- 1-Synthesis of optically active derivatives of bicycl ic chiral diols with C 2 symmetry

Efficient synthesis, besides other, of dibromide, diazide, diamine and diesters derived from (11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dimethanol (3), a chiral bicyclic diol with C2 symmetry, was developed. Esterification of 3 with saturated and unsaturated carboxylic acids and acids chlorides leads to the corresponding normal-, olefinicand acetylenic diesters in average yields of 81%. Also more efficient techniques for the preparation of starting diol 3 in higher yields as well as for a very simple separation of DCU from reactions carried out following DCC/DMAP method are described.


Introduction
Chiral dihydroethano-and ethenoanthracene derivatives are versatile organic molecules with C 2 symmetry that have been used in synthetic and biological applications.They have also been used as chiral ligands in enantioselective reactions, attached to a metal as catalytically active species, and as chiral polymer´s precursors. 1,2Derivatives of C 2 -symmetric dicarboxylic acids are of interest since they can often be prepared on a large scale from easily available starting materials.The numerous routes from L-tartaric acid ilustrate this point well. 3At present, we are interested in reactions that involve the use of C 2 symmetry substrates as precursors for the synthesis of optically active molecules with potential biological activity.Thus, we have reported the physical characteristics of a series of new TADDOL´s unsaturated esters 4a and the use of these in the synthesis of macrolides via cyclohydrostanation reactions.4b In this context, we considered its convenient to synthesize a series of derivatives of the chiral diol (11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12dimethanol (3) and to study some reactions of them.

Results and Discussion
Diol 3 was prepared using a variation of a synthetic route which involved an asymmetric carbo-Diels-Alder reaction as the key step, as shown in Scheme 1. 4,5 The use of (S)-(-)-methyl lactate instead of the of (S)-(-)-ethyl lactate used initially and, specially, small variations in the experimental techniques enabled us to increase the global yield of the synthesis.Thus using fumarate 1 in a ratio 1/anthracene = 1:3.5 (originally 1:5), after 4 days of reaction (6 in the original paper 5 ) diester 2 was obtained enantiomerically pure in yields of 65-68% after recristallyzation from ethyl [A014]  acetate/hexane (original paper 50-60%).Then, diester 2 was reduced with LiAlH 4 in boiling ether leading to the chiral diol 3 in a 92% yield of pure compound.It should be noted that the increase in the yield (in the original paper 75%) was achieved simply by increasing the amount of LiAlH 4 .Scheme 1. Synthesis of bicyclic chiral diol 3.
The reaction between diol 3 and carbon tetrabromide in the presence of triphenylphosphine, carried out in methylene dichloride at 0 °C leads to (11 R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dimethylene dibromide (4) in 82% yield, as shown in Scheme 2. Oxidation of diol 3 with pyridinium dichromate (PDC) in anhydrous methylene dichloride afforded the corresponding dialdehyde, (11R,12R)-9,10-dihydro-9,10-ethano anthracene-11,12-dicarbaldehyde (5), in 80% yield (Scheme 2).Similarly, the reaction of 3 with dichloromethoxyphosphine in the presence of anhydrous triethylamine in toluene leads to phosphatricyclodione 6 in 85% yield.We then attempted the synthesis of diamine 8 via the reaction between chiral dibromide 4 and potassium phthalimid (Gabriel synthesis).This reaction was carried out at r.t., 50 °C, 80 °C and at 130 °C without suc cess.In order to synthesize diamine 8, first diazide 7 5,6 was prepared in excellent yield via the reaction between chiral diol 4 and sodium azide in dry dimethylformamide (DMF) at As shown in Scheme 4, starting from diester 2 we were able to obtain a secuence of interesting optically actives functionalizated derivatives following adaptations of the Fürstner´s procedures. 9Thus, hydrolisis of diester 2 with LiOH in MeOH/THF/H 2 O at room temperature leads to the diacid 9 almost cuantitatively and without further purification, was treated with DIPEA, HN(OMe)Me, DCC and DMAP in CH 2 Cl 2 to yield 90% of (11R,12R)-dicarboxamide 10 after chromatography.Further treatment with MeMgBr in THF at 0 °C lead to the corresponding (11 R,12R)-diketone 11 in 80% yield after chromatography.Treatment of 11 with MePPh 3 I and t-BuOK gave the (11R,12R)diolefinic derivative 12 in 78% yield after heating one hour in toluene (Scheme 4).We also report here the synthesis of saturated and unsaturated diesters with C 2 symmetry derived from diol 3.In this case, we have found just one reference on the synthesis of the corresponding (11R,12R)-dimethacrylate 17. 10 It should be noted that ester 17 has been used in studies connected with the synthesis of optically active polymers. 10We first studied the esterification of benzoic and phenylacetic acids with 3 using N,N´-dicyclohexylcarbodiimide (DCC)/4-(N,N-dimethylamino)pyridine (DMAP)

