Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet-Spengler-Type Reactions.

A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles (THCAs) has been developed. The strategy relies on two types of 6-exo-trig cyclization of 3-substituted indole substrates. Enantioselective domino Friedel-Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid derivatives (with up to >99% ee), and the first examples of exocyclic Pictet-Spengler reactions to form THCAs are reported.

Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes and Activated Carboxylic Acids.

A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched α-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance.

A Protocol for the exo-Mono and exo,exo-Bis Functionalization of the Diazocine Ring of Tröger's Base.

An efficient protocol has been developed for the exo-mono and exo,exo-bis functionalization of Tröger's base in the benzylic 6 and 12 positions of the diazocine ring. The lithiation of Tröger's base using s-BuLi/TMEDA followed by electrophilic quench affords exo-mono- and exo,exo-bis-substituted derivatives of Tröger's base in good to excellent yields. The variation of the number of equivalents of s-BuLi/TMEDA and the order of addition of the electrophile strongly govern the outcome of the reaction for each electrophile.

Resolution and Determination of the Absolute Configuration of a Twisted Bis-Lactam Analogue of Tröger's Base: A Comparative Spectroscopic and Computational Study.

The first reported twisted bis-lactam, a racemic Tröger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (-)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P212121 using Cu-irradiation resulting in a very low Flack parameter of -0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Tröger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (-)-(S,S)-2.

Highly diastereo- and enantioselective CuH-catalyzed synthesis of 2,3-disubstituted indolines.

A diastereo- and enantioselective CuH-catalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles, olefins, and substituted aromatic groups, renders this technique highly valuable for the synthesis of a variety of cis-2,3-disubstituted indolines in high yield and enantioeselectivity.

Intermixed adatom and surface-bound adsorbates in regular self-assembled monolayers of racemic 2-butanethiol on Au(111).

In situ scanning tunneling microscopy combined with density functional theory molecular dynamics simulations reveal a complex structure for the self-assembled monolayer (SAM) of racemic 2-butanethiol on Au(111) in aqueous solution. Six adsorbate molecules occupy a (10×√3)R30° cell organized as two RSAuSR adatom-bound motifs plus two RS species bound directly to face-centered-cubic and hexagonally close-packed sites. This is the first time that these competing head-group arrangements have been observed in the same ordered SAM. Such unusual packing is favored as it facilitates SAMs with anomalously high coverage (30%), much larger than that for enantiomerically resolved 2-butanethiol or secondary-branched butanethiol (25%) and near that for linear-chain 1-butanethiol (33%).

Controlling the stereochemistry and regularity of butanethiol self-assembled monolayers on au(111).

The rich stereochemistry of the self-assembled monolayers (SAMs) of four butanethiols on Au(111) is described, the SAMs containing up to 12 individual C, S, or Au chiral centers per surface unit cell. This is facilitated by synthesis of enantiomerically pure 2-butanethiol (the smallest unsubstituted chiral alkanethiol), followed by in situ scanning tunneling microscopy (STM) imaging combined with density functional theory molecular dynamics STM image simulations. Even though butanethiol SAMs manifest strong headgroup interactions, steric interactions are shown to dominate SAM structure and chirality. Indeed, steric interactions are shown to dictate the nature of the headgroup itself, whether it takes on the adatom-bound motif RS(•)Au(0)S(•)R or involves direct binding of RS(•) to face-centered-cubic or hexagonal-close-packed sites. Binding as RS(•) produces large, organizationally chiral domains even when R is achiral, while adatom binding leads to rectangular plane groups that suppress long-range expression of chirality. Binding as RS(•) also inhibits the pitting intrinsically associated with adatom binding, desirably producing more regularly structured SAMs.

Synthesis of oxacyclic scaffolds via dual ruthenium hydride/Brønsted acid-catalyzed isomerization/cyclization of allylic ethers.

A ruthenium hydride/Brønsted acid-catalyzed tandem sequence is reported for the synthesis of 1,3,4,9-tetrahydropyrano[3,4-b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Brønsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa-Pictet-Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.

Ruthenium hydride/Brønsted acid-catalyzed tandem isomerization/N-acyliminium cyclization sequence for the synthesis of tetrahydro-ß-carbolines.

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-ß-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to N-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient "aldehyde-free" alternative to the classical Pictet-Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/N-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively.

Tröger's base twisted amides: endo functionalization and synthesis of an inverted crown ether.

Taking advantage of the unconventional reactivity of twisted mono- and bis-amides of Tröger's base (TB), rac-6 and rac-7, respectively, the first synthesis of a 6-endo-monosubstituted TB analogue, rac-9, and the first rational synthesis of a 6,12-endo,endo-disubstituted TB analogue, rac-11, have been achieved. The bis-TB crown ether, meso-13, was prepared starting from rac-7. Meso-13 constitutes a rare example of a crown ether with an inverted methylene bridge-to-bridge bis-TB conformation both in solution and in the solid state, resulting in a reluctance to act as a receptor for cations.

Synthesis of tetrahydro-ß-carbolines via isomerization of N-allyltryptamines: a metal-catalyzed variation on the Pictet-Spengler theme.

An efficient and broadly applicable alternative to the classical Pictet-Spengler synthesis of tetrahydro-ß-carbolines is presented. The method relies on metal-catalyzed isomerization of allylic amines to form reactive iminium intermediates which can be trapped by a tethered indole nucleophile.

Build/couple/pair strategy combining the Petasis 3-component reaction with Ru-catalyzed ring-closing metathesis and isomerization.

A "build/couple/pair" pathway for the systematic synthesis of structurally diverse small molecules is presented. The Petasis 3-component reaction was used to synthesize anti-amino alcohols displaying pairwise reactive combinations of alkene moieties. Upon treatment with a ruthenium alkylidene-catalyst, these dienes selectively underwent ring-closing metathesis reactions to form 5- and 7-membered heterocycles and cyclic aminals via a tandem isomerization/N-alkyliminium cyclization sequence.