Evolution of a Strategy for the Unified, Asymmetric Total Syntheses of DMOA-Derived Spiromeroterpenoids

Abstract

DMOA-derived spiromeroterpenoids are a group of natural products with complex structures and varied biological activities. Recently, we reported the first enantioselective total synthesis of five spiromeroterpenoids based on a fragment coupling strategy. This full account describes details of a strategy evolution that culminated in successful syntheses of the targeted natural products. Although our alkylative dearomatization methodology was unable to deliver the desired spirocyclic products in our first-generation approach, our second-generation approach based on oxidative [3 + 2] cycloaddition produced the asnovolin H core along with several complex dimers. Challenges with the dearomatization approach finally led us to develop a third generation, non-dearomatization approach based on a fragment coupling strategy to construct the conserved, sterically hindered bis-neopentyl linkage of the spiromeroterpenoids through 1,2-addition. To enable scalable access of the natural products, a refined, multigram-scale synthesis of the coupling partners was developed. A series of stereoselective transformations were developed through judicious choice of reagents and conditions. Finally, modular spirocycle construction logic was demonstrated through the synthesis of a small library of spiromeroterpenoid analogues.

Figure 1.

Representative DMOA-derived spiromeroterpenoids

Figure 2.

Key reactions to form the C1’ all-carbon quaternary carbon center of select meroterpenoids

Figure 3.

First generation dearomatization approach to asnovolin H and subsequent model study

Figure 4.

Second generation approach to asnovolin H

Figure 5.

X-Ray crystal structure of dimer 36 with ellipsoids at the 50% probability level

Figure 6.

Third generation retrosynthesis of asnovolin A

Figure 7.

DFT calculations for the Curtin–Hammett-driven HAT reduction at M06-2X/6-31G(d,p)/PBF (EtOH).

Figure 8.

¹H-NMR study of the Sc(OTf)₃ chelation effect on as-novolin J. top: asnovolin J + Sc(OTf)₃ (3 equiv.), bottom: asnovolin J.

Scheme 1.

Complete biosynthesis for novofumigatonin

Scheme 2.

Oxidative dimerization reactivity of methyl atratate

Scheme 3.

PIDA-mediated oxidative [3+2] cycloaddition.

Scheme 4.

Divergent oxidative cyclization reactivity of differentially protected DMOA substrates

Scheme 5.

Attempted [3+2] cycloaddition using a cyclic carbonate as a possible phenoxonium precursor.

Scheme 6.

Scalable synthesis of DHDMP

Scheme 7.

Interrupted Pummerer reaction for phenol umpolung and application to a DMOA methyl ester substrate.

Scheme 8.

Synthesis of fragments 66 and 67.

Scheme 9.

Forward synthesis of spirocycle 84 and attempted alkene isomerization.

Scheme 10.

Synthesis of key intermediate 80 and collective synthesis of five spiromeroterpenoids.

Scheme 11.

Synthesis of a small spirocycle library