Chiral sulfoxides Michael addition

Mainly sulfoxide groups are introduced as chiral auxiliaries for the modification of a,/J-unsat-urated enones (see Section D.1.5.3.5.). Chiral imine derivatives have also been used (see Section D.1.5.3.1.). Various chiral alcohols, and in particular 8-phenylmenthol, have been successfully used as auxiliaries, mainly in two-fold Michael additions to a,/ -unsaturatcd esters. 

Michael-Additions The most important application of this type of reaction is the carbon-carbon bond formation p to a carbonyl function by the addition of carbanion. The asymmetric version of the Michael-addition has been known since 1973. An optically active vinyl sulfoxide served as chiral auxiliary198). 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

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... 

Michael additions of organotitanium or zirconium reagents remain to be explored systematically. Recently, Stork described an interesting stereoselective intramolecular Michael addition in which zirconium enolates appear to be involved113). In another Michael type process, methyltitanium triisopropoxide 6 was added enantioselectively to a chiral a, p-unsaturated sulfoxide, but CH3MgCl was more efficient114). 

Enantiomeric enriched a-thiosulfoxides 391 can be prepared by addition of a-thiomethyllithiums to p-tolyl sulfinate601. The deprotonation of p-tolyl (p-tolylsulfanyl)methyl sulfoxide (403) took place with w-BuLi at — 78 °C to afford the enantioenriched lithium derivative 404602. The addition to benzaldehyde followed by methylation of the hydroxy group and deprotection gave a-methoxyphenylacetaldehyde with 70% ee. This chiral formyl anion gave diastereoselectively Michael addition to a-substituted cyclopentenones603. The acylation of compound 404 followed by LAH reduction allowed the diastereoselective preparation of compounds 405 up to 99% de (Scheme 105)604. 

Spiroketal cyclization. Intramolecular spiroketal cyclization via Michael addition of an alcohol to a chiral a,p-unsaturated sulfoxide can proceed with high stereoselectivity. Reactions with KH are more stereoselective than those with NaH or n-BuLi. Thus cy-... 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

This new centre does not appear in the natural product 76. It is oxidised to the ketone and both alkenes reduced catalytically, both hydrogen molecules being added from the exo-face to set up both chiral centres in one step. The THF is finally oxidised to the lactone with Ru(IV). After the initial Michael addition, controlled by the sulfoxide, every chiral centre depends on the folded or bowl-shaped molecule. 

We view acetylenic sulfoxide 1 as a two-carbon synthon in alkaloid synthesis. Our general approach, as depicted in Scheme 4, called for a Michael addition of Nu1 to the terminal acetylenic position followed by a cyclization by Nu2 (an intramolecular second Michael addition). This Michael addition cyclization step will build up the basic skeleton of the alkaloid system and at the same time control the absolute stereochemistry of the newly created chiral center through asymmetric induction of the chiral sulfoxide moiety. Finally, the sulfoxide can be transformed to another functional group (X) or used to promote the formation of another bond with Nu3 via trapping of the sulfenium ion intermediate under Pummerer rearrangement conditions (Scheme 4). 

Our first attempt was an enantioselective synthesis of (k)-(+)-carnegine [7,8]. Michael addition of 2-(3,4-dimethoxyphenyl)ethylamine (7) to (R)-(+)-l took place readily at room temperature in chloroform (Scheme 5). Without isolation of any intermediate, the reaction mixture was treated with excess trifluoroacetic acid to effect the cyclization. Depending on the reaction conditions and the aryl substituent of the chiral sulfoxide, different levels of diastereoselectivity were observed. The results are summarized in Table 1. Under proper conditions (TFA, 0°C, 4h), 10b could be obtained in 65% yield as the only isolated product (Scheme 5) (Table 1). 

Table 1. Michael addition-cyclization of 7 with chiral acetylenic sulfoxides...

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

Chiral a,P-unsaturated sulfoxides 1.136 (Y = Tol, R = R CH=CH) also have been used in asymmetric synthesis. These compounds are prepared either by treatment of 1.137 with vinylic organometallic reagents, or from saturated precursors by classical chemical transformations [102, 173, 476, 484-487], Michael additions to these electrophiles are interesting only if R = CF3 [161], Organometallic additions or [4+2] cycloadditions require the introduction of a second electron-withdrawing substituent [73, 102], and acyclic 1.138 and cyclic 1.139 gem-di substituted sulfoxides have seen many interesting applications [101, 102,... 

