BEt₃-initiated thiol–ene click reactions are an interesting alternative to the generally used thermal or photochemical thiol additions. The reactions proceed under very mild conditions, and require only 10 mol-% of BEt₃, and an almost stoichiometric amount of thiol. In this regard, this method is an attractive alternative to the other protocols, which often use the thiol component in a large excess.

Straightforward synthetic protocols for the synthesis of new ethyl-substituted dichlorinated chondramides with different methyl-substitution patterns in the polyketide fragment have been developed. The methyl groups at the ϵ-position can be removed completely without a significant influence on the biological activity. In contrast, after removal of the α-methyl group, a significant drop in activity is observed. This is also observed if the configuration of the α-methyl group is inverted.

Removing the methyl groups and the stereogenic centers from the ω-hydroxy acid of the chondramides results in a significant drop in the cytotoxicity of these interesting depsipeptides. This effect can be almost compensated for by introduction of a second chlorine atom on the β-tyrosine moiety of the natural products. These simplified chondramides are much easier accessible than natural chondramides.

Deprotonated tert-butyl glycolates were found to be suitable nucleophiles for Pd-catalyzed allylic alkylation reactions to generate γ,δ-unsaturated α-hydroxy acid derivatives. This protocol is suitable for the introduction of different side chains and includes stannylated ones. These can be subjected to further cross-coupling reactions, which gives access to a wide range of structural motifs.

The miuraenamides, relatively simple representatives of a class of cyclodepsipeptides with high antitumor activity, can be easily and flexibly obtained by the concept of peptide modification. A reaction sequence consisting of an aldol reaction, oxidation, and methylation of the glycine subunit of the cyclodepsipeptides allows the incorporation of the unusual α,β-unsaturated dehydroamino acid in one of the last steps of the synthesis.

Chiral α-amino ketones are excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.

Chirale α-Aminoketone sind hervorragende Nukleophile für hoch stereoselektive Palladium-katalysierte allylische Alkylierungen, sowohl mit chiralen als auch achiralen Allylsubstraten, wobei die Steuerung über das chirale Ketonenolat überwiegt. Die erhaltenen substituierten Aminoketone lassen sich anschließend stereoselektiv reduzieren, wobei bis zu fünf benachbarte Stereozentren erhalten werden können. Dies ermöglicht auch den Aufbau eines hoch substituierten Piperidinderivates.

Miuraenamide, vergleichsweise einfache Vertreter einer Klasse von Cyclodepsipeptiden mit hoher Antitumor-Aktivität, lassen sich nach dem Konzept der Peptidmodifizierung schnell und flexibel aufbauen. Die Einführung der ungewöhnlichen α,β-Dehydroaminosäure gelingt durch Aldolreaktion/Oxidation an einem Glycin-haltigen Cyclodepsipeptid in einer der letzten Stufen der Synthese.

N-Protected amino acid allyl amides with an allylic leaving group can be used as substrates in palladium-catalyzed allylic alkylation. Whereas intermolecular allylations proceed with excellent yields under standard conditions for enolate reactions, the intramolecular version is not a trivial issue. N-Protected glycine amides preferentially form piperidinones through N-allylation, but the corresponding sarcosine derivatives provide γ-lactams in acceptable to good yields in dichloromethane, especially when the corresponding titanium enolates are formed.

Lithiated allylamines are easily available by tin–lithium exchange from stannylated allylamines and are suitable nucleophiles for a wide range of conversions. With aldehydes and ketones, aminomethylated allyl alcohols are formed, whereas the reaction with α-brominated ketones gives rise to vinyl epoxides or aldehydes, depending on the reaction and workup conditions used.

