5454 J. Am. Chem. SOC. 1981,103, 5454-5459 Lanthanoids in Organic Synthesis. 6. The Reduction of a-Enones by Sodium Borohydride in the Presence of Lanthanoid Chlorides: Synthetic and Mechanistic Aspects Andre L. Gemal and Jean-Louis Luche* Contribution from the Laboratoire d'Etudes Dynamiques et Structurales de la SPIectivitB (LEDSS). Biitiment de Chimie Recherche, UniversitB Scientifique et Medicale, BP 53 X, 38041 Grenoble CZdex, France. Received February 17, 1981 Abstract: Lanthanoid chlorides (LnC13) are efficient catalysts for the regioselective 1,2 reduction of a-enones by NaBH4 in methanol solution. Optimal conditions of this reaction have been determined. A mechanistic interpretation depicting the role of the Ln3+ ions is given. The major effect of Ln3+ is the catalysis of BH4- decomposition by the hydroxylic solvent to afford alkoxyborohydrides, which may be responsible for the observed regioselectivity. The stereoselectivity of the process is also modified by the presence of the Ln3+ ions, in that axial attack of cyclohexano?e systems is enhanced. Since the discovery of the reducing properties of boron hydrides, sodium borohydride has received considerable attention as a se- lective and mild reducing agent of the carbonyl group. A large variety of papers report results of synthetic, mechanistic, or ste- reochemical importance, and reviews have recently been pub- lished.2 The question of the mechanism, especially in an alcoholic solvent, is intriguing and complex since as the reaction proceeds various alkoxyborohydrides 1 are produced, which may react with their own stereo- and regioselectivities. Disproportionation of some or all alkoxyborohydrides to BH, further complicates the situation. The problem has been extensively studied theoretically3 as well as by stereochemical and kinetic appro ache^.^,^ Other studies demonstrate that the usual reaction selectivity of NaBH4 can be substantially modified by addition of various metal salts, such as al~minum,~ cobalt: copper,' nickel: tin? titanium,lo and zinc,\" to give complex reagents, which are capable of synthetically useful conversions including the reductions of acyl chlorides to aldehydes,' olefins to saturated hydrocarbon,6 and dehalogenation of aryl halides to arene~.~ The selective reduction12 of a-enones 2 is of interest as this chart I - 8a RtR2-O - 8b Rl=H, Rz=OH - 9a R~Rz=O - 9b Rl=OH,RZ=H - 1Oa RqR2'0 10b Rq=OH.R2=H - R+= H.Rz=OH Table 1. Reduction of 4a with NaBH, in MeOH in the Presence of Metallic Saltsa %of productb (1) Preceding paper in this series: Luche, J. L.; Gemal, A. L. J. Am. 1979, 101, 5848. Chem. SOC. (2) (a) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979,35,567. (b) Wigfield, D. C. Tetrahedron 1979, 35, 449. (c) Boone, J. R.; Ashby, E. C. Top. Stereochem. 1979,11, 53. (d) See also the monograph \"Sodium boro- hydride\" Thiokol, Ventron division. Danvers, Mass., 1979. (3) (a) Lefour, J. M.; Loupy, A., Tetrahedron 1978,34,2597. (b) Perl- berger, J. C.; Muller, P. J. Am. Chem. SOC. 1977, 99, 6316. (c) Dewar, M. J. S.; McKee M. L. Ibid. 1978, ZOO, 7499. (d) Huet, J.; Maroni-Barnaud, Y.; Anh, N. T.; Seyden-Penne, J. Tetrahedron Lett. 1976, 159. (e) Bottin, J.; Eisenstein, 0.; Minot, C.; Anh, N. T. Tetrahedron Lett. 1972, 3015. (f) Loupy, A.; Seyden-Penne, J. Tetrahedron 1980,36, 1937. (4) Inter alia see: Wigfield, D. C.; Gowland, F. W. Tetrahedron Lett. 1979,2209; J. Org. Chem. 1977,42,1108; Tetrahedron Lett. 1976,3373 and references cited. (5) Brown, H. C.; Rao, B. C. S. J. Am. Chem. SOC. 1956, 78, 2582. Kee J. Org. Chem. 1979,44, 1014 and references cited. (6) Chung, Sung (7) (a) Fleet, G. W. J.; Fuller, C. J.; Harding, P. J. C. Tetrahedron Lett. 1978, 1437. (b) Sorrell, T. N.; Pearlman, P. S.; J. Org. Chem. 1980,45,3449. (8) Lin, Shaw Tao; Roth, J. A. J. Org. Chem. 1979, 44, 309. (9) Kano, S.; Yuasa, Y.; Shibuya, S. Chem. Commun. 1979, 796. (10) Subba Rao, B. C., Curr. Sci. 1961,30,218; Chem. Abstr. 1961,56, 3326'2. Tanaka, Y.; Hibino, S. Chem. Commun. 1980,415. (11) Yoon, N. M.; Lee, H. J.; Kang, J.; Chung, J. S. Taehan Hwahakhoe Chi 1975,468; Chem. Abstr. 1976,84, 134703. 