GB2332428A - Synthesis of 1-methyl-7-(1rs,2r,3s,4s,5s)-2,3,4,5,6-pentabenzyloxy-1-hydroxyhexyl-3,5,8-trihydroxyanthra-9,10-quinone-2-carboxylic acid and intermediates - Google Patents

Abstract

1-Methyl-7-(1RS,2R,3S,4S,5S)-2,3,4,5,6-pentabenyloxy-1-hydroxyhexyl-3, 5,8-trihydroxyanthra-9,10-quin one-2-carboxylic acid (5, R = H) an intermediate for the synthesis of 6-deoxycarminic acid (I, R = H) is synthesized by the reaction of methyl leuco-6-deoxykermesate (4, R = Me) with 2,3,5,5,6-penta-O- benzyl-D-glucose under aqueous alkaline aldol reaction conditions. Alkyl 6-deoxykermesates (3, R = alkyl) are converted chemically to alkyl leuco-6-deoxykermesates (4, R = alkyl) and benzyl 6-deoxykermesate (3. R = benzyl) is hydrogenolysed catalytically to leuco-6-kermesic acid (4, R = H). Although (4, R = Me) under the prolonged aldol reaction non-aqueous conditions in ethanol containing piperidinium acetate with paraformaldehyde gives methyl 3,5,9-trihydroxy-1,6-dimethylanthra-9,10-quinone-2-carboxylate, (4, R = Me) in aqueous methanolic alkaline reaction conditions gives the 1,7-dimethyl isomeric compound. Under mild conditions the 7-α-hydroxyalkyl compound is formed as a precursor of the 7-alkyl compound and thus with these mild aqueous alkaline reaction conditions the synthesis of (5, R = H) from (4, R = Me) is effected, the methyl group being hydrolyzed in the process.

Description

BRITISH PATENT SPECIFICATION

2332428 Synthesis of 1 -methyl -7-(1 RS,2R,3 S,4S, 5 S)-2,3,4,5,6-pentabenzy loxy- 1 -hydroxyhexy 1-3,5,8 tnhydroxyanthra-9,10-quinone-2-carboxylic acid and of leuco intermediates Description

This invention relates to a synthesis 1 -methyl -7-(1 RS,21,3 S,4S,5 S)2, 3,4,5,6-pentabenzyP 1 hydroxyhexyl-3,5,8-tnhydroxyanthra-9,10-quinone-2carboxylic acid (5; R = Me) a key intermediate towards 6-deoxycarminic acid (7-0-D-glucopyranosyl-l-methyl-3,5,8trihydroxyanthra-9,10-quinone-2carboxylic acid) (1; R = Me) a precursor for the important colourant, carminic acid (2; R = OH).

Me 0 01a OR 9Bn 0Bn (5-1 R = Me) RO 1 C - - - 0Bn 6Bn 6Bn 190 (1; R = Me) RO2C me 0 019 05 1 1 E0 019 lao 01a 0 0Iff me 0 01a 1102c 0 01S (2, R = OH)) E0 011 1 R 'a 01a Carminic acid, the colourant principle of cochineal, is commercially extracted from the dried female bodies of the scale insect species Dactylopius coccus Costa which feed on the cacti Opuntia and Nopallea coccinellifera. However, the supply of cochineal from this source is variable and the price is liable to Wide fluctuations and accordingly as is often the case with natural products the total synthesis of carminic acid has become of interest.

Although not in itself a natural product like carminic acid, synthetic 6deoxycarminic acid can be readily converted to it by acetoxylation at the 6-position through the Thiele reaction and thence conversion of the acetoxy group to the hydroxy group. The formation of the 6-acetoxy compound has been described previously (0. Dimroth and H. KAmmerer, Ber., 1920, 53, 1471) by the reduction of carminic acid with zinc dust to 6deexycarminic acid and then reconverting it to carminic acid by the said Thiele reaction followed by hydrolysis..

This invention relates to a novel method of synthesising 6-deoxycarininic acid from an open chain D-glucose derivative an intermediates not previously used and different from those described in European Patent Specification EP 0 602 027 B1 and in US Patent 5 424 421which are bassed on the use of cyclic D-glucose intermediates.

