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Org. Synth. 2015, 92, 277-295

DOI: 10.15227/orgsyn.092.0277

One-pot Hydrozirconation/Copper-catalyzed Conjugate Addition of Alkylzirconocenes to Enones

Submitted by David Arnold, Tanja Krainz, and Peter Wipf^*1

Checked by Koichi Fujiwara and John Wood

1. Procedure

A. Tripent-4-enyl borate (1). A 300-mL, three-necked, flame-dried, round-bottomed flask equipped with a Teflon-coated stir bar (3 cm), two septa (Necks 1 and 3) and a Dean-Stark trap (20 mL, Neck 2) wrapped in aluminum foil and fitted with a reflux condenser (20 cm), and a nitrogen gas inlet adaptor (Note 1) is charged with boric acid (886 mg, 14.3 mmol, 1.0 equiv) (Note 2), toluene (70 mL) (Note 3), and 4-penten-1-ol (4.48 mL, 43.4 mmol, 3.0 equiv) (Note 2) at room temperature (Figure 1). The resulting suspension is slowly heated in an oil bath (135-136 °C) to reflux over 30 min and heating is continued at reflux for 1.5 h (Note 4). The reaction mixture turns homogeneous after 50 min of heating.

Figure 1. Apparatus Assembly for Step A

After heating at reflux for 1.5 h, the flask is removed from the oil bath and stirred at room temperature for 10 min before the septum (Neck 1) is replaced with a thermometer adaptor/thermometer (Note 5) and the Dean-Stark trap/reflux condenser (Neck 2) is replaced with a dry reflux condenser (20 cm) equipped with a nitrogen gas inlet adaptor (Figure 2). The resulting apparatus is further cooled for 20 min with the aid of an ice/water bath (Note 4) to 23-24 °C (internal temperature). The cooling bath is removed and the in situ generated tripent-4-enyl borate used directly for the next step (Note 6).

Figure 2. Apparatus Assembly for Step B

B. Tris[5-(bis(cyclopentadienyl)zirconium(IV)chloride)pentyl] borate (2). To the clear tripent-4-enyl borate solution is quickly added THF (50 mL) by syringe (Note 3), followed by Cp₂ZrHCl (14.7 g, 57.0 mmol, 4.0 equiv) (Note 7) in one portion via a powder funnel (Neck 3) at 24 °C (internal temperature) (Note 8). The resulting white suspension (Figure 3) bubbles gently for approximately 5 s, turns yellow/orange in color (Figure 4), and then clear (Figure 5) after approximately 15 min (Note 9). The hydrozirconation reaction is complete after 2 h (Note 10), and the solution of the alkyl zirconocene product formed is used without purification for the next step.

Figure 3. Initial white solution formed in Step B

Figure 4. Yellow suspension formed in Step B

Figure 5. Clear solution formed in Step B

C. 3-(5-Hydroxypentyl)cyclohexan-1-one (3). To the crude tris[5-(bis(cyclopentadienyl)zirconium(IV)chloride)pentyl] borate solution is added 2-cyclohexen-1-one (4.58 mL, 47.3 mmol, 3.3 equiv) by syringe (Notes 8 and 11) followed by CuBr●Me₂S (884 mg, 4.30 mmol, 0.3 equiv) (Note 8) via a powder funnel (Neck 3) in one portion at 24 °C. A strongly exothermic reaction ensues upon addition of CuBr●Me₂S, with the reaction temperature rising from 24 °C to 38 °C within 10 min (Note 12). The heterogeneous reaction mixture turns black (Figure 6) (Note 13) and the conjugate addition reaction is found to be complete after 2 h (Note 14).

Figure 6. Black solution formed in Step C

The reaction is quenched by pouring the reaction mixture into a 500-mL Erlenmeyer flask that contains a concentrated NH₄OH solution (150 mL) (Note 3) and a Teflon-coated stir bar (5.0 cm). The remaining residue in the three-necked, round-bottomed flask is transferred to the Erlenmeyer flask with an ether wash (100 mL) (Note 3) and the resulting heterogeneous, biphasic, grey mixture is vigorously stirred at room temperature for 2 h.

