Isolation and structure determination of a tetrameric sulfonyl dilithio methandiide in solution based on crystal structure analysis and 6Li/13C NMR spectroscopic data.

Dilithio sulfonyl methandiides are a synthetically and structurally highly interesting group of functionalized geminal dianions. Although very desirable, knowledge of the structure of dilithio methandiides in solution was lacking up to now. Herein, we describe the isolation and determination of the structure of tetrameric dilithio (trimethylsilyl)(phenylsulfonyl) methandiide in solution and in the crystal. The elucidation of the structure of the tetramer is based on crystal structure analysis and 13C/6Li NMR spectroscopic data. A characteristic feature of the structure of the tetramer is the C 2 symmetric C-Li chain, composed of four doubly Li-coordinated dianionic carbon and five Li atoms. Three Li atoms are devoid of a contact to a dianionic C atom. The tetramer, the dianionic C atoms of which undergo fast exchange, is in THF solution in fast equilibrium with a further aggregate, which is stable only at low temperatures.

Nickel-Catalyzed Anionic Cross-Coupling Reaction of Lithium Sulfonimidoyl Alkylidene Carbenoids With Organolithiums.

The mechanistic platform for a novel nickel0 -catalyzed anionic cross-coupling reaction (ACCR) of lithium sulfonimidoyl alkylidene carbenoids (metalloalkenyl sulfoximines) with organometallic reagents is reported herein, affording substituted alkenylmetals and lithium sulfinamides. The Ni0 -catalyzed ACCR of three different types of metalloalkenyl sulfoximines, including acyclic, axially chiral and exocyclic derivatives, with sp2 organolithiums and sp2 and sp3 Grignard reagents has been studied. The ACCR of metalloalkenyl sulfoximines with PhLi in the presence of the Ni0 -catalyst and precatalyst Ni(PPh3 )2 Cl2 afforded alkenyllithiums, under inversion of configuration at the C atom and complete retention at the S atom. In a combination of experimental and DFT studies, we propose a catalytic cycle of the Ni0 -catalyzed ACCR of lithioalkenyl sulfoximines. Computational studies reveal two distinctive pathways of the ACCR, depending on whether a phosphine or 1,5-cyclooctadiene (COD) is the ligand of the Ni atom. They rectify the underlying importance of forming the key Ni0 -vinylidene intermediate through an indispensable electron-rich Ni0 -center coordinated by phosphine ligands. Fundamentally, we present a mechanistic study in controlling the diastereoselectivity of the alkenyllithium formation via the key lithium sulfinamide coordinated Ni0 -vinylidene complex, which consequently avoids an unselective formation of an alkylidene carbene Ni-complex and ultimately racemic alkenyllithium.

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion.

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described. The CCR generally requires dual Ni catalysis and MgBr2 promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr2 in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl2 as a precatalyst and MgBr2 with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh3 )2 Cl2 as a precatalyst and ZnPh2 does not require salt promotion and is stereoretentive. The reaction with Zn(CH2 SiMe3 )2 , however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh3 )2 Cl2 . Ni-Catalyzed and MgBr2 -promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh2 and Zn(CH2 SiMe3 )2 is stereoretentive with Ni(dppp)Cl2 and Ni(PPh3 )2 Cl2 . CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.

Experimental and Computational Studies of the Structure of Sulfonimidoyl Vinyllithiums.

