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The effect of halogen-to-hydrogen bond substitution on the binding energetics and biological activity of a human aldose reductase inhibitor has been studied using X-ray crystallography, IC50 measurements, advanced binding free energy calculations, and simulations. The replacement of Br or I atoms by an amine (NH2) group has not induced changes in the original geometry of the complex, which made it possible to study the isolated features of selected noncovalent interactions in a biomolecular complex.

Unsymmetrically 3,3'-substituted axially chiral bis(tetrahydroisoquinoline) N,N'-dioxides can be prepared in just three steps. They exhibit unique catalytic activity (turnover frequency, enantioselectivity, substrate scope) in the asymmetric allylation of aromatic aldehydes (up to 96% ee). The product of the enantioselective allylation of benzaldehyde served as a building block for the preparation of an intermediate useful in the enantioselective synthesis of diospongines.

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The invention and development of highly enantioselective catalytic reactions with a low catalyst loading is one of the current challenges in organic chemistry. One such area is the activation of reactants by Lewis base/acid pairing.[1] Especially attractive in this regard is the enantioselective allylation of carbonyl compounds (Sakurai-Hosomi reaction) with allylmetals to give chiral homoallylic alcohols that can be used as building blocks in the synthesis of complex molecules. [2] In the last decade, considerable attention has been paid to a possible variant of this reaction based on the activation of allyltrichlorosilane or its derivatives by chiral Lewis bases, such as pyridine N-oxides. A variety of bi-or monodentate [2][3][4][5][6] catalysts have been synthesized and applied in the catalytic allylation of aromatic aldehydes, which is used as a benchmark reaction to assess the catalytic activity and the scope of asymmetric induction. Although in some cases high enantioselectivity was observed, this trend was not general and the asymmetric induction was often highly dependent on the presence of electron-accepting or -donating groups. Another problem is the synthesis of the catalyst being often complicated.We showed that the above-mentioned problems could be overcome by the use of unsymmetrical diastereoisomeric bis(tetrahydroisoquinoline) N,N'-dioxides 1 and appropriate choice of solvent.[7] Lewis bases 1 were prepared in three steps by a one-pot microwave-induced cross-cyclotrimerization [8] of hexadecatetrayne with benzonitrile and (R)-tetrahydrofurannitrile followed by oxidation with MCPBA.The presence of the additional center of chirality within the molecular framework allowed easy separation of both diastereoisomers by using simple column chromatography on silica gel. The correct configuration was unequivocally confirmed by a single-crystal X-ray analysis (Figure 1). Second, the allylation of various benzaldehydes catalyzed by 1 (1 mol %, À78 8C, 1 h) in THF proceeded with high enantioselectivity (up to 96 %) and high yields regardless of electronic properties of the substituents on the aromatic ring. [7a] Although the N-oxide-catalyzed allylation of benzaldehydes has been extensively studied, the reaction with a,bunsaturated aldehydes has been rather neglected. There have been reported allylations of three aldehydes: cinnamaldehyde, [3, 4b,c, 5b-d, 9-11] a-methylcinnamaldehyde, [5c, 9] and 2-decenal [3] with maximum enantioselectivities of 83, 76, and 81 % ee, respectively. The lack of data in this area provided the necessary impetus to study enantioselective allylation by using 1.Initially, the allylation of cinnamaldehyde 2 a with allyltrichlorosilane in the presence of (R,R)-1 (1 mol %, 1 h) was carried out in various solvents and gave 3 a with the following results: 92 % yield, 97 % ee in THF; 40 % yield, 88 % ee in dichloromethane; 43 % yield, 88 % ee in toluene; 84 % yield, 96 % ee in methoxycyclopentane; and 52 % yield, 96 % ee in 2-methylTHF [12] . Interestingly, the reaction in MeCN did n...

Dedicated to Professor František Tureček on the occasion of his 60th birthdayLewis base catalysed enantioselective allylation of aldehydes 1 with allyltrichlorosilanes 2 (Scheme 1) has become an efficient tool for C À C bond formation, thereby providing a robust alternative to the use of allylboranes carrying stoichiometric amounts of chiral auxiliaries.[1] The resulting homoallylic alcohols 3 are popular building blocks in targetoriented synthesis. However, in contrast to the more widely known and better-developed boron analogues, the synthetic applications of allyltrichlorosilanes are currently limited to simple alkyl homologues (R 2 = alkyl). Recently, we have demonstrated that alcohols 3, resulting from the addition of g-substituted allylsilanes 2, can themselves serve as efficient allylating reagents for aldehydes 4, which has broadened the scope of the method considerably.[2] A further advancement can be achieved by attaching additional functionality to allylsilane 2, and thus to the resulting alcohol 3, that will enable further synthetic development.[3] Herein, we introduce the new bifunctional allyldisilane 6 and demonstrate its applicability in a highly stereoselective triple allylation of aldehydes, resulting in a stereocontrolled construction of trisubstituted tetrahydrofurans 8 (Scheme 2).The synthesis of allyldisilane 6 started from tetrahydropyranyl (THP)-protected propargyl alcohol 9 (Scheme 3), for which deprotonation with nBuLi, followed by alkylation with iodomethyltrimethylsilane, afforded trimethylsilyl (TMS) derivative 10 (83 %). After deprotection, the resulting alcohol was reduced with lithium aluminium hydride to give (E)-4-trimethylsilylbutenol 11 (47 % over two steps) as a pure stereoisomer. The conversion of alcohol 11 into the corresponding chloride 12 required a great deal of optimisation and the protocol employing N-chlorosuccinimide with triphenylphosphine turned out to be the most efficient, as it preserved the regio-and stereo-integrity and afforded the required allylic chloride 12 in good yield (80 %).[4] Finally, a CuCl-mediated coupling of 12 with trichlorosilane in the presence of an equimolar amount of the Hünig base [5] afforded the required allyldisilane (E)-6 (60 %) as a liquid, which can be used in situ or isolated by distillation.With the geometrically pure (E)-allyldisilane 6 in hand, we first explored a racemic variant of the allylation of aldehydes 1, employing DMF as the Lewis base activator (1-3 equiv). The reaction proceeded readily, producing ex- [a] O.

Four bis(tetrahydroisoquinoline) N,N′-dioxides were used as catalysts for the epoxide ring opening with tetrachlorosilane under various conditions. A strong solvent effect on asymmetric induction was observed for each of the used catalysts. The highest achieved asymmetric induction for the opening of meso-stilbene oxide was 69% ee. Regarding the cycloalkene oxides, 56% ee was obtained in the reaction with cyclooctene oxide.

We report a systematic study of the allylation of ortho‐substituted benzaldehydes under catalysis of a Lewis base (N,N‐dioxide), a Lewis acid (Keck allylation), and a Brønsted acid. ortho‐Halobenzaldehydes were used as the aldehydic substrates, and special attention was paid to ortho‐vinyl and alkynyl benzaldehydes, which might serve as interesting synthons for the preparation of more complex chiral compounds. Similar enantioselectivities were achieved under catalytic conditions. In the case of ortho‐halobenzaldehydes, Lewis base catalysis proved to be more efficient, and the highest asymmetric induction for allylation of ortho‐fluorobenzaldehyde reached 82 % ee, which is comparable to other used catalytic conditions. In cases of ortho‐vinylbenzaldehyde, the Keck allylation provided the product in 88 % ee. An enantioenriched homoallylic alcohol was used as the starting material for the synthesis of a sertraline intermediate.