A. I. Gurevich, M. G. Karapetyan, M. N. Kolosov, V. G. Korobko, V. V. Onoprienko, Academician M. M. Shemyakin

SYNTHESIS OF HYDRONAPHTHACENES RELATED TO ANHYDROTETRACYCLINES

Thanks to the discovery of the reaction of photochemical \(C_6\)-hydroxylation of anhydroaureomycin \((^1)\), 5a,6-anhydrotetracyclines (I) have acquired importance as intermediates for obtaining natural tetracyclines (II). In this connection we undertook investigations in a series of anhydrotetracyclines with the aim of finding rational routes for their synthesis. First of all, we carried out the synthesis of hydronaphthacene triketoamides of type (XVI), which created the prerequisites for accomplishing the total synthesis of the 5a,6-anhydrotetracyclines themselves.

![[chemical structures (I) and (II)]]

The key compounds in our synthesis were 2,3-unsaturated 4-ketones (VI) and (VIII), of which the first had been described earlier \((^2)\), while the second was obtained by the following route (constants and analytical data of the synthesized—

Table 1

* Crystallosolvate with 0.5 mol AcOEt.

…of the compounds are given in Table 1). 9-Keto-4,10-diol (IIIa)² was converted by the action of acetic anhydride in pyridine into 4,10-diacetoxy-9-ketone (IIIb), which was reduced with 0.3 mole of LiAlH₄ in tetrahydrofuran at −60° to the 9α-hydroxy-4,10-diacetate (IV) (the configuration of the asymmetric center C₉ in this compound was assigned on the basis of Cram’s rule). The hydroxyl group was then protected by alkylation with benzyl bromide in the presence of silver oxide, and the resulting 5,9-dibenzyloxy-4,10-diacetate (Va) was saponified with aqueous methanolic KOH to the 4,10-diol (Vb), and the latter was oxidized to the 10-hydroxy-4-ketone (VIII).

\[ \begin{gathered} \text{(IIIa): } R = H \qquad \text{(IIIb): } R = Ac \\ \text{(IV)} \\ \text{(Va): } R = Ac \qquad \text{(Vb): } R = H \\ \text{(VI)} \qquad \text{(VII)} \qquad \text{(VIII)} \\ \text{(IX)} \qquad \text{(Xa): } R = H \qquad \text{(Xb): } R = Me \qquad \text{(XI)} \end{gathered} \]

Introduction of the carbon chain necessary for construction of the fourth ring into position 2 of ketols (VI) and (VIII) was accomplished by condensation of these compounds with sodium malonate according to Michael. In the case of ketol (VIII), addition of the malonic residue to the double bond was accompanied by dehydration of the β-hydroxy ketone grouping, leading to the 4a,10-unsaturated keto ester (XI); on heating the latter with alcoholic H₂SO₄, the tetrahydroanthracene keto ester (Xa) was obtained. The Michael condensation with ketodiol (VI), or its O₁₀-acetate, proceeded analogously; depending on the reaction conditions, the keto ester (VII) or its C₂-epimer (IX) was formed predominantly. Both of these keto esters, on dehydration with H₂SO₄, were converted into compound (Xb).

Saponification of keto esters (X) to the corresponding dicarboxylic acids proceeded unsatisfactorily, since under the action of bases compounds (X) undergo retro-Michael cleavage with elimination of malonic ester and formation of 5-benzyloxyanthrols-1. Therefore, for conversion into keto acids (XIV), keto esters (X) were first reduced with NaBH₄ in neutral solution and then saponified with alkali to the hydroxy acids (XII); the latter were decarboxylated by heating in pyridine, and the resulting hydroxy acids (XIII) were oxidized to the keto acids (XIV).

Further construction of ring \(A\) was carried out by a method which is basically analogous to that proposed earlier \((^3)\), but is more convenient experimentally. The keto acids (XIV), by the action of phosgene on their triethylammonium salts in tetrahydrofuran at \(-70^\circ\), were converted into mixed anhydrides; acylation of an ethoxymagnesium derivative of \(N\)-tert-butylmalonamic ester with these anhydrides led in high yield to diketo amido esters (XV). Attempts to close ring \(A\) in these compounds by intramolecular acylation of the 3,4-methyleneketone group with the ester residue on heating with freshly prepared sodium amide, triphenylmethylsodium, or finely dispersed sodium (average granule size \(1\ \mu\)) in various solvents were unsuccessful. Cyclization of the diketo amido esters (XV) was accomplished with the aid of NaH in dimethyl sulfoxide \((^4)\), as a result of which tetracyclic triketo amides (XVI) were obtained in yields of up to 80%.

The synthesis described opens the possibility of obtaining by an analogous route not only various hydronaphthacene compounds of type (XVI), but also 5a,6-anhydrotetracyclines (I) and, consequently, the natural tetracyclines themselves (II). Thus, for example, condensation of the unsaturated oxydiketone (XVII) synthesized by us earlier \((^5)\) with nitroacetic ester in the presence of triethylamine gives the adduct (XVIII); dehydration of this adduct with mineral acids affords the tetrahydroanthracene nitrooxy keto ester (XIX), which is a key intermediate for the total synthesis of anhydrotetracycline.

Institute of the Chemistry of Natural Compounds
Academy of Sciences of the USSR

Received
29 XI 1963

CITED LITERATURE

1. A. I. Scott, C. T. Bedford, J. Am. Chem. Soc., 84, 2271 (1962).
2. M. N. Kolosov, S. A. Popravko, M. M. Shemyakin, DAN, 150, 1285 (1963).
3. L. H. Conover, K. Butler et al., J. Am. Chem. Soc., 84, 3222 (1962).
4. E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc., 84, 866 (1962).
5. M. N. Kolosov, S. A. Popravko, M. M. Schemyakin, Lieb. Ann., 668, 86 (1963).