合成路线1

The reaction of ascomycin (I) with Tbdms-Cl and imidazole gives the bis silylated compound (II), which is regioselectively monodesilylated by means of aq. HF in acetonitrile to yield the monosilylated compound (III). The silylation of (III) with 2-bromophenyldimethylsilyl chloride (IV) and imidazole affords the new disilylated compound (V), which is submitted to radical translocating/reducing conditions by means of Et3N/O2 as radical initiator and Bu3Sn2H as deuterium source. Under these conditions a mixture of labeled compounds (VI) and (VII) is obtained where about 70% is the ascomycin labeled compound (VI) and 30% the aromatic labeled compound (VII).

合成路线2

This mixture is desilylated by means of aq. HOAc in THF to yield a 53:47 mixture of labeled and unlabeled ascomycin.

合成路线3

The silylation of the known compound FK-520 by means of tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the disilylated compound (II), which is selectively monodesilylated by means of 40% HF in acetonitrile for 2 h at 0 C yielding the monosilylated compound (III). The chlorination of (III) by means of triphenylphosphine in refluxing CCl4 gives the chloro derivative (IV), which is finally desilylated with 40% HF in acetonitrile at room temperature.

合成路线4

Ascomycin (I) was protected as the C24,C32-bis(tert-butyldimethyl- silyl)ether (II), and then was selectively desilylated at the C32 position with p-toluenesulfonic acid in MeOH-CH2Cl2. The resulting monosilylated compound (III) was treated with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid to provide the C32 allyl ether (V). Subsequent dihydroxylation of the allyl group of (V) using N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 afforded glycol (VI), and further oxidative cleavage of (VI) with sodium metaperiodate produced aldehyde (VII).

合成路线5

In a further procedure, 3,5-dimethoxybenzoic acid (X) was converted to the acetophenone (XI) using methyllithium. Treatment of (XI) with phenyltrimethylammonium tribromide provided the dibromoacetophenone (XII) which, upon reaction with morpholine at 55 C, followed by hydrolysis with aqueous HCl, gave the phenylglyoxal (VIII). Alternatively, (VIII) was prepared directly by treating acetophenone (XI) with DMSO and HBr or by oxidation with SeO2. Condensation of the phenylglyoxal (VIII) with methyl glyoxylate hemiacetal (XIII) and ammonium acetate produced the phenylimidazole (XIV), which was protected as the tetrahydrofuranyl derivative (XVI) with dihydrofuran and catalytic p-TsOH. Reduction of the protected imidazole ester (XVI) with LiBH4 provided alcohol (XVII), and then reaction of (XVII) with trichloroacetonitrile in the presence of DBU furnished the acetimidate (XVIII). Finally, the target compound was obtained by reaction of ascomycin (I) with trichloroacetimidate (XVIII) in the presence of fluoboric acid etherate, followed by hydrolytic deprotection.

合成路线6

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylate hemiacetal (II) and ammonium acetate in acetonitrile gives the imidazole derivative (III), which is protected with dihydrofuran (IV) and TsOH, yielding compound (V). The reduction of the ester group of (V) with LiBH4 affords the carbinol (VI), which is esterified with trichloroacetonitrile (VII) to provide the trichloroacetimidate (VIII). The condensation of (VIII) with ascomycin (IX) by means of CF3SO3H in N,N-dimethylpivalamide gives the adduct (X), which is finally deprotected with hot aqueous CF3SO3H.

合成路线7

The title compound was obtained by treatment of ascomycin (I) with triphosgene and 4-dimethylaminopyridine at -78 C to produce selectively the 32-hydroxyl mono-acylated product (II), which was subsequently condensed with phenylhydrazine yielding the target phenylcarbazate.

合成路线8

Protection of ascomycin (I) by means of tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of 2,6-lutidine provided the 14,4''-disilylated derivative (II). Selective removal of the 4''-silyl group of (II) with para-toluenesulfonic acid in MeOH-CH2Cl2 yielded the 14-protected compound (III). This was converted to allyl ether (V) upon treatment with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid. Dihydroxylation of the allyl double bond of (V) with OsO4 and N-methylmorpholine-N-oxide, followed by oxidative cleavage of the resulting diol (VI) with sodium metaperiodate furnished aldehyde (VII).

合成路线9

The condensation of the 32-OH of ascomycin (I) with the diazoketone (II) by means of a Rh catalyst gives the addition product (III), which is silylated at the 24-OH with TES-Cl yielding the silyl ether (IV). The reduction of the new carbonyl group of (IV) with the chiral reducing agent (S)-OAB/BH3 and TEA affords the silylated target compound (V), which is finally treated with HCl to eliminate the TES- group.

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