Pseudoephenamine: A practical chiral auxiliary for asymmetric synthesis

Article abstract of DOI:10.1002/anie.201200370

Unrestricted: Pseudoephenamine is introduced as a versatile chiral auxiliary and an alternative to pseudoephedrine in asymmetric synthesis. It is free from regulatory restrictions and leads to remarkable stereocontrol in alkylation reactions, especially in those that form quaternary carbon centers. Amides derived from pseudoephenamine exhibit a high propensity to be crystalline substances, and provide sharp, well-defined signals in NMR spectra. Copyright

Full text of DOI:10.1002/anie.201200370

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Angewandte
Communications
DOI: 10.1002/anie.201200370
Synthetic Methods
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 and provides ready
access to enantiomerically enriched carboxylic acids, alde-
hydes, 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, thus complicating its use in industrial and
academic settings.[2] Herein we report that (1S,2S)- and
(1R,2R)-2-methylamino-1,2-diphenylethanol (synonymously,
(1S,2S)- and (1R,2R)-pseudoephenamine,[3] respectively)
have a broad range of utilities in asymmetric synthesis that
meet or exceed those that previously characterized the
pseudoephedrine system alone, with several advantages.
Scheme 1. Synthesis of (À)-(1S,2S)-pseudoephenamine by a modified
Specifically, 1) these auxiliaries are free from regulatory
restrictions and are not known to be transformable into illicit
substances, 2) asymmetric alkylation reactions that employ
pseudoephenamine as a directing group proceed with equal or
greater diastereoselectivities in relation to the corresponding
reactions that employ 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 crys-
talline substances compared with the corresponding pseu-
doephedrine derivatives and provide sharp, well-defined
signals in NMR spectra.
Tishler protocol followed by N-methylation.
both enantiomers of threo-1,2-diphenyl-2-aminoethanol from
the appropriate erythro-diastereomer (both erythro diaste-
reomers are commercially available in enantiomerically pure
form and are widely used as chiral auxiliaries themselves, for
example, in the Williams amino acid synthesis).[6–8] Subse-
quent N-methylation of threo-1,2-diphenyl-2-aminoethanol
was achieved in 97% yield by N-formylation with acetic
formic anhydride followed by reduction with lithium alumi-
num hydride.[9] The product was recrystallized from hot
ethanol to produce large, orthorhombic, colorless crystals
(m.p. 109–1108C).[10] We have routinely prepared 20–40 g
batches of (1R,2R)- or (1S,2S)-pseudoephenamine by the
described four-step sequence, which proceeds in 87% yield
and requires no column chromatography.[11,12] X-ray crystallo-
graphic analysis revealed that pseudoephenamine adopts
a conformation identical to pseudoephedrine in the solid
state, with gauche orientations between both the amino-
methyl and hydroxy substituents as well as the two phenyl
substituents (Figure 1).
Both enantiomeric forms of pseudoephenamine are easily
prepared with 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 form-
amide, invertive cyclization to form the corresponding oxazo-
line using thionyl chloride, and hydrolytic ring-opening under
acidic conditions.[4,5] By employing a small but important
modification (that is, the use of formamide containing
approximately 0.2 equivalents ammonium formate for N-
formylation rather than pure formamide, the use of which
leads to a reduced yield and yellowing of the product), we
have applied the Tishler protocol for large-scale synthesis of
Amide derivatives of pseudoephenamine were prepared
from the corresponding carboxylic acid chlorides or anhy-
drides by routine methods and, in most cases, were crystalline
solids (see the Supporting Information). Pseudoephenamine
[*] M. R. Morales, K. T. Mellem, Prof. A. G. Myers
Department of Chemistry and Chemical Biology, Harvard University
Cambridge, MA 02138 (USA)
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.
Figure 1. X-ray crystal structures of (À)-(1S,2S)-pseudoephenamine
(left) and (+)-(1S,2S)-pseudoephedrine[13] (right). Thermal ellipsoids
are at 50 % probability.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200370.
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amide enolates were generated with lithium diisopropylamide
(2.2 equiv) in tetrahydrofuran (THF) at –78 8C in the
presence of a saturating amount of anhydrous lithium
chloride (ca. 6 equiv), which are conditions identical to
those employed for enolization of pseudoephedrine amides.
