Syn-selective reactions

The Sn2" product was shown to be the result of a syn-selective reaction, the stereochemistry being opposite to that of the 5 2 product, which has the incoming group anti to the leaving group. The reason for the observed syn selectivity is not clear, but the authors proposed the initial formation of the two distinct Cu(III)-allyl complexes 12 and 13 for the 5 2" and 5 2 pathways in Scheme 8.12. 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

The tau bond model appears to provide a quick and easy explanation. An anti interaction between each of the breaking bonds and the lower tau bond leads overall to a syn selective reaction for each diastereoisomer. 

With protected ketone 85 in hand, the next aldol coupling required its syn-selective reaction with aldehyde 74 to install the C15-C16 stereocenters in 86 (Scheme 9-28). A boron triflate reagent would be expected to generate the desired (Z)-enolate. However, studies earned out on the separate components indicated that this was a mismatched reaction, and it did not prove possible to overturn the aldehyde facial bias by use of a chiral reagent. 

In more recent work, germanium catalysts such as GeClq gave a highly diastereoselective Reformatsky reaction favoring the syn diastereomer.228 Another syn selective reaction was reported using TiCl2 and Cu.229 Enantioselective Reformatsky reactions have also used chiral amino alcohols as additives.220... 

The tin(II) enolate prepared from (1), tin(II) trifluoromethane-sulfonate, and 1-ethylpiperidine reacts with aldehydes in the presence of A(, fY,fV -tetramethylethylenediamine (TMEDA) to afford the anti aldol adducts in good yields with good selectivities (eq 1). Interestingly, syn selective reactions proceed in the absence of TMEDA. Optically active antf aldol adducts can be obtained in the presence of chiral diamine (2) instead of TMEDA. 

Type 2 syn-selective reactions Independent of the ally geometry (SI, Sn) Type 3 antl-seiective reactions independent of the allyl geometry (Ti, Cr, Zr)... 

The (Z)-enamine transition state 31 was proposed as the intermediate in the syn-selective reaction of an acyclic ketone donor with an aldehyde acceptor catalyzed by 22. In this type of reaction, formation of the ( )-enamine of the acyclic ketone is disfavored due to steric repulsion between R and substituents (Figure 28.3) [18]. The (F)-enamine formed by an aldehyde donor with the axially chiral catalyst 23 can react with an aldehyde acceptor that is activated by the proximal acidic proton of 23 via transition model 33, thus affording the syn-aldol product [19],... 

Tine force field was then used to predict the results for fhe addition of the E and Z isomers c Ihe enol boronate of butanone (R = Me) to ethanol (R = Me). The relevant transitio. Iructures are shown in Figure 11.34. A Boltzmann distribution, calculated at the ten perature of the reaction (—78°C), predicted that the Z isomer would show almost complel syn selectivity syn anti = 99 1) and that the E isomer would be selective for the an product anti syn = 86 14). These results were in good agreement with the experunenti... 

It IS likely that the syn selectivity exhibited in cycloadditions of fluoroallene IS due to electrostatic interactions [23 25] As in the case of difluoroallene the reactions of fluoroallene with diazoalkanes and nitrile oxides are facile, but such reactions, other than that shown in equation 18, are neither regio nor stereospeutic [23, 25] Indeed, the addition of phenylnitrile oxide to fluoroallene occurs with preferential anti addition for both regioisomenc products (equation 20)... 

Fluoroallene also undergoes reaction exclusively at the C(2)-C(3) it bond and exhibits a slight syn selectivity in its Diels-Alder reactions [25, 26, 93] (equation 80), much less than that observed in its 1,3-dipolar cycloadditions... 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

Treatment of cyclic vinylaziridine 105 with organocuprates of the R2CuLi type proceeds in a highly syn-selective manner (Scheme 2.29) [46], The syn stereochemistry of the reaction reflects the effect of the acetonide group, which directs the nucleophilic attack to the less hindered a-face. The formation of SN2 products 109 from the cyclic (chlorovinyl)aziridine 107 can be explained by assuming a syn-SN2 ... 

With respect to the nucleophilic addition of organocopper reagents, a sharp contrast between the rigid isopropylidene glyceraldehyde and its open-chained analog, 2,3-bis(benzyloxy)propanal. was observed (compare Tables 15 and 16). With the isopropylidene-protected aldehyde a high syn diastereoselectivity could only be obtained when tetrahydrofuran was used as reaction solvent, and the diastereoselectivity dropped considerably in diethyl ether. In contrast, the latter solvent allows excellent syn selectivities in additions to the dibenzyl-protected glyceraldehyde81. On the other hand, tetrahydrofuran yields better results than diethyl ether in the... 

