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Acetylenes having both electrondonating and electronaccepting groups (1) may be obtained in good yield from the correspondingly substituted olefines via bromination and elimination of HBr. The reaction of the acetylene aldehyde 1a with proton acids yields, after rearrangement of the primary adducts, the β-substituted acrylamides. Addition of nucleophiles leads to the β-disubstituted α.β-unsaturated carbonyl compounds. With hydrazines one obtains pyrazoles and pyrazolones. The acetylenes 1 undergo [2+2]-, [2+3]- and [2+4]-cycloaddition reactions.

Sulfoximine-substituted bis(allyl)titanium complexes, which are configurationally labile at the Cα-atoms, have emerged as valuable reagents in asymmetric synthesis. Their highly selective reactions with aldehydes and N-sulfonyl imino esters allow the attainment of enantio- and diastereomerically pure sulfoximine-substituted homoallylic alcohols and homoallylic amines, respectively, which are valuable starting materials for the asymmetric synthesis of homopropargylic alcohols, 2,3-dihydrofurans, medium-sized carbocycles and lactones, unsaturated mono- and bicyclic prolines, β-amino acids, and vinyl oxiranes, respectively. The high synthetic versatility of the sulfoximine group stems from its ability to function as a chiral carbanion-stabilizing nucleofuge. © 2007 Wiley Periodicals, Inc. 18:472–481, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20331

3 The chiroptical properties of the diastereomeric alcohols (E)-(3S,4S)-4-methyl-1-tributylstannyloct- 1-en-6-yn-3-ol ((S,S)-) and (E)-(3R,4S)-4-methyl-1-tributylstannyl-oct-1-en-6-yn-3-ols ((R,S)- 3) have been studied experimentally as well as by quantum-chemical calculations. The structures of 20 conformers of each isomer, which were found to represent local minima at the MNDO level, have been optimized with density functional theory (DFT). Based on these geometries the excitation energies and oscillator as well as rotational strengths have been calculated using a time-dependent DFT (TDDFT) method. The CD spectra of the compounds were then obtained as superposition of Boltzmann-weighted spectra for each of the structures. By comparison of the calculated and the experimental CD spectra the absolute configurations have been assigned to the investigated compounds.

Asymmetric total syntheses of 3-oxacarbacyclin (4) and 3-oxaisocarbacyclin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium (R,R)-bis(phenylethyl)amide (12) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14−19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω-side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd-catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49. The key step in the construction of the α-side chain in 4 is a Horner-Wadsworth-Emmons reaction of ketone 7c with the 8-phenylnormenthol-containing phosphonoacetate 56 which gave ester 60 of 90% de. Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β-unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ-unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β-unsaturated ester 61 was converted to the s,γ-unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.

The acyclic and cyclic allylic tert -butyl sulfones 3 , ent - 3 , 11a , 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac - 1a , rac - 1b , rac - 10a , rac - 10b and rac - 14a–c with LiO 2 S t -Bu in the presence of the chiral ligands 2a , ent - 2b and 12 . Formation of the n -butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac - 1a and 1b / ent - 1b with LiO 2 S t -Bu in the presence of 2a and ent - 2b , respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert -butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac - 1b with Me 3 SiS t -Bu in the presence of ent - 2b .

Colyophilization of pig liver esterase with methoxypolyethylene glycol gave a catalyst, PLE/MPEG, which showed an enhanced activity in organic solvents. The PLE/MPEG catalyzed transesterification of the alcohols rac- 1a–d with vinyl propionate in toluene proceeded with good to high selectivities. The addition of up to 1% of water to the reaction mixture resulted in a significant increase in enantioselectivity. Immobilization of PLE/MPEG for the batch-wise resolution was accomplished by its spontaneous adsorption on an ultrafiltration membrane.

Racemic S-methyl-S-phenylsulfoximine (±)-1 can be resolved with only 0.6 equivalents of (+)-camphorsulfonic acid by avoiding any recrystallization to give (+)-1 of ⩾99% ee in 80% yield and (−)-1 of 97–99% ee in 74% yield. This procedure, which is based on the separation of the diastereomeric salt (+)-1/(+)-CSA and the sulfoximine (−)-1, should be suited for a large scale application.

Titanation of the lithioallyl sulfoximines E-2 and Z-2 with ClTi(NEt2)3 gives allyltitanium species which react with aldehydes highly regio- and diastereoselectively at the α-position to form the syn-α-hydroxyalkyl allyl sulfoximines E-3 and Z-3, respectively. With ClTi(OiPr)3 as the titanation reagent anti-γ-hydroxyalkyl vinyl sulfoximines are obtained instead with equally high selectivities. NMR spectroscopic evidence points to the formation of the monoallyltitanium sulfoximine E-4 upon reaction of E-2 with ClTi(NEt2)3.

MPEG-PLE was prepared by modification of PLE with 1 and characterized by gel electrophoresis, size exclusion chromatography, anion exchange chromatography and photon correlation spectroscopy. It retains the activity of native PLE in the enantioselective hydrolysis of prochiral diesters 2, 4, 6 and 8 to the monoesters 3, 5, 7 and 9, respectively, in water. MPEG-PLE is soluble and active in organic solvents. The MPEG-PLE catalyzed acylation of prochiral diols 10 and 11 with vinyl acetate in toluene leads to monoacetates ent-5 and 9, respectively.

