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Total Synthesis of Phorbazole B molecules Article Total Synthesis of Phorbazole B Yngve Guttormsen 1 , Magnus E. Fairhurst 2, Sunil K. Pandey 2, Johan Isaksson 1 , Article Bengt Erik Haug 2,* and Annette Bayer 1,* Total Synthesis of Phorbazole B 1 Department of Chemistry, UiT The Arctic University of Norway, Hansine Hansens veg 54, 9037 Tromsø, Norway; [email protected] (Y.G.); [email protected] (J.I.) Yngve Guttormsen 1, Magnus E. Fairhurst 2, Sunil K. Pandey 2, Johan Isaksson 1, 2 DepartmentBengt Erik of Haug Chemistry 2,* and andAnnette Centre Bayer for Pharmacy,1,* University of Bergen, Allégaten 41, 5007 Bergen, Norway; [email protected] (M.E.F.); [email protected] (S.K.P.) 1 * Correspondence: Department of [email protected] Chemistry, UiT The Arctic (B.E.H.);University [email protected] of Norway, Hansine Hansens (A.B.); veg 54, Tel.: +47-55-58-34-689037 Tromsø, Norway; (B.E.H.); [email protected]+47-77-64-40-69 (A.B.) (Y.G.); [email protected] (J.I.) 2 Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, Academic Editors:5007 Bergen, Magne Norway; Olav [email protected] Sydnes and Joanne Harvey(M.E.F.); [email protected] (S.K.P.) Received:* 19Correspondence: September 2020; bengt Accepted:[email protected] 18 October (B.E.H.); 2020; [email protected] Published: 21 October(A.B.); 2020 Tel.:+47-55-58-34-68 (B.E.H.); +47-77-64-40-69 (A.B.) Abstract:AcademicPhorbazoles Editors: Magne are polychlorinated Olav Sydnes and Joanne heterocyclic Harvey secondary metabolites isolated from a marine spongeReceived: and several 19 September of these 2020 natural; Accepted: products 18 October have2020; Published: shown inhibitory21 October 2020 activity against cancer cells. In this work, a synthesis of the trichlorinated phorbazole B using late stage electrophilic chlorination Abstract: Phorbazoles are polychlorinated heterocyclic secondary metabolites isolated from a was developed. The synthesis relied on the use of an oxazole precursor, which was protected with an marine sponge and several of these natural products have shown inhibitory activity against cancer iodine incells. the In reactive this work, 4-position, a synthesis followed of the bytrichlorinated complete chlorinationphorbazole B ofusing all pyrrolelate stage positions. electrophilic Attempts to preparechlorination phorbazole was developed. A and C, The which synthesis contain relied a 3,4-dichlorinatedon the use of an oxazole pyrrole, precursor, were which unsuccessful was as the desiredprotected chlorination with an iodine pattern in onthe thereactive pyrrole 4-position could, notfollowed be obtained. by complete The chlorination identities of of theall pyrrole dichlorinated intermediatespositions. and Attempts products to prepare were phorbazole determined A and using C, which NMR contain techniques a 3,4-dichlorinated including pyrrole, NOESY were/ROESY, 1,1-ADEQUATEunsuccessful and as the high-resolution desired chlorination CLIP-HSQMBC. pattern on the pyrrole could not be obtained. The identities of the dichlorinated intermediates and products were determined using NMR techniques including NOESY/ROESY, 1,1-ADEQUATE and high-resolution CLIP-HSQMBC. Keywords: phorbazole; oxazole; pyrrole; late-stage chlorination Keywords: phorbazole; oxazole; pyrrole; late-stage chlorination 1. Introduction 1. Introduction Phorbazoles A–D (1–4, Figure1) are polychlorinated heterocyclic secondary metabolites isolated Phorbazoles A–D (1–4, Figure 1) are polychlorinated heterocyclic secondary metabolites isolated from thefrom marine the marine sponge spongePhorbas Phorbas aff. aff. Clathrata Clathratao offff the the coast of of South South Africa Africa in 1994 in 1994 [1]. [1]. FigureFigure 1. 1.Phorbazoles Phorbazoles A A–D–D (1 (–14–).4 ). The phorbazoles were the first natural compounds isolated with the 2-(2′-pyrrolyl)oxazole The phorbazoles were the first natural compounds isolated with the 2-(20-pyrrolyl)oxazole fragment.fragment. They They were were also also the the first first examplesexamples of ofchlorinated chlorinated pyrroles pyrroles found in found nature. in Later nature. on, a N Later- on, methylated analogue of 1 and the 9-chlorinated analogue of 4 were isolated from the marine mollusk N 1 4 a -methylatedAldisa andersoni analogue [2]. No of bioactivityand the has 9-chlorinated so far been reported analogue for 2– of4, whilewere 1 and isolated its N-methylated from the marine molluskanalogueAldisa andersoni and the 9[-2chlorinated]. No bioactivity analogue has of so4 have far been been reported found to forhave2 –a4 feeding, while deterrence1 and its N effect,-methylated analogue and the 9-chlorinated analogue of 4 have been found to have a feeding deterrence effect, Molecules 2020, 25, x; www.mdpi.com/journal/molecules which suggests that they are involved in chemical defense [2]. The two latter compounds have also been found to inhibit growth of cancer cells in vitro [2]. While the phorbazoles are biosynthetically Molecules 2020, 25, 4848; doi:10.3390/molecules25204848 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 