N-sulfinyl metalloenamine conjugate additions: asymmetric synthesis of piperidines

[reaction: see text] The first examples of conjugate additions of N-tert-butanesulfinyl metalloenamines are reported. Highly stereoselective conjugate additions (97:3 to 99:1 dr) were observed between metalloenamines derived from N-sulfinyl ketimines and alpha,beta-unsaturated ketones bearing either alkyl or aryl substituents. The conjugate addition products could rapidly be converted with high diastereoselectivity to 2,4,6-trisubstituted piperidines, which are difficult to access by other methods.     

Cr(salen) catalysed asymmetric ring opening of monocyclic terpene-epoxides

The racemic Cr^III(salen) complex was found to be an efficient catalyst for the asymmetric ring opening (ARO) with TMSN₃ of cyclic 1,2-epoxy-terpenes bearing C₄-substituents.     

An alternative stereoselective synthesis of the macrocyclic fragrances (R)-12-methyltridecanolide and (S)-muscolide by means of an asymmetric catalytic conjugate addition/Baeyer–Villiger oxidation

We show herein an alternative catalytic, highly enantioselective approach to (R)-12-methyltridecanolide and (S)-muscolide, that is, chiral macrocyclic lactones which are good musk odorants. In fact, they can be efficiently prepared by a sequence of reactions consisting of a catalytic asymmetric conjugated addition of dimethylzinc to suitable α,β-unsaturated enones followed by a Baeyer–Villiger oxidation. Interestingly, high enantiomeric excesses (up to 92%) are obtained in the asymmetric conjugate addition by means of the ‘tropos’ phosphoramidite L1.     

Efficient cu-catalyzed asymmetric conjugate additions of alkylzincs to trisubstituted cyclic enones

The first examples of efficient catalytic asymmetric conjugate addition (ACA) of alkylzincs to trisubstituted cyclic enones is disclosed. These Cu-catalyzed reactions proceed efficiently with five- and seven-membered ring substrates to afford the desired products in >/=95% ee. Intermediate enolates can be trapped with alkyl halides to generate a quaternary stereogenic center. The requisite chiral ligand is prepared from commercially available materials and can be used in situ without further purification in the presence of commercial grade (CuOTf)2.PhMe.     

Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to acyclic aliphatic enones

Cu-catalyzed enantioselective conjugate additions to acyclic aliphatic enones are reported. The resulting enolates may be functionalized intra- and intermolecularly, leading to the formation of an additional C-C bond. The utility of the present method is not limited to reactions involving Et2Zn; a variety of alkylzincs may be used. Moreover, many of the requisite substrates can be easily accessed through catalytic olefin cross metathesis.     

Stereodivergency in catalytic asymmetric conjugate addition reactions of glycine (ket)imines

Stereodivergent catalytic asymmetric conjugate reactions of glycine (ket)imines with nitroalkenes have been achieved using various chiral catalyst systems derived from a multidentate amino alcohol (1). The stepwise nature of the [3 + 2] cycloaddition reactions of N-metalated azomethine ylides has also been demonstrated by highly enantio- and diastereoselective syntheses of exo-5 and endo-8 from the respective syn-4 and anti-7 conjugate addition products in a one-pot tandem fashion.     

Chiral bicyclic [2.2.2] octadiene ligands for Rh-catalysed catalytic asymmetric conjugate additions to acyclic enones: a quantitative structure-property relationship

A series of chiral bicyclic [2.2.2]diene ligands gave variable ee values for Rh-catalysed asymmetric conjugate addition to an acyclic enone. The interplay between electronic and steric effects was captured in a robust predictive quantitative structure-property relationship (QSPR) model for enantioselectivity.     

Synthesis of enantiomerically enriched β-hydroxy selenides by catalytic asymmetric ring opening of meso-epoxides with (phenylseleno)silanes

The first example of the enantioselective ring opening of meso-epoxides by (phenylseleno)silanes using salen(Cr)complexes as catalyst is described. This desymmetrization reaction constitutes a simple and convenient approach to synthetically versatile optically active β-hydroxy selenides.     

