((Catch Phrase))

DOI: 10.1002/anie.200((will be filled in by the editorial staff))

Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis
Marvin R. Morales, Kevin T. Mellem, and Andrew G. Myers*
Pseudoephedrine is widely employed as a chiral auxiliary in diastereoselective alkylation reactions, providing ready access to enantiomerically enriched carboxylic acids, aldehydes, ketones, and alcohols.[1] Because pseudoephedrine can be transformed into methamphetamine and other illegal drug substances, many countries restrict or ban its sale and distribution, which can complicate its use in industrial and academic settings.[2] Here we report that (1S,2S)and (1R,2R)-2-methylamino-1,2-diphenylethanol (synonymously, (1S,2S)- and (1R,2R)-pseudoephenamine,[3] respectively) enable a broad range of utilities in asymmetric synthesis that meet or exceed those that previously characterized the pseudoephedrine system alone, with several advantages. Specifically, (1) these auxiliaries are free from regulatory restrictions and are not known to be transformable into illicit substances, (2) asymmetric alkylation reactions employing pseudoephenamine as a directing group proceed with equal or greater diastereoselectivities vis-à-vis the corresponding reactions employing pseudoephedrine, with notable improvements in the selectivities of alkylation reactions that form quaternary stereocenters, and (3) amides derived from pseudoephenamine exhibit a greater propensity to be crystalline substances relative to the corresponding pseudoephedrine derivatives and provide sharp, well-defined peaks in NMR spectra. Both enantiomeric forms of pseudoephenamine are easily prepared using well-established methods (Scheme 1). In 1951, Tishler and co-workers at Merck reported a process for the transformation of erythro-1,2-diphenyl-2-aminoethanol (1R,2S or 1S,2R) into the corresponding threo-diastereomer (1S,2S or 1R,2R, respectively) by N-formylation with formamide, invertive cyclization to form the corresponding oxazoline using thionyl chloride, and hydrolytic ring-opening under acidic conditions.[4,5] Employing a small but important modification (the use of formamide containing ~0.2 equiv ammonium formate for Nformylation rather than pure formamide, which leads to yellowing and a reduced yield of the product), we have applied the Tishler protocol for large-scale synthesis of both enantiomers of threo-1,2diphenyl-2-aminoethanol from the appropriate erythro-diastereomer (both erythro diastereomers are commercially available in enantiomerically pure form and are widely used as chiral auxiliaries themselves, e.g., in the Williams amino acid synthesis).[6–8] Subsequent N-methylation of threo-1,2-diphenyl-2-aminoethanol was then achieved in 97% yield by N-formylation with acetic formic anhydride followed by reduction with lithium aluminum hydride.[9] The product was recrystallized from hot ethanol to produce large, orthorhombic, colorless crystals (mp 109–110 ºC).[10] We have routinely prepared 20–40-g batches of (1R,2R)- or (1S,2S)pseudoephenamine by the 4-step sequence described, which proceeds in 87% yield and requires no column chromatography.[11,12] X-ray crystallographic analysis revealed that pseudoephenamine adopts a conformation identical to pseudoephedrine in the solid state, with gauche orientations between both the aminomethyl and hydroxyl substituents as well as the two phenyl substituents (Figure 1).
O H 2 NH2 OH 1 NH2 N H O H

HCO2NH4 150 ºC

OH

(–)-(1R,2S)-1,2-diphenyl-2-aminoethanol

SOCl2, 0 ! 23 ºC; H2O, reflux O O O H NH2 OH (–)-(1S,2S)-1,2-diphenyl-2-aminoethanol

1. H3C N H CH3

2. LiAlH4

OH

(–)-(1S,2S)-pseudoephenamine

Scheme 1. Synthesis of (–)-(1S,2S)-pseudoephenamine by a modified Tishler protocol followed by N-methylation.

(–)-(1S,2S)-pseudoephenamine

(+)-(1S,2S)-pseudoephedrine

Figure 1. X-ray crystal structures of (–)-(1S,2S)-pseudoephenamine [13] and (+)-(1S,2S)-pseudoephedrine.