4
-4 -method (Method A, Scheme 5).The separation of N,N´-dicyclohexylurea (DCU) and some unreacted 3 was carried out by percolation of the crude reaction mixture through a fritted Büchner funnel containing two layers of about 1 cm deep each: the lower of silica gel and the upper layer of celite.As shown in Scheme 5, both esters, i.e., dibenzoate 13 and diphenylethanoate 14 were obtained in excellent yields as only products of these reactions.Similar yields were obtained starting from the corresponding acid chlorides (Method B) (Table 1).Taking into account these results, then we studied the synthesis of unsaturated esters of 3 by means of the DCC/DMAP method (Scheme 6).Reactions were carried out by mixing diol 3 in dry CH 2 Cl 2 with DCC, p-toluensulphonic acid (TsOH) and DMAP, then adding the unsaturated acids to the mixture at 0 ºC.After 12 hs at r.t. the crude products were purified as above.
On the other hand, using the reaction between diol 3 and the corresponding α,β−unsaturated acyl chlorides at 0 ºC in the presence of n-butyllithium (BuLi) we succeded in obtaining the corresponding (11R,12R)-diesters according to Scheme 6 in good to excellent yields.These reactions lead in all cases to the corresponding diesters as only products.The global average yield of these reactions, after purification, was around 83% (Table 2) We also investigated the synthesis of unsaturated esters of diol 3 through the reaction between (11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dimethylene dibromide (4) and the silver salts of the unsaturated acids, as shown in Scheme 6.These reactions were carried out in toluene under reflux.Unfortunately all the attempts made were unsuccessful and compound 4 was quantitatively recovered in all cases.Scheme 6. Synthesis of Olefinic Diesters 15-22 Method A [a] yield (%) [b] Method B [a] yield (%) [b] 15 Finally, we studied the esterification of propyn-, octyn-and phenylpropyonic acids with diol 3 using Method A as shown in Scheme 7.These reactions were carried out as described above for the case of substituted propenoic acids.As shown in Scheme 6, the reactions lead in all cases to the corresponding (11R,12R)-acetylenic diesters of 3 as only products.It should be noted that in the case of esterification with propynoic acid we were unable to isolate pure diester 23 due to decomposition on purification.The new unsaturated esters were obtained in an average yield of 86%.The esterification using Method B lead to the corresponding diesters 24 and 25 in high yields, as shown in Table 3.All attempts to obtain similar acetylenic esters in the case of TADDOL were unsuccessful.
From a synthetic point of view this study shows that the esterification of normal and unsaturated carboxylic acids with chiral diol (11R,12R)-9,10-dihydro-9,10-ethano anthracene-11,12-dimethanol (3) can be carried out efficiently using both, the DCC/DMAP method and the reaction with the acid chloride derived from the same carboxylic acid.Both methods lead to the corresponding new (except 17) diesters in high yield and could be considered complementary in that those esterifications which cannot be carried out by Method A are successful with Method B. Also more efficient techniques for the preparation of diol 3 in higher yield as well as for a very simple separation of DCU and unreacted 3 from the reactions carried out following Method A are described.Besides an efficient procedure for the preparation of new optically active functional derivatives 4-6, 10-16 and 18-25 is reported.The reaction between the fumarate of (S)-methyl lactate (1) 5 and anthracene was carried out according to ref. 5 in toluene at 110 ºC.The following variations of the original technique were performed: ratio 1/anthracene = 1:3.5 (original paper 1:5); reaction time 4 days (originally 6 days).Under these reaction conditions, diastereomerically pure compound 2 was obtained in 60-68% yield (original paper 50-60%) by recrystallization from ethyl acetate/hexane.

Reduction of 2.
To a suspension of LiAlH 4 (4.07 g, 107.18 mmol) in dry diethyl ether (125 mL), under atmosphere of argon and at room temperature, was added dropwise a solution of diester 2 (10.0 g, 21.44 mmol) in dry diethyl ether (100 mL) with vigorous stirring.The mixture was heated under reflux for 1 h and then was stirred at room temperature for 3 h, cooled down to 0 ºC and water (60 mL) was added dropwise with stirring.After acidifying with 1 N HCl, the aqueous layer was extracted with diethyl ether (3 x 50 mL) and the combined organic extracts were washed with a sat.NaCl solution and dried over anhydrous Na 2 SO 4 .The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60, hexane-Et 2 O, 50:50) to give 3 (5.26g, 19.73 mmol, 92% yield) as a white powder, m.p.: 123-125 ºC.
To a suspension of LiAlH 4 (0.17 g, 4.48 mmol) in dry diethyl ether (5 mL), under atmosphere of argon and at room temperature, was added a solution of (11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dimethanazide (7) (0.14 g, 0.44 mmol) in dry diethyl ether (5 mL) dropwise and with vigorous stirring.The mixture was heated under reflux for 2 h and then stirred at room temperature for 8 h.After cooling down to 0 ºC water (5 mL) was added dropwise with stirring.The organic layer was was washed once with HCl 10% (10 mL) and water (10 mL) and the aqueous layer was extracted with Et 2 O (3 x 10 mL).The combined organic extracts were dried with anhydrous Na 2 SO 4 .The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60, hexane-Et 2 O, 50:50) to give 8 (0.07 g, 0.26 mmol, 60%) as a white solid.
Then, the reduction of 7 carried out with LiAlH 4 in refluxing ether gave (11R,12R)-diamine 8 in good yield (60%).Diamine 8 was previously obtained by another procedure mediated by resolution of the brucine salt of the carboxylic acid precursor and was tested as chemosensitizers against chloroquine resistant Plasmodium falciparum, responsible for Malaria´s disease.