Stereoselective synthesis diastereoselectivity

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

For the purpose of stereoselective synthesis the selective elimination at the stage of the /3-hydroxysilane 5 is not a problem the diastereoselective preparation of the desired /3-hydroxysilane however is generally not possible. This drawback can be circumvented by application of alternative reactions to prepare the /3-hydroxysilane 2 however these methods do not fall into the category of the Peterson reaction. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

The carbonyl addition reactions of benzylmetals, compared to the allylic counterparts, have found few applications in stereoselective synthesis, apparently for the following reasons The carbonyl addition of alkali metal salts (M = Li, Na, K, Cs) of benzyl anions, with few exceptions, usually proceeds with low levels of simple diastereoselectivity affording mixtures of syn- or <7 / -diastereomers (see Section 1.3.2.3.1.). 

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

Allylic titanates having an electrofugal leaving group, e.g., trimethylsilyl68 75 - 77, at the 3-position are powerful reagents for the highly stereoselective synthesis of 1-hetero-substituted 3-alkadienes. For the carbonyl addition of the appropriate titanated allyl sulfides ( ) or carbamates ( and ), reliable y-selectivity and anti diastereoselectivity are reported. The... 

There are very few examples of asymmetric synthesis using optically pure ions as chiral-inducing agents for the control of the configuration at the metal center. Chiral anions for such an apphcation have recently been reviewed by Lacour [19]. For example, the chiral enantiomerically pure Trisphat anion was successfully used for the stereoselective synthesis of tris-diimine-Fe(ll) complex, made configurationally stable because of the presence of a tetradentate bis(l,10-phenanthroline) ligand (Fig. 9) [29]. Excellent diastereoselectivity (>20 1) was demonstrated as a consequence of the preferred homochiral association of the anion and the iron(ll) complex and evidence for a thermodynamic control of the selectivity was obtained. The two diastereoisomers can be efficiently separated by ion-pair chromatography on silica gel plates with excellent yields. 

Another anionic/radical one-pot sequence was developed by Guindon and coworkers for the stereoselective synthesis of substituted pentanoates 2-718 (Scheme 2.158) [365]. Such structures are found in polyketides and are, therefore, of great interest. The described approach offers a diastereoselective access to all four possible stereoisomers of 2-718 through a Mukaiyama aldol/radical defunctionalization sequence starting from 2-716 and 2-717 with addition of Bu3SnH after completion of the first step. 

The addition of alkyl nitronate anions to imines in the presence of a Lewis acid proceeds in high yield with up to 10 1 diastereoselection favoring the anti isomer. This reaction is used for the stereoselective synthesis of 1,2-diamines (Eq. 4.121).167 Scandium triflate catalyzes the addition of 1-trimethylsilyl nitropropanoate to imines with a similar selectivity.35... 

Diastereoselective conjugate addition of nucleophiles to enones, enals, and enoates occurs with high stereocontrol and constitutes a powerful method in stereoselective synthesis.185... 

The enolates derived from 2,6-disubstituted phenyl propionates appear to exhibit the higliest levels of threo aldol diastereoselection yet reported for lithium-mediated condensations (33). These substrates should enjoy widespread use in stereoselective synthesis. 

On the other hand, selective, usually applied to a synthesis, means that of all the possible isomers only one isomer is obtained. However, if the reaction product was/is a mixture of isomers one could speak then of the "degree of selectivity". Since usually one of the isomers will be the predominant isomer, we may say that the reaction (or the synthesis) is selective with respect to this particular isomer. As in the case of "specificity", we may refer to "regioselectivity" or to "stereoselectivity" (either diastereoselectivity or enantioselectivity) and may say, for instance, that a synthesis is 80% diastereoselective. According to the most updated terminology "diastereomers" are all the "stereoisomers" that are not "enantiomers", so geometrical isomers are also included in such a definition. 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

The stereoselective synthesis of carbohydrates from acyclic precursors is a research topic that has attracted considerable attention over the past decadeT Efforts in this area are easily justified and have maximum impact particularly when directed toward rare sugars or other polyhydroxylated molecules that are not conveniently accessed via classical "chiron" approaches.2 An underlying theme of such efforts, of course, is the development of practical synthetic methodology that will find broad application in the enantio- and diastereoselective synthesis of natural products, their analogues, and other compounds of biological interest. 