A heterodinuclear asymmetric catalyst for conjugate additions of alpha-hydroxyketones to beta-substituted nitroalkenes

[Structure: see text] The bis-ProPhenol ligand was designed to facilitate formation of hetereodinuclear complexes based upon the large difference in pKa of the one phenolic OH group to the tertiary OH groups. In exploring the first example of hydroxyacetophenones as donors in asymmetric Michael reactions with nitroalkene acceptors, the best stereocontrol was observed with a zinc/magnesium dinuclear complex where enantiomeric excesses ranged up to 92% for the major anti diastereomer.     

Synthesis of naproxen via regioselective ring opening of (2S,3S)-epoxy-1-butanol

(S)-Naproxen was synthesized by the regioselective and stereospecific epoxide ring opening of (2S,3S)-epoxy-1-butanol (2) with diethyl-2-(6-methoxynaphthyl)aluminium (5) as the key step. Thus, treatment of di-ethylaluminate of 2 with 5 at 0° afforded (2S,3S)-3-(6-methoxy-2-naphthyl)butan-1,2-diol (6) , which was oxidized by sequential treatment with sodium periodate and potassium permanganate in a mixture of tert-butyl-alcohol and phosphate buffer (pH 7.0) to give naproxen in high enantiomeric purity.     

Efficient Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to aromatic and aliphatic acyclic nitroalkenes

An efficient and highly enantioselective (up to 95% ee) Cu-catalyzed method for asymmetric conjugate addition (ACA) of alkylzinc reagents to acyclic disubstituted nitroalkenes is presented. Reactions are typically effected at ambient temperature in the presence of 2 mol % chiral dipeptide phosphine and 1 mol % (CuOTf)(2).C(6)H(6). Nitroalkenes bearing aromatic as well as aliphatic substituents readily undergo asymmetric additions. [reaction: see text]     

Enantioselective total synthesis of erogorgiaene: applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones

The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs to acyclic alpha,beta-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)(2).C(6)H(6). Moreover, several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the total synthesis; these include the significance of various structural features of the amino acid-based chiral ligands and the chiral ligand's effectiveness in reactions involving achiral and chiral substrates. In addition, the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly effective catalyst for olefin cross-metathesis.     

Eight- and 16-membered cyanuric-sulfanuric ring systems: C2N4S2-->C2N3S ring contraction

Eight- and 16-membered cyanuric-sulfanuric ring systems of the type Ar2C2N4S2(O)2Ar'2 (3a, Ar = 4-BrC6H4, Ar' = Ph; 3b, Ar = 4-CF3C6H4, Ar' = Ph; 3c, Ar = 4-CF3C6H4, Ar' = 4-CH3C6H4) and Ar4C4N8S4(O)4Ar'4 (4b, Ar = 4-CF3C6H4, Ar' = Ph; 4c, Ar = 4-CH3C6H4, Ar' = Ph; 4d, Ar = 4-CF3C6H4, Ar' = 4-CH3C6H4), respectively, were prepared in good yields by the reaction of the corresponding sulfur(IV) systems with m-chloroperbenzoic acid. The X-ray structures of 3b, 3c.C7H14, 4b.CH2Cl2, 4c, and the S(IV) system Ar4C4N8S4Ar'4 (2c, Ar = 4-CH3C6H4, Ar' = Ph) were determined. Upon oxidation the two oxygen atoms in 3b and 3c.C7H14 adopt endo positions leading to a twist boat conformation for the C2N4S2 ring. The 16-membered C4N8S4 rings in 4b and 4c retain a cradle conformation upon oxidation. The S-N bond distances are ca. 0.06 A shorter in all the S(VI) systems compared to those in the corresponding S(IV) rings. The thermolysis of 3b at ca. 220 degrees C occurs primarily via loss of a sulfanuric group, NS(O)Ph, to give the six-membered ring (4-CF3C6H4)2C2N3S(O)Ph (6). The structure of 6 was confirmed by X-ray crystallography. Crystal data: 2c, triclinic, space group P1 with a = 13.917(2) A, b = 15.610(4) A, c = 13.491(3) A, alpha = 95.77(2) degrees, beta = 114.82(1) degrees, gamma = 76.21(2) degrees, V = 2583(1) A3, and Z = 2; 3b, monoclinic, space group P2(1)/a with a = 7.316(2) A, b = 29.508(5) A, c = 12.910(2) A, beta = 101.30(2) degrees, V = 2733(1) A3, and Z = 4; 3c.C7H14, triclinic, space group P1 with a = 12.849(4) A, b = 12.863(4) A, c = 12.610(7) A, alpha = 110.61(3) degrees, beta = 105.77(3) degrees, gamma = 62.77(2) degrees, V = 1719(1) A3, and Z = 2; 4b.CH2Cl2, triclinic, space group P1 with a = 12.647(3) A, b = 19.137(3) A, c = 12.550(2) A, alpha = 105.765(11) degrees, beta = 93.610(15) degrees, gamma = 88.877(16) degrees, V = 2917.2(9) A3, and Z = 2; 4c, orthorhombic, space group Pba2 with a = 22.657(2) A, b = 10.570(2) A, c = 10.664(3) A, alpha = beta = gamma = 90 degrees, V = 2554(1) A3, and Z = 2; 6, triclinic, space group P1 with a = 7.4667(8) A, b = 11.3406(12) A, c = 13.5470(14) A, alpha = 108.000(2) degrees, beta = 105.796(2) degrees, gamma = 94.300(2) degrees, V = 1033.8(2) A3, and Z = 2.     