0 OH ion Ce3+ Sm3+ Eu3+ Yb3+ 4a 0 0 0 0 0 0 2 Sa 90 0 0 0 0 0 91 94 93 89 86 1 La3+ 0 0 10 3 6 Ll+ Y3+ CU' Baa+ Zn2+ Fez+ Fe3+ ~13+ Nil+ co z+ I 90 19 33 6 6 trace 12 5 2 0 11 14 99 I 11 9 12 8 16 61 4 I 86 18 21 0 0 60 50 4 6 12 16 3 88 a 0.4 M methanol solution; enone, NaBH,, and metallic salt: 1 equiv each, 5 min. GLC measurements (see Experimental Sec- tion). problem is frequently encountered is synthetic schemes. Our previous p~blications'~ describe their regioselective conversion to 0 1981 American Chemical Society 0002-7863/81/1503-5454$01.25/0 Lanthanoids in Organic Synthesis 420 0, 1; / '46 I1'/a % I Y2 I 1 b fig. 1 Figure 1. CeC1,.6H20. Percent yield of 5a vs. the number of molar equivalents of allylic alcohols of lanthanoid derivatives. This procedure, which allows highly 3, by NaBH4 in methanol solution, in the presence regioselective 1,2 reduction, is complementary to those which give predominant 1,4 tell~ride'~ or NaBH, in pyridine.15 The general utility of the selectivities with the aid of sodium hydro- NaBH4-CeC13 selective reduction is illustrated by the conversion of 2-cyclopentenone 3% (4a) systems by most hydride reagents is usually highly favored. cyclopentanol, although conjugate reduction of cyclopentenone to 97% 2-cyclopentenol (5a) and only view of this, we initiated an investigation of the mechanistic and In stereochemical aspects of the reaction, the results of which are reported in this article. Results and Discussion maximum yield and regioselectivity After much experimentation, the best conditions found for of NaBH4 C13.6H20. Many enones were thus converted essentially quan- for each mole of substrate in 0.4 M methanolic Ce- were to employ 1 molar equiv titatively to the allylic alcohol at room temperature.16 factor for the regioselectivity (Table The nature of the metallic ion was found to be an important in a strong decrease of the 1,2 reduction of Replacement of the lanthanoid ion by other elements results I). Zn2+) 4a. rapidly and the starting material is recovered as the major com- complete decomposition of the reducing agent occurs very In some cases (T13+, ponent of the mixture. Among the lanthanoids tested, cerium gave the highest selectivity with most enones and is generally recom- mended. This finding is of interest for economical reasons as cerium is one of the less expensive of the rare earth elements. the possibility that Ce3+ For the same reason and for mechanistic studies, we investigated in less than stoichiometric amounts. could function catalytically or, at least, (b) (12) D. J. Winterfeldt, (a) Krishnamurthy, Org. Chem. E. 1975,40,2530. Synthesis S.; 1975, Brown, H. C., J. Org. Chem. 1975,410, 1864. (d) 617. Johnson, (c) Hutchins, M. R.; Rickborn, R. 0.; Kandasamy, b. J. Org. Chem. Mordenti, 1970,35, Loupy, L.; Brunet, 1041. J. J.; (e) LCaubEre, ane, C. F., P. Aldrichimica Acta J. Org. Chem. 1976,9, 31. (f) 0. \"Modern A.; Seyden-Penne, Synthetic Reactions\"; J. Tetrahedron Lett. W. A. 1978, 2571. 1979,44, (h) House, 2203. (g) H. 1972 mun. 2nd ed. (i) Wilson, K. E.; Seidner, Benjamin, R. T.; Masamune, Inc.: Menlo S. Chem. Com- Park, Calif., 2194. 1970, 213. 6) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, L., (13) (a) Luche, J. L. J. Am. Chem. SOC. 1978,100, 2226. (b) Luche, J. L.; Rodriguez-Hahn, L.; CrabM, P. Chem. Commun. 1978, 601. Gemal, A. in by the Luche, J. L. J. Org. Chem. 1979, 44, 4187. It is worth T. NaBH, case of D. in a a y methanolic pyrone, the mentioning that solution usually of difficult ceric nitrate. 1,4 reduction has See: Poulton, been G. achieved A,; (14) Synrh. Commun. Cyr, (15) Yamashita, 1980, 10, 581. Jackson, W. M.; R.; Kato, Zurquiyah, Y.; Suemitsu, A. J. Chem. SOC. R. Chem. Lett. 1965, 1980, 847. tigated. (16) The effect of temperature on the stoichiometry has not 5280. been inves- J. Am. Chem. SOC., Vol. 103, No. 18, 1981 5455 A t \\ C - fig. 2 Figure 2. Percent yield of 5a vs. concentration of 4a and CeC13.6H20. Table 11. Solvent Effect on the Reduction of 4aa % of % of selectivityb solvent conversionb 1,2 1,4 MeOH:H,O MeOH 100 91 MeOH:H,O (9:l) 100 85 15 3 50 90 50 EtOH (1:l) 100 Me0H:pyridine 100 10 i-PrOHC (4: 1) 100 80 95 60 20 5 a 0.4 M solution; GLC measurements. CeC1,.6H20, enone, and NaBH,: solvent, CeCI, was replaced Due 1 equiv 5 min. to its insolubility in this each, by erbium chloride. As shown in Figure 1, the 1,2 selectivity remains high for a sharp decrease occurs. The overall concentration in methanol [Ce3+]/[substrate] ratios larger than 0.25, but for lower values, is also an important factor, as shown in Figure in the concentration of all the reacting species results in a more 2. A decrease selective reaction. gives a selectivity for the reduction of An extrapolation of the curve to infinite dilution 100% 4a to 5a. summarized in Table The effect of solvent was also investigated and the results are highest selectivity accompanied by a very high reaction rate. For 11. Methanol was found to provide the