Browsing by Author "Kinzel, Tom"

Novel chiral auxiliaries for the stereoselective allylation of aliphatic methyl ketones with allyltrimethylsilane and their use in the synthesis of homoallylic ethers are described. In a multicomponent domino process catalyzed by trifluoromethanesulfonic acid, the allyl moiety and the auxiliary are transferred onto the substrate to yield tertiary homoallylic ethers. The most useful auxiliary for a general application turned out to be the trimethylsilyl ether of phenyl benzyl carbinol with an induced diastereoselectivity of 90:10 using ethyl methyl ketone and 94:6 using isopropyl methyl ketone as substrates. The transferred substituted benzyl moiety has good protecting properties in Subsequent transformations and can easily be removed under reductive conditions to provide the corresponding homoallylic alcohol. The origin of the high selectivity could be elucidated by identifying the relevant transition states using quantum-chemical calculations. An excellent agreement between calculated and experimentally observed selectivities was obtained assuming an oxocarbenium ion as intermediate.

Computational investigations on the highly stereoselective allylation of butanone in the presence of a chiral norpseudoephedrine-derived auxiliary have been performed. They suggest an S(N)1-type mechanism via the attack of allyltrimethylsilane to an intermediately formed oxocarbenium ion. The identification of preferred transition states (TSs) leads to a straightforward rationalization of the observed selectivity which can be extended to analogues of the auxiliary. A screening process has been devised to select 61 potentially relevant TSs from a total of almost 300 theoretically possible TSs. Final results were obtained from gas-phase calculations employing the B3LYP/6-31+G(d) level of theory as well as in dichloromethane solution using the B3LYP/6-311 ++ G(2d,p)//B3LYP/6-31 +G(d) level of theory in combination with polarizable continuum model and the UAKS set of radii. The agreement of theoretically predicted and experimentally observed selectivities is very good in both cases. However, the relative energy differences for several relevant TSs differ significantly when going from gas phase to solution, thus illustrating the necessity of performing calculations in solution to draw correct conclusions.

We report on experimentally determined and computationally predicted diastereoselectivities of (a) multicomponent crotylation (MCC) reactions of simple aliphatic aldehydes and ketones and (b) of acetal substitution (AS) reactions of aldehyde dimethyl acetals with E- and Z-configurated crotyl trimethylsilane to give homoallylic methyl ethers bearing two newly formed stereogenic centers. We found that corresponding MCC and AS reactions give nearly equal syn/anti ratios. While the crotylations of acetaldehyde and propionaldehyde mainly result in the syn product for E-configurated silane and in the anti product for Z-configurated silane, the syn product is found as main product for the crotylation of pivaldehyde regardless of substrate double bond geometry. Using butanone as substrate, the anti product is found as main product in both cases. By computational investigation employing the B3LYP/6-31+G(d) level of theory in dichloromethane solution (PCM/UAKS), we found that the attack of O-methyl-substituted carboxenium ions by crotyl silane explains the experimentally observed selectivities, indicating that these crotylations in fact proceed in an S(N)1-type reaction via this ionic intermediate. Comparison of relevant open transition-state structures leads to a rationalization of the observed selectivities. For all systems studied, three transitionstate conformations are necessary and sufficient to determine the selectivity. This has been confirmed by studying the MCC reactions of isobutyraldehyde. Activation energies for the stereogenic step have been determined by calculation of the transition state and substrate structures in dichloromethane solution at the B3LYP/6-311+G(2d,p)//B3LYP/6-31+G(d) level of theory in dichloromethane solution. The possibility to predict simple diastereoselectivity in general Lewis acid-mediated crotylations of aldehydes and ketones is discussed.

Auxiliary-mediated domino crotylations and pentenylations of butanone yield homoallylic ethers with two newly formed stereogenic centers. With our norpseudoephedrine-derived auxiliary, we observed the formation of anti isomers exclusively, and the nature of the major isomer was independent of the substrate double bond geometry. Interestingly, there is a switch in induced selectivity when going from crotylation to pentenylation. Here, we present the computational rationalization for this behavior by identification of the relevant transition states (TSs), the energies of which were determined by using the B3LYP/6-31+G(d) level of theory in combination with the PCM/UAKS method to include the effects exerted by the solvent dichloromethane. To quickly narrow down the number of potentially relevant TSs from the whole set of 288 and 864 TSs for the crotylation and pentenylation, respectively, we employed a screening process based on B3LYP//AM1 energies. The predicted selectivities are in good agreement with experimentally determined ones. Furthermore, the obtained results also facilitate an explanation of the selectivities obtained in hexenylations and heptenylations. Finally, activation energies were determined that account for the significantly longer reaction times than those for the domino allylation with unsubstituted trimethylallylsilane.

Palladium-catalyzed transformations are of great importance in modern synthetic organic chemistry. The vast number of reactions that can be catalyzed by Pd-0- as well as Pd2+-complexes in combination with the relative stability of the intermediates offers the intriguing opportunity of carrying out multiple consecutive bond-forming processes. They can be even performed in a domino fashion and in the presence of chiral ligands to allow the efficient preparation of almost enantiopure compounds. In this article, the use of double Heck, Tsuji-Trost-Heck, and Wacker-Heck reactions for the total syntheses of estradiol, spinosyn A analogs, cephalotaxine, and vitamin E is described.

Stereoselective allylations of carbonyl compounds such as aldehydes and ketones are Useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks In the synthesis of biologically active natural Compounds and pharmaceuticals. Although researchers have developed several methods for the facially selective allylation of aldehydes, the stereoselective allylation of ketones still poses a severe problem. We have developed a highly diastereoselective domino multicomponent allylation reaction of a ketone and allyltrimethyl silane Using the trimethylsilyl ether of a norpseudoephedrine or mandelic acid derivative as an auxiliary with a diastereoselectivity of up to 98:2. The reaction is performed at -78 degrees C In the presence of a catalytic amount of trifluoromethanesulfonic acid and leads to the corresponding tertiary ethers. The procedure can also be Used for the allylation of aliphatic aldehydes with a diastereomeric ratio >99:1. Ketones give the 4,1'-syn product while the aldehydes give the reversed selectivity to yield a 4,1'-anti product. In addition, the reaction of gamma-substituted allyl silanes with ketones yields a product with two stereogenic centers and an anti diastereoselectivity of >99:1. The homoallylic ethers formed In the domino multicomponent process can be used In further synthetic transformations: the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. Based on a number of both experimental and theoretical studies of the reaction mechanism, we conclude that an intermediate oxocarbenium ion is formed in the reaction of ketones. The oxocarbenium ion is attacked by the allyl silane during the stereogenic step. Using density functional theory methods, we could trace the observed stereoselectivity phenomena back to open transition states (TSs) where there is no interaction between the silane's trimethylsilyl group and the former carbonyl oxygen. On the contrary, the reaction with aldehydes forms an intermediate oxazolidinium salt, which explains the opposite selectivity. We have used the new allylation procedure in several total syntheses of natural products such as vitamin E, (+)-hydroxymyoporone, 5,6-dihydrocineromycin B, and polyoxygenated cembrenes.