Annulated Diketopiperazines from Dipeptides or Schöllkopf Reagents via Tandem Cyclization−Intramolecular N-Arylation

Abstract

Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in new approaches to enantio-pure polycyclic diketopiperazines from easily assembled dipeptides or functionalized Schöllkopf reagents.Several molecules containing a 2,5-diketopiperazine (1, DKP) moiety show promising biological activities which are helpful in treating human diseases (e.g., 2, 3). 1 However, there is no general method for the synthesis of enantiopure pyrazino[1,2-a]indole-1,4-diones (2), which have potent immunosuppressive and antimicrobial activities. Reported nonstereoselective methods for this important pharmacophore used a stepwise synthesis starting from indole 2-carboxylic acid derivatives. 2 Our studies in the area had its origin in an approach to lyngbyatoxin A, a potent PKC inhibitor, in which we planned to use a biosynthesisinspired 3 N-arylation to construct the 9-memebered lactam ( Figure 2). While investigating the properties of a dipeptide precursor (4, X = Y = Br) for this intramolecular N-arylation, we have uncovered a number of potentially useful transformations that are relevant to the synthesis of functionalized diketopiperazines, and here we report the details of these investigations.Our studies started with the assembly of the indolyldipeptide 13b (Scheme 1). 4 The starting point for the synthesis is a one-step preparation of 4,7-dibromo-indole 5 via the Bartoli protocol. 5 Reaction of 5 with POCl 3 and DMF gives the carboxaldehyde 6, which after BOCprotection of the nitrogen is converted into the dehydroamino acid derivative 12 via a modified Horner-Emmons reaction using the phosphonate 11. 6 Schmidt's phosphonate 11 was prepared by Rh-catalyzed carbene-insertion into an N-H bond of the amide 9. 7 The Horner-Emmons reaction of the aldehyde 7 with the phosphonate 11 under the prescribed procedure gives 71% of the pure Z-dehydrodipeptide 12 after column chromatography. Installation of the additional chiral center in 12 turned out to be more challenging than we anticipated as even the best Rhcatalysts give only modest diastereoselectivity in the asymmetric hydrogenation reaction. Selected results of Rh-catalyzed hydrogenation of 12 with various catalysts are reported in Table 1 With the appropriately protected substrates 13b and 13c in hand we first examined various intramolecular amination procedures to prepare the 9-membered lactam. Our initial attempts focused on Pd-catalyzed N-arylation reactions [9] of 13c, under conditions remniscent of Buchwald's synthesis of dehydrobufotenine. 10 These experiments (Table 2, Supporting Information) 4 were uniformly unsuccessful and lead to no discernable products. Next we turned our attention to the Fukuyama modification 9f of the Ullmann-Goldberg reaction, which he has used very effectively to prepare highly functionalized nitrogen heterocyles. 11 Studies 4 of various substrates quickily revealed that the the substrate 13b, with both amines deprotected, is compatible with the standard conditions...

Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation

“…For the synthesis of the heterocycle-based fragments C (Scheme 3), we started with commercially available Boc- l -Val-OH, which was easily converted to the known [35,36] amide 16 . Careful amide dehydration by means of cyanuric chloride in DMF afforded the corresponding nitrile 17 , avoiding possible racemisation [37].…”

A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

“…In general, there is also a whole variety of possible stereoselective synthetic methods available to synthesize modified α-amino acids, such as the classical Schöllkopf-method [10] or catalytic approaches [11–12]. The unit B precursor of cryptophycin is a phenylalanine derivative.…”

Bartoli Indole Synthesis

“…Entries 5-8 feature the use of diethyl ether as a cosolvent with slight improvement in reaction yield. Murugan and colleagues prepared 4,7-diarylindole iodide-fluorescent sensors using 4,7-dibromoindole prepared in a Bartoli synthesis [39], and this latter indole was used by RajanBabu and coworkers to synthesize enantiopure polycyclic diketopiperazines [40]. Nevertheless, several combinations of Grignard reagent and nitrobenzene substrate in some cases failed to afford any indole; for example, the N-Boc nitrobenzene in Entry 7 gave no desired product upon reaction with 1-methyl-1-propenylmagnesium bromide and with 2-methyl-2-butenylmagnesium bromide.…”