Ralf Warmuth

Edge-Directed Dynamic Covalent Synthesis of a Chiral Nanocube

The dynamic multicomponent syntheses of nanometer-sized chiral molecular cubes 1a and 1b from 8 tritopic 90 degree corner units and 12 linear spacers using an edge-directed approach is described. Thus, the TFA-catalyzed reaction of 8 equiv C3-trihexadecyloxy-triformylcyclotribenzylene 2 as corner unit with 12 equiv of 1,4-phenylenediamine 3a or benzidine 3b as spacers yields nanocubes 1a and 1b, respectively in close to quantitative yield. The same reactions carried out with enantiomerically pure (P)-2 (>99% ee) gave the homochiral cubes (all-P)-1a and (all-P)-1b. Force field calculations predict an edge length of 17 A and 21 A for 1a and 1b, which is consistent with their dimensions estimated from DOSY experiments. Furthermore, the asymmetric synthesis of (P)-2 through a dynamic thermodynamic resolution is described. This approach is based on the TFA-catalyzed reaction of racemic 2 with (R,R)-1,2-diaminocyclohexane (R)-5, which leads to a chiral cryptophane (>90% yield) that is built-up from two (P)-2 linked together with three diamines (R)-5. Hydrolysis of this cryptophane provides (P)-2 with >99% ee.

Inner‐Phase Stabilization of Reactive Intermediates

Molecular container compounds are spherical, hollow molecules with inner cavities (inner phases) that are large enough to accommodate a single guest molecule. These inner phases are superb environments for the stabilization and spectroscopic investigation of important reactive intermediates. The surrounding host protects the incarcerated reactive intermediate from dimerization or from a reaction with bulk-phase reactants that are too large to enter the inner phase by passing through a portal in the host shell.

Chemistry and properties of cycloheptatetraene in the inner phase of a hemicarcerand.

Low-temperature photolysis of phenyldiazirine, incarcerated inside a hemicarcerand which is built from two cavitands connected by four butane-1,4-dioxy linker groups, yields transient phenylcarbene; this carbene then undergoes ring photochemical expansion to cycloheptatetraene in low yield. Competitively, the transiently formed phenylcarbene reacts with the surrounding hemicarcerand. The yield of the photochemical ring expansion was increased when the photolysis was carried out inside a partially deuterated hemicarcerand. Two insertion products resulting from an intramolecular phenylcarbene insertion into an acetal C-H(D) bond or an alpha-C-H bond of a butane-1,4-dioxy linker group have been isolated and characterized. The measured isotope effect for insertion into an acetal C-H(D) bond at 15.5 K is consistent with a reaction of singlet phenylcarbene. Incarcerated cycloheptatetraene is stable for a limited time at 100 degrees C and almost infinitely stable at room temperature in the absence of oxygen. NOESY experiments provide the distance ratio r21/r23 = 1.134 +/- 0.01 between protons H1-H2 and H2-H3 of cycloheptatetraene which is consistent with its twisted structure. Low-temperature photolysis of phenyldiazirine, incarcerated inside a chiral hemicarcerand which is built from two cavitands connected with three butane-1,4-dioxy and one (S,S)-2,3-O-isopropylidene-2,3-dihydroxybutane-1,4-dioxy linker group yields two diastereomeric cycloheptatetraene hemicarceplexes in a 2:3 ratio (30% total yield). Variable temperature 1H NMR studies provided a lower limit of deltaG++ = 19.6 kcalmol(-1) for the enantiomerization barrier of cycloheptatetraene. Incarcerated cycloheptatetraene reacts rapidly with oxygen to yield benzene and carbon dioxide via the 1,2-dioxaspiro[2,6]nona-4,6,8-triene intermediate. Different mechanisms for the formation of this spirodioxirane intermediate are discussed based on the measured rate of the oxygen addition. The activation parameters for the decarboxylation of the spirodioxirane have been measured in different bulk solvents. The free energy of activation shows very little solvent dependency. However. a strong propensity for enthalpy-entropy compensation due to a solvent reorganization that accompanies the reaction coordinate is observed.

Thermodynamically Controlled Synthesis of a Chiral Tetra-cavitand Nanocapsule and Mechanism of Enantiomerization.

The dynamic covalent synthesis, structure and conformational dynamics of a chiral polyimine nanocapsule 1a are reported. Reaction of four tetraformyl cavitands and eight H(2)N(CH(2))(2)NH(2) yields quantitatively 1a, which has a compact, asymmetrically folded, pseudo-C(2)-symmetric structure, as determined by X-ray crystallography, and encapsulates four CHCl(3) and three CH(3)OH guests in the solid state. In solution, 1a enantiomerizes by passing over a barrier of ΔG(298)(double dagger) = 21.5 ± 0.7 kcal mol(-1) via a refolding process.

