Huge thanks go to Professor Andy Myers for the professionalism, enthusiasm, advice and encouragement he provided as my mentor, and for the creativity, knowledge and erudition he offered as my research director. I am also grateful for the chance to work on a methodology project that was challenging and educational, yet practical and broadly applicable. I know that not everyone gets a second chance, and I feel privileged for the opportunity I was given.
Thanks also to Jim Gleason and Mike Kort for being great instructors in our problem sessions, and to Steve Arvedson for the great times we had both in the lab and with CBB. Both enantiomers of pseudoephedrine are free chemicals and can be N-acylated in high yields to form tertiary amides. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols.
For the current application, the chiral auxiliary is typically covalently bound to a carboxylic acid equivalent, and when it has served its purpose, it is cleaved from the substrate. The first practical demonstration of the use of a chiral auxiliary for the asymmetric alkylation of a carboxylic acid enolate equivalent was reported by Meyers and co-workers in 1976.2 In this pioneering work, oxazoline anions were shown to originate from chiral.
Scheme I
The asymmetric alkylation of the α-carbon of carboxylic acid derivatives is a reaction of fundamental importance in modern synthetic organic chemistry.1 With few exceptions, this type of transformation is carried out by means of a chiral auxiliary, a molecule that can control the stereochemistry of the alkylation step on a such a way that a product of the desired configuration is obtained. Because chiral auxiliaries are required in stoichiometric amounts, it is advantageous that they are inexpensive and/or recoverable. To be able to access both enantiomers of a given product, it is also useful if both antipodes (or the synthetic equivalent) are readily available.
Later, Evans and Takacs3a and Sonnet and Heath3b independently demonstrated that alk:ylations of tertiary ami des enolates derived from the amino alcohol prolinol occurred with higher diastereoselectivities (Scheme II, 76–94% de).
These alkylation products were then transformed into chiral carboxylic acids with synthetically useful optical purities (51-86% ee). An important contribution in this area is the development of the camphor-discovered sultam auxiliaries by Oppolzer and co-workers.6 In addition to the practical feature that the auxiliaries can be readily cleaved under mild conditions (Scheme IV), the alkylation reactions are typically highly diastereoselective, and many of the alkylation products are crystalline and readily emissive to:;:::99% de.
OAN~CH3
Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, determined that the ratio of the (2R,4S,6S) diastereomer to the (2S,4S,6S) diastereomer was 66:1. Purification of the residue by flash column chromatography (40% ethyl acetate-hexanes) afforded amide 34 as a viscous oil (1.25 g, 94%). Chiral capillary GC analysis43 of the corresponding acetate ester, prepared as described above for amide 28, determined that the ratio of the (2S,4S,6S) diastereomer to the (2S,4S,6S) diastereomer was 199:1.
Purification of the residue by flash column chromatography (72% ethyl acetate-hexanes) afforded amide 35 as a viscous oil (124 mg, 84%). Purification of the residue by flash column chromatography and elution with a gradient of ethyl acetate-hexanes afforded amide 37 as a white crystalline solid (232 mg, 72%). 1H NMR analysis (300 MHz, C6D6) and chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 3 was 6 of 93% de.
Recrystallization of the solid (1.0 g, obtained from the combined yields of several of the above reactions) from hot ethyl acetate (70 °C, 10 mL) gave This is an excellent alternative method and was used, for example, for the hydrolysis of the 2-methylsuccinic acid derivative 15 (74% yield, 94% ee), where the poor ether solubility of the product, 2-methylsuccinic acid, precluded the use of tetra-n- . One of the problematic substrates for both the basic and acidic hydrolysis was the a-benzyloxymethyl-substituted substrate 13.
Basic hydrolysis (tetra-n-butylammonium hydroxide, water-tert-butyl alcohol, reflux) of amide 13 resulted in a 92% yield of the corresponding acid, but the ee was only 64%. Although water soluble, this hydrosulfate salt can be salted out of the aqueous phase with sodium chloride and extracted with ethyl acetate. Attempts to protect the nitrogen as the corresponding trifluoroacetamide, acetamide, or priopionamide (to prevent 0 ~ N acyl transfer), followed by alkaline hydrolysis of the ester functionality, gave only fair yields of the desired acid.
Although ester functionalities are usually more susceptible to hydrolysis than amide functionalities, the rate of hydrolysis of the ester functionality was likely slowed due to increased steric hindrance. After a second extraction workup, exposure of the amine-borane complex to aqueous tetra-n-butylammonium hydroxide (5 equivalents) at 23 °C resulted in hydrolysis of the ester to release the desired carboxylate product. Application of this methodology to the hydrolysis of α-benzyloxymethyl-substituted amide 13 gave acid 41 in 80% yield and 88% ee, and hydrolysis of benzylated pseudoephedrine propionamide (11) gave acid 39 in 79% yield and >99% .