Die Entwicklung einer neuen photolabilen Schutzgruppe mit integrierter Allyleinheit ermöglicht die Synthese cyclischer photoaktivierbarer Naturstoffderivate. Die Cyclisierung erfolgt dabei über die Allyleinheit der Schutzgruppe und eine zweite Doppelbindung durch Ringschlussmetathese. Die so induzierte Konformationsänderung soll zum einen die biologische Aktivität des Naturstoffs verringern, und durch die Cyclisierung soll gleichzeitig seine metabolische Stabilität erhöht werden. Photochemische Ringöffnung bewirkt schließlich eine Aktivierung des Wirkstoffs. Am Beispiel von Tubulysin-Derivaten wird gezeigt, wie in nur zwei Stufen ausgehend von einfachen Bausteinen durch Ugi-Reaktion und Ringschlussmetathese cyclische photoaktivierbare Wirkstoffe hergestellt werden können. Die photolabile Schutzgruppe wird dabei über die Isocyanid-Komponente während der Ugi-Reaktion eingeführt.

The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring-closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring-closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction.

Chelated amino acid ester enolates are excellent nucleophiles for ruthenium-catalyzed allylic alkylations. Although [Cp*Ru(MeCN)₃]PF₆ was found to be the most reactive catalyst investigated, with the resulting allyl complexes reacting at temperatures as low as −78 °C, unfortunately the process took place with only moderate regio- and diastereoselectivity. In contrast, [(p-cymene)RuCl₂]₂ allowed allylations to be performed with a high degree of regioretention. Secondary allyl carboxylates with a terminal double bond were found to be the most reactive substrates, giving rise to the branched amino acids with perfect regioretention and chirality transfer. In this case, no isomerization of the Ru–allyl complex formed in situ was observed, in contrast to the analogues palladium complexes. This isomerization-free protocol can also be used for the synthesis of (Z)-configured γ,δ-unsaturated amino acid derivatives, starting from (Z)-allylic substrates. Here, the more reactive phosphates were found to be superior to the carboxylates, providing the required amino acids in almost quantitative yield with perfect regio- and stereoretention. Therefore, the Ru-catalyzed allylation reactions are well positioned to overcome the drawbacks of Pd-catalyzed processes.

Ferrocenylallyl carbonates have been found to be suitable substrates for palladium-catalyzed allylic alkylation reactions. Amino acid ester and peptide enolates were employed as nucleophiles for the regio- and stereoselective introduction of the redox-active ferrocenyl unit into peptide chains.

Terminal γ,δ-unsaturated amino acids, easily available by Claisen rearrangement or palladium-catalysed allylic alkylation, are excellent substrates for radical thiol additions. These click reactions allow the introduction of highly functionalized side-chains into a given amino acid or peptide. This protocol is suitable for the modification of all kinds of terminal alkenes, such as allyl protecting groups.

A wide range of functionalized compounds can easily be obtained by a Pd-catalyzed one-pot hydrostannylation/elimination/distannylation/radical allylation sequence. The Pd catalyst used can be involved in up to five different reaction steps.

The chelate Claisen rearrangement is a versatile tool for the stereoselective synthesis of β-substituted γ,δ-unsaturated amino acids, which can be converted into β-substitutedaspartates by oxidative cleavage. These are ideal precursors for the synthesis of hydroxamate-type MMP inhibitors.

The syntheses of new tubulysin analogues are described, in which the central amino acid, tubuvaline, is replaced by the rather simple building blocks phenyltubuvaline and phenoxytubuvaline. These analogues can be obtained in only two to three steps from easily accessible starting materials. Although the new derivatives are less active than the tubulysins, their activities towards U-2 OS tumor cells are still in the nanomolar range.

Wilkinson's catalyst, RhCl(PPh₃)₃, was found to be an excellent catalyst not only for highly regio- but also chemoselective allylic alkylations of chelated enolates. In contrast to Pd-catalyzed reactions, the Rh-catalyzed version shows also a high degree of regioretention and proceeds without isomerization. Allylic substrates with competitive allylic subunits react selectively at the sterically least hindered allylic position, in comparison to Ru-catalyzed processes.

Stannylated allylic substrates are versatile building blocks for organic synthesis. Pd⁰-catalysed coupling reactions of 2-stannylated allylic carbonates, acetates and phenoxides with amines, malonates, phenoxides, imides and distannanes provide the corresponding substituted allylic compounds, which are suitable for subsequent modifications including Stille coupling reactions. The reaction mechanisms are dependent on the temperature and the nucleophiles used. Tsuji–Trost allylic substitution takes place with organic nucleophiles at low temperature. When distannane is employed at higher temperature, on the other hand, Pd⁰-catalysed bismetallation of allenes formed in situ by elimination of tributyltin methoxide predominates.