In the synthesis described in those patents it was necessary to use protected derivatives in order to achieve specific reaction at the desired site. Thus the methyl group was used in the intermediate alkyl 3, 5,8,9,10-pentamethoxyanthracene-2-carboxylates both to activate and protect the molecule during reaction. Such protection entailed a preliminary insertion step of the protective methyl group, a subsequent demethylation stage and therefore added extra steps in the synthetic sequence.

It was the objective in the present application to devise a series of reactions in which the least number of protective groups were required and thus to obtain a simpler synthesis of the key intermediate, 6deoxycarminic acid. The steps in the new synthesis are shown in the following scheme The first required intermediate is methyl 6-deoxykermesate (3; R = Me) a compound obtainable from the Diels-Alder addition of 2-chloronaphthazann (2-chloro-5,8dihydroxynaphtho-1,4-quinone) With 3-alkoxycarbonyl-2,4- bis(trimethylsilyloxy)penta-1,3dienes followed by removal of the trimethylsilyl groups. This reaction has been described in the two patents referred to and by P.Allevi, M, Anastasia, S1 Bingham, P. Cluffreda, A, Fiecchi, G. Cighetti, M. Mulr, A. Scala and J.H.P. Tyman, J Chem. Soc.. Perkin I Trans (in press). The methyl, ethyl and benzyl esters have been used. An alternative method is from the Friedel-Crafts reaction of alkyl esters of the methyl ether of coccinellic anhydride with 1,4-di m ethoxy benzene in an aluminium chloride /sodium chloride melt. In this process 6deoxykermesic acid is produced (3; R = H) and this can be reestenfied to give the alkyl ester (3; R = alkyl). This method is referred to in the two Patents previously mentioned and by S1 Bingharn and J.H.P. Tyman, JChem. Soc., Perkin I Trans, 1997, 3637.

The first novel step in the synthesis is the formation of methyl leiteo-6deoxykermesate (41 R = Me) by either catalytic reduction with hydrogen of methyl 6-deoxykermesate in tetrahydrofuran containing palladium-carbon or by chemical reduction with sodium dithionite in aqueous methanol containing sodium hydroxide.

In the attachment of an alkyl chain we have found, remarkably, that under two different aldol reaction conditions with methyl leueo-6deoxykermesate an aldehydic group reacts specifically at the 6-position and under the other, at the 7-position. Thus in model experiments With formaldehyde and methyl leuco-6-deoxykermesate (3; R = Me) With the conditions of Lewis (J Org. Chem., 1970, 35, 2938) the initially 6hydroxymethyl compound afforded the final 6-methyl compound, methyl 1,6dimethyl-3,5,8-trihydroxyanthra-9, 1 0-quinone-2 -carboxy late. By contrast under aqueous alkaline conditions (similar to those described by C. Marschalk Bull. Soc. Chim. Fr., 1939, 6, 655), methyl leuco-6deoxykermesate and formaldehyde reacted to give first the 7-hydroxymethyl compound which was then dehydrated on prolonged reaction to give then methyl 1, 7-di m ethyl - 3,5,8 -trihy droxy anth ra--9,1 0- quinone-2 carboxy late, the 7methyl compound. The close spectroscopic properties of these two isomeric compounds did not permit them to be di stingui shed except by an X-ray structure determination. This clearly showed that Lewls conditions gave the 6-methyl and not the 7-methyl compound. This latter a substitution only occurred under aqueous alkaline conditions which were of value to us in our synthetic objective.

However a further novel requirement was to restrict the the extent of the reaction to enable the hydroxyalkyl intermediate to be isolated and to avoid its dehydration. Model experiments under very mild conditions at O'C to ambient temperature proved the feasibility of this modification and in a number of experiments of methyl leuco-6-deoxykermesate with aldehydes under these mild conditions 7-a-hydroxyalkyl products resulted.

Although the objective was to employ the minimum number of protective groups for the attachment of a glucosidic side-chain, the cyclic (pyranose) structure of glucose lacking a free aldehyde group, required reaction of the 2,3,4,5,6-hydroxy groups order to obtain the open chain form having an aldehyde group for aldol reaction purposes.

