ANÁLISIS E INTERPRETACIÓN DE RESULTADOS DE LA ENCUESTA REALIZADA A LOS ESTUDIANTES DE LA UNACH.

This work dealt with both the investigation and applications of the distinct stereochemical behaviours of carbon-metal bonds. Therefore, a novel practical access to stereodefined C-Li bonds was established via a stereoretentive I-Li exchange on cyclohexyl iodides which allowed a thorough examination of their configurational stabilities and the stereochemistry of their quenching with various electrophiles. Mechanistic studies on the configurational stability of the C-Zn bond in substituted cyclohexylzinc reagents showed that distinct stereochemical pathways are responsible for the observed stereoconvergence in the diastereoselective Pd- catalyzed cross-couplings. Thereby, the equatorial C-Zn bond reacts with retention and the axial C-Zn bond with inversion of its stereoconfiguration under suitable reaction conditions. The highly diastereoselective Pd-catalyzed cross-coupling methodology was extended to functionalized cyclohexyl derivatives and an enantio- and diastereoselective method for the preparation of chiral arylated functionalized cyclohexanes was developed. Highly diastereoselective cross-coupling was also established for piperidinylzinc derivatives. Selective access to both the cis- and trans-2,4-disubstituted piperidine derivatives was enabled.

5.1.

Stereoselective Preparation, Configurational Stability and Reactivity of

Substituted Cyclohexyllithium Derivatives

Although the stereoselective generation and stereochemistry of α-heteroatom-substituted alkyl-, benzylic and allylic organolithium reagents are well studied, the stereoselective preparation of non-stabilized secondary alkyllithiums has remained a major synthetic challenge. A practical stereoretentive synthesis to unstabilized stereodefined cyclohexyllithium reagents from the readily available organic iodides via I-Li exchange has been presented in this work. Using this approach a detailed study on the configurational stabilities, stereochemical behaviour and reactivities of various axially and equatorially substituted cyclohexyllithium reagents was performed. Thus, the stereochemical paths (SE2

vs. Si2) of the quenching reactions were shown to depend on the respective cyclohexyllithium

diastereomer and the electrophile. In all cases, the axial cyclohexyllithium was found to almost completely equilibrate into the configurationally stable, equatorial diastereomer. This inversion process was followed for differently substituted cyclohexyllithiums over time

B. Results and Discussion 70 showing distinct behaviour. DFT-calculations demonstrated that the formation of oligomeric cyclohexyllithium structures is the key determinant for the observed stereochemical preference. 0 3 6 0 30 60 90 a x ia l L i (% ) time (h) cis-trans equilibration

Scheme 46: A new practical stereoretentive I-Li exchange reaction for the stereoselective preparation of cyclohexyllithiums. The behaviours of the resulting diastereomeric substituted cyclohexyllithium reagents were studied.

5.2.

Novel Insights into the Stereochemical Behaviour of Diastereomeric

Cyclohexylzinc

Reagents

–

Stereoconvergence

through

Distinct

Stereochemical Pathways

A novel revised mechanistic view of the stereoconvergent Negishi-cross-coupling of substituted cyclohexylzinc reagents has been established through our investigations. The observed high configurational stability of the C-Zn bond excludes a mechanism based on a dynamic kinetic resolution process, since flipping of the C-Zn bond takes place too slowly. Via deuterolysis and protolysis experiments, we were able to show that high stereoselectivities can be achieved in quenching diastereomeric cyclohexylzinc reagents with preference of the all equatorially substituted products, excluding an equilibration on the stage of the cyclohexyl-palladium intermediates as key factor for the stereoconvergence. Moreover, both diastereomers were observed to react with the same observable rate at the NMR time scale in slow addition/protolysis. In combination, these crucial results along with the fact that only one Pd-intermediate could be observed in the cross-coupling68 show that the equatorial C-Zn bond must react with retention and the axial C-Zn bond with inversion of the stereoconfiguration in the transmetalation step to ArPdLnX thus leading to stereoconvergence

