Expedient Synthesis, on Large Scale, of Aliphatic Chaetomellic Anhydrides from N-Allyl-2,2-dichlorocarboxyamides

Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor

“…The conversion was efficiently achieved in four easy steps: i ) reaction of the anhydride with a stoichiometric amount of NaOH in THF/H 2 O, ii ) evaporation of the solution under vacuum, iii ) re-dissolution of the remaining material in water, and finally iv ) freeze-drying. 19a Using this procedure we also prepared the sodium maleates 2 and 26 , from the anhydrides 3 and 18 secured in this work, and 28 , from 3-hexadecyl-4-methylfuran-2,5-dione 21c that we had in stock (Figure 3). …”

“…21a,b The same strategy was then applied to N -(2-pyridyl)- N -allyl-2,2-dichlorohexadecanamide 6 (Scheme 3), the preparation of which uses a more accessible secondary allylamine. The lack of the Cl atom in the allyl moiety, in this case, called for the introduction of an oxidative extra step in the synthetic route.…”

“…The lack of the Cl atom in the allyl moiety, in this case, called for the introduction of an oxidative extra step in the synthetic route. 21c …”

“…The former is the use of α-perchlorocarboxylic acids (these starting materials are not very easy to prepare), while the latter is the lack of a perfect control of the ATRC stereoselectivity. This is a critical event for the economy of the process since the FR reaction is viable only in the case of cis -lactams, 21b,22 and the cis/trans ratio of the γ-lactams, delivered by the ATRC step, is acceptable only when these lactams carry a bulky substituent at C-3 and a chloro- or a dichloro-methyl group at C-4. In fact, when we tested the viability of the complementary strategy, in which the methyl substituent is introduced through the acid reagent while the long aliphatic chain is added through the allylamino moiety, the stereoselectivity of the ATRC lactam was disappointing (the dichloro-γ-lactam from the cyclization of N -benzyl- N -[( E )-2-hexenyl)]-2,2-dichloropropanamide was recovered as a 66/34 cis/trans mixture of four diastereomers).…”

“…In fact, when we tested the viability of the complementary strategy, in which the methyl substituent is introduced through the acid reagent while the long aliphatic chain is added through the allylamino moiety, the stereoselectivity of the ATRC lactam was disappointing (the dichloro-γ-lactam from the cyclization of N -benzyl- N -[( E )-2-hexenyl)]-2,2-dichloropropanamide was recovered as a 66/34 cis/trans mixture of four diastereomers). 21c Since a practical route to functionalized 2,2-dichloro acids appeared impracticable, the ATRC-FR approach to chaetomellic acid A analogues lost any appeal.…”