tBuCH=C(Li)S(O)(NSO2 Tol)Ph⋅L (L=2THF, TMEDA) (1⋅L) in THF solution is a monomer with a C-Li bond according to NMR spectroscopy and cryoscopy. It was identified as CIP through the scalar 13 C,6 Li coupling and 6 Li,{1 H} NOE experiments. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure. 6 Li,1 H FUCOUP and 6 Li,1 H HMQC NMR experiments of 1⋅TMEDA revealed a scalar 6 Li,1 H coupling across the Li-C=C-H bonds. According to the NMR data the π-bond of 1⋅L is polarized by the negative charge of the anionic C atom. tBuCH=C(Li)S(O)(NMe)Ph (2⋅L) is most likely also a monomer with a C-Li bond. According to 6 Li,{1 H} NOE experiments it has a four-membered C-Li-N-S chelate ring structure. 13 C NMR spectroscopy showed the C-Li bonds of 1⋅L and 2⋅L to be fluxional. 1 H NMR spectroscopy and 1D TOCSY experiments of Ph2 C=C(Li)S(O)(NSO2 Tol)Ph revealed topomerization of the phenyl groups, which is attributed to a fast positional exchange of the Li atom and the sulfonimidoyl group. The fluxionality of the C-Li bond and the interchange of the Li atom and the sulfonimidoyl group at the anionic C atom of sulfonimidoyl vinyllithiums, which result in a low configurational stability, most likely involve the formation of O,Li and N,Li CIPs through heterolysis of the C-Li bond. Ab initio calculation of MeCH=C(Li)S(O)(NMe)Ph yielded an energy minimum structure with a C-Li bond, a four-membered C-Li-N-S chelate ring and a strongly expanded C=C-Li bond angle. According to calculation of MeCH=C(Li)S(O)(NMe)Ph, [MeCH=CS(O)(NMe)Ph]- and MeCH=C(H)S(O)(NMe)Ph deprotonation is not accompanied by a shortening of the C-S bond. Ab initio calculation of MeCH=C(Li)S(O)(NSO2 Me)Ph gave a structure with a C-Li bond and a six-membered C-Li-O-S-N-S chelate ring. 6 Li,1 H NOE experiments and cryoscopy of LiCH2 S(O)(NSO2 Tol)Ph (3) revealed a monomeric CIP with a C-Li bond. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure found in polymeric 3 in the crystal.

Chiral Lithiated Allylic α-Sulfonyl Carbanions: Experimental and Computational Study of Their Structure, Configurational Stability, and Enantioselective Synthesis.

X-ray crystal structure analysis of the lithiated allylic α-sulfonyl carbanions [CH2 CHC(Me)SO2 Ph]Li⋅diglyme, [cC6 H8 SO2 tBu]Li⋅PMDETA and [cC7 H10 SO2 tBu]Li⋅PMDETA showed dimeric and monomeric CIPs, having nearly planar anionic C atoms, only OLi bonds, almost planar allylic units with strong CC bond length alternation and the s-trans conformation around C1C2. They adopt a C1S conformation, which is similar to the one generally found for alkyl and aryl substituted α-sulfonyl carbanions. Cryoscopy of [EtCHCHC(Et)SO2 tBu]Li in THF at 164 K revealed an equilibrium between monomers and dimers in a ratio of 83:17, which is similar to the one found by low temperature NMR spectroscopy. According to NMR spectroscopy the lone-pair orbital at C1 strongly interacts with the CC double bond. Low temperature (6) Li,(1) H NOE experiments of [EtCHCHC(Et)SO2 tBu]Li in THF point to an equilibrium between monomeric CIPs having only OLi bonds and CIPs having both OLi and C1Li bonds. Ab initio calculation of [MeCHCHC(Me)SO2 Me]Li⋅(Me2 O)2 gave three isomeric CIPs having the s-trans conformation and three isomeric CIPs having the s-cis conformation around the C1C2 bond. All s-trans isomers are more stable than the s-cis isomers. At all levels of theory the s-trans isomer having OLi and C1Li bonds is the most stable one followed by the isomer which has two OLi bonds. The allylic unit of the C,O,Li isomer shows strong bond length alternation and the C1 atom is in contrast to the O,Li isomer significantly pyramidalized. According to NBO analysis of the s-trans and s-cis isomers, the interaction of the lone pair at C1 with the π* orbital of the CC double bond is energetically much more favorable than that with the "empty" orbitals at the Li atom. The C1S and C1C2 conformations are determined by the stereoelectronic effects nC -σSR * interaction and allylic conjugation. (1) H DNMR spectroscopy of racemic [EtCHCHC(Et)SO2 tBu]Li, [iPrCHCHC(iPr)SO2 tBu]Li and [EtCHC(Me)C(Et)SO2 tBu]Li in [D8 ]THF gave estimated barriers of enantiomerization of ΔG(≠) =13.2 kcal mol(-1) (270 K), 14.2 kcal mol(-1) (291 K) and 14.2 kcal mol(-1) (295 K), respectively. Deprotonation of sulfone (R)-EtCHCHCH(Et)SO2 tBu (94 % ee) with nBuLi in THF at -105 °C occurred with a calculated enantioselectivity of 93 % ee and gave carbanion (M)-[EtCHCHC(Et)SO2 tBu]Li, the deuteration and alkylation of which with CF3 CO2 D and MeOCH2 I, respectively, proceeded with high enantioselectivities. Time-dependent deuteration of the enantioenriched carbanion (M)-[EtCHCHC(Et)SO2 tBu]Li in THF gave a racemization barrier of ΔG(≠) =12.5 kcal mol(-1) (168 K), which translates to a calculated half-time of racemization of t1/2 =12 min at -105 °C.

