AbstractTiCl4−Et3N or −Bu3N reagent conducted a highly (Z)-stereoselective carbon homologation (dehydration type Ti-Claisen condensation) of alkyl α-heteroatom (halo and sulfonyloxy)-substituted acetates (XCH2CO2R) with alkyl formates (HCO2R) to afford various alkyl β-alkoxy-α-halo or sulfonyloxy-substituted acrylates (24 examples; 51%–91% yield). Stereoretentive Suzuki-Miyaura, Negishi, and Sonogashira cross-couplings using the obtained methyl β-methoxy-α-halo or sulfonyloxy-substituted acrylates proceeded smoothly to produce a variety of β-alkoxy-α-substituted acrylates in moderate to high yield (35 examples; 29%–99% yield). As a successful application, a 3-step straightforward synthesis of strobilurin A was performed utilizing the present reaction sequence (dehydration type Ti-Claisen condensation and Suzuki-Miyaura cross-coupling), wherein the geometry of the three consecutive olefins (2E,3Z,5E) was completely maintained.

A versatile, robust, and stereocomplementary synthesis of fully-substituted (E)- and (Z)-stereodefined α,β-unsaturated esters 3 from accessible α-substituted β-ketoesters 1via (E)- and (Z)-enol phosphonates was achieved. The present method involves two accessible reaction sequences: (i) (E)- and (Z)-stereocomplementary enol phosphorylations of a wide variety of β-ketoesters 1 (24 examples; 71–99% yield, each >95:5 ds), and (ii) (E)- and (Z)-stereoretentive Suzuki–Miyaura cross-coupling (16 examples; 71–91% yield, >81/19 ds) and Negishi cross-coupling (32 examples; 65–96% yield, >95:5 ds) using (E)- and (Z)-enol phosphonates 2. 1H-NMR monitoring for a key reactive N-phosphorylammonium (imidazolium) intermediate I and an application in the synthesis of both (E)- and (Z)-tamoxifen precursors 6 are described.

Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-2,5-dione chiral template and its successful application to total synthesis of chiral alternaric acid are described.

The NaOH-catalyzed first sequential Mukaiyama–Michael reaction/crossed-Claisen condensation is developed using two molar ketene silyl acetals and one molar α,β-unsaturated esters in either a stepwise or one-pot manner.

An (E)- and (Z)-stereocomplementary preparative method for α,β-disubstituted α,β-unsaturated esters is performed via three general and robust reaction sequences: (i) Ti−Claisen condensation (formylation) of esters to give α-formyl esters (12 examples, 60−99%), (ii) (E)- and (Z)-stereocomplementary enol p-toluenesulfonylation (tosylation) using TsCl−N-methylimidazole (NMI)−Et3N and LiOH (24 examples, 82−99%), and (iii) stereoretentive Suzuki−Miyaura cross-coupling (18 examples, 64−96%).

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).(1R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC26H20Cl2O3[α]D23=+34.1 (c 1.80, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R)-[(R)](1S)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC26H20Cl2O3[α]D23=-38.6 (c 0.90, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1S)-[(R)](1R)-[(R)-2′-Methoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC25H18Cl2O3[α]D23=+36.9 (c 1.35, CHCl3)Source of chirality: (R)-1,1′-binaphthol monomethyl etherAbsolute configuration: (1R)-[(R)](1S)-[(R)-2′-Methoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC25H18Cl2O3[α]D24=-39.7 (c 4.2, CHCl3)Source of chirality: (R)-1,1′-binaphthol monomethyl etherAbsolute configuration: (1S)-[(R)](1R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dimethylcyclopropanecarboxylateC28H26O3[α]D25=+7.4 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R)-[(R)](1R,3R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl]3-(2′,2′-dimethylethenyl)-2,2-dimethylcyclopropanecarboxylateC32H32O3[α]D24=+88.5 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R,3R)-[(R)](1S,3S)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl]3-(2′,2′-dimethylethenyl)-2,2-dimethylcyclopropanecarboxylateC32H32O3[α]D23=-53.5 (c 1.35, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1S,3S)-[(R)](1R,3S)-[(R)-2′-Ethoxy-1,1′binaphth-2-yl] 3-(2′,2′-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylateC30H26Cl2O3[α]D29=+77.4 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R,3S)-[(R)](1S,3R)-[(R)-2′-Ethoxy-1,1′binaphth-2-yl] 3-(2′,2′-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylateC30H26Cl2O3[α]D25=-40.2 (c 4.45, CHCl3)Source of chirality: (R)-1,1′-binaphtholAbsolute configuration: (1S,3R)-[(R)](1R,3S)-2,2-Dimethyl-3-(2′,2′-dichloroethenyl)cyclopropanecarboxylic acidC8H10Cl2O2Ee = 99%[α]D23=+25.1 (c 1.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)(1R,3S)-2,2-Dimethyl-3-(2′,2′-dimethylethenyl)cyclopropanecarboxylic acidC10H16O2Ee = 98%[α]D23=-38.6 (c 0.90, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)