2,3,4,5,6-Penta-0-benzyl-Dglucose was prepared readily in 76% yield from the diethyldithioacetal of D-glucose by perbenzylation with benzyl chloride in dimethylfonnamide containing sodium methoxide and then removal of the thioacetal group with mercuric oxide in aqueous tetrahydrofuran containing boron trifluonde-etherate. The 2,3,4,5,6-penta0-methylD-glucose was prepared from the diethyldithioacetal by methylation with methyl iodide and removal of the thioacetal group with Nbromosuccinimide in aqueous acetone.

Methyl leueo-6-deoxykermesate was reacted in aqueous methanol containing sodium hydroxide with 2,3,4,5,6-penta-0-benzylglucose with the addition during the reaction of finely powdered potassium hydroxide to give 1 methyl -7-(1 RS,2R,3 S,4S, 5 S)2,3,4,5,6pentabenzyloxy-l-hydroxyhexyl-3,5, 8-trihydroxyanthra-9,10-qwnon e-2-carboxylic acid (5; R = H) in 50% yield as a mixture of diastereoisomers which was purified by column chromatography.

Catalytic hydrogenolysis of (5) in methanol/ethyl acetate/acetic acid containing palladisedcarbon would provide the C-glycoside, 6deoxycarminic acid (1) in the manner described for a related open chain (W. Frick and R.R.Schmidt, Liebigs Ann Chem., 1989, 565) The synthesis according to the invention with reference to Scheme 1 shown is described with practical details.

Scheme 1 The synthesis of (3; R = Me) by the two methods referred to is shown in Scheme 2.

me o OH RO,C 1I0 0 OH (3;R = me) Me OH 0 RO,C HO OH 0 (4; R = Me) Me o OH OH QBn 0Bn RO,C 0Bn 6Bn 6Bn HO 0 OH (5; R = Yle) Me 0 OH OH gH OH Me 0 OH RO2C ' - - OH iv RO2C OH 5H 6H HO OH HO 0 OH (6; R = H) HO 013 0 OH U;R = H) 3 Scheme 2 me 0 Me 0 0 11e02C Meo2C 1: Meo me me 0 "Ar lao 0 10( 0 Meo: 0 --bo. bl'E02C 0Sime3.4111 0 Me3S'o Me C) OE cl Meo2C ao 0 OE (3; R = Me) Methyl 2,3-dihydro-7,9,10-trihydroxy-5-methylanthracene-1,4-dione-6carboxylate (methyl leuco-6-deoxykermesate, (4; R = Me) To a stirred slurry of methyl 6-deoxykermesate (3) (0.200g, 0.6lmmol) and sodium dithionite (0.200g) under nitrogen was added aqueous methanolic (L1) sodium hydroxide (5 CM3) togive a dark red solution which after 10m turned red-brown. The mixture was acidified, extrated with di chlo ro methane, the extracts were dried and concentration to dryness gave a yellow solid (0.199g, 99%), mp, 229'C; (Found: M-330.0740. Calc. for C17H1407 330.0739); a,,,a,,/ cm-' (KBr), 3300br (OH), 2943 (aliph. C-H), 1740 and 1695 (C=O), 1635 and 1595 (aryl), 1510, 1425, 1390, 1280, 1240, 180, 1110, 1050, 1010,970, 940, 855, 800; (MeOH)nm, (log s), 262 (4.30, 281 (4.31), 306 (4.33), 421 (4.09), 443 (4.10); 5M (80 MHz, WC13), 3.03 (4H, s, 2-H,2a-H,3-H.3a-H), 3.05 (3H, s, 5-Me), 4.04 (3H, s, 6-CO.,Me), 7. 84 (IH, s, 8-H), 9.26 (1 H,s, 7-OH, exch. D.0); m/z (M), 3 3 0 (M-, 3 7%), 299 (22), 298 (100), 296 (11), 270 (31), 242 (15).

By catalytic reduction of methyl 6-deoxykermesate (0.050g, 0.15 mmol), in THF (10cm') containing 10% Pd-C With hydrogen at atmospheric pressure and temperature, during 3h, followed by filtration and evaporation of the filtrate to dryness gave the same yellow product (0.048g, 95%) mp 229' which had the same sparal properties as the leuco form obtained by chemical reduction.

