Organic Syntheses Procedure

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Org. Synth. 2018, 95, 142-156

DOI: 10.15227/orgsyn.095.0142

Enantioselective Synthesis of (S)-Ethyl 2-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-4-oxobutanoate

Submitted by Thibault J. Harmand, Claudia E. Murar, Hikaru Takano, and Jeffrey W. Bode^1*

Checked by Jacob C. Timmerman, Yu-Wen Huang, and John L. Wood

1. Procedure (Note 1)

A. tert-Butyl (tert-butyldimethylsilyl)oxycarbamate (1). N-Boc hydroxyl-amine (44.0 g, 330 mmol, 1.0 equiv) (Note 2) is introduced into a 2-L round-bottomed flask equipped with a 4-cm oval Teflon-coated stir-bar and is dissolved with CH₂Cl₂ (1.10 L). The reaction mixture is cooled to 4 °C in an ice-water bath after which a 250-mL addition funnel is attached. Triethylamine (49.0 mL, 363 mmol, 1.10 equiv) is transferred into the addition funnel via a graduated cylinder, and added dropwise over 15 min. Dichloromethane (20 mL) is used to ensure that no reagents are left on the side. tert-Butyldimethylsilylchloride (49.7 g, 330 mmol, 1.0 equiv) is dissolved in CH₂Cl₂ (150 mL) and added dropwise over 60 min via the addition funnel at 4 ºC. Dichloromethane (50 mL) is used to ensure that no reagent is left on the side of the addition funnel (final concentration of substrate is 0.25 M). The addition funnel is removed, the flask is equipped with a nitrogen inlet, and the reaction is stirred for 16 h at 23 °C under nitrogen (Note 3). Water (250 mL) is added and the mixture is poured into a 2-L separatory funnel. The reaction flask is rinsed with CH₂Cl₂ (50 mL) and the combined organic layer is separated and washed with saturated aqueous NaCl (250 mL). The organic layer is dried over MgSO₄ (20 g) and filtered by suction using a fritted funnel. Dichloromethane (50 mL) is used to wash the MgSO₄ and the filtrate is concentrated by rotary evaporation in a 2-L round-bottomed flask (40 °C bath, 425-30 mmHg). The resulting oil, which contains tert-butyl (tert-butyldimethylsilyl)oxycarbamate, is transferred to a 500-mL round-bottomed flask using CH₂Cl₂, which is then evaporated (40 °C bath, 425-30 mmHg). The product is dried on the vacuum pump (0.5 mmHg) for 48 h affording the desired compound (81.3 g, 329 mmol, 99.5% yield, 97.5% purity) as a white solid (Notes 4 and 5).

B. (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (2). (S)-(-)-α, α-Diphenyl-2-pyrrolidinylmethanol (25.0 g, 98.8 mmol, 1.0 equiv) (Note 6) is introduced in a 1-L three-necked round-bottomed flask (equipped with a 4-cm oval Teflon-coated stir-bar, an internal thermometer, and a glass stopper) and is dissolved with THF (220 mL). To the resulting solution, imidazole (20.0 g, 294 mmmol, 3.0 equiv) is added in one portion. After complete dissolution of the imidazole, the reaction mixture is cooled to 4 ºC in an ice-water bath. A 250-mL addition funnel is attached and then charged with trimethylchlorosilane (31.3 mL, 247 mmol, 2.50 equiv) via a 50 mL syringe. The TMSCl is added dropwise via the addition funnel over 20 min (Figure 1). Tetrahydrofuran (50 mL) is used to rinse the addition funnel and ensure that no reagent is left on the side of the addition funnel. The addition funnel is removed, the flask is equipped with a nitrogen inlet, and the reaction is stirred for 15 h at 23 °C under nitrogen. Methyl tert-butyl ether (MTBE) (150 mL) is added and the reaction stirred for an additional 15 min. The resultant heterogeneous mixture is filtered through a 10 cm diameter fritted funnel packed with Celite, and MTBE (3 x 50 mL) is used to wash the precipitate.

