Reinvigorating the Chiral Pool: Chemoenzymatic Approaches to Complex Peptides and Terpenoids

Abstract

Biocatalytic transformations that leverage the selectivity and efficiency of enzymes represent powerful tools for the construction of complex natural products. Enabled by innovations in genome mining, bioinformatics, and enzyme engineering, synthetic chemists are now more than ever able to develop and employ enzymes to solve outstanding chemical problems, one of which is the reliable and facile generation of stereochemistry within natural product scaffolds. In recognition of this unmet need, our group has sought to advance novel chemoenzymatic strategies to both expand and reinvigorate the chiral pool. Broadly defined, the chiral pool comprises cheap, enantiopure feedstock chemicals that serve as popular foundations for asymmetric total synthesis. Among these building blocks, amino acids and enantiopure terpenes, whose core structures can be mapped onto several classes of structurally and pharmaceutically intriguing natural products, are of particular interest to the synthetic community.In this Account, we summarize recent efforts from our group in leveraging biocatalytic transformations to expand the chiral pool, as well as efforts toward the efficient application of these transformations in natural products total synthesis, the ultimate testing ground for any novel methodology. First, we describe several examples of enzymatic generation of noncanonical amino acids as means to simplify the synthesis of peptide natural products. By extracting amino acid hydroxylases from native biosynthetic pathways, we obtain efficient access to hydroxylated variants of proline, lysine, arginine, and their derivatives. The newly installed hydroxyl moiety then becomes a chemical handle that can facilitate additional complexity generation, thereby expanding the pool of amino acid-derived building blocks available for peptide synthesis. Next, we present our efforts in enzymatic C-H oxidations of diverse terpene scaffolds, in which traditional chemistry can be combined with strategic applications of biocatalysis to selectively and efficiently derivatize several commercial terpenoid skeletons. The synergistic logic of this approach enables a small handful of synthetic intermediates to provide access to a plethora of terpenoid natural product families. Taken together, these findings demonstrate the advantages of applying enzymes in total synthesis in conjunction with established methodologies, as well as toward the expansion of the chiral pool to enable facile incorporation of stereochemistry during synthetic campaigns.

Figure 1.

Comparison between prior applications of amino acid and terpenes in chiral pool synthesis and the approaches advanced by our group.

Figure 2.

(A) Native function and substrate scope of GriE. (B) Use of GriE in the chemoenzymatic synthesis of manzacidin C (11). (C) Synthesis of various proline analogues via GriE-catalyzed iterative C5 oxidation.

Figure 3.

(A) Chemoenzymatic synthesis of 3-hydroxy-3-methylproline (18) utilizing UcsF and GetF. (B) GriE-enabled synthesis of Fmoc-protected 4-methylproline monomer 21. (C) One-pot solid-phase peptide synthesis of cavinafungin B (22).

Figure 4.

(A) Characterization of lysine hydroxylase GlbB and selected substrate scope. (B) Nine-step total synthesis of cepafungin I empowered by lysine hydroxylation with GlbB. (C) PSMB5 inhibitory assay results with synthetic analogues of 38.

Figure 5.

(A) Characterization and rational engineering of GetI. (B) Retrosynthetic analysis of GE81112 B1.

Figure 6.

(A) Representative α-pyrone meroterpenoids and meroditerpenoids. (B) Retrosynthetic analysis of the two meroterpenoid families.

Figure 7.

Snapshot of platensimycin biosynthesis involving hydroxylases PtmO5 and PtmO6; proposed application of biocatalytic oxidation to the steviol skeleton.

Scheme 1.

Total Chemoenzymatic Synthesis of Tambromycin (37)

Scheme 2.

Total Chemoenzymatic Synthesis of GE81112 B1 and Structure-Activity Relationship of Synthetic Analogues.

Scheme 3.

Enzymatic Hydroxylation in (A) Total Synthesis of α-Pyrone Meroterpenoids from Sclareolide and (B) Total Synthesis of Meroditerpenoids from Sclareol.

Scheme 4.

Applications of Enzymatic C–H Oxidation in (A) Total Synthesis of ent-Kaurane Diterpenes. (B) Carbocationic Rearrangement of the ent-Kaurane Skeleton and Synthetic Studies Toward ent-Atisane Natural Products. (C) Total Synthesis of ent-Trachylobane Natural Products.