1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecanes: novel spirofused bis-trioxane peroxides.

A set of new bis-spirofused 1,2,4-trioxanes 4a-d was obtained from the reaction of cyclohexane-1,4-dione with allylic hydroperoxides 2a-d, bearing an additional hydroxy group in the homoallylic position, by diastereoselective photooxygenation of allylic alcohols 1a-d and subsequent BF(3)-catalyzed peroxyacetalization with the diketone. From the reaction of a monoprotected cyclohexane-1,4-dione 5 with the allylic hydroperoxide 6 derived from the singlet oxygenation of methyl hydroxytiglate, one monospiro compound was obtained, the 1,2,4-trioxane ketone 7, as well as a mixture of the diastereoisomeric syn- and anti bis-1,2,4-trioxanes 8. The structures of bis-1,2,4-trioxanes were examined theoretically by DFT methods and compared with X-ray structural data in order to evaluate the preferential trioxane ring conformational orientation.

Highly enantioselective epoxidation of 2-methylnaphthoquinone (vitamin K3) mediated by new cinchona alkaloid phase-transfer catalysts.

In the area of catalytic asymmetric epoxidation, the highly enantioselective transformation of cyclic enones and quinones is an extremely challenging target. With the aim to develop new and highly effective phase-transfer catalysts for this purpose, we conducted a systematic structural variation of PTCs based on quinine and quinidine. In the total of 15 new quaternary ammonium PTCs, modifications included, for example, the exchange of the quinine methoxy group for a free hydroxyl or other alkoxy substituents, and the introduction of additional elements of chirality through alkylation of the alkaloid quinuclidine nitrogen atom by chiral electrophiles. For example, the well-established 9- anthracenylmethyl group was exchanged for a "chiral" anthracene in the form of 9-chloromethyl-[(1,8-S;4,5-R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracene. The asymmetric epoxidation of vitamin K(3) was used as the test reaction for our novel PTCs. The readily available PTC 10 (derived from quinine in three convenient and high-yielding steps) proved to be the most enantioselective catalyst for this purpose known to date: At a catalyst loading of only 2.50 mol %, the quinone epoxide was obtained in 76 % yield and with 85 % ee (previously: < or =34 % ee), using commercial bleach (aqueous sodium hypochlorite) as the oxidant. To rationalize the sense of induction effected by our novel phase-transfer catalysts, a computational analysis of steric interactions in the intermediate chlorooxy enolate-PTC ion pair was conducted. Based on this analysis, the sense of induction for all 15 novel PTCs could be consistently explained.

Enantiomerically pure isophorone diamine [3-(aminomethyl)-3,5,5-trimethylcyclohexylamine]: a chiral 1,4-diamine building block made available on large scale.

Isophorone diamine [IPDA, 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] is a chiral non-C2-symmetric 1,4-diamine which is produced industrially on large scale as the mixture of all four stereoisomers (cis/trans ca. 3:1). Starting from this industrial bulk product, the preparation of the bis-tosyl, bis-Fmoc, bis-Boc and bis-Z derivatives of cis-IPDA, the preparation of the pure cis enantiomers by HPLC on chiral stationary phase, and the assignment of absolute configurations to the isolated enantiomers are described. We furthermore report an efficient method for the optical resolution of IPDA by salt formation with dibenzoyl tartaric acid. The latter method conveniently affords enantiomerically pure cis-IPDA in 100 g quantities. A number of salen ligands have been prepared from this enantiomerically pure 1,4-diamine and fully characterized. The nickel complex of one of the salen ligands was prepared and analyzed by X-ray crystallography. The crystal structure of the Ni4L4 complex illustrates the pronounced preference of cis-IPDA for adopting the chair conformation in which both the amino- and the aminomethyl substituents occupy equatorial positions. As a consequence, the two salicylidene imine moieties of one ligand molecule do not converge on one metal ion, but act as bridging ligands between two nickel ions.

Structural optimization of thiourea-based bifunctional organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones.

This article describes the synthesis of a library of structurally diverse bifunctional organocatalysts bearing both a quasi-Lewis acidic (thio)urea moiety and a Brønsted basic tertiary amine group. Sequential modification of the modular catalyst structure and subsequent screening of the compounds in the alcoholytic dynamic kinetic resolution (DKR) of azlactones revealed valuable structure-activity relationships. In particular, a "hit-structure" was identified which provides e.g.N-benzoyl-tert-leucine allyl ester in an excellent enantiomeric excess of 95%.

The X-ray structure of the pyochelin Fe3+ complex.

