Sulfoxides, vinyl conjugate additions

Conjugate addition of methylamine to vinyl alkynyl sulfoxides and sulfones also led to formation of 1,4-thiazine 1-oxides and 1,1-dioxides (Equation 74) <1979S47>. 

Since early investigations about the asymmetric addition of diethyl sodiomalonate to optically active vinylic sulfoxides,100-101 Posner and his coworkers102-117 have developed a highly useful methodology based on the conjugate addition of carbon nucleophiles to homochiral a-arylsulfinyl-a,(J-unsaturated carbonyl compounds. While acyclic derivatives still lead only to moderate results,103 the strength of this method is for cyclic systems. For example, the 2-sulfinyl-2-cycloalkenones (94) and (95), the 2-sulfinyl-2-alkenolides (96) and (97), as well as their respective enantiomers are excellent substrates. All these compounds are quite readily accessible in enantiomeric purities of >98% and are configurationally stable, at least for several months at 0 C. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Addition to allylic mesylates.6 Conjugate addition of organocyanocuprates to acyclic allylic mesylates substituted at the P-position with a chiral sulfoxide group involves an SN2 -substitution with high Z/E stereoselectivity and high asymmetric induction. This reaction provides a route to chiral trisubstituted vinyl sulfoxides. 

Acyclic stereocontrol remains a challenging problem in synthesis. While enan-tiomerically pure sulfoxides are valuable synthetic intermediates for enantiocon-trolled carbon-carbon bond formation by conjugate addition in cyclic cases, their usefulness for such alkylations in acyclic cases has not been firmly established. Moreover, most sulfoxide directed alkylation protocols utilize the valuable sulfur auxiliary just once, which limits the synthetic versatility of the process. Marino et al. have recently reported SN2 displacements of acyclic allylic mesyloxy vinyl sulfoxides with organocopper reagents (Scheme 10).33 In addition to the excellent observed stereoselectivities, the newly created chiral center is adjacent to a vinyl sulfoxide which should allow for subsequent chirality transfer operations. On treatment with organocopper nucleophiles, both sulfoxide diastereoisomers 40b and 43b underwent SN2 displacements with high Z selectivity to yield products 42b and 45b, respectively (Table 2). The oxidation state on the sulfur was varied... 

The conjugate addition step can also be intramolecular. For instance, Tanaka and coworkers studied the case of a lithiated vinyl sulfoxide that undergoes intramolecular conjugate addition in high yields and complete diastereocontrols (Scheme 32)148. 

Vinyl sulfones are superior to the sulfoxides (see Section 7.3.1.2.2.) for the diastereoselective synthesis of / -hydroxy-a-amino acids via intramolecular conjugate addition of a carbamate nitrogen. 

The sulfinyl group is a useful temporary chiral auxiliary for the activation of a carbon carbon double bond towards nucleophilic addition as both enantiomers of a,//-unsaturated vinyl sulfoxides are available in enantiomerically pure form91. Both intermolecular and intramolecular conjugate additions of V-nucleophiles have been investigated. 

Piperidine and benzylamine have been utilized in diastereoselective addition reactions to other a,/ -unsaturated vinyl sulfoxides bearing the R absolute configuration92,93 at sulfur. A conjugate addition of piperidine to (f )-l-methyl-4-[(Z)-l-propenylsulfinyl]benzene (20) in a polar solvent such as methanol gives an 83 17 (21A/21B) diastereomeric mixture of adducts94,95. 

The carbanions of allylic sulfoxides undergo kinetically controlled conjugate additions to give vinylic sulfoxides as a single diastereoisomer (Scheme... 

A versatile non-Friedel-Crafts approach to naphthols is provided by condensation of the toluic acid sulfoxide with substituted acrylates or methyl vinyl ketone. Sequential conjugate addition and acylation of the first formed anion leads to the tetralone. Pyrolysis leads to aromatiza-tlon by loss of sulfinic acid. 

The cerium(III)-mediated conjugate addition of a difluoromethylphosphonate carbanion to a wide range of aliphatic nitroalkenes,acyclic and cyclic vinyl sulfones,5 and vinyl sulfoxides has been reported recently (Scheme 3.85). 

The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (i )-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed 189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl IR-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-oxo-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps ketalization of an oxo group, reduction of lactam, and deketali-zation)(/S9). 

