Mohan, H Rama

Rao, A S

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Indian Journal of ChemistryVol. 37B, January 1998, pp. 78 - 79Enantioselective synthesis of (R)-( +)-safroleoxidetlH Rama Mohan & A S Rao·Indian Institute of Chemical Technology, Hyderabad 500007,IndiaReceived 26 March 1997; accepted 20 June 1997The first synthesis of (R)-( +)safroJe oxide 4, startingfrom safrole 2 employing Sharpless asymmetric dihydro-xylation as the key step, has been reported.Safrole oxide 1 is used for estimating epoxidehydratase and for the synthesis of some lignanlactones'. Though the racemic epoxide 1 has beensynthesised'", there are no reports on the synthesisof pure enantiomers of 1. We now report thesynthesis of (R)-(+)-safrole oxide 4 according toScheme I.o~(I 0o ~Usually asymmetric hydroxylations of terminalalkenes proceed with moderate enantioselectivity.However, we have now observed that asymmetrichydroxylation of the terminal alkene in safrole 2with the reagent AD-mix-f33 furnished the diol 3ahaving 88% ee; the hydroxylation product has beenassigned (R) configuration based on observationsmade with related compounds such as I-decene4.For further identification 3a was converted todiacetate 3c by reaction with AC20. Tosylation ofthe diol 3a proceeded with high regioseIectivity tofurnish the primary tosylate 3b, which on treatmentwith K~C03 in absolute methanol furnished the(R)-(+)-epoxide 4.Experimental SectionGeneral. The AD-mix-f3 and safrole employedfor this study were purchased from Aldrich andFluka respectively. Silica gel (60-120 mesh) was'ucr Communication No. 3411!Taken in part from Ph.D thesis ofH Rama Mohan submittedto Osmania University. Hyderabad, 1995.Noteii!}-'--Reagents: il AD-mix- ••• CH,.so"NH,. aq tert. BuOH II tosyl chloride. CH,CI,. Et.N. DMAPiiil K,COs- absolute methanolScheme Iused for column chromatography. 'H NMR spectrawere recorded on a Varian FT-200 spectrometer(200 MHz) using TMS as internal standard.Optical rotations were measured on a JASCO DIP370 digital polarimeter at 25°C.(R)-( +)-5-(2,3-Dihydroxypropyl)-1,3-benzodioxole3a. A mixture of 2 (0.162 g, 1.0 mmole), AD-mix-f3(1.4 g) and methanesulfonamide (95 mg) in 50%aqueous tert. BuOH (10 mL) was stirred at O°C for30 hr. To the mixture was added Na2S03 (1.5 g) andafter I hr at room temperature the reaction mixturewas extracted with ethyl acetate (5 mLx3). Theorganic layer was washed with brine, dried overNa2S04 and evaporated under reduced pressure toafford 3a as a white solid (0.170 g, 87%). 'H NMRspectrum of the Mosher ester prepared according toknown procedure from the crude diol 3a showed88% ee. Sample recrystallized from EtOAc gavecolourless crystals, mop. 93°; [a]D+32° (c, 1.65,CHCb); 'H NMR (CDCI3): 8 2.6-2.8 (m, 2H), 3.4-3.7 (octet, 2H), 3.75-3 ..95 (m, IH), 5.9 (s, 2H), 6.62(d, J=8 Hz, IH), 6.70 (s, IH), 6.73 (d, J=8 Hz, IH);Anal. Found: C, 61.27; H, 6.04. Ca\cd for C'OH'204:C, 61.21; H,6.17%.(R)-( - )-5-(2,3-Diacetoxypropyl)-1,3-benzodioxole3c. A mixture of 3a (0.020 g, 0.102 mmole), aceticanhydride (0.041 g, 0.408 mmole) and pyridine(0.032 g, 0.408 mmole) was stirred at 25°C for 12hr. Work-up afforded the diacetate which waspurified by column chromatography with hexane aseluent to furnish 3c (0.027 g, 96%); [a]J)-1.0° (c.2.75, CHCh); 'H NMR (CDCh): 8 2.04 (s, 3H).2.06 (s, 3H), 2.8 (octet, 2H), 3.9-4.3 (octet, 2H).5.2 (m, IH), 5.9 (s, 2H), 6.62 (d, ./=8 Hz, 1H), 6.70p(s, IH), 6.72 (d, J=8 Hz, IH); Anal. Found: C,59.74; H, 5.64. Calcd for C'4H'606: C, 59.99; H,5.75%.(R}5-(2-Hydroxy-3-tosyloxypropyl}l,3-benzodioxole3b. Tosylation of 3a (0.140 g, 0.714 mmole) withtosyl chloride (0.149 g, 0.785 mmole), triethyl-amine (0.18 g, 1.78 mmole) and 4-dimethylamino-pyridine (0.010 g) in dry CH2Ch (5 mL) wascarried out at O°C for 36 hr. The resulting tosylateafter work-up· was column chromatographed using1:9 mixture of ethyl acetate-hexane as eluent tofurnish 3b (0.231 g, 92%); 'H NMR (CDCh): 02.48 (s, 3H), 2.75-2.9 (m, 2H), 3.9-4.1 (m, 3H), 5.9(s, 2H), 6.6-6.9 (m, 3H), 7.38 (d,J=8 Hz, 2H), 7.81(d, J=8 Hz, 2H); Anal. Found: C, 58.14; H, 5.12.Calcd for C17H'806S: C, 58.28; H, 5.18%.(R)-(+)-5-0xiranylmethyl-l,3-benzodioxole 4. Toa stirred mixture of tosylate 3b (0.125 g, 0.357mmole) in absolute methanol (20 mL), K2C03(0.493 g, 3.57 mmole) was added and stirred thesuspension vigorously for 30 min. Methanol wasremoved under reduced pressure on a rotavapor.The residue was diluted with water (5 mL) andextracted into ethyl acetate (5 mLx2). The organic/NOTES 79layer was dried over Na2S04 and after removal ofsolvent the residue was purified using 5% EtOAc-hexane as eluent to afford 4 (0.051 g, 79%);[a]D+13° (c, 1.04; CHCh); 'H NMR (CDCh): 02.50 (dd, J=5.5 and 2.5 Hz, IH), 2.7-2.9 (m, 3H),3.02-3.10 (m, IH), 5.92 (s, 2H), 6.65 (d, J=8 Hz,IH), 6.72 (s, IH), 6.74 (d, J=8 Hz, IH); Anal.Found: C, 67.38; H, 5.70. Calcd for CIOHIO03: C,67.40; H, 5.66%).AcknowledgementWe thank Dr A V Rama Rao for his keeninterest in our work and the CSIR, New Delhi forawarding Emeritus Scientistship to one of us(A S R).ReferencesI Sanghvi Y S, Dabral v, Bhat K S & Rao A S, Indian JChern, 23B, 1984, 12.2 Aiba C J & Gottlieb 0 R, Phytochemistry, 14,1975,253.3 Sharpless K B, Amberg W, Beller M, Chen H, Hartung J,Kawanami Y, Lubben 0, Manuary E, Ogino Y, Shibata T& Ukita T, J Org Chern, 56, 1991,4585.4 Sharpless K B, Amberg W, Bennani Y L, Crispino G A,Hartung J, Jeong K -S, Kwong H -L, Morikawa K, WangZ -M, Xu 0 & Zhang X -L, J Org Chern, 57, 1992,2768.5 Ward 0 E & Rhee C K, Tetrahedron Left, 32, 1991, 7165.

Enantioselective synthesis of (R)-(+)-safrole oxide

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Enantioselective synthesis of (R)-(+)-safrole oxide

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