Publications - Bioorganic Chemistry

Macrocyclic natural products often display remarkable biological activities, and many of these compounds (or their derivatives) are used as drugs. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design. Therefore, a database of naturally occurring macrocycles was analyzed for ring size, molecular weight distribution, and the frequency of some common substructural motifs. The underlying principles of the chemical diversity are reviewed in terms of biosynthetic origin and nature’s strategies for diversity and complexity generation in relation to the structural diversity and similarities found in the macrocycle database. Finally, it is suggested that synthetic chemists should use not only nature’s molecules, but also nature’s strategies as a source of inspiration. To illustrate this, the biosynthesis of macrocycles by non-ribosomal peptide synthetases and terpene and polyketide cyclases, as well as recent advances of these strategies in an integrated synthesis/biotechnology approach are briefly reviewed.

Naturally occurring macrocycles often exhibit remarkable biological activities and, therefore, constitute an attractive starting point for diversity-oriented synthesis for lead discovery in drug development. Multicomponent reactions have been used for the introduction of chemical diversity in strategies towards macrocycle libraries, mostly by combinational synthesis of a linear precursor combined with a subsequent macrocyclization reaction. The Ugi reaction in particular may be used for the macrocyclization itself as well, and a library of natural product-like macrocycles can be constructed in a single step from simple precursors. The efficiency and versatility of both strategies is immense and is exemplarily illustrated by the construction of small libraries of cyclopeptide alkaloid derivatives and biaryl ether macrocycles. The syntheses of the latter compound group are examples of multiple multicomponent macrocyclizations including bifunctional building blocks (M3iB3 or MiB), of which the Ugi-MiBs and their variations are discussed in more detail.

A new method for the stereoselective synthesis of libraries of 2,3,5-trisubstituted tetrahydro-γ-pyrones and the corresponding tetrahydropyran-4-ols is reported. Dienes with a chiral moiety at position 5 were synthesized starting from (triphenylphosphoranylidene)acetone. In hetero-Diels−Alder (HDA) reactions, especially with α,β-unsaturated aldehydes, they induce diastereomeric ratios from 4:1 to 14:1. Through selective epimerization and reduction, further building blocks are available. These constitute ideal starting points for their use in the total synthesis of complex polyketide macrocycles, especially with the vinyl group available for metathetic coupling.

Numerous biologically active macrocycles, including antibiotic, antifungal, and antitumor compounds, have been isolated from natural sources. In recent years the number of such structures has steadily increased, predominantly by polyketide- and peptide-derived compounds from various microorganisms. Macrocycles can combine the right amount of rigidity and flexibility and often exhibit unrivalled activity, thereby deviating from the current paradigm that medicinally active compounds should be small, nitrogen-rich heterocycles. Their challenging structures and intriguing activities have motivated organic chemists to find synthetic access to these compounds. Total synthesis plays a crucial role in the medicinal chemistry efforts towards macrocycles of already defined activity, as well as in the development of new and selective macrocyclization reactions. For lead discovery purposes, however, isolation or classical total synthesis may lack structural variability or prove to be too time consuming and impractical. A more rapid solution may be provided by diversity-oriented synthesis (DOS) of natural product-like molecules. A compromise between total synthesis and combinatorial chemistry, DOS concerns molecules displaying sufficient molecular complexity to resemble natural products, but features a more straightforward synthesis, thus allowing introduction of significant structural diversity. A brief review of flexible macrocyclization strategies and applications of DOS is given, as well as an overview of contributions to total and diversity-oriented synthesis of macrocycles from our laboratory.

Polymer-supported benzylhydrazines were synthesized using poly(ethylene glycol) acrylamide (PEGA) resin. They can be used to scavenge electrophiles reactive with hydrazine. Especially aromatic aldehydes can be captured selectively, monoprotected, and reversibly linked in the presence of other functional groups, including electrophilic ones. Various reactions can be performed on these protectively linked aldehydes, which afterward can be released either with full restoration of the aldehyde function or, alternatively, with simultaneous conversion.

The asymmetric synthesis and kinetic resolution of a series of acyloins (α-hydroxy ketones) suitable as building blocks for the northern half of epothilones was studied. Three methods were applied to obtain nonracemic compounds at the eventual epothilone C15-position: asymmetric synthesis with Evans’ auxiliary, chemical resolution and enzymatic resolution. The success rate in small scale applications increased in the order given, and the enzymatic resolution was studied in more detail. Out of a set of nine lipases and esterases, lipases from Burkholderia cepacia, Pseudomonas sp., lipase B from Candida antarctica and recombinant esterases from Streptomyces diastatochromogenes exhibited the highest enantioselectivities with E-values ranging from 60 to >200. Pig liver esterase exhibited inverse enantiopreference and only with recombinant enzyme could a moderate selectivity (E = 50, commercial PLE: E = 8) be observed.

A series of 16 different 3‐acyloxy methyl ketones, the acyloin acetates and butyrates (±)‐5 , was synthesised by a straightforward new method through alkylation of tert‐butyl 2‐acyloxyacetoacetates 3 , followed by chemoselective dealkoxycarbonylation of the tert‐butyloxycarbonyl group in the presence of other ester groups. Subsequent hydrolysis of (±)‐5 can be achieved with base to give racemic acyloins 6 , or with lipase catalysis to afford the corresponding non‐racemic acyloins (S )‐6 . The remaining (R )‐acyloin esters 5 can be racemised and resubjected to the procedure, or hydrolysed chemically. The kinetic resolution with two of the six tested enzymes, CAL‐B and BCL (PS) lipase, proceeded selectively [enantiomeric ratio (E ) values between 50 and > 200] and most of the acyloins (S )‐6 were obtained in very high enantiomeric excesses (up to > 99% ee ).