Asymmetric allylic substitution [Eq. (1)] is a potentially powerful method for creating chiral centers in readily available starting materials. Great efforts have been made to control the chemo-, regio-, and enantioselectivities of the reaction products. [1] In contrast to other metals (Pd, Mo, and Ir, for example), [2] copper allows harder nucleophiles, such as alkyl groups, to be used. Increasing interest is being shown in catalytic systems where the copper center is coordinated to a chiral ligand, [3] such as with Grignard [4] and organozinc reagents.[5]The research in our group has focused on the development of efficient ligands for the substitution of allylic chlorides by Grignard reagents. Previously, we showed that phosphorus ligands derived from tetraaryl-1,3-dioxolane-4,5-dimethanol (taddol) were highly effective chiral reagents in the reaction with cinnamyl chloride (g/a = 94/6, 73 % ee).[4d]Our second-generation phosphoramidite ligands improved on this result, with an ee value of 79 % being observed. They also allowed a wider scope of applicability.[4e] Herein, we report new phosphoramidite ligands for the same application that are also compatible with our previously described one-pot Ru-catalyzed metathesis procedure.[4e] These third-generation ligands give ee values of up to 96 % in most cases and can be applied to Ir-catalyzed allylic substitution.The biphenol 1 a [6] and binaphthol-based ligands 2 a and 3 a [7] (see Scheme 1) were used as the starting compounds, and related ligands were prepared by structural modifications, either at the biphenol (or binaphthol) or the amino functionality. Ligands 1 b-3 b (Scheme 1) which contain an amine group as well as ortho-methoxy substituents on the phenyl rings [8] provided greatly improved results both in the regioselectivity and the enantioselectivity of the products. Previously, [4e] we showed that 1 a gave an ee value of 79 % and a regioselectivity of 91:9 in favor of the g product resulting from the addition of 5 a to 4 a ( Table 1, entry 1). The binaphtholbased ligand 2 a induced a similar enantioselectivity although the regioselectivity was poorer (entry 2). The reaction with ligand 3 a was not as regioselective, but did not invert the absolute configuration of 6 (entry 3). For this case we could hypothesize that the amine functionality in the ligand dictates the absolute configuration of the product. This is in contrast to the behavior of these ligands in conjugate addition.[6] The modified ligand 1 b, in comparison with 1 a, gave an increased regioselectivity (98/2) and a similar enantioselectivity (entry 4). Two diastereomeric ligands 2 b and 3 b containing binaphthol units were also prepared to evaluate the effect of a fixed atropoisomerism.Although ligand 2 b gave poor regio-and enantioselectivities (entry 5), ligand 3 b gave spectacular results (entry 6), with excellent regioselectivity (99/1) and enantiomeric excess (96 %) being demonstrated. This is the highest reported ee Scheme 1. Phosphoramidite ligands.

A new phosphoramidite ligand was used in the iridium-catalyzed allylic substitution reaction. This permitted high regio- and enantioselectivities on a wide variety of substrates and nucleophiles. Because of the stereospecificity of the reaction obtained by using branched substrates, a kinetic resolution reaction was attempted. The origin of the impressive efficiency of this ligand in terms of kinetics was explored in detail, as was the role of the substituent in the ortho-position of the amine moiety.

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.

[reaction: see text] Linear or branched allylic carbonates or acetates undergo enantioselective iridium-catalyzed allylic substitution with sodium malonate. The reaction is wide in scope and affords the branched product in high yield and with high regio- (up to >99:1) and enantioselectivity (up to 98%). Ten aromatic or aliphatic substrates were successfully tested.

Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent strategy employed relies on an intramolecular oxa-Michael addition/aldol/dehydration cascade reaction to cast the ABCD ring framework of the molecule and both Sonogashira and Suzuki-Miyaura coupling reactions to assemble the necessary building blocks into the required heptacyclic skeleton. A divergent approach from a late-stage epoxy ketone leads to both target molecules in a stereoselective manner. The developed synthetic technologies were applied to the construction of several analogues of the cortistatins which were biologically evaluated and compared to the natural products with regards to their antiproliferative activities against a variety of cancer cells. Analogues 8 and 81, lacking both the dimethylamino and hydroxyl groups of cortistatin A, were found to exhibit comparable biological activity as the parent compound, leading to the conclusion that such functionalities are not essential for biological activity.