Totally stereoselective additions to 2,6-disubstituted 1,3-dioxin-4-ones (chiral acetoacetic acid derivatives).  Synthetic and mechanistic aspects of remote stereoselectivity

Seebàch, Dieter; Zimmermann, Juerg; Gysel, Urs; Ziegler, Regula.; Ha, T.‐K.

doi:10.1021/ja00222a039

Cited by 130 publications

(38 citation statements)

References 9 publications

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“…[32] . It has been proposed that reactions at a pyramidalized double bond occur preferentially trostatic interaction between the methylene group of CH 2 N 2 and C1 of the lactone carbonyl group (Figure 7), from the direction of the pyramidalization of the Catom(s) [28] . This model has been successfully applied to which would be expected to stabilize this transition state.…”

Section: Resultsmentioning

confidence: 99%

Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-1. Retrosynthesis and π-Facial Differentiation in Palladium-Catalyzed and Dipolar [3 + 2]-Cycloaddition Reactions of Bicyclic Alkenes: Evidence for Electrostatic Control of Stereoselectivity

Rosenstock

Gais²,

Herrmann

et al. 1998

Eur. J. Org. Chem.

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A successful new strategy for the asymmetric synthesis of pentalenolactone E (2a) and pentalenolactone F (2b) has been developed. This strategy involves the assembly of ring A of 2a and 2b through a Binger‐type Pd‐catalyzed [3 + 2]‐cycloaddition reaction of diquinene 7 with the diphenyl‐substituted methylenecyclopropane 18. Diquinene 7 is available in an enantiomerically pure state in 8 steps from diester 8 by using a pig liver esterase catalyzed enantioselective hydrolysis as the key step. Unexpected facial selectivities of 1,3‐dipolar and Pd‐catalyzed [3 + 2]‐cycloaddition reactions as well Michael reactions of 7 have been observed. Thus, 7 reacted with CH2N2 with a stereoselectivity of 98% or greater in favour of reaction at the concave side, with formation of the cisoid triquinane 27. A Trost‐type Pd‐catalyzed reaction of 7 with 11 gave the transoid triquinane 6 and the cisoid triquinane 12 in ratios of 1:1.7 to 1:5.3 depending on the polarity of the solvent. Binger‐type Pd‐catalyzed cycloaddition reactions of 7 with methylenecyclopropane (13) in toluene afforded a mixture of 6 and 12 in a ratio of 1:7. In the Pd‐catalyzed reaction of 7 with the phenyl‐substituted methylenecyclopropanes 14a/b the cisoid triquinane 15 was obtained with a selectivity of 6.7:1 or above. Pd‐catalyzed reactions of 7 with the disubstituted methylenecyclopropanes 16 and 18 gave, however, the transoid triquinanes 17 and 19, respectively, with selectivities of 23:1 and 7:1, respectively. Nakamura‐type cycloaddition of 7 to the methylenecyclopropanone ketal 20 led to the quantitative formation of the transoid triquinane 21a and the cisoid triquinane 22a in a ratio of 1:2. The structures of cycloadducts 12, 15, 19 and 27 were determined by X‐ray analyses. The π‐facial differentiation may be ascribed mainly to a stabilization of the concave transition states by an electrostatic interaction between the lactone carbonyl group and the nucleophilic reagents. The stereoselectivity model proposed has been substantiated by a study of the analogous cycloaddition reactions of diquinenes 29a−c, which exhibited only a low π‐facial stereoselectivity, and by an X‐ray structure analysis of 7, which revealed a slight concave pyramidalization of the double bond. X‐ray structure analysis and NMR spectroscopy of diquinane 28a showed the 5E‐conformation, in which the hydroxy group occupies the pseudoaxial position, to be the more stable one. According to force‐field calculations, the 5E‐conformation seems to be stabilized by an intramolecular electrostatic interaction between the hydroxylic oxygen atom and the lactone carbonyl group, corresponding to the initial step of an intermolecular nucleophilic attack at the carbonyl group. The O−C1 distance and the O−C1−O angle found in the crystal structure of 28a support this notion.

