Synthesis of a biphenyl-based axially chiral amino acid as a highly efficient catalyst for the direct asymmetric aldol reaction

A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the use of only 0.1 mol % of (S)-2 was sufficient to complete the reaction between acetone and 4-nitrobenzaldehyde, giving the corresponding aldol adduct in good yield with an excellent enantioselectivity.     

Highly diastereo- and enantioselective direct aldol reactions promoted by water-compatible organocatalysts bearing a pyrrolidinyl-camphor structural scaffold

Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor containing organocatalysts (1-10). Structural modifications were made by varying the stereo- and electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts (20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the stereochemical bias of the asymmetric aldol reaction is presented.     

The cooperative effect of a hydroxyl and carboxyl group on the catalytic ability of novel β-homoproline derivatives on direct asymmetric aldol reactions

Novel β-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a-d, were synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to 69% ee, 95% yield), which was similar to the results catalyzed by l-proline (71% ee, 96% yield). Relatively low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for example, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected carboxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high diastereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reactions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.     

Pyrrolidine as an efficient organocatalyst for direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal (1) with ketones or aldehydes was described. In the presence of 20 mol % of pyrrolidine, the reaction proceeded smoothly at room temperature to afford the aldol products in good to excellent yields (up to 95%). Pyrrolidine showed a much higher catalytic activity than piperidine in the reaction with less reactive ketones. GC analysis clearly indicated that the catalyst and the enamine intermediates were kept at extremely low concentration during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction. In addition, the asymmetric aldol reaction of 1 with cyclohexanone catalyzed by l-proline derivatives was also discussed.     

Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K

In this account we detail the asymmetric synthesis of 1, a potent azepanone-based inhibitor of cathepsin K (K_i = 0.16 nM), which has been shown to inhibit the production of biomarkers of bone resorption in monkeys. The key steps in the synthesis sequence were the utility of the Evans aldol reaction coupled with the ring closing olefin metatheses to assemble the azepanone core contained within 1.     

Highly efficient prolinamide-based organocatalysts for the direct asymmetric aldol reaction in brine

Four prolinamide-based organocatalysts were readily synthesized and applied to the direct asymmetric aldol reactions of ketones and aromatic aldehydes in brine. When 2,4-dinitrophenol (DNP) was used as an acidic additive, 1 mol % low loading of 2b afforded aldol products with excellent diastereoselectivity of up to 98/2 dr and high enantioselectivity of up to 97% ee.     

Construction of polyheterocyclic spirotetrahydrothiophene derivatives via sulfa-Michael/aldol cascade reaction

A series of polyheterocyclic spirotetrahydrothiophene derivatives were obtained in moderate to excellent yields via a catalyst-free sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 under mild conditions. We also present the first asymmetric sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 with moderate to good enantioselectivities catalyzed by readily available chiral phase-transfer catalysts (PTCs).     

Biomimetic asymmetric aldol reactions catalyzed by proline derivatives attached to β-cyclodextrin in water

Two proline derivatives, (S)-2-aminomethylpyrrolidine and (R)-2-aminomethylpyrrolidine modified β-CD (CD-1, CD-2) were synthesized in the yields of 31% and 14%. Their self-inclusion conformations were characterized by ¹H ROESY NMR studies and quantum calculation. When CD-1 was applied to asymmetric aldol reactions, up to 94% ee was obtained. Substrate selectivity was also observed in these asymmetric aldol reactions.     

Synthesis of chiral cyclohexane-backbone P,N-ligands derived from pyridine and their applications in asymmetric catalysis

P,N-ligands trans-4 and cis-5 with a cyclohexane backbone were easily synthesized. The key step was chiral resolution of (±)-trans-2-pyridylcyclohexanols with DBTA. Enantiopure trans isomer was subjected to Mitsunobu reaction and deprotection to give the corresponding cis isomer. These ligands have been successfully used in asymmetric hydrogenation of arylalkenes with up to 93% ee using 5 and 90% ee using 4 and asymmetric allylic alkylations with up to 95% ee using 5 and 93% ee using 4. Trans and cis P,N-ligands 4 and 5 all gave the product with the same configuration. It was suggested that the absolute configuration of the product was controlled by the configuration of the stereogenic pyridyl-bearing carbon of the ligands.     