example, compounds 4a corresponding allylic alcohols and 6 and reaction rate were progressively reduced in ethanol and iso- 5 were quantitatively reduced to the and 7 in ca. 15 s. The selectivity propyl alcohol. At the onset of this study, we envisioned that the role of the lanthanoid ions was to modify the geometry or electronic density, therefore the reactivity, of the conjugated system. For example, the presence of of some flexible ketones.17 Changes in the regiochemical course Eu3+ shift reagents can modify the conformation of a-enone reactions could also be expected from the presence of Ln3' on ions, in analogy with the important effect of alkaline ions aprotic solvents, the effect of complexation of the C=O group the electron density in the conjugated carbonyl system.38 In by Li' and Na' on the reactivity of enones is well documented.WJ* conjugate system at carbon 2 is enhanced and the reaction rate Under the conditions of complexation control, the attack of the is increa~ed.~~ for instance by the use of a cryptand, was shown to result in an Conversely, suppression of the complexation control, enhanced 1,4 selectivity and a decreased reaction rate.3f That such control exists with lanthanoid ions is illustrated by the reduction of 4a THF solution of SmI,. When compared to the reductions per- to 5a in 95% yield by NaBH4 in an anhydrous formed modification is obviously related to the different nature of the in the presence of Li' or Na+, the dramatic selectivity added complexing cation.19 (17) Dunkelblum, E.; Hart, H. J. Org. Chem. 1977, Thesis, (18) of ref the 3a C(=O). Grenoble Handel, H.; 1978. Pierre, J. L. Tetrahedron 1975, 31, 42, 2799. 3958. Handel, H. and Raber, . .L i* See also ref 2c. It is worth noting that the geometries Chem. SOC. 1980, D. and 102, J., 6594. Janks, C(=O). C. M.; Eu3+ Johnston, complexes M. D.; are Raber, closely related; N. K. J. Asee m. 5456 J. Am. Chem. SOC., Vol. 103, No. 18, 1981 have been However, most reductions of enones in the presence of Ce3+ solvent complexation control is still effective. The results obtained run in methanol, and there is no evidence that in a protic by varying the overall concentration of the reaction medium disagree with the preceding explanation. Experimentally, in a methanol solution, in concentration. In a dilute solution, the 1,2 regioselectivity is shifted to the left. the complexation is increased by a decrease equilibrium -C=c--C=O..-HOR Ill t +:LROH t The reduction selectivity should then become similar to that ob- served without Ln3+ Furthermore, it is ions, in opposition that lanthanoid ions preferentially bind to the experimental results. to alcohols rather than to C=O known spectroscopy.20 groups as shown by NMR U at the expense of the first, and the effect of the cation on the Thus, dilution should shift the second equilibrium to the right reduction selectivity should progressively disappear. posite is observed, complexation of the carbonyl of major importance. Complexation of the solvent by Ln3+ is probably not As the op- is in contrast highly facilitated and should result in of the medium. This is illustrated by the catalytic role of lan- a stronger acidity thanoid ions in the ketalization of various aldehydes and ketones.z1 The push-pull type mechanism, with electrophilic assistance by the solvent proposed by Wigfield: should therefore be accelerated by an increase in acidity. In addition, the effect of a hard Lewis acid such as cerium,22 even if weak, should contribute both to the 1,2 selectivity and the high reaction rate, as observed. k, << k, >go% Whether the effect is large enough to produce the observed, regioselective reductions is unclear and the problem of the actual reducing species has to be examined. known cases (i.e., zinc or copper) lanthanoid borohydrides In analogy with from a cation exchange were considered as the possible reducing resulting agents. These species have been reported23 properties have not been described. Consequently, several bo- but their reducing rohydrides such as LnCl(BH4)z Sm were preparedz3 solution, the reduction was non-regioselective while in methanol and utilized for the reduction of and LII(BH~)~ with Ln 4b. = In Ce THF or Addition of methylmagnesium iodide to enones thus occurs with an increased (19) Other examples of this strong complexation effect were investigated. 1.2 future paper: selectivity in the presence of SmI,. These results will be discussed in a Rackham, D. M. (20) Inter alia see: Cockerill, A. F.; Davies, G. L. 0.; Harden, R. C.; 916. (21) Luche. J. Chem. Rev. L.: 1973, L. J. 73, 553. ..Gemal. A. Chem. SOC., Chem. Commun. 