Approaches to the stereocontrolled synthesis of anthracyclinones : preparation of optically pure bicyclic intermediates for the regioselective construction of the tetracyclic skeleton

The synthesis of two enantiomerically pure bicyclic fragments are reported, the 2-bromo dimethylhydroquinone 6 (as a precursor of the corresponding bromo-quinone) and quinone monoketal 5. They are presumably able to control the regioselectivity in their reactions with appropriated dienes or nucleophiles, to afford the tetracyclic skeleton of chiral anthracyclinones.


Introduction
The clinical value of the anthracyclinone antibiotics in the treatment of a large variety of human cancers 1 has increased the interest in methods for their synthesis, to improve the previously described synthesis, 2 and to prepare analogs exhibiting better properties. 3The two main problems of the different strategies used for synthesizing anthracyclinones are related to the stereoselective construction of the A ring containing the chiral center, 4 and the regioselective preparation of the tetracyclic skeletons from bicyclic fragments. 5In the first context we have reported a versatile method based on the use of the sulfinyl group as a chiral auxiliary for creating the tertiary carbinol in high enantiomeric excess, 6 and for achieving the intramolecular asymmetric Pummerer reaction affording the bicyclic precursors of the anthracyclinones 1 (Scheme 1). 7

Scheme 1
The regioselective construction of the tetracyclic skeletons has been a central issue for those anthracyclinones bearing some oxygenated substituent (equation 1, Scheme 2).Many strategies have been used, those involving the coupling of bicyclic fragments containing the AB rings being among the most successful.In this context, bromoquinones 8 and quinone monoketals 9 (see 2 and 3 in Scheme 2) have shown to be efficient in controlling the regioselectivity of their reactions as dienophiles or electrophiles; however the synthetic sequences affording these intermediates are rather long.With these precedents we decided to perform the synthesis of the enantiomerically pure bromoquinone 4 and quinone monoketal 5 starting from compound 1 (equation 2, Scheme 2) making use of short synthetic sequences.The results obtained in this study are reported in this paper..

Results and Discussion
For synthesizing the bicyclic bromoquinones 4, we first tried the strategy shown in Scheme 3 consisting in the regioselective bromination of compound 1 with NBS 10 and further oxidation of the brominated hydroquinone 6 into 4.However, under the bromination conditions previously reported 10 we could only detect the oxidation products of the sulfinyl group, which gave mixtures of sulfinyl hydroquinones without affecting the aromatic ring.

Scheme 3
As the NBS could not be used in the presence of the STol group, despite having shown its efficiency in the completely regioselective bromination of other monoalkyl hydroquinones, 10 we decided to perform the synthesis of 6 according to the sequence indicated in Scheme 4. This involves the bromination of the sulfoxide 7, which had been used as precursor in the synthesis of 1 (Scheme 1), and the conversion of 8 into 6 following a sequence similar to that shown in Scheme 1. 6

Scheme 4
Reaction of 7 with NBS in acetonitrile yielded the brominated derivative 8 in almost quantitative yield with complete regioselectivity under mild conditions (Scheme 4).In order to obtain the tertiary carbinol with the proper configuration (C-9 in the final anthracyclinones, Scheme 2), two nucleophilic reagents were added to the carbonyl group of compound 8, Et 2 AlCN or HCCMgBr, which allow the introduction of nitrile and ethynyl groups.These could eventually be transformed easily into any of the groups present in the natural or synthetic anthracyclinones.Reaction with Et 2 AlCN proceeds in a completely stereocontrolled manner, yielding a single cyanohydrin (9a) in almost quantitative yield.This result was predictable according to the behavior observed in the hydrocyanation of other β-ketosulfoxides. 11The reaction of ethynyl magnesium bromide with 8 afforded a 87:13 mixture of two diastereomeric ethynylcarbinols (9b and 9'b) in 85% combined yield, which could be separated by chromatography.This lower stereoselectivity was not unexpected, according to previous results concerning alkylation of β-ketosulfoxides. 12The configurational assignment of all these compounds was performed by comparison of their spectroscopic parameters with those of the corresponding debrominated substrates reported previously. 6he next step was the cyclization of 9a and 9b under the Pummerer conditions (TMSOTf/DIPEA). 7Mixtures of two bicyclic bromohydroquinones (6 and 6'), epimers at thiosubstituted carbon, were obtained (Scheme 5).It is noteworthy that the stereoselectivity observed in the reaction of 9b is very low (20% de), whereas that of the corresponding debrominated hydroquinone had been shown to be complete (de > 98%). 7This suggests that the orientation of the methyl group (and therefore the lone electron pair) of the OMe group next to the bromine, is quite important in the stereoselectivity control of the cyclization under Pummerer conditions.