Biomimetic syntheses of ineleganolide and sinulochmodin C from 5-episinuleptolide via sequences of transannular Michael reactions

Treatment of a solution of the macrocyclic norcembranoid 7 with lithium hexamethyldisilazide in THF at −78 °C to 0 °C, leads to the polycyclic norcembranoids ineleganolide 1 and sinulochmodin C (2) (65%), which are found in the corals Sinularia inelegans and Sinularia lochmodes, respectively. The conversions are believed to be biomimetic, and occur by successive transannular Michael reactions in 7. Under different temperature conditions the novel polycycle 30 is the main product, alongside small quantities of 1 and 2. The polycycle 30 is possibly produced from ineleganolide 1, following a reverse oxy-Michael reaction and two successive aldol reactions. The significance of the synthesis of ineleganolide 1, sinulochmodin C (2) and the structure 30 from 5-episinuleptolide 7, to the likely biosynthesis of the related norcembranoids scabrolide A (3), scabrolide B (4) and horiolide 31 found in Sinularia sp. is discussed.     

Thermal hydrosilylation of olefin with hydrosilane. Preparative and mechanistic aspects

The reaction of trichlorosilane (1a) at 250 °C with cycloalkenes, such as cyclopentene (2a), cyclohexene (2b), cycloheptene (2c), and cyclooctene (2d), gave cycloalkyltrichlorosilanes [C_nH_2n−1SiCl₃: n = 5 (3a), 6 (3b), 7 (3c), 8 (3d)] within 6 h in excellent yields (97-98%), but the similar reactions using methyldichlorosilane (1b) instead of 1a required a longer reaction time of 40 h and afforded cycloalkyl(methyl)dichlorosilanes [C_nH_2n−1SiMeCl₂: n = 5 (3e), 6 (3f), 7 (3g), 8 (3h)] in 88-92% yields with 4-8% recovery of reactant 2. In large (2, 0.29 mol)-scale preparations, the reactions of 2a and 2b with 1a (0.58 mol) under the same condition gave 3a and 3b in 95% and 94% isolated yields, respectively. The relative reactivity of four hydrosilanes [HSiCl_3−mMe_m: m = 0-3] in the reaction with 2a indicates that as the number of chlorine-substituent(s) on the silicon increases the rate of the reaction decreases in the following order: n = 3 > 2 > 1 ? 0. In the reaction with 1a, the relative reactivity of four cycloalkenes (ring size = 5-8) decreases in the following order: 2d > 2a > 2c > 2b. Meanwhile linear alkenes like 1-hexene undergo two reactions of self-isomerization and hydrosilylation with hydrosilane to give a mixture of the three isomers (1-, 2-, and 3-silylated hexanes). In this reaction, the reactivity of the terminal 1-hexene is higher than the internal 2- and 3-hexene. The redistribution of hydrosilane 1 and the polymerization of olefin 2 occurred rarely under the thermal reaction condition.     

Chiral Pt(II)/Pd(II) pincer complexes that show C-H?Cl hydrogen bonding: Synthesis and applications to catalytic asymmetric aldol and silylcyanation reactions

A chiral C₂-symmetric NCN ligand, (5R,7R)-1,3-bis(6,6-dimethyl-5,6,7,8-tetrahydro-5,7-methanoquinolin-2-yl)benzene has been synthesized. A direct cyclometalation of this ligand with K₂MCl₄ (M = Pt, Pd) in dry acetic acid offered the corresponding pincer complexes, [(5R,7R)-1,3-bis(6,6-dimethyl-5,6,7,8-tetrahydro-5,7-methanoquinolin-2-yl)phenyl]platinum(II) chloride 5a and its palladium(II) analogue 5b. The Pt(II) and Pd(II) complexes 5 were characterized by NMR spectroscopy, and X-ray crystal structure analysis was done for the Pt(II) complex. The NMR data for both the complexes and X-ray crystal structural data for the chloro-Pt(II) complex indicate the existence of intramolecular C-H?Cl hydrogen bonding both in solution and in solid states. Chloride abstraction from 5a by treatment with silver triflate resulted in the corresponding triflate complex 6a, which generates the corresponding cationic aqua complex 7a in the presence of water molecules. The Pt(II) complex 6a/7a was used as asymmetric catalyst in the aldol reaction between methyl isocyanoacetate and aldehydes and also in the silylcyanation of aldehydes.     

