Direct Amino Acid Catalyzed Asymmetric α Oxidation of Ketones with Molecular Oxygen (2004)

A possible prebiotic pathway for the asymmetric incorporation of molecular oxygen into organic compounds involves the amino acid catalyzed reaction of molecular singlet oxygen with ketones. Amino acids and their derivatives mediate the reaction between oxygen and ketones with high efficiency to produce α-hydroxyketones (see scheme). Molecular oxygen is fundamental for the existence of complex multicellular life on earth. The initially very small amounts of molecular oxygen is believed to have been formed around 4 billion years ago by the decomposition of CO2 and water promoted by UV irradiation from the sun.1 Molecular oxygen can be transferred between its more reactive singlet state (1O2) and its non-excited triplet state (3O2).2 Singlet molecular oxygen (1O2) plays a significant role in several biochemical processes. For example, it is involved in the development of different diseases and biochemical oxidations.3, 4 Furthermore, chemists have utilized photo- or chemically generated molecular 1O2 as an oxygen source for several synthetic transformations.1, 5 For example, it is used in the formation of allylic hydroperoxides (analogous to the "ene" reaction) and to generate cyclic peroxides (analogous to a Diels–Alder-type reaction). There is a demand in today's society for the development of sustainable chemistry from renewable resources.6 The content of molecular oxygen in air is 21 %, which allows its use in oxidation reactions. Thus, molecular oxygen is one of the ultimate oxidants for oxidation of organic molecules and the development of sustainable chemistry. In an initial experiment, cyclohexanone 1 a (1 mmol) was added to a vial containing dimethyl sulfoxide (DMSO) (1 mL), L-proline (20 mol %) and tetraphenylporphine (TPP) (1 mol %). A continuous flow of O2 or air was bubbled through the vial and the reaction was exposed to visible light from a 250-W high-pressure sodium lamp (Scheme 1). To our delight, complete conversion had occurred after one hour, and the reaction was quenched by aqueous workup. The crude ketone 2 a existed as a mixture of dimeric and oligomeric products. The crude product mixture was purified by silica-gel column chromatography to yield α-hydroxyketone 2 a with 18 % ee.13, 14 We also performed the reaction with in situ reduction of α-hydroxyketone 2 a with NaBH4 to afford the corresponding optically active trans- and cis-diols 3 a (trans/cis=3:1) in 95 % combined yield after silica-gel column chromatography. The enantiomeric excess of the pure trans-3 a diol was determined by chiral-phase GC analyses to be 18 % ee. Amino acid catalyzed asymmetric α oxidation of cyclohexanone to give 2 a and in situ reduction to diol 3 a. Next, we screened several natural amino acids and their derivatives for their potential in catalyzing the introduction of 1O2 at the α position of 1 a and to improve the stereoselectivity of the reaction (Table 1). We found that several of the amino acids investigated catalyzed the α oxidations with molecular 1O2 with high efficiency and chemoselectivity. The simple amino acids alanine and valine mediated the reaction with the highest stereoselectivity. In fact, this is the first case in which an acyclic amino acid provides higher asymmetric induction than proline and its derivatives in organic solvents. In previously reported direct organocatalytic intermolecular transformations, the catalyst required a cyclic five-membered ring to allow high efficiency and enantioselectivity.7 However, a higher enantioselectivity was obtained with L-α-methylproline than with L-proline (increase from 18 to 48 % ee for 2 a). Thus, the presence of a methyl group at the α position of proline significantly increased the stereoselectivity. In contrast, this effect was not observed when comparing valine with α-methylvaline. The asymmetric α oxygenation reactions that were catalyzed by a D-amino acid afforded the opposite