Asymmetric Total Synthesis of Havellockate.

The first total synthesis of the furanobutenolide-derived cembranoid diterpenoid havellockate is disclosed. Our convergent strategy employs a Julia-Kocienski olefination to join two enantioenriched fragments to produce a diene that is subsequently used in a propiolic acid esterification/Diels-Alder cascade. This sequence generates the fused carbocyclic core of the natural product in short order. A challenging Zn-mediated Barbier allylation then forges the final C-C bond and also establishes two vicinal stereogenic centers. Finally, a Cu-catalyzed aerobic oxidation facilitates the formation of the ß-hydroxybutanolide to complete the total synthesis.

Global Diastereoconvergence in the Ireland-Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids.

A dual experimental/theoretical investigation of the Ireland-Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, ß-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z- and E-enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence. This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Acyclic α-N-Pyrrolyl/Indolyl Ketones.

The synthesis of fully substituted α-N-pyrrolyl and indolyl ketones via enantioselective palladium-catalyzed allylic alkylation is described. The acyclic ketones are alkylated in high yields with high enantioselectivities through the use of an electron-deficient phosphinooxazoline ligand, furnishing a highly congested and synthetically challenging stereocenter. The obtained alkylation products contain multiple reactive sites poised for additional functionalizations and diversification.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Protected Benzoin-Derived Enol Carbonates.

The enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted α-hydroxy acyclic enol carbonates providing tetrasubstituted benzoin derivatives is reported. Investigation into the transformation revealed that preparation of the starting material as a single enolate isomer is crucial for optimal enantioselectivity. The obtained alkylation products contain multiple reactive sites that can be utilized toward the synthesis of stereochemically rich derivatives. COMMUNICATION.

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones.

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle for the preparation of tertiary α-amino ketones and related derivatives in an asymmetric fashion.

Palladium-catalyzed enantioselective decarboxylative allylic alkylation of fully substituted N-acyl indole-derived enol carbonates.

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted N-acyl indole-derived enol carbonates forming acyclic all-carbon quaternary stereocenters is reported. Excellent yields up to 99% and enantioselectivities up to 98% ee are obtained through the use of a new electron-deficient phosphinoxazoline (PHOX) ligand. Control of substrate enolate geometry is crucial for high selectivity. The obtained α-quaternary N-acyl indoles are formal ester equivalents, and represent a useful handle for further synthetic transformations.

Palladium-catalyzed α,ß-dehydrogenation of acyclic ester equivalents promoted by a novel electron deficient phosphinooxazoline ligand.

A unique example of Pd-catalyzed decarboxylative dehydrogenation of fully substituted N-acyl allyl enol carbonates is enabled by a new electron deficient phosphinooxazoline (PHOX) ligand. The reaction proceeds from the Z-enol carbonate to provide dehydrogenation products exclusively in high E/Z selectivity, while the E-enol carbonate provides the α-allylation product with only minor dehydrogenation. The reaction proceeds with a broad scope of (Z)-enol carbonates derived from N-acyl indoles to furnish acyclic formal α,ß-unsaturated ester equivalents.

Origin of Panchromaticity in Multichromophore-Tetrapyrrole Arrays.

Panchromatic absorbers that have robust photophysical properties enable new designs for molecular-based light-harvesting systems. Herein, we report experimental and theoretical studies of the spectral, redox, and excited-state properties of a series of perylene-monoimide-ethyne-porphyrin arrays wherein the number of perylene-monoimide units is stepped from one to four. In the arrays, a profound shift of absorption intensity from the strong violet-blue (B y and B x) bands of typical porphyrins into the green, red, and near-infrared (Q x and Q y) regions stems from mixing of chromophore and tetrapyrrole molecular orbitals (MOs), which gives multiplets of MOs having electron density spread over the entire array. This reduces the extensive mixing between porphyrin excited-state configurations and the transition-dipole addition and subtraction that normally leads to intense B and weak Q bands. Reduced configurational mixing derives from moderate effects of the ethyne and perylene on the MO energies and a more substantial effect of electron-density delocalization to reduce the configuration-interaction energy. Quantitative oscillator-strength analysis shows that porphyrin intensity is also shifted into the perylene-like green-region absorption and that the ethyne linkers lend absorption intensity. The reduced porphyrin configurational mixing also endows the S1 state with bacteriochlorin-like properties, including a 1-5 ns lifetime.

Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates.

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted acyclic enol carbonates providing linear α-quaternary ketones is reported. Investigation into the reaction revealed that the use of an electron-deficient phosphinooxazoline ligand renders the enolate geometry of the starting material inconsequential, with the same enantiomer of product obtained in the same level of selectivity regardless of the starting ratio of enolates. As a result, a general method toward acyclic all-carbon quaternary stereocenters has been developed.

Tailoring Panchromatic Absorption and Excited-State Dynamics of Tetrapyrrole-Chromophore (Bodipy, Rylene) Arrays-Interplay of Orbital Mixing and Configuration Interaction.

Three sets of tetrapyrrole-chromophore arrays have been examined that exhibit panchromatic absorption across large portions of the near-ultraviolet (NUV) to near-infrared (NIR) spectrum along with favorable excited-state properties for use in solar-energy conversion. The arrays vary the tetrapyrrole (porphyrin, chlorin, bacteriochlorin), chromophore (boron-dipyrrin, perylene, terrylene), and attachment sites (meso-position, ß-pyrrole position). In all, seven dyads, one triad, and nine benchmarks in toluene and benzonitrile were studied using steady-state and time-resolved absorption and fluorescence spectroscopy. The results were analyzed with the aid of density functional theory (DFT) and time-dependent DFT calculations. Natural transition orbitals (NTOs) were constructed to assess the net change in electron density associated with each NUV-NIR absorption transition. The porphyrin-perylene dyad P-PMI displays the most even spectral coverage from 400 to 700 nm, with an average ε ∼ 43 000 M-1 cm-1. A significant contributor is a chromophore-induced reduction in the configuration interaction involving the four frontier molecular orbitals of benchmark porphyrins and associated constructive/destructive transition-dipole interference that results in intense (ε ∼ 400 000 M-1 cm-1) NUV and weak (<20 000 M-1 cm-1) visible features. P-PMI has an S1 lifetime (τS) of 4.7 ns in toluene and 1.3 ns in benzonitrile. Bacteriochlorin analogue BC-PMI has more extended spectral coverage (350-750 nm) and τS = 2.8 ns in toluene and 30 ps in benzonitrile. Terrylene analogue P-TMI has intermediate optical characteristics with τS = 310 ps in toluene and 150 ps in benzonitrile. The NTOs for most arrays show that S0 → S1 primarily involves the tetrapyrrole, but for P-TMI the NTOs have electron density delocalized over the two units as a result of extensive orbital mixing. Collectively, the insights obtained should aid the design of tetrapyrrole-based architectures for panchromatic light-harvesting systems for solar-energy conversion.

Enantioselective Pd-Catalyzed Decarboxylative Allylic Alkylation of Thiopyranones. Access to Acyclic, Stereogenic α-Quaternary Ketones.

A catalytic, enantioselective decarboxylative allylic alkylation of 4-thiopyranones is reported. The α-quaternary 4-thiopyranones produced are challenging to access by standard enolate alkylation owing to facile ring-opening ß-sulfur elimination. In addition, reduction of the carbon-sulfur bonds provides access to elusive acyclic α-quaternary ketones. The alkylated products are obtained in up to 92% yield and 94% enantiomeric excess.

Tuning the Electronic Structure and Properties of Perylene-Porphyrin-Perylene Panchromatic Absorbers.

