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Org. Synth. 2011, 88, 42-54
DOI: 10.15227/orgsyn.088.0042
THE PREPARATION OF (2R,5S)-2-t-BUTYL-3,5-DIMETHYLIMIDAZOLIDIN-4-ONE
Submitted by Thomas H. Graham, Benjamin D. Horning, and David W. C. MacMillan1.
Checked by David Hughes2
1. Procedure
A. (S,E)-2-(2,2-dimethylpropylidenamino)-N-methylpropanamide (2). A tared 1-L round-bottomed flask (Note 1) equipped with a 3-cm oval PTFE-coated magnetic stir bar is charged with a 31 wt% solution of methylamine in ethanol (112 mL, 85 g, 0.85 mol, 3.0 equiv) (Note 2) and placed in a room temperature water bath. To the stirred solution is added L-alanine methyl ester hydrochloride (40.0 g, 0.287 mol, 1.0 equiv) (Note 3) via a powder funnel followed by a rinse with ethanol (10 mL). The flask is fitted with a rubber septum through which is inserted both an 18-gauge needle connected to a nitrogen inlet with a gas bubbler and a thermocouple probe (Note 4). The mixture is stirred at 20-22 °C for 4 h (Notes 5 and 6). The stir bar is removed, and the mixture is concentrated by rotary evaporation (20 mm Hg, 45 °C bath temperature) to provide a wet solid (60 g). Toluene (100 mL) (Note 7) is added to the mixture, which is concentrated by rotary evaporation (20 mm Hg, 45 °C bath temperature) to provide a wet solid (65 g). The toluene (100 mL) flush is repeated, and the mixture is concentrated to 49 g of solids, which are dried in a vacuum oven (20 mmHg, 45 °C) for 4 h to afford the crude L-alanine-N-methylamide 1 as a pasty solid (45 g) (Notes 8 and 9).
The 1-L flask containing the crude L-alanine-N-methylamide 1 is equipped with a 3-cm oval PTFE-coated magnetic stirring bar. The solids are scraped off the walls using a spatula (Note 10). The flask is immersed in a room temperature water bath and charged with anhydrous magnesium sulfate (30 g) and dichloromethane (140 mL) (Note 11). The mixture is stirred at ambient temperature and treated sequentially with triethylamine (60.0 mL, 43.6 g, 0.425 mol, 1.5 equiv) and pivaldehyde (95% purity, 35 mL, 28 g, 0.31 mmol, 1.07 equiv corrected for purity) (Notes 11 and 12). The flask is fitted with a rubber septum through which is inserted both an 18-gauge needle connected to a nitrogen inlet with a gas bubbler and a thermocouple probe (Note 4). The reaction mixture is stirred for 4 h at ambient temperature (Notes 13 and 14). Additional pivaldehyde (3 mL) and magnesium sulfate (5 g) are added, and the mixture is stirred for an additional 30 min at ambient temperature. The septum is removed and replaced with a 250-mL addition funnel. Toluene (200 mL) is added over 10 min, and the mixture is stirred for an additional 15 min. The mixture is then filtered through a 350-mL medium porosity sintered glass funnel to remove the triethylamine hydrochloride and magnesium sulfate. The filter cake is washed with toluene (3 × 50 mL). The combined filtrate is concentrated by rotary evaporation (100 mmHg initially to 20 mmHg, 45 °C bath temperature) to 70 g. Additional triethylamine hydrochloride precipitates during this concentration, so additional toluene (100 mL) is added and the mixture is filtered through a 60-mL medium porosity sintered glass funnel. The filtrate is concentrated by rotary evaporation (20 mmHg, 50 °C bath temperature), then vacuum dried (0.1 mmHg, 23 °C) for 4 h to afford (S,E)-2-(2,2-dimethylpropylidenamino)-N-methylpropanamide (2) (44.2-46.5 g, 95% purity, 86-90% yield) as a pale yellow oil. (Notes 15 and 16)
B. (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (3). A 500-mL round-bottomed, three-necked flask, equipped with a 3-cm oval PTFE-coated magnetic stirring bar, is fitted with two septa and a 100-mL pressure-equalizing addition funnel connected to a nitrogen inlet with a gas bubbler. A thermocouple probe is inserted through one septum (Note 4). The flask is charged with ethanol (140 mL), placed in an ice-water bath, and cooled to 1-3 °C. The addition funnel is charged with acetyl chloride (22.3 mL, 24.5 g, 0.312 mol, 1.1 equiv) (Note 17). The acetyl chloride is added dropwise over 15 min to the stirred ethanol solution, resulting in a temperature