[∗]

M. R. Morales, K. T. Mellem, Prof. A. G. Myers Department of Chemistry and Chemical Biology Harvard University Cambridge, Massachusetts 02138 (USA) Fax: (+) 1-617-495-4976 E-mail: myers@chemistry.harvard.edu [∗∗] We gratefully acknowledge the NSF (CHE-0749566) and the NIH (CA-047148) for financial support of this research. We also wish to thank Dr. Shao-Liang Zheng for X-ray crystallographic analyses and Dr. David Kummer for helpful discussions. Supporting information for this article is available on the WWW under http://www.angewandte.org.

Amide derivatives of pseudoephenamine were prepared from the corresponding carboxylic acid chlorides or anhydrides by routine methods and, in most cases, were crystalline solids (see Supporting Information). Pseudoephenamine amide enolates were generated with lithium diisopropylamide (2.2 equiv) in tetrahydrofuran (THF) at –78 °C in the presence of a saturating amount of anhydrous lithium chloride (ca. 6 equiv), conditions identical to those employed for enolization of pseudoephedrine amides.[1e] Pseudoephenamine propionamide was poorly soluble in THF alone, precluding the use of this solvent for enolization; a 1:1 mixture of THF-pyridine proved to be a viable reaction solvent for generation

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Table 1. Diastereoselective Alkylation of Pseudoephenamine Amides.

Chart 1. Transformations of Pseudoephenamine Amides into Enantiomerically Enriched Carboxylic Acids, Alcohols, and Ketones. Carboxylic Acids (via acidic or basic hydrolysis):[a]
O HO CH3 CH3
HO O CH3

O N CH3 R1

1. LDA, LiCl, THF 2. R2X X!–

O R1 R2

OH

O HO CH3

Entry [a]

Product
O

Crude dr[b]

Isolated dr [b]

Yield (%)

mp (ºC) 93%, 95% ee 97%, ≥95% ee 98%, 98% ee 99%, 95% ee
O HO CH3
HO

CH3

1

X!–

CH3

89%, 92% ee 94%, 91% ee
O CH3

95:5

≥99:1

85

128–129
HO

O

O

2

X!–

CH3

95:5
CH3

98:2

97

NA

CH3

93%, ≥97% ee

99%, 92% ee

98%, 90% ee

O

Ketones (via aryl or alkyllithium addition): ≥94:6 98:2 96 NA
O H3C CH3

3

X!–

CH3 CH3

O CH3
H3C

O CH3

O

4

X!– CH3
O

CH3

≥96:4

≥99:1

87

89–90

CH3

95%, ≥95% ee

96%, ≥93% ee

98%, ≥95% ee

Alcohols (via LAB reduction):
CH3

5

X!–

≥98:2

≥99:1

99

112–114
HO

CH3

HO

CH3

HO CH3

O

6

X!– CH3
O

CH3

95:5

98:2

84

77–79

91%, 98% ee

89%, 95% ee

94%, 87% ee

7

X!– CH3

98:2
O

98:2

92

NA

[a] Acidic hydrolysis was achieved by heating the amide to 115 ºC with 9 N sulfuric acid in dioxane. Basic hydrolysis was achieved by heating the amide to 95 ºC with tetrabutylammonium hydroxide in a [1e] 3:1 mixture of tert-butyl alcohol and water.

X!–

8
CH3

≥99:1

≥99:1

99

109–111

[a] Entries 1, 2, and 3 were conducted in 1:1 THF-pyridine as solvent; all other entries were conducted in THF alone as solvent. All reactions were conducted with excess alkyl halide (1.5–4.0 equiv). [b] Diastereomeric ratios were determined by HPLC analysis; for entries 1 and 7, the corresponding trimethylsilyl ethers were analyzed by HPLC.

of a soluble enolate in this case (also in the presence of a saturating amount of LiCl, Table 1, Entries 1–3). Subsequent addition of various alkyl halides (1.5–4.0 equiv) to these enolate solutions at temperatures ranging from –78 to 0 ºC led to alkylated products in 84–99% yields (after purification by flash column chromatography or recrystallization) with uniformly high diastereoselectivities [diastereomeric ratios (dr) of isolated products ranged from 98:2 to ≥99:1; crude dr values are listed in Table 1]. Reaction diastereoselectivities were initially measured by direct HPLC analysis of the products, but we later determined that they were also readily assessed by 1H NMR analysis of the corresponding oxazolinium triflate derivatives, obtained by invertive cyclization with triflic anhydride (see Supporting Information for details).[14] Diastereoselectivities were uniformly high, as in the corresponding alkylation reactions of pseudoephedrine amides. The majority of the alkylation products were solids.