Figure 1. Addition of trimethylchlorosilane in Step B

The filtrate is poured into a 2-L separatory funnel. MTBE (50 mL) is used to rinse the flask and ensure that no reagents are left on the side of the flask. The organic layer is separated and washed with H₂O (3 x 150 mL) and saturated aqueous NaCl (2 x 250 mL). The organic layer is dried over MgSO₄ (10 g) and filtered by suction using a fritted funnel. Methyl tert-butyl ether (MTBE) (50 mL) is used to wash the MgSO₄ and the filtrate is concentrated by rotary evaporation into a 2-L round-bottomed flask (40 °C bath, 425-30 mmHg). The resulting oil containing 2 is transferred to a 250-mL round-bottomed flask using MTBE (10 mL), which is evaporated (40 °C bath, 425-30 mmHg) to provide the crude product (29.24 g, 89.8 mmol, 90.9%, purity <85%) (Note 7). The material is further purified by column chromatography to provide the desired compound (22.7 g, 69.8 mmol, 70.6% yield, 97.7% purity) as a pale yellow oil (Note 8 and 9).

C. (S)-Ethyl 2-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-4-oxobutanoate (3). A solution of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether 2 (19.0 g, 58.6 mmol, 0.50 equiv) in chloroform (120 mL) is transferred to a 1-L, three-necked, round-bottomed flask equipped with a 4-cm Teflon-coated magnetic stir-bar, a 250-mL addition funnel, a thermometer fitted with a glass adaptor, and a rubber septum through which nitrogen atmosphere is ensured (Figure 2). The flask is cooled to 4 ºC using an ice-water bath. Using a 20 mL syringe, ethyl (2E)-4-oxo-2-butenoate (14.1 mL, 117 mmol, 1.0 equiv) (Note 10) is added to the addition funnel.

Figure 2. Reaction Assembly for Step C

The enoate is then added to the flask dropwise via the addition funnel over 15 min, maintaining the internal temperature at 4 ºC. Chloroform (10 mL) is used to rinse the additional funnel. tert-Butyl (tert-butyldimethylsilyl)oxycarbamate 1 (34.8 g, 141 mmol, 1.20 equiv) is dissolved in chloroform (60 mL), placed in the addition funnel, and added dropwise over 1 h. The internal temperature is maintained at 4 ºC throughout the course of the addition. Chloroform (10 mL) is used to wash both the flask that contained the tert-butyl (tert-butyldimethylsilyl)oxycarbamate and the addition funnel. The final concentration of the substrate is 0.6 M. The reaction is stirred for 12 h under nitrogen at 23 °C, and the reaction is monitored by TLC (Note 11). The reaction mixture is transferred to a 1-L round-bottomed flask and concentrated by rotary evaporation (40 °C bath, 325-30 mmHg). The residue is dried on the vacuum pump (0.5 mmHg) for 5 h, after which the crude compound is purified by column chromatography (Note 12). The desired fractions are collected and concentrated by rotary evaporation (40 °C bath, 325-30 mmHg) to provide 13.3 g (30.1%) of the desired product. Impure fractions from the initial column are combined and further purified by column chromatography (Note 13). The desired fractions are collected and concentrated by rotary evaporation (40 °C bath, 325-30 mmHg) to provide 3.4 g (7.7%) of the product. The residual oils are further dried for 5 h under vacuum pump (0.5 mmHg) to afford the desired compound as a pale yellow oil (combined yield of 16.7 g, 37.8%, >98.5% purity, 94% ee) (Notes 14, 15, 16, and 17).

2. Notes

1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at https://www.nap.edu/catalog/12654/prudent-practices-in-the-laboratory-handling-and-management-of-chemical). See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with N-Boc hydroxylamine, triethylamine, dichloromethane, tert-butyldimethylsilyl chloride, ninhydrin, ethyl acetate, hexanes, sodium chloride, magnesium sulfate, (S)-(-)-α, α-Diphenyl-2-pyrrolidinylmethanol, tetrahydrofuran, imidazole, trimethylchlorosilane, methyl tert-butylether, Celite, ethyl (2E)-4-oxo-2-butenoate, chloroform, and potassium permanganate.