2,3-Dihydro-5-methyl-7,9,10-trihydroxyanthracene-1,4-dione-2-carboxylic acid (4-, R = H) Benzyl 6-deoxykermesate (0.050g, 0. 12mmol) in tetrahydrofuran (1 Ocm3) containing 1 0% PdC (0.013g) was hydrogenolysed with hydrogen at ambient pressure and temperature during 4h. Filtration of the mixture gave a greenish-yellow solid, the leuco compound, 2,3dihydro-5methyl-7,9,10-trihydroxyanthracene-1,4-dione-2-carboxylle acid (4; R = H) (0.039g, 100%), - (Found: M-, 316.0583. Calc. for C,,H, '07 -' (KBr), 3280br mp > 300'Cl 3 16.0 5 8 3; /cm (O-H), 1690 (CO,H), 1610 (dione), 1480, 1380, 1310. 1210, 1170, 1110, 1010, 940, 840, 730; 6,, (80Nffiz, (CD3).SO, 2.79 (3H, s, I-CLI3), 3.05 (4H, s, H-2,2a,3 and 3a), 7.64 (IH, s, H-6), m/z 316 (M-, 23%), 298 (57), 10.70br (IH, s, 7-Offi, 13,42 (2H, s, exch. DO, 9- and 10-H)l 9_ 272 (34), 270 (100), 256 (24), 252 (21), 44 (22), 31 (29), 18 (51). Methyl 3,5,8-trihydroxy-1,6-dimethylanthra-9,10-quinone-2-carboxylate, Methyl leuco-6-deoxykermesate (0.200g, 0.6lmmol), piperidinium acetate (0. 90g, 0.63minol) and paraformaldehyde (.045g, 1.50mmol) in ethanol (10cm') methyl 3,5,8-trlhydroxy-1,7dimethyl anthra-9, 1 0-quinone-2-carboxy late was obtained after column chromatography (silica gel -chloroform) as a red-orange solid (0. 1 84g, 89%), crystallising as dark red plates (ethanot) mp 247T, Rf 0.31 (chloroform); (Found: C, 63.01; H, 4.03. Cl,H1, 07 requires C, 63.16; H, 4.12%); u.a. /cm-'(KBr), 3450br (O-H), 1700 (C=O, ester), 1680, 1630 (C=O, qwnone), 1590 (aryl); 8,, (80MHz, WC13) 2.33 ( 3H, s, 6-Me), 2.95 (3H, s 1 -Me), 4.03 (3H, s, 2-CO2Me), 7.11 (IH, s, 7H), 7.78 (IH, s 4-H), 10.35 (IH, s, exch. WO, 3-OH) 13.03, 13.14 (2H, 2s, exch. D20, 5- and 8-OH); m/z (M), 342 (M', 16%), 310 (51), 240 (100), 239 (17).

This compound was found suitable for X-ray structure determination. Methylation gave the 3,5,8-trimethyl ether.

Methyl 3,5,8-trimetboxy-1,6-dimethylanthra-9,10-quinone-2 carboxylate From methyl 3,5,8-trihydroxy- 1,6-dimethylanthra-9,1 0-quinone-2-carboxy late (.050g, 0.15mmol), potassium carbonate (1.00g, 7.25minol) and dimethyl sulfate (0. 50cin', 0.67g, 5.3mmol) in refluXing dry acetone (20CM3), the product was obtained after prep TLC (silica gel, CH03-Et0Ac, 10: 1) as a yellow solid (0.051g, 91%) which crystallised (ethanol) as fine yellow needles mp 180C, Rf 0.61 (above solvent); (Found: C, 63.35;H, 5.24. CIH_,007 requires C, 65.62; H, 5.24%; (KBr), 3960 (C-H, aliph.), 1740 (C=O, ester), 1680 (C=O, quinone), 1590 (aryl); 8. (80MHz, CDC13) 2.49 (31- s, 6-Me), 2.62 (3H, s, 1-Me), 3.87, 3.92, 3.93 (4x3H, 3s, 3-,5-, 8-OMe and 2-CO,Me), 7.11 (IH, s, 7-H), 7.51 (IH, s, 4-H); m/z (S), 385 (23), 384 (Nr, 100%), 370 (17), 369 (80), 367 (33), 338 (13), 337 (22), 325 (10), 323 (16).

