合成路线1

Benzylic bromination of 3-bromo-o-xylene (IX) with NBS in the presence of benzoyl peroxide in refluxing CCl4 or chlorobenzene at 80 °C gives 1-bromo-2,3-bis(bromomethyl)benzene (X), which then cyclizes with benzylamine in the presence of KHCO3 in acetonitrile to yield 2-benzyl-4-bromoisoindoline (XI). Alkenylation of compound (XI) with tributyl(vinyl)tin (XII) by means of Pd(PPh3)4 in toluene provides the isoindoline (XIII), which is then deprotected by means of 1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-dichloroethane to afford 4-vinylisoindoline (XIV). Finally, coupling of 4-vinylisoindoline (XIV) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously activated with CDI, in DMF at 60 °C results in carbamate (XVI) .
Alternatively, debenzylation of 2-benzyl-4-bromoisoindoline (XI) by means of ACE-Cl in chlorobenzene at 90 °C, followed by condensation of the deprotected isoindoline (XVII) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously treated with CDI, by means of DIEA in DMF at 50 °C furnishes carbamate (XVIII). Then, alkenylation of the aryl bromide (XVIII) with potassium vinyltrifluoroborate (XIX) and Et3N in refluxing EtOH affords the vinyl isoindoline derivative (XVI) .
Finally, Boc-deprotection of proline derivative (XVI) by means of HCl in dioxane gives the corresponding amine (XX), which is then coupled with the L-tert-leucine carbamate derivative (XXI) in the presence of EDC, DIEA and HOAt or HOBt in DMF to yield the building block diene (I) .
The L-tert-leucine carbamate (XXI) is prepared by alkylation of ethyl isobutyrate (XXII) with 4-bromo-1-butene (XXIII) and LDA in HMPA, followed by ester group reduction with LiAlH4 in Et2O, affording 2,2-dimethyl-5-hexen-1-ol (XXIV) . After treatment of hexenol (XXIV) with triphosgene by means of DIEA and NaOH in 1,4-dioxane, the resulting chloroformate is condensed with L-tert-leucine (XXV) to give carbamate (XXI) .