Competitive Cationic Pathways and the Asymmetric Synthesis of Aryl-Substituted Cyclopropanes

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol063026p.html

From Prof. Richard E. Taylor's group at the University of Notre Dame, Notre Dame, IN

A new cyclopropanation method specifically for the construction of phenyl vinyl cyclopropane was reported in Org lett ASAP.

The method relied on the cyclization homoallylic alcohol allylic trimethylsilane. The authors previously reported a similar method for cyclopropane formation of alkyl homoallyic alcohol allylic silane in high diasteroeselectivity (trans) on the basis of cationic cyclization pathways with the proposed transitions states as shown in the figures below.

In the current study, a substrate where R group is a simple phenyl group (5d) was first tested. Therefore, the substrate was constructed from benzaldehyde. Brown's asymmetric allylation of aldehyde 3d afforded the homoallylic alcohol 4d in good yield and excellent er (95:5).

Cross-metathesis with allyltrimethylsilane afforded the allylsilane in 86% with modest 66:34 selectivity for the E isomer. The geometry of the double bond does not matter for the selectivity in the cyclopropanation, and therefore the E/Z mixture was used directly. Treatment of 5d with mesyl anhydride furnished cyclopropane 6d in good yield and diastereoselectivity (9:1 trans/cis isomer). The er was determined by conversion of the alkene via a two-step process to the alcohol and the er was measured using 19F NMR of the Mosher ester of the alcohol 8d.

In the cyclopropanation step, it was found necessary to use Ms2O in place of Tf2O (which the authors used in their previous studies) to prevent silyl migration from allylsilane to OH to form Si-O bond, which essentially shut down the cyclopropanation. Scope of the reaction was studied and several phenyl vinyl cyclopropanes could be prepared in good yields, diastereoselectivity, and enantioselectivity. The cyclization substrates 5a-g were prepared in similar fashion to 5d.

The cyclization process was stereospecific - the sterechemistry of the alcohol determined the outcome in the stereochemistry of the cyclopropane, thus the er of the product. Two different cationic pathways are shown below.

In general, the reaction proceeds through the enantiospecific pathway. But when the phenyl group contained a strongly electron-donating group, the ionization of the mesylate to form a more stable benzyl cation could take precedent leading to increase in racemization in products. This problem could be overcome by installing the electron-donating group after cyclopropanation through cross-coupling reaction. The bromophenyl derivative was found to be appropriate.

For example, 9 could be prepared in good yield and diastereo- and enantioselectivities (entry 5 in the table above). This phenyl bromide underwent smooth Kumada coupling and after deprotection with TBAF afforded 8a in virtually identical er to 9. Compare to entry 1 in the table, 8a was obtained in increased er, though through longer number of steps.

Similarly, bromide 9 underwent Hartwig's Pd-catalyzed amination with diethylamine to give the aniline derivative 10 after deprotection with TBAF in good yield and in almost identical er to 9. Although longer number of steps, electron-rich phenyl cyclopropane could be obtained in high overall yield and diastereo- and enantioselectivities.