Concise and Scalable Total Syntheses of Lamellarin Z and other Natural Lamellarins: Regiocontrolled Assembly of the Central Pyrrole Core and Cross Dehydrogenative Coupling Enroute to the Pentacyclic Coumarin-Pyrrole-Isoquinoline Scaffold

An efficient construction of the central 1,2,4-trisubstituted pyrrole core via one-pot [3+2] cycloaddition/elimination/aromatization sequence-based domino process and subsequent Pd-mediated cross dehydrogenative coupling between the C-H bonds of pyrrole and the peripheral aryl rings enables rapid access to the pentacyclic coumarin-pyrrole-isoquinoline scaffolds which were smoothly elaborated to the targeted lamellarins alkaloids. The total synthesis of lamellarins Z and S with the highest overall yield reported till date, besides the synthesis of several other natural lamellarins have been realized in 5-6 steps with overall yields ranging from 20-27%.


Introduction
Lamellarins constitute one of the most attractive marine pyrrole alkaloids which have engaged the attention of synthetic organic and medicinal chemists for more than past two decades [1,2] and continue to do so [3]. The underlying fact behind the world-wide attention enjoyed by these secondary metabolites is their interesting structural architecture comprising of a highly oxygenated pentacyclic coumarin-pyrroleisoquinoline scaffold, typically in the type I and type II lamellarins ( Figure 1) [4]. Also, the type III lamellarins with a relatively simple non-fused 3,4-diarylated pyrrole core with diverse oxygenation patterns on the aryl rings have been considered attractive targets for total synthesis [5]. Besides striking structural attributes, lamellarins have also equally fascinated the chemists with their interesting bioactivity profile including antitumor activity, multi-drug resistant (MDR) reversal activity in cancer cells, HIV integrase inhibitor activity, antibacterial and antioxidant activity among others [1,4a, 6].
Several reviews pertaining to the synthetic contributions from various groups and SAR development in the context of lamellarins are testimony to the enormous popularity enjoyed by these marine pyrrole alkaloids [1,2,4a,6].
From the total synthesis perspective, most of the approaches reported towards lamellarins could be segregated into two categories. The first category of modular approaches originating from a commercially available pyrrole core involves functionalization of the heterocyclic core enroute to the natural alkaloid; while the second category involves the construction of the functionalized central pyrrole core enroute to the natural product [1b,2a]. Though, most of the second category approaches emanate from isoquinoline derivatives, recently some innovative approaches involving the construction of the pre-functionalized pyrrole core have surfaced in the literature [3a,7]. One such approach was recently reported by us [8], which discloses a novel one-pot domino process involving [3+2] cycloaddition of unactivated aziridine with β-bromo-β-nitrostyrene which interestingly affords 1,2,4trisubstituted pyrrole core in a highly regioselective manner instead of the expected 1,2,3-trisubstituted pyrrole core (Scheme 1) [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].
Scheme 1: One-step domino process for the synthesis of functionalized central pyrrole core.
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 marine pyrrole alkaloids (MPAs).

Results and Discussion
A concise retrosynthetic strategy as depicted in Scheme 2 and similar to the one explored by us earlier [10] to access the targeted type I and type II lamellarins was 5 adopted in order to facilitate the rapid acquisition of the pentacyclic coumarin-pyrroleisoquinoline scaffold. Annulation of aziridine-2-carboxylate (1) with substituted βbromo-β-nitrostyrene (2) as per our reported condition [8] was planned to arrive at the pyrrole-2-carboxylate (3). 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 Pd-mediated cross dehydrogenative coupling (CDC) reaction between sp 2 C-H bonds of central pyrrole core and peripheral aryl rings was conceptualized to arrive at the pentacyclic type I lamellarin scaffold [10,13], from which the type II lamellarin scaffold could also be accessed through a dehydrogenation reaction.

Scheme 2:
Retrosynthetic Strategy towards Type I and Type II lamellarins.
Toward the operationalization of the devised retrosynthetic plan outlined in Scheme 2, initially, we choose to target lamellarins S and Z. In this context, the Nsubstituted aziridine-2-carboxylate (5) was subjected to annulation with β-bromo-βnitrostyrene (6a) as depicted in Scheme 3 under our reported optimized condition [8] to arrive exclusively at the pyrrole-2-carboxylate (7) in good yield. The ethyl ester (7) was then elaborated to the phenyl esters (10a,b) through a 2-step synthetic manoeuvre 6 involving hydrolysis followed by EDC.HCl mediated coupling of the resultant pyrrole-2carboxylic acid (8) with phenol 9a,b [14,15]. After having access to 10a,b we then executed the key Pd-mediated CDC reaction in presence of Cu(OAc)2 as cooxidant to establish two C-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 (11a,b) in moderate yields [10,13]. Subsequently, exhaustive deisopropylation of the isopropyl ethers present on the aryl rings using BCl3 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 [16,17].

