Enantioselective Synthesis of Azamerone Matthew L. Landry, Grace M. McKenna, Noah Z. Burns* Department of Chemistry, Stanford University, Stanford, California 94305, United States *To whom correspondence should be addressed: [email protected] ABSTRACT: A concise and selective synthesis of the di- and an electronically mismatched late-stage tetrazine chlorinated meroterpenoid azamerone is described. The Diels–Alder reaction were thus identified as the key chal- paucity of tactics for the synthesis of chiral organochlo- lenges for chemical synthesis. rides motivated the development of unique strategies for A. Napyradiomycin meroterpenoids O Me accessing these motifs in enantioenriched forms. The O OH O route features a novel enantioselective chloroetherifica- Cl Cl N Cl tion reaction, a Pd-catalyzed cross-coupling between a N O Me HO Me Me quinone diazide and a boronic hemiester, and a late-stage OH HO O Me Me tetrazine [4+2]-cycloaddition/oxidation cascade. H O Me Me Me Me Me Cl 1: azamerone 2: napyradiomycin A1 OH O Cl The napyradiomycins are a diverse class of halogenated Cl Cl Me O Cl meroterpenoids that have been isolated from terrestrial HO 1 O Me and marine actinomycetes (Figure 1A). Initial isolation HO O Me Me efforts were driven by a desire to identify novel antibiotic O O Me HO scaffolds; the napyradiomycins have since demonstrated H + + Me potent inhibition of gastric (H -K )-ATPase, nonsteroidal Me Me Br estrogen antagonism, cancer cell cytotoxicities, and activ- 3: napyradiomycin B3 4: napyradiomycin C1 ity against Gram-positive bacteria.1c-f Of the 40 members within this class, only napyradiomycin A1 has suc- B. Proposed biosynthesis (Moore) Me O 2 OH O Me O cumbed to synthesis (2, Figure 1A). Syntheses of more Cl Me Cl highly oxidized members of the napyradiomycins, which Me HO Cl+ –CO HO2C 2 feature densely functionalized, chiral halocycle append- O O Me 1 OH [O] Me –H2O ages, remain elusive (e.g. 1 and 3, Figure 1A) and repre- N2 O Me N HO Me Me HN sent inspiring targets for synthetic development. Me Me HO H Me Azamerone is structurally unique among the napyradi- Cl 5: SF2415A1 6 omycins. It is the only known example of a phthalazi- none-containing natural product and the second known C. Azamerone retrosynthesis O Me O 3,4 [4+2] enantioselective Cl chloroetherification example of a pyridazine-containing natural product. O Me N N O Moore has postulated that this nitrogen–nitrogen bond- N N O Me Cl Me containing heterocycle arises from oxidative rearrange- N 8 O 7 3,4 ment of SF2415A1 (5) via intermediate 6 (Figure 1B). N Me HO Me O Me OH X Using 13C- and 15N-labeled precursors, they were able to OH Me O Me show that both nitrogens in azamerone originate from the H C–C bond H Me Me formation Me diazo group in 5. In addition to its unusual hetereocycle, Me Me OH Cl Cl azamerone’s highly oxidized structure, diversity of het- 9 O 10 1: azamerone eroatoms, two chiral sterically-hindered tertiary alcohols, and two distinct chlorine-bearing stereogenic centers Figure 1. (A) Representative napyradiomycin meroterpe- pose significant synthetic challenges. To address these de- noids. (B) Proposed biosynthesis of azamerone. (C) Retro- manding structural elements, we devised a convergent synthetic analysis of azamerone. synthesis of azamerone. We envisaged that azamerone could be retrosynthetically traced to a chlorobenzopyran, Our synthetic approach first required the assembly of tetrazine, and chlorocyclohexane of general forms 7, 8, enantioenriched chlorocycles 7 and 9. Biosynthetically, and 9. A challenging enantioselective chloroetherification chlorocycle motifs found in 7 and 9 are postulated to de- rive from chloronium-initiated cyclizations of the prenyl on trisubstituted olefin-containing hydroxyquinone 10, a 5 hindered carbon–carbon bond formation between 9 and 7, and geranyl fragments within 5 (Figure 1B). Neither of these transformations have enantioselective, synthetic enantioselectivity.6,7 After intensive investigation of po- parallels.6 In fact, the use of enantioselective halogena- tential substrate structures and chiral catalysts, we discov- tion in natural product synthesis has been limited thus far ered that prenylated hydroxyquinone 11 could be chloro- to enantioselective bromochlorination and dichlorination cyclized to a benzochloropyran by a TADDOL-ligated ti- of olefins.2b,6d Cognizant of these methodological gaps tanium complex and tert-butyl hypochlorite in modest and the challenge of chiral organochloride synthesis in yield and 10% ee (entry 1, Table 1). Application of other general, we set out to develop a new method for enanti- common systems for enantioselective chlorofunctionali- oselective chloroetherification to produce a benzochloro- zation returned