Efficient asymmetric synthesis of α‐alkylated 1,4‐cyclohexanedione derivatives, important chiral building blocks in the synthesis of natural products

A General Synthetic Route to Differentially Functionalized Angularly and Linearly Fused [6−7−5] Ring Systems: A Rh(I)-Catalyzed Cyclocarbonylation Reaction

“…Alkylation of the N,N-dimethylhydrazone of 1,4-cyclohexanedione monoethylene ketal (13) with (5-iodopent-1-ynyl)trimethylsilane 13 gave 14 following a selective hydrolysis of the hydrazone in the presence of the ketal with oxalic acid (Scheme 5). 14 Hydrazone formation was necessary due to the low yields obtained of the monoalkylation product when direct alkylations of 1,4-cyclohexanedione monoethylene ketal were attempted using a variety of conditions (LDA, THF; KHMDS, THF or 1:1 toluene/DMF; KH, THF). Addition of ethynylmagnesium bromide (4a) or propynylmagnesium bromide (4b) followed by in situ acetylation using acetyl chloride furnished the corresponding propargyl acetates, which upon S N 2′ addition of a dialkyl cuprate gave allene-ynes 15a and 15b in 55% and 40% yield, respectively, for three steps.…”

“…Allene−ynes type C were prepared as follows. Alkylation of the N , N -dimethylhydrazone of 1,4-cyclohexanedione monoethylene ketal ( 13 ) with (5-iodopent-1-ynyl)trimethylsilane gave 14 following a selective hydrolysis of the hydrazone in the presence of the ketal with oxalic acid (Scheme ) . Hydrazone formation was necessary due to the low yields obtained of the monoalkylation product when direct alkylations of 1,4-cyclohexanedione monoethylene ketal were attempted using a variety of conditions (LDA, THF; KHMDS, THF or 1:1 toluene/DMF; KH, THF).…”

Rh(I)-Catalyzed Cyclocarbonylation of Allenol Esters To Prepare Acetoxy 4-Alkylidenecyclopent-3-en-2-ones

“…Preparation of cyclohexane-based substrates began by alkylating the lithium enolate of dimethyl hydrazone 4 , with the corresponding halides or triflates 5a − c (Scheme ) . Acidic hydrolysis with oxalic acid gave ketones 6a and 6c ( n = 1, 3) in 44% and 83% yield . Ketone 6b was obtained in only 5% yield, possibly due to a competing E2 elimination of the triflate to form an enyne.…”

Synthesis of geminal bisphosphonates via organocatalyzed enantioselective Michael additions of cyclic ketones and 4-piperidones

“…Enantioselective alkylation of 1f provides a route to a-alkylated 1,4-cyclohexanedione derivatives, which are also important building blocks for the synthesis of natural products. 33 The enantiomeric excesses of the disubstituted ketones 3b-f and 6 were determined by HPLC. For this purpose, it was necessary to prepare racemic standards for comparison of retention times, and this was done via a Michael addition reaction of ketone enolates formed in the presence of DBU to vinyl bisphosphonate 2, in an adaptation of the method developed by Schlachter et al 11a and Nugent et al 11b for the synthesis of geminal bisphosphonates F and G (Scheme 3).…”

“…The diastereoisomers separate partially during chromatography, but complete separation requires several chromatographies. (16), 351 (7), 317 (24), 301 (22), 289 (10), 288 (100), 273 (5), 271 (5), 261 (29), 244 (6), 233 (14), 205 (6), 187 (8), 177 (6), 171 (5), 165 (6), 159 (8), 152 (21), 136 (5), 122 (7), 112 (5), 110 (7), 109 (7), 98 (7), 97 (8), 96 (5), 95 (7), 83 (10), 82 (6), 81 (8), 79 (5), 72 (23), 70 (5), 69 (12), 67 (9), 59 (32), 57 (18), 55 (20) (33), 144 (25), 133 (16), 132 (12), 118 (12), 117 (34), 116 (20), 115 (37), 109 (17), 105 (18), 104 (28), 99 (10), 98 (11), 93 (10), 91 (17), 89 (13), 79 (10), 77 (17), 76 (19), 74 (12), 69 (10), 67 (10), 63 (11), 57 (34), 58 (10), 55 (18), 51 (12), 50 (13), 46 (12), 45 (26) (Found C, 50.62; H, 9.05 (major + minor). Calcd for C 20 H 40 O 7 P 2 : C, 52.86; H, 8.87).…”