Application of Allylzinc Reagents as Nucleophiles in Matteson Homologations

: Allylzinc reagents are versatile nucleophiles that can be used in Matteson homologations. The linear substitution products are formed almost exclusively, and excellent ( E )-selectivities are observed in reactions of reagents with sterically demanding or aryl substituents on the double bond. The allylated boronic esters obtained can be converted into trifluoroborates or subjected to further homologations. Ozonolysis of the double bond provides aldehydes or ketones, and therefore, allyl zinc reagents are useful acetaldehyde or ketone enolate equivalents. . The Matteson homologation, the stereoselective stepwise prolongation of an alkylboronic ester, is an extremely powerful tool in natural product syntheses. 1-3 Addition of (dichloromethyl)lithium to boronic esters generates boronate complexes which undergo 1,2-metallate trans-position to α-chloroalkylboronic esters A (Scheme 1A). 4,5 Excellent stereoselectivities are obtained if chiral diols are used as chiral auxiliaries in the boronic esters. 6-8 The α-chloroalkylboronic esters react further with nucleophiles such as alkyllithium or Grignard reagents. 9 Diastereomeric ratios up to > 99:1 can be obtained in this double homolo-gation sequence, 10 which is extremely appealing for total syntheses. In general, excellent yields are obtained in reactions of lithium or magnesium reagents, but also other nucleophiles can be used, such as alkoxides. 3 Their use allows the direct introduction of protected