Bis-paracyclophane N-heterocyclic carbene-ruthenium catalyzed asymmetric ketone hydrosilylation

New chiral bis-paracyclophane N-heterocyclic carbene (NHC) ligands 1-3 have been explored for ruthenium catalyzed asymmetric hydrosilylation of ketones using diphenylsilane to give enantioenriched alcohols. These ligands provide for efficient asymmetric reduction in the presence of silver(I) triflate (1 mol %) at room temperature with high reactivity and selectivity. Acetophenone 4 was reduced with 1 mol % catalyst in 96% isolated yield, 97% ee. Following removal of the silyl ether, various alcohols 5 were obtained from aromatic ketones in high yield and selectivity.     

A solvent-free protocol for the synthesis of 3-formyl-2H-chromenes via domino oxa Michael/aldol reaction

A new solvent-free, TBD-catalyzed protocol for the synthesis of 3-formyl-2H-chromenes is presented. Substituted salicylaldehydes 1 and 3-methyl-2-butenal 2 in the presence of 10 mol % of TBD underwent a domino oxa Michael/aldol reaction to effectively yield the corresponding 2H-chromene derivatives 3. The methodology represents an improvement either in terms of efficiency and sustainability as a small amount of catalyst is required and the work-up procedure is simple and straightforward.     

Quantum chemical study of ethylene addition to group-7 oxo complexes MO2(CH3)(CH2) (M = Mn, Tc, Re)

Quantum chemical calculations using DFT at the B3LYP level have been carried out for the reaction of ethylene with the group-7 compounds ReO₂(CH₃)(CH₂) (Re1), TcO₂(CH₃)(CH₂) (Tc1) and MnO₂(CH₃)(CH₂) (Mn1). The calculations suggest rather complex scenarios with numerous pathways, where the initial compounds Re1-Mn1 may either engage in cycloaddition reactions or numerous addition reactions with concomitant hydrogen migration. There are also energetically low-lying rearrangements of the starting compounds to isomers which may react with ethylene yielding further products. The [2 + 2]_Re,C cycloaddition reaction of the starting molecule Re1 is kinetically and thermodynamically favored over the [3 + 2]_C,O and [3 + 2]_O,O cycloadditions. However, the reaction which leads to the most stable product takes place with initial rearrangement to the dioxohydridometallacyclopropane isomer Re1a that adds ethylene with concomitant hydrogen migration yielding Re1a-1. The latter reaction has a slightly higher barrier than the [2 + 2]_Re,C cycloaddition reaction. The direct [3 + 2]_C,O cycloaddition becomes more favorable than the [2 + 2]_M,C reaction for the starting compounds Tc1 and Mn1 of the lighter metals technetium and manganese but the calculations predict that other reactions are kinetically and thermodynamically more favorable than the cycloadditions. The reactions with the lowest activation barriers lead after rearrangement to the ethyl substituted dioxometallacyclopropanes Tc1a-1 and Mn1a-1. The manganese compound exhibits an even more complex reaction scenario than the technetium compounds. The thermodynamically most stable final product of ethylene addition to Mn1 is the ethoxy substituted metallacyclopropane Mn1a-2 which has, however, a high activation barrier.     