By X-ray structure analysis it could be shown that from the solution equilibrium of pyochelin I and II, differing in the stereochemistry at C-2" (1a and 1b), crystals of the Fe3+ complex of the steroisomer 1a are formed with a 1:1 metal-to-ligand ratio. Ligand sites are the carboxylate and the phenolate anions and the two nitrogen atoms. Two equivalent ferri-pyochelin moieties are held together by a hydroxy and an acetate unit which satisfy the remaining two coordination sites of Fe3+.

Total synthesis of (-)-colchicine via a Rh-triggered cycloaddition cascade.

[reaction: see text] A synthesis of the antimitotic alkaloids (-)-colchicine and (-)-isocolchicine is reported. Important steps are (a) enantioselective transfer-hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic acylation, (c) Rh-catalyzed transformation of an alpha-diazoketone into an oxatetracyclic key intermediate through intramolecular [3 + 2]-cycloaddition of an in situ generated carbonyl ylide, and (d) regioselective conversion of the cycloadduct into a tropolone derivative. The new synthetic strategy opens an efficient enantioselective access to colchicine and structural analogues.

Second-generation organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones.

Bifunctional organocatalysts of the thiourea-tert-amine type, carrying two "matched" elements of chirality, effect the alcoholytic dynamic kinetic resolution of a variety of azlactones with up to 95% ee.

Novel spiroanellated 1,2,4-trioxanes with high in vitro antimalarial activities.

A remarkable increase in antimalarial in vitro activity was achieved by integration of spiroadamantane motifs in 6-alkylidene 1,2,4-trioxanes 3a-h via diastereoselective photooxygenation of allylic alcohols and subsequent BF(3)-catalyzed peroxyacetalization with adamantanone to give the active compounds 3e-h.

Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity.

A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-1-yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3-trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s >/= 40 at -78 degrees C) by means of an oxazaborolidine-catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd(0)-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD50 values down to 9 microM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis.

Enantioselective synthesis of DIANANE, a novel C2-symmetric chiral diamine for asymmetric catalysis.

DIANANE (endo,endo-2,5-diaminonorbornane) is a novel chiral C(2)-symmetric diamine, based on the rigid bicyclo[2.2.1]heptane scaffold. Schiff-base ligands derived from DIANANE have already found use in asymmetric catalysis, e.g., in the highly enantioselective Nozaki-Hiyama-Kishi reaction. We herein describe a practical synthesis of enantiomerically pure DIANANE, starting from norbornadiene in four steps: (i) Pd-MOP catalyzed Hayashi-hydrosilylation/Tamao-Fleming oxidation, (ii) oxidation to norbornane-2,5-dione, (iii) endo-selective reductive amination with benzylamine, and (iv) hydrogenolytic debenzylation. None of the steps involves chromatographic purification. For the Tamao-Fleming oxidation, the use of hydrogen peroxide in the form of its urea clathrate instead of aqueous solution proved beneficial. By the above sequence, enantiomerically pure (ee >or=99%) DIANANE was obtained from norbornadiene in 40-50% overall yield. The relative and absolute configuration of DIANANE was confirmed by X-ray crystallography of the DIANANE bis-tosylamide, and of its bis-camphorsulfonamide. Furthermore, the synthesis and X-ray crystal structure of the Schiff-base ligand derived from DIANANE and 3,5-di-tert-butyl salicylic aldehyde are reported.

Stereoselective generation of vicinal stereogenic quaternary centers by photocycloaddition of 5-methoxy oxazoles to alpha-keto esters: synthesis of erythro beta-hydroxy dimethyl aspartates.

The photocycloaddition of methyl pyruvate and methyl phenylglyoxylate, respectively, to 5-methoxy oxazoles bearing additional substituents at C-2 and C-4 leads to bicyclic oxetanes 2 and 3 with high to moderate (exo) diastereoselectivity that can be easily ring-opened to give bis-quaternary aspartic acid diester derivatives 4 and 5.

Synthesis of erythro-alpha-amino beta-hydroxy carboxylic acid esters by diastereoselective photocycloaddition of 5-methoxyoxazoles with aldehydes.

A new photoaldol route to alpha-amino-beta-hydroxy carboxylic acid esters is initiated by the photocycloaddition of aromatic or aliphatic aldehydes to 5-methoxyoxazoles. The 4-unsubstituted 5-methyloxazole 1 gave the cycloadducts 8a-f in high yields and excellent exo-diastereoselectivities. Hydrolysis of 8a-f gives the N-acetyl alpha-amino-beta-hydroxy esters 9a-f, which could be subsequently converted into the corresponding Z-didehydro alpha-amino acids 10a-f. Quartenary alpha-amino-beta-hydroxy esters 12, 14, 16, 18, and 20, which are stable against dehydration, were obtained from the 4-alkylated 5-methoxyoxazoles 2-6, in most cases highly erythro-selective due to the high degree of stereocontrol (exo) at the photocycloaddition (to give 11, 13, 15, 17, and 19) level. The relative configurations of the N-acetyl alpha-amino-beta-hydroxy esters were determined by NMR spectroscopy and comparison with chiral pool-derived compounds as well as by X-ray structure determination of the ester 23, formed by hydrolysis of the cycloadduct 22, derived from photocycloaddition of propionaldehyde to the isoleucine-derived oxazole 21.