How torsional effects cause attack at sterically crowded concave faces of bicyclic alkenes.

Cycloadditions of 1,3-dipoles and related species to a cis-oxabicyclo[3.3.0]octenone occur on the more sterically crowded concave face. These cycloadditions were studied experimentally by Gais and co-workers in 1998 (Eur. J. Org. Chem. 1998, 257-273) and have now been studied computationally with density functional theory (DFT). Transition states have been computed for various types of (3 + 2) cycloadditions, including diazomethane 1,3-dipolar cycloadditions, a thermally promoted methylenecyclopropane acetal cycloaddition, and a Pd-catalyzed cycloaddition of methylenecyclopropane to an oxabicyclo[3.3.0]octenone. The concave stereoselectivities arise from alkene predistortion that leads to torsional steering in the transition states.

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.

Redox reaction of the Pd0 complex bearing the Trost ligand with meso-cycloalkene-1,4-biscarbonates leading to a diamidato Pd(II) complex and 1,3-cycloalkadienes: enantioselective desymmetrization versus catalyst deactivation.

The Pd(0) complex 1 that bears the Trost ligand 2 undergoes a facile redox reaction with 1,4-biscarbonates 5b-d and rac-22 under formation of the diamidato-Pd(II) complex 7 and the corresponding 1,3-cycloalkadienes 8b-d. The redox deactivation of complex 1 was the dominating pathway in the reaction of 5b-d with HCO(3)(-) at room temperature. However, at 0 degrees C the six-membered biscarbonate 5b, catalytic amounts of complex 1, and HCO(3)(-) mainly reacted in an allylic alkylation, which led to a highly selective desymmetrization of the substrate and gave alcohol 6b with > or = 99% ee in 66% yield. An increase of the catalyst loading in the reaction of 5b with 1 and HCO(3)(-) afforded the bicyclic carbonate 12b (96% ee, 92%). Formation of carbonate 12b involves two consecutive inter- and intramolecular substitution reactions of the pi-allyl-Pd(II) complexes 16b and 18b, respectively, with O-nucleophiles and presumably proceeds through the hydrogen carbonate 17b as key intermediate. The intermediate formation of 17b is also indicated by the conversion of alcohol rac-6b to carbonate 12b upon treatment with HCO(3)(-) and 1. The Pd(0)-catalyzed desymmetrization of 5b with formation of 12b and its hydrolysis allow an efficient enantioselective synthesis of diol 13b. The reaction of the seven-membered biscarbonate 5c with ent-1 and HCO(3)(-) afforded carbonate ent-12c (99% ee, 39%). The Pd(0) complex 1 is stable in solution and suffers no intramolecular redox reaction with formation of complex 7 and dihydrogen as recently claimed for the similar Pd(0) complex 9. Instead, complex 1 is rapidly oxidized by dioxygen to give the stable Pd(II) complex 7. Thus, formation of the Pd(II) complex 10 from 9 was most likely due to an oxidation by dioxygen. Oxidative workup (air) of the reaction mixture stemming from the desymmetrization of 5c catalyzed by 1 gave the Pd(II) complex 7 in high yield besides carbonate 12c.