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Section: Resultsmentioning

confidence: 99%

Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-1. Retrosynthesis and π-Facial Differentiation in Palladium-Catalyzed and Dipolar [3 + 2]-Cycloaddition Reactions of Bicyclic Alkenes: Evidence for Electrostatic Control of Stereoselectivity

Rosenstock

Gais²,

Herrmann

et al. 1998

Eur. J. Org. Chem.

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“…,Ti [153] Me [153], Bu [153], Ph [153] Me 11531, Bu [153] Me [153] Me [152] Bu [152] Me [179] [258],CH(OH)(C,H,,) [258], CH(Me)Ph [240], CH(Me)CH,NO, 12401, (CH,),Ph [240],CH,CH =CHMe [240]. CH,C(CO,Me)= CH, [240], (CH,),CI [240], (CH,),CI [240] Self-Regeneration of Stereocenters El [82], IPK [82], Bn [82], Et [82].…”

Section: Reviewsmentioning

confidence: 99%

Self‐Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle

Seebàch¹,

Sting²,

Hoffmann³

1996

Angew. Chem. Int. Ed. Engl.

520

299

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In the same manner that the Nasobem, Stiimpke's mythical creature, teaches his child the peculiar way of life of the species Nasobema lyricum, the work of Seebach et al. on the self-regeneration of stereocenters has been governed by a fanciful idea. On the way, many tricks have been learned and much knowledge gained. Finally, they have come back down to earth and find themselves once again in the unimaginative world of enantiomer separation for the synthesis of enantiomerically pure compounds. In order to replace a substituent at a single stereogenic center of a chiral molecule without racemization, a temporary center of chirality is first generated diastereoselectively, the original tetragonal center is then trigonalized by removal of a substituent, a new ligand is introduced, again diastereoselectively, and finally, the temporary center is removed. By means of these four steps (the "Self-Regeneration of Stereocenters", SRS), 2-and 3-amino-, hydroxy-, and sulfanylcarboxylic acids have been successfully alkylated with formation of tertiary carbon centers and without the use of a chiral auxiliary. Use of this methodology has allowed the potential of these inexpensive chiral building blocks to be expanded considerably. This article aims to demonstrate (using, in part, examples from natural product syntheses) that chiral heterocyclic acetals with enamine, enol ether, enolate, dienolate, enoate, radical, and acyliminium functionalities and also those that are potential reactants for Michael additions and pericyclic processes (for example, electron-rich and electronpoor dienophiles and dienes) are now easily accessible, more often than not, in both enantiomeric forms. Stereogenic nitrogen atoms of aziridines, boron atoms of cyclic or linear systems, and stereogenic planes of x-complexes can also be used as the temporary chirality element in other approaches to the realization of the SRS principle. Enantiomerically pure derivatives of, for example, glycine, hydroxy-and sulfanylacetic acid, 3-aminopropanoic acid, and 3-oxocarboxylic acids can be prepared by resolution of racemic mixtures via diastereoisomeric salts or by chromatography on a chiral column. Hence, the extensive reactivity of compounds developed to test the SRS principle and, above all, the outstanding stereoselectivities of the reactions can be put to good use even when no suitable chiral precursor is availabl-ven though this amounts to an abandonment of the principle! The readily available 2-tertbutyl-l,3-imidazolidin-3-one, -0xazolid-in-5-one, -dioxin-3-one, and -hydropyrimidinone (all of which contain a single stereogenic center at the acetal C atom) can thus be used in the preparation of a vast range of 2-amino-and 3-hydroxycarboxylic acids, and no chiral auxiliary has to be removed or regenerated during these procedures. (One example is the synthesis of 4-fluoro-MeBmt, a derivative of the C, amino acid found in cyclosporin.) In the final chapter we will discuss the most useful findings gained from investigations into both the self-regeneration of ste...