Optically active carboxylic acids, ketones, and alcohols were obtained directly from alkylated pseudoephenamine amides using methods paralleling those previously employed for similar transformations of pseudoephedrine amides (Chart 1). Thus, hydrolysis of pseudoephenamine amides under both acidic and basic conditions provided carboxylic acids in high yields with little or no epimerization of the α-carbon center (89-99% yield), addition of organolithium reagents to pseudoephenamine amides afforded enantiomerically enriched ketones (95-98% yield), and reduction of pseudoephenamine amides with lithium amidotrihydroborate (LAB)[15] gave the corresponding primary alcohols (89-94% yield).[1e] Preliminary experiments exploring the direct transformation of pseudoephenamine amides to aldehydes using lithium triethoxyaluminum hydride as reductant have not yet provided high yields of product (~30–60%).

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Table 2. Quaternary Carbon Centers Formed by Enolization– Alkylation of α,α-Disubstituted Pseudoephenamine Amides.

Table 3. Quaternary Carbon Centers Formed by Conjugate AdditionAlkylation of α,β–Unsaturated Pseudoephenamine Amides.
1. CH3Li, LiCl, –78 ºC, THF 2. R2Li, –78 to –40 ºC 3. R3X (≥ 2 equiv) –40 ºC X!" R3 R1

O N CH3 CH3 R1

1. LDA, LiCl, THF, 0 ºC 2. DMPU, R2X (1 equiv) –40 ! 0 ºC X"#

O R1 R2 CH3
OH

O N CH3 R1

O R2

OH

(1.2 – 1.5 equiv)

Entry
X!"

Product
O CH3 CH3

Yield (%)

dr [a]

Entry
O X!"

Product
CH3 CH3

Yield (%)

dr [a]

1

85

≥19:1 (≥19:1)

1

75

≥19:1 (10.1:1)

O

O CH3 CH3

2

X!"

99

≥19:1 (14:1)

2

X!" CH3

CH3

77

≥19:1 (11.1:1)

O

O
CH3 CH3

3

X!" Br O

91

OCH3

≥19:1 (7.3:1)

3

X!" CH3
O

80

≥19:1 (≥19:1)

4

X!" CH3

CH3

87

≥19:1 (8.3:1)

4

X!"

CH3 CH3 CH3 CH3

85

≥19:1 (12.5:1)

O

O

5
CH3

X!" H3C
O X!" H3C

5

X!"

82

≥19:1 (≥19:1) 6

CH3

CH3 CH3 CH3

79

≥19:1 (9.1:1)

O

6

X!" CH3 CH3

CH3 CH3 CH3

80

9.9:1[b] (6.2:1)

76

CH3

≥19:1 (8.2:1)

[a] Diastereomeric ratios in parentheses correspond to the analogous transformations with pseudoephedrine. [b] The product diastereomers were separated using radial chromatography. The major diastereomer was isolated in 71% yield (≥19:1 dr), and the minor diastereomer was isolated in 6% yield (≥19:1 dr).

[a] Diastereomeric ratios in parentheses correspond to the analogous transformations with pseudoephedrine.

Two methods for the alkylative construction of quaternary carbon centers using pseudoephenamine as a chiral auxiliary were investigated, and, in both cases, significant enhancements in diastereoselectivities were observed compared to the corresponding transformations using pseudoephedrine. The first method involved sequential enolization-alkylation of α,α-disubstituted pseudoephenamine amides (Table 2), while the second method used a conjugate addition-alkylation protocol[16] with α-alkyl-α,βunsaturated pseudoephenamine amides (Table 3).[17] In nearly all of the alkylation reactions, the 1H NMR spectra of the crude reaction products were exceptionally clean and, indeed, in many cases the unpurified products appeared to be diastereomerically pure. The 1H NMR spectra were further simplified by the fact that the products appeared to exist in a single rotameric form; X-ray crystallographic analysis of the product of Entry 1 (Table 2) revealed that, in the solid state, this substance adopts the rotameric form in which the Nmethyl group is cis to the quaternary center, and we believe that this is likely the case in solution as well. We confirmed that the isolated products were formed with ≥19:1 dr by 1H NMR analysis of the corresponding oxazolinium triflate derivatives, formed with triflic anhydride. Only the example of Entry 6 (Table 2) proceeded with a diastereomeric ratio <19:1 (dr 9.9:1), and, in this instance, the