After 2 h, the mixture turns light blue in color (Figure 7) and is suction filtered (37 mmHg) through a 350-mL glass filter (porosity: 40-60 µm) into a 1000-mL filtration flask. The resulting pale blue solids and the 500-mL Erlenmeyer flask are washed with deionized water (3 x 40 mL) followed by ether (3 x 40 mL), and the filtrate is transferred to a 500-mL separatory funnel (Figure 8).

Figure 7. Light blue solution formed in Step C

The dark yellow ether layer is removed and the dark blue aqueous layer is extracted with ether (2 x 100 mL). The ether extracts are combined in a 1000-mL Erlenmeyer flask, dried over Na₂SO₄ (20.3 g, 15 min) (Note 15) and filtered (slight over pressure of air) through a plug of SiO₂ (25.0 g, height = 10.0 cm, diameter = 2.5 cm) into a 1000-mL round-bottomed flask with excess ether (100 mL), which is also used to rinse the Erlenmeyer flask. The yellow filtrate is concentrated by rotary evaporation (20 to 50 °C/50 mmHg) and the resulting oil (Note 16) is loaded with a 1:1 hexanes:EtOAc solution (10.0 mL) onto a 4.5-cm diameter flash column, dry packed (pre-flushed with 1:1 hexanes:EtOAc solution until uniformly solvated) with SiO₂ (162 g) (Note 17). Following the sample addition, the column is eluted with a 1:1 hexanes:EtOAc solution (1.6 L total volume, 33 mL/min. average flow rate) and the first 325 mL of eluent are collected as one fraction.

Figure 8. Biphasic solution in separatory funnel

At this time, a yellow band (Note 18) begins to elute from the column and fractions 60 mL in volume are collected. The desired product elutes over fractions 13-52 and a sample of the desired product enriched with the regioisomeric byproduct 3-(5-hydroxypentan-2-yl)cyclohexanone (4) is isolated over fractions 53-60 (Notes 19 and 20). Fractions 13-52 are combined (each test tube is rinsed with ether (2 mL)), concentrated by rotary evaporation (20 to 40 °C/50 mmHg), transferred to a pre-weighed 50-mL round-bottomed flask with ether (10 mL), re-concentrated by rotary evaporation (20 to 40 °C/50 mmHg) and dried under high vacuum (14 mmHg, 12 h) to afford 3-(5-hydroxypentyl)cyclohexan-1-one (3) as a pale yellow oil (5.20 g, 66%) (Notes 21 and 22).

2. Notes

1. All glassware contained 24/40 joints and was either flame-dried or oven-dried (110 °C) overnight prior to use, if not otherwise noted. All reaction steps and reagents were performed under a partial positive nitrogen gas atmosphere using a nitrogen gas line connected to an external mineral oil bubbler.

2. Copper(I)bromide dimethylsulfide (99%, Acros Organics), 4-penten-1-ol (99%, Acros Organics), and boric acid (>95%, Fisher Scientific, Reagent grade) were used as received. 2-Cyclohexene-1-one (>95%, Sigma-Aldrich) was freshly distilled (76 °C, 37 mmHg) prior to use. The submitters mentioned boric acid was either used as received or recrystallized two times from boiling deionized water and dried under high vacuum.² No appreciable difference in overall yield or reactivity was observed by the checkers using recrystallized vs. non-recrystallized boric acid.

3. Toluene and tetrahydrofuran were dried using a solvent purification system manufactured by SG Water U.S.A., LLC. Column chromatography solvents EtOAc and hexanes were used as received. Diethyl ether (ACS grade) and NH₄OH (ACS grade) were used as received.

4. A Pyrex® crystallization dish with a diameter of 15.0 cm and a height of 7.0 cm was used.

5. A mercury thermometer with a range of -20 to 110 °C was used.

6. The submitter followed the reaction progress by removing an aliquot (0.15 mL) of the reaction mixture after cooling to 22-23 °C and directly transferring it to an NMR tube for ¹H NMR analysis. The analysis showed ~85% conversion of the reagents to a single borate species: ¹H NMR (300 MHz, dry CDCl₃) δ: 1.77-1.84 (m, 2 H), 2.26-2.29 (m, 2 H), 3.94-3.99 (m, 2 H), 5.11-5.22 (m, 2 H), 5.92-6.06 (m, 1 H). This reaction has been performed under the same reaction conditions on a 1.0-mmol scale in both benzene and toluene at reflux furnishing the crude tripent-4-enyl borate, after removal of the reaction solvent via distillation and high vacuum, with 95-98% mass recoveries and in nearly identical purity to that of this reaction as analyzed by ¹H NMR.