Inherently chiral calix[4]arene-based bifunctional organocatalysts for enantioselective aldol reactions

Two optical pure m-dimethylamino substituted inherently chiral calix[4]arene derivatives 8a and 8b bearing an l-prolinamido group have been synthesized by two routes, and structurally studied by the usual spectroscopic methods and X-ray crystallographic analysis. It was found that both of 8a and 8b could be utilized as bifunctional organocatalysts to efficiently promote the aldol reactions between aromatic aldehydes and ketones in the presence of acetic acid. Especially, with 8a as the catalyst, the reaction between 4-nitrobenzaldehyde and cyclopentanone at −20 °C gave the anti-aldol product up to 94% ee, while the anti-aldol product in up to 94:6 dr and 79% ee was obtained when 4-cyanobenzaldehyde was used as the aldol donor. Moreover, it was also demonstrated that the inherently chiral calixarene skeleton with (cS)-conformation in 8a was identified as the matched configuration of the stereogenic elements, and the inherently chiral moiety might play an important role in helping to stereocontrol the reaction.     

Platinum-catalyzed double silylations of alkynes with bis(dichlorosilyl)methanes

Bis(dichlorosilyl)methanes 1 undergo the two kind reactions of a double hydrosilylation and a dehydrogenative double silylation with alkynes 2 such as acetylene and activated phenyl-substituted acetylenes in the presence of Speier’s catalyst to give 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes 4 as cyclic products, respectively, depending upon the molecular structures of both bis(dichlorosilyl)methanes (1) and alkynes (2). Simple bis(dichlorosilyl)methane (1a) reacted with alkynes [R¹-CC-R²: R¹ = H, R² = H (2a), Ph (2b); R¹ = R² = Ph (2c)] at 80 °C to afford 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 as the double hydrosilylation products in fair to good yields (33-84%). Among these reactions, the reaction with 2c gave a trans-4,5-diphenyl-1,1,3,3-tetrachloro-1,3-disilacyclopentane 3ac in the highest yield (84%). When a variety of bis(dichlorosilyl)(silyl)methanes [(Me_nCl_3 − nSi)CH(SiHCl₂)₂: n = 0 (1b), 1 (1c), 2 (1d), 3 (1e)] were applied in the reaction with alkyne (2c) under the same reaction conditions. The double hydrosilylation products, 2-silyl-1,1,3,3-tetrachloro-1,3-disilacyclopentanes (3), were obtained in fair to excellent yields (38-98%). The yields of compound 3 deceased as follows: n = 1 > 2 > 3 > 0. The reaction of alkynes (2a-c) with 1c under the same conditions gave one of two type products of 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes (4): simple alkyne 2a and terminal 2b gave the latter products 4ca and 4cb in 91% and 57% yields, respectively, while internal alkyne 2c afforded the former cyclic products 3cc with trans form between two phenyl groups at the 3- and 4-carbon atoms in 98% yield, respectively. Among platinum compounds such as Speier’s catalyst, PtCl₂(PEt₃)₂, Pt(PPh₃)₂(C₂H₄), Pt(PPh₃)₄, Pt[ViMeSiO]₄, and Pt/C, Speier’s catalyst was the best catalyst for such silylation reactions.     

Asymmetric aldol reactions using catalytic d(+)-proline: a new, economic and practical approach to a commonly employed C1-C6 keto-acid synthon of the epothilones

A new approach to ketoacid 4, a common C1-C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance 5, catalyzed with d-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired product 4. None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available d-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its construction.     

Preparation of 2,2-difluoro-1-trialkylsilylethenylstannanes and their cross-coupling reactions

Reaction of 2 with bis(tributyltin) in the presence of 3 mol % Pd₂(dba)₃, 6 mol % XPhos, and 30 equiv of LiBr in wet and air bubbled THF at reflux for 8 h afforded the desired products 3 in 73–74% yields. The cross-coupling reaction of 3a with aryl iodides in the presence of 10 mol % Pd(PPh₃)₄ and 10 mol % CuI afforded the coupled products 4a–p in 47–90% yields. The coupling reaction of 3b with various alkynyl bromides having aryl-, alkyl, or trialkylsilyl group also afforded the corresponding 1,3-enynes 5a–g in 61–77% yields.     

Direct asymmetric aldol reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts

Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee. Fluorous organocatalyst 3 is easily recovered by solid-phase extraction using fluorous silica gel and can be reused up to five times without purification.