Eine Frage des Potentials: In Gegenwart von Redox-Katalysatoren geeigneten Oxidationspotentials werden organische Verbindungen durch unedle Metalle sauber reduziert. Zu den aromatischen Kohlenwasserstoffen, die üblicherweise als Redox-Katalysatoren eingesetzt werden, haben sich vor kurzem Me₃Fe^IILi und verwandte at-Komplexe gesellt. Das Schema zeigt als Beispiel den Katalysezyklus für die reduktive Spaltung von Phenylsulfonamiden mit Magnesium.

In contrast to the simple 4,4′-bi-1,3-dioxanyl derivative 6, which has no conformational preference at the inter-ring bond, the derivatives 9 and 10, which have two strategically placed axial methyl groups, show conformational preferences exceeding 95 %. This is related to the conformational preference found in one of the substructures of the natural product prymnesin. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

{[2-(Trimethylsilyl)ethoxy]methyl} (SEM)-protected pederic acid 16 was prepared by deriving the stereogenic center at C(7) from mannitol and those at C(2) and C(3) (mycalamide numbering) from trans-2,3-dimethyloxirane. Routes to pederamides involving a late oxygenation at C(7) were explored.

Bicyclic acetal derivatives of the type 3 were prepared based either on a dihydroxyaldehyde 5 or an oxiranebutanal 6 (cf. Scheme 2). Lewis acid catalyzed reaction of the bicyclic acetal with allyltrimethylsilane introduces the side chain (as yet unfunctionalized) and sets the stereogenic centers at the tetrahydro-2H-pyran ring of the pederin moiety.

A small number of macrocyclic dilactones of type 3, i.e., 9, 10, 11, and epi-11, comprising a 3,4-dihydroxypentanoic acid unit, the pharmacophore of aplysiatoxin, and a conformationally preorganized ω-hydroxynonanoic acid unit were synthesized. Conformational analysis – based on ²J and ³J NMR coupling constants – of the dihydroxypentanoyl part of these macro-dilactones indicates the extent to which a conformation induction across the macro-dilactone ring occurs from the stereogenic centres implemented in the ω-hydroxynonanoic acid part.

Das Methoden-Arsenal der stereoselektiven Synthese scheint nach mehr als einem Vierteljahrhundert intensiver Entwicklung voll ausgereift zu sein. Im Einklang damit wird auch das Potenzial, das meso-Verbindungen in der stereoselektiven Synthese zukommt, klar erkannt. Es ist deswegen überraschend, dass die Anwendung von meso-Verbindungen in der stereoselektiven Synthese in keiner Weise diesem Potenzial entspricht, denn ironischerweise ist die Synthese von meso-Verbindungen selbst ein Problem der stereoselektiven Synthese – ein Problem, für dessen Lösung die heutigen Methoden nur bedingt hilfreich sind. In diesem Aufsatz werden die Strategien vorgestellt, die sich für die Synthese komplizierterer meso-Verbindungen eignen, deren stereogene Zentren einen Abstand >1,4 haben. Hierbei werden auch meso-Verbindungen mit mehr als vier stereogenen Zentren berücksichtigt. Die Kriterien zur Bewertung der verschiedenen Strategien und deren Kombinationen in der Synthese werden herausgestellt.

After more than a quarter of a century of development, the methodology of stereoselective synthesis appears to be fully matured. In line with this, the potential that meso compounds offer in stereoselective synthesis is clearly recognized. The use of meso compounds in synthesis is, however, in no way commensurate with this potential, because, ironically, the synthesis of meso compounds in the first place is a problem of stereoselective synthesis. Present-day methodology does not provide many useful solutions to this problem. This Review therefore addresses the strategies available for the synthesis of more elaborate meso compounds whose stereogenic centers have a distance >1,4 between them. meso Compounds with more than four stereogenic centers are also considered. The criteria used in choosing from several strategies in the synthesis of such compounds are discussed.

