柳澤 章

Described herein is a diastereoselective protonation of a chiral enolate with chiral imides. When the lithium enolate of (-)-menthone was protonated by (S,S)-imide 1 or (R)-imide 9, cis-ketone 7 was the major product formed (trans-pmduct 6:cis-product 7 = 26:74 ∼ 19:81). In contrast, a high trans-selectivity (6:7 = 93:7 ∼ 97:3) was obtained for the reaction with (R,R)-imide 8 or (S)-imide 10. The catalytic process of this diastereoselective protonation has been realized using a catalytic amount of these chiral imides and stoichiometric amount of an achiral proton source.

Allylation reaction of aldehydes with allyltributyltin was achieved using Sn catalysts in acidic aqueous media. Exclusive aldehyde selectivity was observed for competitive reactions of aldehydes and ketones with allyltributyltin in the presence of 5 mol% of tetraallyltin or SnCl4 in a mixture of aqueous HCl solution and THF.

The regioselective coupling reaction of epoxides with allylic barium reagents was achieved. All reactions resulted in high yields with remarkable α-selectivities. 2-Propynylbarium reagent afforded exclusively the corresponding acetylenic alcohol.

Aldimines are transformed into homoallylic amines by treatment with allylic barium reagents in which both the α- and γ-adducts are selectively obtained by simply changing the reaction temperature.

Regioselective cross-coupling reactions of allylic alcohol derivatives with allylic metal reagents were achieved using bis(2,2,2-trifluoroethyl)phosphate as a leaving group. Reaction with allylic magnesium reagent resulted in α,γ' cross-coupling, whereas α,α' cross-coupling occurred with allylic barium reagent. When a 1:1 mixture of (E)-2-octenyl 1-bis(2,2,2-trifluoroethyl)phosphate and (E)-2-decenyl chloride was treated with 1 equiv of reactive barium, the cross-coupling products were obtained with 86% selectivity and an α,α'/α,-γ' ratio of 94/6.

The catalytic enantioselective protonation of simple enolate was achieved using chiral proton source, (S,S)-imide 1 which possesses an asymmetric 2-oxazoline ring, as a catalyst. Treatment of the lithium enolate 4 with (S,S)-imide 1 (0.1 equiv) followed by addition of bulky phenol derivative or beta-diketone as achiral proton source (1 equiv) afforded (R)-2,2,6-trimethylcyclohexanone (5) with high enantioselectivity.

The highly alpha,alpha' selective and stereocontrolled homocoupling reaction of allylic halides was achieved using barium reagent. The double-bond geometry of the starting allylic chloride was completely retained. The alpha,alpha' cross-coupling products were also prepared stereospecifically and regioselectively by this method.

The first direct preparation of allylbarium reagents by reaction of in situ generated reactive barium with various allylic chlorides and their new and unexpected selective allylation reactions with carbonyl compounds are disclosed. Highly reactive barium was readily prepared by the reduction of barium iodide with 2 equiv of lithium biphenylide in dry THF at room temperature. A variety of carbonyl compounds reacted with barium reagents generated from (E)- or (Z)-allylic chlorides in THF at -78 °C. All reactions resulted in high yields with remarkable a-selectivities not only with aldehydes but also with ketones. The double bond geometry of the starting allylic chloride was completely retained in each case. Stereochemically homogeneous (E)- and (Z)-β,7-unsaturated carboxylic acids were easily prepared in good yields by highly α-selective carboxylation of allylic barium reagents with carbon dioxide. A selective Michael addition reaction with α,β-unsaturated cycloalkanone was also achieved using an allylbarium reagent. Treatment of 2-cyclopentenone (1 equiv) with allylbarium chloride (2 equiv) in THF at -78 °C for 20 min afforded 3-allylcyclopentanone in 94% yield with a 1,4/1,2 ratio of >99/l. Furthermore, the in situ generated barium enolate was efficiently trapped with various kinds of electrophiles (Me2C=CHCH2Br, nC5H11CHO, and CH3COCl). © 1994, American Chemical Society. All rights reserved.

