literature report ( Advance organic chemistry)

Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes

Introduction

Allenic compounds are abundantly found in nature and biological processes. For example, poison-dart frogs ( Dendrobates ) have allenic alkaloids on their skin, the flightless grasshopper Romelea microptera secretes an allenic terpenoid when in distress to ward off predators, and Aplysia brasiliana synthesizes Panacene (a bromoallene) to protect it against fish. 2 There are several other examples, as these axially chiral allenic compounds comprise a broad class of natural products that can be of great use because they make bioactive molecules more metabolically stable, bioavailable, and potent. 1

Although these compounds are found abundantly in nature, researchers have been developing synthesis pathways in order to take advantage of the usefulness of these compounds. Through these reactions, several new stereocenters can be created. Previous methods synthesized tri- and tetra-substituted allenes 4,5 or directly converted prochiral 1,3-enynes to enantioenriched allenes, 4 through nucleophilic displacement, rearrangement, or elimination reactions and racemic allene resolution ( Figure 1a ). Unfortunately, the products of these reactions were limited to allenyl esters, allenyl alcohols, and allenyl amines. Bayeh-Romero and Buchwald reported that there was indeed a need for a selective synthesis of various 1,3-disubstituted axially chiral allenes, like Enprostil in Figure 1b , from prochiral molecules. 1 Therefore, they set out to develop and test a synthesis route in order to do so.

Figure 1. a) Previous synthesis routes toward allene synthesis. b) Example of 1,3-disubstituted allene. Enprostil; an allene used to inhibit HCl secretion in the GI system.

Results

Bayeh-Romero and Buchwald went through several steps to optimize the reaction producing the chiral LCuH complex that catalyzes the semi-reduction of 1,3-enynes. They varied the reaction temperature, solvent, proton source, and silane until they got the maximum percent conversion, percent yield, and e.r. The desired (R) product was formed at 90% yield with an e.r. of over 99:1 at -10⁰C, using 1,2-dimethoxy- ethane (DME) as a solvent, H 2 O as a proton source, and 2,4,6,8-tetramethylcyclotetra- siloxane (TMCTS) as the silane hydride source ( Figure 2a ). These optimized reaction conditions were then used for the asymmetric semi-reduction of various 1,3-enynes to allenic compounds, catalyzed by LCuH. They found that this reaction was tolerated for 1,3-enynes with and without various functional groups that were either protected or unprotected, as well as chiral enynes as in Figure 2b .

a)

b) Figure 2. a) Optimized reaction conditions used to create chiral LCuH complex that will catalyze the semi-reduction of 1,3-enynes. b) Example of catalyst control of LCuH in a semi-reduction reaction, giving enantioenriched products. 0.25 equivalents of H 2 O used under N 2 atmosphere.

There was a difficulty in the semi-reduction of internal 1,3-enynes due to a larger energy barrier for hydrocupration and competitive overreduction, so the researchers combatted this by using the slow addition of H 2 O. As shown in Figure 3 , as a proof of principle they were able to convert a fatty acid isolated from the shrub Capparis zelyanica into the nonconjugated allenic natural product from the Leonitis nepetaefolia plant, laballenic acid (among other compounds). 6 Based on previous experimentation, 7, 8 they were able to postulate a potential catalytic cycle for the conversion of 1,3-enynes to allenes ( Figure 4 ). High performance liquid chromatography, supercritical fluid chromatography, gas chromatography, and hydrogen and carbon nuclear magnetic resonance were all used to for structure and compound elucidation throughout the synthetic steps.

Figure 3. The LCuH-catalyzed semi-reduction of an internal enyne to the natural product laballenic acid with 50% yield and 93:7 e.r. H 2 O slow addition over 16 hours under N 2 atmosphere. DMMS used to protect carboxylic acid.

Figure 4. 1 Catalytic cycle using LCuH as a catalyst in order to convert 1,3-enynes to 1,3-disubstitued allenes.