7. Cp₂ZrHCl was prepared employing a method reported by Buchwald and co-workers.³ The activity of this reagent was measured by a convenient ¹H NMR assay: To a suspension of Cp₂ZrHCl (0.05 mmol, 12.9 mg, 1.0 equiv) in dry CH₂Cl₂ (0.50 mL) was immediately added tert-butyldiphenyl(prop-2-ynyloxy)silane (0.05 mmol, 14.7 mg, 1.0 equiv). The resulting homogeneous pale yellow reaction mixture was stirred at room temperature for 15 min, quenched by the addition of saturated NH₄Cl solution (0.50 mL), and stirred for 5 min. The organic solvent layer was separated, filtered through a 1" plug of Celite contained in a disposable 5 ¾" Pasteur pipette, washed with additional CH₂Cl₂ (1.5 mL) and concentrated by rotary evaporation (40 °C). The resulting white solids were dried under high vacuum for 30 min. This procedure was repeated three times on three different samples for each new batch of Cp₂ZrHCl. The percent conversion for each reaction was then determined via a ¹H NMR (300 MHz, CDCl₃) analysis by comparison of the integrated areas for the alkyne CH₂O peak at δ 4.32 (d, J = 2.4 Hz, 2 H) to the alkene CH₂O peak at δ 4.22 (dt, J = 4.5, 2.0 Hz, 2 H). Typical values for the average % conversion among the three experiments were found to be 73-83%. The numerical value for the average % conversion for a particular batch of Cp₂ZrHCl was used to calculate the number of equivalents of Cp₂ZrHCl (by mass) used in these hydrozirconations, ensuring that only a slight excess of Cp₂ZrHCl (3.1 equiv) was used in each experiment. Sample calculation: average % conversion = 78%; 3.1 active equiv of Cp₂ZrHCl = (X equiv of Cp₂ZrHCl) x 0.78 => X = 4.0 equiv of Cp₂ZrHCl.

8. The septum in Neck 3 was removed with the apparatus under a positive pressure of nitrogen gas atmosphere and then immediately replaced after the addition of reagent.

9. No exotherm was noted upon the addition of Cp₂ZrHCl to 1. The submitter mentioned that this observation stands in contrast to the reaction of 4-penten-1-ol (2.07 mL, 20.0 mmol, 1.0 equiv) with Cp₂ZrHCl (11.1 g, 43.0 mmol, 2.15 equiv) in THF (50 mL) at 25 °C (internal temperature) which was found to be exothermic (reaction temperature increasing to 34 °C) and accompanied by a vigorous (H₂) gas release, which persisted for 2 min, as a result of the deprotonation of 4-penten-1-ol with Cp₂ZrHCl.

10. The submitter followed the reaction progress by ¹H NMR (300 MHz, CDCl₃) analysis of aliquots (0.10 mL) of the reaction mixture. An approximate % conversion for the hydrozirconation reaction can be obtained by comparing the integrated areas for the tripent-4-enyl borate olefin proton resonance δ 4.97-5.10 (m, CH₂) vs. the newly formed tris[5-(biscyclopentadienyl)zirconium(IV)chloride)pentyl] borate methylene proton resonance δ 0.90-0.97 (m, 2H). This analysis gave 90%, 97% and 96% conversions for reactions run on 7%, 50% and 100% scales, respectively. Thin layer chromatography (Whatman®, aluminum backed, 250 µm thickness) analysis using a 1:1 mixture of hexanes:EtOAc as the eluent and a p-anisaldehyde solution (2.5 mL of p-anisaldehyde, 2.0 mL of AcOH, and 3.5 mL of conc. H₂SO₄ in 100 mL of 95% EtOH) for visualization showed a dark green/brown spot with an R_f = 0.03 for the hydrozirconation product.

