Scalable Total Syntheses of Some Natural and Unnatural Lamellarins: Application of a One-Pot Domino Process for Regioselective Access to the Central 1,2,4-Trisubstituted Pyrrole Core

Abstract

Short and scalable total syntheses of lamellarin G trimethyl ether, lamellarin D trimethyl ether, lamellarin H, lamellarin η, dihydrolamellarin η, and lamellarin U have been realized in four to six linear steps with an overall yield of ≤22%. Highlights of the synthesis include single-step access to the central 1,2,4-trisubstituted pyrrole core in a highly regioselective manner via a one-pot [3+2] cycloaddition/ elimination/aromatization sequence-based domino process. Subsequent, palladium-mediated double C−H oxidative coupling in a single-pot operation provides access to the pentacyclic coumarin-fused pyrrolo-dihydroisoquinoline core present in lamellarins.

Concise and Scalable Total Syntheses of Lamellarin Z and other Natural Lamellarins

“…Next, the crucial Pd-mediated CDC reaction in presence of Cu (OAc) 2 as cooxidant was executed on 14 a,b, to arrive at the pentacyclic lactones (15 a,b) in moderate yields. [10,15] Lastly, BCl 3 mediated selective deprotection of the isopropyl ethers present on the aryl rings efficiently furnished lamellarin G and lamellarin L in 88 % yields. On the other hand, the subjection of the pentacyclic lactone (15 b) first to a DDQ mediated oxidation of the fused dihydroisoquinoline ring, followed by BCl 3 mediated selective deprotection of the isopropyl ethers present on the aryl rings in 16, effortlessly delivered lamellarin N. Also, the NMR spectral data for the synthetic lamellarins G, L and N were in close agreement with the reported data.…”

“…Swapping of the alkyl ester in 3 with appropriately substituted phenyl esters through a straightforward 2-step synthetic manoeuvre was the next planned task to access the key intermediate (4). Then, a crucial one-pot Pdmediated cross dehydrogenative coupling (CDC) [14] reaction between sp 2 CÀ H bonds of central pyrrole core and peripheral aryl rings was conceptualized to arrive at the pentacyclic type I lamellarin scaffold, [10,15] from which the type II lamellarin scaffold could also be accessed through a dehydrogenation reaction.…”

“…[16,17] After having access to 10 a,b we then executed the key Pd-mediated CDC reaction in presence of Cu (OAc) 2 as cooxidant to establish two CÀ C bonds in a consecutive manner between the central pyrrole core and the appended phenyl rings in the ester functionality as well as the phenyl ring of phenethyl substitution on the pyrrole-N-atom, to arrive at the pentacyclic lactones (11 a,b) in moderate yields. [10,15] Subsequently, exhaustive deisopropylation of the isopropyl ethers present on the aryl rings using BCl 3 smoothly delivered the target MPAs, lamellarin S and lamellarin Z in excellent yields. The NMR spectral data of the synthetic lamellarins S and Z were found to be in decent agreement with the data reported for the natural products.…”

“…[8,9] Also, subsequent elaboration of the 1,2,4-trisubstituted pyrrole core to several natural and unnatural lamellarins was then demonstrated in an elegant manner with reasonably good overall yield. [10] Our continuing interest in marine pyrrole alkaloids (MPAs) [8,10] gave us the realization that despite numerous synthetic efforts towards various members of the lamellarin family, there still exist some members for which either no chemical synthesis subsists or there are very few reports. This prompted us to further validate the generality and flexibility of our already reported synthetic strategy towards lamellarins by demonstrating its applicability for the total synthesis of lamellarins Z, [11,12] G, and S besides other frequently targeted biologically significant lamellarins L, N and D. In this article, we present the details of our synthetic investigation in the context of these natural MPAs.…”

Synthesis of lactone-fused pyrroles by ruthenium-catalyzed 1,2-carbon migration-cycloisomerization

“…2 Compound 9 is also the intermediate of Lamellarins, and the conversion of 9 into Lamellarin G trimethyl ether 27 and subsequent transformation to Lamellarin H were reported. 28 Therefore, we achieved the formal total synthesis of natural products, Ningalin B and Lamellarin H.…”