Nonsilyl Bicyclic Secondary Amine Catalysts for the Asymmetric Transfer Hydrogenation of α,ß-Unsaturated Aldehydes.

The first chiral synthesis of nonsilyl bicyclic secondary amine organocatalysts and their application to the asymmetric transfer hydrogenation of α,ß-unsaturated aldehydes are disclosed. A lower catalytic loading (5 mol %) is demonstrated for the reduction of a wide range of α,ß-unsaturated aldehydes (up to 97% yield and up to 99% ee). The application of this scalable methodology is showcased for the asymmetric synthesis of bioactive molecules such as phenoxanol, citronellol, ramelteon, and terikalant.

Direct Catalytic Asymmetric Synthesis of Disubstituted 4-Oxocyclohexanecarbaldehydes from Acetone and Cinnamaldehyde Derivatives.

A first catalytic asymmetric reaction of acetone with cinnamaldehyde for the synthesis of disubstituted 4-oxocyclohexanecarbaldehyde is developed. A variety of substituted cinnamaldehydes are successfully tested under the optimized reaction conditions. Both the enantiomers of the same diastereomeric products are achieved in good yield and diastereoselectivity with an excellent enantioselectivity by changing the enantiomer of one of the two chiral catalysts. The practicality of this methodology is demonstrated by the gram-scale synthesis.

Stereodivergent Synthesis of 1-Hydroxymethylpyrrolizidine Alkaloids.

A first stereodivergent strategy for the asymmetric synthesis of all stereoisomers of 1-hydroxymethylpyrrolizidine alkaloids is developed using an asymmetric self-Mannich reaction as a key step. An anti-selective self-Mannich reaction of methyl 4-oxobutanoate with the PMP-amine catalyzed by a chiral secondary amine is successfully optimized for the asymmetric synthesis of (+)-isoretronecanol and (-)-isoretronecanol. A syn-selective self-Mannich reaction catalyzed by proline is utilized for the asymmetric synthesis of the diastereomer, (+)-laburnine, and its enantiomer, (-)-trachelanthamidine.

Enantioselective Total Synthesis of Potent 9ß-11-Hydroxyhexahydrocannabinol.

The first total synthesis of potent cannabinoid, 9ß-11-hydroxyhexahydrocannabinol, is achieved through a proline-catalyzed inverse-electron-demand Diels-Alder reaction. Using this asymmetric catalysis, the cyclohexane ring is constructed with two chiral centers as a single diastereomer with 97% ee. The creation of the third chiral center and benzopyran ring is demonstrated with the elegant synthetic strategies. This mild and efficient synthetic methodology provides a new route for the asymmetric synthesis of the other potent hexahydrocannabinols.

Stereodivergent Synthesis of Chiral Paraconic Acids via Dynamic Kinetic Resolution of 3-Acylsuccinimides.

A direct N-heterocyclic carbene (NHC) catalysis of maleimides with alkyl aldehydes is established for the synthesis of 3-acylsuccinimides. The first dynamic kinetic resolution of 3-acylsuccinimides is accomplished through asymmetric transfer hydrogenation. These two catalytic methodologies are utilized for the synthesis of each enantiomer of trans-paraconic acids in three steps and cis-paraconic acids in four steps with good yields and high stereoselectivities. This stereodivergent synthetic methodology is applied for the synthesis of seven bioactive paraconic acid natural products.

Catalytic Regioselective γ-Methylenation of α,ß-Unsaturated Aldehydes Using Formaldehyde via Vinylogous Aldol Condensation.

The first vinylogous aldol condensation of α,ß-unsaturated aldehydes using aqueous formaldehyde is developed under mild reaction conditions to form the γ-methylenated products with excellent regioselectivity. Using this methodology, a short synthesis of α-triticene, an antifungal compound, is achieved in two steps. The practicality of this methodology is demonstrated by the gram-scale synthesis. Formation of the unusual double γ-functionalized products from crotonaldehyde and a direct asymmetric vinylogous aldol product from phenylglyoxal is also described.

Highly regioselective α-alkylation of α,ß,γ,δ-unsaturated aldehydes.

The first α-alkylation of α,ß,γ,δ-unsaturated aldehydes is achieved under mild reaction conditions. Several α,ß,γ,δ-unsaturated aldehydes and diarylcarbinols are successfully tested for the synthesis of MBH-type α-alkylated products with an excellent regioselectivity. Simple pyrrolidine is efficiently used as a catalyst to achieve a perfect E/Z selectivity of the α-alkylated products.

Catalytic Asymmetric Synthesis of 3,4-Disubstituted Cyclohexadiene Carbaldehydes: Formal Total Synthesis of Cyclobakuchiols A and C.

The first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron-demand Diels-Alder reaction is described. A variety of arylacetaldehydes and α,ß,γ,δ-unsaturated aldehydes are tested under the mild reaction conditions catalyzed by l-proline to obtain the trans diastereomeric products with good yields and high enantioselectivities. The scope of this methodology is further extended to the asymmetric synthesis 3,4-disubstituted cyclohexane carbaldehydes and their derivatives. The practicality of this method is demonstrated by the gram-scale synthesis. This methodology is successfully applied for the formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C.