The first general method of direct and highly stereoselective Ti-mediated Mannich reaction between three types of simple esters and E and Z mixtures of oximeethers (aliphatic and aromatic) is accomplished.

We performed an efficient practical and systematic optical resolution method for gem-dihalo- and monohalocyclopropanecarboxylic acids 1 and 5 utilizing chiral 1,1′-binaphthol monomethyl ether (R)-2 as the key auxiliary. Direct esterification of 1 with (R)-2 gave two 1R- and 1S-diastereomeric esters3 with marked different Rfvalues, both of which were easily separated using simple column chromatography. Monodehalogenation of separated chiral esters3 using t-BuMgCl and cat. Co(dppe)2Cl2 gave two 1,2-trans- and 1,2-cis-diastereomers4 with markedly different Rf values, both of which were similarly separated using simple column chromatography. The obtained diastereomers 3 and 4 were easily hydrolyzed to the desired enantiopure acids 1 (>99%) and 5 (>99%), respectively, with recovery of (R)-2, both in good to excellent yields. Utilizing the present method, important chiral agrochemicals, carpropamid6 and fencyclate7, were readily synthesized. Pyrethroid 9 with three asymmetric centers was efficiently synthesized in a much better yield compared with the reported method.

An efficient TiCl4–Et3N or Bu3N-promoted aldol-type addition of phenyl and thiophenyl esters or thioaryl esters with aldehydes and ketones was performed (total 46 examples). The present method is advantageous from atom-economical and cost-effective viewpoints; good to excellent yields, moderate to good syn-selectivity, substrate variations, reagent availability, and simple procedures. Utilizing the present reaction as the key step, an efficient short synthesis of three lactone [2(5H)-furanone] analogs of jasmine perfumes was performed. Among them, the lactone analog of cis-jasmone had a unique perfume property (tabac).

A pentafluorophenylammonium triflate (PFPAT) catalyst (1–10 mol%) efficiently promoted esterification and thioesterification between a 1 : 1 mixture of carboxylic acids and alcohols or thiols in good to excellent yield under mild reaction conditions. Transesterification of carboxylic esters with a slight excess of alcohols (1.5 equiv.) also proceeded using the PFPAT catalyst. The PFPAT-catalyzed 13 to 17 membered macrolactone formation of ω-hydroxycarboxylic acids was successfully performed using 10 mol% of the catalyst (total 44 examples). These catalytic condensations have advantages from the viewpoint of green chemistry. PFPAT organocatalyst is air-stable, cost-effective, easy to handle, and easily removed from the reaction mixtures. The operation is quite simple, because a dehydrating system such as the Dean–Stark apparatus is not necessary.

We have developed an efficient water-solvent method for p-toluenesulfonylation (tosylation) and methanesulfonylation (mesylation) of primary alcohols using p-toluenesulfonyl chloride and methanesulfonyl chloride, respectively, promoted by KOH and catalytic amines. The reaction was performed by maintaining the pH at around 10 using a pH controller to prevent the undesirable decomposition of sulfonyl chlorides. Several primary alcohols were smoothly sulfonylated in excellent yield. The choice of the amine catalyst (0.1 equiv.) was important: N,N-dimethylbenzylamine, a sterically unhindered and lipophilic tertiary amine, was effective for the tosylation, whereas N,N-dimethylbutylamine and triethylamine were effective for the mesylation. The present Schotten–Baumann-type method is the first example of catalytic sulfonylation using sulfonyl chlorides, and is a green chemical process due to the use of water as the solvent.

We have developed a practical crossed Claisen condensation between ketene silyl acetals and methyl esters using catalytic NaOH to obtain α-monoalkylated β-keto esters and inaccessible α,α-dialkylated β-keto esters.

