The Unexpected Reductive Products of δ-Alkoxyenal by Sodium Borohydride in Methanol with A Trace of

Chinese Chemical Letters Vol. 13, No.9, pp 809 - 810, 2002809http://www.imm.ac.cn/journal/ccl/htmlThe Unexpected Reductive Products of δ- Alkoxyenal by SodiumBorohydride in Methanol with A Trace of Magnesium MethoxideYu XIA, Xiang Shu XIAO, Xu Chang HE, Dong Lu BAI*Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, ChineseAcademy of Sciences, Shanghai 20003 1Abstract: Reduction of δ alkoxy enal 1 and 4 by sodium borohydride in methanol with a catalyticamount of magnesium methoxide gave unexpected methoxylated poducts 3 and 6 respectively.Keywords: Sodium borohydride, Magnesium methoxide, Michael addition.The selective 1,2-reduction of a, β unsaturated carbonyl compounds such as enones andenals, has been achieved by NaBH4. In the course of our studies toward the totalsynthesis of macrolactin A, it was found that reduction of enal 1 by NaBH4 in MeOH,which contained a trace of Mg(OMe)2 from the preparation of absolute MeOH, formedan unexpected product 3 (Table 1).According to the known procedues', allylic alcohol 2 was normally formed in 78%yield by reduction of enal 1 with NaBH in MeOH at -78°C. However, when methanolcontained a catalytic amount of Mg(OMe)2, the reduction of 1 gave methoxy compound3 instead of 2 in 54% yield. The structure of the unexpected reductive product 3, whichis a mixture of two diastereomers in a ratio of 1:1, was confirmed by 'H NMR, H-HCOSY, MS and IR'. The acetate' of 3 was also prepared in order to assist the structureassignments of the product. To further understand this reaction, experiments werecarried out with δ-silyloxy enal 4 and 7-alkoxy enal 7. Enal 4 gave the 1,2-reductionproduct 5 in 92% yield via procedure i, while a saturated methoxy alcohol 6 was formedin 66% yield via procedure ii. However, enal 7 only gave allylic alcohol 8 by bothprocedures in a yield around 90% (Table 1).In respect of the mechanism of the distinct reductive products of enal 1, 4 and 7 viaprocedure i and ii, we suppose that a catalytic amount of Mg(OMe)2 and the δ-alkoxygroup of a, B-unsaturated aldehyde are requisite for the Michael addition of methoxygroup. A possible mechanism is envisioned in Scheme 1, in which magnesium firstcoordinates with the oxygen of 8-alkoxy group, forming a six-member cyclic transitionstate, then one methoxy group of Mg(OMe)2 adds to the β carbon atom of enal followedby the reduction of aldehyde group. This mechanism can explain well why themethoxy addition did not occur to enal 7, considering the disfavor of forming an eight-member ring transition state.E-mail: dlbai @ mail.shcnc.ac.cn中国煤化工MHCNMH G.810Yu XIA et al.Table 1 Reduction of enal by NaBH via procedure ior iiproduct and yield (%)substrateprocedure iprocedure ii助v道。Bna_心^oH 78batuon 54)TBS入ms。，9Procedure i 1.5 molar equiv. of NaBH for each mole of enal in MeOH at -78°C, 0.5 h. i: Thesame conditions as in i except the MeOH containing a catalytic amount of Mg(OMe)2-Scheme 1OMe)RMasMg(OMe)2 、RO pMepR oMeβa不。十or人人人。PR MeQR gMMeOHIn summary we found that reduction of ~alkoxy a, β unsaturated aldehyde byNaBH4/ MeOH with a catalytic amount of Mg(OMe)2, gave methoxy alcohol viaMichael addition and reduction.AcknowledgmentWe thank the National Natural Sciences Foundation of China and State Key Laboratory ofBioorganic and Natural Products Chemistry for financial supports.References and Notess.w.Chaikin, W.G.Brown, J. Am. Chem. Soc., 1949, 71, 122.D.C.Whirtenour, S.Masamune, J. Org. Chem., 1989, 54, 2817.All products show satisfactory spectroscopic data. Selected data for compound 3. H NMR(600MHz,CDCl) δ: 7.23-7.34 (m, 5H), 4.54 (s, 2H), 3.73-3.78 (m, 2H), 3.70 (dd, 1H J=3.4,Hz,), 3.47 (s,1.5H), 3.40 (S, 1.5H), 3.25-3.30 (m,1H),3.14-3.21 (m, 1H), 2.83-296 (m,1H), 2.36 (brs, 1H), 1,78-190 (m, 2H); MS(m/z, %);: 252(M,3.1), 149 (38), 91 (10).4. Alcohol 3 was converted to the corresponding acetate under standard conditions (Ac,O:py:DMAP=1.5:2.0: 0.1, CH2Cl, 0-259 C, 1 h) in quantitative yield. 'H NMR (400MHz,CDCl) δ:2.82- 2.93 (m,1H), 2.04 (brs, 1H), 1,80-2.00 (m, 2H); iMS(m/z. %): 294(M), 91(84), 71(100)."Received 24 October, 2001中国煤化工MHCNMH G.