Total Synthesis of Isokidamycin

Abstract

The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O → C-glycoside rearrangement.

Kidamycin (1) is a member of the pluramycin class of C-aryl glycoside antibiotics that was isolated from Streptomyces phaeoverticillatus and displays a broad range of antibacterial, antifungal and anticancer properties.ⁱ Like other pluramycins, 1 binds to DNA, leading to single strand cleavage.ⁱⁱ Kidamycin possesses an angular anthrapyranone tetracyclic core that is adorned with a β-angolosaminyl C-glycoside substituent at C(8) and an α-N,N-dimethylvancosaminyl C-glycoside group at C(10).ⁱⁱⁱ Kidamycin (1) is both light and acid sensitive and is easily transformed into isokidamycin (2) upon treatment with acid.^iiia,iv No doubt owing to their complex structures and labile functionality, none of the bis-C-arylglycoside antibiotics of the pluramycin family have succumbed to total synthesis. Indeed, few have even dared to embark on such a challenging enterprise.^v

Several years ago we reported a unified strategy for preparing the four major classes of C-aryl glycoside antibiotics.^vi The approach relies on the ring-opening of glycosyl-substituted oxabicycles that are produced by the Diels–Alder reactions of substituted arynes with glycosyl furans. A significant feature of this novel entry to C-aryl glycosides is that it couples the introduction of the C-aryl glycoside moiety with the annelation of a new aromatic ring, thereby leading to a rapid increase in complexity. We subsequently applied this method to the syntheses of several C-aryl glycoside natural products.^vii However, we wished to extend this methodology to the synthesis of a more complex member of the pluramycin family. We now report our efforts in this area that resulted in the total synthesis of isokidamycin (2), the first bis-C-arylglycoside antibiotic to be prepared by total synthesis.

The essential elements of our approach to kidamycin are outlined in Figure 1. Given the known propensity for the N,N-dimethylvancosamine moiety at C(10) of 1 to suffer epimerization at the anomeric center to give 2, we favored the late stage introduction of this residue from the advanced intermediate 3 using the O→C-glycoside rearrangement that had been pioneered by Suzuki and had been shown to be applicable to the preparation of some α-C-aryl glycosides.^viii We envisioned that anthrol 3 would be accessible from 4 by cleavage of the disposable silicon tether, ring-opening of the oxabicycle, and annelation of the substituted pyranone ring. Intermediate 4 would then be formed by the pivotal intramolecular naphthyne-furan cycloaddition that would be initiated by reductive dehalogenation of 5, which would be assembled via the union of the substituted naphthalene 6 and the protected amino glycosyl furan 7.

Figure 1.

Retrosynthesis of kidamycin (1) and isokidamycin (2).

The preparation of 7 began with the Friedel–Crafts alkylation of furan with the known mixture of azidoacetates 9,^ix which were obtained from commercially available glycal 8 and subsequent saponification of the acetate moiety of the intermediate furyl glycoside to deliver 10 in 60% overall yield. (Scheme 1). A straightforward four-step sequence involving protection of the secondary alcohol in 10, reduction of the azide, protection of the resultant primary amine, and N-methylation gave the carbamate 11 in 90% overall yield. The silicon tether, which was to be utilized as the key regiocontrol element in the planned cycloaddition, was then installed by reaction of the lithiated derivative of the glycosyl furan 11 with chlorodimethylvinylsilane to give 12, and subsequent hydroboration/oxidation delivered 7.

Scheme 1^a.

^aReaction conditions: (a) BF₃•OEt₂, furan, MeCN, 78%; (b) K₂CO₃, MeOH, 60%; (c) BnBr, NaH, DMF; (d) LiAlH₄, Et₂O; (e) Boc₂O, CH₂Cl₂; (f) MeI, NaH, DMF, 90% (4 steps); (g) s-BuLi, THF, −78 → − 50 °C; chlorodimethylvinylsilane, −78 °C, 82%; (h) 9-BBN, THF; H₂O₂, NaOH, 84%.