enantiomer of 2 a to that obtained in the reactions catalyzed by the corresponding L-amino acid, without affecting the asymmetric induction. Furthermore, amino alcohols, dipeptides, amino acids with amide and amine functionalities, and synthetic amino acid derivatives catalyzed the direct asymmetric introduction of molecular oxygen into ketones with a similar efficiency to that of the amino acids. However, the amino acid catalysts were superior to the amino alcohols with regards to stereoselectivity. It should be noted that the direct introduction of 1O2 into ketones was also readily catalyzed by glycine and ethanolamine, providing a novel inexpensive entry to α-oxygenated compounds. Entry Amino acid Product Yield [%][b] ee [%][c] 1 L-alanine ent-2 a 93 56 2 D-alanine 2 a 88 57 3 L-valine ent-2 a 78 49 4 D-valine 2 a 77 48 5 L-proline 2 a 95 18 6 D-proline ent-2 a 93 16 7 L-hydroxyproline 2 a 88 11 8 L-α-methylproline 2 a 20 48 9 L-α-methylvaline ent-2 a 15 6 10 L-α-phenylglycine ent-2 a 70 20 11 L-phenylalanine ent-2 a 89 38 12 D-α-phenylglycine 2 a 71 21 13 L-threonine ent-2 a 20 10 14 L-phenylalinol ent-2 a 67 <2 15 0 2 a 62 11 16 glycine 2 a 85 – 17 ethanolamine 2 a 81 – 18 0 2 a 97 <5 We also performed a solvent screen of the L-alanine-catalyzed asymmetric incorporation of molecular oxygen into 1 a in different solvents (Table 2). Direct L-alanine-catalyzed asymmetric α oxidations with 1O2 proceeded smoothly in DMSO, N-methylpyrrolidinone (NMP), and N,N-dimethylformamide (DMF). In contrast, L-alanine only furnished trace amount of product in MeOH, trifluoroethanol (TFE), and CHCl3. Hence, the best selectivity and efficiency is obtained in the more polar aprotic solvents. We did not observe any significant temperature dependence of the stereoselectivity in DMSO. Furthermore, the reactions were also efficient in aqueous media with air as the molecular oxygen source, which could allow the development of environmentally benign reaction conditions. Entry Solvent T [°C] Yield [%][b] ee [%][c] 1 MeOH RT traces n.d. 2 DMSO 40 79 55 3 DMSO RT 93 56 4 DMSO 0→RT 80 48 5 DMSO[d] RT 82[d] 56[d] 6 NMP RT 86 48 7 DMF RT 82 49 8 TFE RT traces n.d. 9 phosphate buffer[e] RT 80[e] 18[e] 10 H2O[e] RT 77[e] 19[e] 11 CHCl3 RT traces n.d. Next, we investigated the amino acid catalyzed asymmetric α oxidations with molecular oxygen of various ketones (Table 3). The direct amino acid catalyzed asymmetric α-oxygenation reactions progressed with excellent chemoselectivity and furnished the corresponding α-oxygenated adducts ent-2 a and 2 b–e with good enantioselectivity. For example, L-alanine catalyzed the formation of 2 c in 67 % yield with 72 % ee. Furthermore, the amino acid catalyzed reactions with linear acyclic ketones progressed with excellent regioselectivity, and molecular oxygen was asymmetrically incorporated at the most substituted side of the ketone. Moreover, the reactions were readily scaled up and performed on the gram scale. The amino acids were also able to catalyze the asymmetric incorporation of molecular oxygen into unmodified aldehydes.15 For example, L-α-methylproline furnished (R)-2-hydroxy-3-phenylpropanal with 65 % ee. The direct amino acid catalyzed α oxygenation with molecular 1O2 may be considered as a new, simple, metal-free entry into the synthesis of α-hydroxyketones and diols. Entry Product Amino acid Yield [%][b] ee [%][c] 1 0 L-alanine 93 56 2 0 L-valine 50 28 3 0 L-valine 75 69 4 L-alanine 67 72 5 0 L-alanine 61[d] 60 6 0 L-alanine 58[d] 52 We also tested the amino acid-catalyzed α-oxidations of unmodified ketones with molecular 3O2 as the electrophile in the presence of triethylphosphite.16 The reactions with molecular 3O2 did not provide the α-hydroxyketone adducts 2 or the diol 3. Thus, molecular 1O2 is the more reactive electrophile and not 3O2. Moreover, no products were formed in the absence of the amino acid catalysts. We also investigated the possibility of background oxidation by α-hydroperoxide ketone intermediates