Stereoselective synthesis of a series of 1,3-dioxan-4-ylmethanes 1−9 has been achieved by use of solely substrate-based asymmetric induction. The simple C₂-symmetric bis(dioxanyl)methane 1 has a greater than 99% conformational preference at the two inter-ring bonds for the conformation 1a. The homologous structures 3−9 contain up to five dioxanylmethane units, maintaining a high conformational preference in each of the bis(dioxanyl)methane units. Thus, these flexible compounds reach a conformational preference in excess of 90% over up to eight rotatable inter-ring bonds. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Bis(1,3-dioxan-5-yl)ethanes 4, 30, 32, and 33 were synthesized in order to verify the high conformational preferences of their flexible backbones predicted by force-field calculations. Conformational analysis based on ³J_H,H coupling constants gave results different from expectations based on the force-field calculations. The MM3* force-field of MACROMODEL was apparently not parametrized suitably to deal with the double-gauche interactions occurring along the backbones of compounds 30, 32, and 33. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Whereas simple 4,4′-bi(1,3-dioxanyl)s 16 and 19 displayed little conformational preference at the inter-ring bond, their derivatives 4 and 13, with equatorial methyl groups in the 5- and 5′-positions, each showed a strong conformational preference to populate a conformation with a gauche arrangement of the oxygen atoms. These results form the basis of a modular approach to oligo-1,3-dioxanyls 5, 6, and 29, in each of which a strong conformational preference prevails at all of the inter-ring bonds. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A convergent synthesis of the meso-ter(1,3-dioxanyls) 8−11 has been achieved, starting from two enantiomeric building blocks in each case. The stereogenic centres in the central linkage region were set up by stereocontrolled aldol additions. Structure assignment of the final products was based on comparisons between experimental and calculated ³J_H,H coupling constants, which reflect distinct conformer populations. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Rational conformation design led us to a synthesis of the ω-amido-undecenamide 4, which was shown by theoretical means (simulated annealing techniques) and by NMR and IR spectroscopy to have a high tendency to populate a conformation corresponding to a natural β-II′-type hairpin, despite possessing a conformationally fully flexible open-chain backbone.

A set of three-armed urea-containing anion receptors was prepared. The receptors all have the same binding topology but differ in the level of conformational preorganisation with respect to the arrangement of the side-arms relative to the platform and within the side arms themselves. This is mirrored in a specific increase (×2.5) in the binding constant for chloride and in a 12-fold increase in the chloride/nitrate-selectivity.

Efforts are described to design simple, fully flexible but conformationally preorganised ω-hydroxy-nonanoic acids that could serve as the conformation controlling unit in analogues of the potent protein-kinase C activator aplysiatoxin. Such analogues are macrodilactones incorporating the designed ω-hydroxy-nonanoic acid and 3,4-dihydroxy-pentanoic acid, which contains the pharmacophoric groups. The design process (replacement of CH₂ groups by an oxygen atom, annelation of a six-membered ring and placement of alkyl substituents) of the ω-hydroxy-nonanoic acids was monitored by force-field calculations. In the end of this process simple analogues of aplysiatoxin are proposed in which the proper disposition of the pharmacophoric groups is secured by a conformationally flexible but preorganised template structure as part of the macrodilactone ring. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 405–418, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10038

An isobutyl group placed equatorially in the 2-position of a 1-equatorially substituted cyclohexane adopts a preferred conformation (cf. 5). This also holds when it is placed in the 2-position on a 3-equatorially substituted tetrahydropyran (cf. 6). The same conformational preference is found for 2-methoxypropyl residues in the 2-position of 3-substituted tetrahydropyrans (cf. 8 and 10). The latter compounds chelate lithium cations as analogues of 1,2-dimethoxyethane. Through this complexation, it is possible to effect a change in the side chain conformation.

A 2,4-dimethylpentane unit can be rendered monoconformational by the presence of a conformation-inducing group (an inductor group) at C-1 (cf. 6). The resulting entity may serve as an inductor group to control in turn the conformation of a neighboring dimethylpentane segment (cf. 7). This holds if the inducing dimethylpentane segment is isotactic (cf. 15, 25), but not when it is syndiotactic (cf. 28).

Compounds 12−15, meso-type 2,3,4,5,6,7-hexasubstituted octane derivatives, have been synthesized using solely substrate-based asymmetric induction. Thanks to the specific relative configurations at the six stereogenic centres, these compounds have a high tendency to populate the conformation with a fully extended zig-zag backbone chain.