rise to 18 °C. The solution is cooled to 5 °C with an ice bath. The addition funnel is replaced with a standard tapered glass funnel, and maintaining ice bath cooling, the crude imine (2) (45.7 g, 95% pure, 0.255 mol) is poured into the HCl/ethanol solution as one portion over 30 s. The flask that contained 2 is rinsed with ethanol (3 × 10 mL), and the rinses are added to the HCl/ethanol solution via the tapered glass funnel. The glass funnel is removed and replaced with an inlet adapter connected to a nitrogen line and gas bubbler. The reaction temperature rises from 5 °C to 30 °C over a 3 min period after addition of the imine, and crystallization occurs within 10 min (Note 18). The ice-bath is removed and replaced with a heating mantle, and the stirred mixture is warmed to 70 ± 2 °C over 30 min and held at this temperature for 20 min (Note 19). The mixture remains heterogeneous. The heating mantle is removed, and the stirred mixture is allowed to cool to 23 °C over 1.5 h, and stirring is continued for 2 h at ambient temperature. The resulting crystals are vacuum filtered using a 350-mL sintered glass funnel. The filter cake is washed with ethanol (2 × 30 mL) and air-dried to afford (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (3) (43.2 g) as white crystalline material (Note 20). The mother liquors are concentrated to 80 mL by rotary evaporation (20 mmHg, 50 °C bath temperature) in a 500-mL round-bottomed flask, and the crystallization process is repeated to afford a second batch of 3 (3.9 g) as white crystalline material (Note 21). The first and second batches are combined to afford 47.1 g of 3 (89% yield for this step, 77-80% for 3 steps) (Notes 22 - 26).
2. Notes
1. A 1-L flask was used to minimize bumping during concentration after completion of the reaction.
2. Methylamine (33 wt% in ethanol) was purchased from Sigma-Aldrich and used as received. 1H NMR analysis with a 5 second delay indicated the reagent contained 31 wt% methylamine and 69 wt% ethanol. The use of less than 3 equiv of methylamine led to incomplete conversion to the N-methyl amide.
3. L-Alanine methyl ester hydrochloride (1) was purchased from Sigma-Aldrich (99%) and Alfa Aesar (99%) and used as received. The hydrochloride salt is hygroscopic and was weighed into a bottle that was capped after weighing to avoid exposure to air prior to addition to the reaction. 1H NMR analysis of this starting material is recommended as one sample contained 15% of the diketopiperazine impurity. Water content was measured by Karl-Fischer titration and ranged from 0.2 to 1.0% for the various lots of material used.
4. The internal temperature was monitored using a J-Kem Gemini digital thermometer with a Teflon-coated T-Type thermocouple probe (12-inch length, 1/8 inch outer diameter, temperature range −200 to +250 °C).
5. The mixture warms from 21 °C to 29 °C within 5 min of solids addition, then cools to 20-22 °C over 15 min in the water bath. In the hands of the checker the reaction solution remained heterogeneous throughout. In one experiment, an aliquot of the reaction mixture was filtered at the end of the reaction. The solids were determined to be methylamine hydrochloride by 1H NMR analysis (CD3OD).
6. The reaction progress is monitored by 1H NMR analysis (CD3OD) of aliquots of the reaction mixture. The starting material resonances at 3.74 (s, 3 H, OCH3) and 1.34 (d, 3 H, CHCH3) are monitored vs. product at 2.78 (s, 3 H, NHCH3) and 1.29 (d, 3 H, CHCH3). The reaction is complete after 1.5 h (<1% starting material based on a spiking experiment with starting material).
7. Toluene (ACS reagent grade, >99.5%) was purchased from Sigma-Aldrich and used as received
8. The solids are a mixture of methylamine and L-alanine-N-methylamide. The level of methylamine was typically ~40 mol% vs. product. The solids are vacuum dried until the level of ethanol and toluene are <3 mol% by 1H NMR analysis. One experiment in which the toluene flushes were omitted afforded material that contained 15 mol% ethanol and 70 mol% methylamine relative to amide product. This material resulted in a 10 % lower yield in the imine formation.
