S_N2′ Alkylation of Chiral Allylic Cyanohydrin O‐Phosphates with Organocuprates

Abstract

Dedicated to Prof. Henri B. Kagan for its pivotal contribution in asymmetric synthesis Received (will be filled in by the editorial staff) copper / allylic substitution / asymmetric synthesis/ unsaturated nitriles/cyanophosphates Abstract: Enantiomerically enriched cyanohydrin O-phosphates, prepared by enantioselective cyanophosphorylation of α,β-unsaturated aldehydes, react regioselectively with organocuprates derived from alkyl Grignard reagents and CuCN at the γ-position to afford chiral γ-alkyl substituted α,β-unsaturated nitriles. The configuration of the new C-C double bond is mainly E when the reaction is performed at -78 ºC and Z at higher temperatures (0 ºC). A high transfer of the chirality in the new stereocentre is observed according to a stereospecific anti-attack onto the cyanophosphate.Enantiomerically enriched (E)-γ-alkylated α,β-unsaturated esters are prepared after subsequent methanolysis in a three step sequence from the corresponding α,β-unsaturated aldehydes. In addition, the synthesis of (R)-4-methylnonan-1-ol, also known as the sex pheromone of the yellow mealworm Tenebrio molitor L, and its (S)-enantiomer are carried out in a four-step route from (E)-oct-2-enal.

Recent Progress in the Chemically Catalyzed Enantioselective Synthesis of Cyanohydrins

“…Nájera and Saá and co‐workers reported the cyanophosphorylation of aldehydes with commercially available diethyl cyanophosphonate as a source of cyanide with various Lewis acids under different reaction conditions 40a. Under the optimized conditions, as shown in Scheme , the product cyanophosphates were obtained in high yields (up to 90 %) with ee values of up to 98 % using 10 mol‐% of the catalyst ( S )‐ 23 in 1.5–50 h. Recently, these authors published a detailed report on the cyanophosphorylation of various aldehydes with mechanistic studies using the same catalyst under similar reaction conditions 40b,40c…”

Regio- and Stereocontrol in the Reactions of α-Halo-β,γ-enoates and α-O-Phosphono-β,γ-enenitriles with Organocuprates

“…Previous studies [RMgX (3.0 equiv), CuX (1.5 equiv)] only examined the E-isomer (i.e., an analogue of 21a) and concluded that steric factors involving the transferable ligand were unimportant in determining the Z-selectivity. 7 Slightly higher Z-stereoselectivity is achieved in Et 2 O than in THF for 21a ( Table 6, entries 1 vs 2), with use of CuBr·SMe 2 for preparation of the lithium cuprates (entries 4 vs 2) and with magnesium rather than lithium cuprates (entries 5 vs 4), consistent with complexation phenomena. 2d A 1,3 -strain generally leads to formation of the E-diasteromeric alkene product, and formation of the Z-isomer is often accounted for on the basis of intramolecular cuprate complexation to a heteroatom moiety within the substrate.…”

Stereoselective synthesis of the sex pheromone of the yellow mealworm using (S)-4-benzyloxazolidinone as chiral auxiliary

“…Bioassays of the two possible stereoisomers of 1 revealed that the (R) isomer was the active form of the pheromone and the (S) isomer had minimum activity [2]. Since effective and cost-efficient control of the yellow mealworm populations can be foreseen with the aid of the sex pheromone, several total syntheses of the racemate and (R)-1 have been published [3][4][5][6].…”

“…After evaporation of the solvent, the aqueous layer was extracted with ethyl ether, and the organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. Purification of the crude product by silica gel column chromatography (n-hexane-EtOAc, 6 . To a solution of 6 (2.0 g, 6.70 mmol) in dry dimethyl sulfoxide (40 mL) was added sodium cyanide (0.34 g, 7.38 mmol), and the mixture was stirred at 90qC for 5 h. After evaporation of the solvent under reduced pressure, the residue was dissolved in CH 2 Cl 2 (50 mL), and the resulting mixture was washed with dilute HCl, aqueous saturated NaHCO 3 , and brine, dried over MgSO 4 , filtered, and concentrated to give a colorless oil 7 (0.86 g, 83.7%).…”

“…Bioassays of the two possible stereoisomers of 1 revealed that the (R) isomer was the active form of the pheromone and the (S) isomer had minimum activity [2]. Since effective and cost-efficient control of the yellow mealworm populations can be foreseen with the aid of the sex pheromone, several total syntheses of the racemate and (R)-1 have been published [3][4][5][6].The Michael addition reaction of organometallics is an important method for carbon-carbon bond formation in organic synthesis [7][8][9]. Organocopper reagents are among the most versatile reagents available for Michael addition reactions [10][11][12][13].…”