Reactivity and Enantioselectivity in the Reactions of Scalemic Stereogenic α-(N-Carbamoyl)alkylcuprates

Abstract

Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN.2LiCl react with vinyl iodides, vinyl triflates, beta-iodo-alpha,beta-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the alpha-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.

Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters

“…With the exception of organozincs, which display unusually high configurational stability, a general trend can be applied across transmetalating agents that the rate of racemization decreases as the covalent character of the C–M bond increases (Scheme 14). 42 For example, secondary organomagnesium reagents racemize at –10 °C with a half life of about 5 h. 43 By comparison, enantioenriched secondary alkylboron reagents are reported to be configurationally stable to reaction temperatures above 70 °C for over 16 h. 44 The rate of racemization must be taken into consideration when synthesizing the reagent as well as when identifying conditions for cross-coupling reactions.…”

Total Syntheses of the Tylophora Alkaloids Cryptopleurine, (−)‐Antofine, (−)‐Tylophorine, and (−)‐Ficuseptine C

“…The enantiomers can be separated by chiral HPLC (Chiralpak AD-H (250 mm 4.6 mm), n-heptane/isopropanol 4:1, 0. 5 (30): [38] A solution of Boc-prolinol 29 (7.44 g, 36.95 mmol) [32] and NMO (6.57 g, 56.07 mmol) in CH 2 Cl 2 (75 mL) was treated with powdered molecular sieves (3 , 19.2 g) and then with TPAP (649 mg, 1.85 mmol), [33] resulting in a brief exothermic reaction. The dark mixture was stirred at ambient temperature for 3.5 h and then filtered through a silica gel column with tert-butyl methyl ether.…”

Boron trifluoride etherate-assisted ring opening of ethylene oxide by a chiral organolithium: enantioselective synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine

“…No reaction was observed in either case, and unreacted starting materials were recovered. Modifying the reactivity of the chiral organolithium/ sparteine complex by transmetallation to copper 25,26 or magnesium, 27 also failed to yield any desired alkylation.…”