2. N-Boc-Hydroxylamine was obtained from Chem-Impex International, Inc (catalog number 29751) and used without further purification. The following reagents and solvents are used as received: methanol (Sigma-Aldrich, chromasolv, ≥99.9%), chloroform (Sigma-Aldrich, chromasolv, ≥99.8%), and tetrahydrofuran (Merck, ACS, reag ≥99.8%). The checkers purchased THF from Fisher Scientific (HPLC, >99.9%). The submitters purchased dichloromethane from Sigma-Aldrich (chromasolv, ≥99.5%), and the checkers purchased DCM from VWR (J.T. Baker, >99.5%). The submitters purchased tert-butyl methyl ether from Fluka (≥99%), and the checkers purchased MTBE from Fisher Scientific, (>99%). Triethylamine (Sigma-Aldrich, ≥99.5%) and imidazole (Sigma-Aldrich) were purchased and used as received. The submitters purchased tert-butyldimethylchlorosilane (TBDMSCl) from Fluorochem Ltd, and the checkers purchased TBDMSCl from Oakwood Chemical (99%). Trimethylchlorosilane was purchased from Sigma-Aldrich, and magnesium sulfate was purchased from Fisher Chemical. The submitters used silica gel (Fluka, high purity grade, pore size 60 Å, 230-400 mesh), and the checkers purchased silica gel from Silicycle, pore size 60 Å, 230-400 mesh particle size). Chloroform-D was purchased from (Armar, 99.8 atom%, submitters) and from Sigma-Aldrich (99.8 atom% D, checkers). The submitters purchased 1,3,5-trimethoxybenzene from ABCR (99%), and the checkers purchased that material from Sigma-Aldrich (99%). Deionized water is used throughout the procedure. The submitters purchased glass-backed, extra-hard layer TLC plates (60 Å, 250 μm thickness containing F-254 indicator) from Silicycle, and the checkers purchased identical TLC plates from EMD Millipore.

3. TLC analysis was performed on silica: Compound 1 has an R_f = 0.8 in 40% EtOAc in hexanes using ninhydrin as stain (product color is fuschia).

4. The identity of the product (1) was established with the following characterization data. ¹H NMR pdf(400 MHz, CDCl₃) δ: 0.14 (s, 6H), 0.93 (s, 9H), 1.45 (s, 9H), 6.68 (s, 1H); ¹³C NMR pdf(101 MHz, CDCl₃) δ: -5.80, 18.01, 25.87, 28.15, 81.55, 157.89; HRMS (ESI+) calc. for C₁₁H₂₅NO₃Si [M+Na]⁺ 270.1496, found 270.1498. The purity of the compound was calculated by qNMR pdf with a delay of relaxation of 30 seconds using 15.6 mg of 1,3,5-trimethoxybenzene (purity 99%) and 20.9 mg of the compound 1.

5. A second run on full scale provided 79.3 g (97%) of the same product.

6. (S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol was obtained from Combi-Blocks and used without further purification.

7. The crude compound 2 obtained by the checkers contained impurities that could be seen in the ¹H NMR spectrum. Purification was performed by silica gel column chromatography (9 x 55 cm) with 500 g of silica gel packed with 2 L of 30% diethyl ether/hexanes. Fraction collection (500 mL per fraction) begins immediately with 3 L of 30% diethyl ether/hexanes, then 2 L of 60% diethyl ether/hexanes. Fractions 4-16 contain the desired compound (2) and are collected. The combined fractions are concentrated by rotary evaporation (40 °C bath, 325-30 mmHg) and then dried on the vacuum pump for 10 h.

8. The identity of the product (2) was established with the following characterization data. ¹H NMR pdf(400 MHz, CDCl₃) δ: -0.06 (s, 9H), 1.38-1.47 (m, 1H), 1.47-1.65 (m, 2H), 1.73 (bs, 1H), 2.79-2.91 (m, 1H), 4.06 (t, J = 7.2 Hz, 1H), 7.22-7.32 (m, 6H), 7.39 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 7.2 Hz, 2H). ¹³C NMR pdf(101 MHz, CDCl₃) δ: 2.2, 25.0, 27.5, 47.1, 65.4, 83.2, 126.7, 126.9, 127.5, 127.5, 127.6, 128.4, 145.8, 146.8. HRMS (ESI+) calc. for C₂₀H₂₈NOSi [M+H]⁺ 326.1940, found 326.1938. The purity of the compound was calculated by qNMR pdf with a delay of relaxation of 30 seconds using 18.56 mg of 1,3,5-trimethoxybenzene (purity 99%) and 33.19 mg of the compound 2.

9. A second run on full scale provided 31.6 g (98%) of 2 with purity sufficient to avoid chromatography.

10. Ethyl trans-4-oxo-2-butenoate was obtained from ABCR-Chemicals (96%) and must be purified prior to use. Purification can be performed by either column chromatography or by distillation under reduced pressure.

