The methylation of N-(benzyloxycarbonyl)-L-isoleucine (I) with Me-I and NaH in THF gives the N-methyl derivative (II), which is reduced with BH3 in THF to yield the isoleucinol (III). The oxidation of (III) with SO3/pyridine in DMSO affords the isoleucinal (IV), which is condensed with tert-butyl acetate (V) by means of BuLi and THF to afford the chiral beta-hydroxyheptanoate (VI). Finally, this compound is O-methylated by means of diazomethane and BF3 in ethyl ether/dichloromethane and N-deprotected by hydrogenation with H2 over Pd/C in ethyl acetate/methanol to provide the desired intermediate, the chiral tert-butyl heptanoate (VII).
The reaction of L-prolinol (VIII) with Boc2O gives N-Boc-L-prolinol (IX), which is oxidized with SO3/pyridine in DMSO to afford N-Boc-L-prolinal (X). The condensation of (X) with the propionate ester (XI), by means of LDA in THF, affords the 3-hydroxy-3-(2-pyrrolidinyl)propionate ester (XII), which is methylated with diazomethane and BF3 in dichloromethane to provide the corresponding methoxy derivative (XIII). The epimerization of the (S)-methyl group of group of (XIII) by means of t-Bu-OK in THF gives the corresponding (R)-methyl derivative (XIV), which is finally hydrogenolyzed with H2 over Pd/C in ethyl acetate/methanol to yield the desired pyrrolidinylpropionic acid intermediate (XV).
The reduction of N-Boc-L-phenylalanine (XVI) with diborane in THF gives N-Boc-L-phenylalaninol (XVII), which is oxidized with SO3/pyridine in DMSO to yield N-Boc-L-phenylalaninal (XVIII). The cyclization of (XVIII) with 2-sulfanylethylamine (XIX) affords the thiazolidine (XX), which is dehydrogenated by means of MnO2 to provide the thiazole derivative (XXI). Finally, compound (XXI) is N-deprotected by a treatment with TFA to provide the 2-phenyl-1(S)-(2-thiazolyl)ethylamine intermediate (XXII).
The condensation of N-(benzyloxycarbonyl)-L-valine (XXIII) with intermediate heptanoate (VII) by means of NMM and Piv-Cl gives the dipeptide (XXIV), which is N-deprotected by means of H2 over Pd/C to yield the dipeptide (XXV). The condensation of (XXV) with N,N-dimethyl-L-valine (XXVI) (obtained by reductomethylation of L-valine (XXVII) with formaldehyde and H2 over Pd/C) by means of pentafluorophenyl trifluoroacetate and TFAA in pyridine affords the tripeptide (XXVIII), which is treated with TFA to cleave the tert-butyl group, yielding the tripeptide (XXIX). The condensation of (XXIX) with intermediate dipeptide (XXX) by means of DEPC provides the target pentapeptide dolastatin 10. The intermediate dipeptide (XXX) is obtained by condensation of intermediate (XV) with intermediate (XXII) by means of DEPC to give the dipeptide (XXXI), which is N-deprotected by treatment with TFA to afford the desired dipeptide (XXX).
The reaction of N-Boc-L-isoleucine (I) with O-methylhydroxylamine (II) by means of PyBOP gives the corresponding amide (III), which is condensed with allylmagnesium bromide (IV) to afford the octenone (V). The reduction of (V) with NaBH4 yields the carbinol (VI), which is N- and O-methylated with Me-I and NaH to provide the dimethylated compound (VII). Finally, the terminal double bond of (VII) is oxidated by means of NaIO4 and RuO2 to furnish the desired intermediate, the amino acid (VIII).
The reaction of N-Boc-L-proline (IX) with O-methylhydroxylamine (II) gives the corresponding amide (X), which is reduced with LiAlH4 to N-Boc-L-prolinal (XI). The condensation of (XI) with boronate (XII) yields the carbinol (XIII) as the greater isomer, and it is methylated with Me-I and NaH to afford the methyl ether (XIV). Finally, the terminal double bond of (XIV) is oxidated by means of RuO4 to furnish the desired intermediate, the amino acid (XV).
The reduction of N-(benzyloxycarbonyl)-L-phenylalanine (XVI) gives the corresponding aldehyde (XVII), which is cyclized with 2-sulfanylethylamine (XVIII) to yield the thiazolidine (XIX). The dehydrogenation of (XIX) by means of MnO2 affords the thiazole derivative (XX). Finally, the amino group of (XX) is deprotected with HBr to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XXI). Alternatively, N-(benzyloxycarbonyl)-L-phenylalanine (XVI) can be converted into the corresponding amide (XXII), which is treated with the Lawesson's reagent to yield the thioamide (XXIII). Finally, the cyclization of (XXIII) with 2-bromoacetaldehyde (XXIV) gives already reported thiazole derivative (XX) (partial racemization occurs during the synthetic process). Enantiomeric separation takes place in a later stage.
