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SYNTHESIS OF 6-ALLYL-7-HYDROXY-5-METHOXY-4-METHYLPHTHALIDE, AKEY INTERMEDIATE IN THESYNTHESIS OF MYCOPHENOLICACIDAdrián Covarrubias-Zúnniga a , José Diaz-Dominguez a & José S. Olguín-Uribe ba Instituto de Quimica, Universidad NacionalAutónoma de México, Circuito Exterior, CiudadUniversitaria, Coyoacán, 04510, Mèxicob Universidad Autónoma Metropolitana,Ixtapalapa, MèxicoPublished online: 09 Nov 2006.

To cite this article: Adrián Covarrubias-Zúnniga , José Diaz-Dominguez &José S. Olguín-Uribe (2001) SYNTHESIS OF 6-ALLYL-7-HYDROXY-5-METHOXY-4-METHYLPHTHALIDE, A KEY INTERMEDIATE IN THE SYNTHESIS OF MYCOPHENOLICACID, Synthetic Communications: An International Journal for Rapid Communicationof Synthetic Organic Chemistry, 31:9, 1373-1381, DOI: 10.1081/SCC-100104047

To link to this article: http://dx.doi.org/10.1081/SCC-100104047

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SYNTHESIS OF 6-ALLYL-7-HYDROXY-5-

METHOXY-4-METHYLPHTHALIDE,

A KEY INTERMEDIATE IN THE

SYNTHESIS OF MYCOPHENOLIC ACID

Adrian Covarrubias-Zuniga,1,* Jose Diaz-Dominguez,

1

and Jose S. Olguın-Uribe2

1Instituto de Quimica, Universidad Nacional Autonoma deMexico, Circuito Exterior, Ciudad Universitaria,

Coyoacan 04510, Mexico2Universidad Autonoma Metropolitana

Ixtapalapa, Mexico

ABSTRACT

A convergent aromatic annulation strategy based on theMichael addition of the dimethyl 1-allyl-1,3-acetonedicarbox-ylate anion 8 to 4-pivaloyloxy-2-butynal 9, followed bya regiocontrolled Dieckmann-type cyclization over theadequate methyl ester group, has been applied to an efficientformal synthesis of the antitumor antibiotic, mycophenolicacid 1. This tandem annulation reaction generates the fullysubstituted aromatic intermediate 12, which was transformedby a simple six-step sequence to 2, and even to 1 by themethodology of Birch et al.15

1373

Copyright & 2001 by Marcel Dekker, Inc. www.dekker.com

SYNTHETIC COMMUNICATIONS, 31(9), 1373–1381 (2001)

*Corresponding author.

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Mycophenolic acid (1) is produced as a metabolite of a number ofPencillium spp., notably brevi-compactum.1–3 Its structure was proposed byRaistrick.4 The synthesis of a degradation product with the phthalidic ske-leton was realized by Logan and Newbold,5 which confirmed the structureexcept for the configuration of the double bond. The biosynthesis of 1 hasbeen reported.6 It has diverse in vitro and in vivo biological activities,including antifungal,7,8 antibacterial,9–10 antiviral,11 and immunosuppres-sive12 properties. It has been tested clinically against various tumors withoutsuccess13 and has been found to be effective as an antipsoriatic.14

As far as we are aware, there are seven total syntheses15–21 and sixformal syntheses22–27 of 1 reported in the literature. The subject of thisarticle is a new formal synthesis of 1 through the phthalide 2 (Scheme 1),which has been reported as an intermediate in Birch’s15 and in Patterson’stotal syntheses of 1.19

The route to 2 described herein is based on the experience we acquiredin the synthesis of phenols28 3 and resorcinols29 4 using tandemreactions of dimethyl 1,3-acetonedicarboxylate anion 5 with alkynals 6

and alkyl alkynoates 7, respectivelty, (Scheme 2) and from a total synthesisof mycophenolic acid.30

RESULTS AND DISCUSSION

We now report the extension of these annulation strategies to a formalsynthesis of 1 that assembles the requisite aromatic unit present therein in asingle step, with all substituents already in place with high regiocontrol. Thekey step in this approach is the construction of the hexasubstituted resorci-nol derivative 12 (Scheme 3) via Michael addition of the carbanion 8 to thealkynal 9, followed by a regioselective Dieckmann-type cyclization of theresulting enolate 10, followed by a spontaneous aromatization of 11 to give12 in 32% yield.

1374 COVARRUBIAS-ZUNIGA ET AL.

Scheme 1.

