Boron aldolate

Boron aldol reactions have been used to stereoselectively construct the anti-3-hydroxy-2-methylcarbonyl system from carboxylate esters,58 and to combine a-hetero-substituted thioacetates with aldehydes or silyl imines enantio- and/or diastereo-selectively.59... 

The final aldol reaction used in our synthesis of spongistatin 1 was one of the more remarkable reactions of this type our group has witnessed over the years. The aldol union of ketone 64 with ( )-4-chloro-2,4-pentadienal 65 required the creation of the (475) stereochemistry in the resultant alcohol 66. Formally, this would require 1,5-syn induction from the ketone 64, which is opposite to that observed previously for boron aldol reactions with simple [i-alkoxy methyl ketones. However, ketone 64 is densely packed with stereocentres, and predicting the influence of these remote centres on the reaction outcome was not possible with any degree of certainty. It was hoped that should 64 display undesirable 1,5-anti bias, this may be overturned by appropriate choice of Ipc ligands on boron. 

Hydrogen bonding and steric effects have been investigated in a theoretical study of the origin of the diastereoselectivity in the remote 1,5-stereoinduction of boron aldol (g) reactions of /3-alkoxy methyl ketones 125 high levels of 1,5-anti-stereocontrol have been achieved in such reactions of tf-methyl-a-alkoxy methyl ketones, giving both Felkin and anti-Felkin products.126 (g)... 

German, C. Vulpetti, A. Pain, G. Highly enantio- and diastereoselective boron aldol reactions of a-heterosubstituted fhioacetates with aldehydes and silyl imines. Tetrahedron 1997, 53, 5909-5924. 

Boron-mediated ketone-ketone aldol reactions have been described, using boron enolates formed with dicyclohexylboron chloride and triethylamine.124 Following addition of the acceptor ketone to form a boron aldolate, oxidation with peroxide yields the aldol product. 

In the synthesis of RK-397 (18), Denmark and Fujimori prepared an anft -diol using the Evans-Chapman-Carreira protocol5 (Scheme 4.2f). The (3-hydroxy ketone 21, obtained by a diastereoselective boron aldol reaction between 19 and 20, was reduced with tetramethylammonium triacetoxyborohydride to afford the anti-diol derivative 22 in greater than 19 ldiastereoselectivity. 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

Murga, J., Falomir, E., Gonzalez, F., Carda, M., Marco, J. A. Influence of the protecting groups on the syn/anti stereoselectivity of boron aldol additions with erythrulose derivatives. A theoretical and experimental study. Tetrahedron 2002, 58, 9697-9707. 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

B. The boron aldol reaction. Into a dry, 2-L flask equipped with a large magnetic stirring bar 1s Introduced 21.2 g (0.091 mol) of the acylated oxazolidinone. The flask is sealed with a rubber septum and swept with nitrogen. The solid is dissolved in 200 mL of anhydrous dichloromethane (Note 6), which is introduced via syringe. A thermometer is inserted through the... 

The diastereoselectivity of the aldol condensation varies with the substituents on the carbonyl precursor to the boron enolate. The boron enolates derived from ketone 274 are shown in Table 9.9.1 1 The lithium enolate of 274 reacted with a boron triflate to give the (Z) enolate 275 and the E) enolate 276. Reaction with an aldehyde gave the syn boron aldolate (277) and the anti boron aldolate (278). The boron aldolates were... 

For the preparation of the imide 2, use Bu2BOTf and EtjN (CH2CI2,0 °C). The boron aldol reaction often benefits from a work-up with H2O2, to cleave the boron-oxygen bond and release the alcohol product. 

SCHEME 20 Boron aldol with a model vinylogous ester. 

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