TiCl4–Bu3N-mediated condensation of ketones with α,α-dimethoxyketones afforded trialkylsubstituted 2(5H)-furanones in a one-pot manner, wherein aldol addition and furanone formation occurred sequentially; its application to straightforward synthesis of (R)-mintlactone and (R)-menthofuran, two representative natural mint perfumes, is demonstrated.

2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and cyanohydrin ester 3, a couple of pyrethroids with three asymmetric centers, were synthesized. Of each of the four diastereomers of 2 and 3, only the (1R*,2R*,3R*)-2a and 3a showed significant insecticidal activities. Dual sets of enantiomers [(1R,2R,3R)-(−)-2a and (1S,2S,3S)-(+)-2a] and [(1R,2R,3R)-(−)-3a and (1S,2S,3S)-(+)-3a] were synthesized through the asymmetric cyclopropanation using the Aratani catalyst. Significant separations of insecticidal activities were observed between both the enantiomers against the tobacco cutworm (Spodoptera litura) and the common mosquito (Culex pipiens pallens); (1S,2S,3S)-(+)-2a and (+)-3a showed higher activities than their antipodes (1R,2R,3R)-(−)-2a and (−)-3a. This result is the second example of such synthetic pyrethroids with three asymmetric centers.

The first general method of direct and highly stereoselective Ti-mediated Mannich reaction between three types of simple esters and E and Z mixtures of oximeethers (aliphatic and aromatic) is accomplished.

We performed an efficient practical and systematic optical resolution method for gem-dihalo- and monohalocyclopropanecarboxylic acids 1 and 5 utilizing chiral 1,1′-binaphthol monomethyl ether (R)-2 as the key auxiliary. Direct esterification of 1 with (R)-2 gave two 1R- and 1S-diastereomeric esters3 with marked different Rfvalues, both of which were easily separated using simple column chromatography. Monodehalogenation of separated chiral esters3 using t-BuMgCl and cat. Co(dppe)2Cl2 gave two 1,2-trans- and 1,2-cis-diastereomers4 with markedly different Rf values, both of which were similarly separated using simple column chromatography. The obtained diastereomers 3 and 4 were easily hydrolyzed to the desired enantiopure acids 1 (>99%) and 5 (>99%), respectively, with recovery of (R)-2, both in good to excellent yields. Utilizing the present method, important chiral agrochemicals, carpropamid6 and fencyclate7, were readily synthesized. Pyrethroid 9 with three asymmetric centers was efficiently synthesized in a much better yield compared with the reported method.

An efficient TiCl4–Et3N or Bu3N-promoted aldol-type addition of phenyl and thiophenyl esters or thioaryl esters with aldehydes and ketones was performed (total 46 examples). The present method is advantageous from atom-economical and cost-effective viewpoints; good to excellent yields, moderate to good syn-selectivity, substrate variations, reagent availability, and simple procedures. Utilizing the present reaction as the key step, an efficient short synthesis of three lactone [2(5H)-furanone] analogs of jasmine perfumes was performed. Among them, the lactone analog of cis-jasmone had a unique perfume property (tabac).

A versatile, robust, and stereocomplementary synthesis of fully-substituted (E)- and (Z)-stereodefined α,β-unsaturated esters 3 from accessible α-substituted β-ketoesters 1via (E)- and (Z)-enol phosphonates was achieved. The present method involves two accessible reaction sequences: (i) (E)- and (Z)-stereocomplementary enol phosphorylations of a wide variety of β-ketoesters 1 (24 examples; 71–99% yield, each >95:5 ds), and (ii) (E)- and (Z)-stereoretentive Suzuki–Miyaura cross-coupling (16 examples; 71–91% yield, >81/19 ds) and Negishi cross-coupling (32 examples; 65–96% yield, >95:5 ds) using (E)- and (Z)-enol phosphonates 2. 1H-NMR monitoring for a key reactive N-phosphorylammonium (imidazolium) intermediate I and an application in the synthesis of both (E)- and (Z)-tamoxifen precursors 6 are described.

The NaOH-catalyzed first sequential Mukaiyama–Michael reaction/crossed-Claisen condensation is developed using two molar ketene silyl acetals and one molar α,β-unsaturated esters in either a stepwise or one-pot manner.

Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-2,5-dione chiral template and its successful application to total synthesis of chiral alternaric acid are described.