Methyl 3,5,8-trimethoxy-1,7-dimethylanthra-9,10-quinone-2-carboxylate From methyl leuco-6-deoxykermesate (0.200g, 0.6lmmol) and 37% formaldehyde solution (80gl, 0.99minol) in a mixture of THF (Scm')., methanol (5CM3) and LIM aqueous sodium hydroxide (5 CM3), a mixture of methyl 6-deoxykermesate and methyl 3,5,8-trthydroxy-1,7dimethylanthra-9,1 0-quinone2-carboxyl ate resulted; (for the latter) 8H (80MHZ, CDC13), 3.3 5 (3H, s, 7-Me), 2.96 (3H, s, 1-Me), 4.02 (3H, s, 2-CO,Me), 7.06 (IH, s, 6-H), 7.78 (IH,s, 4H), 10.25 (IH, s, exch. D20, 3-OH), 13.37,13.53 (2H, 2s, exch. D,0,5- and 8-OH).

Methylation in acetone (20cm 3) containing potassium carbonate (1.0g, 7. 25minol) and dimethyl sulfate (0. 50cm) and purification by prep TLC (silica gel, CHCl, -IEt0Ac,l: 1) gave the product as a yellow solid (0. 1 14g, 49%), which crystallised (ethanol) as orange prisms, mp 1.72'C, Rf 0.61 (above system); (Found: C, 65.65; H, 5.18. C,1H,007 requires C, 65.62; H, 5.24%); (KBr), 2960 (C-H, aliph.), 1740 (C=O, ester), 1675 (C=O, quinone), 1590 (aryl); 8. (80 NS&, CDC13), 2.39 (3H, s, 7-Me), 2,61 (3H, s, 1-Me), 3.84, 3.92, 3.95x2 - m/z (E1), 385 (20), (4x3H, 3s, 3-, 5, 8-OMe, 2-CO,Me), 7.04 (IH, s, 6-H), 7.52 (IH, s, 4-H)l 384 (M-, 100%), 370 (10), 369 (75), 367 (33), 354 (11), 353 (28), 352 (15), 351 (30), 338 (10), 337 (25), 325 (11), 33 (16).

Methyl 3,5,8-tiihydroxy-7-(a-hydroxybenzyl)-1-methylanthra-9,10-quinone-2carboxyla te To methyl 6-deoxykermesate (0.200g, 0,61Ommol) and sodium dithionite (0.200g) in methanol (5cm') under nitrogen, 1. 1 M aqueous sodium hydroxide (5 CM3) was added. After 10min. the solution which had turned from dark purple to a muddy brown was cooled to O'C and benzaldehyde (0.130g, 1.22mmol) in tertrahydrofuran (5 CM3). The mixture was stirred for 45min. after which air was passed through the solution for 10min. at OOC to restore the J1- quinone. The mixture was acidified with acetic acid, extracted with dichloromethane, the extracts were dried, concentrated in vacou and the residue purified by column chromatography (silica gel-chloroform) to give a red solid (0.188g, 71%) which crystallised (toluene) as red needles, mp 194-186'C, Rf 0.18 (CHG3); (Found: C, 66.21; H, 4.24. C24H1,0, requires C, 66.36; H, 4.1M u,,,,.,/cm-1 (KBr), 3520 (O-H), 1720 (C=O, ester), 1690, 1630 (C=O, quitione), 1590 (aryl); 6H (80MHz, CDC13),2.77 (IH, d, J 5Hz, exch. D.0) 6/7-CH(QH),Pli), 2.98 (3H, s, 1-Me), 4.03 (3H, s, 2-COMe), 6. 47 (IH, d, J5Hz, becomes a singlet on D.0 exch., 6/7-CH(OH)Ph), 7.2-7.9 (6H, m, 6-H and 6/7-CH(OH)Ph), 7.51 (IH, s, 6/7-H), 7.82 (114, s, 4-H), 13.13 and 13.18 (2H, 2s, exch. D,O, 5-OH and 8-OH); mIz (E1), 424 (M' 62%), 418 (59), 416 (63), 387 (31), 386 (96), 384 (100), 383 (72).