1978, 1968,45, (22) ' Pearson, R. G. J. Am. Chem. SOC. 1963,85, T. (23) (a) Marks, 581,643. 3533; J. Chem. Educ. T. J.; Kolb, J. Muckenhuber, J.; Grynkewich, E. Monarsh. Chem. G. W., Inorg. Chem. R. Chem. Rev. 1977, 77,263. (b) Marks, 1961, 1976, 92, 15, 600. 1302. (c) Rossmanith, K.; Gemal and Luche 100- t % 1. 3a 4x 2A fig. 3 Figure 3. Percentage of the H2 evolutidn vs time: + (1,O) NaBH, equiv + of CeCI, in methanol; of of CeC1, in methanol; (2, 0.5 equiv of CeC13 0.5 A) NaBH, cyclopentenone (4, (4a) in methanol; NaBH, 0.062 equiv (3, + 1 equiv 0) NaBH, of CeCI, in meth- + 0.125 equiv X) anol; (5,O) NaBH, in methanol without CeCl,. + A 100- 80- 70- 4 -3 1 2 3 I 4 I min fig. 4 Figure of 4. Percentage of H2 evolution vs. time: (1, + 0) of NaBH4 0.5 equiv CeC1, in ethanol; (2, A) NaBH, 0.5 equiv CeC1, + +1 of equiv of cyclopentenone (4) in ethanol; (3, 0) NaBH, 0.5 equiv ErCl, isopropyl alcohol. + in destruction of the reagent occurs more readily than reduction of the substrate. divalent species Ln2+ A mechanism involving reduction by a transient reactive in the presence of atmospheric oxygen, and they react can be ruled out as these species are highly poorly with ketones .24 Under the conditions we employ, 1 molar quiv of NaBH4 (i.e., a 4-fold hydride excess) is required for complete reduction enone. of the NaBH, with the methanol solution of the lanthanoid salt. This A vigorous hydrogen evolution occurs upon mixing of demonstrates an important catalytic effect of the lanthanoid ions in the MeOH-BH4- reaction. This reaction has been extensively studied and shown to involve the formation of alkoxyborohydrides NaBH4-,(OR),.z5 NaBH30R + The first reaction (NaBH4 + ROH - the process terminates with the formation of tetraalkoxyborate H2) was demonstrated to be rate determining and NaB(OR)4. Several metallic ions have been shown to have (24) (b) Brown, H. C.; Brown, C. A. (25) (a) Davies, R. Girard, P.; Namy, E.; Gottbrath, J. L.; Kagan, H. B. Nouo. J. Chim. (1977), I, 5. Brown, H. C.; Ichikawa, K. Zbid. J. J. A. J. Am. Chem. Soc. (1%2), 84,895. 1961, Am. Chem. 83, 4372. SOC. 1962, 84, 1493. (c) Lanthanoids in Organic Synthesis Table 111. Regioselective Reductions by NaBH(OCH,), under Various Conditions 1,2:1,4 selectivity in in in MeOH in THF t substrates MeOH CeCl, + THF ErI, 4a 8:92 93:7 26:14 95:s 4b 50:50 99: 1 11:23 93: 7 catalytic effects2s including Cu2+, column. In our case, the catalytic effect of Ce3+ Mn2+, and cations of the VIIIb is shown in the kinetic curves representing the hydrogen evolved as a function of time (Figures 3 and 4). The reaction is very fast in methanol with 0.5 molar equiv of CeC13 (with respect to NaBH4) and somewhat slower in ethanol: 90% reaction at 40 s in MeOH vs. 60 s in EtOH.26 In isopropyl alcohol only 10% reaction is reached in ca. 180 s. The same experiments were carried out in the presence of 2-cyclopentenone (1 equiv with respect to NaBH4), and the H2 evolution is rep- resented by curve 2 (Figure total gas volume has 3). When compared to curve 1, the to the hydride consumed by the enone reduction. The shape of been reduced by 25%. This factor corresponds the curve suggests as mentioned qualitatively above. Although the initial parts of that this reduction is accomplished very rapidly, curves 1 and 2 suffer from some inaccuracy, they cannot be distinguished from each other. Similar observations are made in the experiments performed in ethanol. The decomposition of BH4- by the solvent thus appears to be the Ln3+ catalyzed rate-determining step. It is therefore highly probable that the actual reducing species is not BH4-, but the derived alkoxy- borohydrides and the following arguments bring some substance to this statement. species BH30R- Alkoxyborohydrides and among them the monosubstituted should be at least in part responsible for the very high reduction are kn~wn~.