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With compound 12 on hand, the completion of the synthesis wasaccomplished by employing the six-step sequence shown in Scheme 4.Dimethylation of resorcinol 12 with NaH and Me2SO4 in dry DMF gavecompound 13 in 86% yield, and subsequent reduction of the formyl groupwith NaBH4 in dry MeOH gave alcohol 14 in 86% yield. Alcohol 14 was

MYCOPHENOLIC ACID INTERMEDIATE 1375

Scheme 2.

Scheme 3.

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mesylated with MsCl and Et3N in CH2Cl2, and the crude mesylate wasreduced with NaBH4 to compound 15, in 80% overall yield from 12. Theformation of phthalide 16 was effected in quantitative yield on treatment of15 with K2CO3 in anhydrous MeOH. Finally, selective cleavage of 16 to 2

was achieved with BCl3 in CH2Cl2 as described by Birch et al.15

In conclusion, the synthesis reported in this article serves to highlightthe utility of our aromatic regiocontrolled annulation method as an efficientmethod for the rapid assembly of complex polysubstituted aromatic com-pounds. This highly convergent route, which delivers phthalide 2 in sevensteps from 8 and 9 (16% overall yield), can be effected at an multigram scale;it is noteworthy that the framework of the key aromatic intermediate 2 isformed in one regiocontrolled step from two aliphatic easily obtained com-pounds. This makes the synthesis of many analogues by the Patterson’s totalsynthesis19 easily feasible.

Melting points are uncorrected. Thin-layer chromatography was per-formed on silica gel 60 F254 plates and visualized by UV irradiation. 1HNMR spectra was recorded earlier at 200 or 300MHz, while 13C NMRspectra were run at 75MHz in CDCl3 solution. Low and high-resolutionmass spectra were measured at 70 eV (EI). Elemental analyses wereperformed by Galbraith Laboratories, Inc.; column chromatographypurifications were carried out using silica gel (70–230 mesh).

1376 COVARRUBIAS-ZUNIGA ET AL.

Scheme 4.

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Dimethyl 1-Allyl-1.3-acetonedicarboxylate (8)

Dimethyl 1,3-acetonedicarboxylate (18 g, 0.1 mol) was added dropwiseto a mixture of NaH (60%, 4.4 g, 0.11 mol) and dry THF (180 mL) withmagnetic stirring. To the resulting solution, allyl bromide (97%, 8 mL, 0.09mol) was added. After 14 h, the mixture was poured into dilute HCl (100mL), extracted with ethyl ether, and the organic phase was washed withwater (50 mL), dried over anhyd Na2SO4 and concentrated. The residuewas subjected to column chromatography (360 g of silica gel) and the ketoe-ster 8 (10.2 g, 53% yield) was eluted using 5% ethyl acetate in hexane. IR(neat) 1745, 1718, 1240 cm–1; 1H NMR � ppm 2.63 (tt, 2H, J ¼7, 1), 3.61(d, 2H, J ¼4.7), 3.70 (m, 1H), 3.73 (s, 6H), 5.00–5.20 (m, 2H), 5.60–5.82(m, 1H); 13C NMR � ppm 31.9, 48.1, 52.5, 58.1, 117.8, 133.7, 166.9, 169.0,196.7; MS m/z (relative intensity) 190 (Mþ -24. 100), 172 (40), 144 (27), 115(26). Anal. calc. for C10H14O5: C, 56.07; H, 6.54. Found: C, 56.01; H, 6.49.

4-Pivaloyloxy-2-butynal (9)

2-Butyn-1,4-diol (99%, 86.9 g, 1 mol) was dissolved in a mixture of drypyridine (160 mL) and dry CH2Cl2 (3 L). To the magnetically stirred sol-ution was added dropwise over a period of 6–8 h pivaloyl chloride (99%,99.6 mL, 0.8 mol). The mixture was stirred overnight at room temperature,then washed with H2O (2�1 L), dried with Na2SO4. The CH2Cl2 was dis-tilled and the pyridine removed by azeotropic distillation with toluene, togive a syrup that was purified by column chromatography (869 g silica geland 2% ethyl acetate in hexane as eluent), yielding 70.7 g of 4-pivaloyloxy-2-butynol as an oil (56% yield). 1H NMR � ppm 1.22 (s, 9H), 4.18 (t, 1H, J¼1.88), 4.30 (td, 2H, J ¼1.88, 6.08), 4.70 (t, 2H, J ¼1.88). Anal. calc. forC9H14O3: C, 63.52; H, 8.23. Found: C, 63.58; H, 8.23. Found: C, 63.58; H,8.29. This alcohol was oxidized to 9 according to the procedure of Velievand Guseinov31 in 38–42% yield. 1H NMR � ppm 1.24 (s, 9H), 4.86 (s, 2H),9.24 (s, 1H). Anal. calc. for C9H12O3: C, 64.28; H, 7.14. Found: C, 64.33;H, 7.16.

