Aldol reactions With boron enolates

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

The general trend then is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. They also have the advantage of providing access to both stereoisomeric enol derivatives. Table 2.3 gives a compilation of some of the data on stereoselectivity of aldol reactions with boron enolates. 

Organoaluminum reagents, 202 1,1,1-Trifluoroacetone, 323 Trityllithium, 338 Zinc chloride, 349 Stereoselective aldol reactions With boron enolates Boron trichloride, 43 Chlorodimethoxyborane, 73 9-(Phenylseleno)-9-borabicyclo-[3.3.1]nonane, 245 With silyl enol ethers... 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

Perkins and coworkers reported on stereoselective aldol reactions with boron and titanium ketone enolates (equations 30 and 31) for the construction of a spiroacetal-dihydropyrone (108) related to natural products auripyrone A and Both are cytotoxic... 

The only main Group III metal, other than boron, that has been utilized in the aldol reaction is aluminum, the enolates of which behave rather capriciously in terms of stereochemistry. The A1—C bond is relatively weak. However, aldol reactions with aluminum enolates derived from chiral acyl-iron complexes proceed with high asymmetric induction. 

The synthesis of three fragments 278, 282, and 285 for the C21-C42 bottom segment is summarized in Scheme 41. The Eschenmoser-Claisen rearrangement of amido acetal of 276, which was prepared via 2-bromocyclohexenone by Corey s asymmetric reduction, afforded amide 277. Functional group manipulation including chain elongation provided Evans-type amide 278. The Evans aldol reaction of boron enolate of 279 with aldehyde 280 stereoselectively afforded 281, which was converted into aldehyde 282 through a sequence of seven steps... 

Aldol Reactions. - Seebach et al. have published a detailed study of the diasteroselective aldol reaction of boron enolates, generated from an ethyl ketone by treatment with boron trichloride or an alkoxydichloroborane in the presence of Hunig s base. The reaction was found to occur with ul topicity in selectivities from 90-99%... 

Preparation of the left-hand fragment, which incorporates the C-11 to C-13 portion of 18, utilizes the aldol reaction of / -boron enolate 10 with propionaldehyde to provide the a-hydroxy acid 11 in 85% yield and 100 1 stereoselectivity. Subsequent diazomethane esterification, O-silylations, DIBAL reduction, and Collins oxidation affords the optically pure aldehyde 12 in an overall yield of 75%. 

Excellent results have been obtained by using boron enolates (alkenyloxyboranes or enol borinates), in what is commonly known as a boron-mediated aldol reaction. The boron enolates are prepared easily from the corresponding ketone and a dialkylboron trifluoromethanesulfonate (dialkylboron triflate, R2BOTf) or chloride (R2BCI) and a tertiary amine base. Boron enolates react readily with aldehydes to give, after oxidative work-up of the resulting borinate species, high yields of the desired aldol product (1.58). 

There have been several recent solid-phase and solution-phase libraries reported that contain the spiroketal moiety (Figure 7.5). These libraries introduce additional structural complexity and new interaction modes of carbohydrate-like molecules with biological targets. Ley and cowoikers reported the solid-supported synthesis of spiroketals. Using stereoselective aldol reactions of boron enolates, the Waldmann and Paterson groups reported the solid-phase synthesis of 6,6-spiioketals. The 1,7-dioxaspiro [5.5]undecane spiroketal served as the core template for Porco s three-point diversity library to explore protein-protein interactions. ... 

The driving force of the above-mentioned aldol reaction with boron eno-late is considered to be the interconversion of enol ketones (boron enolates) to their more stable ketones (j5-boryloxy ketones) [17]. When the boron... 

Here we will illustrate the method using a single example. The aldol reaction between an enol boronate and an aldehyde can lead to four possible stereoisomers (Figure 11.32). Many of these reactions proceed with a high degree of diastereoselectivity (i.e. syn anti) and/or enantioselectivity (syn-l syn-Tl and anti-l anti-lT). Bernardi, Capelli, Gennari,... 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Very recently, a tandem sequence consisting of enolboration/hydroform-ylation/aldol reaction has been described [88]. Here configuration of the enol boronate is transferred to the aldol product, allowing good to excellent di-astereoselectivities in the hydroformylation/aldol reaction. With this method, 5-7-membered rings are obtained in excellent yields (Scheme 35). 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

Boron enolates of a-benzyloxy esters.1 The triflate 1 converts alkyl benzyloxy-acetates (2) into the boron enolate, which readily undergoes aldol reactions with high yyn-diastereoselectivity. Somewhat higher syn-selectivity obtains with dicyclopen-tylboryl triflate, whereas use of LDA results in slight anti-selectivity (synlanti=34-37 66-63). Diisopropylethylamine is essential for the aldol reaction. Syn-3 is re-... 

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