New Techniques Advance Asymmetric Synthesis

September 29, 2014
Cynthia A. Challener
Cynthia A. Challener

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

PTSM: Pharmaceutical Technology Sourcing and Management

PTSM: Pharmaceutical Technology Sourcing and Management-10-01-2014, Volume 10, Issue 10

A literature survey underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds.

Although significant attention has recently been directed towards biocatalysis as the way forward for commercial-scale asymmetric synthesis, chiral transformations mediated by traditional metal-based and organic catalysts remain important for the manufacture of pharmaceutical intermediates and APIs. In addition, much effort continues to be invested in the development of novel enantioselective methods for the synthesis of building blocks necessary for the manufacture of biologically active molecules. A brief survey of recent literature underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds. Selected examples are highlighted in the following.

Amino acid derivatives

Many natural and non-natural amino acids and derivatives contain both nitrogen and sulfur substituents, thus the synthetic methods for the enantiomeric synthesis of building blocks containing these two elements are of significant interest. Scott Denmark and Hyung Min Chi reported an enantioselective route to chiral pyrrolidines, piperidines, and azepanes bearing thiol substituents (1). In their method, terminal and trans disubstituted alkenes with a pendant tosyl-protected amine group are converted to the desired products through the formation of a thiiranium intermediate via Lewis base-catalyzed intramolecular sulfenoamination using a chiral BINAM (1,1’-binaphthyl-2,2’-diamine)-based selenophosphoramide catalyst.

Tsuyoshi Mita and Yoshhihiro Sato at Hokkaido University in Japan reported the asymmetric synthesis of α-amino acids via the stereopsecific carboxylation of optically active α-amino silanes, which were obtained through the enantioselective silylation of N-tert-butylsulfonylimines using a Cu-secondary diamine complex (2). The carboxylation proceeded under 1 atmosphere of CO2. Spirocyclic oxindolo-β-lactams were prepared in high yields with excellent diastereo- and enantioselectivities by Song Ye at the Chinese Academy of Sciences (3). In this case, ketenes were subjected to an N-heterocyclic carbene (NHC)-catalyzed Staudinger reaction with isatin-derived ketimines using NHCs with free hydroxyl groups as the catalyst.

Fluorinated compounds
Chiral fluorinated compounds are also of interest, because incorporation of the highly electronegative fluorine atom can have an impact on the physico-chemical properties of APIs. Gregory Fu and colleagues at the California Institute of Technology tackled the challenge of preparing chiral tertiary alkyl fluorides, and particularly α-fluorocarbonyl compounds (4). They reported a method for the asymmetric synthesis of tertiary α-fluoroesters via the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide and C6F5ONa as a nucleophile using a chiral ferrocenyl PPY (4-pyrrolidinopyridine) catalyst. The alkoxide was crucial for freeing the catalyst from an acylated intermediate. Meanwhile, Qing-Yun Chen and Yong Guo at the Chinese Academy of Sciences reported the asymmetric synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones using a palladium/phosphinooxazoline catalyst (5). The desired products were obtained in up to 90% yield with up to 90% enantiomeric excess (ee).

The preparation of chiral compounds with trifluoralkyl groups is also important for drug development. Liang Hong and Rui Wang at Lanzhou University in China developed a practical method for the enantioselective introduction of a monofluoroalkyl group into the oxindole framework (6). The reaction of a wide range of 3-bromooxindoles and α-fluorinated β-keto gem-diols afforded the desired products with diastereoselectivities of >20:1 and enantioselectivities of 93-99%. Xufeng Lin and colleagues at Zhejiang University reported the first highly enantioselective iso-Pictet-Spengler reaction of C-2-linked o-aminobenzylindoles with trifluoromethyl ketones (7). The reaction is mediated by chiral spirocyclic phosphoric acids as organocatalysts, and the benzazepinoindoles bearing trifluoromethylated quaternary stereocenters were obtained in up to 98% yield and up to >99.5% ee.

Asymmetric hydrogenation
Asymmetric hydrogenation is one of the most widely used enantioselective chemocatalytic reactions used at commercial scale. Even so, advances in this technology, including its application to a widening range of substrates, continue. A recent example was reported by Xumu Zhang at Wuhan University in China (8). His group developed a Rh-DuanPhos ((1R,1′R,2S,2′S)-2,2′-di-tert-butyl-2,3,2′,3′-tetrahydro-1H,1′H-(1,1′)biisophosphindolyl) complex for the synthesis of chiral cyclic allylic amines with up to 99% ee from cyclic dienamides. The products are ideal building blocks for the preparation of chiral, cyclohexane derivatives with multiple substituents. Meanwhile, Virginie Ratovelomanana-Vidal at PSL Research University and Zhaoguo Zhang at Shanghai Jiao Tong University reported the enantioselective synthesis of γ-hydroxy amides with up to 99% ee via the asymmetric hydrogenation of γ-ketoamides in the presence of a Ru-Xyl-SunPhos-Daipen catalyst (9).