The palladium-catalyzed asymmetric sulfonylation of allylic substrates rac- 7a,b and rac- 8a,b in the presence of the chiral phosphino-oxazoline ligand 3a gave the allylic sulfones 9a and 9b with ee-values of 59% and 88%, respectively, in high yield. In the presence of ligand ent- 3b the enantiomeric allylic sulfones ent- 9a and ent- 9b were obtained with ee-values of 57% and 93% in high yield.

Thermolysis of the enantiomerically pure allylic sulfoximines 3a,b leads to their partial rearrangement to the isomeric allylic sulfinamides 5a,b and 6a,b, respectively, with complete retention of configuration at the S-atom. Racemization of the allylic sulfoximines 3a,b at the S-atom does not occur.

New quinine-based polyfunctional aryl phosphite was synthesized. The phosphorus center in the new compound is characterized by a large cone angle (θ = 190°). The new compound can be used in the Pd-catalyzed enantioselective rearrangement of cyclic O-allylic thiocarbamate into S-allylic thiocarbamate in an optical yield of up to 47% with a quantitative conversion.

Thermolysis of the enantiomerically pure allylic sulfoximines 3a,b leads to their partial rearrangement to the isomeric allylic sulfinamides 5a,b and 6a,b, respectively, with complete retention of configuration at the S-atom. Racemization of the allylic sulfoximines 3a,b at the S-atom does not occur.

MPEG-PLE was prepared by modification of PLE with 1 and characterized by gel electrophoresis, size exclusion chromatography, anion exchange chromatography and photon correlation spectroscopy. It retains the activity of native PLE in the enantioselective hydrolysis of prochiral diesters 2, 4, 6 and 8 to the monoesters 3, 5, 7 and 9, respectively, in water. MPEG-PLE is soluble and active in organic solvents. The MPEG-PLE catalyzed acylation of prochiral diols 10 and 11 with vinyl acetate in toluene leads to monoacetates ent-5 and 9, respectively.

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.

Titanation of the lithioallyl sulfoximines E-2 and Z-2 with ClTi(NEt2)3 gives allyltitanium species which react with aldehydes highly regio- and diastereoselectively at the α-position to form the syn-α-hydroxyalkyl allyl sulfoximines E-3 and Z-3, respectively. With ClTi(OiPr)3 as the titanation reagent anti-γ-hydroxyalkyl vinyl sulfoximines are obtained instead with equally high selectivities. NMR spectroscopic evidence points to the formation of the monoallyltitanium sulfoximine E-4 upon reaction of E-2 with ClTi(NEt2)3.

MPEG-CCL was prepared by acylation of CCL with MPEG-OCH 2 COOSu and characterized by FPLC and PAGE. MPEG-CCL is soluble in benzene and it retains 31% of the activity of CCL. In benzene MPEG-CCL has a significantly higher activity than CCL. The enantioselectivities of CCL- and MPEG-CCL-catalyzed acylations are similar. MPEG-CCL-catalyzed acylations with isopropenyl methoxyacetate and hydrolyses of methoxyacetates have especially high rates.

Racemic S-methyl-S-phenylsulfoximine (±)-1 can be resolved with only 0.6 equivalents of (+)-camphorsulfonic acid by avoiding any recrystallization to give (+)-1 of ⩾99% ee in 80% yield and (−)-1 of 97–99% ee in 74% yield. This procedure, which is based on the separation of the diastereomeric salt (+)-1/(+)-CSA and the sulfoximine (−)-1, should be suited for a large scale application.

Colyophilization of pig liver esterase with methoxypolyethylene glycol gave a catalyst, PLE/MPEG, which showed an enhanced activity in organic solvents. The PLE/MPEG catalyzed transesterification of the alcohols rac- 1a–d with vinyl propionate in toluene proceeded with good to high selectivities. The addition of up to 1% of water to the reaction mixture resulted in a significant increase in enantioselectivity. Immobilization of PLE/MPEG for the batch-wise resolution was accomplished by its spontaneous adsorption on an ultrafiltration membrane.

The acyclic and cyclic allylic tert -butyl sulfones 3 , ent - 3 , 11a , 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac - 1a , rac - 1b , rac - 10a , rac - 10b and rac - 14a–c with LiO 2 S t -Bu in the presence of the chiral ligands 2a , ent - 2b and 12 . Formation of the n -butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac - 1a and 1b / ent - 1b with LiO 2 S t -Bu in the presence of 2a and ent - 2b , respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert -butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac - 1b with Me 3 SiS t -Bu in the presence of ent - 2b .

Asymmetric total syntheses of 3-oxacarbacyclin (4) and 3-oxaisocarbacyclin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium (R,R)-bis(phenylethyl)amide (12) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14−19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω-side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd-catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49. The key step in the construction of the α-side chain in 4 is a Horner-Wadsworth-Emmons reaction of ketone 7c with the 8-phenylnormenthol-containing phosphonoacetate 56 which gave ester 60 of 90% de. Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β-unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ-unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β-unsaturated ester 61 was converted to the s,γ-unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.

New quinine-based polyfunctional aryl phosphite was synthesized. The phosphorus center in the new compound is characterized by a large cone angle (θ = 190°). The new compound can be used in the Pd-catalyzed enantioselective rearrangement of cyclic O-allylic thiocarbamate into S-allylic thiocarbamate in an optical yield of up to 47% with a quantitative conversion.

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.