Asymmetric transformations of 1,1-disubstituted alkenes provide important building blocks for chemical synthesis, but are often plagued with low stereoselectivities because it can be difficult for a chiral reagent or catalyst to discriminate between the enantiotopic faces of these substrates. [1] Among the available methods, asymmetric dihydroxylation (AD) stands out as one of the more successful, and can provide high enantioselectivities in certain cases (Scheme 1, 1!2). [2,3] However, low enantioselectivities are usually observed when the two alkene substituents are of similar steric demand. [4,5] A possible solution to this problem is to employ b,b'disubstituted enol derivatives 3 as the substrates, where discrimination of the enantiotopic faces is expected to be more straightforward (Scheme 1, 3!2). An additional benefit of this approach is that asymmetric dihydroxylation results in chiral a-hydroxyaldehydes 4, which are themselves valuable compounds, and which can be reduced to 1,2-diols 2 if required. To ensure high enantioselectivity in the dihydroxylation event, the substrate 3 must be obtained in high stereoisomeric purity. [6] Unfortunately, existing methods to prepare these compounds typically proceed with poor E/Z stereoselectivity, [7][8][9] and the resulting geometric isomers can be difficult to separate.
Partial solutions to these problems have been described recently. [10] Ready and co-workers have developed stereocontrolled syntheses of b,b'-disubstituted enol esters and enol silanes involving carbocupration [10a] or carboalumination [10b] of terminal alkynes, oxidation of the resulting alkenylmetal species using a metal tert-butyl peroxide, and trapping of the resulting enolate with an acylating or silylating agent. [10] Furthermore, asymmetric dihydroxylation of enol benzoates containing methyl substitution on the alkene was demonstrated. [10b] Nevertheless, improvements with these approaches can be envisaged. In the carbocupration procedure, [10a, 11] the organocopper reagents are generated from organolithium or Grignard reagents, which pose restrictions on the functional groups that may be present in the organometallic reagent. Although functionalized organocopper reagents may be obtained from the corresponding organozinc halides, these reagents are poorly reactive towards unactivated terminal alkynes. [12] In addition, because only alkylcopper reagents exhibit sufficient reactivity in alkyne carbocupration, the introduction of important groups such as (hetero)aryl substituents is usually not possible. In the carboalumination procedure, [10b, 13] only methyl groups can be transferred. Therefore, full exploration of asymmetric dihydroxylation of enol derivatives 3 to access chiral a-hydroxyaldehydes 4 and diols 2 is compromised by these limitations.
Our research group has recently developed rhodiumcatalyzed carbometalation reactions that offer solutions to many of these drawbacks. [14] Instead of providing enol derivatives 3, these reactions furnish b,b'-disubstituted enamides 6 [15] from the corresponding ynamides 5 [16] (Scheme 2). Collectively, these processes enable the introduction of alkyl, alkenyl, aryl, heteroaryl, benzyl, and alkynyl groups, and the presence of sensitive functional groups such as esters [14a-c] and ketones [14c] on the organometallic reagent is permitted. Accordingly, asymmetric dihydroxylation of enamides 6 should provide access to a much wider range of chiral products than is possible using comparable methods. [10b] To our knowledge, there are only limited reports of Sharpless asymmetric dihydroxylation of enamides, where cyclic substrates were oxidized with modest ( 77 % ee) enantioselectivities. [17] Herein, we report highly enantioselective dihy-Scheme 1. Asymmetric dihydroxylation (AD) routes to tertiary-alcoholcontaining terminal 1,2-diols 2. Scheme 2. Asymmetric dihydroxylation of enamides prepared by rhodium-catalyzed carbometalation of ynamides. [