Highly Enantioselective α Alkylation of Aldehydes with 1,3‐Benzodithiolylium Tetrafluoroborate: A Formal Organocatalytic α Alkylation of Aldehydes by the Carbenium Ion

Abstract

A formal formyl: The organocatalytic stereoselective addition of formyl equivalents to aldehydes (see scheme) tolerates a large variety of functional groups to afford products with high enantioselectivity (92–97 % ee) and good yields (up to 95 %). The benzodithiol group can be easily removed with Raney Ni or metalated with nBuLi, thus giving access to a methyl group or to a wide range of useful intermediates. The benzodithiol heterocycle 1 (Scheme 1) is an interesting and readily available synthon for organic synthesis.1 The application of the easily formed carbanion 2 and carbocation 3 can give considerable advantages when designing complex syntheses. The anion 2, which is a practical acyl anion equivalent, can be easily generated by simple deprotonation with strong bases such as nBuLi.2 The carbenium ion 3 is also a useful electrophile,3 and can be easily prepared by hydride exchange with triphenyl carbenium salts.4 The stability of 3 is between that of the tropylium and tritylium carbenium ions.5 The stable benzodithiolylium tetrafluoborate 3 a is commercially available and can be easily handled without any precautions. Benzodithiol as precursor of anionic 2 and cationic 3. Several significant results in the field of α alkylation of aldehydes were recently reported, in which attempts were made to solve what is considered the “Holy Grail” of organocatalysis.6, 7 We have recently contributed to this field, and have focused our attention on the development of new methodologies for the α alkylation of aldehydes8 by SN1-type reactions9 with alcohols.10, 11 We have also found that stable and isolable carbenium ions can be used in organocatalytic enantioselective α alkylation of aldehydes12 by using secondary amines (MacMillan catalyst).7c The stability and reactivity of the versatile 1,3-benzodithiolylium cation attracted our attention. Not only can the organocatalytic α alkylation of 3 constitute the addition of a formyl equivalent, but the introduction of the 1,3-benzodithiol group in a stereoselective fashion can also allow the generation of an anionic (2) or cationic (3) equivalent. Furthermore, deprotection of 1,3-benzothiole with Raney Ni can give direct access to a methyl group.13 Herein we report the first practical and highly organocatalytic stereoselective addition of the commercially available cation 3 a to various functionalized aldehydes and the easy functionalization of the isolated adducts. Formylation of aldehydes is of major importance in synthesis,14 and the cationic formylation of enolates has also been studied.15, 16 Scolastico, Hopper, and their respective co-workers used ephedrine in the synthesis and use of chiral formyl cations.17 Furthermore, the diastereoselective addition of an enamine to a chiral formyl cation was reported.18 We have investigated the model reaction (Table 1) with different bases and organocatalysts. In general, the reaction was poorly promoted by proline derivatives. The presence of the base was necessary to capture the HBF4 liberated by the reaction of the carbenium ion. The nature of the base was crucial for the reaction; organic bases such as 1,6-dimethylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or Et3N resulted in poor yields because of side reactions of the 1,3-benzodithiol unit.19 Inorganic bases were more suitable for the transformations; in terms of yield, NaH2PO4 was found to be most suitable. Enantiomeric excesses and yields were further optimized by screening different organocatalysts 5 a–f in different solvents and reaction conditions. The desired product was produced with excellent enantioselectivity and high yields in a 1:1 mixture of CH3CN and H2O after reduction to the corresponding alcohol by NaBH4 in MeOH. The use of the easily prepared and commercially available catalysts 5 a in the presence of water20 gave excellent enantiocontrol in the reaction with propanal. The stability of the 1,3-benzodithiolylium carbenium is high in the presence of water and no decomposition of the carbenium ion occurs. The scope and limitations of this new formylation reaction have been extensively investigated (Scheme 2). Aldehydes bearing a variety of functional groups were investigated by using the optimized protocol. Notably, a wide array of aldehydes are applicable to this formylation reaction. The reaction was quite tolerant of a large variety of functional groups such as chloro and cyano groups, and amides and acetals. The enantiomeric excesses obtained were in the range 92–97 % with different batches of MacMillan catalyst and carbenium ions.21 Remarkably, the formylation provides straightforward access to a variety of valuable precursors. Also, as the 1,3-benzodithiol group can be easily removed by Raney Ni in the presence of hydrogen,22 this organocatalytic formylation provides a convenient procedure for the challenging organocatalytic α methylation of aldehydes. Organocatalytic alkylation of functionalized aldehydes 4 b–i with the cation 3 a. Entry[a] Cat. Solvent Yield [%][b] ee [%][c] 1 5 a CH2Cl2 90 50 2 5 b CH2Cl2 26 25 3 5 c CH2Cl2 50 40 4 5 d CH2Cl2 30 30 5 5 e CH2Cl2 87 6 6 5 a H2O 54 87 7 5 d H2O 42 80 8 5 e H2O 51 36 9 5 f H2O 