11. The submitter mentioned that a mild exotherm was noted upon the addition of 2-cyclohexen-1-one to the reaction mixture with the reaction temperature rising from 23 °C to 25 °C. This exothermic reaction is quite possibly the result of the reaction of any excess Cp₂ZrHCl with 2-cyclohexen-1-one, since it was found that an exothermic reaction took place upon the addition of Cp₂ZrHCl (134.0 mg, 0.52 mmol, 1.0 equiv) to a solution of 2-cyclohexen-1-one (47.4 μL, 0.52 mmol, 1.0 equiv) in THF (3.0 mL) with the reaction temperature rising from 25 °C to 32 °C. This reaction provided 2-cyclohexen-1-ol in good conversion by crude ¹HNMR (300 MHz, CDCl₃) analysis and demonstrates the importance of using a slight excess of 2-cyclohexen-1-one in the above protocol.

12. The reaction mixture slowly re-cooled to 23 °C over 1.5 h.

13. The black color is a result of precipitation of copper(0) from the reaction mixture.

14. The submitter reported that the reaction progress was monitored by thin layer chromatography (Whatman® aluminum backed, 250 µm thickness) using a 1:1 mixture of hexanes:EtOAc as the eluent and a p-anisaldehyde solution for visualization. After 2 h reaction time, the conversion of 2-cyclohexen-1-one (R_f = 0.72) to the product 3-(5-hydroxypentyl)cyclohexan-1-one (R_f = 0.43) ceased after near complete consumption of 2-cyclohexen-1-one.

15. Anhydrous sodium sulfate (EMD, ACS grade, granular powder) was used as received.

16. A 3.0 mg sample of the crude mixture was dissolved in CH₂Cl₂ (1.0 mL) and analyzed by GC (HP-5ms agilent 30 m x 0.25 mm x 0.25 µm, helium flow 1.0 mL/min, temperature gradient 110 °C to 280 °C at 30 °C/min, FID detector). GC analysis showed a >96:4 ratio of the desired product 3-(5-hydroxypentanyl)cyclohexanone (3) (retention time of 4.74 min) to the side product 3-(5-hydroxypentan-2-yl)cyclohexanone (4).

17. SiO₂ 40-63 µm D (Silicycle, Quebec City, Canada) was used.

18. The submitter noted that the yellow band was found to contain a complex mixture of reaction byproducts including 2-cyclohen-1-ol, 4-penten-1-ol and 1-pentanol as determined by ¹H NMR (300 MHz, CDCl₃) analysis.

19. Column chromatography conditions to completely separate 3-(5-hydroxypentyl)cyclohexan-1-one and the minor regioisomer 3-(5-hydroxypentan-2-yl)cyclohexanone have not been identified. The chromatography conditions reported above allow for a partial separation of the two reaction products in which the last fractions of 3-(5-hydroxypentyl)cyclohexan-1-one are enriched with the byproduct 3-(5-hydroxypentan-2-yl)cyclohexanone. Collection, combination and concentration of column fractions 53-60 led to an enriched sample (90 mg) containing a 94:6 mixture of 3-(5-hydroxypentyl)cyclohexan-1-one (3): 3-(5-hydroxypentan-2-yl)cyclohexanone (4), as determined by GC (conditions in Note 16) and ¹H NMR pdf(400 MHz, CDCl₃) analysis. The isomer 3-(5-hydroxypentan-2-yl)cyclohexanone (4) can be identified by ¹H NMR (400 MHz, CDCl₃) as a result of its characteristic methyl peak at δ 0.89 (d, J = 6.8 Hz, 3 H, -CH₃).

20. The submitters reported that attempts to optimize this reaction included: (A) Reacting 4-penten-1-ol (0.269 mL, 2.58 mmol) with 2.0 equivalents of Cp₂ZrHCl (1.33 g, 5.16 mmol) at 5 °C in THF (10 mL) either by the addition of 4-penten-1-ol to a suspension of Cp₂ZrHCl (2.0 equiv) in THF at 5 °C followed by warming to 20 °C over 20 min or by sequentially reacting Cp₂ZrHCl (1.0 equiv) with 4-penten-1-ol (1.0 equiv) at 5 °C and then warming the mixture to 20 °C over 20 min before adding a second equivalent of Cp₂ZrHCl. The optimized procedure was found to give a cleaner hydrozirconation reaction product by ¹H NMR (300 MHz, CDCl₃) analysis. (B) The reaction mixtures were heated to 40 °C for 15-20 min to effect the hydrozirconation reaction, followed by cooling to 25 °C. (C) To the alkyl zirconocene solutions were added 2-cyclohexen-1-one (0.255 mL, 2.58 mmol, 1.0 equiv) followed by CuBr●Me₂S (53.5 mg, 0.258 mmol, 1.0 equiv) at 25 °C and the resulting brown mixtures were heated to 40 °C for 30 min to effect the transmetallation/conjugate addition reaction. Finally, these reactions were quenched with NH₄OH (14.8 M, 50 mL). While these reaction variants successfully produced 3-(5-hydroxypentyl)cyclohexan-1-one in comparable yields (60-70%, 283-337 mg), the isolated products were found to be contaminated with ca. 8-10% of the 3-(5-hydroxypentan-2-yl)cyclohexanone byproduct (4).

