Internal diastereoselectivity

Discussing the stereochemical outcome of the Claisen rearrangements, two aspects had to be considered. On one hand, the relative configuration of the new stereogenic centers was found to be exclusively syn in 308 and 309 suggesting a chair-like transition state c-a and c-fS, respectively, including a Z acyl ammonium enolate structure (complete simple diastereoselectivity/internal asymmetric induction, Scheme 10.64). 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

Representatives of the bridged sulfone system 70 have been subjected to ruthenium catalysed ring-closing metathesis reactions (Grubbs catalyst) and shown to afford, in low yields, a few selected cyclic dimers and trimers, of all the possibilities available. The diastereoselectivities observed were rationalised in terms of kinetic control involved with internal ruthenium/sulfonyl oxygen coordination . 

The N, C -coupling reactions of primary amines with BENAs are very sensitive to steric factors in BENAs. For example, the reactions with terminal BENAs are difficult to stop at the mono-alkylation step, whereas in internal BENAs, it is very difficult to isolate the bis-coupling product. A special procedure, based on this fact, enables one to synthesize bis-oximes (460) containing various oximinoalkyl substituents at the nitrogen atom. It should be emphasized that diastereoselectivity of /V,( -coupling reactions of amines with terminal BENA is very low. 

By contrast, L-phenylalanine methyl ester does not react with BENA generated from 1-nitropropane (R =H) due apparently to low nucleophilicity of the amino group. However, the N, C -coupling reaction of the ester of this amino acid with another internal BENA (R = CC>2Me) proceeds rather readily but is characterized by extremely low diastereoselectivity. Probably, the last N,C-coupling does not occur via an intermediate a-nitroso alkene but by a classical Michael addition to BENA MeCH=C(C02Me)N(05i )2 as to Michael substrate. 

In comparison with the platinum catalysts, rhodium catalysts are much more reactive to effect addition of bis(catecholato)diboron even to non-strained internal alkenes under mild reaction conditions (Equation (5)).53-55 This higher reactivity prompted trials on the asymmetric diboration of alkenes. Diastereoselective addition of optically active diboron derived from (li ,2i )-diphenylethanediol for />-methoxystyrene gives 60% de (Equation (6)).50 Furthermore, enantioselective diboration of alkenes with bis(catecolato)diboron has been achieved by using Rh(nbd)(acac)/(A)-QUINAP catalyst (Equation (7)).55,56 The reaction of internal (A)-alkenes with / //-butylethylene derivatives gives high enantioselectivities (up to 98% ee), whereas lower ee s are obtained in the reaction of internal (Z)-alkenes, styrene, and a-methylstyrene. 

When internal trans alkenes were subjected to diazoester in the presence of 80 CuOTf, cyclopropane ent-56, formed in high enantioselectivity, was slightly favored over its isomer (56). The use of ethyl diazoacetate improved diastereoselec-tion relative to the bulkier /-Bu ester. Unfortunately, ee values were somewhat lower with the ethyl ester, Eq. 39. Ito and Katsuki (56) propose the model in Fig. 7 to account for this selectivity. Approach of the trans alkene is controlled by the stereocenter on the bipyridines, directing the bulky group cis to the ester moiety. Larger esters lead to an increased steric interaction in this position and the net result is an erosion in reaction diastereoselectivity. 

In all the examples commented upon so far, we have dealt with reactions with internal diastereoselective induction. However, when a chiral centre is already present in one of the components [12] we must refer then to a relative diastereoselective induction, and Cram s rule [13] must be taken into account when the chiral centre is present at the a-position of the aldehyde (28). For instance, in the reaction shown in Scheme 9.7 of the four possible diastereomers only two are formed, the Cram-i yn-aldol 30a being the predominant diastereomer (see below 9.3.3). 

It has been demonstrated that excellent diastereoselectivities for enolate alkylation also are obtained when alkyl substituents are positioned at C(4), C(5) or C(6) of benzamide 5. AryE and methoxy substituents at C(5) also are compatible, but a methyl group at C(3) leads to an inversion of the diastereoselectivity of enolate alkylation. The inverted sense of stereoselection is thought to be a result of a disruption of the internal chelation shown in enolate 6 by steric effects of the neighboring methyl substituent. 5... 

The chiral enolate-imine addition methodology was examined in detail (Thiruvengadam et al., 1999). Enolate formation proceeds to completion within an hour at temperatures from — 30 to 0°C with either 1 equiv. TiCl4 or TiClaO-iPr (preformed or prepared in the presence of substrate by addition of TiCl4 and followed by a third of an equivalent Ti(0-iPr)4 and two equivalents of a tertiary amine base). Unlike the aldol process with the same titanium enolate, the nature of the tertiary amine base had no effect on the diaster-eoselectivity. The diastereoselectivity is maximized by careful control of the internal temperature to below — 20°C during the imine addition (2 equiv.) as well as during the acetic acid quench. The purity of the crude 2-amino carboxamide derivatives (17a or... 

An internal diastereoselective alkylation reaction leading to cyclopropane formation 24 has been reported40. Although the 2-oxazolidinone moiety employed was not chiral, it should be possible to perform this reaction using a chiral auxiliary of the oxazolidinone type. 

A variation of this reaction on an alkynyloxirane substrate was employed to prepare a deuteriated allenylcarbinol (equation 21)13. The reaction afforded a 70 30 mixture of diastereomeric products, indicating that the presumed internal Sjv2 cleavage of the epoxide is not highly diastereoselective. 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

Lomolder, R. and Schafer, H.J. (1987) Low-temperature photolysis of peracetylated dodecanoyl peroxides of tartaric acid and D-gluconic acid in the solid state- a diastereoselective radical coupling. Angewandte Chemie, International Edition, 26, 1253-1254. 

The crossed intramolecular [2 + 2]-photocycloaddition of allenes to a, 3-unsat-urated y-lactones has been extensively studied by Hiemstra et al. in an approach to racemic solanoedepin A (87). The sensitized irradiation of butenolide 85 in a 9 1 mixture of benzene and acetone, for example, led selectively to the strained photocycloadduct 86 (Scheme 6.31) [89]. The facial diastereoselectivity is determined by the stereogenic center, to which the allene is attached. The carbon atom in exposition to the carbonyl carbon atom is attacked from its re face, forming a bond to the tertiary allene carbon atom, while the P-carbon atom is being connected to the internal allene carbon atom by a si face attack. The method allows facial diaster-eocontrol over three contiguous stereogenic centers in the bicyclo[2.1.1]heptane part of the natural product. 

For the control of the diastereoselectivity in multistep reactions see (a) Buschmann H, Scharf H-D, Hoffmann N, Esser P. Angew Chem Intern Ed Engl 1991 30 477-515 (b) Cainelli G, Giacomini D, Galletti P. Chem Commun 1999 567-572. 

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