From Kemp's tricarboxylic acid the (S,S)‐imide 1 and its enantiomer, as well as related imides, were synthesized. With this new chiral reagent, lithium enolates of α‐monoalkylated cycloalkanones can be protonated. For instance, 2 can be transformed into 3. (Figure Presented.) Copyright © 1994 by VCH Verlagsgesellschaft mbH, Germany

SN2-selective Grignard coupling with primary allylic diphenylphosphates was successfully achieved using Ni or Fe catalyst. In sharp contrast, a catalytic amount of CuCN·2LiCl promoted a SN2′-selective coupling reaction. In the presence of the copper catalyst, stereochemically homogeneous γ- disubstituted allyl Grignard reagents reacted at the less substituted allylic terminus (α-position) with an allylic diphenylphosphate selectively without losing the double bond geometry. © 1994.

Reaction of a variety of 1,2-epoxyalkanes with 2.5 equiv. of bulky metal amide-lithium 2,2,6,6-tetramethylpiperidide-affords the corresponding aldehydes exclusively in high yields this is the first example of base-promoted isomerization of monosubstituted epoxides to aldehydes.

The S(N)2'-selective Grignard coupling with primary allylic diphenylphosphates was successfully achieved in the presence of a catalytic amount of CuCN.2LiCl. Gamma-substituted allyl Grignard reagents reacted with allylic phosphates selectively at the less substituted allylic terminus.

The highly alpha,alpha' selective and stereocontrolled homocoupling reaction of allylic halides was achieved using barium reagent. The double-bond geometry of the starting allylic chloride was completely retained. alpha,alpha' Cross-coupling products were also prepared stereospecifically and regioselectively by this method.

Stereochemically homogeneous (E)- or (Z)-beta,gamma-unsaturated carboxylic acids were easily prepared in good yield by highly alpha-selective carboxylation of allylic barium reagents derived from the corresponding allylic chlorides with carbon dioxide.

Regioselective allylation and propargylation were achieved using acylsilanes as electrophiles and this methodology was applied to the synthesis of PGE3 and F3α methyl ester. © 1992.

Treatment of primary allylic phosphates in tetrahydrofuran with Grignard reagents in the presence of an iron catalyst gave cross-coupling products with high S(N)2 selectivity. Among several phosphate leaving groups, diphenylphosphate ester showed the highest regioselectivity.

Treatment of secondary allylic chlorides or allylic phosphates in tetrahydrofuran with prenyl Grignard reagent in the presence of CuCN · 2 LiCl gave geraniol or farnesol derivatives with high S(N)2' selectivity. Phosphate leaving groups were highly transstereoselective for the formation of (E,E)-farnesol derivatives. Furthermore, complete anti-S(N)2' selectivity was observed in the alkylation of optically active allylic phosphates. The present method appears to be an excellent carbon-carbon coupling reaction with high regio-, (E)-, and enantioselectivity. Coenzyme Q10 (ubiquinone 10) was efficiently synthesized using this methodology.

Regioselective propargylation and allylation were achieved using acylsilanes as electrophiles, and this methodology was applied to the synthesis of PGE3and F3α, methyl ester. © 1989, American Chemical Society. All rights reserved.

Regioselective allylmetallation of allylic alcohol has been accomplished by treatment with allylzinc in the presence of a nickel catalyst. Benzylic protective group of allyl alcohol facilitates the allylmetallation. © 1989.