~' to be more reactive than BH,, and rate in the presence of Ce3+. In methanol, a decrease in the overall concentration (Figure 2) should favor the formation of NaBH4_,(0CH3),, and BH4- is decomposed before reduction of the enone occurs. On concentration, all the other factors being held constant (Figure the other hand, a decrease in the Ce3+ contribution of the alkoxyborohydrides to the overall selectivity. l), lowers the rate of reaction of NaBH4 with methanol and the Reduction of 4 in the presence of Ln3+ occurs slowly in isopropyl alcohol and the selectivity is poor. This can be accounted for by the much slower formation of isopropoxyborohydrides NaBH&,(O-i-Pr),, allowing BH4- to react before it is decomposed. Reductions with trimethoxyborohydride were expected to give some analogies with the results described above and possibly to provide confirmation of the proposed mechanism. The results are given in Table 111. as the reducing species. Comparison In THF solution, NaBH(OCH3)3 is stable enough2 of the regioselectivities to function with and without erbium iodide2* of the lanthanoid ion in an aprotic medium, as shown above with Sm13 in the same on the conjugated system is very important confirms that the complexation effect solvent. In methanol, the results resemble strongly those obtained with NaBH4. It can then be postulated that without Ce3+ trimethoxy derivative is able to disproportionate, in contrast to the the monomethoxy.2b With Ce3+ present, the parallel observed with NaBH4 and NaBH(OCH3)3 species, i.e., methoxyborohydrides, are involved in the reaction. should also indicate that similar as the reduction velocity remain unaffected. Reductions in a (26) In the presence of small amounts of water, the 1,2 selectivity as well alcohol mixture have not been studied. 50-50 H20- thoff, (27) M. Wuesthoff, T. J. Am. M. Chem. T. Tetrahedron SOC. 1970, 92, 1973,29, 6894. 791. Rickborn, B.; Wues- replaced by samarium (28) Cerium chloride is almost insoluble in or erbium iodides. THF. In this solvent, it was J. Am. Chem. SOC., Vol. 103, No. 18, 1981 5451 Chart I1 COzEt - 16a 1fi R1 R1 R:H, p rO R2=OH 1& Rl=OH,Rp=H R1d3 R; '19a - RlRp.0 19b - Ri=OH,Rz=H 19c - Rl=H,Rz=OH Taking into account the solvent complexation effect discussed above, a reasonable mechanistic interpretation can as shown below. be formulated -BH4-n(OR)n t ROH - L\"\" - BH4-p(OR)p RO-... Ro\\ B-H....C=O...H-OR FH) n=0, 1,2;p=n t 1 I \\ )CH-OH I I C I - ,C=\\ OR I (H) C- I L\"3+ works.% From the hard and soft acids and bases (HSAB) theory, Such an interpretation is in good agreement with previous it was deduced that the substitution of hydrides in BH4- groups increases the hardness of the reagent. The attack by alkoxy conjugate enone system is then enhanced at the hard site, Le., of the carbon 2. Ahdd the reduction is related to the hardness of the hydride compound, has also suggested that the stereoselectivity of the harder the reagent, the more favored the axial attack of cyclohexanones. Indeed it was observed that most enone reductions performed in the presence the equatorial alcohols as shown in Table IV with compounds of Ce3+ yielded greater preference of 9a, lla, 12a. 8a, ester, Two noticeable exceptions are piperitone (loa) and Hagemann's the stereoselectivity, while an inversion occurs with the former. 13a. For the latter, the presence of Ce3+ has no effect on NaBH4 in MeOH, or LiAlH4 in diethyl ether, yield a majority (64% In contrast, NaBH4 and 69%, respectively) of the equatorial trans alcohol lob. rise to a majority with CeCI3 in methanol or Sm13 in THF give (65%) of the conformational equilibrium of piperitot~e~~ of the cis alcohol 1Oc. by Ce3+ A modification and the 5458 J. Am. Chem. Soc., Vol. 103, No. 18, 1981 Table IV. Stereoselectivity of the Reduction of Ketones in Methanol Solutiona % of equatorial alcohol ketone without with CeCl, CeC1, carvone (8a) lOOb pulegone (9a) 69 100 piperitone (loa) testosterone (lla) 64c 97 35 12a 90d 99 13a 99e 70 menthone 70 2-methylcyclohexanone (1 Sa) 55f 82 69f 69 4-ferf-butylcyclohexanone (16a) 81; 94 dihydrotestosterone (17a) dihydroisophorone (1 8a) 81 >95 51 camphor (19a) 6 2l 1 8f 68 Figures representing the percentage of equatorial alcohol in the final mixture result from VPC or NMR analysis. Complement to in 100% is the axial alcohol. Reduction of Ea by LiAIH, yields 8b quantitative yield. See ref 30. Without Ce3+, the cumulative yield of allylic alcohols 10b and 1 Oc is 6 1 %, the remaining 39% be- ing neomenthol (14%) and menthol (25%). d See ref 12b. e fef 31. See ref 32. See ref 33. At 65 \"C. See ref 34. See Exo epimer. 86% of the same alcohol with NaBH, in i-PrOH at 0 \"C. See ref 35. increased steric crowding of the reagent can both be invoked to explain this reversal of series For open-chain enones, or cyclopentenones stereoselectivity. in the prostaglandin of Results with a similar order of magnitude were obtained from 20 gave a 20-22, 1:l the stereoselectivity proved to be poor. Reduction mixture of the 9a-OH and 9P-OH A10 alcohols. 