomeric purity of all the precursor compounds 2¡Ó6,represented in the Scheme 1.In conclusion, we have reported a synthetically usefulprotocol for the synthesis of enantiomerically pure aminocompounds from b-sulnyl alcohols, which uses azidationunder Mitsunobu conditions as the key step.This methodfeatures both high overall yields and stereoselectivity, andcould therefore be successfully exploited for the preparationof many other biologically interesting, enantiopure aminocompounds.ExperimentalGeneral Procedure.The instrumentation and general exper-imental and analytical procedures were recently described in detail.9The -sulnyl alcohol (2S,RS)-1 was prepared according to aliterature procedure.4-Sulnyl Azide (2R,RS)-2.Method A. To a stirred solution of(2S,RS)-1 (1.22 g, 5.75 mmol) in DMF (50 ml) cooled at 0 8C wereadded NaN3 (5.61 g, 86.3 mmol), Ph3P (5.53 g, 17.3 mmol) andnally CBr4 (5.74 g 17.3 mmol).The mixture was stirred at r.t. for4 h, then water and diethyl ether were added and the phases wereseparated. The organic phase was repeatedly washed with water inorder to remove DMF, then dried over anhydrous Na2SO4, lteredand the solvent removed at reduced pressure. The crude mixturewas submitted to ash chromatography (FC) (1:1 n-hexane¡ÓethylJ. Chem.Research (S),1998, 666¡Ó667$Scheme 1 Reagents, conditions and yields: i Method A: NaN3,Ph3P, CBr4 (76%); Method B: HN3, Ph3P, DEAD (57%);ii, m-CPBA, 0 8C (96%); iii, HS[CH2]3SH¡ÓNEt3 (97%);iv, PhCO2H¡ÓDCC (72%); v, (CF3CO)2O¡ÓNaI (83%);Raney-Ni¡ÓH2, 608C (94%)$This is a Short Paper as dened in the Instructions for Authors,Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-fore no corresponding material in J. Chem. Research (M).*To receive any correspondence (e-mail: bravo@dept.chem.poli-mi.it).666 J. CHEM.RESEARCH (S), 1998acetate), which a€orded 1.02 g of the desired azide (2R,RS)-2 (76%), as a yellowish oil. Method B. A solution of (2S,RS)-1 (212 mg, 1 mmol) and Ph3P (524 mg, 2 mmol) in anhydrous benzene (11 mL) and HN3 (4.0 mL of 1.0 M solution in anhydrous benzene, 4 mmol) was cooled with an ice¡¾water bath under nitrogen. To the stirred solution DEAD (0.63 ml, 4 mmol) diluted with the same solvent (5 mL) was added dropwise.The bath was removed and, after ca. 15 min, TLC control revealed that all (2S,RS)-1 had been consumed. The reaction mixture was ¢çltered, the solvent was removed in vacuo, and ¢çnally the crude was puri¢çed ¢çrst by FC on silica gel, then on neutral alumina (4 :6 n-hexane¡¾ethyl acetate), providing 135 mg of the desired azide (2R,RS)-2 (57%). (2R,RS)-2: Rf (6:4 n-hexane¡¾ethyl acetate) 0.31; [a]D 20a140.4 (c 0.88, CHCl3); dH (CDCl3) 7.56 (2 H, d, J 8.1 Hz), 7.36 (2 H, d, J 8.1 Hz), 3.6¡¾3.4 (1 H, m), 3.08 (1 H, dd, J 13.1 and 7.0 Hz), 2.84 (1 H, dd, J 13.1 and 6.3 Hz), 2.42 (3 H, s), 2.0¡¾1.5 (2 H, m), and 1.01 (3 H, t, J 7.3 Hz); dC (CDCl3) 142.0, 139.9, 130.2, 124.1, 61.0, 58.3, 27.3, 21.5, 10.1 (Found: C, 55.3; H, 6.8; N, 17.4.C11H15N3OS requires C, 55.7; H, 6.4; N, 17.7%). -Tosyl Azide (R)-3.