Application of intramolecular carbonyl-ene reaction towards the synthesis of idarubicinone scaffold

Intramolecular aromatic carbonyl-ene reaction (ICE) † has been combined with a modified Hauser annulation to offer a facile access to the tetracyclic idarubicinone core. The required key dihydroxyanthraquinone aldehyde precursor was assembled in one step by modified Hauser annulation of a functionalized benzoquinone. Its ene reaction in the presence of SnCl 4 ·5H 2 O directly led to the formation of idarubicinone core. Also described are an unprecedented thermal cascade involving a thermal ICE en route to α -naphthols, and exploratory studies on model elaboration of anthracycline A rings.


Introduction
4][5][6][7][8] However, its aromatic version (eqn.0][11][12][13][14][15] It is a significant advancement in the area of ICE, in view of its success despite the conformational constraint imposed by a benzene ring.Furthermore, the placement of the benzylic hydroxyl group in the product obviates the problems of benzylic bromination under radical conditions on a large scale. 16,17However, its application to simple naphthalenes and anthracenes are problematic due to the susceptibility of the incipient ene products to aromatization.In a recent report 18 from our laboratory, we have demonstrated that the ICE can be manoeuvred to prevent aromatization of the ene products, thus permitting synthesis of non-aromatized ene products i.e. hydroaromatic products.We also included development of a synthesis of ortho methallylbenzaldehydes based upon Suzuki coupling reactions.Scheme 1. Type II carbonyl-ene reaction. In seeking an application of the aromatic ICE in developing a simpler route to anthracyclines 1-5 (Figure 1), the most widely used anticancer drugs [19][20][21][22] , we chose to assemble the tetracycline framework of idarubicinone (3) as shown in Scheme 2. The salient features of the retrosynthesis are i) modified Hauser annulation of 6 and 7 to assemble dihydroxy intermediate 8 and ii) its direct use as the ene substrate to produce tetracyclic intermediate 9.It may be mentioned that the reactivity of the 1,4-dimethoxy analog of quinone 8, prepared by Claisen rearrangement, was examined towards the aromatic ICE. 23No further elaboration was attempted probably due to the problem with deprotection of the aromatic methoxy groups without affecting the A-ring.In devising the synthesis of 3, we, therefore, envisioned investigations with dihydroxy intermediate 8.It was anticipated that the corresponding ene product i.e. 9 would be sufficiently stable due to intramolecular hydrogen bonding for further elaborations without resorting to a deprotection.
In this study, the potential of the aromatic ICE approach in creating an asymmetric centre at C7 position of anthracyclines is proposed.Asymmetric epoxidations or hydroxylations or nucleophilic additions can be invoked for further elaborations, as indicated in Scheme 2. Asymmetric dihydroxylation of the ene product 9 is proposed to give 10 and then 3. In the second approach, tetracycle 11 is expected to produce compounds 12 and 13 and 3 (Scheme 2).

Results and Discussion
To perform a model study of idarubicinone (3) utilizing Hauser annulation, we first decided to synthesize the Michael acceptor 14 (cf 7, Scheme 2) (Scheme 3).This proposal stemmed from our previous study on the Scheme 3. Preparation of alcohol 20.
For an alternative route to 20, we examined the possibility of Claisen rearrangement of a related aldehyde precursor, and for the model study we chose aldehyde 21 26 (Scheme 4).

Scheme 4. Thermal rearrangement of aldehyde 21.
When it was heated in refluxing DMF, the desired Claisen product was not obtained.Instead, the reaction resulted in formation of three products 22 (4%), 23 (7%) and 24 27 (23%) (Scheme 4).Formation of the naphthol 22 is accounted for by Claisen rearrangement of 21 to intermediate 25 followed by thermal ICE of 25 through 26 to 27, its dehydration and isomerization.The formation of 23 is very striking in that its formation must involve a reduction, since there is a decrease in the oxidation level. 28The probable mechanism is shown in Scheme 5, where DMF acts as the hydride donor.The structure of 23 is further confirmed by transforming it into its acetate.It may be noted that the product 23 was not obtained when the reaction was carried out in 1,2-dichlorobenzene.Formation of 24 is explicable in terms of its Claisen rearrangement of 21 followed a 5exo-trig cyclization of 25.Scheme 5. Proposed mechanism for the transformation of 21 to 23.
In view of the problems with above Claisen rearrangement methodology, the synthesis of quinone 14 was started from the known aldehyde 28. 18It was converted into quinone 14 in two steps.NaBH4 reduction of 28 gave alcohol 20 in 86% yield, which was oxidized with CAN to give 14 in 66% yield.It was then converted into THP ether 29 by treatment with DHP in dry DCM in the presence of a catalytic amount of PPTS (Scheme 6).Scheme 6. Alternative synthesis of alcohol 20 and acceptor 29.
Both the quinones 14 and 29 were subjected to Hauser annulations with phthalide 30 29 .In the presence of LiOBu-t, the annulation 24 of 30 with 14 gave annulation product 31, but in only 10% yield.Assuming that the free -OH in 14 interfered the annulation, we examined its protected form i.e. 29.Annulation of phthalide sulfide 30 with 29 under similar conditions gave dihydroxyanthraquinone 32 in 68% yield.Deprotection of 32 with PPTS-MeOH provided alcohol 31 in 76% yield.PCC oxidation of 31 furnished aldehyde 33 in 69% yield.This was then subjected to ICE under a variety of conditions.Gratifyingly, we obtained tetracycle 11 as the sole product representing the core structure of idarubicinone (3) on treatment with SnCl4•5H2O.It was sufficiently stable to be purified by chromatography on silica gel (Scheme 7).600), respectively.IR spectra were recorded with a Perkin-Elmer FTIR instrument using a KBr pellet.HRMS spectra were obtained on XEVO-G2QTOF machine.The phrase "usual work-up" or "worked up in the usual manner" refers to washing of the organic phase with water (2 x 1/4 of the volume of the organic phase) and brine (1 x 1/4 of the volume of the organic phase), drying (Na2SO4), filtration, and concentration under reduced pressure.

4-Methoxy-3-(2-methallyloxy)benzaldehyde (21)
. 26 To a stirred solution of isovanillin (8.8 g, 57.9 mmol) in dry acetone (300 mL) was added solid K2CO3 (8.0 g, 57.9 mmol) at 0 °C followed by addition of methallyl bromide (8.8 mL, 86.9 mmol).The reaction mixture was stirred for 24 h and filtered.The filtrate was concentrated and extracted with ethyl acetate (250 mL).Organic layer was washed with H2O (3 x 100 mL) and brine (100 mL).Combined organic layer was dried over Na2SO4 and evaporated under vacuum to afford the crude material.It was purified by performing flash column chromatography on silica gel with 1:5 ethyl acetate/hexane solvent to afford 21 (10.9 g, 52.7 mmol) in 91% yield.Yellow oil; 1   (20). 25To a stirred solution of compound 28 (0.44 g, 2 mmol) in THF (10 mL) and MeOH (3 mL) at 0 °C was added NaBH4 (84 mg, 2.2 mmol) in portions.The resulting mixture was stirred at rt for overnight.Then it was quenched with saturated NH4Cl (3 mL).Extraction of the reaction mixture with EA (3 x 10 mL) followed by drying over Na2SO4 and removal of solvent gave a residue.Flash column chromatography of the residue on silica gel with 1:2 EA/hexane solvent afforded product 20 (0.38 g, 1.72 mmol) as colorless liquid in 86% yield.