Imino thioesters

Imino Esters (Imidates), Imino Thioesters, and Their Salts... 

NR2 R — SR3 Imidic acid thioesters (thioimidates, imino thioesters) 7, 12... 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

A second enzyme (of mass 100 kDa) is needed for activation of phenylalanine. It is apparently the activated phenylalanine (which at some point in the process is isomerized from l- to D-phenylalanine) that initiates polymer formation in a manner analogous to that of fatty acid elongation (Fig. 17-12). Initiation occurs when the amino group of the activated phenylalanine (on the second enzyme) attacks the acyl group of the aminoacyl thioester by which the activated proline is held. Next, the freed imino group of proline attacks the activated valine, etc., to form the pentapeptide. Then two pentapeptides are joined and cyclized to give the antibiotic. The sequence is absolutely specific, and it is remarkable that this relatively small enzyme system is able to carry out each step in the proper sequence. Many other peptide antibiotics, such as the bacitracins, tyrocidines,215 and enniatins, are synthesized in a similar way,213 216 217 as are depsipeptides and the immunosuppresant cyclosporin. A virtually identical pattern is observed for formation of polyketides,218 219 whose chemistry is considered in Chapter 21. 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

Mercaptoalkylamines (353) give Az-thiazolines (354) on reaction with esters, imino esters or thioesters. This method has been particularly successful with cysteine and its derivatives (Scheme 224) (16B1110). 

If we put two of these functions on the same carbon, in principle, one may be able to produce a maximum of two C-C bonds in reactions with appropriate carbon nucleophiles. Which functions are these Acetals, thioacetals, aminals, a-dihalidcs, and so on. Then, all of them should be FN = 2 groups. This analogy continues with triheterosubstituted (FN = 3) and tetraheterosubstituted (FN = 4) carbon functions. Unsaturated systems are also classifiable in these terms. Every one knows that a ketone can yield two C-C bonds. This circumstance evolves into the realization that the tt and the a bonds of C=X both serve their individual purpose as potential precursors of C-C bonding. This allows the inclusion of imines, thioketones, and diazocompounds as functions capable of forming a maximum of two (FN = 2) C-C bonds. Similarly, esters, imino- and thioesters, and acyl halides display central carbons with FN = 3, while carbonates, carbamates, ureas, and carbon dioxide are all FN = 4 groupings. 

An alternative elegant native ligation approach has recently been proposed where the Staudinger reaction is exploited to couple the carboxy component as a thioester via trans-thioesterification to a suitable phosphine scaffold that reacts with azidoacyl peptides to produce the imino-X, -phosphine. This chemical ligation is followed by nucleophilic attack by the imino-X -phosphine nitrogen on the thioester to form the amide bondt °°l (Section 2.2.1.10). 

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