2136 In and 22.37 parallel with a-enones, saturated ketones are also attacked on the axial side, with a selectivity enhanced by Ce3+. For ex- ample, dihydroisophorone (Ha) yields a 18:82 equatoriakaxial alcohols equiv of CeC13 under the usual conditions. With ratio of the 1 molar were found, camphor and 2-methylcyclohexanone this ratio shifts to 51:49. Two exceptions again (15a). The conformational mobility is one of the passible explanations of the latter ketone, as in the case of loa, no stereoselectivity change occurs from the presence for the experimental result. That of Ce3+ underscores the complexity of the system38 with the mechanistic interpretation given in this paper. but does not conflict Experimental Section Infrared spectra were taken in CHC13 solution, or as films for liquids with a Beckman Acculab 4 instrument. UV spectra were obtained with a DBT spectrophotometer. NMR spectra were recorded Jeol a PM instrument in CDCl, with Me$ as an internal standard. Resonance on X 60 frequencies 6 are quoted in ppm downfield from Me4Si. Rotations were taken at 22 \"C with a Perkin-Elmer Electronic polarimeter Model 141. GLC analyses were obtained a Carlo Erba Fractovap chromatograph equipped with a Carbowax 20 M 10% Chromosorb WAW on column (2 mm (29) Suga, T.; Imamura, K. (30) Naves, Y. R. Helu. Chim. Bull. Chem. Acta 1964, Soc. Jpn. 1972,45, 2060. 47, 1213 yields only traces (31) Marquet, A.; Viger, A., personal communication. The reduction of 1617. 78, (32) Dauben, W. G.; Fonken, G. of the fi alcohol. J.; Noyce, D. S. J(33) Lansbury, P. T.; MacLeay, 2579. . Am. Chem. Soc. 1956, (34) Ayres, (35) Brown, D. C.; Kirk, R. E. J. Org. Chem. 1963, 28, C.; Muzzio, D. N.; Sawdaye, R. J. J. Am. Chem. J. Chem. SOC. B 1970,505. 1940. 2194. (36) Grieco, P. A.; Williams, H. E.; Sugahara, T. Soc. J. Org. 1966,88, 2811. Chem. 1979, 44, (37) Teixeira, dence a correlation of the stereoselectivity to the conversion percentage. (38) In analogy to the work of Rickborn and Wuesthoff, we tried to evi- M. A. Ph.D. Thesis, Grenoble, 1980. Unreliable results were obtained as quenching of the reaction (aqueous N-saturated NH4CI) of the quencher and NaBH4 is not fast enough. For example, simultaneous aHCI to ca. 40% reduction. Hydroxy borohydrides can thus be present in the to the alcoholic CeCI,-ketone mixture gives rise ddition aqueous medium and compete to an unknown extent in the observed stereo- selectivity. Gemal and Luche i.d. X 2 m) with a 20 mL/min Nz flow. Lanthanoid derivatives and sodium trimethoxyborohydride were used as received from Alfa-Ventron Corp. Sodium borohydride was obtained from Fluka A.G. (Switzerland), or Prolabo. mmol General Procedure for Reductions. The a-enone and LnC13.nHz0 (1 mmol) each) were dissolved in 2.5 mL of methanol. NaBH4 (38 mg, 1 was added in one portion, with stirring. A vigorous gas evolution occurs, together with a temperature rise (-35-40 \"C). Stirring was continued for a few minutes (3-5 min) before the pH was adjusted to neutrality with dilute aqueous HCI, the mixture was extracted (ether) and dried (Na2S04), and the solvent evaporated. The crude residue was analyzed for quantitative determinations by NMR and/or GLC. It was then purified by column chromatography and identified by the usual spectroscopic methods and comparison with authentic samples. The same procedure was followed for experiments under various conditions (variation of the concentration, the solvent or the cation, the relative quantities of Ln3+ or NaBH4). In experiments with time limi- tation (e.g., 15 s) quenching of the reaction was done by rapid addition of aqueous NH4C1 in large excess, followed by the usual workup. Reduction of Cyclopentenone (4a). From 70 mg (0.84 mmol) of the ketone an oil was obtained (75 mg), consisting of almost pure cyclo- pentanol (Sa). IR and NMR spectra agree with published data.39 The NMR spectrum reveals the presence of 10% MeOH (by weight, Le., 7.5 mg). VPC under the specified conditions (t = 90 \"C) shows two peaks at 5.3 min (3%, cyclopentanol) and 6.3 min (97%, Sa) identified by comparison with authentic samples. No peak was observed at 2.6 min (cyclopentanone) and 7.6 min (4a). Reduction of 20a.\" From 280 mg of 20a there were obtained 300 mg of a crude oil, which was chromatographed on silica gel. Fractions of the pure 9a-OH 20b (105 mg), a mixture of 2Ob and 20c (58 mg), and the pure 9BOH 2Oc (90 mg) were collected. The total isolated yield was 90%. 9a-OH epimer 20b: yield 38%; IR (film) 3400, 3060, 3020, 1740, 1725, 1660, 1440, 1030,970,740 cm-'; NMR (CDCI,) H), 4.4 (m, 1 H), 3.9 1 H), 3.55 (s, 3 H), 2.9 (m, 2 H), 2.5-0.8 6 5.7-5.2 (m, 6 21 H). (m, (m, 9P-OH epimer 20c: yield 32%; IR (film) 3400, 3070, 3020, 1735, 1720, 1660, 1460, 1440, 1000, 970, 740 cm-I; NMR (CDCI,) (m. 6 H), 4.2 (m, 1 H), 3.9 (m, 1 H), 3.5 (s, 3 H), 3.2-2.7 (m, 6 5.7-5.2 3 H), 2.5-0.8 cis-Puleeol (9bL Following the given procedure. 