Scheme 5
According to Scheme 3, it was now necessary to oxidize the hydroquinones 6 into the bromoquinones 4, but unfortunately the two reactions used so far have been unsuccessful.The oxidation of 6b with CAN, one of the reagents used most to prepare quinones from hydroquinones, 13 afforded complex mixtures of compounds under different conditions.As the presence of the easily oxidation of the SMe group at 6b could once more be responsible for the formation of mixtures, we decided to remove it before oxidizing the hydroquinone ring.This sequence would provide the hydroquinone 4´, which is also appropriate for achieving the regioselective coupling with dienes or nucleophiles.The reaction of 6b with Raney-Nickel followed by oxidation with CAN yielded compound 10b instead of the expected 4´, which indicates that reduction of the triple bond and hydrogenolysis of the C-Br bond is taking place simultaneously with the breaking of the C-S bond (Scheme 6).As the evolution of 9b is not expected to be highly regioselective, we are currently exploring other reactions allowing the synthesis of 4 or 4´ from 6.As these substrates can be prepared by oxidation of hydroquinone mono-ethers 14 we first tried to obtain these compounds by partial hydrolysis of the hydroquinones 1.However, after trying these substrates with various reagents (MeSLi/DMF, 100 ºC; EtSH/AlCl 3 , 0 ºC; AlCl 3 /PhNO 2 ) described in the literature 15 as being efficient for transforming aromatic ethers into phenols, no successful result was obtained, presumably owing to interferences of the reagents with the substituents at the chiral carbon.
We then tried to obtain quinone monoketals by regiocontrolled partial hydrolysis of their corresponding bis-ketals, which in their turn could be obtained by anodic oxidation of the hydroquinone derivatives. 16The substrates studied and the results obtained in these transformations are indicated in Scheme 7. Anodic oxidation of hydroquinones 1a-d 6,7 was performed at 0 ºC using the pair Pt (anode) / Cu (cathode) in methanolic KOH (2%) and 100 mA (direct current). 16The bis-ketals 11a-d were obtained as dark oils with yields ranging between 50% and 97%, with the best results obtained for tertiary alcohol derivatives.Under the anodic oxidation conditions TMS derivatives are transformed into the free alcohols.Compounds 11a-d were used in the further step without prior purification.
The partial hydrolysis of the bis-ketals into their corresponding monoketals was not an easy task because of the ease of the total hydrolysis into quinone rings.A number of mild conditions was tried.AcOH (5%) 17 in acetone at -20 ºC for 12 hours provides 75:25 mixtures of monoketals 12 and 12' starting from 11a-c.After chromatographic separation of the mixtures, by using silica gel previously deactivated with Et 3 N (5%), the major regioisomers 12 were obtained in 40% yield.Lower regioselectivity was obtained from 11d with acetic- 17 or oxalic acid 18 in acetone for 1 hour (62:38 mixtures of 12d and 12'd).Under milder conditions (acetone/water, RT, 3 days), a 72:28 mixture of 12d and 12'd was obtained, with the major mono-ketal being isolated in 30% yield after chromatographic purification.
The major regioisomers (12) exhibit δ values for the α-and β-protons which are slightly higher and lower, respectively, than those for the minor regioisomers (12').Thus, the ∆δ values for the olefinic protons [δH(β) -δH(α)] are always lower for 12.The structural assignment of both regioisomers was made by assuming that the sulfur function should retard the hydrolysis of its nearest acetal group by steric effects. 19The unequivocal assignment of the regioisomers was made for compounds 12a and 12'a by studying the coupling between the proton at C-1 and the carbonyl carbon.Only compound 12a exhibited such a vicinal coupling constant ( 3 J H,CO = 3.0 Hz), which was absent in compound 12'a.
In summary, we have described the synthesis of enantiomerically pure bicyclic intermediates which are potentially useful for synthesizing anthracyclinones in a highly regioselective way.Bicyclic mono-ketals containing the A/B rings of the tetracyclic skeletons were obtained by partial hydrolysis of the corresponding bis-ketals resulting in the anodic oxidation of the hydroquinones.Precursors of the bicyclic bromoquinones have also been prepared.The reactions of these bicyclic intermediates with the appropriate fragments as precursors of the C/D rings of tetracyclic skeletons are currently being studied and the results will be reported in the due course. 20perimental Section General Procedures.All moisture-sensitive reactions were performed in flame-dried glassware equipped with rubber septa under positive pressure of argon.Silica gel 60 (230-400 mesh ASTM) and DC-Alufolien 60 F 254 were used for flash column chromatography and analytical TLC, respectively.Melting points were determined in a Gallenkamp apparatus in open capillary tubes.Microanalyses were performed with Perkin Elmer 2400 CHN and Perkin Elmer 2400 C-10II CHNS/O analyzers.NMR spectra were determined in CDCl 3 solutions, unless otherwise indicated, at 300 and 75 MHz for 1 H-and 13 C-NMR respectively; chemical shifts (δ) are reported in ppm and J values are given in Hertz.The IR spectra frequencies are given in cm -1 .RT denotes room temperature.

[(S)R]-4-(4-Bromo-2,5-dimethoxyphenyl)-1-p-tolylsulfinylbutan-2-one (8).
To a solution of 2.56 g of β-ketosulfoxide 7 in 50 mL of CH 3 CN was added 1.45 g of NBS (8.2 mmol) at RT.The reaction was monitored by TLC and when the reaction was finished (1 h), the solvent was evaporated.To the resulting mixture was added 10 mL of CCl 4 , to deposit a white solid.This solid was removed by filtration, and the solvent was recovered.Finally, the solvent was evaporated under reduced pressure, giving 3.

General methods for the hydrolysis of the bis(dimethyl)ketal of benzoquinones 11 Method 1.
To a solution of the corresponding bis-ketal 11 (0.1 mmol) in 1 mL of acetone at -30 ºC, was added 0.5 mL of AcOH (5%).After 2 hours Et 2 O was added, and washed with saturated NaHCO 3 .The organic phase was dried over anhydrous Na 2 SO 4 and the solvent eliminated under reduced pressure.Both regioisomers could be separated by chromatography (eluent hexane/AcOEt 7/3) using previously neutralized silica gel (12 h in hexane with 5% Et 3 N).