The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

The optimization of asymmetric catalysts for enantioselective synthesis has conventionally revolved around the synthesis and screening of enantiopure ligands. In contrast, we have optimized an asymmetric reaction by modification of a series of achiral ligands. Thus, employing (S)-3,3'-diphenyl BINOL [(S)-Ph(2)-BINOL] and a series of achiral diimine and diamine activators in the asymmetric addition of alkyl groups to benzaldehyde, we have observed enantiomeric excesses between 96% (R) and 75% (S) of 1-phenyl-1-propanol. Some of the ligands examined have low-energy chiral conformations that can contribute to the chiral environment of the catalyst. These include achiral diimine ligands with meso backbones that adopt chiral conformations, achiral diimine ligands with backbones that become axially chiral on coordination to metal centers, achiral diamine ligands that form stereocenters on coordination to metal centers, and achiral diamine ligands with pendant groups that have axially chiral conformations. Additionally, we have structurally characterized (Ph(2)-BINOLate)Zn(diimine) and (Ph(2)-BINOLate)Zn(diamine) complexes and studied their solution behavior.

The C-Si bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous C-TBDPS and C-TBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of I(+), such as N-iodosaccharin, 1,3-diodohydantoin, and Ipy(2)BF(4)). The desired iodoalkenes are obtained stereospecifically without byproducts, provided that the reactions are carried out in CF(3)CHOHCF(3) and, in general, with 30 mol % of Ag(2)CO(3) (or AgOAc/2,6-lutidine) as an additive. Fragment C10-C18 of cytotoxic amphidinolides B1-B3 and D has been synthesized using this improved procedure.

Enantioselective catalysis has witnessed explosive growth in the last two decades as it has become the most versatile and efficient method for the preparation of molecules of high enantiomeric excess. 1 Of the numerous contributions that have shaped our understanding of catalytic asymmetric reactions, few have had such a profound impact as the experimental and theoretical description of nonlinear effects by Kagan and coworkers. [2][3][4][5] Before this seminal work, 2 it was generally believed that a strictly linear correlation existed between the ee of the catalyst and the ee of the product. However, Kagan demonstrated that this assumption was not valid 2 and many systems have since been shown to exhibit nonlinear behavior. 3,4 The consequences of strong positive nonlinear effects are remarkable. 3,4,6-8 For example, Noyori used the DAIB ligand (eq 1) of only 15% ee in the asymmetric addition of alkyl groups to aldehydes from which a product of 95% ee was generated. When enantiopure DAIB was used in this reaction, the product was generated in 98% ee. 9 Soai has demonstrated that ligands with very low ee, or even traces of chiral material, can be used in an autocatalytic asymmetric process to generate product in high ee. [10][11][12][13] The only drawback to using partially resolved catalysts exhibiting strong positive nonlinear behavior such as DAIB in production of enantioenriched material is that they display a lower overall rate than when they are enantiomerically pure. 7Because nonlinear effects are so easily detected, 3 many asymmetric catalysts have now been tested. However, we are unaware of studies of nonlinear effects that focus on the substrate dependency of this behavior. The substrate dependency of nonlinear effects has important implications for two primary reasons: (1) in the optimization of asymmetric processes it is beneficial to determine the ee of the ligand necessary to obtain a product of the desired ee and (2) substrate dependency of nonlinear effects can be used to probe the mechanism of asymmetric reactions. In this Communication we present a study of the substrate dependency of nonlinear effects using the MIB ligand of Nugent (eq 1). 14 This ligand is closely related to the DAIB ligand 1 that has been extensively studied by Noyori and co-workers. 9,15-18 We find that simply modifying the electronic properties of benzaldehyde derivatives results in a change in the product ee (ee p ) of over 30% in the asymmetric addition (eq 1) with 10% ee of MIB. This effect is even more pronounced with aliphatic aldehydes. Equally important, the current model for the mechanism of the asymmetric addition reaction (eq 1) with DAIB is not consistent with the observed substrate dependency of the nonlinear effect with MIB.We chose to employ the MIB ligand because of its ease of synthesis and its stability on long-term storage. 14 Asymmetric addition reactions (eq 1) were conducted using 4 mol % MIB of 10, 20, and 100% ee of the ligand at 0°C (Table 1). These additions were performed by combining the ligand an...

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.