Application of the Tethered Biginelli Reaction for Enantioselective Synthesis of Batzelladine Alkaloids. Absolute Configuration of the Tricyclic Guanidine Portion of Batzelladine B

Abstract

Tethered Biginelli condensation of enantioenriched hexahydropyrrolopyrimidines 8 with beta-ketoesters provides efficient asymmetric access to tricyclic guanidines 9 having a syn relationship of the angular C2a and C8a hydrogens. This reaction was employed to realize the first practical enantioselective access to this fragment of batzelladine alkaloids B (2) and E (5). The efficiency of this strategy is illustrated in the synthesis of the dextrorotatory enantiomer of batzelladine B methanolysis product 10 in 10 steps and 25% overall yield from 2-nonanone and methyl acetoacetate. The asymmetric synthesis of 10 establishes that the absolute configuration of the tricyclic portion of batzelladine B (2) is 25aR,28S,30R. The 4-methyl-7-alkyl-1,2,2a,3,4,5,6,7,8,8a-decahydro-5,6,8b-triazaacenaphthalene-3-carboxylic acid subunit, e.g., 29, of batzelladine alkaloids A (1), D (4), F (6), and G was also prepared for the first time by catalytic hydrogenation of tricyclic guanidines 26 having the 2a,8a-anti stereochemistry.

Total Synthesis of (+)‐Batzelladine A and (−)‐Batzelladine D, and Identification of Their Target Protein

“…The TBS group of 20 was removed and oxidation of the resulting primary alcohol was performed with Jones reagent to give the carboxylic acid 9 22. The structure of 9 was confirmed by further conversion into the known ester 22 , reported by Overman,23 through treatment of 9 with (trimethylsilyl)diazomethane and subsequent deprotection of the Cbz group with hydrogen over 10 % Pd/C.…”

The Generation of Dihydropyrimidine Libraries Utilizing Biginelli Multicomponent Chemistry

“…A special variant of the Biginelli reaction are intramolecular or so-called tethered Biginelli condensations developed by Overman and co-workers, where the aldehyde and urea component are linked together in one building block (Scheme 15) [46,47]. The ™tethered Biginelli strategy∫ has been used in the synthesis of various polycyclic guanidinium alkaloids that all have the hexahydropyrrolo[1,2-c]pyrimidine fragment 50 in common and display a range of interesting biological activities.…”

“…The ™tethered Biginelli strategy∫ has been used in the synthesis of various polycyclic guanidinium alkaloids that all have the hexahydropyrrolo[1,2-c]pyrimidine fragment 50 in common and display a range of interesting biological activities. [47,48] For example, condensation of the chiral hemiaminal precursor 49 with a suitable b-ketoester leads to the desired hexahydropyrrolo[1,2-c]pyrimidine scaffold [47]. Importantly, depending on the reaction conditions (A or B), both the syn and anti stereoisomers of 50 can be obtained with high selectivities.…”

Functionalized Diphenyl‐Imidazolo‐Pyrimidines

“…Heterocycles have been known for providing important building blocks for natural bioactive compounds and pharmaceuticals . Dihydropyrimidines (DHPMs), synthesized via Biginelli reaction, proved to be useful for both anticancer, for example, Monastrol ( 1 ; Fig.…”