1-Methyl-7-(1 RS,2 R,3S,4S,5 S)-2,3,4,5,6- pen ta benzyl'o xy- 1-hyd ro xyh exyl-3,5,8trihydroxyanthra-9,10-quinone-2-carboxylic acid, (5; R = H) For this reaction 2,3,4,5,6-pentaO-benzylglucose, was prepared from Dglucose diethyldithioacetal (prepared in 64% yield) by benzylation with benzyl chloride in DMI containing sodium methoxide (88% yield) and the dithioacetal group removed by treatment in aqueous THIF with boron trifitionde etherate and red mercuric oxide to give the product in 86% yield. The overall yield was 76% compared with that more recently describedof 64% (R.R. Schmidt and W. Frick, Tetrahedron, 1988, 44, 7163).

To methyl leuco-6-deoxykermesate (0.005g, 1.508x10-'mmol) in aqueous methanol (Icm') and IM aqueous NaOH (Icm') at O'C, 2,3,4,5,6-penta-0benzyl-D-glucose (0.019g, 3.016x10-2 mmol) was added and the reaction mixture monitored by TLC. Powdered potassium hydroxide was added until the mixture assumed a muddy brown colour and TLC indicated a strong red spot in addition to those for methyl 6-deoxykermesate, 6-deoxykermesate salts and 2,3,4,5,6penta-0-benzylglucose. The mixture was acidified and extracted with dichloromethane, the extracts dried and column chromatographed to give (i) 2,3,4,5,6-penta-0-benzylglucose, (11) 6deoxykermesic acid (111) a red syrup (7.5mg) containing (5; R = H); [m/z (FAB): 967 (C57H.530,3 Na, requires 967)1; u,,,a., /cm-'(film), 3400 (OH), 1950, 1880, 750, 700 (CH.Ph); 8H (200MHz, CD30D), 7.25 (4-H, 6-H).

Claims (1)

1. Claims (1) The synthesis of methyl leuco-6-deoxykennesate by chemical and

   catalytic methods.

   (2) The synthesis of 1 -methyl - 7-(1 RS,2R, 3 S,4 S, 5 S)- 2,3,4,5,6 pentabenzy 1 oxy - 1 -hy droxyhexy I3,5,8-trihydroxyanthra-9, 1 0-quinone.

   (3) Conditions for the formation of 7-(a-hydroxyalkyl) derivatives of methyl 6deoxykermesate from methyl 6-deoxykermesate.

   (4) Conditions for the formation of 7-((x-hydroxyalkyl)derivatives of 6deoxykermesic acid.

   (5) The synthesis of 1 -methyl 7-(1 RS,2R,3 S,4S,5S)-2,3,4,5,6pentabenzyloxy- 1 -hydroxyhexyl- 3 n 1 1 1 1 3,5,8-t "hydroxyanthra-9,10-qu'none-2-carboxyl'c acid and its methyl ester.

   1 AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS 1 The synthesis of alkyl 1-methyl-7-(IRS,2R,3S,4S, 5S)-2,3,4,5,6pentabenzyloxy-lhydroxyhexyl-3,5,8-trihydroxyanthra-9,10-qui none-2carboxylates from the reaction of alkyl leuco-6-deoxykermesates with 2,3, 4,5,6-penta-0-benzyl-D-glucose. 2 The synthesis of 1-methyl-7-(IRS,2R,3S, 4S,5S)-2,3,4,5,6-pentabenzyloxy-lhydroxyhexyl-3,5,8-tnhydroxyanthra-9,10quinone-2-carboxylic acid by the same process. 3 The synthesis of alkyl leuco-6-deoxykermesates by chemical and catalytic methods. 4 The synthesis of methyl leuco-6-deoxykermesate from methyl 6-deoxykermesate. 5 The synthesis of leuco-6-deoxykerrnesic acid from benzyl 6- deoxykermesate. 6 Reaction conditions for the formation of 7-((x- hydroxalkyl) derivatives of 6deoxykermesic acid.

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