A convergent synthesis of antineoplastic (7E)- and (7Z)-punaglandin 4 is described, dictating revision of the originally postulated structures, 1 and 2, to the stereoisomers, 3 and 4, respectively. Condensation of (R)-3-chloro-4-(tert-butyldimethylsiloxy)-2-cyclopentenone (5) and the organolithium derivative generated from 3-(trimethylstannyl)-l,2-octadiene (27) and methyllithium gives after desilylation the crystalline acetylenic diol 28. Partial hydrogenation of the triple bond using Lindlar catalyst followed by oxidation of the secondary alcohol with pyridinium dichromate affords the hydroxy enone 31. The whole punaglandin skeleton is constructed by aldol condensation of the silyl-protected hydroxycyclopentenone 32 and (2R,3S)-2,3-diacetoxy-6-carbomethoxyhexanal (7). Dehydration of the resulting aldol followed by removal of the silyl protective group leads to a mixture of 3 and 4, identical with the naturally occuring sample in all respects. The enantiomers and some other stereoisomers exhibit similar inhibitory effects on L1210 leukemia cell proliferation. © 1988, American Chemical Society. All rights reserved.

A convergent one-pot construction of the prostaglandin (PG) framework has been accomplished by the organo-copper-mediated conjugate addition of the S configurated ω side-chain unit to a protected (R)-4-hydroxy-2-cyclopentenone followed by trapping of the enolate intermediate by α side-chain alkyl halides. Transmetalation with use of triphenyltin chloride at the enolate stage serves as key operation for the successful three-component coupling synthesis. The use of methyl (Z)-7-iodo-5-heptenoate as the αside-chain component allows short synthesis of PGE2and PGD2. Introduction of a triple bond at the C-5-C-6 positions with methyl 7-iodo-5-heptynoate as the αside-chain synthon has opened a general entry of PGs. The protected 5, 6-didehydro-PGE2derivatives are convertible to a variety of PGs of 1 and 2 series by the controlled hydrogenation of the C-5-C-6 unsaturated bonds and α-selective (100%) reduction of the C-9 keto function, if necessary. Lithium aluminum hydride reagents modified by (R)- and (S)-2,2'-dihydroxy-1,1'-binaphthyl exhibit a unique kinetic discrimination in reduction of PGE type compounds. A protected 5,6-didehydro-PGF2αhas been transformed stereoselectively to PGI2by using intramolecular alkoxypalladation/depalladation as the key step. © 1988, American Chemical Society. All rights reserved.

Prostacyclin (PGI_2, 1) and its stable analogue, isocarbacyclin 2, have been synthesized from the readily available common intermediate 3. Prostacyclin: Reduction of the C-9 carbonyl of 3 by L-Selectride gives the 9α-alcohol 4 exclusively. The intramolecular alkoxypalladation/depalladation using PdCl_2(C_6H_5CN)_2 and then ammonium formate leads to (Z)-2-alkylidenetetrahydrofuran structure 6 with high stereo-selectivity (5Z/5E > 33: 1). Deprotection of 11- and 15-hydroxyls and alkaline hydrolysis of the ester group complete the synthesis of 1. Isocarbacyclin: Conversion of 3 to the α-silylated alcohol 10 has been accomplished by the following four-step sequence: (1) methylenation of the 9-keto group using a Zn-CH_2Br_2-TiCl_4 mixed reagent, (2) stereoselective hydroboration by 9-borabicyclo[3.3.1]-nonane and oxidative workup, (3) oxidation of the primary alcohol with pyridinium dichromate, (4) silylation of the aldehyde with the reagent prepared by mixing of copper(I) cyanide and 2 equiv of dimethylphenyl-silyllithium. The m-trifluoromethylbenzoate 11 undergoes photochemical radical cyclization in aqueous THF containing N-methylcarbazole and Mg(ClO_4)_2 to lead to the allylsilane 13. The same allylsilane is also accessible by reaction of the xanthate 12 with tributyltin hydride in the presence of di-t-butyl peroxide. Deprotection of 11- and 15-hydroxyls, regiospecific protodesilylation of the allylsilane, and alkaline hydrolysis of the ester group give 2.

