Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 10. trans-2-(1-Methyl-1-phenylethyl)cyclohexanol as a New Auxiliary Scott E. Denmark* and Atli Thorarensen Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801 Received May 17, 1996 The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vinyl ethers has been extensively explored in recent years. 1 To date, the chiral vinyl ethers that have been utilized in the tandem sequence are derived from bornane-2,3-diol, 1, trans-2- phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3, Figure 1. These auxiliaries have served admirably in many aspects of the cycloaddition process, but some limitations still exist, such as the following: (1) length of synthesis, (2) low selectivity in exo mode cycloadditions or (3) unavailability in both enantiomeric series. In the course of a number of total synthesis projects that employ the tandem sequence, we were forced to consider alternatives that addressed some of the limita- tions noted above. 2 In particular, material through-put became an important issue since the critical unmasking of the nitroso acetals to R-hydroxy lactams involves up to a 50% mass loss due to the size of the chiral auxiliaries employed. Thus, it is of critical importance that the auxiliaries be easily prepared and inexpensive. Comins has recently disclosed the use of an easily prepared auxiliary, trans-2-cumylcyclohexanol, 4 (TCC), for the diastereoselective addition of Grignard reagents to alkoxy- pyridines. 3 The preparation of TCC by Comins is con- siderably more simple than that previously reported by Whitesell, making this auxiliary an interesting alterna- tive for use in the nitroalkene cycloaddition chemistry. 4 By analogy with the preparation of the vinyl ethers derived from phenylcyclohexanol, 2, and 2,2-diphenylcy- clopentanol, 3, the transetherification of 4 with a vinyl ether was explored. 5 TCC is a very sterically crowded auxiliary, since the 1-methyl-1-phenylethane presents a larger steric bulk than the phenyl group in 2-phenylcy- clohexanol. Therefore, a higher boiling vinyl ether was required for the trans-etherification. n-Butyl vinyl ether was found to be the vinyl ether of choice as was also the case for 2,2-diphenylcyclopentanol. 6 Optimized reaction conditions employed two portions of 0.6 equiv of mercury- (II) acetate in a dilute solution of n-butyl vinyl ether as solvent, Scheme 1. The vinyl ether, (-)-5, was isolated in 62% yield along with 33% of recovered alcohol, (-)-4. To evaluate the utility of this new auxiliary in the tandem [4 + 2]/[3 + 2] cycloaddition, the nitroalkene 6 was selected as the model substrate since it had been used previously with all the other chiral vinyl ethers. 6 Furthermore, it was imperative to deduce the sense of asymmetric induction exercised by this new auxiliary. We, therefore, needed to establish to which enantiomeric series the final R-hydroxy lactam belonged. Accordingly, slow addition of the nitroalkene 6 to a cold solution of methylaluminum bis(2,6-diphenylphenoxide) (MAPh) 7 and vinyl ether (+)-5 afforded the nitroso acetal 7 in 85% yield, Scheme 2. By 1 H NMR analysis of HC(6) the product composition was estimated to be a 145/1.8/1.0 (exo/exo/endo) mixture of diastereomeric nitroso acetals. The major diastereomer was assumed to have a trans relationship between HC(4a) and HC(6) on the basis of the documented preference of MAPh to promote exo-mode [4 + 2] cycloadditions. 8 The nitroso acetal 7 was then unmasked under the standard hydrogenolysis conditions (Raney nickel/1 atm H 2 /rt/MeOH). The R-hydroxy lac- tam, (-)-8, isolated in 76% yield (along with an (1) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (2) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Org. Chem. 1995, 60, 3574. (3) (a) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656. (b) Comins, D. L.; Salvador, J. M. Tetrahedron Lett. 1993, 34, 801. (c) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1994, 35, 7343. (4) Whitesell, J. K.; Lawrence, R. M. Chimia 1986, 40, 318. (5) The vinyl ether of phenmenthol has been prepared earlier in a two-step procedure, by the preparation of the acetylenic ether followed by a partial reduction. Denmark, S. E.; Senanayake, C. B. W.; Ho, G. D. Tetrahedron 1990, 46, 4857. (6) (a) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859. (b) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thorarensen, A. J. Org. Chem. 1995, 60, 3205. (7) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 4573. (b) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (c) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 9011. (d) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310. (8) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859. Figure 1. Chiral auxiliaries employed in the tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. Scheme 1 Scheme 2 6727 J. Org. Chem. 1996, 61, 6727-6729 S0022-3263(96)00912-7 CCC: $12.00 © 1996 American Chemical Society