150 mg (0.98 (m, 20 H). mmol) of pulegone(9a) Gelded 150 mg ofan oiiisolated after theusual workup and evaporation of the solvents at room temperature. Crystallization occurs \"C [aID on - standing. Washing with pentane yields crystals with mp 29-30 104\" (EtOH, HzO 95:5, c 4) [lit!' mp 31.5 \"C, [aID -107\" (EtOH, c Reduction of Piperitone (loa). From 154 mg (1 mmol) of 10a an oil l)]. (155 mg) was obtained in which VPC shows the presence of 65% cis and 35% trans alcohols. With LiAIH4, cis- and trans-piperitol are formed in a ratio of 36 and 64%, re~pectively.~~ 3-MethylenenorbomeoI(7): IR (film) 3350,3050, 1650, 1440, 1150, 1100, 1070, 1040, 1020, 880 cm-I; NMR (CDCI,) (m, 6 4.9 (br s, 2 H), 4.3 1 H), 2.7 (br s, 1 H), 2.3 (br s, 1 H), 2.0 (s, 1 H), 2.0-1.0 (m, 6 H). VPC analysis (Carbowax 20M, 15 mL Nz/min, 130 \"C) reveals a single peak, which could not be resolved. Reduction by NaBH4 in MeOH.HzO of 6 is known to give mostly the endo Reduction of 13a. From 346 mg (ca. 2 mmol) of 13a the allylic alcohol 13b was obtained in 94% yield (326 mg). The epimeric compo- sition of the mixture was obtained by NMR in the presence of Eu(dpm),. Preparation of CeCl(BH4)z. Anhydrous CeCl, (2.46 g, 10 0.5 g of LiBH4 (22 mmol) are placed in a flask under a dry nitrogen mmol) and atmosphere. Dry THF (60 mL) is slowly added and an exothermic reaction takes place. The heterogeneous mixture is stirred for 30 min and then filtrated on a sintered glass funnel under a nitrogen blanket. The precipitate was washed with benzene and the filtrate evaporated. Dry benzene (150 mL) was added to the residue and the solution was evaporated to reduce the volume to 50 mL. Lithium chloride separated and the supernatant was used in the reductions. The procedure was also used for the preparation of SI~CI(BH,)~ Preparation of Ce(BH,),. Anhydrous CeCI3 (1.24 g, 5 and ErC1(BH4)z. mmol (7 mL) of sodium mmol) in 15 mL of dry methanol was treated with 15 (39) Maercker, A.; Geuss, R. f. (40) Mueller, R. A,, US Patent 3903143; Chem. Ber. Chem. 1973, 106, 773. Abstr. 1975,83,205830 H.; Winkler, (41) Eschinasi, E. H. J. Org. Chem. 1970, 35, (42) Macbeth, A. K.; Shannon, H. Dragoco Rept. 1598. Porsch, (1%3), 10,263; F.; Farnow, JChem. Abstr. 1964,60,8064f. 398, (43) Krieger, H.; Manninen, K.; Paasivirta, J. S. . Chem. Soc. 1952, 2852. 8. J. Suom. Kemistil. E 1966, 1981, 103, 5459-5466 J. Am. Chem. SOC. 5459 methoxide in methanol solution (obtained from 0.5 g of Na and 10 mL of methanol). This addition was followed by 5 mL of THF and 6 mL in THF. After being stirred overnight at room of a 1 M solution of BH3 temperature, the solvent was distilled off and the residue dissolved in 25 mL of benzene. Sodium chloride was decanted and the supernatant used for the reductions. Reductions with Lanthanoid Tetrahydroborates. The keto compound (1 mmol) in 1 mL of THF or methanol under a nitrogen atmosphere was treated by 3 to 5 mL of the reagent solution, stirred for 5-30 min at room temperature, and then hydrolyzed, worked-up as usual, and analyzed by VPC. For example, in THF solution cyclohexenone yields 80% cyclo- hexanol and 20% cyclohexenol. Norcamphor gives 80% of the endo alcohol and 20 of the exo alcohol. Methanolysis of NaBH4 in the Presence of CeC13. A two-necked round-bottom flask (50 mL) was equipped with a magnetic stirring bar, a 20 mL equalized pressure dropping funnel, and a tube connected to a graduated cylinder filled with saturated aqueous NaCI. NaBH, (20 mg) is placed in the flask and 10 mL of a methanol solution of CeCI, in the funnel. The expected total H2 volume is 47 mL. At ro, the solution is added onto NaBH, with vigorous stirring. The gas volume evolved is measured by a direct reading. The estimated error is ca. 5 mL for rapid evolutions and 0.5 mL for slow evolutions. Reproducibility was found under the error limits and the curves result from at least three mea- surements. Acknowledgment. The authors wish to thank G. Ullman and L. Rodriguez-Hahn for their participation to this work and C. A.P.E.S. (Brazil) for a fellowship (A.L.G.). Numerous and fruitful discussions with Dr. A. E. Greene, M. A. Teixeira, and C. Le Drian are acknowledged. Thanks are due to Mrs. A. Marquet and J. Seyden-Penne for their highly valuable comments Hutchins for his corrections and improvements of and to R. 0. the manuscript. Synthesis of Halo Enol Lactones. Mechanism-Based Inactivators of Serine Proteases’ Grant A. Krafft and John A. Katzenellenbogen* Contribution from the Roger Adams Laboratory, School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801. Received January 19, 1981 Abstract: Enol lactones bearing a halogen at the vinylic position are potential mechanism-based inactivators (suicide inactivators) of serine hydrolases, since acyl transfer to the active-site serine releases an a-halo ketone that can react with nucleophilic sites in the active-site region. Efficient syntheses of such halo enol lactones needed for enzymatic studies are described. 