Advancing Chiral Chemistry in API Synthesis

November 2, 2009
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-11-02-2009, Volume 33, Issue 11

Functionalized supramolecular catalysts and an enantioselective route to unnatural amino acids are some recent developments.

The goal of reaching desired enantioselectivity of active pharmaceutical ingredients (APIs) is an ongoing challenge for process chemists. Chemocatalysis and biocatalysis play an important role in asymmetric synthesis, and there have been several interesting developments in these areas.

Patricia Van Arnum

Supramolecular catalysts

Researchers at the Graduate School of Engineering at Nagoya University in Nagoya, Japan, recently reported that they developed an asymmetric catalyst that assembles spontaneously, a development that lays the groundwork for further designing functional supramolecular catalysts. Their work involved using chiral organic ion-pair catalysts assembled through a hydrogen-bonding network (1). The researchers pointed out that overall development of structurally discrete, chiral supramolecular catalysts for asymmetric organic transformations has been met with limited success. In their work, however, the researchers reported that a chiral tetraaminophosphonium cation, two phenols, and a phenoxide anion appeared to have self-assembled into a catalytically active supramolecular architecture through intermolecular hydrogen bonding. The researchers developed the catalyst for the highly enantioselective conjugate addition of acyl anion equivalents to α-, β-unsaturated ester surrogates (1).

Catalytic asymmetric synthesis for nonnatural amino acids

Eric Jacobsen, professor of chemistry at Harvard University, and his research team detailed an improved method for making bulky nonnatural amino acids, which are used as building blocks for APIs and in chiral catalysts (2). The researchers point out that although there are efficient chemo–enzymatic methods for producing enantioenriched α-amino acids, obtaining nonnatural amino acids has been more difficult. The researchers explained that although alkene hydrogenation is useful for the enantioselective catalytic synthesis of many amino acids, it is not possible to obtain α-amino acids with aryl or quarternary alkyl α-substituents with this approach (2).

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The researchers addressed this problem by developing a scaleable catalytic asymmetric Strecker synthesis of unnatural α-amino acids. The Strecker synthesis is an approach to produce racemic α-amino acids, but catalytic asymmetric methods have been limited to small scales. The Strecker synthesis involves the reaction of an imine or imine equivalent with hydrogen cyanide followed by nitrile hydrolysis. Existing catalytic methods and the use of hazardous cyanide materials in the asymmetric Strecker reaction however, limits its application in large-scale reactions (2).

To resolve that issue, Jacobsen and his team developed a new catalytic asymmetric method for producing enantiomerically rich nonnatural amino acids using a chiral amidothiourea catalyst to control the hydrocyanation step. The researchers report that this approach is compatible with aqueous cyanide salts, which are safer than other cyanide sources, which allows the process to be run at larger scales (2).

Ligand selection in asymmetric transition-metal catalysis

Researchers at McGill University in Montreal reported on an approach for ligand selection in asymmetric transition-metal catalysis. The approach in chiral catalyst formation involved coupling a pool of Brønsted acids, specifically amino-acid derivatives, with adjustable ligands on copper catalysts. The researchers reported that the system can be used to generate various chiral environments by changing the amino acid or ligand and therefore is a suitable approach for screening and identification of possible combinations to achieve high enantioselectivity. An example of this approach is shown with the copper-catalyzed alkynylation of imines in enantiomeric excess of up to 99% (3).

Chiral separations.

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).

Biocatalysis at work

An example of a successful process substitution using biocatalysis was recently reported for producing an intermediate used in the synthesis of aliskiren, a renin inhibitor used to treat hypertension. A key step in the synthesis of aliskiren is an enzymatic resolution catalyzed by pig-liver esterase (PLE). PLE is a versatile biocatalyst because it has a broad substrate spectrum and excellent enantio- and regio-selectivity. Commercially available PLE is animal derived, which can result in variability. To address this problem, DSM (Heerleen, The Netherlands) and its collaboration partner, the Graz University of Technology in Austria, identified different isoforms of PLE. Using capabilities in enzyme development and production, a highly efficient and patented microbial expression system and fermentation process was developed for different isoforms of PLE that runs at a 25,000-L scale at DSM. This system delivers nonanimal-derived PLE isoforms (PharmaPLEs, DSM) at a large scale for pharmaceutical applications (13).

In another development, researchers at Merck & Co. (Whitehouse Station, NJ) reported on the pilot-scale asymmetric synthesis of 4,4-dimethoxytetrahydro-2H-pyran-3-ol with a ketone reductase and in situ cofactor recycling using glucose dehydrogenase in high yield and enantiomeric excess (11, 12).

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com

References

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2. S.J. Zuend et al., Nature 461 (7266), 968–970 (2009).

3. Y. Lu, T.C. Johnstone, and B.A. Arndtsen, J. Am. Chem. Soc. 131 (32), 11284–11285 (2009).

4. M. Penner et al., J. Am. Chem. Soc. 131 (40), 14216–14217 (2009).

5. P. Van Arnum, Pharm. Technol. 32 (9), 60–64 (2008).

6. E. Balskus and E. Jacobsen, Science 317 (5845), 1736–1740 (2007.)

7. J. Kim, J.A. Ashenhurst, and M. Movassaghi, Science 324 (5950), 238–241 (2009).

8. J. E. Wilson, A.D. Caserez, and D.W.C. MacMillan, J. Am. Chem. Soc. 131 (32), 113332–11334 (2009).

9. P. Van Arnum, Sourcing and Management, July 8, 2009, PharmTech.com/ptsm.

10. T.V. RajanBabu et al., J. Am. Chem. Soc., 130 (25), 7845–7847 (2008).

11. P. Van Arnum, Sourcing and Management, Sept. 1, 2009, PharmTech.com/ptsm.

12. I. Andrews et al., Org. Process Res. Dev. 13 (3), 397–408 (2009).

13. P. Van Arnum, Pharm. Technol. 33 (9) API Synthesis and Formulation suppl. s34–s38 (2009).