Boronic acid, Mannich reactions

Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction. 

The reaction is also referred to as the Boronic Acid Mannich Reaction, since it proceeds via an imine with the organic ligand of the boronic acid acting as the nucleophile, similar to the role of the enolizable ketone component in the original Mannich Reaction. 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

The mechanism of the Petasis boronic acid-Mannich reaction is not fully understood. In the first step of the reaction, upon mixing the carbonyl and the amine components, three possible products can form iminium salt A, diamine B, and a-hydroxy amine C. It was shown that preformed iminium salts do not react with boronic acids. This observation suggests that the reaction does not go through intermediate A. Both intermediate B and C can promote the formation of the product. Most likely, the reaction proceeds through intermediate C, where the hydroxyl group attacks the electrophilic boron leading to an ate -complex. Subsequent vinyl transfer provides the allylic amine along with the boronic acid sideproduct. 

Cytoxazone is a novel cytokine modulator. The total synthesis of this natural product and its enantiomer was accomplished by S. Sugiyama. The 3-amino-1,2-propanediol moiety was synthesized by a Petasis boronic acid-Mannich reaction between DL-glyceraldehyde, (R)-1-(1-naphthyl)ethylamine and 4-methoxyphenylboronic acid to provide a 1 1 mixture of the diastereomeric products. The diastereomers could be separated at a later stage in the synthesis and transformed into (-)- and (+)-cytoxazone. 

R.A. Batey and co-workers developed a modification of the Petasis-boronic acid-Mannich reaction that occurs via N-acyliminium ions derived from A/-protected-2,3-dihydroxypyrrolidine and 2,3-dihydroxypiperidine derivatives. This method was utilized in the total synthesis of (+)-deoxycastanospermine. The formation of the A/-acyliminium ion was achieved by treating A/-Cbz-2,3-pyrrolidine with BF3-OEt2. ° Subsequent vinyl transfer from the alkenylboronic ester provided the product with excellent yield and diastereoselectivity. 

McReynolds, M. D., Hanson, P. R. The three-component boronic acid Mannich reaction structural diversity and stereoselectivity. Chemtracts 200i, 14, 796-801. 

Petasis, N. A., Akritopouiou, i. The boronic acid Mannich reaction a new method for the synthesis of geometricaliy pure aiiyiamines. Tetrahedron Lett. 1993, 34, 583-586. 

Portlock, D. E., Naskar, D., West, L., Li, M. Petasis boronic acid-Mannich reactions of substituted hydrazines synthesis of a-hydrazino... 

Eor pioneering examples, see (a) N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34, 583-586. The boronic acid Mannich reaction a new method for the synthesis of geomet-ricaUy pure aUylamines. (b) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445-446. A new and practical synthesis of a-amino acids from alkenyl boronic acids, (c) N. A. Petasis, A. Goodman, I. A. Zavialov, Tetrahedron 1997, 53, 16463-16470. A new synthesis of a-arylglycines from aryl horonic acids. 

Moreover, recently the boronic acid Mannich reaction, mostly referred to as Petasis reaction [163,164], has evolved as a powerful entry to polyhydroxylated pyrrolizidine, indol-izidine, and tropane alkaloids, among others [165, 166]. For example, Pyne and coworkers disclosed a short total synthesis of calystegine (270) starting from (-)-o-lyxose in 4.7% overall yield (Scheme 11.55), which involved, besides a ring-closing metathesis, the Petasis reaction as key step [167]. In a similar fashion, castanospermine (86) was prepared in 14 steps from (-)-L-xylose in 1.5% overall yield (Scheme 11.55) [168]. 

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