Article pubs.acs.org/OPRD
Facile Production Scale Synthesis of (S)‑Taniguchi Lactone: A Precious Building-Block Fredrik von Kieseritzky,*,† Yeliu Wang,‡ and Magnus Axelson§ †
Arubedo AB, Brahegatan 32, 114 37 Stockholm, Sweden Bejing Honghui Meditech Co Ltd, Bld 10, 9 Tianfu Street CBP, Daxing, 102600 Beijing, China § Department of Clinical Chemistry, Karolinska University Hospital, 171 76 Stockholm, Sweden ‡
ABSTRACT: A cost-efficient and facile synthesis of (S)-4-vinyldihydrofuran-2(3H)-one ((S)-1), better known as (S)-Taniguchi lactone, is described. Racemic Taniguchi lactone rac-1 was ring-opened with (S)-1-benzylmethylamine providing a diastereomeric mixture of hydroxyl-amides. The desired diastereomer (S,S)-2 was isolated by crystallization and subjected to acidic hydrolysis to release enantiopure title compound in good overall yield with an er in excess of 99%. The process was successfully scaled up to kilogram quantities.
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h, vacuum filtration afforded (S,S)-2 with a dr value measured at above 99% by HPLC. The yield was good (70% of theory). With the diastereopure intermediate in hand, considerable effort was invested in unearthing suitable hydrolysis conditions to efficiently furnish the enantiopure (S)-form of Taniguchi lactone. It should be noted that hitherto published procedures rely on rather harsh and basic conditions at high temperatures, and give moderate yields and utilize work-up conditions that are not appropriate for large scale synthesis.1,8 After some endeavor, we discovered a much more benign protocol, relying instead on acidic hydrolysis at a considerably lower temperature. Heating (S,S)-2 in a mixture of 2 M aqueous sulfuric acid and 1,4-dioxane (1:1) at 80 °C for 12 h provided, after work-up and concentration, pure (S)-4-vinyldihydrofuran-2(3H)-one in excellent yield (er > 99%, 8.4 kg, 90% yield). In conclusion, we have developed a facile, cost-efficient, and scalable synthetic route to (S)-Taniguchi lactone, free of chromatographic work-up and well-suited for large scale production. Also, we have discovered new conditions for ring-opening lactones with amines to yield hydroxyl-amides that do not rely on pyrophoric reactants such as alkylaluminum species, or other protocols that demand rigorous work-up. We have good reasons to believe that our Ti(i-OPr)4 method is generally applicable. In addition, we have shown that ringclosure/hydrolysis of hydroxyl-amides to lactones proceeds at significantly more benign conditions under mildly acidic conditions, in contrast to the strongly basic protocols previously reported. Finally, given the number of synthetic routes starting with the title compound, we believe that our findings should be of interest to chemists in academia and industry.
INTRODUCTION A recent project demanded large amounts of (S)-4-vinyldihydrofuran-2(3H)-one, also known as (S)-Taniguchi lactone.1 This valuable moiety has seen use as a starting point in a great number of natural syntheses.1−7 However, in our hands the published syntheses of the title compound were not suitable for production of the required amounts. Herein, we describe a concise synthesis of (S)-1 on large scale that proceeds in four steps from readily available and affordable starting materials (Scheme 1).
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RESULTS AND DISCUSSION Racemic lactone was easily obtained via scaling up a published hydroquinone catalyzed oxy-Claisen condensation between 2butene-1,4-diol and triethyl orthoacetate.8 The starting materials were heated at 120 °C until condensation of ethanol ceased, and subsequently heated at 150 °C for 48 h, after which GCMS indicated full consumption of the starting materials. Reduced pressure distillation and collection of a fraction (70− 80 °C at 2−3 mmHg) provided rac-1 (43.8 kg, 84% yield.). Although ring-openings of achiral, racemic, and chiral lactones using chiral amines have been reported numerous times,1,7,9−13 none of the attempted methods gave satisfactory yields or easily separable diastereomers. In an effort to improve matters, the readily available and affordable14 (S)-1-benzylmethylamine was identified and employed as a chiral auxiliary, and was heated in the presence of rac-1 with a slight excess of Ti(iOPr)4 as a dehydrating agent in THF at 75 °C. We were gratified that after 12 h analysis by GCMS revealed complete conversion to the desired ring-opened product. To the best of our knowledge, ring-opening of lactones under these conditions has not previously been reported. To our delight, it turned out that the desired hydroxyl-amide (S,S)-2 was crystalline, while the undesired diastereomer (R,S)2 was a viscous oil at room temperature, which opened up the way for a swift, simple, and highly selective separation by crystallization. Specifically, the diasteromeric mixture of hydroxyl-amides was duly dissolved in MTBE, the mixture cooled to 5 °C, seeded with pure (S,S)-2,15 and stirred. After 2 © 2014 American Chemical Society