The syntheses of new heterocyclic isoxazoline amino acids are described based on a domino Michael addition/nitrile oxide formation/[3+2] cycloaddition approach. Chelated amino acid ester enolates can be added to nitroalkenes, and the generated nitronates are directly converted into nitrile oxides. These can be trapped intramolecularly by an alkene as a dipolarophile. The alkene can be introduced either via the nitroalkene or via the chelated enolate. Therefore, different types of heterocyclic amino acids can be obtained in a simple one-pot protocol.

In contrast to Brønsted and other Lewis acids ClTi(OiPr)₃ is especially suited to catalyze the formation of amino-substituted coumarins from aminophenols and functionalized β-oxo esters in a Pechmann condensation. This straightforward protocol allows the synthesis of fluorescence labels and false fluorescent neurotransmitters.

Chelate-Claisen rearrangement of a chiral allylic ester allows the synthesis of the unusual epoxyketo amino acid Aoe found in chlamydocin, one representative of a group of peptide-based HDAc inhibitors. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Various types of hydroxy isocyanides have been prepared from the corresponding amino alcohols. These hydroxy isocyanides are interesting building blocks for multicomponent reactions and the synthesis of (hydroxyalkyl)oxazoline ligands. The isocyanides are susceptible to cyclization, giving rise to oxazolines. Therefore, they should be prepared freshly before use or be stored below –30 °C.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Pretubulysin, a biosynthetic precursor of the tubulysins, shows potent biological activity in the subnanomolar range towards various tumor cell lines. Its activity is only slightly less than those of the structurally more complex tubulysins. With a straightforward synthesis to hand, pretubulysin is an ideal lead structure for the development of tubulysin-based anticancer drugs(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The Mo-catalyzed hydrostannation of propargylic amines and amides gave rise to functionalized vinylstannanes in good yield. The α-stannylated products were formed preferentially, which are interesting synthetic building blocks. If halogenated aromatic amines were subjected to this protocol, the products obtained could be converted into indole and isoquinoline derivatives through intramolecular Stille couplings. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Zn-chelated glycine ester enolates are highly efficient nucleophiles for the synthesis of conformationally constrained glutamates via domino sequences of Michael additions and subsequent ring closures (MIRC). This protocol allows the generation of 3–6-membered ring systems in high yields and excellent diastereoselectivities. Depending on the reaction conditions either carbocyclic or heterocyclic ring systems are obtained. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Syntheses of stannylated allyl and vinylphosphonates by molybdenum-catalyzed hydrostannation of the corresponding propargyl- and alkynylphosphonate derivatives proceed with high regioselectivities. The stannylated phosphonates obtained are versatile building blocks for further modifications, such as iodinations or cross coupling reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Isomerization-free reactions of dienyl carbonates with chelated amino acid ester enolates at –78 °C provide important information concerning the mechanism of these dienylations. The formation of regioisomeric products can be explained by competing S_N2/S_N2′ reactions, and the product distribution can be influenced by the proper choice of the reaction conditions. Chiral allylic substrates show a significant transfer of chirality. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Chelated amino acid ester enolates are excellent nucleophiles for palladium-catalyzed allylic alkylations. These enolates react rapidly at −78 °C and in general without isomerization of π-allyl palladium complexes. Therefore, they are good candidates for mechanistic studies and regioselective reactions. Terminal π-allyl palladium complexes are preferentially attacked at the least hindered position giving rise to linear products, as illustrated with several (E)-configured allylic substrates. Under isomerization free conditions the branched products are formed preferentially from the corresponding (Z)-allyl substrates. An interesting behavior is observed in the reaction of secondary allylic substrates. Aryl-substituted substrates show a significant memory effect which can be explained by an asymmetric π-allyl complex. For alkyl-substituted substrates a strong dependence of the regioselectivity on the leaving group is observed, which can be explained by different conformations in the ionization step. Under isomerization free conditions the product ratio gives important information about this step.