Purification by column chromatography: A column (5 x 35 cm) is packed with 75 g of silica gel in 5% EtOAc:hexanes (200 mL). Ethyl trans-4-oxo-2-butenoate (20 mL) is directly loaded on the column. The elution is performed with 5% EtOAc:hexanes and fractions are collected in 200 mL Erlenmeyer flasks. The first 100 mL are discarded. The collection is started and the desired product is generally obtained in fractions 2-9, which are concentrated by rotatory evaporation and (40 °C bath, 325-30 mmHg) and high vacuum. The recovery yield is generally >90 %.

Purification by distillation: Ethyl trans-4-oxo-2-butenoate is placed in a 100 mL flask with a 2.5-cm Teflon-coated magnetic stir bar. The flask is equipped with a Vigreux column containing a thermometer on its top, a water condenser on the side to collect the distillate, and attached to a vacuum source. The purified product distills at 35 °C at 6.10^-2 mmHg.

11. TLC analysis is performed with 25% EtOAc in hexanes using KMnO₄ as stain. The product 3 has an R_f = 0.6, the starting material 1 has an R_f = 0.7, and the aldehyde starting material has an R _f = 0.5.

12. A column (15 x 45 cm) is packed with 1.5 kg of silica gel with 5% EtOAc:hexanes (~3 L). The crude material is dissolved in 20 mL eluent (heating at 35° C is required to fully dissolve) and loaded onto the silica gel. The flask is washed with 30 mL eluent in order to ensure that no products are left on the side of the flask. Sand (600 g) is added to the top of the silica gel and provides a layer of 2 cm. Elution is performed with 5% EtOAc:hexanes and collected in 250-mL Erlenmeyer flasks, from which the first 5.0 L are discarded. The eluent is increased to 10% EtOAc:hexanes and collection with 250-mL fractions is started. After elution with 5 L, fractions 6-18 contain compound 1 whereas fractions 19-20 contain mixture of compounds 1 and 3. Elution is then performed with 15% EtOAc:hexanes until the product (3) has fully eluted. No pressure is applied. Fractions 1-3, obtained from the 15% EtOAc:hexanes elution, contain a mixture of 1 and 3. The desired product is obtained in fractions 4-20, which are concentrated by rotary evaporation (40 °C bath, 325-30 mmHg).

13. The remaining impure fractions were combined, concentrated and purified again with a second column (9 x 55 cm) packed with 750 g of silica gel. The silica gel is loaded in 5% EtOAc:hexanes (~3 L), and the crude material is loaded on the silica gel. The flask is washed with 5 mL eluent in order to ensure that no products are left on the side of the flask. Sand (200 g, ~2 cm) is added to the top of the silica gel. The elution is performed with 5% EtOAc:hexanes, in 250-mL Erlenmeyer flasks and the first 4.0 L are discarded. Elution with 5% EtOAc:hexanes is continued for another 5 L, and 150-mL fractions are collected. These fractions (1-39) contain compound 1. The eluent is increased to 10% EtOAc:hexanes and collection of 150-mL fractions is performed. Fractions 9-12 contain desired compound 3, and the eluent is increased to 20% EtOAc:hexanes (~1.5 L) to flush out the remaining compound 3. No pressure is applied before 20% EtOAc:hexanes is added. The desired fractions are collected and concentrated by rotary evaporation (40 °C bath, 325-30 mmHg).

14. The identity of the product (3) was established with the following characterization data. ¹H NMR pdf(400 MHz, CDCl₃) δ: 0.15 (d, J = 7.2 Hz, 6H), 0.90 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 2.78 (dd, J = 17.6, 5.2 Hz, 1H), 3.21 (dd, J = 17.6, 8.0 Hz, 1H), 4.11-4.25 (m, 1H), 4.89 (dd, J = 8.0, 5.2 Hz, 1H), 9.80 (s, 1H); ¹³C NMR pdf(101 MHz, CDCl₃) δ: -4.8, -4.7, 14.1, 17.9, 25.8, 28.1, 42.8, 60.5, 61.6, 82.5, 157.9, 169.0, 198.7; HRMS (ESI+) calc. for C₁₇H₃₃NO₆Si [M+Na]⁺ 398.1975, found 398.1973. IR (thin film): 3393, 3187, 3029, 2953, 2982, 2895, 2656, 1735, 1617, 1462, 1252, 1091, 836, 775 cm^-1 . The purity of the compound was calculated by qNMR pdf with a delay of relaxation of 30 seconds using 16.40 mg of 1,3,5-trimethoxybenzene (purity 99%) and 31.09 mg of compound 3.