Anionic cross-coupling reaction of alpha-metallated alkenyl sulfoximines and alkenyl sulfoximines with cuprates featuring a 1,2-metal-ate rearrangement of sulfoximine-substituted higher order alkenyl cuprates and an alpha-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.

Asymmetric synthesis of spiroketal, spiroether, and oxabicycle building blocks via stereoselective spiro- and bicycloannulation of 2-hydroxy dihydropyrans.

A modular asymmetric synthesis of spiroketal, spiroether, and oxabicycle building blocks is described based on the spiro- and bicycloannulation of alpha-hydroxy dihydropyrans, which were obtained from sulfoximine-substituted homoallylic alcohols. Key steps of the syntheses are stereoselective Ferrier-type O- and C-glycosidation, ring-closing metathesis, and stereoselective Prins cyclization.

Modular asymmetric synthesis of functionalized azaspirocycles based on the sulfoximine auxiliary.

A modular asymmetric synthesis of the functionalized azaspirocycles 6 (m = 2, n = 1), 7 (m = 1, n = 2), 8 (m = n = 2), 12, 20, and 24 from the cyclic allylic sulfoximines 1 is described. The synthetic strategy is based on the stereoselective construction of the carbocycle 4 containing the amino-substituted tertiary C atom from 1 followed by the generation of the azaspirocycle. Three different routes have been followed for the synthesis of the heterocyclic ring: N,C-dianion cycloalkylation, ring-closing metathesis, and N-acyl iminium ion formation.

Asymmetric synthesis of highly substituted gamma-amino acids from allyltitanium sulfoximines.

[structure: see text]. Asymmetric syntheses of the highly substituted protected gamma-amino acids 10a, 10b, 18, and 21 have been developed starting from the allyltitanium sulfoximines V and VI, respectively, and furan-2-carbaldehyde.

Asymmetric synthesis of substituted homoallyl alcohols, halomethyl tetrahydrofurans, and chloro-amino sulfones from allyltitanium sulfoximines and alpha-hetero aldehydes.

Asymmetric syntheses of the iodomethyl-substituted bicyclic tetrahydrofuran 22 and the chloro-amino sulfone 30 from the allylic sulfoximine 15 and the alpha-hetero aldehydes 2 and 23, respectively, are described. Further examples for the asymmetric synthesis of chloromethyl tetrahydrofurans and chloro-amino sulfones are given. The synthesis of 30 features as key step the stereoselective Cl-substitution of a hydroxy group under neighboring group participation by an aminosulfoxonium group which is converted to a sulfonyl group. [reaction: see text].

Asymmetric synthesis of 3-oxa-15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin and its neuroprotective analogue 15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin based on the conjugate addition-azoalkene-asymmetric olefination strategy.

A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy. Key building blocks are the readily available bicyclic azoalkene 14 and the alkenylcopper derivative 15. The stereoselective conjugate addition of 15 to 14 gave hydrazone 13, which was stereoselectively converted to the bicyclic ketone 11. The key steps for the construction of the alpha side chain of 7 a and 7 b and the regioselective introduction of the endocyclic Delta6,6a double bond are: 1) a highly selective asymmetric olefination of ketone 11 with the chiral Horner-Wadsworth-Emmons reagent 28 and 2) a regioselective deconjugation of the alpha,beta-unsaturated ester (E)-10 with the chiral lithium amide 29, which gave the beta,gamma-unsaturated ester anti-9 with high selectivity. The homoallylic alcohol 8 served at a late stage as the joint intermediate in the syntheses of 7 a and 7 b. While an etherification of 8 furnished, after hydrolysis and deprotection, 3-oxa-15-deoxy-TIC, its alkylation afforded alcohol 37, the known precursor for the synthesis of 15-deoxy-TIC.

Asymmetric modular synthesis of highly functionalized medium-sized carbocycles and lactones via ring-closing metathesis of sulfoximine-substituted trienes.

