Boronic acid-Mannich

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... 

In its most general form, the boronic acid Mannich or Petasis reaction18 involves the reaction of boronic acid 22, a carbonyl compound 8, and an amine 23 to produce secondary amines 24. If one uses a-keto acid 25 for the carbonyl component then the corresponding product from the Petasis reaction was a-amino acid 26. The key mechanistic step was proposed to occur intramolecularly with alkyl migration from intermediate boronate ester 28 formed from aminol 27. 

In its most general form, the boronic acid Mannich or Petasis reaction involves the reaction of boronic acid 96, carbonyl compound 95, and amine 97 to produce secondary amine 98. 

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. 

Subsequent to this, there have been numerous reports of the use of this reaction using alkenyl, alkynyl and arylboronic adds or esters in reactions with a range of amines and aldehydes. This reaction has been variously named the boronic Acid Mannich , boronic Mannich , boro-Mannich , Petasis boronic acid-Mannich , Petasis borono-Mannich , and Petasis" reaction. The more indusive term of Petasis borono-Mannich reaction will be used throughout this chapter. 

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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