Total Synthesis of Aburatubolactam A

Recently Uemura and co-workers described the structure of aburatubolactam A (1, Figure 1), a macrolactam isolated from the culture broth of a Streptomyces sp. bacterium, SCRC-A20, that was separated from a marine mollusk collected near Aburatubo, Kanagawa Prefecture, Japan.[1a] Aburatubolactam A is a member of a growing class of tetramic acid-containing macrolactams including cylindramide A,[1b] geodin A,[1c] xanthobaccin A,[1d] ikarugamycin,[1e] discodermide,[1f] and the alteramides.[1g] These mixed polyketide-amino acid metabolites have been isolated from a number of sources including sponges, marine bacteria and terrestrial bacteria,[2] and display a diverse range of biological activities including cytotoxicity, anti-microbial activity, and inhibition of superoxide generation. In this Communication we describe a synthesis of aburatubolactam A. Figure 1 Structure of Aburatubolactam A (1) and synthesis strategy. Our strategy for the synthesis of aburatubolactam A is based on the coupling of two domains: a subunit containing the bicyclo[3.3.0]octane (2), and a 3-hydroxyornithine-derived subunit (3, Figure 1). The bicyclo[3.3.0]octane ring system was ultimately envisioned to arise from a ring-opening—ring-closing metathesis of functionalized bicyclo[2.2.1]heptene 4. [3,4] The synthesis commenced with a Diels-Alder reaction of commercially available ketone 6 with cyclopentadiene in the presence of 20 mol % of MacMillan's catalyst 8 to give ketone 7 in 65% yield (endo:exo >98:2, 93% ee, Scheme 1).[5] Conversion to the enone 4 was readily achieved in 80% yield by Saegusa oxidation of the trimethylsilyl enol ether derived from 7.[6] When enone 4 was subjected to 2.5 mol% of Grubbs’ catalyst 9 under an ethylene atmosphere, rapid and smooth reorganization to the desired bicyclo[3.3.0]octene 5 occurred in 90% yield.[7] Scheme 1 Synthesis of the bicyclo[3.3.0]octene. a) 20 mol% 8, H2O, 65%; b) LiHMDS, TMSCl, THF then Pd(OAc)2, MeCN, 80%; c) 2.5% 9, CH2=CH2 (1 atm), CH2Cl2, 90%. LiHMDS=lithiumhexamethyl disilazide, TMS=trimethylsilyl. Further elaboration of 5 was accomplished by reduction of both alkenes (Pd/C, H2) to give fused bicyclic ketone 10 in 94% yield (Scheme 2). Introduction of the C6 and C13 side chains was achieved by a sequence beginning with enolate acylation with Mander's reagent,[8] followed by reduction of the ketone with NaBH4. Elimination of the resultant alcohol by mesylation and treatment with sodium hydride in MeOH-THF (5:1) provided 11 in 64% overall yield from 10. The C13 side chain was introduced by employing Majetich's fluoride-mediated Sakurai allylation9 in DMF-DMPU to give 12 in 78% yield as a 4:1 mixture of inseparable C6 diastereomers favoring the undesired stereochemistry (viz 12a). This ratio could be improved to 2:1 in favor of the desired stereochemistry (viz 12b) by protonation of the silylketene acetal derived from 12a with HCl. Subsequent iodolactonization facilitated separation of the diastereoisomers, and gave 13 in 58% yield for the two steps, along with recovered 12a. This sequence also provided a mechanism for recycling material. Treatment of iodolactone 13 with Zn dust in AcOH/EtOH, followed by reduction of the acid with LAH provided alcohol 14 in 86% yield (2 steps). Scheme 2 Elaboration of the bicyclo[3.3.0]octene. a) 10% Pd/C, EtOAc, H2 (balloon), 94%; b) 1. LDA, NCCO2Me, THF-DMPU then NaBH4, MeOH, 74% (2 steps); 2. MsCl, DMAP, Et3N, CH2Cl2 then NaH, THF-MeOH, 87% (2 steps); c) allyltrimethylsilane, TBAF, THF-DMPU, 78%, ... Advancement of alcohol 14 to 2 involved cross metathesis of butene-1,4-diol derivative 16 catalyzed by 15 to give 13 in 95% yield (Scheme 3). Oxidation with Dess-Martin periodinane, followed by olefination with (iodomethylene)triphenylphosphorane under Stork-Zhao[10] conditions provided vinyl iodide 19 in 82% yield. Conversion of the iodide to the stannane by treatment with tert-BuLi in the presence of tributyltin chloride also resulted in removal of the pivalate to give alcohol 20 in 85% yield. Treatment of this alcohol with Dess-Martin periodinane and subsequent Horner-Wadsworth-Emmons reaction yielded stannyl dioxenone 2 in 60% overall yield (2 steps). Scheme 3 Completion of the carbocyclic domain 2. a) 16, 10% 15, CH2Cl2, 95%; b) 1. Dess-Martin periodinane, CH2Cl2; 2. [Ph3P+ CH2I]I-, NaHMDS, THF, 82% (2 steps); c) t-BuLi, Bu3SnCl (internal quench), THF, 85%; d) 1. Dess-Martin periodinane, CH2Cl2; 2. 17, KHMDS, ... The synthesis of the β-hydroxyornithine subunit 3 began with Sharpless asymmetric dihydroxylation of α,β-unsaturated ester 21 to give diol 22 in 90% yield and >98% ee (Scheme 4). Introduction of the nitrogen was achieved by cyclic sulfite formation and opening with sodium azide. Subsequent silylation provided ether 23 in 80% yield over the three steps. Reduction of the azide and nosylation[11] led to 24 in 94% yield, and was followed by introduction of the methyl group by Mitsunobu reaction to give 25, and removal of the nosyl group with thiophenoxide provided amine 3 (82% from 24). Scheme 4 Synthesis of the β-hydroxyornithine subunit. a) AD mix α, 90%; b) 1. SOCl2, Et3N; 2. NaN3, DMF, 55°C; 3. TBSOTf, 2-6-lutidine, CH2Cl2, 80% (3 steps); c) 1. Pd/C, H2, EtOAc; 2. NsCl, i-Pr2NEt, CH2Cl2, 94% (2 steps); d) MeOH, Ph ... After exploring a number of unsuccessful end game strategies that paralleled those employed for cylindramide, the synthesis was completed as shown in Scheme 5.[12] Coupling of the two halves of the molecule was achieved by heating dioxenone 2 with amine 3 in toluene under reflux for 6 hours (Scheme 5). Subjection of the sensitive β-ketoamide product to Stille coupling with tert-butyl-β-iodoacrylate, followed by Lacey-Dieckmann cyclization, led to tetramic acid 26 in 50% yield (over three steps from 2). Macrocyclization was achieved by simultaneous removal of the Boc carbamate and tert-butyl ester with TFA and treatment of the resulting compound with DEPC[ and Et3N in DMF for 12 hours. Removal of the TBS group with HF provided aburatubolactam A in 46% yield for the 3 steps. Data for an analytical sample of synthetic aburatubolactam A obtained by semi-preparative HPLC matched that obtained for an authentic sample provided by Professor Daisuke Uemura. Scheme 5 Completion of the synthesis. a) 1. PhMe, 110 °C; 2. tert-butyl-β-iodoacrylate, Pd2(dba)3, Ph3As, NMP; 3. NaOMe, MeOH, 50% (3 steps); b) 1. TFA, CH2Cl2; 2. DEPC, Et3N, DMF, rt; 3) HF, MeCN, 46% (3 steps). NMP=N-methylpyrrolidinone, TFA=trifluoroacetic ... In conclusion, we have described a 23 step route that leads to aburatubolactam A and that further highlights the utility of tandem metathesis reactions in a target oriented setting.