21. The product isolated in fractions 13-52 was found to be 97.6% pure by GC (conditions in Note 16) and contain 0.8% of 3-(5-hydroxypentan-2-yl)cyclohexanone. The product has the following characteristic physicochemical properties: ¹H NMR pdf(400 MHz, CDCl₃) δ: 1.23-1.39 (m, 7 H), 1.49-1.69 (m, 3 H), 1.68-1.80 (m, 2 H), 1.81-2.08 (m, 3 H), 2.18-2.42 (m, 3 H), 3.60 (t, J = 6.6 Hz, 2 H); ¹³C NMR pdf(100 MHz, CDCl₃) δ: 25.4, 25.9, 26.6, 31.4, 32.7, 36.6, 39.1, 41.6, 48.3, 62.9, 212.4; IR (neat) 3412, 2927, 2856, 1704, 1447, 1421, 1346, 1313, 1279, 1053 cm^-1; ESI-MS m/z 185 (24), 207 (100); HRMS (ESI) m/z calcd for C₁₁H₂₁O₂ [M+H]^+• 185.1536, found 185.1536. A 2.0 g sample was subjected to bulb-to-bulb distillation (150-151 °C/4.0 mmHg) affording 0.957 g (48% recovery) of the product as a clear oil. Anal Calcd for C₁₁H₂₀O₂: C, 71.70; H, 10.94; O, 17.36; Found: C, 71.53, H, 11.10.

22. A reaction checked at half-scale provided 2.69 g (68%) of the product. The submitters report that reactions run on 7% and 50% scales produced the product under identical reaction/workup conditions in 65% yield for both reactions with measured GC purities of ≥98% (conditions in Note 16).

Working with Hazardous Chemicals

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In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.

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3. Discussion

The copper-catalyzed conjugate Michael reaction and related additions of alkylzirconocenes to α,β-unsaturated carbonyl compounds have emerged as synthetically useful C-C bond forming processes.⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶ Recent examples include catalytic asymmetric additions to α,β-unsaturated lactones and enones.¹⁷^,¹⁸ The scope of this reaction has been previously investigated and some representative examples are shown in Table 1.⁹^,¹¹^,¹² As shown, these reactions are tolerant of cyclic and acyclic alkenes, as well as silyl ether, silyl ester and acetal functionalities. A variety of enones have also been successfully employed, including cyclic, acyclic, sterically hindered and chiral substrates.

The hydrozirconation/copper-catalyzed conjugate addition reaction of 3,4-dihydro-2H-pyran (DHP) with cyclohexen-1-one was shown to produce the title compound 3-(5-hydroxypentyl)cyclohexan-1-one in 85% yield.¹¹^,¹² The sequence of steps for this reaction is reported to involve an initial hydrozirconation of DHP followed by β-elimination to form intermediate (I), and then a second hydrozirconation of (I) generating intermediate (II) which undergoes the copper-catalyzed conjugate addition reaction with 2-cyclohexen-1-one (Scheme 1). Analysis of the reaction sequence suggested that this reaction could be generalized to include the conjugate addition of unprotected alkenyl alcohols. To test this hypothesis, reaction conditions were optimized for the reaction of 4-penten-1-ol with 2 equiv of Cp₂ZrHCl in THF (Note 20). This reaction proceeds through the initial deprotonation of 4-penten-1-ol with 1 equiv of Cp₂ZrHCl at 5 °C to generate the common intermediate (I), followed by hydrozirconation of (I) at 40 °C forming (II) which undergoes the copper-catalyzed conjugate addition to 2-cyclohexen-1-one in 60-70% yield (Scheme 1). While the yields for this addition reaction are acceptable, the isolated products are contaminated with 8-10% of the regioisomeric 3-(5-hydroxypentan-2-yl)cyclohexanone.