9. Spectroscopic data for crude L-alanine-N-methylamide hydrochloride: 1H NMR pdf (400 MHz, CD3OD) δ: 1.49 (d, J = 7.1 Hz, 3 H, CHCH3), 2.79 (s, 3 H, NHCH3), 3.93 (q, J = 7.0 Hz, 1 H, CHCH3); 13C NMR pdf (100 MHz, CD3OD) δ: 17.8, 26.5, 50.4, 171.6. Methylamine: 1H NMR (400 MHz, CD3OD) δ: 2.55 (s); 13C NMR (100 MHz, CD3OD) δ: 25.5.
10. Material dried on the walls of the flask tends not to react so optimum yields are obtained when this material is dislodged from the walls. L-Alanine-N-methylamide that is chunky or pasty in consistency performs well in the imine formation. The submitters report that thoroughly dried amide must be ground to a powder for optimum results.
11. The following reagents and solvents were used as received for the imine formation: anhydrous magnesium sulfate powder (Fisher), toluene (Sigma-Aldrich, ACS reagent grade, >99.5%), triethylamine (Sigma-Aldrich, 99%), and dichloromethane (Fisher Optima, >99.5%). Pivaldehyde (96%) was purchased from Sigma-Aldrich; 1H NMR analysis revealed a number of low level impurities that collectively integrated to ~5%. The material was charged based on 95% purity.
12. The mixture warms from 24 °C to 30 °C over a 5 min period after addition of pivaldehyde.
13. The reaction progress is followed with 1H NMR by adding an aliquot of the reaction mixture to CDCl3 and filtering the sample. To determine the level of pivaldehyde remaining, the sample is analyzed directly, comparing the aldehyde proton (9.5 ppm) of pivaldehyde to the corresponding proton of the imine (7.6 ppm). To accurately measure unreacted amide, the solution is evaporated to remove dichloromethane, then taken up in CDCl3 for analysis (imine CHCH3 quartet at 3.7 ppm compared to amide at 3.5 ppm).
14. Complete consumption of pivaldehyde typically occurs within a two hour reaction time but depends on the consistency of the amide (chunky material takes longer to react). The reaction typically stalls at 91-94% conversion, requiring an additional charge of pivaldehyde and magnesium sulfate. Addition of 10% more pivaldehyde or 25% more magnesium sulfate at the beginning of the reaction does not lead to increased conversion.
15. By 1H NMR analysis, the imine contained 1.5 wt% unreacted amide and 3.5 wt% toluene. Toluene levels up to 8% were used with no impact for the next step. Amide levels up to 8% were used for the next step with no impact for the first and second crop isolations but co-crystallized with product if a third crop was isolated. The submitters stored the imine under vacuum. The checker stored the imine in a flask sealed with a septum and observed approximately 2% hydrolysis to the amide in a week at room temperature.
16. Spectroscopic data for 2: 1H NMR pdf (400 MHz, CDCl3) δ: 1.08 (s, 9 H, C(CH3)3), 1.31 (d, J = 7.1 Hz, 3 H, CHCH3), 2.84 (d, J = 5.0 Hz, 3 H, NCH3), 3.68 (q, J = 7.0 Hz, 1 H, CHCH3), 6.9 (bs, 1 H, HNCH3), 7.52 (s, 1 H, (CH3)3CHN); 13C NMR pdf (100 MHz, CDCl3) δ: 21.6, 26.0, 26.9, 36.6, 67.7, 173.2, 174.8.
17. Ethanol (ACS reagent, >99.5%, water content 0.37 mg/mL based on Karl Fischer titration) and acetyl chloride (reagent grade, 98%) were purchased from Sigma-Aldrich and used as received.
18. The reaction progress is monitored by 1H NMR of a sample dissolved in CD3OD. The reaction is complete within 10 min of imine addition with no resonances corresponding to the imine detectable.