C-H insertion
Functionalization of chiral intermediates can also be achieved via asymmetric C-H insertion reactions. In 2013, the H.M.L. Davies group at Emory University reported the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans from derivatives of veratrol and anisole via two sequential enantioselective C-H insertions involving an intermolecular carbene insertion catalyzed by rhodium followed by an intramolecular C-H alkoxylation reaction catalyzed by palladium (10). The products could also be further functionalized via a palladium-catalyzed intermolecular Heck-type sp2 C-H functionalization reaction.

Carbon-carbon coupling
Carbon-carbon (C-C) coupling reactions have become key tools in the synthesis of pharmaceutical  and other fine chemical intermediates, and chiral C-C coupling reactions are highly valued. Several new methods have been reported recently, including the diastereo- and enantioselective coupling of alcohols and vinyl epoxides to form asymmetric quaternary carbon centers, which was developed by Michael J. Krische at the University of Texas at Austin (11). In this iridium-catalyzed reaction, primary alcohol oxidation leads to reductive C-O bond cleavage in isoprene oxide to generate aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, many of which are observed in terpenoid-type natural products. Notably, the reaction proceeds without the use of premetalated reagents or unwanted stoichiometric byproducts.

Meanwhile, Brian M. Stoltz at the California Institute of Technology prepared (trimethylsilyl)ethyl ester protected enolates via fluoride-induced “thermodynamic” enolate formation and used them in palladium-catalyzed asymmetric allylic alkylation reactions to obtain α-quaternary six- and seven-membered ketones and lactams (12). The reaction expands the scope of allyl substrates beyond traditional β-ketoesters and has a high tolerance for reactive functionality.

Two rhodium-catalyzed enantioselective C-C coupling reactions were also recently reported. Vy M. Dong at the University of California, Irvine reported the enantioselective cross-coupling of aldehydes and α-ketoamides via intermolecular hydroacylation to provide α-acyloxyamides using a new Josiphos ligand (13). Separately, Chen-Guo Feng and Guo-Qiang Lin developed the enantioselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines, which provides chiral sulfamidates that can be readily reduced to chiral β-alkyl-β-aryl amino alcohols (14).

Finally, Amir Hovedya at Boston College reported the copper/NHC-catalyzed enantioselective allylic substitution of di- and trisubstituted alkenes with readily accessible (pinacolato)alkenylboron compounds to generate 1,4-dienes bearing an asymmetric tertiary carbon (15). The reaction tolerates a wide range of olefins and provides the desired products in up to >98% yield with >98:2 selectivity for the SN2′ vs. SN2 addition and a 99:1 enantiomeric ratio (er). The group also demonstrated the applicability of the reaction in the synthesis of several natural products.

Multicomponent coupling
Multicomponent reactions are attractive because they often enable the synthesis of complex intermediates in an atom-economical manner from basic starting materials. These reactions are even of more interest when they proceed with high stereo- and regioselectivity. At the Universidad de Oviedo in Spain, Francisco J. Fañanás and Félix Rodríguez developed a one-pot, gold phosphate-catalyzed, three-component coupling reaction of alkynols, anilines, and glyoxylic acid that generates sprioacetals with incorporated α-amino acid functionality (16).

Cascade reaction
Cascade reactions, like multicomponet reactions, are attractive because they provide direct access to complex structures in one pot with few or no undesirable byproducts. Adrien Quintard and Jean Rodriquez of Aix Marseille Université developed a cascade reaction involving the enantioselective reaction of allylic alcohols with diketones catalyzed by an iron catalyst with iminium activation followed by chemoselective acyl transfer (17). The γ-chiral alcohol products (3-alkylpentanols) are obtained in up to 96% yield with a 96:4 er and are useful for natural products synthesis.

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3. H.-M. Zhang et al., Org. Lett. 16 (11) 3079-3081 (2014).
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5. W. Wang et al., J. Org. Chem. 79 (13) 6347-6353 (2014).
6. C. Wu et al., Org. Lett. 16 (7) 1960-1963 (2014).
7. X. Li et al., Chem. Commun. 50, 7538-7541 (2014).
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9. S.Y. Lee et al., J. Am. Chem. Soc. 136 (25) 8899-8902 (2014).
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11. J. Feng et al, J. Am. Chem. Soc. 136 (25) 8911-8914 (2014).
12. C.M. Reeves et al., Org. Lett. 16 (9) 2314-2317 (2014).
13. K.G.M. Kou et al., J. Am. Chem. Soc. 136 (26) 9471-9476 (2014).
14. Y.-J. Chen et al., Org. Lett. 16 (12) 3400-3403 (2014).
15. F, Gao et al., J. Am. Chem. Soc. 136 (5) 2149-2161 (2014).
16. L. Cala et al., Chem. Commun. 49 (26) 2715-2717 (2013).
17. M. Roudier et al., Org. Lett. 16 (11) 2802-2805 (2014). PT