Rhodium‐Catalyzed Enantioselective 1,2‐Addition of Aluminum Organyl Compounds to Cyclic Enones

Abstract

Among carbon-carbon bond-forming processes the 1,2-addition of metal organyl compounds to carbonyl moieties is one of the major reactions in organic synthesis. In the last decade methods based on transition-metal catalysis have been developed that allow stereoselective reactions with a broad spectrum of aldehydes.[1] However, ketones and especially enones still are problematic substrates for which only few catalyst systems are suitable.[2] In contrast, asymmetric 1,4-additions of a variety of organometallic compounds to enones by copper, palladium, and rhodium catalysis are well-established.[3] During our studies towards the total synthesis of the natural product spirodionic acid [4] we envisaged such Rhcatalyzed enantioselective Michael additions to cyclic enones, yet employing aluminum organyl compounds, which-to the best of our knowledge-have hitherto not been used in combination with Rh catalysts. [5] Cyclohex-2-enone (2) was treated with [{Rh(cod)Cl} 2 ] (cod = cyclooctadiene) and an equimolar amount of AlMe 3 to give the desired 3-methylcyclohexanone (1, Scheme 1). To perform the transformation enantioselectively, in situ prepared [{Rh[(S)-binap]Cl} 2 ] was used next; yet the use of this complex led to a dramatic change of the reaction course. Highly selective 1,2-addition was observed and 1-methylcyclohex-2-enol (3) was formed with 96 % ee. Since this compound is a known aggregation pheromone of the Douglas-fir beetle, previously only available in multistep syntheses, [6] the R configuration could be assigned to the product 3 based on the reported optical rotation.The formation of 3 from 2 appears to be the first example of an enantioselective Rh-catalyzed 1,2-addition to an enone; thus, the reaction conditions were optimized. [7,8] On lowering the temperature to 0 8C or À20 8C the enantioselectivity was only slightly increased to 98 % ee, while the reaction was significantly retarded (Table 1, entries 1-3). Variation of the precatalyst led to similar results when starting from complexes with noncoordinating or bidentate counterions (Table 1, entries 4 and 5), yet significant improvements were achieved when using [{Rh(cod)OMe} 2 ], thus increasing the yield to 97 % with 99 % ee (entry 6). In a second set of experiments the catalyst loading was reduced, which still gave good results with 1 mol %, but almost no conversion with 0.1 mol % (Table 1, entries 7-9).Furthermore, the influence of the solvent was examined, revealing that THF is the best choice. With other ethers the yield decreased in the order 1,2-dimethoxyethane > dioxane > Et 2 O; hydrocarbons such as toluene proved unsuitable owing to significant background reactivity.[9] To gain insight into the sudden change of the reaction course, various monoand bidentate phosphine ligands were tested (PPh 3 , PnBu 3 , dppe, dppb, diop), [10] yet none of them led to the formation of the 1,4-adduct 1 or the 1,2-adduct 3 in more than 10 % yield. Furthermore, no conversion occurred in the presence of binap when omitting the Rh precatalyst, thus proving catalysis...

Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

“…With respect to use of enones with substitutions at 3-and 4-positions it is noteworthy that they represent substitution patterns difficult to obtain using conventional methods, such as palladium-catalyzed π-allyl substitution or dynamic kinetic resolution. The formation of quaternary allylic stereogenic centers with good enantio-control by nonresolution methods is a highly challenging task (38). Using the present conditions, a variety of allylic alcohols carrying a quaternary allylic center are formed with enantioselectivities up to 99% ee.…”

First Synthesis of (−)-Altenuene-D3 Suitable as Internal Standard for Isotope Dilution Mass Spectrometry

“…With the labile iodo substrate 5a limiting the number of applicable reagents, we envisioned the usage of the much more stable bromo enone derivative 10b, which should allow us to investigate other organometallic reagents. Thus, bromination of the known enone 9 obtained in 4 steps from inexpensive D-(−)-quinic acid (8) We then focused on the optimization of the inefficient methylation of halo enones 10a and 10b ( Any attempts to further improve the diastereoselectivity of the 1,2-addition by employing either chiral catalytic systems (e.g., BINAP + Josiphos, which is actually known to promote 1,4-addition [11]) and/or alternative methyl donating reagents (e.g., AlMe 3 , DABAL, ZnMe 2 ) [12][13][14] resulted in the formation of either the 1,4-addition product or only traces of the desired alcohol 5b (Table 1, Entries 4,5,10-14).…”

“…Molecules 2019, 24 4 Any attempts to further improve the diastereoselectivity of the 1,2-addition by employing either chiral catalytic systems (e.g., BINAP + Josiphos, which is actually known to promote 1,4-addition [11]) and/or alternative methyl donating reagents (e.g., AlMe3, DABAL, ZnMe2) [12][13][14] resulted in the formation of either the 1,4-addition product or only traces of the desired alcohol 5b (Table 1, Entries 4,5,[10][11][12][13][14].…”

Kinetic Resolution of Chiral Cyclohex-2-enones by Rhodium(I)/binap-Catalyzed 1,2- and 1,4-Additions

“…The absolute configuration was assigned in analogy to the respective transformation of cyclohex-2-enone. 9 Prepared according to GP 1 with (R)-5-methylcyclohex-2-en-1-one (58.2 µL, 55.1 mg, 500 µmol) for 1 h at rt. MPLC purification (pentane/Et 2 O 20:1, 4 g SiO 2 , 30 µm particle size) furnished 55.1 mg (87%) of (1R,5R)-1,5-dimethylcyclohex-2en-1-ol as a colorless oil, R f = 0.28 (pentane/Et 2 O 2:1).…”

“…The relative configuration was determined by comparison with NMR data in the literature, 10 and is consistent with the absolute configuration of the starting material in combination with the expected configuration at C-1 compared to the respective transformation of cyclohex-2-enone. 9 as well as the enantiomeric excess of 2f were determined by GC analysis, ee 2f: >99%. The dr of 3fm was determined by integration of the benzylic signals in the 1 H NMR spectrum of the crude product and the enantiomeric excesses of trans-3fm and cis-3fm were determined by HPLC analysis (IA column) after column chromatography.…”