Highly Regio- and Stereoselective Addition of Organolithium Reagents to Extended Conjugate Amides Using (S,S)-(+)-Pseudoephedrine as Chiral Auxiliary

Abstract

The conjugate addition of organolithium reagents to polyunsaturated conjugate amides containing (S,S)-(+)-pseudoephedrine as chiral auxiliary has been studied in detail. The reaction proceeded with good 1,4-selectivity and excellent stereoselectivity, affording the corresponding addition products with good yields and as highly diastereoenriched isomers. Removal of the chiral auxiliary by reduction or hydrolysis has allowed the preparation of polyfunctionalized chiral building blocks incorporating an alkene moiety suitable for further transformations.The asymmetric conjugate addition of organometallic reagents to R, -unsaturated carbonyl compounds or related derivatives is considered as one of the most powerful methods for the stereocontrolled formation of C-C bonds. 1 In this context, many enantio-and diastereoselective versions of this transformation have been reported using a wide variety of different organometallic reagents. 2 However, when the conjugate addition reaction is carried out on extended Michael acceptors, besides the typical stereochemical issues to consider, regioselectivity shows up as a challenging element to be controlled. 3 In general, nucleophiles may undergo addition to R, ,γ,δ-unsaturated carbonyl compounds in a 1,2-, 1,4-, or 1,6-fashion, and this might lead to the formation of mixtures of all of the possible regioisomers. 4,5 In this context, literature shows that the 1,4-addition of organometallic reagents to polyunsaturated Michael acceptors leads in most cases to the formation of other regioisomers in variable ammounts. 5 On the other hand, despite their availability, literature furnishes little information regarding the use of organolithium reagents in asymmetric conjugate additions to extended conjugate carbonyl compounds, 6 mainly because these reagents usually undergo 1,2-addition to the carbonyl moiety rather than giving any conjugate addition product. 7 Related to this topic, we have recently published a very efficient procedure for carrying out asymmetric conjugate additions of organolithium reagents to R, -unsaturated amides derived from (S,S)-(+)-pseudoephedrine. 8 In this context, we wish to present herein the use of this aminoalcohol as chiral auxiliary 9 in the stereocontrolled conjugate addition of organolithium reagents to extended conjugate acceptors, also showing that the reaction always proceeds with full 1,4-regioselectivity. In addition, the highly efficient conversion of the obtained adducts into enantioenriched -branched alcohols containing an additional alkene (1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992. (2) For some reviews, see: (a) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279. (b) Lopez, F.; Minnaard, A. J.; Feringa, B. L. For some examples focused on achieving 1,6-addition, see: (a) den Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2008, 47, 398. (b) Okada, S.; Arayama, K.; Murayama, R.; Ishizuka, T.; Hara, K.; Hirone, N...

Iridium-Catalyzed Enantioconvergent Allylation of a Boron-Stabilized Organozinc Reagent

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.37–7.31 (m, 2H), 7.26–7.21 (m, 3H), 6.01 (ddd, J = 13.6, 8.0, 6.0 Hz, 1H), 5.14–5.07 (m, 2H), 3.70–3.60 (m, 2H), 3.50 (ddd, J = 7.6, 7.6, 7.6 Hz, 1H), 2.09–1.94 (m, 2H); 13 C­{ 1 H} NMR (101 MHz, CDCl 3 ) δ 143.8, 142.0, 128.7, 127.7, 126.5, 114.6, 61.1, 46.4, 38.1; HPLC (AD-H, hexanes/ i PrOH 99.6:0.4, flow rate of 1 mL/min, λ = 210 nm), t R = 61.2 min (major), t R = 66.2 min (minor); [α] D 20 = −69.8 (c = 1.5, CHCl 3 ). The analytical data are consistent with the literature …”

Conjugate addition reactions of carbon nucleophiles to electron-deficient dienes

“…With regard to regio-and stereocontrol with organolithiums, Carrillo, Badı´a et al have recently studied the addition of RLi reagents to the extended conjugate amides 17 with (S,S)-(+)-pseudoephedrine as a chiral auxiliary (Scheme 6). 5 The reaction took place with excellent diastereoselectivity and good selectivity for the 1,4-adducts 18 when using PhLi, t BuLi and TMSCH 2 Li. However, variable amounts of the 1,2-adducts were observed for other linear or branched organolithiums.…”

“…4 Scheme 6 1,4-Addition of RLi reagents to (S,S)-(+)-pseudefedrine dienamides. 5 Scheme 7 1,6-Addition of lithium divinylcuprates to pentadienoates. 6 regioselectively the corresponding 1,6-adducts 23a,b.…”

Enantioselective Synthesis of Angularly Substituted 1-Azabicylic Rings: Coupled Dynamic Kinetic Epimerization and Chirality Transfer

“…Diphenylphosphoryl azide (0.33 mL, 1.5 mmol) was added dropwise via syringe to a solution of ( R , E )-3-phenylhex-4-enoic acid 36 (0.29 g, 1.5 mmol) and Et 3 N (0.21 mL, 1.5 mmol) in t -BuOH (2.2 mL) at room temperature. The resulting solution was heated at 85 °C for 48 h, cooled to room temperature, diluted with EtOAc (50 mL), and washed sequentially with H 2 O (10 mL), saturated aqueous NaHCO 3 (10 mL), and brine (10 mL).…”