Synthesis of Azido Analogues of Medermycin

Abstract

The synthesis of azido analogues 2a,2b of the pyranonaphthoquinone antibiotic medermycin 1 has been achieved in eight steps from naphthol 8 and azido glycosyl sugar 7 in 9.3% overall yield. Key steps include the direct BF 3 ×Et 2 O promoted C-glycosylation of naphthol 8, introduction of an acetyl group onto a bromonaphthoquinone via Stille coupling with (a-ethoxyvinyl)tributyltin, furofuran annulation of a naphthoquinone to a furonaphthofuran using 2-trimethylsilyloxyfuran 5 and oxidative rearrangement of a furonaphthofuran to a furonaphthopyran.Medermycin (1) was isolated from Streptomyces tanashiensis and possesses a pyranonaphthoquinone skeleton with an additional b-C-glycoside linkage to the amino sugar, D-angolosamine. 1 Medermycin 1 is highly active against several micro-organisms, 2 is effective against antibiotic resistant cell lines of L5178Y lymphoblastoma and Ehrlich carcinoma in mice, and exhibits inhibition of human leukemia K 562 cells. 3 Platelet aggregation is inhibited by medermycin (1), 4 as is protein and RNA synthesis. 5 The important biological activity reported for medermycin (1) together with its interesting structure, being a member of the pyranonaphthoquinone family of antibiotics 6 that also contains a C-glycoside moiety, renders it a suitable target for synthesis.To date only one long, thirty two step synthesis of medermycin (1) has been achieved by Tatsuta et al. 7 in which the pyranonaphthalene skeleton was assembled via addition of a sulfonyl-phthalide to an enone. The C-glycosidic linkage was introduced as a D-olivoside early in the synthetic sequence before the phthalide annulation step, rendering it necessary to manipulate the functional groups on the sugar moiety to give the desired D-angolosaminide amino sugar at the conclusion of the synthesis. Notably the dimethylamino group on the sugar was introduced via a four step sequence, two of which only proceeded in 37% yield. We therefore herein report an efficient synthesis of an azido analogue 2 of medermycin (1) in which the key C-glycoside linkage was constructed at an early stage in the synthesis using an azido-sugar as a latent dimethylamino group that could be unmasked at a later stage. The synthesis of this azido analogue provides an important analogue for probing structure-activity relationships and the mode of action of this class of compounds that have been proposed to act as bioreductive alkylating agents. 8 Synthetic methodology developed by this research group has established an efficient synthesis of several simpler members of the pyranonaphthoquinone family of antibiotics. [9][10][11] The key steps in these syntheses involved addition of 2-trimethylsilyloxyfuran to an activated 2-acetyl-1,4-naphthoquinone followed by oxidative rearrangement of the resultant furonaphthofuran ring system to a furonaphthopyran ring system. In order to apply this synthetic methodology to the C-glycoside antibiotic, medermycin (1), an effective method to introduce the aryl Cglycoside 12 moiety is required.Our synthetic approach to mederm...

Suzuki–Miyaura homocoupling of naphthyl triflates using bis(pinacolato)diboron: approaches to the biaryl skeleton of crisamicin A

“…Alternatively, 2-acetylnaphthalene 40 could be prepared from acetate 21 via selective bromination at C-2 followed by Stille coupling with α-(ethoxyvinyl)tributylstannane as used by this research group in the synthesis of C-glycosylpyranonaphthoquinones. 5 Unfortunately bromination of acetate 21 took place in the more electron rich ring affording the undesired C-8 bromide 41. In an attempt to direct bromination to the C-2 position naphthol 18 was treated with N-bromosuccinimide and diisopropylamine in dichloromethane, however this resulted in a 79% yield of dimer 42, a product of phenolic coupling formed due to the presence of electron donating groups on naphthol 18.…”

“…The combined organic extracts were washed with water (50 mL) and brine (50 mL) then dried over magnesium sulfate and evaporated to dryness to give a brownish-yellow oil, which was purified by flash column chromatography using 2 : 8 ethyl acetate-hexane as eluent to give the title compound 23 (0.11 g, 89%) as a light yellow solid, mp 79. 5 (13), 191 (19), 149 (5), 91 (100).…”

“…The organic extract was washed with dilute HCl (10 mL) and water (10 mL) then dried over magnesium sulfate and concentrated in vacuo to give a green solid. This solid was purified by flash column chromatography using 2 : 8 ethyl acetatehexane as eluent to give the title compound 17 (14 (7), 191 (100), 175 (10), 147 (8), 119 (5), 91 (7). To a stirred solution of PdCl 2 (dppf ) (43 mg, 0.0053 mmol) in dry 1,2-dichloroethane (0.52 mL), was added triflate 17 (35 mg, 0.089 mmol), dry triethylamine (0.074 mL, 0.533 mmol) and pinacolborane (0.040 mL, 0.266 mmol) under an atmosphere of argon and the mixture heated with stirring at reflux for 1.5 h. The reaction mixture was extracted with ethyl acetate (2 × 20 mL).…”

“…3 Our initial synthetic work in this area focused on the synthesis of the monomeric pyranonaphthoquinone antibiotics via addition of 2-trimethylsilyloxyfuran to a 2-acetyl-1,4-naphthoquinone followed by rearrangement of the resultant furonaphthofuran ring system to a furonaphthopyran ring system using ceric ammonium nitrate (CAN). This approach has been successfully used to prepare analogues of the carbohydrate containing pyranonaphthoquinone antibiotics griseusin A 4 and medermycin 5 as well as simpler members of the family such as the arizonins 6 and kalafungin. 7 The focus of the work reported herein is directed towards the synthesis of the more complex dimeric pyranonaphthoquinones such as actinorhodin 1 and the crisamicins A 2 and C 3.…”

Synthesis of regioisomeric analogues of crisamicin A

“…After stirring for 1 h at 0 ЊC the solvent was removed under reduced pressure to afford an orange oil. Purification by flash column chromatography using ethyl acetate-hexane (2 : 1) as eluent afforded a 1 : 1 mixture of the title adducts 13a and 13b (5 To a vigorously stirred solution of adducts 13a and 13b (5 mg, 0.008 mmol) in acetonitrile (1 cm 3 ) at 0 ЊC was added a solution of ceric ammonium nitrate (18 mg, 0.032 mmol) in water (2 cm 3 ). After 15 min the reaction mixture was extracted with dichloromethane (2 × 10 cm 3 ).…”