Good to excellent diastereoselectivities have been reported when 2-(trimethylsilyl)thiazole (3), an effective equivalent of an aldehyde group, is used as nucleophile24,27. Thus, addition to TV-Boc-protected amino aldehydes in dichloromethane at — 30 C afforded mixtures of amino alcohols in comparatively good yields with reasonable syn selectivity. However, the stereoselectivity decreased substantially when the reaction was carried out in tetrahydrofuran at 25 °C. 

The syn selectivity in the titanium(IV) chloride mediated reactions can be explained by an intermolecular chelation, with transition state 21A being sterically favored over 21B. On the other hand, nonchelation control governs the stereochemistry of the boron trifluoride mediated reactions. Thus, the sterically favored transition state 21 C leads to the observed anf/ -diastereo-mer12. 

The syn selectivity of boron trifluoride promoted 2-butenylstannane-aldehyde reactions has been examined for a range of different systems less useful syn selectivity was observed for reactions of 2-butenylstannanes with alkyl 2-oxopropanoates68, but better selectivity was found with alkyl 2-oxoacetates69. 

The reaction of propargylic ethers proceeds through an addition-elimination pathway, which docs not involve the coppcr(III) intermediate. The stereochemical outcome varies with the nature of the halogen component of the Grignard reagent of RMgX6Sc. If the halogen is chloride, overall syn selectivity is obtained however, anti substitution results in the case of iodide. 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

High syn selectivity can be obtained from the addition of enamines to nitroalkenes. The reaction of 4-(1-cyclohexenyl)morpholine with ( )-l-bromo-4-(2-nitroethenyl)benzene gives, after acid hydrolysis, exclusively the. ryw-adduct, the relative configuration of which was unequivocally... 

The Strecker reaction has been performed on the aldehyde 182 prepared from L-cysteine [86] (Scheme 28). The imine was formed in situ by treatment with benzylamine, then TMS cyanide was added to afford prevalently in almost quantitative yield the syn-diamine 183, which is the precursor of (-l-)-biotin 184. The syn selectivity was largely affected by the solvent, toluene being the solvent of choice. Since the aldehyde 182 is chemically and configurationally unstable, a preferred protocol for the synthesis of 183 involved the prehminary formation of the water-soluble bisulfite adduct 185 and the subsequent treatment with sodium cyanide. Although in this case the syn selectivity was lower, both diastereomers could be transformed to (-l-)-biotin. 

Tin enolates are also used in aldol reactions.27 Both the Sn(II) and Sn(IV) oxidation states are reactive. Tin(II) enolates can be generated from ketones and Sn(II)(03SCF3)2 in the presence of tertiary amines.28 The subsequent aldol addition is syn selective and independent of enolate configuration.29 This preference arises from avoidance of gauche interaction of the aldehyde group and the enolate P-substituent. The syn stereoselectivity indicates that reaction occurs through an open TS. 

Certain other metal ions also exhibit catalysis in aqueous solution. Two important criteria are rate of ligand exchange and the acidity of the metal hydrate. Metal hydrates that are too acidic lead to hydrolysis of the silyl enol ether, whereas slow exchange limits the ability of catalysis to compete with other processes. Indium(III) chloride is a borderline catalysts by these criteria, but nevertheless is effective. The optimum solvent is 95 5 isopropanol-water. Under these conditions, the reaction is syn selective, suggesting a cyclic TS.63... 

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

These reactions have been applied to a-benzyloxy and a-(r-butyldimethylsiloxy)-thioacetate esters.164 The benzyloxy derivatives are anti selective, whereas the siloxy derivatives are syn selective. These differences are attributed to a chelated structure in the case of the benzyloxy derivative and an open TS for the siloxy system. 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

The proline-catalyzed reaction has been extend to the reaction of propanal, butanal, and pentanal with a number of aromatic aldehydes and proceeds with high syn selectivity.197 The reaction can also be carried out under conditions in which the imine is formed in situ. Under these conditions, the conjugative stabilization of the aryl imines leads to the preference for the aryl imine to act as the electrophile. A good yield of the expected P-aminoalcohol was obtained with propanal serving as both the nucleophilic and the electrophilic component. The product was isolated as a 7-amino alcohol after reduction with NaBH4. 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

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