Enantioselective synthesis of pyrroloindolines and tryptophan derivatives by an asymmetric protonation reaction

Pyrroloindoline and unnatural tryptophan motifs are important targets for synthesis based on their incorporation into a diverse array of biologically active natural products. Both types of alkaloids have also found applications as chiral catalysts and tryptophan derivatives are commonly employed as biological probes. On account of their applications, these frameworks have inspired the development of numerous enantioselective, catalytic reactions. In particular, the past few years have witnessed an impressive number of novel approaches for pyrroloindoline formation.

The first project described herein involves our contribution to pyrroloindoline research. We have developed an (R)-BINOL•SnCl₄-catalyzed formal (3 + 2) cycloaddition reaction between 3-substituted indoles and 2-amidoacrylates that affords pyrroloindoline-2-carboxylates bearing an all-carbon quaternary center. Mechanistic studies have elucidated that the enantiodetermining step is a highly face-selective catalyst-controlled protonation reaction. The subsequent application of this asymmetric protonation strategy to the synthesis of a variety of enantioenriched tryptophan derivatives is also discussed.

Carrier-envelope phase control of carrier-wave Rabi flopping in asymmetric semiparabolic quantum well

We investigate the carrier-wave Rabi flopping effects in an asymmetric semiparabolic semiconductor quantum well (QW) with few-cycle pulse. It is found that higher spectral components of few-cycle ultrashort pulses in the semiparabolic QW depend crucially on the carrier-envelope phase (CEP) of the few-cycle ultrashort pulses: continuum and distinct peaks can be achieved by controlling the CEP. Our results demonstrate that by adjusting the CEP of few-cycle ultrashort pulses, the intersubband dynamics in the asymmetric semiparabolic QW can be controlled in an ultrashort timescale with moderate laser intensity. (c) 2008 Optical Society of America.

Intensity-dependent asymmetric photoionization in few-cycle laser pulses

The asymmetric photoionization of atoms irradiated by intense, few-cycle laser pulses is studied numerically. The results show that the pulse intensity affects the asymmetric photoionization in three aspects. First, at higher intensities, the asymmetry becomes distinctive for few-cycle pulses of longer durations. Second, as the laser intensity increases, the maximal asymmetry first decreases then increases after it has reached a minimal value. Last, the value of the carrier-envelope phase corresponding to the maximal asymmetry varies with the pulse intensity. This study reveals that the increasing of pulse intensity is helpful for observing the asymmetric photoionization.

Use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis

The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is describe. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective a1kylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, and aldehydes. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols.

The development of an asymmetric palladium-catalyzed conjugate addition and its application toward the total syntheses of taiwaniaquinoid natural products

The asymmetric synthesis of quaternary stereocenters remains a challenging problem in organic synthesis. Past work from the Stoltz laboratory has resulted in methodology to install quaternary stereocenters α- or γ- to carbonyl compounds. Thus, the asymmetric synthesis of β-quaternary stereocenters was a desirable objective, and was accomplished by engineering the palladium-catalyzed addition of arylmetal organometallic reagents to α,β-unsaturated conjugate acceptors.

Herein, we described the rational design of a palladium-catalyzed conjugate addition reactions utilizing a catalyst derived from palladium(II) trifluoroacetate and pyridinooxazole ligands. This reaction is highly tolerant of protic solvents and oxygen atmosphere, making it a practical and operationally simple reaction. The mild conditions facilitate a remarkably high functional group tolerance, including carbonyls, halogens, and fluorinated functional groups. Furthermore, the reaction catalyzed conjugate additions with high enantioselectivity with conjugate acceptors of 5-, 6-, and 7-membered ring sizes. Extension of the methodology toward the asymmetric synthesis of flavanone products is presented, as well.

A computational and experimental investigation into the reaction mechanism provided a stereochemical model for enantioinduction, whereby the α-methylene protons adjacent the enone carbonyl clashes with the tert-butyl groups of the chiral ligand. Additionally, it was found that the addition of water and ammonium hexafluorophosphate significantly increases the reaction rate without sacrificing enantioselectivity. The synergistic effects of these additives allowed for the reaction to proceed at a lower temperature, and thus facilitated expansion of the substrate scope to sensitive functional groups such as protic amides and aryl bromides. Investigations into a scale-up synthesis of the chiral ligand (S)-tert-butylPyOx are also presented. This three-step synthetic route allowed for synthesis of the target compound of greater than 10 g scale.

Finally, the application of the newly developed conjugate addition reaction toward the synthesis of the taiwaniaquinoid class of terpenoid natural products is discussed. The conjugate addition reaction formed the key benzylic quaternary stereocenter in high enantioselectivity, joining together the majority of the carbons in the taiwaniaquinoid scaffold. Efforts toward the synthesis of the B-ring are presented.

Tunneling-induced large cross-phase modulation in an asymmetric quantum well

We propose an asymmetric double AlGaAs/GaAs quantum well structure with a common continuum to generate a large cross-phase modulation (XPM). It is found, owing to resonant tunneling, that a large XPM can be achieved with vanishing linear and two-photon absorptions. (c) 2007 Optical Society of America.

Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids

Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.

We have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL•SnCl₄; this complex is a Lewis acid-assisted Brønsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.

Based on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.

Next, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.

I. The crystal structure of trimesic acid. II. Topics in crystallographic calculations

I. Trimesic acid (1, 3, 5-benzenetricarboxylic acid) crystallizes with a monoclinic unit cell of dimensions a = 26.52 A, b = 16.42 A, c = 26.55 A, and β = 91.53° with 48 molecules /unit cell. Extinctions indicated a space group of Cc or C2/c; a satisfactory structure was obtained in the latter with 6 molecules/asymmetric unit - C₅₄O₃₆H₃₆ with a formula weight of 1261 g. Of approximately 12,000 independent reflections within the CuK_α sphere, intensities of 11,563 were recorded visually from equi-inclination Weissenberg photographs.

The structure was solved by packing considerations aided by molecular transforms and two- and three-dimensional Patterson functions. Hydrogen positions were found on difference maps. A total of 978 parameters were refined by least squares; these included hydrogen parameters and anisotropic temperature factors for the C and O atoms. The final R factor was 0.0675; the final "goodness of fit" was 1.49. All calculations were carried out on the Caltech IBM 7040-7094 computer using the CRYRM Crystallographic Computing System.

The six independent molecules fall into two groups of three nearly parallel molecules. All molecules are connected by carboxylto- carboxyl hydrogen bond pairs to form a continuous array of sixmolecule rings with a chicken-wire appearance. These arrays bend to assume two orientations, forming pleated sheets. Arrays in different orientations interpenetrate - three molecules in one orientation passing through the holes of three parallel arrays in the alternate orientation - to produce a completely interlocking network. One third of the carboxyl hydrogen atoms were found to be disordered.

II. Optical transforms as related to x-ray diffraction patterns are discussed with reference to the theory of Fraunhofer diffraction.

The use of a systems approach in crystallographic computing is discussed with special emphasis on the way in which this has been done at the California Institute of Technology.

An efficient manner of calculating Fourier and Patterson maps on a digital computer is presented. Expressions for the calculation of to-scale maps for standard sections and for general-plane sections are developed; space-group-specific expressions in a form suitable for computers are given for all space groups except the hexagonal ones.

Expressions for the calculation of settings for an Eulerian-cradle diffractometer are developed for both the general triclinic case and the orthogonal case.

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