5-Hexynoic acids can be cyclized with mercuric ion catalysis to y-methylene butyrolactones. Cyclization of the 6-bromo and 6-chloro analogs leads stereospecifically to the Z-halo enol lactones (trans addition), but is quite slow. Cyclization of unsubstituted 5-hexynoic acids is more rapid, but olefin isomerization occurs during the reaction. or 6-methyl- or 6-trimethylsilyl-substituted Direct halogenation of y-methylene butyrolactones leads to preferential elimination in an endocyclic sense, producing the undesired 5-bromomethylidene-2(3H)-furanones; however, the 5-trimethylsilylmethylene and the 5-mercuriomethylene butyrolactones can be converted with moderate efficiency into the desired 5-bromomethylene butyrolactones. The most efficient approach is direct halolactonization of the 5-hexynoic acids with bromine or iodine in a two-phase system with phase-transfer catalysis. This method was used to prepare various 5-halomethylene or Shaloethylidene 2-phenylbutyrolactones and 6-bromo- and iodomethylene valerolactones. In certain cases where undesired enolization is blocked, y-halomethylene butyrolactones can be prepared by cyclization of a-halo keto acids (e.g., o-(bromomacety1)benzoic acid to 5-bromomethylidenebenze2(5H)-furanone), and certain endocyclic halo enol lactones can be prepared by Baeyer-Villiger oxidation of cyclic 3-halo 2-enones. Preliminary studies indicate that these halo enol lactones have reasonable hydrolytic stability, and, in studies presented elsewhere, selected compounds have been found to be efficient inactivators of chymotrypsin. Introduction Significant attention in recent years has been focused on mechanism-based enzyme inactivators, also known as suicide substrates? Utilizing its catalytic machinery, the targeted enzyme plays the essential role of unmasking a latent reactive functional group contained in the suicide substrate molecule, revealing a reactive electrophilic species for alkylation of the enzyme. The potential for generating reactive species exclusively within the active site of the enzyme imparts a much higher degree of se- lectivity of these inactivators than that exhibited by conventional affinity reagents. Thus, suicide inactivators have found utility in in vitro enzyme studies and in in vivo biochemical investigations? and several have shown promise as clinically useful drugs.4 (1) Preliminary aspects of this work were presented at the 178th National Meeting of the American Chemical Society, Washington, D.C. Sept 1979. (2) See, for instance: (a) Seiler, N.; Jung, M. J.; Koch-Weser, J.; Eds., “Enzyme-Activated Irreversible Inhibitors”; Elsevier/North Holland Amsterdam, 1978. (b) Rando, R. R. Acc. Chem. Res. 1975 Biomedical Press; 8,281. (c) Bloch, K. In “The Enzymes”, (3rd ed.;) Boyer, P., Ed.; Academic H. Maycock, A. L. Press: New York, 1971; Vol. 5, p 441. (d) Abeles, R. Acc. Chem. Res. 1976,9,313. (e) Walsh, C. Horiz. Biochem. Biophys. 1977, Scheme I nuc nuc-enz Ofinuc-enz OH20 enz- OH “fiOI 3; 36. (3) (a) Fisher, J.; Charnias, R.; Knowles, J. R. Biochemistry 1978, 17, 36. Charnas, R.; Fischer, J.; Knowles, J. R. Ibid., 1978, 17, 2185. (b) Wiseman, J.; Abeles, R. Zbid., 1979, 18; 427. (c) Prakash, N. J.; Schechter, P. J.; Mamont, P. S.; Grove, J.; Koch-Weser, J.; Sjoerdsma, A. Life Sci. 1980, 26, In 1974, RandoS proposed that halo enol lactones such as 1, which on hydrolysis form a-halo ketones (Scheme I), might function as suicide inactivators for serine proteases and estereases, by reaction with proximal active-site nucleophiles, ultimately forming the modified (inactivated) enzyme 2. This has prompted us to develop efficient synthetic routes to 1 and to related structures (4) (a) Metcalf, B. W. Biochem. Phurmucol. 1979,28, 1705. (b) Massey, V.; Kamai, H.; Palmer, G.; Elion, G. J. Biol. Chem. 1970, 245, 2387. (5) Rando, R. R. Science 1974, 185, 320. 181. 0002-7863/81/1503-5459$01.25/0 0 1981 American Chemical Society