15. A second run on full scale provided 15.7 g (35.5%) of the same product.

16. Procedure for preparing the racemic product: To a solution of ethyl trans-4-oxo-2-butenoate (2.0 L, 16.6 mmol, 1.0 equiv) in CHCl₃ (24 mL, 0.75 M), pyrrolidine (0.27 L, 3.3 µmol, 0.2 equiv) was added. The solution was stirred for 5 min and 1 (4.9 g, 19.8 mmol, 1.2 equiv) was added. The mixture was stirred at rt for 16 h, after which it was concentrated to a brown-orange oil. Purification by silica gel chromatography (gradient of 5-15% Et₂O:pentane) gave the racemic material as a colorless oil (0.93 mg, 2.5 µmol, 15% yield).

17. The checkers determine the enantiomeric excess to be 94% by chiral the HPLC on Chiralcel IA column using hexanes/isopropyl alcohol (98:2) at a flow rate of 0.8 mL/min, while monitoring at 210 nm. Retention time (t_R) of the major enantiomer = 7.3 min, and retention time (t_R) of the minor enantiomer = 8.0 min.

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

Enantioenriched β-amino aldehydes are important chiral building blocks that are readily converted into the corresponding amino alcohols and β-amino acids. β-amino carbonyls have broad utility and they are constituents of natural products and pharmaceutical agents. Asymmetric methods have been well documented for their preparation by MacMillan and Cordova via conjugate addition reactions involving N-centered nucleophiles and chiral amine catalysts.³

In the context of expanding the α-ketoacid-hydroxylamine (KAHA)⁴ ligation monomers we have recently published the synthesis of a modified cyclic hydroxylamine by organocatalytic synthesis.⁵ We were intrigued by the key intermediate (S)-ethyl 2-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-4-oxobutanoate obtained via conjugate addition between the N-Boc-protected hydroxylamine and ethyl trans-4-oxo-2-butenoate. We were pleased to find that this intermediate proved to be extremely useful in the synthesis of several other cyclic hydroxylamines and more importantly to (S)-N-Boc-5-oxaproline, which is our preferred building block for KAHA ligation (Scheme 1).

Scheme 1. General use of the β-amino aldehyde intermediate for the synthesis of various hydroxylamines for KAHA ligation or amino-acid analogues1,3

This encouraged us to enable an efficient, practical route that could be easily scaled up to provide enantiopure (S)-ethyl 2-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-4-oxobutanoate based on an enantioselective, organomediated addition reaction between tert-butyl (tert-butyldimethylsilyl)oxycarbamate and ethyl trans-4-oxo-2-butenoate.

For these two reaction partners we have screened three different diphenylprolinol catalysts. We noticed that TBS protected diphenylprolinol 4 proceeded with slightly higher enantioselectivity^6a yet the addition yield was lower than the TMS protected catalyst 2.^6b Unfortunately we could not obtain a satisfying result when using catalyst 5.^6c In order to make the route suitable for a larger scale synthesis we chose the TMS protected diphenylprolinol as the catalyst of choice (Table 1).

Table 1. Screening of catalysts for the addition reaction

The synthesis of the TMS protected diphenylprolinol catalyst was straightforward starting from the commercially available, affordable intermediate (S)-diphenyl(pyrrolidin-2-yl)methanol. Screening of different acid additives as benzoic acid, acetic acid or dimethylhydrogen phosphate did not improve the outcome of the reaction. Stronger acids such as p-toluene sulfonic acid or 2,4-dinitrobenzenesulfonic acid led to equivalent yield. Further evaluation of the conditions for the conjugate addition revealed that using 50% of the organic catalyst and the purification of the commercially available 1,4-unsaturated aldehyde improved the addition yield to 48%. Surprisingly, increasing the quantity of the TMS protected diphenylprolinol to 75% and to an equimolar ratio did not show any yield improvement. Despite all of our attempts to optimize it we were not able to make this process catalytic.

The present synthesis of (S)-ethyl 2-((tert-butoxycarbonyl)((tert-butyldimethylsilyl)oxy)amino)-4-oxobutanoate provides a convenient route to the synthesis of unnatural amino acids and hydroxylamine building blocks for the KAHA ligation. This synthesis will be the starting point for the design and synthesis of a large number of cyclic hydroxylamines as new monomers for KAHA ligation.

