Hans-Joachim Gais

Palladium-catalyzed kinetic resolution of racemic cyclic and acyclic allylic carbonates with sulfur nucleophiles

Abstract A chiral Pd(0) complex bearing the Trost ligand in combination with S-nucleophiles effects the kinetic resolution of cyclic and acyclic allylic carbonates with excellent levels of enantioselectivity to give enantiomerically highly enriched allylic carbonates as well as allylic sulfones and sulfides. This method allows also for a new access to enantiopure cyclic allylic alcohols.

Polyethylene glycol monomethyl ether-modified pig liver esterase: Preparation, characterization and catalysis of enantioselective hydrolysis in water and acylation in organic solvents

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.

Modification and immobilization of proteins with polyethylene glycol tresylates and polysaccharide tresylates: Evidence suggesting a revision of the coupling mechanism and the structure of the polymer-polymer linkage

The isolation of sulfonate-amide 6 from the reaction of tresylate 5 with butylamine in aqueous buffer solution at pH 8.0 suggests a new mechanism for the modification and immobilization of proteins with polyethylene glycol monomethyl ether tresylate (1) and polysaccharide tresylates.

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

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.

Rearrangement of allylic sulfoximines to allylic sulfinamides

Abstract 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.

Anionic Cross-Coupling Reaction of α-Metallated Alkenyl Sulfoximines and Alkenyl Sulfoximines with Cuprates Featuring a 1,2-Metal-Ate Rearrangement of Sulfoximine-Substituted Higher Order Alkenyl Cuprates and an α-Metallation of Alkenyl Sulfoximines by Cuprates

(E)- and (Z)-configured alpha-lithioalkenyl sulfoximines, which are available through lithiation of the corresponding alkenyl sulfoximines, undergo a anionic cross-coupling reaction (ACCR) with organocuprates with formation of the corresponding alkenyl cuprates and sulfinamide. The alkenyl cuprates can be trapped by electrophiles. The ACCR presumably proceeds via the formation of a higher-order sulfoximine-substituted alkenyl cuprate, which undergoes a 1,2-metal-ate rearrangement whereby the sulfoximine group acts as the nucleofuge. The parent (E)- and (Z)-configured alkenyl sulfoximines suffer upon treatment with an organocuprate a deprotonation at the alpha-position with formation of the corresponding alpha-cuprioalkenyl sulfoximines. These derivatives also enter into a similar ACCR with organocuprates. The ACCR of sulfoximines substituted homoallylic alcohols allows a stereoselective access to enantio- and diastereopure substituted homoallylic alcohols.

Chiral Fluorinated α-Sulfonyl Carbanions: Enantioselective Synthesis and Electrophilic Capture, Racemization Dynamics, and Structure

Enantiomerically pure triflones R(1) CH(R(2) )SO2 CF3 have been synthesized starting from the corresponding chiral alcohols via thiols and trifluoromethylsulfanes. Key steps of the syntheses of the sulfanes are the photochemical trifluoromethylation of the thiols with CF3 Hal (Hal=halide) or substitution of alkoxyphosphinediamines with CF3 SSCF3 . The deprotonation of RCH(Me)SO2 CF3 (R=CH2 Ph, iHex) with nBuLi with the formation of salts [RC(Me)SO2 CF3 ]Li and their electrophilic capture both occurred with high enantioselectivities. Displacement of the SO2 CF3 group of (S)-MeOCH2 C(Me)(CH2 Ph)SO2 CF3 (95 % ee) by an ethyl group through the reaction with AlEt3 gave alkane MeOCH2 C(Me)(CH2 Ph)Et of 96 % ee. Racemization of salts [R(1) C(R(2) )SO2 CF3 ]Li follows first-order kinetics and is mainly an enthalpic process with small negative activation entropy as revealed by polarimetry and dynamic NMR (DNMR) spectroscopy. This is in accordance with a Cα S bond rotation as the rate-determining step. Lithium α-(S)-trifluoromethyl- and α-(S)-nonafluorobutylsulfonyl carbanion salts have a much higher racemization barrier than the corresponding α-(S)-tert-butylsulfonyl carbanion salts. Whereas [PhCH2 C(Me)SO2 tBu]Li/DMPU (DMPU = dimethylpropylurea) has a half-life of racemization at -105 °C of 2.4 h, that of [PhCH2 C(Me)SO2 CF3 ]Li at -78 °C is 30 d. DNMR spectroscopy of amides (PhCH2 )2 NSO2 CF3 and (PhCH2 )N(Ph)SO2 CF3 gave NS rotational barriers that seem to be distinctly higher than those of nonfluorinated sulfonamides. NMR spectroscopy of [PhCH2 C(Ph)SO2 R]M (M=Li, K, NBu4 ; R=CF3 , tBu) shows for both salts a confinement of the negative charge mainly to the Cα atom and a significant benzylic stabilization that is weaker in the trifluoromethylsulfonyl carbanion. According to crystal structure analyses, the carbanions of salts {[PhCH2 C(Ph)SO2 CF3 ]Li⋅L}2 (L=2 THF, tetramethylethylenediamine (TMEDA)) and [PhCH2 C(Ph)SO2 CF3 ]NBu4 have the typical chiral Cα S conformation of α-sulfonyl carbanions, planar Cα atoms, and short Cα S bonds. Ab initio calculations of [MeC(Ph)SO2 tBu](-) and [MeC(Ph)SO2 CF3 ](-) showed for the fluorinated carbanion stronger nC →σ* SCF 3 and nO →σ* SCF 3 interactions and a weaker benzylic stabilization. According to natural bond orbital (NBO) calculations of [R(1) C(R(2) )SO2 R](-) (R=tBu, CF3 ) the nC →σ*SR interaction is much stronger for R=CF3 . Ab initio calculations gave for [MeC(Ph)SO2 tBu]Li⋅2 Me2 O an O,Li,Cα contact ion pair (CIP) and for [MeC(Ph)SO2 CF3 ]Li⋅2 Me2 O an O,Li,O CIP. According to cryoscopy, [PhCH2 C(Ph)SO2 CF3 ]Li, [iHexC(Me)SO2 CF3 ]Li, and [PhCH2 C(Ph)SO2 CF3 ]NBu4 predominantly form monomers in tetrahydrofuran (THF) at -108 °C. The NMR spectroscopic data of salts [R(1) (R(2) )SO2 R(3) ]Li (R(3) =tBu, CF3 ) indicate that the dominating monomeric CIPs are devoid of Cα Li bonds.

Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes.

An asymmetric synthesis of densely functionalized 7-11-membered carbocycles and 9-11-membered lactones has been developed. Its key steps are a modular assembly of sulfoximine-substituted C- and O-tethered trienes and C-tethered dienynes and their Ru-catalyzed ring-closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C-tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α-lithiation of alkenylsulfoximines, 3) alkylation, hydroxy-alkylation, formylation, and acylation of α-lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α-formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine-substituted trienes with the second-generation Ru catalyst stereoselectively afforded the corresponding functionalized 7-11-membered carbocyles. RCDEM of diastereomeric silyloxy-substituted 1,6,12-trienes revealed an interesting difference in reactivity. While the (R)-diastereomer gave the 11-membered carbocyle, the (S)-diastereomer delivered in a cascade of cross metathesis and RCDEM 22-membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine- and bissilyloxy-substituted carbocycles were performed including deprotection, cross-coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine-substituted homoallylic alcohol with unsaturated carboxylic acids gave the O-tethered trienes, RCDEM of which yielded the sulfoximine-substituted 9-11-membered lactones. RCEYM of a sulfoximine-substituted 1,7-dien-10-yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second-generation Ru catalyst gave the 9-membered exo 1,3-dienyl carbocycle, the first-generation Ru catalyst furnished a truncated 9-membered 1,3-dieny carbocycle having one CH(2) unit less than the dienyne.

Ring-Closing Metathesis of Sulfoximine-Substituted N-Tethered Trienes: Modular Asymmetric Synthesis of Medium-Ring Nitrogen Heterocycles

A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyzed ring-closing metathesis (RCM) reaction. The highly substituted N-tethered trienes were obtained enantio- and diastereopure through 1) the diastereoselective aminoalkylation of sulfoximine-substituted allyltitanium complexes with N-tert-butylsulfonyliminoester, 2) N-allylation of homoallylic N-sulfonyl amines, 3) allylation, hydroxylalkylation, and formylation of α-lithioalkenylsulfoximines, and 4) allylation of α-formylalkenylsulfoximines. The Ru-catalyzed RCM reaction of the sulfoximine-substituted 1,7,10- and 1,7,12-trienes stereoselectively afforded the corresponding nine-, ten-, and eleven-membered MRNHs in good yields. An interesting difference in reactivity was noted in the case of a sulfoximine-substituted 1,7,10-triene and its corresponding 1,10-diene. While the triene readily underwent a RCM reaction, the diene reacted only in the presence of Ti(OiPr)(4) under formation of the corresponding MRNH. The feasibility of a removal of the sulfoximine auxiliary and the N-sulfonyl protecting group from the MRNHs were demonstrated through reduction and cleavage, respectively, of a nine-membered heterocycle, both of which proceeded readily and gave the corresponding cyclic alkene and amine, respectively.

Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-2. Construction of the Angular Diquinanoid δ-Lactone

A formal asymmetric synthesis of pentalenolactone E (1b) and pentalenolactone F (1a) has been accomplished. Ozonolysis of the diphenyl-substituted triquinane 3 and Kauffmann methylenation of ketone 5 with WOCl3-2 MeLi yielded the unsubstituted triquinane 9. The crucial rearrangement of the linear triquinanoid lactone 11 to the angular triquinanoid lactone 14a was accomplished using orthoformate and acid in methanol. Subjecting triquinanes 14a/b to the selenoxide method gave triquinene 15. Homologation of γ-lactone 15 to the angular diquinanoid δ-lactone 2 via a Horner-Wadsworth-Emmons or Peterson reaction of hemiacetals 16a/b was, however, not successful. Chemoselective reduction of 14a afforded hemiacetals 21a/b, reaction of which with the phosphonate salt 17a ultimately led to the ketene dithioacetal 22. The angular intermediates 25a/b were obtained from 22 by reduction to give the linear hemiacetals 24a/b, which rearranged to the dithio ortholactones 25a/b in the presence of acid. Introduction of the double bond and deprotection were accomplished via selenation of 25a/b with N,N-diethylbenzeneselenylamide and treatment of selenides 30a/b with silver nitrate. The unsaturated aldehydes 28 and 29 thus obtained were converted to 2 and 31, respectively, by oxidation with manganese dioxide in the presence of sodium cyanide, methanol and acetic acid. Alkene 2 was isolated by crystallization.