Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis.

We herein report an asymmetric protocol to access a series of orthogonally functionalized acyclic chiral target molecules containing a quaternary stereogenic center by carrying out the enantioselective α-alkylation of novel orthogonally functionalized dioxolane-containing cyanoacetates under chiral ammonium salt catalysis. By using just 1 mol % of Maruoka's spirocyclic ammonium salt catalysts enantioselectivities up to e.r.=97.5 : 2.5 could be achieved and further functional group manipulations of the products were carried out as well.

Synthesis and characterization of enantiopure planar-chiral phosphorus-linked diferrocenes.

In the course of an ongoing synthetic project on cyclic diferrocenylphosphines, we obtained a group of planar-chiral diferrocenyl compounds useful as precursors for subsequent cyclization. Here we report the crystal structures of two symmetric compounds [(FcA)2(Ph)P], one of which contains four stereogenic centres (two C chiral and two planar chiral centres), i.e. 1,1'-(phenylphosphanediyl)bis{(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocene}, [Fe2(C5H5)2(C24H25O4P)], and the other phosphine sulfide is a purely planar-chiral compound (two planar chiral centres), i.e. bis[(2Sp)--2-ethenylferrocen-1-yl]phenylphosphane sulfide, [Fe2(C5H5)2(C20H17PS)]. Owing to the stereocentres present, reactions performed on [(FcA)2(Ph)P]-type compounds strongly favour one ferrocene unit over the other due to diastereoselectivity. Furthermore, we present four related structures where the ferrocene units are not identical [(FcA)(FcB)(Ph)P]. These are {(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}[(2Sp)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C22H21O2PS)], [(2Sp)-2-ethenylferrocen-1-yl]{(2Sp)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C20H19OPS)], {(2Sp)-2-[(1R)-1-(acetyloxy)ethyl]ferrocen-1-yl}{(2Sp)-2-[(1R)-1-hydroxyethyl]ferrocen-1-yl}phenyl-(R)-phosphine sulfide, [Fe2(C5H5)2(C22H23O3PS)], and {(2Sp)-2-[(1R)-1-benzylamino)ethyl]ferrocen-1-yl}[(2Sp)-2-ethenylferrocen-1-yl]phenyl-(S)-phosphine sulfide, [Fe2(C5H5)2(C27H26NPS)]. All of the structures are accessible in one step from known precursors.

Improved Access to Chiral Tetranaphthoazepinium-Based Organocatalysts Using Aqueous Ammonia as Nitrogen Source.

The class of 3,3'-diaryl substituted tetranaphthobisazepinium bromides has found wide application as highly efficient C2-symmetrical phase-transfer catalysts (PTCs, Maruoka type catalysts). Unfortunately, the synthesis requires a large number of steps and hampers the build-up of catalyst libraries which are often desired for screening experiments. Here, we present a more economic strategy using dinaphthoazepine 7 as the common key intermediate. Only at this stage various aryl substituents are introduced, and only two individual steps are required to access target structures. This protocol was applied to synthesize ten tetranaphthobisazepinium compounds 1a-1j. Their efficiency as PTCs was tested in the asymmetric substitution of tert-butyl 2-((diphenylmethylene)amino)acetate. Enantioselectivities up to 92% have been observed with new catalysts.

Synthesis, Structure, and Reactivity of Binaphthyl Supported Dihydro[1,6]diazecines.

A short approach to chiral diaza-olefines from protected 2,2'-diamino-1,1'-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2'-diamino-1,1'-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained.

Syntheses of Highly Functionalized Spirocyclohexenes by Formal [4+2] Annulation of Arylidene Azlactones with Allenoates.

A straightforward phosphine-catalyzed formal [4+2] annulation between α-branched allenoates and arylidene azlactones has been developed to access highly functionalized spirocyclohexenes. This cyclization favors the γ-addition of the phosphine-activated allenoates over a ß'-addition pathway. Detailed computational studies support the proposed mechanism and provide a reasonable explanation for the observed regioselectivity and the noted effect of the catalyst.

Economy of Catalyst Synthesis-Convenient Access to Libraries of Di- and Tetranaphtho Azepinium Compounds.

Efficient optimization procedures in chiral catalysis are usually linked to a straightforward strategy to access groups of structurally similar catalysts required for fine-tuning. The ease of building up such ligand libraries can be increased when the structure-modifying step (introduction of a substituent) is done at a later stage of the synthesis. This is demonstrated for the extended family of di- and tetranaphtho azepinium compounds, widely used as chiral phase transfer catalysts (PTC). Using 2,6-diiodo-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine and 4,8-diiodo-6,7-dihydro-5H-dibenzo[c,e]azepine, respectively, as key intermediates, 18 spiro-azepinium compounds were synthesized in a total yield of 25-42% over 6-7 steps from 1,1'-binaphthyl-2,2'-dicarboxylic acid or diphenic acid, respectively. The replacement of iodo groups with aryl substituents was performed as the last or the penultimate step of the synthesis.

