A Synthetic Route to β‐Hydroxytyrosine‐Derived Tetramic Acids: Total Synthesis of the Fungal Metabolite F‐14329

Abstract

3-Acyltetramic acids derived from β-hydroxytyrosine are synthetically challenging. The first route to this structural motif, based upon a condensation between a Meldrum's acid conjugate bearing the acyl side chain, and a β-hydroxytyrosinate, N-protected by an ortho-nitrobenzyl group is presented. This group enables the Dieckmann cyclization of the resulting N-(β-ketoacyl)amino ester, after which it can be removed photolytically without compromising the delicate 3'-hydroxy group. This strategy was applied to the first total synthesis of the fungal metabolite F-14329 (1).

Synthetic Access to Hydrophilic Tetramate Derivatives of Cysteine

“…[10][11][12][13] New synthetic routes to these compounds continue to be developed. 10,[14][15][16][17] We have previously reported detailed investigations of bicyclic tetramates which have both demonstrated their ease of synthesis and potent antibacterial activity, at least for Gram positive systems, 18 and more recently in particular that cysteine-derived tetramate analogues with functionalisation at C-2 and C-7 are highly effective (Figure 1); 19,20 however, one key limitation of this and much of our earlier work has been the reliance on a t-butyl ring substituent which has been required for good chemical stability of intermediates, since only limited alternatives appear to be tolerated, and especially for O,N-systems. 18 However, the better stability of S,N-systems offered the possibility to move away from such highly hydrophobic substituents, but even in these cases, in vitro activities diminished when tested in presence of blood, suggesting that plasma protein binding might be impacting upon free blood concentration and hence potency.…”

A Highly Effective Route to Si−O−Si Moieties through O‐Silylation of Silanols and Polyhedral Oligomeric Silsesquioxane Silanols with Disilazanes

“…[1][2][3] There are severalm ethods that utilize different silylating agents( e.g., alkoxy-, [4,5] allyl-, [6,7] vinyl-, [8,9] hydro-, [10][11][12][13][14] and halosilanes, [15,16] and others [17,18] )t om odify various functional groups such as ÀOH, ÀSH, and ÀNH. [1][2][3] There are severalm ethods that utilize different silylating agents( e.g., alkoxy-, [4,5] allyl-, [6,7] vinyl-, [8,9] hydro-, [10][11][12][13][14] and halosilanes, [15,16] and others [17,18] )t om odify various functional groups such as ÀOH, ÀSH, and ÀNH.…”

“…Silylationi so ne of the mostu seful transformations in modern chemistry,a nd silyl protectingg roups are some of the most frequentlyu sed in the synthesis of natural products. [1][2][3] There are severalm ethods that utilize different silylating agents( e.g., alkoxy-, [4,5] allyl-, [6,7] vinyl-, [8,9] hydro-, [10][11][12][13][14] and halosilanes, [15,16] and others [17,18] )t om odify various functional groups such as ÀOH, ÀSH, and ÀNH. Amongt his group, disilazanes, especially hexamethyldisilazane (HMDS), seem to be very effective for the silylationo fÀOH groups and have several advantages over other silylating agents, including mild reaction conditions as well as the formation of ammonia as sole byproduct.…”

Synthesis and Bioactivity of a Macrocidin B Stereoisomer

“…In an analogous reaction with carboxylic acid 3 , the corresponding 4- O -acyltetramate formed yet did not rearrange to the desired 3-acyltetramic acid under the same or any other conditions. Therefore, drawing on our experience with the synthesis of F-14329, a 3-acyltetramic acid carrying two stereogenic centers at C-2′ and C-4′, we intended to first N -acylate protected l -tyrosine ester 4 with 5 , a β-ketoacyl derivative of carboxylic acid 3 . This can be obtained from condensation with Meldrum’s acid.…”

“…Carboxylic acid 3 was prepared starting from but-1-en-3,4diol (8). Its primary hydroxy group was TBS-protected, affording allylic alcohol 9.…”