References and Notes

Eidgenössiche Technische Hochschule Zürich, HCI F317, 8093 Zürich, Switzerland. Email: bode@org.chem.ethz.ch.
Boeckman and co-workers, Org. Synth. 2015, 92, 309-319.
(a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328-9329. (b) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G. L.; Xu, Y.; Córdova, A. Tetrahedron Lett. 2007, 48, 2193-2198. (c) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G. L.; Córdova, A., Chem. Commun. 2007, 849-851.
(a) Pattabiraman, V. R.; Ogunkoya, A. O.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 5114-5118. (b) Ogunkoya, A. O.; Pattabiraman, V. R.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9693-9697.
Murar, C. E.; Thuaud, F.; Bode, J. W. J. Am. Chem. Soc. 2014, 136, 18140-18148.
(a) Fleischer, I.; Pfaltz, A. Chem. Eur. J. 2010, 16, 95-99. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T. Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212-4215. (c) Jensen, K.L.; Dickmeiss, G.; Hao, J.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248-264.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

N-Boc hydroxylamine; (36016-38-3)

tert-Butyldimethylsilyl chloride; (18162-48-6)

Triethylamine; (121-44-8)

(S)-(-)-α,α-Diphenyl-2-pyrrolidinemethanol; (112068-01-6)

Ethyl (2E)-4-oxo-2-butenoate; (2960-66-9)

	Thibault Harmand studied Chemistry at the University of Nantes and Lyon (France). After his master thesis with Prof. George Fleet at the University of Oxford, he joined the group of Prof. Jeffrey Bode at ETH Zurich. His research focuses on the total chemical synthesis of proteins such as the hormone protein betatrophin and the antiviral membrane protein IFITM3 as well as the development of amino acids building blocks for chemical ligation.
	Claudia Murar was born in Deva, Romania in 1988. She moved for her studies to France where she studied chemistry at the National Institute of Applied Sciences (INSA), Rouen (France). She worked for one year at GSK, King of Prussia (USA) after which she completed her master thesis at Novartis, Basel (Switzerland). She joined the group of Prof. Jeffrey Bode at ETH Zurich in 2012 for her Ph.D. Her research focuses on the total chemical synthesis of hormone proteins and therapeutic proteins, development of new building blocks for chemical ligation and synthesis of unnatural amino acids.
	Hikaru Takano was born in Nagasaki, Japan in 1989. He received his B.Eng. degree in 2012 from Saitama University (Prof. Katsukiyo Miura). He then moved to Tokyo Medical and Dental University and is currently pursuing his Ph.D. degree under the supervision of Prof. Hirokazu Tamamura (2012-present). His current research focuses on the development of chemical probes, especially fluorescent dyes, photolabile protecting groups and caged compounds.
	Jeffrey Bode is Professor of Synthetic Organic Chemistry at ETH Zürich. In addition, he serves as an Executive Editor for the Encyclopedia of Reagents for Organic Synthesis, co-Editor in Chief of Helvetica Chimica Acta, and a Principal Investigator at the Institute of Transformative bio-Molecules (ITbM) at Nagoya University in Japan. His research group focuses on the development of new reactions, including methods for N-heterocycles, chemical protein synthesis, bioconjugation, and chemical biology.
	Jacob C. Timmerman graduated from the University of North Carolina at Chapel Hill in 2012 with a B.A. in Chemistry. Later in 2012, Jacob began his graduate studies at Duke University under the advisement of Professor Ross A. Widenhoefer where his research focused on the development and mechanistic studies of gold(I)-catalyzed hydrofunctionalization reac-tions of alkenes. After completing his Ph.D. in 2017, Jacob joined the laboratories of Professor John L. Wood as a postdoctoral research associate where his research focuses on the total synthesis of natural products.
	Yu-Wen Huang was born in Hsinchu, Taiwan (R.O.C.) in 1982. He received his bachelor's degree from National Cheng Kung University in 2005. He then joined the M.S. program at the National Tsing Hua University working under the supervision of Professor Shang-Cheng Hung on carbohydrate synthesis. In 2016, he received his Ph.D. degree from the University of Rochester where he worked with Professor Alison J. Frontier on 1,6-conjugate addition initiated Nazarov reactions and sequential 1,5-hydride transfer chemistry. He is currently a post-doctoral fellow in the CPRIT lab (Baylor University) with Professor John L. Wood working on the total synthesis of natural products.

Notes

References/EndNotes

Article Compounds

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