Boron enolates from ketones

Scheme 2.26 Controlled generation of as- and trans-boron enolates from ketones.

The generation of cis-boron enolates from ketones with dialkylboron chlorides and hindered tertiary amines had been known for some time, from the work of Mukaiyama and Evans [13, 48, 87]. However, the synthesis of the corresponding trans-boron enolates remained problematic. Brown addressed this issue, reporting enolization conditions that provide access to either eno-late diastereomer [88]. The stereochemical outcome of ketone enolization was shown to be dependent both on the electronegative group on boron and on the nature of the alkyl substituents. In this regard, the combination of bulky boron ligands (cyclohexyl), a boron chloride derivative, and an unhindered base (EtjN) proved optimal for the stereoselective synthesis of trans-enolates (166) from a variety of ketones (Scheme 4.16). 

Dialkylboron trifluoromethanesulfonates (Inflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazoiidinones. Recentiy, the combination of dicylohexyiboron trifluoromethanesulfonate and triethyiamine was found to effect the enolization of carboxyiic esters. The boron-mediated asymmetric aldoi reaction of carboxyiic esters is particuiariy usefui for the construction of anti p-hydroxy-a-melhyl carbonyl units. The present procedure is a siight modification of that reported by Brown, et ai. ... 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

The most successful imide systems for diastereoselective aldol addition reactions are, without question, the oxazolidinones 50-52 developed by Evans. These furnish syn aldol adducts with superb selectivity for a broad range of substrates (Scheme 4.5) [6, 13, 45-47). A hallmark of these system is that enolization yields exclusively the Z-enolates, which can be understood on the basis of steric considerations. Two important discoveries in the area proved critical to the unparalleled success enjoyed by Evans auxiliaries for diastereoselective aldol addition reactions. The first of these was the disclosure by Mukaiyama that the combination of di-n-butylboryl trifluorometh-anesulfonate (n-Bu2BOTf) and diisopropyl ethyl amine can be employed for the generation of dialkylboron enolates from ketones [48]. The second key observation was by Roster, who observed that aldol additions of boron enolates proceeded with higher levels of simple induction [49], This phenomenon is attributed to the short B-0 distances in the attendant Zimmer-man-Traxler transition state structure [14, 47]. 

It was anticipated that two of the three stereochemical relationships required for intermediate 12 could be created through reaction of the boron enolate derived from imide 21 with a-(benzyloxy)ace-taldehyde 24. After conversion of the syn aldol adduct into enone 23, a substrate-stereocontrolled 1,2-reduction of the C-5 ketone car-... 

Further insight into the P-borylation reaction of a,P-enones (Scheme 2.32) showed that the reaction can be carried out in THF, and the catalyst generated in situ from CuCl (5 mol%), the imidazolium salt (5 mol%), and NaO Bu (10 mol%), to form the [Cu(O Bu) (NHC)] as the catalysis initiating species. In this case, stable boron enolate products are formed which need to be hydrolysed by methanol to the ketone products [114]. 

Z-Boron enolates can also be obtained from silyl enol ethers by reaction with the bromoborane derived from 9-BBN (9-borabicyclo[3.3.1]nonane). This method is necessary for ketones such as 2,2-dimethyl-3-pentanone, which give E-boron enolates by other methods. The Z-stereoisomer is formed from either the Z- or E-silyl enol ether.20... 

Boron enolates can be obtained from esters40,41 and amides42 by methods that are similar to those used for ketones. Various combinations of borylating reagents and amines have been used and the E.Z ratios are dependent on the reagents and conditions. In most cases esters give Z-enolates, which lead to syn adducts, but there are exceptions. Use of branched-chain alcohols increases the amount of anti enolate, and with t-butyl esters the product ratio is higher than 97 3. 