The Matteson homologation, the stereoselective stepwise prolongation of an alkylboronic ester, is an extremely powerful tool in natural product syntheses. [1][2][3] Addition of (dichloromethyl)lithium to boronic esters generates boronate complexes which undergo 1,2-metallate transposition to α-chloroalkylboronic esters A (Scheme 1A). 4,5 Excellent stereoselectivities are obtained if chiral diols are used as chiral auxiliaries in the boronic esters. [6][7][8] The αchloroalkylboronic esters react further with nucleophiles such as alkyllithium or Grignard reagents. 9 Diastereomeric ratios up to > 99:1 can be obtained in this double homologation sequence, 10 which is extremely appealing for total syntheses. In general, excellent yields are obtained in reactions of lithium or magnesium reagents, but also other nucleophiles can be used, such as alkoxides. 3 Their use allows the direct introduction of protected hydroxy groups into a growing carbon chain, which is promising, e.g., for carbohydrate 11,12 or polyketide synthesis. [13][14][15] Functionalized C-nucleophiles are also highly appealing, but examples are rare in the literature. Matteson proposed that enolates of sterically hindered esters 16,17 or nitriles 18 could be used as well, but their applications are limited. Recently, we showed that ester dienolates could also be applied in the homologation step giving access to α,βunsaturated esters B in a highly stereoselective fashion (Scheme 1B). 19 Limitations regarding the functional groups likely result from their non-compatibility with the commonly used lithium or magnesium reagents. For example, enolates of ketones or aldehydes cannot be used in Matteson homologations, although they would provide interesting polyketide-type structures, which are generally obtained by stereoselective aldol reactions. [20][21][22][23] An equally useful protocol is the combination of carbonyl allylation and oxidative cleavage of the double bond, providing the same structural motifs. [24][25][26][27] Surprisingly, only a few reported studies have used simple unsubstituted allyl Grignard reagents [28][29][30][31] or prenylmagnesium chloride. 32 Hoffmann et al. used lithiated 1,3dioxene as a nucleophile in reactions of racemic α-chloroalkylboronic esters providing a 1:1 diastereomeric mixture of the corresponding allyl boronate C (Scheme 1C). 33 Interestingly, none of these examples addressed stereoselectivity (olefin geometry) or whether the organometallic reagent reacts in a direct SN-reaction or via allyl inversion, making allylations more complex than normal Grignard reactions. Therefore, we decided to examine these reactions closely (Scheme 1D).
To prove the stereochemical outcome of the homologation, we reacted boronic ester 1 in a one-pot reaction first with (dichloromethyl)lithium and in the second step with allylmagnesium bromide (Scheme 2a). The desired allylated boronic ester 2 was obtained in a very efficient reaction in almost quantitative yield. The allyl Grignard reagent was found to be more reactive than alkyl Grignard reagents. The reaction was complete after 1 h at -78 °C, while other Grignard reagents require hours and sometimes days to react completely. The crude product was directly oxidized Scheme 1. Applications of the Matteson homologation Scheme 2. Matteson homologation using allylmagnesium bromides oxidized to the corresponding alcohol 3, which was determined to be almost enantiomerically pure by HPLC. After obtaining this positive result, we investigated reactions of "substituted" allyl Grignard reagents to determine whether the allylation proceeds via allyl inversion (Scheme 2b). Crotylmagnesium chloride (4a) and 1-methyl-2-propenylmagnesium chloride (4a') are both commercially available, but the identity or quality of these products is uncertain. NMR studies by Grutzner et al. indicated that (E)and (Z)-crotylmagnesium halides are in a fast equilibrium, even at -80 °C. 34 Analogous to the allylation reaction, the first examples with the "methylated" allyl Grignard reagents were conducted according to the one-pot protocol, when the α-chloroboronic ester formed in the first step was directly reacted with the Grignard reagents (Scheme 2). 4a and 4a' proved less reactive than unsubstituted AllylMgBr and full conversion was only reached at room temperature. The linear product (Z)-5 was formed preferentially in slight excess but without significant stereoselectivity. Not surprisingly, almost the same result was obtained with the secondary Grignard reagent 4a'. The isomerization of the allylic Grignard reagents obviously also occurs in Matteson homologations, at least under the reaction conditions used.
If the homologations are conducted as one-pot reactions, it is not certain that the Grignard reagents are exclusively responsible for the outcome of the reactions because, in the presence of lithium and zinc ions, transmetallation might also occur (with or without allyl inversion).
Therefore, we decided to execute the reaction in two steps. The α-chloroboronic ester 7 was synthesized separately 35 and reacted with the crotyl organometallics (Table 1) in a second step. The reactions with the Grignard reagents 4a and 4a' were complete after 4 h at room temperature, and the regioselectivities were comparable. However, under these conditions, the branched product was formed preferentially (entries 1 and 2). Transmetalation with the other ions in solution during the one-pot process seemed to play a role. Therefore, we also investigated the reactions of the corresponding crotyllithium and crotylzinc bromide reagents. Crotyllithium (4b) was prepared according to the literature from crotyl phenyl ether and lithium. 36,37 CrotylZnBr·LiCl (4c) was obtained according to Knochel et al. from trans-crotyl bromide and Zn in the presence of LiCl. This method allows the preparation of substituted allylzinc reagents almost without homocoupling. 38,39 The reaction of the boronic ester 7 with Crotyllithium 4b was completely unselective, independent of the reaction conditions used, and multiple side products were formed which could not be separated from the desired product (entry 3). In contrast, the reaction of the zinc reagent 4c proceeded efficiently with excellent selectivity for the linear substitution product 5 and good (Z)-selectivity (entry 4). Zinc reagents, although not used previously in Matteson reactions, are clearly a promising alternative to the standard Grignard and lithium reagents, especially because of their higher functional group tolerance. 40 To investigate Matteson homologations of substituted allyl zinc reagents in more detail, we converted a wide range of substituted allyl bromides 8 into the corresponding zinc reagents 9 via the Knochel protocol 39 and reacted them with α-chloroboronic ester 7 ( Table 2). The (E/Z)-ratios of 10 were analyzed via NMR. In some cases, the signals of the different isomers that superposed the ratios were determined after oxidation of 10 to the corresponding alcohol. In all cases, the linear, unbranched product 10 was formed almost exclusively (> 96%), and only traces of the branched product could be observed. The (E/Z)-selectivity strongly depended on the substitution pattern of the double bond. While crotylzinc bromide (4c) provided the (Z)product preferentially (Table 1, entry 4), larger alkyl chains generated (E/Z)-mixtures with low selectivity ( Table 2, entries 2 to 4). The product ratio was independent of the allyl bromide used. It is clear that either on the stage of the allylzinc intermediate or the borate complex formed, isomerization occurs. The selectivity towards the (E)product increases with the sterical bulk of the substituent. In the case of the tert-butyl substituted double bond, the (E)-product was formed almost exclusively (entry 6). An excellent (E)-selectivity was also observed with cinnamyl bromide, independent of the double bond geometry of the bromide used (entries 7 and 8).
Next, we investigated the influence of the boronic ester on the outcome of the reaction ( Table 3). As previously, some of the substitution products had to be oxidized to determine the (E/Z)-ratio. The substituent on the boronic ester also influences the (E/Z)-selectivity, although its influence is less than that of the substituent on the double bond. Linear alkyl boronic esters provided the (Z)-products preferentially, while α-branched alkyl substituents yielded a higher (E)product ratio. In general, good to high yields could be obtained; only in one case did the yield drop significantly. The oxidations were also effective, and the relatively low yield of 17c can be explained by the volatility of the alcohol. The conversion as such was quantitative.
To confirm that cinnamyl zinc reagents generally provide (E)-configured linear substitution products almost exclusively, we subjected a series of linear and branched functionalized boronic esters to our optimized reaction conditions. In all cases, we observed only a single set of signals in the NMR spectra, clearly indicating that the diastereoselectivity and the (E/Z)-selectivity was optimal (> 96:4) (Scheme 3). Compound 10g was also used to illustrate that the α-allylated boronic esters can be subjected to further homologations (Scheme 4) and that they can be converted into the corresponding trifluoro borates, 41 which might be used in alkyl-Suzuki couplings 42 or amination reactions. 43 In addition, 82% of the chiral auxiliary DICHED could also be recovered. To confirm our initial idea that allylzinc nucleophiles can be used as aldehyde or ketone enolate equivalents after oxidative cleavage of the double bond, we subjected compounds 10a, 10g, and 27 to ozonolysis. In all cases, we obtained the desired ketone 29a or aldehydes 29b-c after reductive workup. Remarkably, the boronic ester moiety remained unaffected by oxidative ozonolysis. (Scheme 5). In conclusion, we showed that allylzinc reagents are versatile nucleophiles that can be used in Matteson homologations. The linear substitution products were formed almost exclusively, in contrast to when other allyl organometallics were used. Excellent (E)-selectivities were observed in reactions of allyl reagents with sterically demanding or aryl substituents, independent of the boronic ester used. The allylated boronic esters obtained could be subjected to further homologations, while ozonolysis of the double bond produced aldehydes or ketones, depending on the substitution pattern. Therefore, the allyl zinc reagents can be used as acetaldehyde or ketone enolate equivalents, a synthetically useful approach. Applications of this protocol in natural product synthesis are currently under investigation.

Supporting Information
Detailed experimental procedures and copies of 1 H and 13 C NMR spectra, HPLC and GC chromatograms. The Supporting Information is available free of charge on the ACS Publications website.

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