Asymmetric activation of tropos catalysts in the stereoselective catalytic conjugate additions of R2Zn to α,β-enones: an efficient synthesis of (−)-muscone

The preparation of a new phosphoramidite starting from (R)-BINOL and a biphenylamine is presented. In such a compound the chirality is due only to atropisomerism and this molecule possesses a flexible biphenylamine residue. Therefore it can work as a tropos catalyst. The catalytic efficiency of this new phosphoramidite has been tested in some asymmetric conjugate additions of dialkylzinc reagents to α,β-enones and compared with that of an analogous already known non-tropos ligand. Interestingly, while comparable results were obtained in the addition of ZnEt₂ to chalcone and cyclohexenone, in the case of the addition of ZnMe₂ to (E)-cyclopentadec-2-en-1-one, the new ligand provides (−)-muscone, a valuable ingredient of the perfume industry, in 84% ee, while the non-tropos ligand gives a much lower (57%) ee value.     

Regioselective ring opening of amino epoxides with nitriles: an easy synthesis of (2R,3S)- and (2S,3S)-1,3-diaminoalkan-2-ols with differently protected amine functions

[reaction: see text] Transformation of enantiopure (2R,1'S)- or (2S,1'S)-2-(1-aminoalkyl)epoxides 1 or 2 into the corresponding (2R,3S)- and (2S,3S)-1,3-diaminoalkan-2-ols 3 or 4 is described. The opening of the epoxide ring with different nitriles (Ritter reaction) takes place with total selectivity and in high yields in the presence of BF3.Et2O. Interestingly, the two amine groups are differently protected. A mechanism to explain this transformation is proposed.     

Hartree Fock instabilities of sulfur-nitrogen ring systems: S2N2

The Hartree-Fock instablities of S₂N₂ are reported and compared with those of S₃N and S₄N. These unsaturated sulfur nitrogen planar rings are π electron rich and although the symmetry adapted HF solutions are singlet stable at the experimental bond lengths they become unstable with only a very modest increase in bond length. The broken symmetry solutions for S₂N₃, S₃N, and S₄N are of planar C_2v type with one of the nitrogens stripped of its π electrons, producing a π hole.     

(S,S)-(+)-Pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/alpha-alkylation reactions

Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding beta-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing alpha,beta-dialkyl-substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic beta-alkyl- and alpha,beta-dialkyl-substituted carboxylic acids and gamma-alkyl- and beta,gamma-dialkyl-substituted alcohols using very simple and high-yielding procedures.