Studies toward the synthesis of angularly-oxygenated angucyclines antibiotics

The [bis(trifluoroacetoxy)]iodobenzene-mediated oxidative dearomatization of 2-alkoxyarenols, followed in situ by trapping of the resulting arenoxenium ions by soft external carbon-based nucleophiles, constitutes a rapid access to highly functionalized naphthoid cyclohexa-2,4-dienones. These synthons can serve as valuable intermediates in the construction of the angularly-oxygenated benz[ a ]anthraquinone ABCD tetracyclic ring system of aquayamycin-like angucyclinones. This methodology so far has led to the elaboration of five-membered ring analogues of the ABC tricyclic unit of these natural products.


Introduction
Angucyclines along with tetracyclines and anthracyclines are the third class of natural antibiotics featuring a carbotetracyclic skeleton. 1,2These natural products are isolated from the fermentation broth of Actinomycetes; they feature a benz[a]anthraquinone framework with varying degree of insaturation and oxygenation, and display a broad spectrum of biological activities including antitumor, antifungal and antiviral properties. 1,2Their structural diversity has provided organic chemists with attractive targets for the development of various synthetic methodologies.Until now, most synthetic efforts have been directed toward angucyclines with an aromatic B ring.4][15][16][17][18][19][20][21][22] However, angucyclines bearing two hydroxy groups at the AB ring junction positions (Figure 1) hold a special status among these targets because (1) their total synthesis still constitutes a real challenge and (2) their biological activities [23][24][25][26][27][28][29] are the most therapeutically significant ones e.g., exhibiting antitumor activity against adriamycin-and doxorubicin-resistant P388 leukemia cells. 1,30In this subclass, two groups are distinguished: angucyclines without and with a C-glycosidic moiety, exemplified by the angucyclinones SS-228Y (1) and aquayamycine (2), respectively.Inhibition of dopamine β-hydrolase has been reported for both 1 (62.5% at 0.29 µM) 31 and 2 (50% at 0.40 µM). 23Aquayamycin (2) is also known as an inhibitor of tyrosine hydroxylase (50% at 0.37 µM). 24Vineomycin A 1 (3) 32 exhibits antitumour activity against Sarcoma 180 solid tumour in mice, and SS-228Y (1) also was found to show cytotoxic activity in vivo. 31,33Saquayamycin A (4) 28 and ritzamycin A (5) display remarkable activities against L-1210 and HT-29 tumor cells, even though certain saquayamycins have shown some levels of toxicity in vivo.

Figure 1
6][37] In both cases, the key A ring annulation step was a pinacoltype coupling.Our previous investigation 38,39 on the formation of naphthoid cyclohexane-2,4dienones via λ 3 -iodane-mediated oxidation of 2-alkoxynaphthols such as 9 followed in situ by regioselective attack of a carbon-based nucleophile such as 10, led us to design a new synthetic approach toward the benz[a]naphthalene ABC unit of angularly oxygenated angucyclines (Scheme 1).We report herein some preliminary results from this novel approach that led to the elaboration of five-membered ring-containing analogues of this angucyclinone unit.

Results and Discussion
The regioselective formation of naphthoid cyclohexa-2,4-dienones by [bis(trifluoroacetoxy)]iodobenzene-mediated (BTI) oxidative dearomatization of 2-alkoxynaphthols in the presence of external carbon-based nucleophiles is a synthetically valuable process that we have recently introduced. 38,39The presence of a strong electron-releasing group, like an alkoxy group at the 2-position of the starting naphthol, is essential for regiochemical control of this reaction.In the context of the synthesis of aquayamycin (2) and its congeners, we used the silyl enol ether 10, which presents the advantage of furnishing in one step a four-carbon side-chain adequately functionalized for the A ring annulation.A mixture of 2-methoxynaphthol (9)