The Claisen rearrangement of allyl vinyl ethers is a classic method for the stereoselective synthesis of y,J-unsaturated esters. The allylic C-H activation is an alternative way of generating the same products [135]. Reactions with silyl-substituted cyclohexenes 197 demonstrate how the diastereoselectivity in the formation of 198 improves (40% to 88% de) for the C-H insertion reactions as the size of the silyl group increases (TMS to TBDPS) (Tab. 14.14). Indeed, in cases where there is good size differentiation between the two substituents at a methylene site, high diastereo- and enantioselectivity is possible in the C-H activation. 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

Allylic esters of fluoroacetic acid were used in the Ireland silyl ketene acetal rearrangement procedures by the Welch group at Albany [164]. For example, Eq. (53) shows a highly diastereoselective rearrangement which formed an early stage in syntheses of 2,3-dideoxy-2-fluoro-3-C-methyl pentose nucleosides [165, 166]. If a stereoselective synthesis of a functionalised monofluorocompound is... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

The (diastereoselective) conjugate addition of silylcuprate reagents to a variety of chiral derivatives of a,(3-unsaturated carboxylic acids can be used to prepare optically active p-silyl esters.258 259 Best results are obtained with substrates of type (25). The (related) p-silyl ketones, which also constitute valuable building blocks for (acyclic) stereoselective synthesis, are now accessible in high ee via palladium-catalyzed enantioselective 1,4-disiiylation of a,p-unsaturated ketones (Scheme 76).260... 

Free-radical cyclization of phenyl selenide 15 to indolizidinone 16 represented a key step in the total synthesis of (—)-slaframine (equation 52). The two pairs of diastereomers were first separated and then hydrolyzed to the corresponding alcohols in 76% overall yield77. (TMS)3SiH-mediated acyl radical reactions from phenylseleno esters 17 have recently been utilized for the stereoselective synthesis of cyclic ethers78. In fact, the experimental conditions reported in equation 53 are particularly good for both improving cis diastereoselectivity and suppressing decarbonylation. 

A stereospecific and stereoselective synthesis of 2-(l-hydroxyalkyl)-l-alkylcyclo-propanols (46) has been realized from a,/3-epoxy ketones and bis(iodozincio)methane (Scheme 22).127 The diastereoselective reaction has been explained by chelation (g) effects. 

Stereoselective synthesis of perylenequinones. Synthesis of the symmetrical perylenequinone phleichrome (4) has been effected by coupling of two identical naphthalene units to provide a binaphthol, which is then oxidized to a perylenequinone. Thus the bromonaphthalene 1 on halo-lithium exchange (f-BuLi) followed by reaction of anhydrous FeCl3 dimerizes to two optically active binaphthyls, (+)-and (— )-2, with 3 1 diastereoselectivity. 

Woerpel and Howard further extended the synthetic utility of this cascade reaction in the stereoselective synthesis of a-hydroxy acids from a-ketoesters (Scheme 7.42).119 In every case, the a-hydroxy acid was formed with excellent diastereoselectivity (dr >98 2). Their method was tolerant of a range of substitution patterns, although diminished yields were obtained as the size of the R1 substituent increased (compare 154a and 154c). In contrast, no decrease in yield was observed over a range of R2 substituents. 

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

A. P. Davis, Diastereoselective Reductions, in Stereoselective Synthesis (Houben-Weyl) 4th ed., 1996, (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E21 (Workbench Edition), 7, 3988 1048, Georg Thieme Verlag, Stuttgart. 

---