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Microwave Chemistry Highlights
A short summary of articles published within the last month on microwave-assisted organic synthesis (MAOS)

Monday, January 15, 2007
Doris Dallinger
Karl-Franzens-University Graz

Oxidative Dearomatization/Transannular Diels-Alder Cascade

The group of Samuel Danishefsky from Columbia University has reported on an oxidative dearomatization/transannular Diels-Alder sequence as key step in the total synthesis of (±)-11-O-debenzoyltashironin (4) (J. Am. Chem. Soc. 2006, 128, 16440. DOI: 10.1021/ja0670254). Upon exposure of 1 to a hypervalent iodine species such as PIDA, a mixture of oxidized intermediate 2 and Diels-Alder adduct 3 was obtained, however subsequent microwave irradiation of this mixture leads exclusively to the cycloadduct 3 in 65% yield. A following series of deprotections and diastereoselective oxidation steps furnished 11-O-debenzoyltashironin (4).

Sequential Coupling-Isomerization-Coupling Reactions

The coupling-isomerization reaction (CIR) of (hetero)aryl halides with propargyl alcohols 1 under Sonogashira conditions for the synthesis of chalcones 2, was disclosed by Thomas Müller and Oana Schramm from the University of Heidelberg (Adv. Synth. Catal. 2006, 348, 2565. DOI: 10.1002/adsc.200600280). The first step in this one-pot synthesis is the Pd/Cu catalyzed alkyne coupling followed by base-catalyzed propargyl alcohol to enone isomerization. The reaction times could be reduced from 16-24 h under conventional heating to only 15-30 min by applying microwave irradiation. In a subsequent publication (Synlett 2006, 3469. DOI: 10.1055/s-2006-956480) Müller and Liao extended this protocol to a coupling-isomerization-coupling (CIC) sequence for the synthesis of chalcones 5. The boronate moiety attached to bromoaryls 3 initially serves as electron-withdrawing substituent for the CIR and after addition of K2CO3, (het)aryl bromides 4 and water, this organometallic group is activated by the alkali base for the Suzuki coupling sequence.

Synthesis of Hydrogen-Bond Surrogate Helices

Paramjit Arora and Ross Chapman from New York University were successful in the solid-phase synthesis of hydrogen-bond surrogate (HBS) α-helices (artificial α-helices where the N-terminal H bond is replaced by a covalent C-C bond) including the ring-closing metathesis (RCM) reaction as key step (Org. Lett. 2006, 8, 5825. DOI: 10.1021/ol062443z). Compared to conventional heating at 60 °C where reaction times up to 72 h are required for maximum conversion, under microwave irradiation the RCM could be accelerated to 2-5 min. Three different substituted 13-membered macrocycles (1) and one 16-membered macrocycle were obtained in high yields either at 120 °C within 2 min when Grubbs II (GII) catalyst is employed or at 200 °C within 5 min for the Hoveyda-Grubbs II (HGII). Importantly, in this HBS approach GII produces the macrocycles in high yields compared to conventional heating, where it showed to be inactive. Additionally, it was found that a greater variety of amino acid residues is tolerated which was also one of the limitations using oil-bath heating.

Intramolecular Alkylation in the Synthesis of (±)-Baccatin III

In the course of the synthesis of (±)-baccatin III (2), a precursor of taxol, Takashi Takahashi and his group from Tokyo Institute of Technology have developed (Chem. Asian J. 2006, 1, 370. DOI: 10.1002/asia.200600156) a microwave-assisted protocol for the key ABC ring construction step. The cyclization of protected cyanohydrin 1, which was synthesized in 36 steps completely with the aid of automated synthesizers, was accomplished by intramolecular alkylation in the presence of excess LiN(TMS)2. The reaction time could be reduced from 10 h in refluxing dioxane employing thermal heating to 15 min at 145 °C using microwave irradiation.

D. Dallinger, Org. Chem. Highlights 2007, January 15.