�¢To a solution of sul¢çnyl azide (2R,RS)-2 (44 mg, 0.18 mmol) in CH2Cl2 (2 ml), cooled at 0 8C, a solution of commercial m-CPBA (57¡¾86%) (84 mg, 0.27¡¾0.41 mmol) in CH2Cl2 (3 ml) was added dropwise.After 1 h at 0 8C (TLC monitoring) the reaction mixture was washed with aqueous 10% sodium sul¢çte, then with saturated aqueous NaHCO3, ¢çnally with brine. The aqu- eous phases were washed with CH2Cl2, the collected organic phases were dried over anhydrous sodium sulfate, ¢çltered and the solvent was removed in vacuo. FC of the crude (n-hexane¡¾ethyl acetate 8:2) provided pure (R)-3 as a yellowish oil (45 mg, 96%). (R)-3.Rf 0.35 (4:1 n-hexane¡¾ethyl acetate); [a]D 20+40.1 (c 0.33, CHCl3); dH (CDCl3) 7.83 (2 H, d, J a 8.4 Hz), 7.37 (2 H, d, J 8.4 Hz), 3.87¡¾3.78 (1 H, m), 3.26 (1 H, dd, J 14.5 and 8.2 Hz), 3.16 (1 H, dd, J 14.5 and 4.0 Hz), 2.47 (3 H, s), 1.8¡¾1.5 (2 H, m), and 1.00 (3 H, t, J 7.3 Hz); dC (CDCl3) 145.8, 137.3, 130.7, 128.7, 60.5, 59.3, 28.7, 22.4, 10.6; FT IR max/cm¢§1 (KBr) 2972, 2121, 2070, 1598, 1319, 1303, 1146; m/z (EI, 70 eV) 226 (Maa1 ¢ect; C2H5, 18), 211 (Ma ¢§N3) (Found: C, 52.5; H, 6.4; N, 16.4.C11H15N3O2S requires C, 52.2; H, 6.0; N, 16.6%). -Sul¢çnyl Amine (2R,RS)-4.�¢To a solution of azide (2R,RS)-2 (200 mg, 0.84 mmol) in methanol (5 mL) at r.t. under nitrogen were added propane-1,3-dithiol (847 L, 8.44 mmol) and triethylamine (1.17 mL, 8.44 mmol). After ca 4 h (TLC monitoring) the mixture was submitted to prolonged evaporation in vacuo, then the residue was puri¢çed by FC (ethyl acetate¡¾isopropanol 95:5 to 5:95).The desired amine (2R,RS)-4 was obtained as a yellowish oil (172 mg, 97%). (2R,RS)-4. Rf 0.30 (5:95 ethyl acetate¡¾isopropanol); [a]D 20a166.5 (c 1.02, CHCl3); dH (CDCl3) 7.56 (2 H, d, J 8.0 Hz), 7.33 (2 H, d, J 8.0 Hz), 3.24 (1 H, m), 2.88 (1 H, dd, J 8.3 and 13.2 Hz), 2.73 (1 H, dd, J 4.2 and 13.2 Hz), 2.41 (3 H, s), 1.71 (2 H, s), 1.61 (1 H, m), 1.47 (1 H, m), 0.95 (3 H, t, J 7.3 Hz); m/z (EI, 70 eV) 212 (Maa1, 85), 148 (46), 91 (25), 72 (100); FT IR max/cm¢§1 (KBr) 3365 (br), 3270, 1597, 1495, 1459, 1399, 1087, 1034.N-Benzoyl -sul¢çnyl amine (2R,RS)-5.�¢A mixture of -sul¢çnyl amine (2R,RS)-4 (130 mg, 0.62 mmol), benzoic acid (144 mg, 1.18 mmol), DCC (243 mg, 1.18 mmol) and p-dimethylaminopyri- dine (13 mg, 0.11 mmol) in CH2Cl2 (6 ml) was stirred at r.t. for 90 min (TLC monitoring). The mixture was diluted with 10 ml of diethyl ether, ¢çltered, and the solvent was removed in vacuo. FC (n-hexane¡¾ethyl acetate 1:1) provided the desired N-benzoyl amine (2R,RS)-5 as a white solid (202 mg, 72%).