19. The cyclization reaction forms a 3:1 mixture of trans:cis (3:4) diastereomers. Warming to 70 °C for 20 min results in equilibration to the thermodynamic ratio of 5:1 (this thermodynamic ratio in ethanol is also established starting with pure 3). At the same time, decomposition of the diastereomers to amide 1 and the diethyl acetal of pivaldehyde occurs. At reflux (79 °C), the equilibration occurs within 5 - 10 min but degradation is also relatively rapid; therefore, the equilibration time and temperature were selected to afford complete equilibration with minimal decomposition (about 2%). The equilibration and decomposition of 3 is likely occurring via a reversible reaction with the imine as outlined below. Equilibration directly between 3 and 4 is unlikely as neither of the protons at positions 2 or 5 is exchanged in CD3OD during equilibration, indicating that a deprotonation/ protonation process is not occurring. Starting with pure 3 in either methanol or ethanol solution, the equilibration of 3 and 4, and their decomposition to amide 1 and the acetal of pivaldehyde, were followed by 1H and 13C NMR.
20. In the lab of the submitters, cooling the solution at a more rapid rate resulted in the entrainment of the minor diastereomer, (2S,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one 4. In addition, the submitters report cooling the solution below 20 °C, or allowing 3 to age with the mother liquors for >6 h, caused the minor diastereomer to begin crystallizing. In the lab of the checker, the minor diastereomer 4 was never detected in crystalline 3 (<0.2% by NMR) even with >12 h crystallization age times. It is important to adequately wash the filter cake to ensure that the mother liquors are not entrained.
21. 1H NMR (CD3OD) analysis of an evaporated sample of the mother liquors indicated a ratio of 3:4:1 of 49:37:12. Heating at 70 ± 2 °C for 20 min resulted in equilibration to a 5:1 ratio of 3:4.
22. A third crop of 3 can be obtained by concentrating the remaining mother liquors to 40 mL and repeating the equilibration/crystallization procedure to afford 1.1 g of 3.
23. (2R,5S)-2-tert-Butyl-3,5-dimethylimidazolidin-4-one (3) has the following physical and spectroscopic data: mp 211-216 °C with decomposition (ethanol); [α]D −43.4 (c 1.0, CH3OH, 23 °C); IR (solid) 2873, 2641, 2514, 1719, 1584 cm−1; 1H NMR pdf (400 MHz, CD3OD) δ: 1.19 (s, 9 H, (CH3)3C), 1.59 (d, J = 7.0 Hz, 3 H, CHCH3), 3.09 (s, 3 H, NCH3), 4.28 (q, J = 7.0 Hz, 1 H, CHCH3), 4.79 (s, 1 H, (CH3)3CCH); 13C NMR pdf (100 MHz, CD3OD) δ: 14.9, 25.5, 32.5, 37.7, 54.9, 82.0, 171.3; HRMS (ESI-TOF) m/z calcd for C9H19N2O ([M+H]+) 171.1492, found 171.1492; Karl Fischer titration: 0.1% water; elemental analysis calcd. for C9H19ClN2O: C, 52.29; H, 9.26; N, 13.55; found: C, 52.53; H, 9.51; N, 13.51; chloride titration (AgNO3) calcd: Cl, 17.15; found Cl, 17.16.
24. The minor diastereomer, (2S,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (4), has the following spectroscopic data: 1H NMR (400 MHz, CD3OD) δ: 1.19 (s, 9 H, (CH3)3C), 1.59 (d, J = 7.2 Hz, 3 H, CHCH3), 3.04 (s, 3 H, NCH3), 4.13 (q, J = 7.1 Hz, 1 H, CHCH3), 4.71 (s, 1 H, (CH3)3CCH); 13C NMR (100 MHz, CD3OD) δ: 14.9, 25.4, 31.5, 35.3, 54.8, 81.8, 171.6.
