Palladium Catalyzed Stereoselective Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism

Andrew J Paterson,Gabriele Kociok-Köhn,Petter Dunås,Martin Rahm,Simon E Lewis,Per-Ola Norrby,Nina Kann

doi:10.1021/acs.orglett.0c00708

Andrew J Paterson, Gabriele Kociok-Köhn + Show 5 more

Open Access

https://doi.org/10.1021/acs.orglett.0c00708

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Abstract

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a Pd-catalyzed Heck reaction effects a regio- and stereoselective arylation of the cyclohexadiene ring, with 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations explain the selectivity both by a kinetic preference for the observed arylation position and by reversible carbopalladation in competing positions. Further product transformation allowed the formation of a tricyclic ketone possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from planar nonchiral benzoic acid in just a few steps.

Highlights

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification
Letter enzymatic cis-dihydroxylation of benzoic acid. This approach allows for a chirality transfer from the diol moieties of these microbial arene oxidation products to a more distal position, increasing the chiral pool of molecules available by enzymatic dearomatization
The reaction effects coupling of a range of aryl iodides in moderate to excellent yields and selectivity and provides the opportunity to form tricyclic scaffolds via further transformations

Summary

Results and Discussion

Ester 2a (Table 1), with an acetal protected cis-diol, was chosen as a suitable substrate and was Scheme 2. We were gratified to see that using iodobenzene, Pd(OAc)[2], and AgOAc in acetonitrile resulted in the completely regio- and diasteroselective arylation of 2a to form diene 3aa in 60% yield (Table 1, entry 1) Through this reaction, stereochemical information initially present in the diol moiety is transferred to a more distal position. We were delighted to see that the use of p-TsOH in wet acetonitrile led to the formation of tricyclic compound 9 This product, which contains four stereogenic centers, forms with complete diastereoselectivity. It corresponds well to previously reported Heck-type migratory insertion transition states, with an almost fully formed Pd−C bond along with a developing C−C bond.[17] Our calculations predict that TS1 is favored by 1.8 kcal/mol over the second lowest, TS2 If formed, IN5 should proceed to form Heckproduct 10 (Figure 2)

Conclusions

■ ACKNOWLEDGMENTS

■ REFERENCES