B. Results and Discussion 71 ∆∆∆∆Gǂ inv ∆∆∆∆Gǂ SE2retdia1 ∆∆∆∆G_0/products ∆∆ ∆∆ ∆∆ ∆∆Gǂ SE2dia1ret-inv ∆∆∆∆Gǂ SE2invdia1 ∆∆ ∆∆∆∆ ∆∆Gǂ SE2dia1inv-ret ∆∆∆∆Gǂ SE2retdia2 ∆∆∆∆Gǂ SE2invdia2 R ZnX ZnX R ax-1 (cis) eq-1 (tr ans) PdL2Ar R eq-2 (trans) Ar R r eductive elimination eq-3 (tr ans) r etention inversion Zn-complexes

conf igur ationally stable New proposal: Ar Pd L X L

Scheme 47: Substituted diastereomeric cyclohexylzinc complexes eq-103 and ax-103 which differ in the configuration of their C-Zn bond undergo distinct stereochemical pathways in the transmetallation to ArPdLnX

thus leading to overall stereoconvergence in the cross-coupling reaction. The energy diagram sums up the experimental observations. The high energetic barrier between the diastereomeric zinc reagents prevents their equilibration. The fact that reaction pathways for diastereomers do not need to be isoenergetic, as is the case for enantiomers, allows distinct stereochemical reactivities. Thus, the axially configured cyclohexylzinc diastereomer reacts with inversion and the equatorially substituted one with retention of the stereoconfiguration resulting in overall stereoconvergence of the reaction.

To the best of our knowledge, this work represents the first experimental proof that diastereomeric organometallics can undergo distinct stereochemical pathways which result in the stereoselective formation of one diastereomerically defined product. We anticipate that in addition to the dynamic resolution processes which have been well established for configurationally unstable organolithiums, these observations will lead to the further understanding and development of stereoconvergent reactions for configurationally stable alkyl organometallics.

5.3.

Diastereo- and Enantioselective Cross-Coupling with Functionalized

Cyclohexylzinc Reagents

Cross-couplings of functionalized cyclohexylzinc reagents such as [2-(1,3-dioxolan-2- yl)cyclohexyl]- and [2-(5,5-dimethyl-1,3-dioxan-2-yl)cyclohexyl]zinc reagents (142, 143 und 140, 141) lead to high diastereoselectivities. β-Hydride eliminations which were observed in cross-coupling reactions of the organizinc iodides 142 and 143 could be avoided by decreasing the temperature to -25 °C. Moreover, it was illustrated that cross-coupling of diorganozinc complexes 140 and 141 can be successfully performed even at higher

B. Results and Discussion 72 temperatures up to 25 °C without loss in diastereoselectivity. Hereby, β-hydride elimination processes did not occur which can be probably explained by the stereochemically pure nature featuring only an equatorial C-Zn bond. Cross-coupling of the chiral organozinc reagents 159 and 160 synthesized via enantioselective hydroboration, proceeded diastereoselectively and furnished the respective arylated 1,2-disubstituted cyclohexanes in moderate enantiomeric excess. Cross-coupling of [8-(ethoxymethoxy)decahydronaphthalen-1-yl](ethyl)zinc (170) was performed with moderate diastereoselectivity. Since the arylation of 170 proceeds with high stereoselectivity, β-hydride elimination processes on the step of the palladium intermediate can be responsible for the observed low diastereoselectivity.

Scheme 48: Enantio- and diastereoselective arylation via a hydroboration/B-Zn-exchange/cross-coupling sequence.

5.4.

Highly Diastereoselective Arylations of Substituted Piperidines

A highly diastereoselective methodology for the preparation of various substituted piperidines via Negishi cross-couplings with (hetero)aryl iodides was developed. Depending on the position of the C-Zn bond relative to the nitrogen (position 2 vs. position 4), the stereoselectivity of the coupling can be directed either towards the trans- or the cis-2,4- disubstituted products. DFT-calculations on the relative stabilities of the Zn- and Pd- intermediates were performed to explain the high diastereoselectivities obtained. A novel Pd- 1,2-migration further expands this method to the stereoselective preparation of 5-arylated 2,5- disubstituted piperidines.

B. Results and Discussion 73

Scheme 49: Switchable stereoselectivity in the cross-couplings of piperidinylzinc reagents and a novel diastereoselective Pd-1,2-migration.