Scheme 2
The desired ortho-quinol ether 8 was obtained in 36% yield as a 1.3:1 mixture of (E)-and (Z)-isomers as determined by NOE spectroscopy.We must emphasize the conciseness of this approach to highly functionalized ortho-quinol ethers that can then be used for annulation to the ABC ring system of angucyclinones.The first annulating strategy we considered was an intramolecular thiazolium ion-catalyzed aldehyde-ketone benzoin-type condensation (Scheme 3). 40,41o cyclization was observed under the conditions applied, the only product isolated after heating 8 at 80 °C in absolute ethanol and in the presence of thiazolium chloride 12 and triethylamine was the thermally-induced Cope rearrangement product 16 (90%) (Scheme 3).The reaction performed at lower temperature only led to the recovery of starting material.The next strategy we examined was derived from Kraus' synthesis of an aquayamycin-type ABC ring system; 22 the construction of the A ring was based on the conversion of a B ringtethered aldehyde into a cyclizing acyl carbanion equivalent.Thus, trimethylsilyl cyanide was added to 8 in the presence of catalytic amounts of potassium cyanide and 18-crown-6, thereby furnishing the protected cyanohydrin 17 in 37% yield (Scheme 5).Treatment of 17 with LDA in THF at -78 °C restored the aldehyde 8.This somewhat surprising recovery can be explained simply by deprotonation at one of the γ-allylic positions in place of the cyanohydrin group.Since the double bond in the carbon side-chain would allow other reactions to compete with the desired cyclization, we introduced the A ring tertiary 3-OH group, or a function convertible into it before carrying out the cyclization.
Inspired by Krohn's work on the synthesis of angucyclinones, 6,7,42 we wanted to install a silyl group as a hydroxyl group surrogate at position 3 (Scheme 5). 43We first verified the feasibility of the conjugate addition of a silyl cuprate onto a β,β'-disubstituted enal: Mesityloxide 18 was treated with (PhMe 2 Si) 2 CuLi to furnish the expected 3-(dimethylphenylsilanyl)-3-methylbutanal (19) in high yield (Scheme 4).However, all attempts to perform similar conjugate additions of silyl cuprates 6,7 or pentamethyldisilane 42 onto 8 only led to the recovery of the starting material (Scheme 5).Another option to oxygenate the exocyclic C=C double bond of 8 was dihydroxylation into diols 21 using catalytic amounts of osmium tetroxide and N-methylmorpholine-N-oxide (NMO).However, we did not isolate the expected diols 21; instead, two diastereoisomers of an unassigned product, [bis(hemiacetal) 22 or ketal-carbaldehyde hydrate 23] in a combined yield of 78% were obtained (Scheme 5).The most promising approach of introducing only one oxygen atom relied on epoxydation and responded to our expectations in part.Treatment of 8 with H 2 O 2 in the presence of Na 2 CO 3 in aqueous EtOH 44 afforded the α,β-epoxyaldehyde 24 (60-65%) (Scheme 6).This epoxide rapidly decomposed on silica gel, and it was very difficult to obtain it in higher yields with satisfactory purity.Its regioselective opening was accomplished by using the organoselenium reagent developed by Miyashita 45 to limit dehydration of the β-hydroxyaldehyde.Treatment of 24 with the phenylseleno(triethyl)borate complex, prepared by reduction of (PhSe) 2 with NaBH 4 in EtOH, gave the five-membered cyclization product 25 (46%) (Scheme 6).Reductive opening of 24 using zinc or samarium diiodide furnished only the dehydrated product 26 in low yield.We treated 25 under mildly basic conditions (i.e., saturated aq.NaHCO 3 , THF, rt, 19 h) with the expectation of converting the five-membered A ring into a six-membered one via a retro-aldol reaction, but the only product isolated was the dehydrated compound 26 (15%), together with recovered starting material 8 (85%).

[Dimethyl(phenyl)silyl]-3-methylbutanal (19).
is in progress.Tetrahydrofuran (THF) and diethyl ether were purified by distillation from sodium/ benzophenone under N 2 immediately before use.CH 2 Cl 2 was distilled from CaH 2 .Light petroleum refers to the 40-60 °C boiling range.Moisture and oxygen sensitive reactions were carried out in flame-dried glassware under N 2 .Evaporations were conducted under reduced pressure at temperatures less than 45 °C unless otherwise noted.Column chromatography was carried out under positive pressure using 40-63 µm silica gel (Merck) and the indicated solvents.Melting points were determined on an Electrothermal IA9100 Digital apparatus.NMR spectra of samples in the indicated solvent were run at 200, 250 or 300 MHz.Carbon multiplicities were determined by DEPT-135 experiments.Electron impact mass spectra (EIMS) were obtained at 50-70 eV.Electron impact and liquid secondary ion mass spectrometry at low and high resolution (EIMS, and LSIMS, HRMS) were obtained using a VG-autospec-Q intrument at the CESAMO mass spectrometry laboratory, Université Bordeaux 1. Dimethylphenylsilyl lithium in THF (0.48 M, 2.3 mL, 1.1 mmol) was added dropwise to a suspension of copper iodide (105 mg, 0.55 mmol) in THF (1 mL) at -78 °C.The reaction mixture was stirred at -25 °C for 30 min, recooled to -78 °C, and the mesityloxide (18, 42 mg, 0.5 mmol) was added.After stirring at -60 °C for 2.5 h, the reaction was quenched with saturated aqueous NH 4 Cl (10 mL) and extracted with Et 2 O (2 × 10 mL).