The synthesis of the substituted naphthol 6 commenced with O-benzylation of the known naphthoquinone 13^x (Scheme 2). Sequential bromination and dehydrobromination transformed 13 into 14, which underwent a second bromination and dehydrobromination to provide the dibromonaphthoquinone 15. Reduction of the quinone moiety and selective methylation of the sterically less hindered hydroxyl group furnished naphthol 6 in 90% yield.

Scheme 2^a.

^aReaction conditions: (a) BnBr, Ag₂O, CHCl₃, 91%; (b) Br₂, CH₂Cl₂, then NEt₃, 97%; (c) PyHBr₃, CH₂Cl₂, 0 °C, 90%; (d) Na₂S₂O₄, CH₂Cl₂, Et₂O, H₂O; Me₃OBF₄, proton sponge, 4 Å molecular sieves, CH₂Cl₂, 90%.

The union of the requisite hydroquinone 6 and glycosyl furan 7 was achieved via a facile Mitsunobu etherification to give the key intermediate 5 in 92% yield, thereby setting the stage for the key intramolecular Diels–Alder reaction (Scheme 3). In the event, dropwise addition of n-BuLi to a solution of 5 in THF at −25 °C delivered oxabicycle 4 as a mixture of diastereomers in 92% yield. Subsequent removal of the silicon tether and O-methylation of the resultant naphthol gave 16. Treatment of 16 with TMSOTf induced the opening of the oxabicyclic ring with concomitant cleavage of the N-tert-butyl carbamate protecting group to furnish anthrol 17 in 85% yield. Processing of 17 by reductive N-methylation, TIPS protection of the anthrol, chemoselective hydrogenolysis of the phenolic benzyl group,^xi ortho-bromination and MOM protection of the intermediate anthrol provided 18 in 47% overall yield.

Scheme 3^a.

^aReaction conditions: (a) DIAD, PPh₃, toluene, 92%; (b) n-BuLi, THF, −25 °C, 92%; (c) TBAF•3H₂O, DMF, 70 °C; MeI, NaH, 0 °C, 85%; (d) TMSOTf, 2,6-tBu₂Py, CH₂Cl₂, 0 °C → rt, 85%; (e) formalin, NaBH(OAc)₃, DCE, 95%; (f) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 80%; (g) H₂, Pd(OH)₂/C (20 mol %), pyridine, MeOH, EtOAc, 90%; (h) NBS, CH₂Cl₂, −78 °C → rt, 77%; (i) MOMCl, NaH, THF, 89%.

At this juncture, it was necessary to annelate a pyranone ring, and we opted for an approach entailing the cyclization of a phenolic acetylenic ketone derived from 18 (Scheme 4).^xii We originally envisioned that 18 might be converted into 19 via a carbonylative cross-coupling reaction that we had developed for transforming hindered aryl halides into acetylenic ketones;^xiii however, all attempts to extend this method to the problem at hand were unsuccessful. On the other hand, subjection of 18 to metal–halogen exchange, followed by trapping of the resultant aryl anion with aldehyde 20 and oxidation with BaMnO₄ furnished ketone 19 in 72% overall yield. Formation of the pyranone ring was then achieved by the Lewis acid-promoted cyclization of an intermediate vinylogous diethylamide; subsequent removal of the phenolic TIPS protecting group afforded 3 in about 50% overall yield from 19.

Scheme 4^a.

^aReaction conditions: (a) n-BuLi, THF, −78 °C, 20 s; then (E)-4-methylhex-4-en-2-ynal (20), 75%; (b) BaMnO₄, PhH, 96%; (c) Et₂NH, EtOH, >99%; (d) LiBF₄, 5% aq. MeCN, 82 °C, μW, 15 min; TBAF, THF, 0 °C, 50%.

The stage was then set for introducing a vancosamine subunit onto 3 via a O→C-glycoside rearrangement. It was first necessary to prepare a suitable glycosyl donor, and we targeted 22 because the protecting group strategy we had adopted was originally designed to enable the simultaneous deprotection of multiple functional groups later in the synthesis. Although there are de novo syntheses of vancosamine derivatives,^xiv we elected a more expedient approach that simply entailed degrading vancomycin by straightforward modification of an established protocol,^xv thereby obtaining the vancosamine donor 22 as a mixture (10:1) of α- and β-anomers, respectively, in 76% overall yield (Scheme 5).