The Inner Phase of Molecular Container Compounds as a Novel Reaction Environment

The conceptual idea of molecular container compoundsand their synthesis has opened an entirely new andvery interesting research field: the chemistry of andwithin molecular container compounds and theircomplexes. Molecular containers have inner phases justlarge enough to accommodate a single guest molecule.Beginning with Donald J. Crams first synthesis of acarcerand, which permanently entrapped a single guestmolecule, many other containers such ashemicarcerands, molecular lantern, self-assembledcapsules and fullerenes have been synthesized andstudied. Not only is the design and development of newcontainer compounds an ongoing challenge for organicchemists, but also the systematic investigation ofchemical reactions within their inner phases. Theresults of a large variety of inner phase reactionsspanning acid-base, reduction, oxidation, nucleophilicsubstitution, addition, thermal, photochemical andpericyclic reactions have provided us with moreinsight into the relationship between bulk phase andinner phase reactants and the mechanism of thetransfer of electrons and photons through theinsulating shell of a container molecule. They havealso led to very spectacular applications of molecularcontainer compounds such as the stabilization ofreactive intermediates by incarceration. Thesehighlights of inner phase chemistry and the currentefforts and successes towards using molecularcontainers as catalytic reaction vessels are presentedand discussed.

Enantioselective synthesis of benzocyclic α,α-dialkyl-amino acids: new insight into the solvent dependent stereoselectivity of the TMSCN addition to phenylglycinol derived imines

Abstract Different benzocycloalkane-1-amino-1-carboxylic acids 1a–e have been synthesized via an asymmetric Strecker reaction using (S)-α-methylbenzylamine and (R)-phenylglycinol as chiral auxiliaries. The Zn2+-catalyzed addition of HCN to (S)-α-methylbenzylamine derived ketimines of 1-tetralone (8a) and 1-benzosuberone (8b) yielded mixtures of diastereomeric aminonitriles (1S,1′S)-10a/(1R,1′S)-10a (10:1 ratio) and (1R,1′S)-10b/(1S,1′S)-10b (56:44 ratio), respectively. These aminonitriles are converted to amino acids 1a,b in two steps. The addition of TMSCN to the (R)-phenylglycinol derived ketimines of 8a, 8b, 1-indanone (8c), 7-fluoro-1-tetralone (8d), 7-fluoro-1-benzosuberone (8e) yielded mixtures of diastereomeric trimethylsilylated aminonitriles (1S,1′R)-14a–e/(1R,1′R)-14a–e. The addition proceeded with diastereofacial selectivities ranging from 1:2.9 to 1:25. The selectivity was found to be temperature and solvent dependent. The diastereomeric ratio (dr) of aminonitriles (1S,1′R)-14a/(1R,1′R)-14a increased in different solvents in the order methanol

Asymmetric synthesis of two new conformationally constrained lysine derivatives

Abstract The asymmetric synthesis of the conformationally constrained l - and d -lysine derivatives methyl (1S,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxylate ( 4 ) and methyl (1R,8S)-1-amino-8-tert-butoxycarbonylamino-1,2,3,4,5,6,7,8-octahydroanthracene-1-carboxylate ( 5 ), respectively are described. Application of the Bucherer hydantoin synthesis to the carbonyl group of 2′,3′,4′,5′,6′,7′-hexahydrospiro[1,3-ethylenedithiole-2,1′-anthracen]-8′-one ( 18 ), which was prepared from 1,8-dichloroanthraquinone ( 14 ) in nine steps and the deprotection of the masked second ketone of 18 yields rac-21. The latter is the precursor for a novel asymmetric reductive amination protocol using (R)-phenylglycinol as a chiral amino auxiliary and NaBH(OAc)3 as a reducing agent. Using this procedure, the asymmetric reductive amination of α-tetralone derivatives and indanone proceeds with >95% de. Lower diastereomeric excesses are observed for benzosuberone (16.7% de) and acetophenone (27.3% de). rac-21 gave (1′S,8′S,1(R)-25a (38% yield) and (1′R,8′S,1(R)-25b (44.5% yield) with greater than 52 and 78% de, respectively. Cleavage of the amino auxiliary of (1′S,8′S,1(R)-25a and of (1′R,8′S,1(R)-25b with lead(IV) tetraacetate and hydrolysis of the hydantoin ring yields the unprotected analogs of 4 and 5 . The latter are transformed into the selectively protected target molecules 4 and 5 through standard protection procedures. The overall yield of the 17- and 18-step synthesis starting from 13 was 0.3% yield for each constrained lysine derivative.