Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

Abstract

SummaryPiperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised.

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

“…1 The product β-nitroamines have emerged as flexible synthetic building blocks due to the complimentary oxidation states of the two nitrogen atoms. They have been used in the synthesis of many nitrogen containing functional groups including α-amino carbonyls, 2, 3 1,2-diamines, [4][5][6][7] peptidomimetics, 8 natural products [9][10][11][12][13][14][15] and many heterocyclic small molecules. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] To address the paucity of structurally diverse nitroalkanes we have developed conjugate addition nitro-Mannich protocols (Scheme 1).…”

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds

“…Piperazirum is an alkaloid isolated from a leaf extract of Arum palaestinum Boiss, which displays significant cytotoxicity against cultured tumor cell lines in vitro. Anderson and coworkers developed a method to produce a synthetic sample to help elucidate its stereochemistry (Figure 6A; Anderson et al, 2013). A reductive nitro-Mannich reaction was used to assemble a 1,2diamine fragment of the molecule ( 83), thus establishing the C-5/C-6 relative stereochemistry.…”

Nucleophilic Imines and Electrophilic o-Quinone Methides, a Three-Component Assembly of Assorted 3,4-Dihydro-2H-1,3-benzoxazines

“…Next, we examined the N-arylated imines 7 and 8 (Figure ). The respective benzoxazines 9 and 10 were again observed to form as a single diastereomer assumed to be >30:1 by 1 H NMR.…”