Biomimetic Synthesis of Meroterpenoids by Dearomatization‐Driven Polycyclization

Abstract

Ab iomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical researchc ommunities.Aconcise synthetic route with the potential to access DMOA-derived meroterpenoids is highly desirable to create alibrary of related compounds.Herein, we report novel dearomatization methodology followed by polyene cyclization to access DMOAderived meroterpenoid frameworks in six steps from commercially available starting materials.F urthermore,s everal farnesyl alkene substrates were used to generate structurally novel, DMOA-derived meroterpenoid derivatives.D FT calculations combined with experimentation provided ar ationale for the observed thermodynamic distribution of polycyclization products. Figure 1. a) RepresentativeDMOA-derived meroterpenoid natural products. b) Biosyntheses of the DMOA-derived meroterpenoids.

Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids

“…However, the terminating cation‐quenching step differs for both products, leading to 11 after C−O bond formation and 12 after C−C bond formation. These products were also recently identified from chemical cyclization of rac ‐ 7 by using EtAlCl 2 /Et 2 AlCl as Lewis acid promoter [11] . The [3.3.1] bridged structure in 12 is also found in asperterpenes A and B, recently isolated and potent BACE1 inhibitors from Aspergillus terreus [20] .…”

“…To overcome this limitation, we recently developed a modular synthesis of the widespread 3,5‐dimethylorsellinic acid (DMOA)‐containing substrate family. The methodology involves base‐mediated, regioselective dearomatization of DMOA with farnesyl electrophiles [11] . We expanded the synthetic scope by employing enantiopure (10R)‐ and (10S)‐epoxyfarnesyl building blocks in this reaction to obtain the naturally occurring substrates (10R)‐ and (10S)‐(2E,6E)‐5′‐DMOA methyl ester ( 7 a , 7 b ), as well as (10R)‐ and (10S)‐(2E,6E)‐3′‐DMOA methyl ester ( 8 a , 8 b ).…”

“…In both cases, the same trans ‐ cis configuration is observed for the A/B/C‐ring system (Scheme 2 C). Compounds 19 and 20 have also recently been identified from chemical cyclization where it was further shown that 20 can be rearranged to 19 by formic acid treatment [11] . To confirm the enzymatic origin of 19 , 20 was incubated under enzyme reaction conditions (KPP pH 7.4, 16 h, 30 °C) but was found to not interconvert to 19 .…”

Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids

“…Them ethodology involves base-mediated, regioselective dearomatization of DMOAw ith farnesyl electrophiles. [11] We expanded the synthetic scope by employing enantiopure (10R)-and (10S)-epoxyfarnesyl building blocks in this reaction to obtain the naturally occurring substrates (10R)and (10S)-(2E,6E)-5'-DMOAmethyl ester (7a, 7b), as well as (10R)-and (10S)-(2E,6E)-3'-DMOAm ethyl ester (8a, 8b). Additionally,wealso accessed unnatural substrates including the (2Z,6E)-epoxyfarnesyl congeners (10R)-and (10S)-(2Z,6E)-5'-DMOAm ethyl ester (9a, 9b)a nd (10R)-and (10S)-(2Z,6E)-3'-DMOAm ethyl ester (10 a, 10 b)u sing the same strategy ( Figure S1, Figure 3).…”

“…These products were also recently identified from chemical cyclization of rac-7 by using EtAlCl 2 /Et 2 AlCl as Lewis acid promoter. [11] The[ 3.3.1] bridged structure in 12 is also found in asperterpenes Aa nd B, recently isolated and potent BACE1 inhibitors from Aspergillus terreus. [20] As can be delineated from the configuration of position 5',P yr4 is able to accept both diastereomers,( 10S,5'S)-7a and (10S,5'R)-7a, to form 11 and 12,respectively.The findings suggest that Pyr4, which usually accepts the bulkier substrate 5,e xhibits some degree of promiscuity towards changes in the polyketide portion.…”