A modular asymmetric synthesis of medium-sized carbocycles and lactones has been developed that affords highly substituted 7-, 9-, and 11-membered rings. The key steps are (1) the highly diastereoselective synthesis of sulfoximine-substituted homoallylic alcohols from allylic sulfoximines and unsaturated as well as saturated aldehydes, (2) an E-stereoselective alkylation and hydroxyalkylation of sulfoximine-substituted alkenyllithium derivatives, (3) the esterification of sulfoximine-substituted homoallylic alcohols, and (4) the ring-closing metathesis reaction of sulfoximine-substituted trienes with the ruthenium catalyst 8. Two examples for the further synthetic elaboration of the sulfoximine-substituted carbocycles are provided. The selective cleavage of the tert-butyldimethylsilyl group of 12 in the presence of the triethylsilyl group afforded the allylic alcohol 18 which was oxidized to enone 19. A cross-coupling reaction of the sulfoximine-substituted carbocycle 9 with LiCuMe2 furnished the methyl-substituted derivative 20.

Fully stereocontrolled syntheses of 3-oxacarbacyclin and carbacyclin by the conjugate addition-azoalkene-asymmetric olefination strategy.

A fully stereocontrolled synthesis of 3-oxacarbacyclin (3) and a formal synthesis of carbacyclin (2) are described. The syntheses are based on the conjugate addition-azoalkene-asymmetric olefination strategy. Its key features are (1) the stereoselective establishment of the complete omega-side chain of 2 and 3 through conjugate addition of the enantiopure C13-C20 alkenylcopper derivative 10 to the enantiopure C6-C12 bicyclic azoalkene 9 and (2) the 5E-stereoselective construction of the alpha-side chain through a Horner-Wadsworth-Emmons olefination of the bicyclic ketone 7 with the chiral lithium phosphonoacetate 26 with formation of ester E-27. The allylic alcohol 6 serves at late stage as the joint intermediate in the synthesis of 2 and 3.

Functionalized chiral vinyl aminosulfoxonium salts: asymmetric synthesis and application to the synthesis of enantiopure unsaturated prolines, beta,gamma-dehydro amino acids, and cyclopentanoid keto aminosulfoxonium ylides.

Methylation of the enantiopure functionalized vinyl sulfoximines 5a-e and 14a-d followed by a F- ion or DBU-mediated isomerization of the vinyl aminosulfoxonium salts 7a-e and 15a-d, respectively, gave the allyl aminosulfoxonium salts 10a-e and 17a-d, respectively. A concomitant intramolecular substitution of the aminosulfoxonium group of 10a-e and 17a-d by the amino group afforded the unsaturated prolines 8a-e and 18a-d, respectively. The starting vinyl sulfoximines are accessible through a highly selective and stereo-complementary aminoalkylation of the corresponding sulfonimidoyl-substituted mono- and bis(allyl)titanium complexes with the imino ester 4. The vinyl aminosulfoxonium salts 34, 7a-d, and E-15c experienced upon treatment with the Cl- ion a migratory substitution with formation of the delta-chloro-beta,gamma-dehydro amino acids 36, E/Z-37a-d, and 38, respectively. A migratory substitution of the hydroxy-substituted vinyl aminosulfoxonium salts 46a and 46b furnished the delta-chloro allyl alcohols E/Z-48a and E-48b, respectively. A facile one-pot conversion of the vinyl sulfoximines 31b, 5c and 45a to the allyl chlorides 36, E/Z-37c and E/Z-48a, respectively, was achieved upon treatment with a chloroformiate. A tandem cyclization of the vinyl aminosulfoxonium salts 7b, Al-7b and 57 with LiN(H)tBu yielded the cyclopentanoid keto aminosulfoxonium ylides 54, Al-54, 59, 60 and 61, respectively. The structure of the tricyclic keto aminosulfoxonium ylide Al-54 has been determined by X-ray crystal structure analysis. Ab initio calculations and a NBO analysis of the tricyclic keto aminosulfoxonium ylide XXIII show a polar structure stabilized by electrostatic interactions between the ylidic C atom and both the carbonyl C atom and the S atom.

Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost.

We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.