The application of chiral sulfoxides to the asymmetric synthesis of biologically active compounds has recently been reviewed [3]. Conjugate addition to chiral vinyl sulfoxides has been used by several research groups to achieve the enantioselective synthesis of natural products. For example, intramolecular asymmetric conjugate addition of a nitrogen nucleophile to a chiral vinyl sulfoxide (Scheme 3) was studied by Pyne and applied to the enantioselective synthesis of (-R)-carnegine and other alkaloid systems (Scheme 3) [10]. 

A new route to pyrroles which begins by conjugate addition of p-ketoesters to phenyl vinyl sulfoxide was developed. <94JCS(P1)2355> The adducts are subjected to Pummerer rearrangement which generates 2-phenylthio-dihydrofurans as intermediates. Treatment with amines and HgClj leads to formation of the pyrroles. 

The asymmetric synthesis of naturai products by intramolecular conjugate addition to enantiomerically pure vinylic sulfoxides... 

Intermolecular Conjugate Addition to Enantiomerically Pure Vinylic Sulfoxides... 

The intramolecular conjugate addition of nucleophiles to chiral vinyl sulfoxides has proved particularly useful in the asymmetric synthesis of a variety of natural products. 

Tanikaga and coworkers have reported the addition of nitroalkane anions to a-halo-a,P-unsaturated sulfoxides [72]. Further development of this work led to the use of nitroalkanes as alkyl group equivalents in conjugate addition to a,P-unsaturated sulfoxides [73-75]. Primary or secondary nitroalkanes such as 2-nitropropane (77), with DBU as a non-nucleophilic base, add to a,P-unsaturated sulfoxides including phenyl vinyl sulfoxide (26) to give products such as (78), which can be denitrated to yield (79) (Scheme 5.25). The Michael addition of nitroalkanes, and of diethyl N-acetylaminomalonate, to racemic phenyl vinyl sulfoxide using solid-liquid phase-transfer catalysis in the absence of solvent has also been accomplished [76]. 

Conjugate addition of lithium enolates onto terminal alkynyl- and allenyl-sulfoxides has been reported to give allylic sulfoxides which undergo Mislow-Braverman-Evans rearrangement to a-keto vinyl carbinols (Scheme 187). (g)... 

During the initial studies on the chemistry of the suifenic acid functionality, Shelton and Davis (1967) observed that t-butylsulfenic acid (103) underwent conjugate addition to a propiolic ester to produce the vinyl sulfoxide (104). Similarly, the azetidinone suifenic acid (105), thermally generated from penicillin sulfoxide (106), was also found to undergo a conjugate addition with dimethyl acetylenedicarboxylate to yield a mixture of epimeric sulfoxides 107 and 108 (Barton et al., 1973 1974). This isomeric mixture could be reduced to the single sulfide (109). The double bond was isomerized to the a,p-unsaturated compound 110 which on progressive ozonolysis first produced the thiooxalate (111) and then the oxamide (112). 

Conjugate Addition to a, -Unsaturated Carbonyl Compounds Other than Ketones. In addition to a, 8-unsaturated ketones, the silylcuprate reagent also reacts with a, 8-unsaturated aldehydes, esters (eq 13), amides, and nitriles, and with vinyl-sulfoxides without needing Lewis acid catalysis as carbon-based cuprates do. With esters, the intermediate enolates, which have the E geometry (20), may be used directly in highly diastereoselective... 

With cyclopentenone derivatives, 1,4-addition is observed for the ester enolates of methyl and f-butyl trimethylsilylacetate, although 1,2-addition occurs with acyclic conjugated enals. With a steroidal cyclopentenone substrate, both 1,2- and 1,4-addition were observed. Conjugate addition is observed for the methyl ester with chiral vinyl sulfoxides. High enantioselectivity can be attained (eq 7). ... 

Mori was clearly intrigued by juvabione. Nearly 25 years after his first synthesis, his group described the third conjugate addition approach we will consider. This synthesis addresses both relative and absolute stereochemistry problems. The plan was to prepare the anion derived from vinyl sulfoxide 149 and examine its reaction with cyclohexenone (127). There was precedence for the 7-carbon of this type of allylic anion to behave as the nucleophile in conjugate additions (Hua). The hope was that this addition would take place with good diastereoselectivity and that the sulfoxide would influence the absolute stereochemistry of the process. 

The energetic driving force for conjugate addition is the replacement of a tt bond by a cr bond. Among Michael acceptors that have been demonstrated to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilyl-vinyl ketone/ methyl a-methylthioacrylate/ methyl methylthiovinyl sulfoxide, and ethyl a-cyanoacrylate. The latter class of acceptors has been shown to be capable of generating contiguous quaternary carbon centers. 

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