Diastereoselective control

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Diastereoselective control through highly ordered transition states... 

The results of the dioxirane epoxidation of some 3-alkyl-substituted cyclohexenes and of 2-menthene indicate that the diastereoselectivity control is subject to the steric interactions of the dioxirane with the substituents of the substrate, while the size of the dioxirane substituents has only a minimal effect . In the favored transition structure, the alkyl groups of the dioxirane cannot interact effectively with the substituents at the stereogenic center of the chiral alkene . ... 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

Several structural features of (-)-rhazinilam 3 raise interesting synthetic challenges the axially chiral phenyl-pyrrole A-C biaryl bond, the fused pyrrole-piperidine C-D rings, the stereogenic quaternary carbon (C-20) ortho to the phenyl-pyrrole axis, the nine-membered lactam firing. Three racemic (Smith, Sames, Magnus) and one asymmetric (Sames) total syntheses have been published to date, which all proceed via construction of the pyrrole ring and diastereoselective control of the axial chirality by the central chirality at C-20. 

Diastereoselective control in the addition ofgrignard reagents to ketones ... 

In a beautifully choreographed sequence of events, Judd and co-workers installed the C3 to C4 bridged bicyclic lactam moiety of 129 with diastereoselective control via an Ugi 4-component coupling, ring-closing metathesis, and Heck reaction <07OL5119>. 

Katagiri, T., Yamaji, S., Handa, M., et al. (2001) Diastereoselectivity controlled by electrostatic repulsion between the negative charge on a trifluoromethyl group and that on aromatic rings. Chem. Commun., 2054-2055. 

In the sections that follow, the discussions progress through simple diastereoselection, control from indigenous chirality present in the substrate, control from a removable chiral auxiliary, ultimately to absolute stereodirection from an external species not formally bound in a covalent fashion to the substrate. There have been several previous reviews of the ene reaction, although none has focused on both relative and absolute stereochemical aspects 6-14 20. 

Diastereoselective control during enolization of allyl esters for Claisen rearrangement leads to predefined stereomers, and amide bases such as enantiomeric 189 are capable of generating chiral products. ... 

Excellent, high diastereoselective control can be achieved with organotin derivatives using potassium hexamethyldisilazanide for deprotonation. As a consequence of the defined enolate geometry by chelation effects, the (/T)-cstcr gives syn-23 as the main product (syn/anti ratio 39 1), whereas the (Z)-esler leads to anti-23 (antijsyn ratio > 40 1)50°. 

Porter and Mero showed that stereochemical control in atom transfer addition can also be obtained by the use of chiral benzyl oxazolidinone with 1-hexene in the presence of Lewis acid [8]. Excellent diastereoselective control was achieved in the presence of Sc(OTf)3, and the expected R configuration was observed as the major product formed (Scheme 12). 

In the literature one can also find the following notations chemioselectivity to describe the ability of a catalyst to discriminate among the different and the same functional group, regioselectivity - selection between several orientations, diastereoselectivity- control of the spatial arrangement of the functional groups in the product and enantioselectivity, - the catalyst ability to discriminate between mirror-image isomers or enantiomers. 

Diastereoselective synthesis of a-aminophosphinates has been achieved by alkylation of iminomethylenephosphinates possessing a (l,l-diethoxyethyl)phosphinyl moiety. The feature of the synthesis is high diastereoselective control by the asymmetric phosphorus atom. The asymmetric addition of diethylzinc to A -diphenylphosphinoylimines afforded Ai-diphenylphosphinoylamides with enan-tioselectivity of up to 90% ee in the presence of a catalytic amount of chiral ligand (S)-iV-ferrocenoyl-2-[(diphenylphosphino)methyl]pyrrolidine (244) and Cu(OTf)2. ... 

Selectivity in favor of five-membered ring formation was reported by Chiba, who employed preformed PhI[N(S02R)2]2 reagents (R = Me, Tol) from Muniz [53]. The reaction follows the mechanistic pathways of the discussed amino-oxygenation reaction and provides the corresponding diamination products 100 with complete diastereoselective control from amidines 99. 

Chiral sulphoxides have again been used, via their lithium salts, to induce chirality into a molecule. For instance, the chiral formyl anion equivalent (19) reacts with benzaldehyde and phenylacetaldehyde, and at the /S-position of cyclopentenones to give adducts with a high level of diastereoselective control. 

Addition of the Cl-anion to aldehyde 30 gave compound 31 in good yield with high diastereoselective control at the new stereogenic center (10 1). Transformation of the Cl-substituted glycal to the C-cellobiose derivative 32 then required a three-step sequence involving reductive removal of the phenylsulfoxide with Raney nickel, a stereoselective hydroboration-oxidation step, and finally catalytic hydrogenation. 

The cobalt complexed cyclopropane diester 4 was then reacted with a variety of aldehydes in the presence of boron trifluoride etherate in dichloromethane to afford the desired tetrahydrofurans 5 in high yields with poor diastereoselective control (Scheme 10.6). The cycloaddition reaction was limited to electron deflcient aromatic, aliphatic, and functionalized aldehydes, where no reaction was observed with electron rich aromatic aldehydes. The tetrahydrofurans were obtained as a 1 1 mixture of cis- and fran -isomers, where the best diastereomeric ratio obtained was 2 1 (5d) in favor of the fran -isomer. Modifying the temperature of the reaction had little effect on the diastereoselectivity. Confirmation of the stereochemistry was achieved by X-ray and NMR analysis of the separated diastereoisomers, including... 

The 2,5-disubstiututed tetrahydrofiirans were obtained in a high degree of diastereoselective control, where the cis-isomers were predominately formed. The reaction proceeded well with both electron-rich and electron-poor aldehydes however, 2-pyridinecarboxaldehyde was unreactive due to the potential coordination of tin triflate with the nitrogen of pyridine. 

Trost BM, Merlic CA. Diastereoselectivity control ele-ments-acyclic diastereocontrol in formation and reactions of y-hydroxysulfones. 7. Am. Chem. Soc. 1988 110(15) 5216-5218. 

For the ene-reaction of tiglic acid derivative 6 (Figure 8.7), a low diastereoselectivity was achieved even at -60°C de 64%). The naphthyl group aligns parallel and next to the tiglate ester group and hence, one of the alkene diastereotopic faces is shielded. From the tiglic amides 7, no diastereoselectivity control... 

Shim, S.C., Kim, D.S., Yoo, D.J., Wada, T., and Inoue, Y., Diastereoselectivity control on photosensitized addition of methanol to ( R)-(-t)-limonene,/. Org. Chem., 67, 5718, 2002. The trans isomer of ether 49 was formed with high diastereoselectivity (>96%) using 0.5 M methanol in ether solution at -75°C and either methyl benzoate or dimethyl phthalate as sensitizer. However, chemical yields were low. 

The reaction works well in most solvents, but diastereoselectivity control is better in polar solvents due a higher reversibility of betaine formation. The best chiral sulhde organocatalysts are those with the sulfur moiety in a cyclic structure. Compound 271 produces the best enantio- and diastereoselectivities with metal complex CuCacac) (Scheme 7.60). It enables the use of substoichiometric amounts of chiral sulhde keeping yields acceptable with excellent diastereo and enantioselectivities. The reaction is very sensitive to the concentration of the sulhde [206]. 

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