Face-selective reactions

Compounds with asymmetric centers can be obtained from prochiral starting molecules by either face-selective reactions [1] (stereoheterotopic facial addition) or group-selective reactions (stereoheterotopic ligand substitution). The transition states of these selective stereodivergent reactions must be diastereomeric, and the kinetics are the same as those of parallel reactions with different products (enantiomers or diastereo-mers). The selectivity in the stereoselective event leading to the different transition states can never be exceeded by the final yield of the major stereoisomer. 

Just and his group have pioneered the use of 7-oxabicyclo[2.2.1]hept-2-enes as starting materials in the synthesis of carbohydrates and analogs [396,397,398,399,400], These bicyclic systems have the advantage to undergo highly face selective reactions. They are obtained simply by Diels-Alder addition of furan to alkene dienophiles [401,402,403,404,405,407],... 

Substrates disubstituted at the methylene group undergo highly face-selective reaction under both nickel(O) and palladium(O) catalyst conditions to afford the type A product in good yield. 

Two highly efficient and very practical alternatives have emerged in recent years (Scheme 1.2). One of these approaches consists of activating the acceptors by reversible conversion into a chiral iminium ion. Thus, the reversible condensation of an a,p-unsaturated carbonyl compound with a chiral secondary amine provides a chiral a,p-unsaturated iminium ion. A face-selective reaction with the nucleophile provides an enamine, which can be either reacted with an electrophile and then hydrolysed, or just hydrolysed to a p-chiral carbonyl compound. The second approach is the enamine pathway. If the nucleophile is... 

A versatile synthetic route to enantiomeric ally pure Diels-Alder adducts was deduced and found dependent on the application of enantiomerically pure 5-methoxy-174a (R=Me) and 5-(l-menthyloxy)-2(5//)-furanones 174b (R = menthyl), which were expected to undergo tt-face-selective cycloaddition with dienes. The reaction was effected by heating no Lewis acid catalysts were required (Scheme 55) (88JOC1127). 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

The hand-in-glove fit of a chiral substrate into a chiral receptor is relatively straightforward, but it s less obvious how a prochiral substrate can undergo a selective reaction. Take the reaction of ethanol with NAD+ catalyzed by yeast alcohol dehydrogenase. As we saw at the end of Section 9.13, the reaction occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of the NAD+ carbon. 

There are four main factors that affect the enantioselectivity of sulfur ylide-mediated reactions i) the lone-pair selectivity of the sulfonium salt formation, ii) the conformation of the resulting ylide, iii) the face selectivity of the ylide, and iv) betaine reversibility. 

Various diastereoselective Michael reactions are based on y-bromo-, y-alkyl-, or y-alkoxy-2(5//)-furanones following the trans-face selectivity shown in Section 1.5.2.3.1.2. Thus the lithium enolates of esters such as ethyl propanoate, ethyl a-methoxyacetate and ethyl a-phenylacetate add to methoxy-2(5/f)-furanone with complete face selectivity269-273 (see Section 1.5.2.4.4.2.). 

If, for the purpose of comparison of substrate reactivities, we use the method of competitive reactions we are faced with the problem of whether the reactivities in a certain series of reactants (i.e. selectivities) should be characterized by the ratio of their rates measured separately [relations (12) and (13)], or whether they should be expressed by the rates measured during simultaneous transformation of two compounds which thus compete in adsorption for the free surface of the catalyst [relations (14) and (15)]. How these two definitions of reactivity may differ from one another will be shown later by the example of competitive hydrogenation of alkylphenols (Section IV.E, p. 42). This may also be demonstrated by the classical example of hydrogenation of aromatic hydrocarbons on Raney nickel (48). In this case, the constants obtained by separate measurements of reaction rates for individual compounds lead to the reactivity order which is different from the order found on the basis of factor S, determined by the method of competitive reactions (Table II). Other examples of the change of reactivity, which may even result in the selective reaction of a strongly adsorbed reactant in competitive reactions (49, 50) have already been discussed (see p. 12). 

