Martin Hiersemann

Catalysis of the Claisen Rearrangement of Aliphatic Allyl Vinyl Ethers

The thermal Claisen rearrangement of allyl vinyl ethers is generally regarded as high-performance method for diastereoselective C−C bond formation. Substrate-induced diastereoselectivity and reagent-induced enantioselectivity with stoichiometric amounts of external chiral auxiliaries have frequently been exploited to control the stereochemical course of the Claisen rearrangement. This review summarizes the attempts to catalyze the Claisen rearrangement of acyclic aliphatic allyl vinyl ethers with chiral and achiral catalysts. The best suited catalysts for the Claisen rearrangement so far identified are Lewis acids. Finally, bis(oxazoline)copper(II) complexes have found a further useful application as chiral catalysts for the first catalytic, enantioselective Claisen rearrangement − 90 years after Ludwig Claisen originally reported a [3,3]-sigmatropic rearrangement of an allyl vinyl ether.

Total Synthesis of Jatrophane Diterpenes from Euphorbia characias

The enantioselective total synthesis of the jatrophane diterpene (-)-15-O-acetyl-3-O-propionylcharaciol is described. Starting from an advanced cyclopentane building block, a B-alkyl Suzuki-Miyaura cross-coupling and carbonyl addition were utilized to assemble a fully functionalized triene, and a ring-closing metathesis was then employed to construct the rigid 12-membered ring. Twenty-five years after the original report on the isolation of the natural product, our total synthesis unambiguously corroborates the original tentative structural assignment.

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13-Jatrophane Diterpenes and Their Evaluation as MDR Modulators

We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.

Gosteli−Claisen Rearrangement of Propargyl Vinyl Ethers: Cascading Molecular Rearrangements

The ambivalent reactivity of 2-alkoxycarbonyl-substituted propargyl vinyl ethers has been explored. Depending on the conditions, the catalyzed and uncatalyzed Gosteli-Claisen rearrangement triggers downstream transformations that cascade from initially formed γ-allenyl α-keto esters to highly substituted furanes and cyclopentenes. In support of a mechanistic hypothesis, the results of a DFT study using the B1B95 and B3LYP functionals are revealed.

Synthetic studies toward jatrophane diterpenes from Euphorbia characias. Enantioselective synthesis of (-)-15-O-acetyl-3-O-propionyl-17-norcharaciol.

The enantioselective synthesis of (+)-17-norcharaciol is described. An uncatalyzed intramolecular carbonyl-ene reaction and a ring-closing metathesis were used as key C/C-connecting transformations to assemble the trans-bicyclo[10.3.0]pentadecane norditerpenoid core. We also report the evolution of our synthetic strategy toward the fully substituted characiol skeleton and the experiences from this venture.

(−)-Lytophilippine A: Synthesis of a C1−C18 Building Block

The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).

Gosteli−Claisen Rearrangement: Substrate Synthesis, Simple Diastereoselectivity, and Kinetic Studies

The results of kinetic studies on the uncatalyzed [3,3]-sigmatropic rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers are reported. Apparently first reported by Gosteli in 1972, this variation of a Claisen rearrangement enjoyed a shadowy existence for three decades until its potential for the development of a catalytic asymmetric Claisen rearrangement was discovered. Inspired by this development, we have studied substituent and solvent rate effects, and we provide evidence that a chairlike transition state is highly favorable for the uncatalyzed Gosteli-Claisen rearrangement.

Gosteli-Claisen Rearrangement: DFT Study of Substituent-Rate Effects

The uncatalyzed Gosteli-Claisen rearrangement of four double bond isomeric allyl vinyl ethers has been studied at the B3LYP/6-31G* and B3LYP/6-31G*+PCM levels of theory. The experimentally determined structure-reactivity relationship was successfully reproduced; the relative reactivity of the (E,E)-, (E,Z)-, (Z,E)-, and (Z,Z)-configured allyl vinyl ethers can be attributed to unfavorable interactions caused by pseudoaxial substituents within the chairlike transition-state structures. As expected, the isolated assessment of the calculated ground-state or transition-state stabilities is not suitable to explain the experimentally observed structure-reactivity relationship.

{1,6}-Transannular catalytic asymmetric Gosteli-Claisen rearrangement.

The first uncatalyzed and [Cu(R-box)L(2)](SbF(6))(2)-catalyzed {1,6}-transannular Gosteli-Claisen rearrangement of cyclic 2-alkoxycarbonyl-substituted allyl vinyl ethers to afford medium- and large-sized carbacycles is disclosed.

Synthesis and Lewis acid catalyzed Claisen rearrangement of 2-(1,3-oxazolin-2-yl)-substituted allyl vinyl ethers

Allyl vinyl ethers containing an acceptor function in the 2-position are useful substrates for the Lewis acid-catalyzed Claisen rearrangement. The first synthesis of acyclic 2-(1,3-oxazolin-2-yl)-substituted allyl vinyl ethers is reported. The Lewis acid catalyzed Claisen rearrangement of these allyl vinyl ethers afforded the rearrangement products with low to moderate diastereo- and enantioselectivity. The catalyzed rearrangement of chiral allyl vinyl ethers was investigated. The combination of substrate- and catalyst-induced diastereoselectivity led to unexpected and unprecedented results.