Pseudoephenamine propionamide was poorly soluble in neat
THF, thus precluding the use of this solvent for enolization;
a 1:1 mixture of THF/pyridine proved to be a viable reaction
solvent for generation 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 À78 to 08C led to alkylated products in 84–99%
yields (after purification by flash column chromatography or
recrystallization) with uniformly high diastereoselectivities
(diastereomeric ratios (d.r.) of isolated products ranged from
98:2 to ꢀ 99:1; d.r. values of crude products are listed in
Table 1). We initially measured the diastereoselectivities of
these reactions by HPLC analysis of the products; however,
we later determined that they could also be readily assessed
by 1H NMR analysis of the corresponding oxazolinium
triflate derivatives, which can be obtained by invertive
cyclization with triflic anhydride (see the Supporting Infor-
mation for details).[14] Diastereoselectivities were uniformly
high, as in the corresponding alkylation reactions of pseu-
doephedrine amides. The majority of the alkylation products
were solids.
Scheme 2. Transformations of pseudoephenamine amides into enan-
Table 1: Diastereoselective alkylation of pseudoephenamine amides.
tiomerically enriched carboxylic acids, alcohols, and ketones. a) Acidic
hydrolysis was achieved by heating the amide to 1158C with 9n
sulfuric acid in dioxane. b) Basic hydrolysis was achieved by heating
the amide to 958C with tetrabutylammonium hydroxide in a 3:1
mixture of tert-butyl alcohol and water.[1e]
Entry[a]
R1
R2
d.r. of
d.r. of
Yield
[%]
m.p.
[8C]
crude
isolated
of the a-carbon center (89–99% yield), addition of organo-
lithium reagents to pseudoephenamine amides afforded
enantiomerically enriched ketones (95–98% yield), and
reduction of pseudoephenamine amides with lithium amido-
trihydroborate (LAB)[15] gave the corresponding primary
alcohols (89–94% yield).[1e] Preliminary experiments explor-
ing the direct transformation of pseudoephenamine amides to
aldehydes with lithium triethoxyaluminum hydride as reduc-
tant have not yet provided the products in high yields ( ꢁ 30–
60%).
product[b]
product[b]
1
2
3
4
5
6
7
8
Me
Me
Me
Et
nBu
nBu
Bn
Bn
nBu
Et
Me
Bn
Me
Me
nBu
95:5
95:5
ꢀ94:6
ꢀ96:4
ꢀ98:2
95:5
98:2
ꢀ99:1
ꢀ99:1
98:2
98:2
ꢀ99:1
ꢀ99:1
98:2
98:2
ꢀ99:1
85
97
96
87
99
84
92
99
128–129
n.a.
n.a.
89–90
112–114
77–79
n.a.
Bn
109–111
[a] Reactions in entries 1–3 were conducted in a 1:1 mixture of THF/
pyridine as solvent; all other reactions were conducted in neat THF 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. Bn=benzyl, n.a.= not applicable.
Two methods using pseudoephenamine as a chiral auxil-
iary were investigated for the alkylative construction of
quaternary carbon centers, and in both cases, significant
enhancements in diastereoselectivities were observed com-
pared to the corresponding transformations with pseudo-
ephedrine. The first method involved sequential enolization–
alkylation of a,a-disubstituted pseudoephenamine amides
(Table 2), while the second method used a conjugate addi-
tion–alkylation protocol[16] with a-alkyl-a,b-unsaturated
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 diaster-
Optically active carboxylic acids, ketones, and alcohols
were obtained directly from alkylated pseudoephenamine
amides by using methods paralleling those previously
employed for similar transformations of pseudoephedrine
amides (Scheme 2). Thus, hydrolysis of pseudoephenamine
amides under both acidic and basic conditions provided
carboxylic acids in high yields with little or no epimerization
1
eomerically pure. The H NMR spectra were further simpli-
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Table 2: Quaternary carbon centers formed by enolization-alkylation of
a,a-disubstituted pseudoephenamine amides.
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 spec-
tra), and that alkylation reactions that form amide products
with a-quaternary carbon centers proceed with notably
higher diastereoselectivites.[18] To the best of our knowledge,
pseudoephenamine is currently not commercially available,
however, it is easily synthesized in large amounts from
starting materials that are available in bulk at very low cost.
Entry
R1
R2
Yield [%]
d.r.[a]
1
2
Me
Me
Bn
allyl
85
99
ꢀ19:1 (ꢀ19:1)
ꢀ19:1 (14:1)
Received: January 13, 2012
Published online: March 27, 2012
3
Me
91
ꢀ19:1 (7.3:1)
4
5
6
nPr
Ph
Ph
Bn
allyl
Et
87
82
80
ꢀ19:1 (8.3:1)
ꢀ19:1 (ꢀ19:1)
9.9:1[b] (6.2:1)
Keywords: alkylation · asymmetric synthesis · chiral auxiliary ·
pseudoephedrine · pseudoephenamine
.
