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We unfold light as a reaction parameter in a continuous-flow photoreactor using 16 LED arrays with different emission bands (350–700 nm) but identical irradiances. For the perfluoroalkylation of 2-methylindole, three reaction mechanisms are revealed wavelength-selectively and subsequently transferred into independent synthetic routes: i) photoredox catalyzed by eosin Y, ii) via amine-based electron donor–acceptor (EDA) complexes (catalyst-free), and iii) via indole-based EDA complexes (catalyst- and additive-free). The presented methodology enables routine and systematic screening of irradiation wavelengths and intensities in photochemical synthesis.

A key challenge in the synthesis of diterpenoid alkaloids lies in identifying strategies that rapidly construct their multiply bridged polycyclic skeletons. Existing approaches to these structurally intricate secondary metabolites are discussed in the context of a “bond‐network analysis” of molecular frameworks, which was originally devised by Corey some 40 years ago. The retrosynthesis plans that emerge from a topological analysis of the highly bridged frameworks of the diterpenoid alkaloids are discussed in the context of eight recent syntheses of hetidine and hetisine natural products and their derivatives. This Minireview highlights the extent to which network analyses of the type described here sufficed for designing synthesis plans, as well as areas where they had to be amalgamated with functional group oriented synthetic planning considerations., A key challenge in the synthesis of diterpenoid alkaloids lies in identifying efficient strategies to construct their multiply bridged polycyclic skeletons. Approaches from eight recent syntheses are discussed in the context of “bond‐network analyses”, highlighting the efficacy of bond‐network analyses for synthesis planning, as well as where other considerations had to be incorporated.

We note that some features of the NMR spectra deposited for the purported isomeric metacolchicines (Chem. Sci.8, 4961 (2017)) are not compatible with the assignment of those isomers as being atrop-diastereomers. We suggest that there are no such isomeric metacolchicines as reported. The differences in the spectra could rather be a consequence of a (precedented) monomer/dimer equilibrium of metacolchicine in solution.

Two carbenoids combine to generate an olefin by a mechanism involving formation of an ate complex, 1,2-metalate rearrangement, and β-elimination. As each stage of this eliminative coupling is stereospecific, the overall stereochemical outcome can be understood and, in principle fully controlled, providing that the absolute stereochemical configurations of the reacting carbenoid species are defined. In contrast to traditional alkene syntheses, the eliminative cross-coupling of carbenoids offers a connective approach to olefins capable of precisely targeting a given isomer regardless of the nature of the features distinguishing the isomers. The formation of olefins by the eliminative dimerization and eliminative cross-coupling of carbenoids is reviewed with a range of illustrative examples, including the reactions of α-lithiated haloalkanes, epoxides, and carbamates. An emphasis is placed on stereochemical analysis and methods to generate sp3 -hybridized carbenoids in stereodefined form are surveyed.

For almost 200 years, the synthesis of natural products has been practiced. In this time span, not only the target structures have become increasingly more complex, the objectives of natural product synthesis have also changed. Likewise, the standards and criteria for the conduction of natural product synthesis have changed. It is these changes that form the subject of this Essay.

This review covers free radical additions, which are initiated by the formal addition of a hydrogen atom to a CC double bond. These reactions originated in the realms of inorganic chemistry, polymer chemistry, and organic chemistry, whereby barriers between these disciplines impeded the rapid implementation of the findings.

This review covers free radical additions, which are initiated by the formal addition of a hydrogen atom to a C[double bond, length as m-dash]C double bond. These reactions originated in the realms of inorganic chemistry, polymer chemistry, and organic chemistry, whereby barriers between these disciplines impeded the rapid implementation of the findings.

"Economy" is referred to as the thrifty and efficient use of material resources, as the principle of "minimum effort to reach a goal." More illuminating is: "the aim to portion one's forces in order to use as little as possible of them to reach a goal." Such statements certainly apply when the goal is to synthesize a complex target molecule. Redox economy then implies the use of as few redox steps as possible in the synthetic conquest of a target compound. While any sort of economy will help to streamline the effort of total synthesis, redox economy addresses a particularly weak area in present-day total synthesis. It is not enough to point out the present deficiencies, rather the purpose of this Review is to serve as a teaching tool for all practitioners of the field by giving and illustrating guidelines to increase redox economy in multistep organic synthesis.