Light-harvesting architectures that afford strong absorption across the near-ultraviolet to near-infrared region, namely, panchromatic absorptivity, are potentially valuable for capturing the broad spectral distribution of sunlight. One previously reported triad consisting of two perylene monoimides strongly coupled to a free base porphyrin via ethyne linkers (FbT) shows panchromatic absorption together with a porphyrin-like S1 excited state albeit at lower energy than that of a typical monomeric porphyrin. Here, two new porphyrin-bis(perylene) triads have been prepared wherein the porphyrin bears two pentafluorophenyl substituents. The porphyrin is in the free base (FbT-F) or zinc chelate (ZnT-F) forms. The zinc chelate (ZnT) of the original triad bearing nonfluorinated aryl rings also was prepared. The triads were characterized using static and time-resolved optical spectroscopy. The results were analyzed with the aid of molecular-orbital characteristics obtained using density functional theory calculations. Of the four triads, FbT is the most panchromatic in affording the most even distribution of absorption spectral intensity as well as exhibiting the largest wavelength span (380-750 nm). The triads exhibit fluorescence yields (0.35 for FbT-F in toluene) that are substantially greater than for the porphyrin benchmarks (0.049 for FbP-F). The singlet excited-state lifetimes (τS) for the triads in toluene decrease in the order FbT-F (2.7 ns) > FbT (2.0 ns) > ZnT (1.2 ns) ∼ ZnT-F (1.1 ns). The τS values in benzonitrile are FbT (1.3 ns) > FbT-F (1.2 ns) > ZnT-F (0.6 ns) > ZnT (0.2 ns). Thus, the free base triads exhibit relatively long (1.2-2.7 ns) excited-state lifetimes in both polar and nonpolar media. The combined photophysical characteristics indicate that FbT and FbT-F are the best choices for panchromatic light-harvesting systems. Collectively, the findings afford insights into the effects of electronic structure on the panchromatic behavior of ethynyl-linked porphyrin-perylene architectures that can help guide next-generation designs and utilization of these systems.

Enantioselective γ-Alkylation of α,ß-Unsaturated Malonates and Ketoesters by a Sequential Ir-Catalyzed Asymmetric Allylic Alkylation/Cope Rearrangement.

A catalytic, enantioselective γ-alkylation of α,ß-unsaturated malonates and ketoesters is reported. This strategy entails a highly regio- and enantioselective iridium-catalyzed α-alkylation of an extended enolate, and a subsequent translocation of chirality to the γ-position via a Cope rearrangement.

Paley's watchmaker analogy and prebiotic synthetic chemistry in surfactant assemblies. Formaldehyde scavenging by pyrroles leading to porphyrins as a case study.

The formation of elaborate molecules is regarded as an essential first step in prebiotic chemistry, but how such transformations could spontaneously occur, particularly in dilute aqueous conditions, remains poorly understood. Here, micromolar concentrations of a 3,4-dialkylpyrrole and excess formaldehyde in aqueous micellar solution (pH 7) at 25 or 50 °C were found to give good yield (up to 40%) of the lipophilic octaalkylporphyrin. The reaction occurs despite a mean occupancy number of ∼0.1 pyrrole molecules/micelle, and <1 of 10,000 micelles initially containing the requisite 4 pyrrole molecules to form the porphyrin assuming a (random) Poisson distribution. Yields of up to 13% were observed in large, unilamellar phosphatidylcholine vesicles, wherein there are ∼15,000 pyrrole molecules per vesicle membrane. Double-labeling crossover experiments (of 3,4-diethylpyrrole and 3,4-dimethylpyrrole) examined by mass spectrometry revealed facile exchange processes of reactive constituents among both micelle and vesicle surfactant assemblies. Together, the exchange of pyrrolic reactants among micelles and the thermodynamic driving force for tetrapyrrole formation overcome the apparent statistical odds against reaction. The fruitful exchange, accumulation and reaction of minute quantities of reactants in aqueous-surfactant assemblies suggest a general means for formation of prebiotically valuable constituents, even when the statistical odds at the outset are overwhelmingly improbable.

Panchromatic absorbers for solar light-harvesting.

A set of panchromatic absorbers exhibiting long excited-state lifetimes in both polar and nonpolar media has been prepared. The architectures are based on a porphyrin strongly coupled electronically to 1-4 perylene-monoimides via ethyne linkers. The constructs should find utility in molecular solar-conversion systems.