25. Imidazolidinone 3 is converted, as follows, to (2S,5S)-benzyl-2-tert-butyl-3,5-dimethyl-4-oxoimidazolidine-1-carboxylate for assessing the enantiopurity:
An 8 mL vial is charged with 3 (100 mg, 0.48 mmol, 1.0 equiv), solid NaHCO3 (200 mg, 2.4 mmol, 5.0 equiv), ethyl acetate (1.0 mL) and water (1.0 mL). The mixture is treated with benzyl chloroformate (100 μL, 0.72 mmol, 1.5 equiv) and stirred at ambient temperature for 16 h. The layers are separated and the aqueous layer is extracted with ethyl acetate (2 mL). The combined organic layers are concentrated and purified on SiO2 (10 g), eluent: 25% ethyl acetate/ hexanes, 10 mL fractions. Fractions 8-13 are concentrated to afford (2S,5S)-benzyl-2-tert-butyl-3,5-dimethyl-4-oxoimidazolidine-1-carboxylate (130 mg, 88%) as a clear, colorless syrup: Rf 0.4 (40% ethyl acetate/ hexanes); [α]D -15.3 (c 1.00, CH2Cl2, 22 °C); IR (neat) 2966, 1699, 1411, 1392, 1251, 1119, 698 cm−1; 1H NMR pdf (500 MHz, CDCl3) matches reported spectrum (Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chim. Acta 1987, 70, 237-261) δ: 0.97 (s, 9 H, C(CH3)3, 1.55 (bs, 3 H, CHCH3), 3.01 (s, 3 H, NCH3), 4.04-4.06 (m, 1 H, CHCH3), 5.05-5.21 (m, 3 H, CHC(CH3)3, PhCH2O), 7.33-7.39 (m, 5 H, ArH); 13C NMR pdf (125 MHz, CDCl3) δ: 18 (br), 26.5, 32.2, 40.7, 56.0, 67.7, 81.2, 128.6, 128.80, 128.81, 136.0, 155 (br), 173.0; HRMS (ESI-TOF) m/z calcd for C17H25N2O3 ([M+H]+) 305.1865, found 305.1865. Since both enantiomers were required to develop a chiral assay, the enantiomer of 3 was prepared from D-alanine methyl ester hydrochloride. Submitters chiral HPLC analysis: AD-H (250 × 4.6 mm, 5μm particle size), isocratic elution with 15% ethanol/hexanes, 1.0 mL/min, 254 nm), Rt(major) = 8.47 min, Rt(minor) = 6.87 min; checkers chiral SFC analysis: AD-H (250 × 4.6 mm, 5μm particle size), isocratic elution with 4% MeOH containing 25 mM isobutylamine, 3.0 mL/min, 200 bar, 35 °C, 215 nm, 6 min total run time; Rt(major) = 3.9 min, Rt(minor) = 4.5 min. None of the minor enantiomer was detected; spiking experiments indicated the ee was >99%.
26. Imidazolidinone 3 is non-hygroscopic at ambient humidity conditions and can be stored in a closed container at ambient temperature with no additional precautions.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Over the past decade, organocatalysis has emerged as a versatile method for the enantioselective preparation of organic molecules.3 Among the numerous organocatalysts developed, the imidazolidinone family is one of the most versatile catalysts, mediating a variety of transformations including Diels-Alder,4 1,3-dipolar cycloadditions,5 1,4-conjugate additions,6 α-oxidations,7 α-chlorinations, α-fluorinations,8 hydride reductions,9 and epoxidations.10 In addition, the mild reaction conditions and selectivity of the imidazolidinone organocatalysts allow for efficient cascade catalysis.11 A new mode of activation, SOMO catalysis, involving the oxidative coupling of enamines and nucleophiles (SOMO-philes) allows for unprecedented enantioselective transformations including α-allylations,12 α-enolations,13α-vinylation,14 α-nitroalkylation,15 α-arylations16 and the carbo-oxidation of styrenes.17
Recently, (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (3) has emerged as a privileged organocatalyst that mediates a variety of useful asymmetric transformations (Scheme 1). The α-chlorination of aldehydes occurs in 75-95% yield and 91-96% ee and the α-chloroaldehydes can be transformed into a variety of enantio-enriched epoxides, aziridines, α-chloro alcohols, α-cyano alcohols, α-hydroxy acids, and α-amino acids (Scheme 1, eq 1).18 The α-trifluoromethylation of aldehydes occurs in 62-86% yield and 93-99% ee using visible light and 0.5 mol% of an iridium photoredox catalyst (Scheme 1, eq 2).19 Similarly, bromoalkanes will add to the aldehyde with visible light and 0.5 mol% of a ruthenium photoredox catalyst (Scheme 1, eq 3).20
Scheme 1.
Scheme 1.