Scheme X
Chiral capillary GC analysis of the corresponding (R)-α-methylbenzylamide, 46 prepared as described above for acid 39, determined acid 40 to be in 97% ee. Chiral capillary GC analysis of the corresponding (R)-α-methylbenzylamide, 46 prepared as described above for acid 39, determined acid 41 to be in 69% ee. Chiral capillary GC analysis of the corresponding (R)-α-rnethylbenzylarnide, 46 prepared as described above for acid 39, determined acid 41 to be in 88% ee.
Chiral capillary GC analysis of the corresponding (R)-α-methylbenzyl amide, 46 prepared as described above for acid 39, showed acid 42 to have 94% ee. Chiral capillary GC analysis of the corresponding (R)-a.-methylbenzyl amide, 46 prepared as described above for acid 39, showed acid 43 to have 82% ee. Chiral capillary GC analysis of the corresponding ( R )- a .- methylbenzyl amide 46 prepared as described above for acid 3 9 showed acid 4 4 to have 93% ee.
Chiral capillary GC analysis of the corresponding ( R )- α -methylbenzyl amide 46 prepared as described above for acid 3 9 showed acid 4 5 to have 84% ee. Chiral capillary GC analysis of the corresponding (R)-α-methylbenzyl amide, 46 prepared as described above for acid 39, showed acid 4 to have 6 64% ee. The de of acid 47 was determined to be 95% by comparing the 1H NMR spectrum with that of acid 48.
The pH of the mixture was adjusted to pH ~ 10 by the slow addition of 2 N aqueous sodium hydroxide solution (40 mL) and the resulting mixture was extracted with ether (3 x 7 mL). The de was determined to be 95% by comparison of the 1H NMR spectrum with that of acid 48. The pH of the mixture was adjusted to pH ::2:10 by the slow addition of 2 N aqueous sodium hydroxide solution (40 ml) and the resulting mixture was extracted with ether (3 x 7 mL).
They were determined to be 93% by comparison of the 1H NMR spectrum with that of acid 47. The cloudy suspension of LAB is then cooled to 0°C and a solution of the pseudoephedrinamide substrate (1 equiv) in THF is added. In general, <4% of the tertiary amine byproduct is produced if care is taken to use at least 4 molar equivalents of LAB in the reaction.
Scheme XI
Scheme XII
The reaction mixture was stirred at 23°C for 6 h before excess hydride was quenched by the addition of 3 N aqueous hydrochloric acid solution (15 mL). Purification of the residue by flash column chromatography (35% ether-petroleum ether) afforded alcohol 50 as a colorless liquid (405 mg, 84%). High-resolution 1H NMR analysis (300 MHz, C6D6) of the corresponding Mosher ester derivative 58 prepared as described above for alcohol 50 determined alcohol 51 to be ∼95% ee.
High-resolution 1H NMR analysis (400 MHz, CDCl3) of the corresponding Mosher ester derivative 58 prepared as described above for alcohol 50. High-resolution 1H NMR analysis (300 MHz, CDCl3) of the corresponding Mosher ester derivative/8, prepared as described above for alcohol 50, showed alcohol 52 to have 91% ee. High-resolution 1H NMR analysis (300 MHz, C6D6) of the corresponding Mosher ester derivative 58 prepared as described above for alcohol 50 revealed that alcohol 53 has ∼95% ee.
High resolution 1H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative, 58 prepared as described above for alcohol 50, established that alcohol 54 was of ∼95% ee. High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, determined that alcohol 55 was of ;;:::95% ee. High resolution 1H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative, 58 prepared as described above for alcohol 50, established that alcohol 55 was of ∼95% ee.
Purification of the residue by flash column chromatography (40% ether-petroleum ether) afforded alcohol 56 as a colorless liquid (67 mg, 83%). High-resolution 1H NMR analysis (400 MHz, CDCl3) of the corresponding Mosher ester derivative 58 prepared as described above for alcohol 50 revealed that alcohol 57 has ∼95% ee. High-resolution 1 H NMR analysis (300 MHz, CDCl 3 ) of the corresponding Mosher ester derivative 58 prepared as described above for alcohol 50 revealed alcohol 57 to have 2':95% ee.
High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative, 58 prepared as described above for alcohol 50, established that alcohol 58 was. Purification of the residue by flash column chromatography (40% ether-petroleum) afforded alcohol 59 as a colorless liquid (350 mg, 78%). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as described above for alcohol 59, determined that alcohol60 was 98% de.