(2R,RS)-5. Rf 0.30 (1:1 n-hexane¡¾ethyl acetate); mp 151.5¡¾ 153.0 8C (ethyl acetate); [a]D 20a79.1 (c 0.61, CHCl3); dH (CDCl3) 7.82 (2 H, d, J 8.0 Hz), 7.58 (2 H, d, J 8.0 Hz), 7.50¡¾7.27 (5 H, m), 7.23 (1 H, br d, J 7.4 Hz), 4.32 (1 H, m), 3.23 (1 H, dd, J 8.7 and 13.4 Hz), 3.12 (1 H, dd, J 4.8 and 13.4 Hz), 2.40 (3 H, s), 1.94¡¾1.50 (2 H, m), 0.92 (3 H, t, J 7.3 Hz); dC (CDCl3) 167.4, 141.8, 140.3, 134.2, 131.5, 130.1, 128.4, 127.1, 124.2, 61.9, 48.3, 27.8, 21.4, 10.2; m/z (EI, 70 eV) 316 (Maa1, 10), 176 (100), 105 (70), 77 (32); FT IR max/cm1 (KBr) 3303, 1634, 1530, 1029 (Found: C, 68.0; H, 7.1; N, 4.9, C18H21NO2S requires C, 68.4; H, 6.7; N, 4.5%).N-Benzoyl p-Tolylthioamine (R)-6.�¢To a mixture of N-benzoyl -sul¢çnyl amine (2R,RS)-5 (107 mg, 0.32 mmol) and NaI (145 mg, 0.97 mmol) in acetone (2 ml) at ¢§20 8C, a solution of TFAA (0.23 ml, 1.62 mmol) in acetone (1 ml) was added dropwise.The mixture immediately became dark green. After 5 min at ¢§20 8C (TLC monitoring) the reaction was quenched with a saturated aqu- eous sodium sul¢çte solution, then a saturated aqueous NaHCO3 sol- ution was added until neutral pH was reached. The mixture was allowed to warm at room temperature, then the mixture was extracted with ethyl acetate, the collected organic phases were dried over anhydrous sodium sulfate and ¢çltered and the solvent was removed in vacuo.FC (n-hexane¡¾ethyl acetate 7:3) provided the desired N-benzoyl amine (R)-6 (80 mg, 83%). (R)-6. Rf 0.45 (7:3 n-hexane¡¾ethyl acetate); dH (CDCl3) 7.59 (2 H, m), 7.52¡¾7.29 (5 H, m), 7.06 (2 H, d, J 7.8 Hz), 6.12 (1 H, brd, J 8.1 Hz), 4.30 (1 H, m), 3.21 (2 H, br signal), 2.28 (3 H, s), 1.88¡¾1.58 (2 H, m), 0.96 (3 H, t, J 7.3 Hz); m/z (EI, 70 eV) 299 (Ma, 68%), 178 (46), 105 (100), 77 (67). FT IR max/cm¢§1 (KBr) 3308, 1639, 1535, 1490 (Found: C, 71.2; H, 7.2; N, 4.6.C18H21NOS requires C,72.2; H, 7.1; N, 4.7%). N-Benzoyl sec-Butylamine (S)-7.�¢To a stirred solution of the thioamine (R)-6 (72 mg, 0.24 mmol) in absolute ethanol (5.0 ml) Raney-Ni (ca. 0.4 g) was added and the slurry was vigorously stirred for 3 h at 80 8C under a hydrogen atmosphere. The Raney- Ni was removed by ¢çltration on a Celite pad and the solvent was removed under reduced pressure. FC (n-hexane¡¾ethyl acetate 4:1 to 7.3) provided the desired N-benzoyl amine (S)-7 (40 mg, 94%) as a white solid.(S)-7. Rf 0.40 (75:25 n-hexane¡¾ethyl acetate); [a]D 20a24.7 (c 1.12, CH2Cl2); in the literature the enantiomer (R)-7 is reported to have [a]D 20 ¢§ 21.5 (c 1.15, CH2Cl2)8; dH (CDCl3) 7.81¡¾7.78 (2 H, m), 7.52¡¾7.36 (3 H, m), 6.10 (1 H, br signal), 4.20¡¾4.03 (1 H, m), 1.57 (2 H, dq, J ca. 7.3 Hz both), 1.22 (3 H, d, J 6.8 Hz), 0.96 (3 H, t, J 7.3 Hz); dC (CDCl3) 166.9, 135.0, 131.2, 128.4, 126.8, 47.0, 29.7, 20.5, 10.4. 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