2-Allyl-6-formyl-4-methoxycarobonyl-5-pivaloyloxymethyl

Resorcinol (12)

(1.2 g, 5.60mmol) was added dropwise to a suspension of NaH (60%,0.28 g, 7.0mmol) in dry THF (12 mL) with magnetic stirring. To the result-ing solution, 4-(Pivaloyloxy)-2-butynal (0.989 g, 5.88mmol) was added and,

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after 2 h, the mixture was poured into dilute HCl (15mL). The organicphase was separated and the aqueous phase was extracted with ethyl acetate.The combined organic phase was washed with bring (50mL), dried overanhyd. Na2SO4, and concentrated. The residue was subjected to columnchromatography, the resorcinol 12 (0.63 g, 32%) being eluted with 5%ethyl acetate in hexane (50 g of silica gel): 12: IR (neat) 3381, 1733, 1668,1638 cm–1; 1H NMR � ppm 1.10 (s, 9H), 3.45 (d, 2H, J ¼ 6), 3.96 (s, 3H),4.90–5.12 (m, 2H), 5.62 (s, 2H), 5.85–6.04 (m, 1H), 10.18 (s, 1H), 11.79 (s,3H), 11.90 (s, 1H); 13C NMR �ppm 26.5, 27.0, 38.8, 53.0, 58.5, 107.2, 113.5,115.3, 115.9, 134.7, 141.8, 165.2, 135.3, 170.6, 177.7, 194.0; MS m/z (relativeintensity) 350 (Mþ, 8), 22(265), 248 (100), 57 (57), Anal. calc. For C18H22O7:C, 61.71; H, 6.28. Found: C, 61.82; H, 6.33.

2-Allyl-6-formyl-4-methyoxycarbonyl-5-pivaloyloxymethyl Resorcinol

Dimethyl Ether (13)

12 (0.6 g, 1.71mmol) was dissolved in dry DMF (12mL) and NaH(0.158 g, 3.9mmol) was added portionwise with stirring. Me2SO4 (0.5 g,4.0mmol) was added dropswise and stirring continued for 6 h. The reactionmixture was poured into water (30mL) and extracted with ether (3�50mL).The organic layer was separated, washed with water (20mL) and brine(20mL), dried (Na2SO4) filtered, and concentrated. The residue was purifiedby column chromatography (eluant ethyl acetate:hexane, 0.3: 9.7, 24 g ofsilica gel) affording 13 (564mg, 87%): IR (neat) 1732, 1694, 1208, 1153 cm–1;1H NMR � ppm 1.15 (s, 9H), 3.47 (d, 2H, J ¼ 4.8), 3.84 (s, 3H), 3.91 (s, 1H),4.95–5.20 (m, 2H), 5.33 (s, 2H), 5.90–6.05 (m, 1H); 10.40 (s, 1H); 13C NMR� ppm 26.8, 27.1, 38.7, 52.7, 59.9, 62.7, 64.6, 116.0, 125.2, 126.9, 128.7,135.2, 160.7, 164.4, 166.9, 177.9, 190.6; MS m/z (relative intensity) 347(Mþ-MeOH), 2), 276 (100), 261 (87), 57 (48),. Anal. calc. for C20H26O7:C, 63.49; H, 6.87. Found: C, 63.57; H, 6.91.

2-Allyl-6-hydroxymethyl-4-methoxycarbonyl-5-pivalyoxymethyl

Resorcinol Dimethyl Ether (14)

13 (0.5 g, 1.3mmol) was dissolved in dry MeOH (5mL) and NaBH4

(49.2mg, 1.3mmol) was added with stirring. After 0.5 h the reaction mixturewas poured into water (15mL), extracted with ether (4� 20mL), the organiclayer was separated, dried (Na2SO4), filtered and concentrated. The residuewas purified by column chromatography (eluant ethyl acetate:hexane,0.6:9.4) affording 14 (434mg, 86%). IR (neat) 3485, 1731, 1202, 1150 cm–1;

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1H NMR � ppm 1.14 (s, 9H), 3.40–3.47 (broad d, 2H), 3.70–3.85 broad s,exchange with D2O, 3.76 (s, 3H), 3.90 (s, 3H), 4.76 (s, 2H), 4.95–5.05 (m,1H), 5.03 (t, 1H, J ¼ 1.8); 5.27 (s, 2H), 5.90–6.05 (m, 1H); 13C NMR � ppm27.0, 28.9, 38.9, 52.4, 56.3, 60.9, 62.7, 63.2, 115.5, 125.7, 128.4, 19.9, 132.9,136.4, 157.0, 159.7, 167.7, 178.6; MS m/z (relative intensity) 363 (Mþ-OH,8), 278 (52), 247 (100), 57 (83). Anal calc. for C20H28O7: C, 63.15; H, 7.36.Found: C, 63.32; H, 7.49.

