Combinatorial Solution-Phase Synthesis of Alkyl (1S*,2S*,3R*,5R*,6R*)-1-Alkyl-3-aryl-6-benzoylamino-1-hydroxy-7- oxo-5-phenylhexahydropyrazolo[1,2-a]pyrazole-2-carboxylates

Abstract

Combinatorial solution-phase cycloadditions of (1Z,4R*,5R*)-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines 3 to beta-keto esters 4 afforded a library of 26 bicyclic pyrazolidinones 5 in 6-89% yields and in 14-100% de. All products were isolated in >90% purity according to 1H NMR, and 25 of them were analytically pure. The structures of cycloadducts were confirmed by NMR and X-ray diffraction. Most of the products were isolated as mixtures of the major (1S*,2S*,3R*,5R*,6R*)-epimers 5 and the minor (1R*,2S*,3R*,5R*,6R*)-epimers 6. Epimerization of cycloadducts 5/6 at the anomeric position 1 in solution was confirmed by 1H NMR.

1,3-Dipolar cycloadditions of azomethine imines

“…However, with ortho-substituted aldehydes diastereomeric adducts 177 were formed. 98,99 Similarly, butyraldehyde and acetone react with pyrazolidinone 171 under acid-catalyzed process to afford the corresponding azomethine imines, which react under In the case of the Cu(I)-catalyzed [3+2] cycloaddition of azomethine imines 172 (Ar = Ph) it takes place at room temperature in acetonitrile using the Hünig's base with methyl propiolate giving the product 178 (Scheme 67). 101 When the chiral ynone 179 was allowed to react with 172 a mixture of diastereomeric cycloadducts 180 was obtained.…”

Cu(I)-catalyzed [3+2] Cycloadditions of tert-Butyl (S)-(3-Oxopent-4- yn-2-yl)carbamate to 1-Benzylidenepyrazole-3-one-derived Azomethine Imines

“…Our previous studies on [3+2] cycloadditions of (1Z,4R*,5R*)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenyltetrahydropyrazol-1-ium-2-ides 1 to various dipolarophiles revealed the general reactiv-ity and selectivity of these cycloadditions [43,44], as well as their applicability in high-throughput synthesis [45,46]. The 4-benzyloxycarbonylamino analogs of 1 were also successfully employed in the synthesis of pyrazolo[1,2-a]pyrazole-based peptide mimetics [47 -50].…”

Recent advances in the synthesis of polysubstituted 3-pyrazolidinones

“…The regioselectivity and stereoselectivity of the cycloadditions and configurations of the major isomers 43, 46, 48, and 49 were in agreement with previous results obtained by cycloadditions of closely analogous dipoles to methyl acrylate 75 and methyl methacrylate. 74 Selectivity of these cycloadditions was somewhat lower than expected on the basis of results with analogous reactions. 9,38,[72][73][74][75] Nevertheless, isolation of multiple isomers may also be advantageous, providing more stereochemical diversity of the 6-amino-7-oxotetrahydropyrazolo[1,2-a]-pyrazole-1(or 2)-carboxylic acid scaffold (c.f.…”

“…74 Selectivity of these cycloadditions was somewhat lower than expected on the basis of results with analogous reactions. 9,38,[72][73][74][75] Nevertheless, isolation of multiple isomers may also be advantageous, providing more stereochemical diversity of the 6-amino-7-oxotetrahydropyrazolo[1,2-a]-pyrazole-1(or 2)-carboxylic acid scaffold (c.f. .…”

“…[40][41][42]44,47,[72][73][74][75][76][77] The 1 H-NMR spectroscopic data of the pyrazolidinones 4 and 25-33 and azomethine imines 24 revealed some interesting structural features of these compounds. In solution, these pyrazolidinone derivatives can equilibrate between two envelope conformers A and C via the planar conformer B (Scheme 21).…”