The condensation of intermediate (XXI) with intermediate (XV) by means of BOP and DIEA gives the dipeptide (XXIV) partially racemized, which is easily purified by chromatography. The deprotection of (XXIV) by means of TFA yields dipeptide (XXV), which is condensed with intermediate (VIII) by means of BOP and DIEA to afford tripeptide (XXVI). The deprotection of (XXVI) by means of TFA yields tripeptide (XXVII), which is condensed with N-(benzyloxycarbonyl)-L-valine (XXVIII) by means of BrOP and DIEA to afford tetrapeptide (XXIX). The deprotection of (XXIX) by means of HBr provides tetrapeptide (XXX), which is finally condensed with N,N-dimethyl-L-valine (XXXI) by means of COMMOD to afford the target dolastatine.
The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 2-bromopropionyloxazolidinone (II) by means of Co(PPh3)4 in THF gives the chiral beta-hydroxyamide (III), which is methylated by means of trimethyloxonium tetrafluoroborate in dichloromethane to yield the methyl ether (IV). Finally, elimination of the chiral auxiliary of (IV) by means of LiOH and H2O2 affords the target amino acid intermediate (V) (see scheme no. 14950701a , intermediate (XV)).
The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 3-propionyloxazolidinone (II) by means of Bu2B-OTf in dichloromethane gives the chiral beta-hydroxyamide (III), which is submitted to elimination of the chiral auxiliary by hydrolysis with LiOH and H2O2 in THF/water to yield the hydroxyacid (IV). The methylation of (IV) with Me-I and NaH in THF affords the methoxyacid (V). The condensation of intermediate (V) with 2-phenyl-1(S)-(2-thiazolyl)ethylamine (VI) by means of (EtO)2P(O)CN and DIEA gives the dipeptide (VII). The deprotection of (VII) by means of TFA yields dipeptide (VIII), which is condensed with the beta-methoxy-gamma-aminoacid (IX) as before to afford tripeptide (X). The deprotection of (X) by means of TFA yields tripeptide (XI), which is condensed with N-Boc-L-valine (XII) by means of BopCl and DIEA to afford tetrapeptide (XIII). The deprotection of (XIII) by means of TFA provides tetrapeptide (XIV), which is finally condensed with N,N-dimethyl-L-valine (XV) by means of (EtO)2P(O)CN and TEA to afford the target dolastatine.
The reaction of N-Boc-L-isoleucine (I) with the lithium derivative of tert-butyl acetate (II) by means of CDI in THF gives the beta-ketoester (III), which is reduced with NaBH4 in methanol to yield the desired (R)-alcohol (IV). N- and O-methylation of (IV) by means of LiHMDS and Me-OTf in HMPA/THF affords the fully methylated ester (V), which is finally hydrolyzed with HCO2H to furnish the desired intermediate, the methylated amino acid (VI).
The reaction of N-Boc-L-prolinal (VII) with the boron enolate (VIII) in ethyl ether gives the chiral beta-hydroxythioester (IX), which is transesterified with K2CO3 and ethanol to afford the beta-hydroxypropionate (X). The methylation of the OH group of (X) with LiHMDS and Me-OTf as before provides the methoxyester (XI), which is finally hydrolyzed with LiOH in aq. ethanol to furnish the desired intermediate, the methoxy amino acid (XII).
The reduction of N-Boc-L-phenylalanine (XIII) with B2H6 in THF gives the expected alcohol (XIV), which is oxidized with SO3/pyridine to yield the corresponding aldehyde (XV). The cyclization of (XV) with 2-sulfanylethylamine (XVI) affords the thiazolidine (XVII), which is dehydrogenated by means of MnO2 to afford the thiazole derivative (XVIII). Finally, the amino group of (XVIII) is deprotected with HCl to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XIX).
The condensation of intermediate (XIX) with intermediate (XII) by means of DEC and TEA gives the dipeptide (XX). The deprotection of (XX) by means of HCl yields dipeptide (XXI), which is condensed with intermediate (VI) by means of DEC and TEA to afford tripeptide (XXII). The deprotection of (XXII) by means of HBr yields tripeptide (XXIII), which is condensed with N-Boc-L-valine (XXIV) by means of BOPCl and TEA to afford tetrapeptide (XXV). The deprotection of (XXV) by means of HCl provides tetrapeptide (XXVI), which is finally condensed with N,N-dimethyl-L-valine (XXVII) by means of DEC and TEA to afford the target dolastatine.
The reaction of the chiral oxazolidinone (I) with (Boc)2O gives the N-protected oxazolidinone (II), which is irradiated with UV light in acetonitrile in the presence of Bu3Sn-SnBu3 and the allylstannane (III) to yield the chiral 5-allyloxazolidinone (IV). Ring cleavage of (IV) by means of Cs2CO3 in methanol affords the N-protected aminoalcohol (V), which is treated with Ms-Cl and TEA in dichloromethane to provide the mesylate (VI). Epimerization of the O-Ms group of (VI) by means of Cs-OAc and 18-crown-6 in refluxing benzene gives the epimeric acetate (VII), which is hydrolyzed with K2CO3 in methanol to yield the N-protected aminoalcohol (VIII). The O-methylation of (VIII) by means of Me-I and Tl-OEt in THF affords the methyl ether (IX), which is N-methylated by means of Me-I and NaH in THF to provide the N-methyl carbamate (X). Finally, the terminal double bond of (X) is oxidated with RuCl3 and NaIO4 in CCl4/acetonitrile/water to furnish the target intermediate, the carboxylic acid (XI) (see scheme no. 149507a, intermediate (VIII)).