Advancing Chiral Chemistry in API Synthesis - Pharmaceutical Technology

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Advancing Chiral Chemistry in API Synthesis
Functionalized supramolecular catalysts and an enantioselective route to unnatural amino acids are some recent developments.


Pharmaceutical Technology
Volume 33, Issue 11, pp. 44-50

Enantioselectivity in natural product synthesis

Natural products offer a source for bioactive molecules, but developing a synthetic route to such compounds can be challenging. Dennis G. Hall, professor of chemistry at the University of Alberta in Edmonton, Alberta, Canada, and his team recently reported on the catalytic asymmetric synthesis of palmerolide A using organoboron chemistry (4). Palmerolide A is a marine natural product that is being developed as a potential drug to treat melanoma. The researchers reported on a catalytic enantioselective synthesis of palmerolide A without using stoichemetric chiral auxiliaries or a chiral pool (4).

Instead, the researchers produced the right half of the molecule by using a variant of the Claisen–Ireland rearrangement using alkenylboronate as a masked hydroxyl. To produce the left half of the molecule, the researchers used a diol–tin (IV) chloride-catalyzed enantioselective crotylboration. The researchers said that this approach may offer a easy way to design simplified analogs of palmerolide (4).

Jacobsen et al. recently reported on a general approach for producing the polycyclic carbon framework shared by terpene natural products (5, 6). Specifically, Jacobsen reported on a catalytic transannular asymmetric Diels–Alder (TADA) reaction for producing polycyclic products in high enantiomeric excess. The catalyst system (derivatives of oxazaborolidine-based Lewis-acid compounds) were used to alter the diastereoselectivity of cyclizations with substrates containing chiral centers. The catalytic enantioselective TADA was used as the key step in synthesizing sesquiterpene 11, 12-diacetoxydrimane. This route may provide a strategy to the polycyclic carbon framework shared by other terpene natural products (5, 6).

Mohammad Movassaghi, associate professor of chemistry at the Massachusetts Institute of Technology (MIT) in Cambridge, recently reported on an 11-step synthesis for producing (+)-11, 11'-dideoxyverticillin A, a naturally occurring alkaloid with anticancer activity. (+)-11, 11'-Dideoxyverticillin A is a densely functionalized, stereochemically complex and dimeric epidithiodiketopiperazine natural product, and the synthesis of epidithiodiketopiperazines represented a challenge (7). The researchers developed an approach for the enantioselective total synthesis of the compound through a biosynthetic route that used stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions and the introduction of the epidithiodiketopiperazine core (7).

Other approaches in asymmetric synthesis

Researchers at Princeton University reported on β-aminocarbonyl synthesis using oxidative organocatalysis. β-aminocarbonyl moities are important to many bioactive molecules such as paclitaxel, β-peptides, and β-lactam antibiotics (8).

Enantioselective catalytic routes to β-aminocarbonyl-containing compounds have involved several different approaches. These approaches include Mannich couplings, enamine hydrogenation, conjugate additions, and Staudinger reactions (8). The researchers developed another strategy based on singly occupied molecular orbital (SOMO) catalysis, by which a three-π electron radical cation species undergoes enantioselective bond formation with π-SOMO to produce α-functionalized aldehyde adducts. The researchers applied the fundamentals of this approach by using silyl nitronates as SOMOphiles to provide enantioselective β-nitroaldehydes. The researchers reported on their strategy for producing β-aminocarbonyl synthesis using oxidative organocatalysis. The approach is important because it achieves enantioselectivity to the syn or anti diastereomers of β-amino acids or 1,3-aminoalcohols (8).

T.V. RajanBabu, professor in the chemistry department at Ohio State University, and his team discovered a new codimerization of ethylene and various functionalized vinylarenes, 1,3-dienes, and strained alkenes (i.e., asymmetric hydrovinylation). This chemistry has applications in the enantioselective synthesis of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, and fenoprofen from the corresponding styrenes and ethylene (9, 10). Specifically, the group developed highly catalytic protocols to allow for the codimerization of ethylene and various functionalized vinylarenes, 1,3-dienes, and strained alkenes under mild reactions conditions to produce 3-arylbutenes. Such chemistry can be applied to the synthesis of select NSAIDs (9, 10).

His work has further application in the synthesis of steroid derivatives. Cyclic and acylic 1,3-dienes can also undergo efficient heterodimerization with ethylene with yields up to 99% for several 1-vinylcycloalkenes and 1-substituted 1,3-butadienes (9, 10). Phospholanes and phosphoramidites can be used for ligands for an asymmetric variation of this reaction with yields up to 99% and enantiomeric excess of 95% for select substrates. An exocyclic chiral center can be used to install other stereocenters in the ring. His work also has involved the synthesis of several new ligands for improving enantioselectivity and the use of hemilabile ligands and their synergy with highly dissociated counterions to enhance selectivity (9, 10).

The very nature of asymmetric synthesis, which lends itself to more efficient transformations, can support the broader goal of applying green chemistry in pharmaceutical applications. A recent review article by the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable reported that more than 150 articles relating to asymmetric hydrogenation were published in 2008, with the majority of articles relating to the modification of the catalyst and ligands (11, 12). An important development that may lead to improving reaction conditions for asymmetric hydrogenation was the use of an iron-catalyst system for asymmetric hydrogenation at 50 C and asymmetric transfer hydrogenation at room temperature that offered transfer hydrogenation activity similar to that of ruthenium-based catalysts (11, 12).


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