73 72 10 5 a CH3CN 76 80 11 5 a H2O/CH3CN 9:1 82 91 12 5 a H2O/CH3CN 1:1 96 96 13 5 a H2O/THF 1:1 44 63 The absolute configurations of the products were determined through the transformation of adducts 6 c and 6 f to the corresponding products 7 c23 and 7 f (Scheme 3).24 In the case of 7 f, HPLC analysis was compared to the reported elution time, while the absolute configuration of 7 c was assigned by comparison with the reported optical rotation value. In both cases, the (S)-MacMillan catalyst gave the (S)-configured product. The reaction with Raney Ni occurs without racemization, as was verified in the case of the substrate 6 f.25 It is worth noting that the elimination of the benzodithiol group in 7 f allows rapid access to anti-inflammatory drugs such as profens.26 Determination of absolute configuration of the products 7 c and 7 f. To prove the versatile and easy transformation of the adduct 6 c obtained by the organocatalytic formylation, we have performed some preliminary investigations (Scheme 4). The product 6 c was transformed in a quantitative manner to the corresponding benzyl ether 8, which was lithiated with nBuLi at 0 °C in THF and treated with MeI and BnBr at 0 °C. The alkylation reaction was fast and quantitative. In the case of the product 10 b, after treatment with Raney Ni, no racemization was observed. On the other hand, adducts 9 a, b are easily transformed into the corresponding ketones 11 a, b by treatment of the 1,3-benzodithiol adducts with HgO in the presence of HBF4.27 The reactions occurred in high yields, and in both cases we observed no racemization in the final products. Alkylation of the benzothiol derivative with MeI and BnBr and successive elimination with Raney Ni and HgO. Bn=benzyl. In the preliminary application of our methodology we have focused our attention on the preparation of a key intermediate in the synthesis of gymnastatin A (Scheme 5) and we have accomplished a straightforward total synthesis of arundic acid (Scheme 6). Gymnastatins have been reported to exhibit antibacterial activity and cytotoxicity towards cultured P388 cancer cells. The total synthesis of gymnastatins A–C has previously been reported.29 In most cases, the lateral acid chain was prepared from (R)-2-methyloctanol by oxidation to the corresponding aldehyde followed by iterative Wittig reactions. The (R)-2-methyloctanol was obtained in a straightforward and direct manner by using our method. Synthesis of (R)-2-methyloctanol, a key intermediate in the synthesis of gymnastatin A. The enantioselective synthesis of arundic acid, with organocatalytic formylation as the key step. Alkylation of octanal with 1,3-benzodithiolylium was catalyzed by the (R)-MacMillan catalyst 5 a to afford 6 c in high yield and stereoselectivity. The product was then treated with Raney Ni, without protection of the alcohol, to afford the (R)-2-methyloctanol 7 c in high yield. Arundic acid 14 is currently undergoing phase II development for the treatment of acute ischemic stroke as well as clinical development for other neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.30, 31 Arundic acid can be prepared in a simple manner by using our methodology. The benzylation of derivative (R)-6 c occurred in a quantitative manner when the alcohol was treated with NaH and BnBr. Derivative 8 was metalated with nBuLi at 0 °C and then alkylated in high yield with EtI. After successive treatment with Raney Ni/H2 and Pd/C/H2,32 we obtained the alcohol 13 in quantitative yield. Oxidation of 13 with NaClO2 in the presence of catalytic amount of NaClO and 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO)33 gave excellent results in terms of yields and selectivity in affording the desired arundic acid. In conclusion, we have described the first organocatalytic stereoselective α addition of a formyl group to aldehydes. The reaction tolerates a large range of functional groups and was performed in the presence of water. The benzodithiol group can be easily metalated with nBuLi and can be further reacted with other electrophiles. The possibility to reduce the benzodithiol with Raney Ni allows easy access to a methyl group. This procedure is therefore a useful methodology in the synthesis of natural products and makes our organocatalytic methodology a surrogate for the quite challenging organocatalytic enantioselective α methylation of aldehydes. Further studies into the application of 1,3-benzodithiol cation in organocatalytic reactions are currently under investigation.35 General procedure: Carbenium ion 3 a (0.1 mmol, 1 equiv) and aldehyde (0.3 mmol, 3 equiv) were added at 0 °C to a vial containing MacMillan catalyst 5 a (0.02 mmol, 20 mol %). PhCOOH (0.02 mmol, 20 mol %) in CH3CN/H2O 1:1 (0.5 mL), and NaH2PO4 (0.1 mmol, 1 equiv) were added at 0 °C. The mixture was stirred for 24 h at same temperature. The solvent was evaporated under reduced pressure and the crude reaction mixture was diluted with MeOH. NaBH4 (2 equiv) was added at 0 °C and the reaction was stirred for a further 30 min. The reaction was quenched with water and MeOH was evaporated under reduced pressure. The aqueous phase was extracted with Et2O (2×5 mL). The collected organic layers were dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (cyclohexane/ethyl acetate 9:1). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.