SynBio-SynChem Approaches to Diversifying the Pacidamycins through the Exploitation of an Observed Pictet-Spengler Reaction

Abstract

A nonenzymatic Pictet-Spengler reaction has been postulated to give rise to a subset of naturally occurring uridyl peptide antibiotics (UPAs). Here, using a combination of strain engineering and synthetic chemistry, we demonstrate that Pictet-Spengler chemistry may be employed to generate even greater diversity in the UPAs. We use an engineered strain to afford access to meta-tyrosine containing pacidamycin 4. Pictet-Spengler diversification of this compound using a small series of aryl-aldehydes was achieved with some derivatives affording remarkable diastereomeric control.

Keywords: Pictet-Spengler; compound diversification; natural products; pacidamycin; semisynthesis; uridyl peptide antibiotic.

Figure 1

Naturally occurring UPAs: parent compounds and those containing bicyclic residues (TIC and its mono and dimethyl equivalents) at their N termini. Reported MIC₉₀ values against P. aeruginosa are given.[ ² , ³ , ¹¹ ]

Scheme 1

Pictet‐Spengler modification of pacidamycin 4 (1) with a range of substituted benzaldehydes (7–14).

Figure 2

Structures of the products for reaction of pacidamycin 4 (1) with aryl‐aldehydes (7–10).

Figure 3

Structures of products for l‐meta‐tyrosine Pictet‐Spengler reaction with 5‐bromo‐salicylaldehyde.