The procedure describes the preparation of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one (3) from L-alanine methyl ester hydrochloride.21 The present method consistently affords 3 as white crystals in good yield (77-80% for 3 steps) and high enantiomeric purity (>99% ee), without intermediate purifications or chromatography.
References and Notes
  1. Merck Center for Catalysis at Princeton University, Frick Laboratory, Washington Road, Princeton University, Princeton, NJ 08544; e-mail:
  2. The checker thanks Zainab Pirzada for development of the chiral assay of the CBZ derivative of compound 3, Mirlinda Biba for the rotation and chloride analyses, and Robert Reamer for NMR support.
  3. (a) MacMillan, D. W. C. Nature 2008, 455, 304-308; (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79-87.
  4. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-4244; (b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458-2460; (c) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616-11617.
  5. Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-9875.
  6. (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370-4371; (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172-1173; (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894-7895; (d) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192-1194; (e) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328-9329.
  7. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808-10809.
  8. Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826-8828.
  9. (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32-33; (b) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662-12663; (c) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438-15439; (d) Ouellet, S. G.; Walji, A.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327-1339.
  10. Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413-11424.
  11. (a) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Nat. Acad. Sci. 2004, 101, 5482-8487; (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051-15053; (c) Walji, A.; MacMillan, D. W. C. Syn. Lett. 2007, 10, 1477-1489; (d) Simmons, B.; Walji, A.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 4349-4353.
  12. Beeson, T. D.; Mastracchio, A.; Hong, J.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582-585.
  13. Jang, H.; Hong, J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004-7005.
  14. Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398-399.
  15. Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11332-11334.
  16. Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11640-11641.
  17. Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494-16495.
  18. Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121-5124.
  19. Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875-10877.
  20. Nicewicz D. A.; MacMillan, D. W. C. Science 2008, 322, 77-80.
  21. (a) Adamson, G. A.; Beckwith, A. L. J.; Chai, C. L. L. Aust. J. Chem. 2004, 57, 629-633; (b) Kazmierski, W. M.; Urbanczyk-Lipkowska, Z; Hruby, V. J. J. Org. Chem. 1994, 59, 1789-1795; (c) Naef, R.; Seebach, D. Helv. Chim. Acta 1985, 68, 135-143.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Acetyl chloride: (75-36-5)

L-Alanine methyl ester hydrochloride: (2491-20-5)

Benzyl chloroformate, carbobenzoxy chloride: (501-53-1)

Methylamine: (74-89-5)

Pivaldehyde, trimethylacetaldehyde: (630-19-3)

Triethylamine, N,N-diethyl-ethanamine: ( 121-44-8)

David W. C. MacMillan received his B.S. degree in chemistry in 1990 from the University of Glasgow, Scotland, and his Ph.D. degree in 1996 from the University of California, Irvine, where he worked under the direction of Professor Larry E. Overman. David then moved to Harvard University and completed his postdoctoral studies with Professor David A. Evans. In 1998, David joined the faculty at the University of California, Berkeley. In 2000, he moved to the California Institute of Technology, where, in 2003, he was promoted to the rank of full professor and the following year, he became the Earle C. Anthony Chair in Organic Chemistry. In 2006, David moved to Princeton University where he is the A. Barton Hepburn Professor of Chemistry, the Director of the Merck Center for Catalysis at Princeton and the Chairperson of the Department of Chemistry.
Thomas H. Graham received his B.S. in Chemical Engineering from Virginia Tech in 1995. He completed his undergraduate research in the laboratory of Professor Neal Castagnoli, Jr. He then moved to Research Triangle Park, North Carolina, where he worked for Eli Lilly and was involved in chemical synthesis, laboratory automation and technology development. From 2000 to 2006, he completed his graduate studies in organic chemistry with Professor Peter Wipf at the University of Pittsburgh. From 2006 to 2008, he was a postdoctoral fellow with Professor David MacMillan at Princeton University. He is currently employed at Merck Research Laboratories in Rahway, New Jersey.
Benjamin D. Horning received his B.S. in Biochemistry at the University of Oregon in Eugene, Oregon in 2007. He did undergraduate research with Professor Michael Haley studying metalla-benzenes. He is currently a graduate student at Princeton University with Professor David MacMillan studying natural product synthesis and cascade catalysis.
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