As a result of the cost of Cp₂ZrCl₂ and the high molecular weight of Cp₂ZrHCl, we were interested in developing a more cost effective and atom economical route involving the temporary protection of alkenyl-alcohol substrates to be utilized in this methodology. We found that the condensation of 4-penten-1-ol with boric acid, which changed the temporary organometallic alcohol protecting group from the zirconate RO-ZrCp₂Cl to the boronate (RO)₃B, was well tolerated in the subsequent hydrozirconation/copper-catalyzed conjugate addition reaction to 2-cyclohexen-1-one, and all steps following the formation of borate could be conducted at room temperature. Significantly, while this reaction led to comparable overall one-pot yields vs. the reaction performed with 2 equivalents of Cp₂ZrHCl, switching the initially produced metal alkoxide from Cp₂ClZr-OR to B-(OR)₃ allowed for a relatively fast hydrozirconation/copper-catalyzed conjugate addition reaction sequence at room temperature, which reduced the 3-(5-hydroxypentan-2-yl)cyclohexanone regioisomer formation to ca. ≤ 3.3% as determined by GC analysis of the crude reaction mixtures at all scales.

The procedure reported herein further exemplifies the utility and scalability of the one-pot tandem hydrozirconation/copper-catalyzed conjugate addition of alkylzirconocenes to enones. This reaction sequence allows for the economical use of unprotected alkenyl alcohols by utilizing the relatively benign B(OH)₃ as a temporary boron-based alcohol protecting group.

References and Notes

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA; Email: pwipf@pitt.edu
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Appendix
Chemical Abstracts Nomenclature (Registry Number)

Boric acid: trihydrooxidoboron; (10043-35-3)

4-Penten-1-ol: pent-4-en-1-ol; (821-09-0)

Cp₂ZrHCl: bis(cyclopentadienyl)zirconium(IV) chloride hydride; (37342-97-5)

2-Cyclohexen-1-one: (930-69-7)

CuBr●Me₂S: bromocopper-methylsulfanylmethane; (54678-23-8)

NH₄OH: ammonium hydroxide; (1336-21-6)

	David M. Arnold obtained his B.S. in Chemistry from Kings College in 2005 and graduated with a Master of Science degree from the University of Pittsburgh in 2010. Under the direction of Prof. Peter Wipf, he worked on the synthesis of biologically active heterocycles and the development of new organometallic methods.
	Tanja Krainz received her Dipl. Ing. from the Vienna University of Technology, Austria. In 2010, she moved to the University of Queensland, Australia and obtained her Ph.D. in 2014 in the field of natural product synthesis under the supervision of Associate Professor Craig M. Williams. She is currently a postdoctoral research associate in the Wipf group.
	Peter Wipf received his Dipl. Chem. in 1984 and his Ph.D. in 1987 from the University of Zürich under the direction of Professor Heinz Heimgartner. After a Swiss NSF postdoctoral fellowship with Professor Robert E. Ireland at the University of Virginia, Wipf began his appointment at the University of Pittsburgh in the fall of 1990. Since 2004, he is a Distinguished University Professor of Chemistry. He also serves as a co-Leader of the UPCI Cancer Therapeutics Program and he is the editor of Volume 87 of Organic Syntheses.
	Koichi Fujiwara received a B.S. degree in Pharmaceutical Sciences in 2010 from the Tokyo University of Science. He then moved to Tohoku University where, under the direction of Professor Takayuki Doi, he earned the M.S and Ph.D. degree in Pharmaceutical Sciences. In 2015, Koichi moved to Baylor University for postdoctoral studies under the direction of Professor John L. Wood.

Notes

4. A Pyrex® crystallization dish with a diameter of 15.0 cm and a height of 7.0 cm was used.

5. A mercury thermometer with a range of -20 to 110 °C was used.

8. The septum in Neck 3 was removed with the apparatus under a positive pressure of nitrogen gas atmosphere and then immediately replaced after the addition of reagent.