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

The ew face selectivities are still recent topics of electrocyclic reactions [39] and transition metal catalyzed reactions [40-47],... 

Steric repulsions come from two orbital-four electron interactions between two occupied orbitals. Facially selective reactions do occur in sterically unbiased systems, and these facial selectivities can be interpreted in terms of unsymmetrical K faces. Particular emphasis has been placed on the dissymmetrization of the orbital extension, i.e., orbital distortions [1, 2]. The orbital distortions are described in (Chapter Orbital Mixing Rules by Inagaki in this volume). Here, we review the effects of unsymmetrization of the orbitals due to phase environment in the vicinity of the reaction centers [3]. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

The heteroatom-assisted Diels-Alder reaction has emerged as an extremely powerful method for the preparation of complex heterocycles. In several cases, such reactions with TADs are described. For example, the reaction of vinyl pyrrolidone 594 with MTAD provides a 7 2 mixture of diastereomers 595 and 596 in 95% combined yield, showing only low face selectivity (Equation 88) <2005JOC5221>. 

The transition-state model of this reaction has been proposed as (1), based on X-ray analyses of single crystals prepared from Ti(OPr )4, (R,R)-diethyl tartrate (DET), and PhCON(OH)Ph and from Ti(OPr )4, and (R,R) N,/V -dibenzyltartramide.30-32 The Z-substituent (R2), located close to the metal center, destabilizes the desired transition state and decreases enantioselectivity (vide supra). When the Z-substituent is chiral, face selection induced by the substituent strongly affects the stereochemistry of the epoxidation, and sometimes reversed face selectivity is observed.4 In contrast, the. E-substituent (R1) protrudes into an open space and E -allylic alcohols are generally good substrates for the epoxidation. 

The Paterno-Buchi photocycloaddition between carbonyl compounds and furans was first described in 1965 (equation 6)80. This report noted that only the head-to-head product 171 was formed, and that high exo face selectivity was exhibited. Subsequent to this and other early reports, this reaction has been systematically explored by several groups, owing largely to the various ways in which the 2,7-dioxabicyclo[3.2.0]hept-3-ene ring system can be exploited730,81. 

Face selectivity in the 1,3-dipolar cycloaddition reactions of benzonitrile oxide and its p-substituted derivatives with 5-substituted adamantane-2-thiones,... 

The palladium-isocyanide catalyst is also effective for the silastannation of cyclopropenes (Equation (115)).158 The reaction proceeds smoothly under mild conditions (RT, 10-30 min) with high face selectivity to give tetrasubstituted... 

The above interesting approach to the asymmetric allyltitanation reaction does, however, have a limitation. Thus, L-glucose is much more expensive that the D-form and, consequently, homoallylic alcohols of the opposite configuration cannot easily be obtained by this method. In an attempt to induce the opposite si face selectivity, other acetonide derivatives of monosaccharides from the xylose, idose, and allose series were tested [42b,42c], The enantiofacial discrimination was, however, much lower than that with DAGOH and both re and si face selective additions to aldehydes were observed. 

E. J. Corey, E-Y. Zhang, re and si-Face-Selective Nitroal-dol Reactions Catalyzed by a Rigid Chiral Quaternary Ammonium Salt A Highly Stereoselective Synthesis of the HIV Protease Inhibitor Amprenavir (Vertex 478) , Angew. Chern. Int. Ed 1999, 38,1931-1934. 

In cyclization reactions of ketyls with hydrazone, Skrydstrup and coworkers used different ligands to control the face selectivity in these coupling reactions [154]. Only low enantioselectivities (< 15%) and moderate yields (< 65%) were obtained for the trans-cyclized products (data not shown). 

Pyramidalization is thought not to be relevant to the different face selectivity of 4 + 2 cycloaddition reactions of diene systems exocyclic to the bicyclo[2,2,l]heptane structure, because selectivity persists for additions to dienes which are not significantly distorted (Gallucci et al., 1985). 

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