2-Allyl-4-methoxycarbonyl-6-methyl-5-pivaloyloxymethyl Resorcinol

Dimethyl Ether (15)

The alcohol 14 (0.45 g, 1.18mmol) was dissolved in dry CH2Cl2(5mL), the solution was cooled in an ice bath and with stirring wereadded dry Et3N (0.35mL, 2.36mmol) and MsCl (0.14mL, 1.77mmol).The solution was stirred at 25�C for 1.5 h, then purified into 10ml ofwater and extracted with ether. The ether extract was dried (Na2SO4), fil-tered, and concentrated to give a residue that was dissolved under a N2 atminto dry DMF (5mL), and NaBH4 (22mg, 0.59mmol)) was added. Thereaction mixture was stirred for 1.5 h at 25�C, then poured into ice water(20mL) and extracted with ether. Drying, filtration, and concentration ofthe organic layer gave an oily residue that was purified by column chroma-tography using ethyl acetate:hexane (0.5:9.5) as eluant. 15 (344mg) wasobtained in 80% yield. IR (neat) 1733, 1204, 1150 cm–1; 1H NMR � ppm1.56 (s, 9H), 2.65 (s. 3H), 3.80–3.95 (broad d, 2H), 4.15 (s, 3H), 4.27 (s, 3H),5.37–4.00 (m, 1H), 5.44 (s, 2H), 6.35–6.45 (m, 1H), 13C NMR � ppm 27.1,28.9, 38.9, 52.3, 60.9, 61.4, 62.8, 115.4, 115.3, 126.0, 127.7, 127.8, 131.8,131.7, 136.7, 154.6, 159.0, 168.1, 178.1; MS m/z (relative intensity) 364(Mþ, 14), 263 (61), 247 (93), 232 (100), 57 (28). Anal. calc. for C20H28O6:C. 65.93; H, 7.69. Found: C, 66.11, H, 7.86.

6-Allyl-5,7-dimethyoxy-4-methylphthalimide (16)

15 (0.25 g, 0.68mmol) was dissolved in dry MeOH (2.5mL) andanhyd.K2CO3 (12.5mg. 0.09mmol) was added with stirring. After 1.5 h,the reaction mixture was poured into H2O (10mL) and extracted withether (4� 15mL). Drying, filtration, and concentration of the organiclayer gave 170mg (quantitative yield) of 16. IR (neat) 1759, 1601, 1131,772 cm–1; 1H NMR � ppm 2.19 (s, 3H), 3.40–3.50 (m, 2H), 3.79 (s, 3H),4.06 (s, 3H), 4.90–5.08 (m, 2H), 5.15 (s, 2H), 5.87–6.11 (m, 1H); 13C NMR �ppm 11.5, 28.5, 29.6, 61.2, 62.8, 68.3, 115.2, 119.9, 127.3, 136.9, 147.0, 156.8,

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162.8, 168.8; MS m/z (relative intensity) 248 (Mþ, 100), 233 (48), 217(90), 207 (50); Anal. calc. for C14H16O4: C, 67.74; H, 6.45. Found:C, 67.83; H, 6.62.

6-Allyl-7-hydroxy-5-methoxy-4-methylphthalide (2)

To 25mg of 16 was added 12mL of BCl3 (1M in Ch2Cl2) with stirring.After 10 days at 25�C. H2O (25mL) was added, the organic layer wasseparated and washed with H2O. Drying over Na2SO4 and evaporation todryness afforded 20mg of 17 (85%) : m.p. 91–92�C (EtOH/H2O) (lit.15,18

91–92�C).

ACKNOWLEDGMENTS

This research was supported by a Grant-in-aid for Scientific researchNo. 27610-\E from CONACYT, Mexico.

The authors thank Professor Joseph Muchowski and Dr. Noe Zunigafor helpful discussions. We thank Messrs. C. Conteras, R. Patino, R.Gavino, L. Velasco, and F.J. Perez. for running the spectra.

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Received in the USA July 24, 2000

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