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“…Fig. 7); bond lengths in A, angles in degrees [183]. B) Pyramidalization at the trigonal centers of norbornene; comparison of observed parameters (Fig.…”

Section: Experimental Design Experimental Procedures Types Of Reactmentioning

confidence: 99%

“…In a formal sense, the P-hydroxy acids shown at the top constitute aldol adducts of aldehydes or ketones with acetic acid, higher acids, or a-branched acids. Directly below these are the nucleophilic and electrophilic intermediates utilized for CC bond formation [183,294,353,354,371,. It is clearly apparent that substituents can also be introduced at C-3 and C-4 of the hydroxybutyric acid without the occurrence of racemization (principle of self-regeneration of a stereogenic center [353, 477, 4781).…”

Section: The Preparation Of Enantiomerically Pure Compounds (Epc)mentioning

confidence: 99%

Organic Synthesis—Where now?

Seebàch¹

1990

Angew. Chem. Int. Ed. Engl.

566

224

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This review article is an attempt to sketch the important developments in organic synthesis during the past 25 years, and to project them into the future.—The primary motivations that once induced chemists to undertake natural product syntheses no longer exist. Instead of target structures themselves, molecular function and activity now occupy center stage. Thus, inhibitors with an affinity for all the important natural enzymes and receptors have moved to the fore as potential synthetic targets.—New synthetic methods are most likely to be encountered in the fields of biological and organometallic chemistry. Enzymes, whole organisms, and cell cultures for enan‐tioselective synthesis of specific substances have already been incorporated into the synthetic arsenals of both research laboratories and industry. In addition, designing appropriate analogues to transition states and intermediates should soon make it possible, with the aid of the mammalian immune system and gene technology, to prepare catalytically active monoclonal antibodies for almost any reaction; perhaps, more important, such processes will increasingly come to be applied on an industrial scale.‐The discovery of truly new reactions is likely to be limited to the realm of transition‐metal organic chemistry, which will almost certainly provide us with additional “miracle reagents” in the years to come. As regards main group elements (“organoelemental chemistry”), we can surely anticipate further stepwise improvements in experimental procedures and the broader application of special techniques, leading to undreamed of efficiency and selectivity with respect to known procedures. The primary center of attention for all synthetic methods will continue to shift toward catalytic and enantioselective variants; indeed, it will not be long before such modifications will be available with every standard reaction for converting achiral educts into chiral products. Analysis, spectroscopy, structure determination, theory, and electronic data processing have all become indispensable in organic synthesis. Only with the aid of these “tools” will the methods of organic chemistry permit selective syntheses of ever larger and more complex systems on both the molecular and supramolecular levels.—Examples have been introduced throughout this discourse to illustrate its many themes, and a very comprehensive bibliography should help the interested reader become more familiar with important keywords and authors.[ ]—This article will have served its intended purpose if it changes the minds of some of those who claim organic chemistry is a mature science, and if it causes students to discover the vitality and forcefulness with which organic synthesis is meeting new challenges and attempting to fulfill old dreams. Er zeigt uns so in seinem wissenschaftlichen Leben, daß die Chemie nicht von einer Theorie, nicht von einer Methode aus zu erschöpfen ist, und daß Erkenntnis und Nutzen in ihr untrennbar verwoben sind. R. Koch, writing about Louis Pasteur

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Totally stereoselective additions to 2,6-disubstituted 1,3-dioxin-4-ones (chiral acetoacetic acid derivatives). Synthetic and mechanistic aspects of remote stereoselectivity

Cited by 130 publications

References 9 publications

Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-1. Retrosynthesis and π-Facial Differentiation in Palladium-Catalyzed and Dipolar [3 + 2]-Cycloaddition Reactions of Bicyclic Alkenes: Evidence for Electrostatic Control of Stereoselectivity

Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-1. Retrosynthesis and π-Facial Differentiation in Palladium-Catalyzed and Dipolar [3 + 2]-Cycloaddition Reactions of Bicyclic Alkenes: Evidence for Electrostatic Control of Stereoselectivity

Self‐Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle

Organic Synthesis—Where now?

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