diastereomers could be separated by radial chromatography (facilitated by the UV activity of the auxiliary). As with the α,αdisubstituted amide products, the majority of α-quaternary amide products are solids, whereas pseudoephedrine α-quaternary amide products are typically oils. Our findings suggest that, in many ways, pseudoephenamine is a superior chiral auxiliary for asymmetric synthesis when compared to pseudoephedrine. Advantages include the fact that pseudoephenamine is free of regulatory restrictions, that pseudoephenamine amides have physical properties that facilitate their physical processing and spectroscopic analysis (greater crystallinity, lack of line-broadening in NMR spectra), and that alkylation reactions that form amide products with α-quaternary carbon centers proceed with notably higher diastereoselctivites.[18] Although pseudoephenamine is not commercially available at this time, so far as we are aware, it is easily synthesized in large amounts from starting materials that are available in bulk at very low cost.
Received: ((will be filled in by the editorial staff)) Published online on ((will be filled in by the editorial staff)) Keywords: pseudoephenamine · alkylation · auxiliary · quaternary · asymmetric

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[1]

a) A.G. Myers, B.H. Yang, H. Chen, J.L. Gleason, J. Am. Chem. Soc. 1994, 116, 9361–9362. b) A.G. Myers, J.L. Gleason, T. Yoon, J. Am. Chem. Soc. 1995, 117, 8488–8489. c) A.G. Myers, L. McKinstry, J. Org. Chem. 1996, 61, 2428–2440. d) A.G. Myers, J.L Gleason, T. Yoon, D.W. Kung, J. Am. Chem. Soc. 1997, 119, 656–673. e) A.G. Myers, B.H. Yang, H. Chen, L. McKinstry, D.J. Kopecky, J.L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496–6511. f) D.A. Kummer, W.J. Chain, M.R. Morales, O. Quiroga, A.G. Myers, J. Am. Chem. Soc. 2008, 130, 13231–13233. Pseudoephedrine is illegal in Mexico, Japan, and Colombia; it is highly regulated by law in the United States and Australia. It is a Table 1 precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances and is a banned item on the World Anti-Doping Agency list. The term “ephenamine” was used in the Federal Registrar (June 7, 1951) to describe (R,S)-2-methylamino-1,2-diphenylethanol in a salt form of penicillin G, an antibiotic/feed additive used to stimulate growth in poultry and livestock. J. Weijlard, K. Pfister, III, E.F. Swanezy, C.A. Robinson, M. Tishler, J. Am. Chem. Soc. 1951, 73, 1216–1218. For the first synthesis and resolution of threo-1,2-diphenyl-2aminoethanol, see: a) E. Erlenmeyer, Annalen. 1899, 307, 113–137. b) E. Erlenmeyer, Chem. Ber. 1899, 32, 2377–2378. c) E. Erlenmeyer, A. Arnold, Annalen. 1904, 337, 307–328. a) P.J. Sinclair, D. Zhai, J. Reibenspies, R.M. Williams, J. Am. Chem. Soc. 1986, 108, 1103–1104. b) R.M. Williams, P.J. Sinclair, D. Zhai, D. Chen, J. Am. Chem. Soc. 1988, 110, 1547–1557. c) R.M. Williams, G.J. Fegley, J. Am. Chem. Soc. 1991, 113, 8796–8806. d) R.M. Williams, M. Im, J. Am. Chem. Soc. 1991, 113, 9276–9286. e) R.M. Williams, W. Zhai, D.J. Aldous, S.C. Aldous. J. Org. Chem. 1992, 57, 6527–6532. For selected other uses of erythro- or threo-1,2-diphenyl-2aminoethanol in asymmetric synthesis, see: a) Y. Hashimoto, K. Takaoki, A. Sudo, T. Ogasawara, K. Saigo, Chem. Lett. 1995, 235– 236. b) L.C. Hirayama, S. Gamsey, D. Knueppel, D. Steiner, K. DeLaTorre, B. Singaram, Tetrahedron Lett. 2005, 46, 2315–2318. c) J. Clayden, S. Parris, N. Cabedo, A.H. Payne, Angew. Chem. Int. Ed. 2008, 47, 5060–5062. d) G.S. Mahadik, S.A. Knott, L.F. Szczepura, S.J. Peters, J.M. Standard, S.R. Hitchcock, J. Org. Chem. 2009, 74, 8164-8173. e) B. Seashore-Ludlow, P. Villo, C. Häcker, P. Somfai, Org. Lett. 2010, 12, 5274–5277. (1S,2S)- and (1R,2R)-1,2-diphenyl-2-aminoethanol are also available from commercial sources, albeit only in small quantities at this time. F. Effenberger, B. Gutterer, J. Jäger, Tetrahedron Asymmetry. 1997, 8, 459–467.