[a] Diastereomeric ratios in parentheses correspond to the analogous
transformations with pseudoephedrine. [b] The product diastereomers
were separated by radial chromatography. The major diastereomer was
isolated in 71% yield (d.r.ꢀ19:1), and the minor diastereomer was
isolated in 6% yield (d.r. ꢀ19:1).
[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.
[2] Pseudoephedrine is illegal in Mexico, Japan, and Colombia, and
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.
Table 3: Quaternary carbon centers formed by conjugate addition–
alkylation of a,b-unsaturated pseudoephenamine amides.
Entry
R1
R2
R3
Yield [%]
d.r.[a]
1
2
3
4
5
6
Me
Me
Me
Me
Et
nBu
nBu
Ph
tBu
tBu
tBu
Bn
allyl
allyl
allyl
Me
Me
75
77
80
85
79
76
ꢀ19:1 (10.1:1)
ꢀ19:1 (11.1:1)
ꢀ19:1 (ꢀ19:1)
ꢀ19:1 (12.5:1)
ꢀ19:1 (9.1:1)
ꢀ19:1 (8.2:1)
[3] The term “ephenamine” was used in the Federal Registrar
(June 7, 1951) to describe (R,S)-2-methylamino-1,2-diphenyle-
thanol in a salt form with penicillin G, an antibiotic/feed additive
used to stimulate growth in poultry and livestock.
n-pentyl
[a] Diastereomeric ratios in parentheses correspond to the analogous
transformations with pseudoephedrine.
[4] J. Weijlard, K. Pfister III, E. F. Swanezy, C. A. Robinson, M.
Tishler, J. Am. Chem. Soc. 1951, 73, 1216 – 1218.
[5] For the first synthesis and resolution of threo-1,2-diphenyl-2-
aminoethanol, see: a) E. Erlenmeyer, Annalen. 1899, 307, 113 –
137; b) E. Erlenmeyer, Chem. Ber. 1899, 32, 2377 – 2378; c) E.
Erlenmeyer, A. Arnold, Justus Liebigs Ann. Chem. 1904, 337,
307 – 328.
[6] 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.
[7] For selected other uses of erythro- or threo-1,2-diphenyl-2-
aminoethanol 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. 2008, 120, 5138 – 5140; 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.
Hꢀcker, P. Somfai, Org. Lett. 2010, 12, 5274 – 5277.
fied 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) showed that, in the solid state, this
substance adopts the rotameric form in which the N-methyl
group is cis to the quaternary center, and we believe that this
is likely the case in solution as well. We confirmed that the
1
isolated products were formed with ꢀ 19:1 d.r. by H NMR
analysis of the corresponding oxazolinium triflate derivatives,
formed with triflic anhydride. Only the example in entry 6
(Table 2) proceeded with a diastereomeric ratio < 19:1 (d.r.
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 a,a-disubstituted
pseudoephenamine amide products, the majority of pseudo-
ephenamine amide products with a-quaternary carbon cen-
ters are solids, whereas the corresponding pseudoephedrine
amide products are typically oils.
Our results suggest that, in many ways, pseudoephen-
amine is a superior chiral auxiliary for asymmetric synthesis
compared with pseudoephedrine. Advantages include the fact
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[8] (1S,2S)- and (1R,2R)-1,2-diphenyl-2-aminoethanol are also
available from commercial sources, albeit only in small quanti-
ties at this time.
[9] F. Effenberger, B. Gutterer, J. Jꢀger, Tetrahedron: Asymmetry
1997, 8, 459 – 467.
[10] A prior report on the synthesis of (1S,2S)-pseudoephenamine
described the compound as a white, needle-like solid (m.p. 125 –
1268C). 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. Yama-
shita, 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.
ephedrine were regenerated at idealized positions by using DS
Visualizer: F. H. Allen, Acta Crystallogr. Sect. B 2002, 58, 380 –
388; c) CCDC 867287 ((À)-(1S,2S)-pseudoephenamine) con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[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.
[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. Palenik, Acta Crystallogr. Sect. B 1977, 33, 1016 –
1022; b) the hydrogen atoms of the benzene ring of pseudo-
[17] a,b-Unsaturated pseudoephenamine amides do exhibit moder-
ate line-broadening in 1H NMR spectra, presumably because of
rotational isomerism.
[18] For a compelling illustration of the superior utility of pseudo-
ephenamine versus pseudoephedrine in the alkylative construc-
tion of quaternary centers within a complex series of alkaloids,
see: J. W. Medley, M. Movassaghi, Angew. Chem., 2012, 124,
4650 – 4654; Angew. Chem. Int. Ed., 2012, 51, 4572 – 4576.
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