The routes leading from lactone A have the advantage of a chiral source of starting materials. With the two chiral centers at C24 and C25 set, the problem reduces down to elaborating the B ring with the appropriate substituents. An early solution was provided in an unusual cyclization of the B ring via an intramolecular Michael addition to the unsaturated aldehyde formed from a nitrile oxide 1,3-dipolar cycloaddition to the allyl methyl ketal of lactone A [76]. This clever use of relative stereocontrol provided by the highly constrained and predictable transition states of both key reactions unfortunately resulted in a low yield. A more conventional approach conceptualized the addition of a sulfoxide [77] to 2 to yield a masked diol-ketone precursor which cyclizes under acidic catalysis. Elimination of the sulfoxide permitted the introduction of the hydroxy substituent at C19 of the spiroketal. 

The synthesis by Paquette (Scheme 11.21) [28] also does a sequential anellation of the rings. Moreover, it uses a sulfoxide as chiral auxiliary and to facilitate a Michael addition. This synthesis obviously focuses on the construction of the skeleton. The decoration with functional groups is attained only late in the synthesis. 

Michael addition of scalemic /3-ketosulfoxides R1COCH2S (0)To1 (chiral at sulfur) to O, /3-unsaturated aldehydes R CH=CHCHO, catalysed by proline derivatives, has been shown to exhibit complete control of configuration at the two newly constructed chiral centres. The configuration at the a-position of the moiety originating from the nucleophile is controlled by the sulfoxide group, whereas the configuration at the -position of the Michael acceptor is controlled by the catalyst, which allows the preparation of all possible diastereoisomers in an enantiomericaUy pure form. Theoretical calculations suggest that enolates, rather than enols, are the active reactants. " ... 

Cyclic (hetero- and carbocyclic) vinyl sulfoxides have been prepared by a tandem Michael addition/Homer olefination reaction of a-phosphorylvinyl sulfoxides and carbonyl compounds bearing a nucleophilic center. Using optically active a-phosphorylvinyl sulfoxides a series of enantiomeric cyclic vinyl sulfoxides in which the chiral sulfinyl group is bonded to a chromene, pyrrazolyne, quinoline or cyclopen-tene ring, has been obtained. The H-W-E reaction of aldehydes with sulfinimine-derived 3-oxo pyrrolidine phosphonates (228) represents a new method for the asymmetric synthesis of ring-functionalized cw-2,5-disubstituted 3-oxo pyrrolidines (229) (Scheme 90). ... 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

As with the Michael reaction (5-17) the 1,4 addition of organometallic compounds has been performed diastereoselectively517 and enantioselectively.518 In one example of the latter,519 a, (3-unsaturated sulfoxides that are optically active because of chirality at sulfur (p. 100) have given high enantiomeric excesses, e.g.,520... 

Proline was among the first compounds to be tested in asymmetric conjugated reactions, both as a chiral ligand [8] and also as an organic catalyst [3]. The earliest asymmetric intermolecular Michael-type addition, in which proline catalyzed the reaction (arguably via enamine formation) was reported by Barbas and colleagues [9, 10] and by List and co-workers [11]. The reaction, which proceeded in high chemical yield (85-97%) and diastereoselectivity, albeit afforded near-racemic products in dimethyl sulfoxide (DMSO) [11] (Scheme 2.37). The enantio-selectivity of the addition was later ameliorated by Enders, who demonstrated that a small amount of methanol rather than DMSO was beneficial to the enantiose-lectivity of the addition reaction [12]. 

NaBHj/NiC or Raney nickel, the menthyloxy group is removed with NaBH /KOH to give 3,4-disubstituted butyrolactones with a high diastereo- and enantioselectivity (Figure 7.69). Corey and Houpis [1458] have described asymmetric Michael reactions of ketone enolates with a 2-thiophenyl crotonate of 8-phenmenthol. Chirality has also been introduced on the amino group of 2-ami-nomethyiacrylates to perform the asymmetric addition of the anion of the tert-Bu ester of cyclopentanecarboxylate [1459], More important developments have been reported with chiral a,p-unsaturated sulfoxides and nitro compounds as Michael acceptors (see below). 

Chiral Michael acceptors underwent asymmetric cyclopropanation. Chiral unsaturated sulfoxide 21 controlled the nucleophilic addition of S-ylides to give chiral cyclopropanes 22 (Scheme 1.17) [29]. The sulfoxide group in 22 was converted into alkyl groups by treatment... 

Lithium A number of Michael-type additions of organolithiums have been described. This is also the case of the reaction of aryllithiums with nitroalkene (389). Deprotonation of the benzylic fluoride (455) with LDA, directed by the neighbouring sulfoxide group, generated the benzyllithium intermediate (456), which underwent addition to the Michael acceptor R CH=CHY (Y = CO2BU, S02Ph R = Ar, alkyl, alkenyl) in a diastereoselective manner controlled by the chiral sulfur to afford the 5yn-configured product (457) with <99 1 dr ... 

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