Diastereomers Diastereoselection

P, P] Seebach and Blarer examined the addition of the enamine derived from proline methyl ether and cyclohexanone to arylidene malonates (Scheme 14, Table 3) (32,33). The process is uniformly selective for the syn, S,S diastereomer. Diastereoselectivities from 88% to > 95% and enantiomeric excesses (for the syn product) of 80-92% were observed. The results were... 

Certain heterocycles, e.g. pyridines or quinolines, bearing of an electron-withdrawing group such as oxazoline, undergo the Michael-type nucleophilic 1,4-addition accompanied with loss of aromaticity to give the new C-C bond. Thus formed dihydropyridine or benzodihydropyridine can be oxidatively aromatized with conservation of chirality, primary induced by an influence of chiral oxazoline moiety. In this manner, Meyers and coworkers [27] described the Michael-type addition of 1-naphthyllithium (609) to the oxazoline 610 at low temperature to form 611 in 90% yield. The latter was oxidatively aromatized to the naphthylquinoline 612 in 87% yield with 88 12 ratio of two diastereomers. Diastereoselectivity in this reaction remained on the same level as obtained by the nucleophilic addition of 609 to 610 indicating the virtually complete conservation of chirahty, from sp -type in the compound 611 to the axially chiral compound 612, Scheme 11. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Three other modifications of the standard conditions provide synthetically useful strategies for the preparation of dihydrofurans. One method, called the interrupted Feist-Benary reaction, utilizes milder reaction conditions to stop the final dehydration step. For example, Calter combined bromide 47 with dicarbonyl 48 to produce dihydrofuran 49 as a mixture of diastereomers. He examined the scope and diastereoselectivity of this process and applied this reaction toward the synthesis of the polycyclic core of the zaragozic acids. A method principally designed to yield practical syntheses of cyclic ketodiesters also furnished a dihydrofuran via a variation of the interrupted Feist-Benary reaction. ... 

The validity of the model was demonstrated by reacting 35 under the same reaction conditions as expected, only one diastereoisomer 41 was formed, the structure of which was confirmed by X-ray analysis. When the vinylation was carried out on the isothiazolinone 42 followed by oxidation to 40, the dimeric compound 43 was obtained, showing that the endo-anti transition state is the preferred one. To confirm the result, the vinyl derivative 42 was oxidized and the intermediate 40 trapped in situ with N-phenylmaleimide. The reaction appeared to be completely diastereoselective and a single diastereomer endo-anti 44 was obtained. In addition, calculations modelling the reactivity of the dienes indicated that the stereochemistry of the cycloaddition may be altered by variation of the reaction solvent. 

For azomethine ylides and carbonyl ylides, the diastereoselectivity is more complex as the presence of an additional chiral center in the product allows for the formation of four diastereomers. Since the few reactions that are described in this chapter of these dipoles give rise to only one diastereomer, this topic will not be mentioned further here [10]. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

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... 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

A synthetically useful diastereoselectivity (90% dc) was observed with the addition of methyl-magnesium bromide to a-epoxy aldehyde 25 in the presence of titanium(IV) chloride60. After treatment of the crude product with sodium hydride, the yy -epoxy alcohol 26 was obtained in 40% yield. The yyn-product corresponds to a chelation-controlled attack of 25 by the nucleophile. Isolation of compound 28, however, reveals that the addition reaction proceeds via a regioselective ring-opening of the epoxide, which affords the titanium-complexed chloro-hydrin 27. Chelation-controlled attack of 27 by the nucleophile leads to the -syn-diastereomer 28, which is converted to the epoxy alcohol 26 by treatment with sodium hydride. 

Similar results are found with the threose derivatives 11 and 13. Both aldehydes can be readily synthesized in either enantiomeric form from l- and D-tartaric acid. The open-chain aldehyde 11 with Grignard reagents affords predominantly the all-.v> n(xj/o)-diastereomer 12. The steric demand of the nucleophile apparently does not affect the diastereoselectivity, and the extremely high selectivity observed with [(l,3-dioxolan-2-yl)methyl]magnesium bromide is attributed to the presence of the dioxolane moiety, which is thought to stabilize the a-chelated transition state. 

Besides 1,3-oxathianes, the 1,3-dithiane 1-oxide moiety can be used for directing the nucleophilic addition of an organometallic reagent to a carbonyl group in a diastereoselective manner. The addition of methylmagnesium iodide to the 2-acyl-l,3-dithiane 1-oxide 23A leads exclusively to the diastereomer which is formed by Re-side attack. On the other hand, addition... 

Another class of configurationally stable a-mctallo amines is derived from the N-tert-butoxy-carbonyl-protected piperidines 32 and 3516, l7. Addition of the lithiated piperidines to aldehydes leads to mixtures of the anti- and. yin-diastereoiners. Although the diastereoselectivity is low, the diastereomers can be readily separated by chromatography since the. vyn-isomer is often in a cyclized form 34. The stereochemistry of the products obtained from piperidines 32 are consistent with an equatorial a-lithiation followed by addition to the aldehyde with retention of configuration. However, with piperidine 35 selective axial lithiation is observed. 

In order to test whether this high level of diastereoselectivity is due to the stereoselective formation of 35 A, or a consequence of rapid equilibration between 35 A and 35 B, both reagents were selectively prepared via the tributylstannanes 38. Treatment of either reagent with chloro-trimethylsilane led to a similar ratio of the diastereomers 36 A/36B, with the anti-diastereomer 36A predominant in both reactions. 

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