Tandem RCM-Claisen rearrangement-[2+2] cycloaddition of O,O'-(but-2-en-1,4-diyl)-bridged binaphthols.

Attempted RCM of 2,2'-bis(allyloxy)-1,1'-binaphthyl resulted in a Claisen-type rearrangement of a postulated labile dioxacyclodecine proceeding at room temperature and followed by [2+2] cycloaddition. Structures of products were confirmed by X-ray crystallography. A mechanistic rationalisation based on relative stabilities of proposed intermediates and transition states is provided.

Synthesis and conformation of chiral biheteroaryls.

Bridging 2,3 and 2',3' positions in 2,2'-dihydroxy-1,1'-binaphthyl and 2,2'-diamino-1,1'-binaphthyl, respectively, resulted in formation of chiral O- and N-bis-tricyclic compounds accessible in 4 steps from known 3,3'-diiodo precursors. In both cases, 2-fold ring closing metathesis of tetraallyl intermediates proceeded regioselectively to give tetrahydrobinaphtho[2,3-b]oxepine and -azepine, respectively. In case of the N-mesyl-N-allyl precursor, three, at room temperature separable, rotamers were isolated and characterized by NMR spectroscopy and X-ray structure determination. Their interconversion (process I) was followed by NMR, yielding rate constants and thermodynamic parameters. The rotamers with either C(1) or C(2) symmetry were stereospecifically cyclized to conformatively moderately stable bis-sulfonamides. Also in this case, the kinetics of their interconversion (process II) was investigated and from two of them the crystal structure was determined. Processes I and II were investigated by a DFT method, M06-2X, to gain insight into electronic and steric peculiarities responsible for the remarkable conformative stabilities. Transition state geometries and energies were calculated and compared with empirical data.

Mechanism of asymmetric hydrogenation of alpha-(acylamino)acrylic esters catalyzed by BINAP-ruthenium(II) diacetate.

The mechanism of asymmetric hydrogenation of alpha-(acylamino)acrylic esters with Ru(CH(3)COO)(2)[(S)-binap] (BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), giving the S saturated products in >90% ee, has been investigated by means of a kinetic study, deuterium labeling experiments, isotope effect measurements, and NMR and X-ray analysis of certain Ru complexes. The hydrogenation in methanol under a low H2 pressure proceeds via a monohydride-unsaturate mechanism that involves the initial RuH formation followed by a reaction with an olefinic substrate. The migratory insertion in the enamide-RuH chelate complex occurs reversibly and endergonically in an exo manner, giving a five-membered metallacycle intermediate. The cleavage of the Ru-C bond is achieved with either H2 (major) or CH3OH (minor). Both of the pathways result in overall cis hydrogenation products. The hydrogen at C3 is mainly from an H2 molecule, and the C2 hydrogen is from another H2 or protic CH3OH. The major S and minor R enantiomers are produced via the same mechanism involving diastereomeric intermediates. The turnover rate is limited by the step of hydrogenolysis of a half-hydrogenated metallacyclic intermediate. The participation of two different hydrogen donor molecules is in contrast to the pairwise dihydrogenation using a single H2 molecule in the RhI-catalyzed reaction which occurs via a dihydride mechanism. In addition, the sense of asymmetric induction is opposite to that observed with S-BINAP-RhI catalysts. The origin of this phenomenon is interpreted in terms of stereocomplementary models of the enamide/metal chelate complexes. A series of model stoichiometric reactions mimicking the catalytic steps has indicated that most NMR-observable Ru complexes are not directly involved in the catalytic hydrogenation but are reservoirs of real catalytic complexes or even side products that retard the reaction.

Novel chiral biferrocene ligands for palladium-catalyzed allylic substitution reactions.

Eleven novel aminophosphine ligands have been synthesized, all of which contain a chiral 2,2' '-bridged biferroceno unit as part of a biferrocenoazepine substructure. The efficiency of these compounds as chiral auxiliaries in palladium-mediated allylic substitution reactions has been investigated. Depending on the degree of (steric) fit between proper ligands and cyclic or noncyclic substrates, reactions with 46-87% ee were achieved. The molecular structure of a palladium dichloride complex of one of the ligands was determined by X-ray diffraction and compared to its binaphthyl analogue. In the solid state, the azepine substructure of these two complexes adopts totally different conformations with either local C(2) (binaphthyl) or local C(1) (biferrocene derivative) symmetry. These structural changes are well-reproduced by empirical force field calculations and are also reflected in significantly different behavior in asymmetric catalysis.