Anregungen fur die organische Synthese: Stufen- und Atomokonomie haben sich als nutzliche Kriterien erwiesen, an denen sich die Effizienz einer Synthese festmachen lasst. Dieser Aufsatz weist auf eine weitere Form der Okonomie hin, die bei der Planung und Bewertung einer mehrstufigen Synthese berucksichtigt werden sollte: die Redoxokonomie. Etliche Beispiele und Leitfaden werden vorgestellt, die das Konzept illustrieren und Anregungen fur die Syntheseplanung geben. “Okonomie” bezeichnet den sparsamen und effizienten Umgang mit materiellen Ressourcen, das Prinzip, sein Ziel mit einem minimalen Aufwand zu erreichen. Vielleicht noch treffender: “Seine Krafte so einzuteilen, um moglichst wenig davon zur Erreichung eines Ziels zu verbrauchen”. Diese Aussagen treffen sicher auch zu, wenn es darum geht, ein komplexes Zielmolekul zu synthetisieren. Redoxokonomie bedeutet dann, so wenig wie moglich Redoxschritte in der Synthese eines Zielmolekuls einzusetzen. Wahrend jede Art von Okonomie hilft, den Aufwand einer Totalsynthese in Grenzen zu halten, betrifft Redoxokonomie einen besonderen Schwachpunkt heutiger Totalsynthesen. Es genugt nicht, auf dieses Defizit zu verweisen, vielmehr soll dieser Aufsatz allen mit Totalsynthese Befassten einen Leitfaden geben und Hinweise beisteuern, wie sich die Redoxokonomie in mehrstufigen Synthesefolgen der organischen Chemie verbessern lasst.

trans- and cis-3-Vinyltetrahydropyran-4-ol (11) and (12) as well as derivatives of trans- and cis-3-vinyl-4-piperidinol (25) and (33) were synthesized by essentially stereospecific intramolecular allylboration reactions: The (Z)-allylboronates 15 and 32 were converted into the cis-disubstituted heterocycles the (E)-allylboronates 9 and 23 into the trans-disubstituted heterocycles.

In einer idealen Synthesesequenz sind CC-Verknupfungen, Aufbau der Chiralitatszentren und Schaffung der endgultigen Funktionalitat in jeweils einem Schritt vereint. Um statt einem Paar diastereomerer Verbindungen gezielt nur das eine oder nur das andere Diastereomer zu erzeugen, braucht man stereoselektive CC-Verknupfungsreaktionen. Diese Selektivitat wird bei der Addition von Crotyl-Bor-, -Aluminium-, -Zinn-, -Titan- und -Chrom-Verbindungen an Aldehyde haufig erreicht. Abhangig davon, ob man von der E- oder Z-Crotyl-Verbindung ausgeht, bildet sich bevorzugt eines der diastereomeren Addukte. Diese Addukte enthalten an der CC-Verknupfungsstelle eine Methyl-Verzweigung. Syntheseziele sind haufig aber auch Verbindungen, die an der Verknupfungsstelle Sauerstoff-Funktionen aufweisen. Zu derartigen Strukturen gelangt man durch Addition von heterosubstituierten Allylboronsaureestern oder analogen Reagentien an Aldehyde.

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.

The carbenoid homologation reaction of α-haloalkyl Grignard reagents 3 with isopropylmagnesium chloride gives rise not only to the expected secondary Grignard reagents 5 but also to substantial amounts of the tertiary Grignard reagent 7. The latter is postulated to arise by a carbenoid C−H insertion reaction within the mixed halide-bridged aggregate 14.

Two constitutionally identical but topologically different groups in a chiral molecule are diastereotopic. Selective modification of one of these groups creates one or several new stereogenic centres. This method of stereoselective synthesis that has been used on several occasions is reviewed here. The intention is to focus on an area of stereoselective synthesis that is still underdeveloped.

On reaction of the 1,1-diiodoalkane 1 with isopropyl Grignard reagents at −78 °C a long-lived intermediate is generated, which was characterized by its UV−vis spectrum, 1H and 13C NMR data, and the...

On reaction of 1,1-diiodoalkanes with Grignard reagents at −78 °C, long-lived α-iodoalkyl iodine ate complexes were generated as observable intermediates. Their lifetime depends on the nature of the Grignard reagent and the nature of the 1,1-diiodoalkane. An α-bromoalkyl iodine ate complex was observable only when generated from a 1-bromo-1-iodoalkane with allyl−MgX. The energetic situations and factors that affect the lifetime of such ate complexes are discussed.

