Syn- selectivity

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. 

For the monoprotected a-amino aldehydes, the best results in yield and stereoselectivity were obtained under kinetic control conditions which gave the expected sw-com pounds. The addition of tin(lV) chloride did not result in increased syn selectivity, and the use of boron trifluoride diethyl ether complex did not provide the ann -isomer as the major product. 

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. 

Bromo-2-phenylsulfonyl-2-butene adds with syn selectivity to aldehydes indicating again that in the intermediate chromium species the 3-alkyl group is forced to occupy the position trims to the bulky 2-substituent20,21. 

The (Z)-2-butenyl compound isomer 3, which is a rapidly interconverting mixture of the endn-and exo-conformers, reacts with syn selectivity, but a slow (Z)-(E) topomcrization competes with the carbonyl addition13, leading to a decrease in diastereoselectivity. 

The lithium enolate of the following (1 /C2.S )-2-phenyl-1-cyclohexylpropionate turns out to provide syn selectivity when reacted with benzaldehyde at —100 °C. However, the syn/anti ratio is only 86 14, and the induced stereoselectivity 92.5 7.522. 

Thus, jyn-adducts arise predominantly, as expected, according to the Zimmerman-Traxier model. Provided that either boron or zirconium is the enolate-metal atom, high syn selectivity is achieved. The total amount of anti-adducts is lower than 2% in the case of amides 1 and 2, and it approaches zero when the other reagents arc used94 . The induced stereoselectivities are impressive for the amides and remarkable in the case of the imides. 

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. 

When the enolate of an ,) - or a /j,y-unsatunited amide is used, it can react in an a or in a y fashion with a,/i-unsaturated esters, however, in most cases only a-selectivity is observed. Using l-(l-oxo-2-butenyl)pyrrolidine and lithium diisopropylamide at — 78 °C in a THF/HM-I A mixture (1 1), high. syn-selective formation of 3-alkyl-5-oxo-5-(l-pyrrolidinyl)-4-vinylpen-tanoates is achieved78,381 382. Related syn- or anti-selective additions of a vinylogous urethane also are known79. 

In contrast to the usual anti selectivity a remarkably high syn selectivity is observed in the addition of thioester enolates to 2-alkylidenealkanones297. The syn selectivity is probably due to a stereoselective internal autoprotonation of the resulting enolates by the dithioester a-pro-tons298 in these cases where the prostereogenic centers reside exclusively in the enone part (see also Section D.2.I.). 

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... 

R2=C02CH3) exhibit little difference in face selectivity, i.e., syn selectivity when subject to NaBH symanti = 65 35 in 18d 62 38 in 18e) and DIBAL-H syn.anti = 66 34 in 18d 61 39 in 18e) reduction. The behavior of 18d and 18e is also consistent with orbital unsymmetrization, as in 19. On the other hand, Mehta et al. suggested the presence of significant electrostatic contributions from exo-electron-withdrawing groups, rationalizing the syn face selectivity in 18b [75]. 

While the steric explanation is consistent with the observed selectivity, it nonetheless presents an incomplete explanation, as alkylation of 2-methyl-4-cyano-l,3-dioxane 17 also proceeded with very high syn-selectivity [11] (Eq. 5). The selective equatorial alkylation can be rationalized as an anfz-anomeric effect that disfavors axial alkylation of the ketene iminate through filled-shell repulsion. Simple lithiated nitriles are known to exist as ketene iminates, but it would be easy to rationalize the preference for equatorial alkylation by considering the relative stability of hypothetical equatorial and axial alkyllithium reagents, vide infra. Preferential equatorial alkylation was also observed by Beau... 

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... 

A related effect is noted with a-alkoxyacyl derivatives. These compounds give mainly the anti adducts when a second equivalent of TiCl4 is added prior to the aldehyde.144 The anti addition is believe to occur through a TS in which the alkoxy oxygen is chelated. In the absence of excess TiCl4, a nonchelated cyclic TS accounts for the observed syn selectivity. 

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. 

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