Discussion

Bayeh-Romero and Buchwald were able to overcome previous limitations and barriers associated with the copper catalyzed semi-reduction reaction that yields the desired allenes. 1,3-Enynes had previously only been reduced using chiral metal reducing agents like aluminum for example. The challenge in these aforementioned experiments lied in the possible silylation of the protonating agent, and lack of control of regioselectivity and enantioselectivity. Also, previous groups could not manipulate the stereochemistry during the reactions because the axis of chirality containing three carbons with only hydrogen substituents.

This catalytic conversion reaction that they developed, Figure 4 , was applied to the selective deuterium incorporation for molecular scaffolds. This has applications in the pharmaceutical industry, mechanistic studies, and protein crystallography. In addition, being able to produce these enantioenriched allene compounds allows further synthetic steps to producing chiral hetercycles. The ability of these reactions to tolerate multiple functional groups allows for a wide range of products and is due to the fact the LCuH is only a mild reducing agent.

Conclusion and Future Work

All in all, the work conducted in this paper done by Bayeh-Romero and Buchwald addressed the need for a catalytic pathway to synthesize 1,3-disubstituted allenes. They used a LCuH catalyst to asymmetrically convert 1,3-enynes to 1,3-disubstituted allenes. This semi-reduction reaction did not only provide high yields (up to 98%), but also lead to enantioenriched products with an e.r. of up to >99:1. Furthermore, their optimized reaction at -10⁰C, with the slow addition of water as the proton source and TMCTS as the hydride source, can tolerate multiple substituents and a variety of functional groups.

Allenes are being studied in the pharmaceutical field to be enzyme inhibitors. 2 One example is that an allenic phosphonate can be used therapeutically to inhibit the sterol biosynthesis of a parasitic pathogen that leads to Pneumocystis-carinii pneumonia (PCP), a disease highly associated with AIDS. 3 Incorporation of deuterium not only gives allenic molecules metabolic stability and safety, but could facilitate deuterium labeling in allenes.

References:

1. Bayeh-Romero, L.; Buchwald, S. L. Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes. J. Am. Chem. Soc. 2019 , 141, 13788−13794.

2. Hoffman-Röder, A.; Krause, N. Synthesis and Properties of Allenic Natural Products and Pharmaceuticals. Angew. Chem. Int. Edit . 2004 , 43 (10), 1196-1216.

3. Beach, D. H.; Chen, F.; Cushion, M. T.; Macomber, R. S.; Krudy, G. A.; Wyder, M. A.; Kaneshiro, E. S. Effects of Steroidal Allenic Phosphonic Acid Derivatives on the Parasitic Protists Leishmania donovani , Leishmania mexicana mexicana , and Pneumocystis carinii carinii . Antimicrob . Agents . Ch . 1997 , 41 (1), 162-168.

4. Han, J. W.; Tokunaga, N.; Hayashi, T.; Palladium-Catalyzed Asymmetric Hydrosilylation of 4-Substituted 1-Buten-3-ynes. Catalytic Asymmetric Synthesis of Axially Chiral Allenylsilanes. J. Am. Chem. Soc. 2001 , 123 (51), 12915-12916.’

5. Poulson, P. H.; Li, Y.; Lauridsen V. H.; Jørgensen D. K. B.; Palazzo, T. A.; Meazza M.; Jørgensen, K. A. Organocatalytic Formation of Chiral Trisubstituted Allenes and Chiral Furan Derivatives. Angew. Chem. Int. Edit. 2018 , 57 (22), 10661-10665.

6. Bagby, M. O.; Smith, C. R.; Wolff, I. Laballenic Acid. A New Allenic Acid from Leonotis nepetaefolia Seed Oil. J . Org . Chem . 1965 ,30 (12), 4227-4229.

7. Huang, Y; Pozo, J.; Torker, S.; Hoveyda, A.H. Enantioselective Synthesis of Trisubstituted Allenyl–B(pin) Compounds by Phosphine–Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu–Allenyl Intermediates. J. Am. Chem. Soc. 2018 , 140 (7), 2643-2655.,

8. Yang, Y; Perry, I. B.; Lu, G.; Liu, P.;Buchwald, S. L. Copper-Catalyzed Asymmetric Addition of Olefin-Derived Nucleophiles to Ketones. Science . 2016 , 353 (6295), 144-150.