Total Synthesis of Nannocystin A

Abstract

Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anticancer properties. Described is the total synthesis of nannocystin A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient assembly of the penultimate open-chain precursor and a pivotal intramolecular Heck cross-coupling for the final macrocyclization.

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

“…Parallel to Xu and Ye's work, we independently achieved total synthesis of 1 [5]. Central to our approach is an intramolecular Heck cross-coupling to forge the strategic C7-C8 bond (Figure 2, method B).…”

“…First, MOM protection of chlorinated tyrosine methyl ester 30 and then amide condensation with 5 (structure shown in Scheme 1) gave, after Boc removal, dipeptide 32 as the first building block. Second, vinylogous Mukaiyama aldol reaction, which is instrumental for asymmetric C-C bond formation in the preceding two syntheses (see Sections 2 and 3) [3,5], again played a key role in the preparation of α,β-unsaturated carboxylic acid 35; but a somewhat differing aspect of Liu's synthesis is the use of dimethyl acetal 33, instead of previously used aldehyde 8 (see Scheme 1), as the electrophilic coupling partner. Thanks to the robustness of Kobayashi's methodology [11] and subsequent improvement by Hosokawa [14,21,22], the reaction produced 34 in 88% yield with a high level of stereoselectivity (diastereomeric ratio (d.r.)…”

“…Ring-closing alkene metathesis as a powerful ring-forming tool was applied by Wang et al in their total synthesis of 1 [4]. This route (Figure 2, method D) seeks piecemeal assemblage of the metathesis precursor 55 from three fragments 49, 27, and 52 (boxed in Scheme 4, the structure of 27 is shown in Scheme 2), among which 27 was also employed in our total synthesis [5] as has been covered in Section 3.…”

“…On behalf of drug discovery, it is not just a prerequisite for SAR study, but a vital way to fine-tune the many physicochemical properties of a natural lead during preclinical development. Thus far seven total syntheses of 1 or 2 have been accomplished [3][4][5][6][7][8][9], with a short summary appearing recently [10]. For efficient macrocycle generation, all synthetic routes embody the principle of convergency.…”

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

“…Consequently, they first planned to connect the north-eastern fragment 5 with the propionate unit 4 by a suitable olefination strategy. Subsequently, for connecting the resulting fragment to the thiazole subunit 6 a Heck reaction was envisioned as part of studies advancing this type of Palladium-catalyzed coupling strategies in complex target synthesis [61–66]. Finally, a HWE-macrocyclization was planned which would likewise set the labile C2–C5 diene and thus concomitantly stabilize this functionality by macrocyclic constraints.…”