Organocatalytic Approach for Short Asymmetric Synthesis of ( R)-Paraconyl Alcohol: Application to the Total Syntheses of IM-2, SCB2, and A-Factor γ-Butyrolactone Autoregulators.

( R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregulators. The chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the literature for the asymmetric synthesis of ( R)-paraconyl alcohol. Herein, we report the first organocatalytic approach for the short asymmetric synthesis of ( R)-paraconyl alcohol in four steps and by a single column purification. Asymmetric syntheses of IM-2, SCB2, and A-factor γ-butyrolactone autoregulators were achieved from ( R)-paraconyl alcohol in three steps.

Deuterium studies reveal a new mechanism for the formose reaction involving hydride shifts.

In the formose reaction, formaldehyde is converted to glycolaldehyde, its dimer, under credible prebiotic conditions. Breslow proposed a mechanism for the process in 1959, but recent studies by Benner showed that it was wrong in detail. Our present studies clarify the mechanism, which involves the original Breslow intermediates but some different connecting steps.

Aromaticity decreases single-molecule junction conductance.

We have measured the conductance of single-molecule junctions created with three different molecular wires using the scanning tunneling microscope-based break-junction technique. Each wire contains one of three different cyclic five-membered rings: cyclopentadiene, furan, or thiophene. We find that the single-molecule conductance of these three wires correlates negatively with the resonance energy of the five-membered ring; the nonaromatic cyclopentadiene derivative has the highest conductance, while the most aromatic of this series, thiophene, has the lowest. Furthermore, we show for another wire structure that the conductance of furan-based wires is consistently higher than for analogous thiophene systems, indicating that the negative correlation between conductance and aromaticity is robust. The best conductance would be for a quinoid structure that diminishes aromaticity. The energy penalty for partly adopting the quinoid structure is less with compounds having lower initial aromatic stabilization. An additional effect may reflect the lower HOMOs of aromatic compounds.

Catalysis of glyceraldehyde synthesis by primary or secondary amino acids under prebiotic conditions as a function of pH.

The synthesis of an excess of D-glyceraldehyde by coupling glycolaldehyde with formaldehyde under prebiotic conditions is catalyzed by L amino acids having primary amino groups at acidic pH's, but at neutral or higher pH's they preferentially form L-glyceraldehyde. L Amino acids having secondary amino groups, such as proline, have the reverse preferences, affording excess L-glyceraldehyde at low pH but excess D-glyceraldehyde at higher pHs. Detailed mechanistic proposals make these preferences understandable. The relevance of these findings to the origin of D sugars on prebiotic Earth is described.

Transketolase reaction under credible prebiotic conditions.

A transketolase reaction was catalyzed by cyanide ion under prebiotic conditions instead of its modern catalyst, thiamine pyrophosphate (TPP). Cyanide ion converted fructose plus glyceraldehyde to erythrose plus xylulose, the same products as are formed in modern biochemistry (but without the phosphate groups on the sugars). Cyanide was actually a better catalyst than was TPP in simple solution, where there is a negligible concentration of the C-2 anion of TPP, but of course not with an enzyme in modern biology. The cyanide ion was probably not toxic on prebiotic earth, but only when the oxygen atmosphere developed and iron porphyrin species were needed, which cyanide poisons. Thus, catalyses by TPP that are so important in modern biochemistry in the Calvin cycle for photosynthesis and the gluconic acid pathway for glucose oxidation, among other processes, were probably initially performed instead by cyanide ion until its toxicity with metalloproteins became a problem and primitive enzymes were present to work with TPP, or most likely its primitive precursors.

γ-Amino alcohols via organocascade reactions involving dienamine catalysis.

Whereas cascade reactions catalyzed by secondary amines combine iminium- and/or enamine-catalyzed reactions, we introduce the feasibility of combining these modes of catalysis with dienamine-catalysis as a new general mechanism for cascade reactions. Enantioenriched ß-functionalized-γ-amino alcohols were produced from simple achiral enals in one flask by combining dienamine- and iminium-catalyzed intermolecular reactions. Reaction products are precursors of γ-amino acids, γ-lactams, and pyrrolidines; one was employed in a synthesis of γ-amino acid (S)-vigabatrin, the bioactive enantiomer of Sabril.

Organocatalytic enantioselective olefin aminofluorination.

Chiral beta-fluoroamines are increasingly prevalent in medicinal compounds, but there are few efficient methods to access them from achiral starting materials. To address this, a multicomponent organocascade reaction was developed in which chiral alpha-fluoro-beta-amino aldehydes were generated in a single flask from achiral alpha,beta-unsaturated aldehydes (2), using catalyst 12a. Conversions up to 85%, dr's up to 98:2 and ee's up to 99% of the corresponding alcohol (9) were achieved in this reaction.