or another peroxide intermediate that potentially could influence the enantioselectivity of the reaction.13–14 However, the use of excess (5 equiv) H2O2, NaClO, m-chloroperbenzoic acid (MCPBA), or oxone as the oxidants for cyclohexanone (1 mmol) in the presence of a catalytic amount of L-proline or L-alanine (20 mol %) in DMSO only provided trace amounts of the diol 3 a after in situ reduction with NaBH4. Furthermore, the L-alanine-catalyzed α oxygenation with 1O2 in the presence of triethylphosphite furnished ent-2 a in 87 % yield with 56 % ee, which is the same ee value of ent-2 a obtained without the addition of phosphite (Scheme 2). Direct L-alanine-catalyzed introduction of molecular 1O2 to 1 a in the presence of triethylphosphite. We also established that natural amino acids catalyze the asymmetric incorporation of molecular oxygen into ketones in aqueous buffer. For example, L-alanine catalyzed the direct asymmetric synthesis of ent-2 a in phosphate buffer at 37 °C. Moreover, the amino acids mediated the direct catalytic asymmetric α oxidations in air with the sun as the light source. Hence, terrestrial and extraterrestrial amino acids were able to catalyze the introduction of molecular oxygen under prebiotic conditions to form α-hydroxyketones. In fact, the amino acids were able to catalyze the α oxidation of acetone with 1O2 to furnish hydroxyacetone and dihydroxyacetone, which are the building blocks and donors in amino acid catalyzed asymmetric synthesis of sugars under prebiotic conditions.12a, 17 Thus, the amino acid catalyzed introduction of molecular oxygen may plausibly have served as the first step in their homochirality transfer of their asymmetry to polyhydroxylated compounds, even in the presence of small amounts of oxygen.12 In conclusion, we have disclosed the unprecedented ability of amino acids to catalyze the direct asymmetric incorporation of singlet molecular oxygen into ketones. The smallest amino acids alanine and valine catalyzed the transformation with the highest stereoselectivity. The direct catalytic α oxygenations are a novel, inexpensive, operationally simple, and environmentally benign entry to the preparation of α-hydroxyketones and diols. All materials in this process stem from renewable sources, thus allowing a highly sustainable catalytic process. Readily available amino acids allow catalytic asymmetric oxidations with molecular oxygen or air, which has previously been considered to be in the domains of enzymes and chiral transition-metal complexes. Typical experimental procedure (Table 1, entry 1): Cyclohexanone (1 mmol) was added to a vial containing TPP (1 mol %) and a catalytic amount of L-alanine (20 mol %) in DMSO (1 mL). A continuous flow of O2 or air was bubbled through the vial, and the reaction was exposed to visible light by a 250-W high-pressure sodium lamp. After 1 hour, complete conversion had occurred, and the reaction was quenched either by the addition of brine followed by extraction with EtOAc to furnish α-hydroxyketone ent-2 a or by in situ reduction with NaBH4 to afford the corresponding optically active crude diol ent-3 a (trans/cis 3:1). The crude ent-2 a existed as an oligomeric mixture that, upon standing, formed the dimer, which was isolated by silica-gel column chromatography (EtOAc/pentane 1:20) with 56 % ee (determined by chiral-phase GC-analysis). GC: (CP-Chirasil-Dex CB); Tinj=250 °C, Tdet=275 °C, flow=1.8 mL min−1, ti=60 °C (9 min), rate=85 °C min−1, tf=200 °C (5 min); retention times of 2 a: tmaj=10.64 min, tmin=10.66 min. The trans-3 a and cis-3 a diols were isolated by silica-gel column chromatography (EtOAc/pentane 1:1) in a combined yield of 92 % with 56 % ee of the pure trans-3 a diol (determined by GC analyses). (1S, 2S)-trans-cyclohexane-1,2-diol: [α]D=+21 (c=0.2, CHCl3); GC: (CP-Chirasil-Dex CB); Tinj=250 °C, Tdet=275 °C, flow=1.8 mL min−1, ti=90 °C (2 min), tf=110 °C, rate=0.3 °C min−1; retention times of acetylated compound: tmaj=9.75 min, tmin=9.61 min.