Palenik, Acta Crystallogr., Sect. B. 1977, 33, 1016–1022. b) The hydrogen atoms of the benzene ring of pseudoephedrine were regenerated at idealized positions using DS Visualizer. F.H. Allen, Acta Crystallogr., Sect. B. 2002, 58, 380–388. [14] W.J. Chain, A.G. Myers, Org. Lett. 2007, 9, 355–357. [15] A.G. Myers, B.H. Yang, D.J. Kopecky, Tetrahedron Lett. 1996, 37, 3623–3626. [16] a) E. Reyes, J.L. Vicario, L. Carrillo, D. Badia, A. Iza, U. Uria, Org. Lett. 2006, 8, 2535–2538. b) E. Reyes, J.L. Vicario, L. Carrillo, D. Badhia, U. Uria, A. Iza, J. Org. Chem. 2006, 71, 7763–7772. [17] α,β-Unsaturated pseudoephenamine amides do exhibit moderate linebroadening in 1H NMR spectra, presumably due to rotational isomerism. [18] For a compelling illustration of the superior utility of pseudoephenamine versus pseudoephedrine in the alkylative construction of quaternary centers within a complex series of alkaloids, see: J.W. Medley, M. Movassaghi, Angew. Chem. Int. Ed. Submitted.

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10] A prior synthesis of (1S,2S)-pseudoephenamine described the compound as a white, needle-like solid (mp 125–126 ºC). R. Lou, A. Mi, Y. Jiang, Y. Qin, Z. Li, F. Fu, A.S.C. Chan, Tetrahedron 2000, 56, 5857–5863. [11] For additional syntheses of pseudoephenamine, see: a) J. Yamashita, H. Kawahara, S. Ohashi, Y. Honda, T. Kenmotsu, H. Hashimoto, Tech. Rep. Tohoku University 1983, 48, 211–219. b) A.I. Meyers, J.M. Marra, Tetrahedron Lett. 1985, 26, 5863–5866. [12] For prior use of pseudoephenamine as a chiral ligand in catalysis, see: a) J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, Chem. Commun. 1996, 233–234. b) Y. Peng, X. Feng, X. Cui, Y. Jiang, M.C.K. Choi, A.S.C. Chan, Synth. Commun. 2003, 33, 2793– 2801.

[13] a) The pseudoephedrine crystal structure was obtained from the Cambridge Crystallographic Database (PSEPED01). M. Mathew, G.J.

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Entry for the Table of Contents (Please choose one layout) Layout 1:

((Catch Phrase))
Marvin R. Morales, Kevin T. Mellem, Andrew G. Myers* __________ Page – Page Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis
H

O N CH3 R2 R1

OH

84–99% yield 98:2 to ≥99:1 dr OH N CH3

(–)-Pseudoephenamine

O N R1 CH3 R3 R2

OH

75–91% yield ≥19:1 dr

Pseudoephenamine is shown to be a versatile chiral auxiliary for asymmetric synthesis. It is free from regulatory restrictions and exhibits remarkable stereocontrol in alkylation reactions, especially those that form quaternary carbon centers. Amides derived from pseudoephenamine exhibit a high propensity to be crystalline substances and provide sharp, well-defined peaks in NMR spectra.

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