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 uberraschend, 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, fur dessen Losung die heutigen Methoden nur bedingt hilfreich sind. In diesem Aufsatz werden die Strategien vorgestellt, die sich fur 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 berucksichtigt. Die Kriterien zur Bewertung der verschiedenen Strategien und deren Kombinationen in der Synthese werden herausgestellt.

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.

An uncharged host 6 for selective binding of chloride is described. This host features a triazine–trione platform, three short side-arms which are conformationally preorganised relative to the platform, and p-nitrophenylsulfonamide groups for hydrogen-bonding to anions. Host 6 binds chloride with K ≈ 150 000 M−1 in CHCl3 and shows a chloride/nitrate selectivity of 102.

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.

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 3JH,H coupling constants, which reflect distinct conformer populations. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

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)

A new long-lived intermediate has been identified in the reaction of iodoform (1) with isopropylmagnesium chloride at −78 °C. The structure of the symmetrical iodine ate complex 7, I2CH−I−CHI2-MgCl+, has been assigned to the deep red intermediate by NMR spectroscopic techniques, supported by calculations of 1JC-H, 2JC-C, and 3JC-H coupling constants.

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.

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).

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.

Alkoxyalkynes 9 may be hydroborated with pinacol borane, preferentially under Cp2ZrHCl catalysis, to give the vinylboronates 10. The latter, when subjected to the Matteson–Brown homologation with LiCH2Cl, give rise to the (E)-γ-alkoxyallylboronates 3 in good yield. This reaction sequence has been used to generate the (E)-γ-alkoxyallylboronates 14, 21, 26 and 31, which were the starting point for intramolecular allylboration reactions leading to the trans-disubstituted tetrahydropyrans 8 and 22, as well as hydrooxepans 27 and 32.

N-Allyl-(E)-γ-aminoallyl boronates 8 and 18, when subjected to hydroformylation conditions, enter into a domino hydroformylation-allylboration-hydroformylation reaction cascade to generate the bicyclic N,O-heterocycles 12 and 20. On reaction of the methallyl compound 8b a stereogenic center is generated in the initial hydroformylation, which controls the relative configuration of the two new stereogenic centers resulting from the allylboration reaction.

The intramolecular carbomagnesiation of a vinylsilane at 25 °C in THF has been found to proceed in a stereospecific (>95%) syn-addition of carbon and magnesium to the double bond. The resulting α-silylalkylmagnesium compounds are not configurationally stable under the reaction conditions. They epimerize with a half-life of 2.7 d at room temperature.

alpha-Chloro- and alpha-bromoalkyl Grignard reagents 11 and 30 with > 97% ee (enantiomeric excess) were generated by a sulfoxide/magnesium exchange reaction from the enantiomerically and diastereomerically pure sulfoxides 25 and 27. The resulting alpha-haloalkyl Grignard reagents are configurationally stable at -78 degrees C. Racemization sets in at or above -60 degrees C, especially when the solution contains bromide ions. In the absence of halide ions, the configurational stability extends up to -20 degrees C, when chemical decomposition commences.

Am Ubergang zum 21. Jahrhundert befasst sich die Chemie zunehmend mit der Funktion, die Molekulen als Wirkstoffen, Rezeptoren oder – im Molekulverband – als Materialien zukommt. Die Tauglichkeit einer Verbindung fur eine molekulare Funktion konnen wir mit den Begriffen der Konstitution und Konfiguration allein nicht ausreichend beschreiben. Eine entscheidende Bedeutung kommt hier zusatzlich der Konformation der Einzelmolekule als Mittler zwischen molekularer Konstitution und molekularer Funktion zu. Formulierungen wie „Aktivkonformation” oder „kompetente Konformation” lassen dies anklingen. Der Chemiker muss ein Verstandnis dafur entwickeln, wie ein flexibles Molekul die fur die jeweilige Funktion optimale Konformation (raumliche Gestalt) einnimmt und wie man dies beeinflussen kann. Am Anfang derartiger Uberlegungen zu einem Konformationsdesign steht die Frage, wie es denn die Natur im Zuge der Evolution ihrer Funktionsmolekule erreicht hat, dass flexible Verbindungen die fur die jeweilige Funktion optimale Konformation einnehmen. Wir berichten in diesem Aufsatz, wie wir zu einem ansatzweisen Verstandnis des „Konformationsdesigns” der Natur im Bereich der Polyketid-Naturstoffe gelangt sind, wie wir diese Erkenntnisse zu einem Konformationsdesign offenkettiger Molekule weiterentwickelt haben und welche Anwendungsmoglichkeiten fur diese Erkenntnisse sich jetzt schon abzeichnen.