racemic product.7 Unexpectedly, under pyran akin to 7 and to discover a means for resolving the these conditions ortho-quinone 12 was formed as the ma- enantiomers of chlorocycle 9, which was previously made jor product. Proposed intermediate 13 is consistent with in racemic form (9, X = OAc, Figure 1C).9a our hypothesis in a related dihalogenation system that a Table 1. Enantioselective chloroetherification optimization coordinatively saturated octahedral titanium complex is necessary for high selectivity.6d Chloroether 12 arises via Me Me trapping by the carbonyl oxygen of the vinylogous car- Cl O Me O ClTi(Oi-Pr)3 (25 mol %) boxylate in 14, however titanium is not necessary for such PhO ligand (25 mol %) PhO Me Cl+ source (1.1 equiv) regioselectivity as the racemic product could be produced OH ± additive (1.0 equiv) O in 52% yield solely by the action of tert-butyl hypo- solvent, −78 ℃ O 11 O 12 chlorite (see Supporting Information). We anticipated that 12 could be leveraged as a precursor to a para-quinone Me Me intermediate such as 7 in the synthesis of azamerone and O O thus pursued optimization of this chloroetherification. Me Me PhO stereoselective PhO chlorination Cl Cl A survey of chiral ligands provided optimal TADDOL O O 8 O t-Bu O t-Bu ligand B, which produced chloropyran 11 in increased O Ti O O Ti O 13 Cl 14 Cl yield but with similarly low enantioselectivity (entry 2, O * O * Table 1). Although comparable to ligand A under the con- entrya conditions yield (%) ee (%) ditions of entry 1 and 2, acyclic ligand B proved to be 1 A, t-BuOCl, DCM 29 10 more selective and higher yielding across a broader range 2 B, t-BuOCl, DCM 39 7 of conditions and was selected for further optimization ef- 3 B, t-BuOCl, hexanes 11 <1 forts. Screening of reaction solvents revealed that 2-me- 4 B, t-BuOCl, PhMe 38 16 thyl-tetrahydrofuran increased the selectivity of the chlo- 5 B, t-BuOCl, Et2O 36 14 6 B, t-BuOCl, t-BuOMe 25 16 roetherification to 57% ee (entries 3–8, Table 1). Use of 7 B, t-BuOCl, THF 18 22 other electrophilic chlorine sources led to a reduction in 8 B, t-BuOCl, 2-Me-THF 33 57 the yield or enantioselectivity of the process (entries 8– 9 B, NCS, 2-Me-THF <5 – 10 B, DCDMH, 2-Me-THF 42 33 11, Table 1). Inclusion of heterocyclic base additives, 11 B, Palau’Chlor, 2-Me-THF 28 29 such as pyridine and quinoline, increased the enantiose- 12 B, t-BuOCl, 2-Me-THF, pyridine 20 78 lectivity of chlorocyclization (entries 12, 13, Table 1); the 13 B, t-BuOCl, 2-Me-THF, quinoline 24 81 precise role of these additives is unclear, but they could 14b B, t-BuOCl, 2-Me-THF, quinoline 68 84 15c B, t-BuOCl, 2-Me-THF, quinoline 45 79 serve as general bases, activating agents for transfer of 16c,d B, t-BuOCl, 2-Me-THF, quinoline 40e 84 electrophilic chlorine, or ligands on titanium. Employing Ph Ph Ar Ar O a stoichiometric amount of titanium and chiral ligand pro- Cl O MeO vided only a modest increase in selectivity but a dramatic Me OH OH O N O Cl N N Cl Me OH OH improvement in yield (entry 14, Table 1). Increasing the O MeO N N OMe MeO Me H H Ph Ph Ar Ar Me O amount of tert-butyl hypochlorite to 1.3 equivalents pro- A B: Ar = 2-naphthyl DCDMH Palau’Chlor vided an improvement in yield with 25 mol % titanium and ligand (entry 15, Table 1). Gratifyingly, performing a. Reactions were conducted on 0.035–0.176 mmol scale, the reaction on 4-gram scale under these conditions re- and 1H-NMR yields are reported based on 1,4-dinitroben- sulted in an isolated 40% yield (entry 16, Table 1). zene as internal standard; b. 100 mol % ClTi(Oi-Pr)3, 100 With an enantioselective chloroetherification in hand, mol % B; c. 1.3 equiv t-BuOCl; d. reaction conducted on 4.0 we commenced our synthesis of azamerone. Prenylqui- grams 11; e. isolated yield. none 11, which is made in two steps from commercially De novo development of an enantioselective chloro- available materials, was cyclized to chloropyran 12 using etherification required the identification of a substrate our optimized conditions (Scheme 1). Treatment of re- which was not only amenable to asymmetric halogenation sulting 1,2-dione 12 with aqueous acid on workup in- but also could be parlayed in to a synthesis of azamerone. duced hydrolysis and isomerization to an intermediate 2- Although considerable advances have been made in the hydroxy-para-quinone which was smoothly converted to area of catalytic, enantioselective chlorolactonization and its corresponding 2-chloro-para-quinone 15 with oxalyl chloroetherification, high selectivity has been achieved chloride and DMF. Pyranoquinone 15 is a common motif only for styrenyl substrates; use of non-stabilized olefins which is embedded within all members of the napyradio- is accompanied by a precipitous drop in mycins (e.g.