Scheme 3:
Total synthesis of lamellarin S and lamellarin Z.
Next, our attention turned towards the synthesis of lamellarins G, L, and N. As highlighted in Scheme 4, a similar reaction sequence as described above was adopted for the other lamellarins. The pyrrole ester (12) accessed from the annulation of the aziridine-2-carboxylate 5 with β-bromo-β-nitrostyrene (6b), was subjected to 7 saponification and subsequently, a coupling of the resultant acid (13) with 9b,c [15,18] to arrive at the phenyl tethered esters (14a,b) in excellent yields. Next, the crucial Pdmediated CDC reaction in presence of Cu(OAc)2 as cooxidant was executed on 14a,b, to arrive at the pentacyclic lactones (15a,b) in moderate yields [10,13]. Lastly, BCl3 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 (15b) first to a DDQ mediated oxidation of the fused dihydroisoquinoline ring, followed by BCl3 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 [19,20]. In our present synthetic endeavour, the final target left was lamellarin D and the substitution pattern present in it dictated for a forward synthesis as captured in Scheme 5. Employing the same aziridine-2-carboxylate (5) as used previously (vide supra), but 8 a different β-bromo-β-nitrostyrene in the form of 6c, the formation of pyrrole ester (17) was facilitated under the optimized condition [8,10]. The pyrrole ester (17) was then elaborated to the phenyl tethered pyrrole-2-carboxylate (19) through a 2 step synthetic protocol via pyrrole-2-carboxylic acid (18). Then, subjection of 19 to the Pd-mediated CDC reaction condition enabled the consecutive C-C bond formation to deliver the pentacyclic isoquinoline-coumarin fused pyrrole 20 [10,13]. With 20 in hand, repetition of a similar sequence of reaction as used for accessing lamellarin N involving DDQ mediated dehydrogenation and BCl3 facilitated deprotection of the isopropyl ethers, effortlessly furnished the targeted lamellarin D in good yield. Also, the NMR spectral data for the synthetic lamellarin D were in close agreement with the reported data [7b].

Conclusion
In conclusion, we have successfully demonstrated the adaptation of our recently disclosed one-pot domino process for the construction of the 1,2,4-trisubstituted central pyrrole core with diverse oxygenation pattern on the aryl rings. Also, a further 9 extension to the pentacyclic lamellarin scaffolds has been demonstrated through a one-pot CDC reaction, thereby enabling a 5-step total synthesis of lamellarins Z and S with the highest overall yields of 27% and 26% respectively, reported till date in the literature. 12,21 Further, the 5-step synthesis of lamellarins G and L accomplished with an overall yield of 26% each, compares reasonably well, either in terms of step economy or overall yield with many of the earlier reported synthesis. Even the 6-step synthesis of lamellarins N and D accomplished with overall yields of 24% and 20% respectively compares satisfactorily with the previous synthetic reports.

3) General procedure for the cross-dehydrogenative coupling (CDC) reaction:
Using the earlier reported procedure, 10,13 an oven-dried schlenk tube was charged with phenyl esters (1 equiv.), Pd(OAc)2 (2 equiv.) and Cu(OAc)2 (6 equiv.) under N2 atmosphere. Then, dimethylacetamide (3 mL/mmol) followed by K2CO3 (2 equiv.) was added maintaining the inert atmosphere and the reaction was allowed to stir at 95 °C for 28-36 h. Upon reaction completion indication by TLC analysis, the reaction was filtered through celite and the celite bed was washed with EtOAc. The filtrates were combined and subjected to solvent removal under reduced pressure to arrive at a crude residue which was purified by SiO2-gel flash column chromatography to access pentacyclic coumarin fused pyrrolo-dihydroisoquinolines.

Supporting Information
1 H and 13 C spectral copies of the synthesized compounds.
Supporting Information File 1: File Name: Supporting Information File Format: PDF