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EXPERIMENTAL SECTION General. GC analysis was performed on Agilent 7890A, and GCMS analysis on Shimadzu QP2010. HPLC analysis was performed on Agilent 1200 C18 (4.6 mm × 150 mm × 5 μm) Received: March 21, 2014 Published: April 22, 2014 643
dx.doi.org/10.1021/op500096j | Org. Process Res. Dev. 2014, 18, 643−645
Organic Process Research & Development
Article
Scheme 1. Four-Step Synthesis of (S)-Taniguchi Lactone
vacuum filtration afforded a white solid (8 kg, 70% yield, dr > 99%). 1 H NMR (CDCl3, 300 MHz) δ 1.48−1.51 (d, 3H), 2.29− 2.45 (m, 2H), 2.62−2.79 (m, 2H), 3.59−3.66 (m, 2H), 5.11− 5.18 (m, 3H), 5.69−5.78 (m, 2H), 5.85 (br s, 1H), 7.30−7.38 (m, 5H). 13 C NMR (CDCl3, 75 MHz) δ 21.6, 38.9, 42.7, 48.9, 65.4, 116.8, 126.2, 127.4, 128.7, 138.1, 142.9, 171.2. MS (ESI): m/z (%) ([M + H], 100). Anal. Calcd for C14H19NO2: C 72.07, H 8.21, N 6.00. Found: C 71.95, H 8.23, N 5.95. [α]D25 −75.50° (c = 2.2 in CHCl3). (S)-4-Vinyldihydrofuran-2(3H)-one, (S)-Taniguchi Lactone ((S)-1). A 200 L reactor was charged with water (60 L), conc. H2SO4 (12.5 L), 1,4-dioxane (32.5 kg), and hydroxylamide (S,S)-2 (19.4 kg, 83 mol). The mixture was heated to 80 °C and stirred for 12 h, at which point TLC showed full conversion of starting material. The reaction mixture was cooled to room temperature and diluted with water (40 L). The mixture was extracted with dichloromethane (50 × 3 L), the combined organic phases washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, a colorless liquid was obtained (8.4 kg, 90% yield, er > 99%). 1 H NMR, 13C NMR, and MS (ESI) were identical to those for rac-1. [α]D25 +7.10° (c = 1.0 in CHCl3).
column with 55−97% acetonitrile (+0.1% NH4OAc) as mobile phase at a flow rate of 0.43 mL/min over 10 min. 1H NMR and 13 C NMR spectra were recorded on Bruker AV300 at 300 and 75 MHz, respectively. Operations except where indicated were performed in ambient atmosphere. Commercial starting materials and solvents were used as received. 4-Vinyldihydrofuran-2(3H)-one, Racemic Taniguchi Lactone (rac-1). In a 200 L reactor, 2-butene-1,4-diol (40.0 kg, 454 mol), triethyl orthoacetate (106.0 kg, 654 mol), and hydroquinone (10.4 kg, 94.5 mol) were mixed and heated at 120 °C under vigorous stirring with the ethanol generated by the reaction continuously removed by distillation. After no more condensation of ethanol was visible, the temperature was increased to 150 °C for 48 h. The residue was distilled under reduced pressure, and a 70−80 °C at 2−3 mmHg fraction was collected as a colorless oil (43.8 kg, 86% yield). 1 H NMR (CDCl3, 300 MHz) δ 2.30−2.39 (dd, J = 17.4 Hz, J = 8.7 Hz, 1H), 2.50−2.61 (dd, J = 17.7 Hz, J = 8.4 Hz, 1H), 3.15−3.26 (m, 1H), 3.61−3.97 (m, 1H), 4.36−4.42 (m, 1H), 5.10−5.17 (m, 2H), 5.68−5.80(m, 1H). 13 C NMR (CDCl3, 75 MHz) δ 34.1, 39.8, 72.2, 115.9, 135.8, 176.5. MS (ESI): m/z (%) 130 ([M+NH4]+, 100). Anal. Calcd for C6H8O2: C 64.27, H 7.19. Found: C 64.02, H 7.34. (S)-3-(Hydroxymethyl)-N-((((S)))-1-phenylethyl)pent4-enamide ((S,S)-2). In a 200 L reactor, a mixture of racemic Taniguchi lactone (rac-1) (25 kg, 223 mol), (S)-1-benzylmethylamine (27 kg, 223 mol) and Ti(i-OPr)4 (76 kg, 345 mol) in THF (50 L) was heated at 75 °C for 12 h. At this point GC showed full conversion. The mixture was cooled to room temperature and 2 M aqueous HCl (80 L) was added. The mixture was stirred for 1 h and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 × 50 L). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated to afford 45 kg of crude diastereomeric mixture of hydroxyl-amides (R,S)-2 and (S,S)-2. The mixture was used as such and dissolved in MTBE (38 L), seeded with pure (S,S)-215 and stirred at 5 °C. After 2 h,
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected], Phone: +46 70 7515353. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The initial small scale experiments were carried out at OnTarget Chemistry AB in Uppsala, Sweden, and the large scale synthesis was undertaken at Bejing Honghui Meditech Co., Ltd in China. Dr. Colin Ray and Mr. Alexander J. Munro are thanked for proofreading the manuscript. 644
dx.doi.org/10.1021/op500096j | Org. Process Res. Dev. 2014, 18, 643−645
Organic Process Research & Development
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Article
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dx.doi.org/10.1021/op500096j | Org. Process Res. Dev. 2014, 18, 643−645