Scheme 5^a.

^aReaction conditions: (a) Cbz-O-Succ, NaHCO₃, dioxane, H₂O; (b) HCl, MeOH, 89% (2 steps); (c) HOAc, H₂O, 100 °C, 71%; (d) Ac₂O, pyridine, DMAP, CH₂Cl₂, 85%.

We were cognizant of the fact that there were only a few examples of O→C-glycoside rearrangements that delivered α-C-aryl glycosides, because the highly Lewis acidic reaction conditions typically promotes epimerization of the kinetically formed α-glycoside to the thermodynamically more stable β-C-aryl glycoside.^vc,xvi In exploratory work using model systems, we experienced some success in intercepting the desired α-anomer of a vancosamine-derived C-arylglycoside. However, these model studies did not transfer to the real system. Namely, when anthrol 3 and the vancosamine donor 22 were coupled using a number of Lewis acid promoters, the β,β-bis-C-aryl glycoside was the major, if not exclusive product. After extensive experimentation and optimization, we discovered that reaction of 3 and 22 in the presence of Sc(OTf)₃ as the promoter, followed by O-acetylation of the intermediate phenol furnished 23 in about 80% overall yield (Scheme 6); none of the desired α-anomer was detected. Although the adverse stereochemical outcome of this reaction would not enable us to complete the total synthesis of kidamycin (1), our disappointment was attenuated by the realization that 23 might serve as a viable precursor of isokidamycin (2).

Scheme 6^a.

^aReaction conditions: (a) 22 (4 equiv), Sc(OTf)₃, Drierite, DCE, −30 → 0 °C, 67 h, 80%; (b) Ac₂O, pyridine, DMAP, CH₂Cl₂, >99%; (c) BBr₃, CH₂Cl₂, −90 °C; TMSI, 2,6-tBu₂Py, CH₂Cl₂, 0 °C, then MeOH, pH = 7 phosphate buffer; NaCNBH₃, formalin, HOAc, MeOH, CH₂Cl₂; K₂CO₃, MeOH, 3 h; MeOH, 3 d, 39%; (d) Ce(SO₄)₂, MeCN, H₂O (9:1), 0°C, 51%.

Removal of the protecting groups from the angolosaminyl and vancosaminyl glycosidic subunits in 23 proved to be more challenging than we had anticipated because of a number of interfering side reactions involving the multiple functional groups. Eventually, we discovered a series of manipulations that reliably transformed 23 into the penultimate intermediate 24 in 39% overall yield. The sequence commenced with the removal of the O-benzyl protecting group in 23 with BBr₃. The N-Cbz protecting group was removed with TMSI, the resultant primary amine was reductively methylated, and the phenolic acetate protecting group was cleaved. Removal of the more hindered acetate group on the vancosamine subunit proved to be rather more problematic as the prolonged exposure to base that was required for its cleavage led to rupture of the pyranone ring; however, we discovered that stirring the O-acetyl derivative of 24 in MeOH for 3 days^xvii cleanly afforded 24. Oxidative demethylation of two methoxy groups on the central ring of the anthracene core of 24 then delivered isokidamycin (2) in 51% yield. The synthetic material thus obtained possessed physical properties identical to those reported in the literature and with an authentic sample.^iv,xviii

In summary, the synthesis of isokidamycin (2), which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features an application of our strategy for using silicon tethers as disposable linkers to control the regiochemistry in Diels-Alder reactions of substituted naphthynes and furans in a highly efficient process that couples the formation of a C-arylglycoside with the annelation of a new aromatic ring. Although introduction of the vancosaminyl donor did not proceed with the correct stereochemistry, the work of McDonald suggests that the application of O→C-glycoside rearrangements involving other vancosamine derivatives might lead to a solution to this problem. Further applications of our general approach to complex C-aryl glycoside natural products are in progress, and the results of these investigations will be reported in due course.