Regio‐ and Stereoselective Synthesis of Bicyclic Limonene‐Based Chiral Aminodiols and Spirooxazolidines

Abstract

A library of monoterpene-based aminodiols was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The reduction of a bicyclic α-methylene ketone, derived from natural (-)-limonene followed by epoxidation, gave the key epoxy alcohol intermediate. Ring opening of the oxirane ring with primary amines induced by lithium perchlorate afforded the required aminodiols. Substituent-dependent ring closure of the secondary aminodiols with formaldehyde resulted in both spirooxazolidines and a fused 1,3-oxazine. Cyclization reactions of the studied aminodiols, resulting in spirocyclic oxazolidines and an isomeric perhydro-1,3-oxazine-fused compound along with the possible iminium intermediates, were analyzed by a systematic series of comparative DFT models performed at the B3LYP/6-31+G(d,p) level of theory.

Chiral Amino and Imino-Alcohols Based on (R)-Limonene

“…The procedure was based on the literature. 25 1.52 g of 1 (10 mmol), 1.3 g of NaN 3 (20 mmol) and 0.54 g of NH 4 Cl (10 mmol) were refluxed in 4 mL of methanol (MeOH) until all limonene oxide was consumed according to TLC (about 32 h). The mixture was allowed to cool to room temperature and the solvent removed.…”

“…The procedure was based on the literature. 25 Under argon atmosphere, 2 mL of dry THF were added on 200 mg of LiAlH 4 (5.26 mmol) in an ice bath. Then, a solution of 699 mg of 2a (3.58 mmol) in 3 mL of dry THF was slowly added, causing N 2 evolution, and the mixture was stirred for 1 h in room temperature.…”

“…The first use of limonenederived chiral ligands in catalytic systems was published by Lahuerta et al 19 in 2000, where the researchers used LiPPh 3 to perform previously reported selective epoxide opening in limonene oxides, 20 generating phosphinealcohols that induced low selectivity in Rh-catalyzed C-H insertion and cyclopropanation reactions. Since then, there was a narrow development in the ligand synthesis starting from limonene, having excellent results in terms of yield and stereoselectivity, however distributed into two main reactions: organozinc additions [21][22][23][24][25] and ruthenium catalyzed asymmetric hydrogen transfer reactions. [26][27][28] Usually, its internal cis and trans-oxides are used as substract for selective epoxide opening with amines in order to produce secondary or tertiary chiral amino-alcohols, although there are some divergent methodologies using amino-oximes 26,29,30 or aziridines.…”

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpen Aminodiols

“…The nucleophilic addition of amines to epoxyalcohols has proved to be an efficient method for the preparation of a highly diverse library of 3-amino-1,2-diols [14,40,41]. The opening of the oxirane ring of 4 was accomplished with different primary and secondary amines, resulting in a library of tridentate aminodiol derivatives (11)(12)(13)(14)(15)(16)(17)(18) presented in Table 1.…”

“…Diasteroisomeric primary aminodiol 23 was prepared by ring opening of trans-epoxyalcohol 5 with benzylamine, followed by hydrogenolysis of 22 over Pd/C. In contrast to the cis counterpart, the treatment of 22 with formaldehyde at room temperature gave an inseparable mixture of spiro-oxazolidine 24A and 1,3-oxazine 24B in a ratio of 24A:24B = 3:1 (Scheme 5) [40].…”