Brown proposed a mechanism where the enolate radical resulting from the radical addition reacts with the trialkylborane to give a boron enolate and a new alkyl radical that can propagate the chain (Scheme 24) [61]. The formation of the intermediate boron enolate was confirmed by H NMR spectroscopy [66,67]. The role of water present in the system is to hydrolyze the boron enolate and to prevent its degradation by undesired free-radical processes. This hydrolysis step is essential when alkynones [68] and acrylonitrile [58] are used as radical traps since the resulting allenes or keteneimines respectively, react readily with radical species. Maillard and Walton have shown by nB NMR, ll NMR und IR spectroscopy, that tri-ethylborane does complex methyl vinyl ketone, acrolein and 3-methylbut-3-en-2-one. They proposed that the reaction of triethylborane with these traps involves complexation of the trap by the Lewis acidic borane prior to conjugate addition [69]. 

Diketones are produced from nitroalkenes and the lithium enolates of ketones. Equation 132 shows the reaction of the enolate of 2-hexanone with 2-nitropropene in the presence of acetic anhydride. The resulting betaine 409, a greenish-blue liquid, is hydrolysed to the diketone by successive treatment with boron trifluoride and water441. 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

A further step towards improved selectivity in aldol condensations is found in the work of David A. Evans. The work of Evans [3a] [14] is based in some early observations from Meyers laboratory [15] and the fact that boron enolates may be readily prepared under mild conditions from ketones and dialkylboron triflates [16]. Detailed investigations with Al-propionylpyrrolidine (31) indicate that the enolisation process (LDA, THE) affords the enolate 32 with at least 97% (Z>diastereoselection (Scheme 9.8). Finally, the observation that the inclusion of potential chelating centres enhance aldol diastereoselection led Evans to study the boron enolates 34 of A(-acyl-2-oxazolidones (33), which allow not only great diastereoselectivity (favouring the 5yn-isomer) in aldol condensations, but offer a possible solution to the problem of enantioselective total syntheses (with selectivities greater than 98%) of complex organic molecules (see below, 9.3.2), by using a recyclisable chiral auxiliary. 

A similar three-component transformation can be achieved using triethylborane-induced radical reactions (Scheme 6.34) [53]. On exposure to air, triethylborane generates the ethyl radical, which abstracts iodine from alkyl iodides to generate the t-butyl radical. Addition of the resulting t-butyl radical to methyl vinyl ketone produces a radical a to the carbonyl group, which is trapped by triethylborane to form a boron enolate with the liberation of ethyl radical, thus creating a chain. 

Simultaneous treatment of a carbonyl compound with a Lewis acid and a tertiary amine or another weak base ( soft enolization ) can sometimes be used to generate enolates of sensitive substrates which would have decomposed under strongly basic reaction conditions [434]. Boron enolates, which readily react with aldehydes at low temperatures, can also be prepared in situ from sensitive, base-labile ketones or carboxylic acid derivatives [293, 295, 299]. Unwanted decomposition of a carbanion may also be prevented by generating it in the presence of an electrophile which will not react with the base (e.g. silyl halides or silyl cyanides [435]). 

The mechanism obviously involves attack by the enol (or boron enolate ) of the ketone on the anhydride, catalysed by the Lewis acid. Probably BF3 or BF2 groups (fluoride can come and go from boron easily) hold the reagent together at all times, much like lithium in the aldol reaction (p. 698). 

Hexafluoroacetone has also demonstrated unusual reactivity when condensed with the boron cnolatc of an optically active oxazolidinone or the boron enolate of the sultam derived from camphorsulfonic acid s to give products 3 and 4, respectively. The absolute stereochemistry of the products 3 and 4 is the opposite of that formed on addition to nonfluorinated ketones and aldehydes. This change was attributed to the involvement of an open transition state in the aldol reaction, a consequence of the diminished basicity of fluorinated carbonyl oxygens. 

Silyl enol ethers, which are readily generated regiospecifically from ketones, can also be reduced to al-kenes, particularly by hydroboration. " Hydroboration of silyl enol ethers results in the addition of boron to the 3-c on of the double bond to afford fra/is-3-trimethylsilyloxy organoboranes, which in cyclic systems undergo anti elimination in the presence of acid to give the alkenic product (Scheme 42). A number of acids have been tested successfully, including carboxylic acids, BF3-Et20 and... 

---