From Target-Oriented to Motif-Oriented: A Case Study on Nannocystin Total Synthesis

Abstract

Natural product total synthesis is in essence target-oriented in that a set of organic transformations are orchestrated into a workable process, leading ultimately to the target molecule with a predefined architecture. For a bioactive lead, proof of synthetic viability is merely the beginning. Ensuing effort repurposes the initial synthesis for structural diversification in order to probe structure-activity relationship (SAR). Yet accessibility is not equal to flexibility; moving from convergency to divergency, it is not always feasible to explore the chemical space around a particular substructure of interest simply by tweaking an established route. In this situation, the motif-oriented strategy becomes a superior choice, which gives priority to synthetic flexibility at the concerned site such that a route is adopted only if it is capable of implementing diversification therein. This strategy was recently devised by Fürstner et al., enabling them to achieve total synthesis of both natural and non-natural nannocystins varied at an otherwise challenging position. The present review examines seven distinctive nannocystin total syntheses reported thus far and showcases the merits of conventional (target-oriented) as well as motif-oriented strategies, concluding that these two approaches complement each other and are both indispensable for natural product based drug discovery.

Keywords: macrocyclization; motif-oriented; nannocystin; total synthesis.

Figure 1

Structures of nannocystin A (1) and nannocystin Ax (2).

Figure 2

Key macrocyclization reactions (methods A–G) employed for the total synthesis of 1 and/or 2 [3,4,5,6,7,8,9].

Scheme 1

Total synthesis of 1 by Xu and Ye et al. featuring macrocyclization via Suzuki cross-coupling (Figure 2, method A) [3].

Scheme 2

Total synthesis of 1 by Zhang and Chen et al. featuring macrocyclization via Heck cross-coupling (Figure 2, method B) [5].

Scheme 3

Total synthesis of 2 by Liu et al. featuring macrocyclization via Stille cross-coupling (Figure 2, method C) [6].

Scheme 4

Total synthesis of 1 and nannocystin A0 (56) by Wang et al. featuring macrocyclization via ring-closing alkene metathesis (Figure 2, method D) [4].

Scheme 5

Total synthesis of 1 by Hu and He et al. featuring macrocyclization via macrolactamization (Figure 2, method E) [7].

Scheme 6

Total synthesis of 2 by Kalesse et al. featuring macrocyclization via macrolactamization (Figure 2, method F) [8].

Figure 3

Retrosynthetic analysis of 2 featuring a motif-oriented late-stage diversification strategy.

Scheme 7

Total synthesis of 2 by Fürstner et al. featuring macrocyclization via ring-closing alkyne metathesis (Figure 2, method G) [9].

Figure 4

X-ray single crystal structure of the key intermediate 102 during Fürstner’s total synthesis of 2 [9], with its propargylic alcohol highlighted. (ORTEP representation is drawn at 50% probability for thermal ellipsoids.).

Figure 5

Novel nannocystins 109a–109j prepared during Fürstner’s motif-oriented total synthesis of 2 [9]. The inset table catalogs their preparation conditions.