Punaglandins (PUGs) are halogenated eicosanoids isolated from a marine source, Telestro riisei. In this family, PUG 3 and 4 have received particular attention because of the potent inhibitory effects on L1210 leukemia cell proliferation. Although the structures have been postulated recently, the grounds afforded by the spectroscopic data and assumed mechanism of the chemical transformation are not sufficiently firm. In addition, the absolute configuration has been suggested on the basis of the biosynthetic pathway of the related marine products, clavulones or claviridenones. Therefore an unambiguous structural elucidation should be made by authentic chemical synthesis using stereodefined building blocks. We report herein a convergent synthesis of naturally occurring (7E)- and (7Z)-PUG 4. © 1986, American Chemical Society. All rights reserved.

Antineoplastic punaglandins and related compounds have been synthesized. Condensation of (S)-3-chloro-4-t-butyldimethylsiloxy-2-cyclopentenone and the lithium derivative generated from 3-tributylstannyl-1,2-octadiene with n-butyllithium at -78℃ gives after desilylation (3R,5S)-1-chloro-3,5-dihydroxy- 3-(2-octyn-1-yl)-cyclopentene. High diastereoselectivity, giving the cis diol, is secured in this propargylation reaction. Partial hydrogenation of the triple bond using Lindlar catalyst followed by oxidation of the secondary hydroxy group with pyridinium dichromate gives (4R)-2-chloro-4-hydroxy-4-((Z)-2-octen-1-yl)-2-cyclopentenone. The punaglandin whole skeleton is constructed by aldol condensation of the lithium enolate of the cyclopentenone and (2R,3S)-6-carbomethoxy-2,3-diacetoxyhexanal at -78℃. Aldol dehydration and removal of the silyl protective group lead to a mixture of punaglandin 4 and its Z-isomer (structures postulated by Scheuer). (±)-5,6-Bisdeacetoxy-14, 15; 17, 18-tetrahydropunaglandin, a structurally simpler punaglandin analogue, shows the antineoplastic activity for L1210 tumor cells comparable to punaglandins.

Facile, convergent entries to prostaglandin D1and D2are outlined. © 1984.

A facile, stereospecific preparation of prostacyclin has been accomplished starting from a 5,6-dehydroprostaglandin F2αderivative. © 1983.

A very short chiral synthesis of primary prostaglandins is disclosed. The key operation is the vicinal carba-condensation with α,β-unsaturated ketones which is based on the conjugate addition of a stoichiometric amount of an organo-copper reagent (formed from an organolithium, copper(I) iodide, and tributyl-phosphine in 1:1:2-3 mol ratio) and trapping of the resulting enolate with an aldehyde. The three-component coupling reaction proceeds in a high yield and in a regiospecific fashion. Combination of (R)-4-tetrahydropyranyloxy-2-cyclopentenone, (S)-(E)-1-iodo-3-tetrahydropyranyloxy-1-octene, and 6-methoxy-carbonylhexanal by this method leads directly to methyl ester of 7-hydroxy-11, 15-O-bis(tetrahydropyranyl)-PGE_1. Dehydration, zinc reduction of the resulting Δ^<7,8> derivative, and removal of the tetrahydropyranyl protective groups gives (-)-PGE_1 methyl ester. Combination of (R)-4-t-butyldimethylsiloxy-2-cyclo-pentenone, (S)-(E)-3-t-butyldimethylsiloxy-1-iodo-1-octene, and 6-methoxy-carbonyl-2-hexynal gives methyl ester of 5,6-dehydro-7-hydroxy-11,15-O-bis(t-butyldimethylsiloxy)-PGE_2. Removal of the 7-hydroxy group is effected by thiobenzoylation followed by reduction with tributyltin hydride to afford a key common intermediate for PG synthesis. PGE_2 methyl ester is obtained by catalytic hydrogenation over Lindlar catalyst, followed by removal of t-butyl-siloxy groups with hydrogen fluoride-pyridine. PGF_<2α> methyl ester is also derived by stereoselective reduction of the 9-keto group, partial hydrogenation of the triple bond, and desilylation.

Reaction of a preformed lithium enolate and trimethyl orthoformate with added boron trifluoride leads to the corresponding α-dimethoxymethyl ketone. © 1982.