Spiroconjugation in spirodicorrolato-dinickel(II).

In the present work the effect of spiroconjugation on the electronic spectrum of the recently synthesized metal complex hexadecaethylspirodicorrolato-dinickel(II) (5) (the corrole units in 5 are isoforms) is investigated. To have a suitable reference compound at our disposal, tetraethylhexamethylisocorrolato nickel(II) (7) has been prepared. On comparing the electronic spectra of this reference compound and the spiro-complex, bathochromic shifts of all absorption bands in the NIR/Vis-region are observed for the latter as well as marked changes in the spectral intensities. A detailed analysis of the spectra supported by semiempirical calculations reveals that at least part of the observed changes can be unambiguously attributed to the spiro effect. This effect is further affirmed by electrochemically measured redox potentials.

Electronically tuned chiral ruthenium porphyrins: extremely stable and selective catalysts for asymmetric epoxidation and cyclopropanation.

We report the use of three enantiomerically pure and electronically tuned ruthenium carbonyl porphyrin catalysts for the asymmetric cyclopropanation and epoxidation of a variety of olefinic substrates. The D(4)-symmetric ligands carry a methoxy, a methyl or a trifluoromethyl group at the 10-position of each of the 9-[anti-(1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracene)]-substituents at the meso-positions of the porphyrin. Introduction of a CF(3)-substituent in this remote position resulted in greatly improved catalyst stability, and turnover numbers of up to 7500 were achieved for cyclopropanation, and up to 14,200 for epoxidation, with ee values typically >90 % and approximately equal to 80 %, respectively. In one example, the axial CO ligand at the ruthenium was exchanged for PF(3), resulting in the first chiral ruthenium porphyrin with a PF(3) ligand reported to date. In cyclopropanations with ethyl diazoacetate, the latter catalyst performed exceedingly well, and gave a 95 % ee in the case of 1,1-diphenylethylene as substrate.

A photochemical route for efficient cyclopeptide formation with a minimum of protection and activation chemistry.

An elaborated protocol is described which allows the efficient transformation of di-, tri-, and tetrapeptides into cyclopeptides with a minimum of protection and activation chemistry using the photoinduced electron transfer initiated decarboxylation of N-phthaloyl peptides resulting in C-C coupling between the initially formed carbon radicals.

Metal complexes of porphycene, corrphycene, and hemiporphycene: stability and coordination chemistry.

Porphyrin (P), porphycene (Pc), corrphycene (Cn), and hemiporphycene (Hpc) represent a series of well defined "4-N in" constitutional porphyrin isomers. These isomers, in the form of their octaethyl derivatives, represent a congruent set of porphyrinoids whose properties can be compared. In this study we report how variations in electronic structure and nitrogen-core size in the free-base forms of these four systems are reflected in the properties of their corresponding metal complexes. Specifically, the effects that these differences have on the axial ligation properties of the Zn(II), Mg(II), Ni(II), and Co(II) complexes of P, Pc, Cn, and Hpc in toluene using pyridine as the axial ligand are detailed. Also reported are the relative stabilities of these complexes under acidic conditions. It is shown that for the zinc, magnesium, and cobalt complexes, there are distinct differences in the ability to maintain four-, five-, or six-coordinate geometries in the presence of similar concentrations of pyridine. By contrast, no apparent differences in axial ligand binding affinity are seen for the four nickel complexes. Little difference in stability was likewise seen when these same complexes were subject to acid-mediated demetallation, with all four falling into stability class II, according to the accepted porphyrin stability ranking system. High stabilities were also seen in the case of the cobalt complexes, with the Pc and Cn complexes being of stability class III and the P and Hpc derivatives falling into stability class II. The Zn(II) and Mg(II) complexes were all far less stable than the corresponding Ni(II) and Co(II) complexes. In this case, semiquantitative analyses of the rate of acid-induced decomposition revealed the following stability sequence P>Cn>Hpc>Pc for both the Zn(II) and Mg(II) complexes. Single-crystal X-ray diffraction structures were solved for the Zn(II), Mg(II), and Ni(II) complexes of the octaethyl derivatives of Hpc, Cn, and Pc as well as a Co(II) octamethylcorrphycene and are reported as part of this study. These solid-state structures confirm four-coordinate species for the Ni(II) complexes, four- and five-coordinate species for the Mg(II) and Zn(II) complexes, and a six-coordinate species for the lone Co(II) complex.