11 Molecules 2020, 25, x 2 of 11 which suggests that they are involved in chemical defense [2]. The two latter compounds have also Moleculesbeenwhich2020 found suggests, 25, 4848 to inhibit that they growth are involvedof cancer in cells chemical in vitro defense [2]. While [2]. Thethe phorbazolestwo latter compounds are biosynthetically have also2 of 10 producedbeen found by to cyclization inhibit growth of dipeptides of cancer of cells tyrosine in vitro and [2].proline, While a synthesisthe phorbazoles of 3 reported are biosynthetically in 2001 relied onproduced a Robinson by cyclization–Gabriel ofcyclodeh dipeptidesydration of tyrosine of a precursorand proline, carrying a synthesis the ofappropriately 3 reported in chlorinated 2001 relied produced by cyclization of dipeptides of tyrosine and proline, a synthesis of 3 reported in 2001 relied on pyrroleon a Robinson [3]. –Gabriel cyclodehydration of a precursor carrying the appropriately chlorinated a Robinson–GabrielpyrroleBreitfussin [3]. cyclodehydrationA–H (5–12, Figure of 2) a precursorconstitute carryingthe second the class appropriately of marine chlorinated natural products pyrrole [3]. BreitfussincontainingBreitfussin A–Hthe pyrroleA (5––H12 (,5-oxazole Figure–12, Figure2 )motif constitute 2) [4,5constitute]. theLike second thethe secondphorbazoles, class ofclass marine ofthe marine naturalbreitfussins natural products are products containinghighly the pyrrole-oxazolehalogenatedcontaining the natural motifpyrrole-oxazole products [4,5]. Like derived motif the phorbazoles,from [4,5]. dipeptide Like the the precursors, phorbazoles, breitfussins but arethewith highly breitfussins tryptophan halogenated areinstead highl naturalofy productstyrosine.halogenated derived natural from dipeptide products derived precursors, from but dipeptide with tryptophan precursors, insteadbut with of tryptophan tyrosine. instead of tyrosine. R2 R5 R2 R5 R3 R6 N N N N 3 6 R1 H R H R O N O N N O N 1 R H O H O O O R4 O Br N Br N H R4 H Br 5 R1 = I, R2N = R3 = R4 = H Br 7 R5 = R6 N= H H H 6 R1 = H, R2 = R4 = H, R3 = Br 11 R5 = H, R6 = Br 5 R1 = I, R2 = R3 = R4 = H 7 R5 = R6 = H 8 R1 = R2 = R3 = R4 = H 12 R5 = Br, R6 = H 6 R1 = H, R2 = R4 = H, R3 = Br 11 R5 = H, R6 = Br 9 R1 = R3 = R4 = H, R2 = H 8 R1 = R2 = R3 = R4 = H 12 R5 = Br, R6 = H 10 R1 = R2 = R3 = H, R4 = I 9 R1 = R3 = R4 = H, R2 = H 1 2 3 4 10 R = RFigure=Figure R = H, 2.R 2.=Breitfussins BreitfussinI s A A–H–H (5 (–512–12). ). Figure 2. Breitfussins A–H (5–12). We haveWe have earlier earlier reported reported on theon the total total syntheses syntheses of of5– 58–,8 which, which were were based based onon thethe utilizationutilization of of two palladium-catalyzedtwo palladiumWe have earlier-cat crossalyzed reported couplings cross on couplings the to total install tosyntheses theinstall indole the of 5indole and–8, which pyrrole and were pyrrole onto based theonto on oxazole the the oxazoleutilization core, core, followed of by halogenationfollowedtwo palladium-catalyzed by ofhalogenation the pyrrole ofcross at the a latecouplingspyrrole stage at inato late theinstall stage case the in of indolethe6 [5 case,6 ].and Anof 6pyrrole alternative[5,6]. An onto alternative synthesisthe oxazole synthesis of core,6 (and by coincidenceoffollowed 6 (and also byby 8halogenationcoincidence) based on applicationalso of the 8) basedpyrrole of on at the application a Robinson–Gabriellate stage ofin thethe Robinsoncase cyclodehydration of 6 [5,6].–Gabriel An alternativecyclodehydration to form synthesis the oxazoleto form the oxazole ring combined with a late stage bromination strategy [7], has also been reported. ring combinedof 6 (and by with coincidence a late stage also bromination8) based on application strategy [ 7of], the has Robinson also been–Gabriel reported. cyclodehydration to formIn the this oxazole work, ring we combined report the with total a latesynthesis stage bromination of 2 via late strategy-stage chlorination [7], has also beenand attemptsreported. at In this work, we report the total synthesis of 2 via late-stage chlorination and attempts at synthesizingIn this work,1 and 3we using report the thesame total strategy. synthesis of 2 via late-stage chlorination and attempts at synthesizing 1 and 3 using the same strategy. synthesizing 1 and 3 using the same strategy. 2. Results and Discussion 2. Results and Discussion 2. Results and Discussion 2.1. Retrosynthetic Analysis of 2 2.1. Retrosynthetic Analysis of 2 2.1. RetrosyntheticWe envisioned Analysis that the of phorbazoles2 should be accessible via chlorination at a late stage, and a Weretrosynthetic envisionedWe envisioned analysis that that the of the2 phorbazoles, which phorbazoles has not should shouldbeen prepared bebe accessible before, viavia is chlorinationshown chlorination in Scheme at a at late 1. a latestage, stage, and a and a retrosyntheticretrosynthetic analysis analysis of 2 of, which2, which has has not not been been prepared prepared before, before, is is shown shown in inScheme Scheme 1.
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