Pseudoephedrine as a practical chiral auxiliary for the synthesis of highly enantiomerically enriched carboxylic acids, alcohols, aldehydes, and ketones

Article abstract of DOI:10.1021/ja970402f

The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is described in full. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, aldehydes, and ketones.

Full text of DOI:10.1021/ja970402f

6496
J. Am. Chem. Soc. 1997, 119, 6496-6511
Pseudoephedrine as a Practical Chiral Auxiliary for the
Synthesis of Highly Enantiomerically Enriched Carboxylic
Acids, Alcohols, Aldehydes, and Ketones
Andrew G. Myers,* Bryant H. Yang, Hou Chen, Lydia McKinstry,
David J. Kopecky, and James L. Gleason
Contribution from the DiVision of Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125
ReceiVed February 6, 1997X
Abstract: The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is described in full.
Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to
form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides
undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford R-substituted products in
high yields. These products can then be transformed in a single operation into highly enantiomerically enriched
carboxylic acids, alcohols, aldehydes, and ketones.
Introduction
are more readily cleaved than amides.5 Foremost among these
are the oxazolidinone auxiliaries of Evans and co-workers,6
which have defined the standard in this area for more than 10
years. Also noteworthy are the important camphor-derived
sultam auxiliaries developed by Oppolzer and co-workers.7 The
same properties that facilitate the acyl cleavage reactions of the
products of the latter reactions also serve to stabilize the
intermediate enolates. As a consequence, oxazolidinone-derived
enolates react efficiently only with reactive halides (e.g., allylic
halides),6 and camphor sultam-derived enolates require the
presence of the reactivity-enhancing ligand hexamethylphos-
phoric triamide (HMPA) for efficient alkylation.7a
In a preliminary communication, we described the use of the
readily available (in both enantiomeric forms) and inexpensive
amino alcohol pseudoephedrine (Sudafed, Suphedrine, etc.) as
a highly practical chiral auxiliary for asymmetric alkylation
reactions.8 Pseudoephedrine amides are easily prepared and are
frequently crystalline. They undergo efficient and highly
diastereoselective alkylation reactions with a wide range of alkyl
halides, to include less reactive substrates such as â-branched
alkyl iodides. Like the starting materials, the alkylated products
are frequently crystalline and are easily enriched to g99% de
upon recrystallization. In this work, we describe in full our
findings on the use of pseudoephedrine as a chiral auxiliary in
asymmetric alkylation reactions.9 The scope of this methodol-
ogy is defined, and possible factors responsible for the
exceptionally high levels of diastereoselectivity observed with
The asymmetric alkylation of the R-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 accomplished using chiral auxiliary-based
methodology. 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, it was shown that oxazoline
anions derived from chiral â-amino alcohols were alkylated by
a range of alkyl halides with high diastereoselectivities. These
alkylation products were then transformed into chiral carboxylic
acids with synthetically useful optical purities (51-86% ee).
Later, Evans and Takacs3a and Sonnet and Heath3b indepen-
dently demonstrated that alkylations of enolates of tertiary
amides derived from the amino alcohol prolinol occurred with
higher diastereoselectivities (76-94% de). Like the Meyers
precedent, this work was influential not only as a practical
addition to synthetic methodology, but also as a paradigm for
the design of new chiral auxiliaries employing rigid cyclic
platforms with well-defined conformational preferences. The
C2-symmetric bis(methoxymethoxymethyl)pyrrolidine auxiliary
of Katsuki et al. exemplifies the degree to which this paradigm
has evolved (alkylation de’s 97 to >98%).4 Subsequent
developments in chiral auxiliary-based alkylation methodology
have focused primarily on the alkylation of acyl derivatives that
(5) For additional examples, see: (a) Davies, S. G. Pure Appl. Chem.
1988, 60, 13. (b) Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. O. Chem.
Ber. 1993, 126, 2663. (c) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune,
S. Angew. Chem., Int. Ed. Engl. 1995, 34, 793.
(6) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Mathre, D. Ph.D. Thesis, California Institute of
Technology, 1985.
(7) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 5603. (b) For a previous camphor-derived system, see: Schmierer, R.;
Grotemeier, G.; Helmchen, G.; Selim, A. Angew. Chem., Int. Ed. Engl.
1981, 20, 207.
(8) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361.
X Abstract published in AdVance ACS Abstracts, June 15, 1997.
(1) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, pp 1-110. (b) Lutomski, K.
A.; Meyers, A. I. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, pp 213-274. (c) Seebach, D.; Imwinkelried,
R.; Weber, T. In Modern Synthetic Synthesis; Scheffold, R., Ed.; Springer:
Berlin-Heidelberg, 1986; Vol. 4, pp 125-259. (d) Crosby, J. Tetrahedron
1991, 47, 4789. (e) Caine, D. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp
1-63.
(2) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem.
Soc. 1976, 98, 567.
(3) (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233.
(b) Sonnet, P.; Heath, R. R. J. Org. Chem. 1980, 45, 3137.
(4) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857.
(9) For the specific case of the alkylation of pseudoephedrine glycinamide
and its application to the preparation of highly enantiomerically enriched
R-amino acids, see: (a) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D.
W. J. Am. Chem. Soc. 1997, 119, 656. (b) Myers, A. G.; Gleason, J. L.;
Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488.
S0002-7863(97)00402-2 CCC: $14.00 © 1997 American Chemical Society

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6497
Table 1. Selective N-Acylation of Pseudoephedrine
intramolecular O f N acyl transfer within pseudoephedrine
â-amino esters occurs rapidly, and because the N-acyl form is
strongly favored under neutral or basic conditions,11c products
arising from (mono)acylation on oxygen rather than nitrogen
are not observed.
entry
R
method (X)a product yield (%)
mp (°C)
The propensity of pseudoephedrine esters to undergo rapid
and efficient intramolecular O f N acyl transfer has been used
to advantage in a development of great practical importance
wherein pseudoephedrine amides are prepared directly from
pseudoephedrine and a carboxylic acid ester in a base-catalyzed
process. This transformation is believed to occur by an initial
base-promoted transesterification reaction of the secondary
hydroxyl group of pseudoephedrine followed by intramolecular
O f N acyl transfer. A variety of bases are employed
effectively in the reaction, to include sodium methoxide, lithium
methoxide, and n-butyllithium. As an illustration, treatment of
pseudoephedrine (1 equiv) with methyl propionate (2 equiv)
and sodium methoxide (0.5 equiv) in THF at 23 °C for 1 h
afforded pseudoephedrine propionamide (1) in 89% yield after
recrystallization of the crude reaction product. Similar proce-
dures have been developed for the preparation of R-hetero
pseudoephedrine amides such as pseudoephedrine R-hydroxy-
acetamide (entry 12, Table 1) and pseudoephedrine glycina-
mide.13
Alkylation of Pseudoephedrine Amide Enolates. Two
general procedures for the diastereoselective alkylation of
pseudoephedrine amides have been developed. In the first, the
alkylation is conducted using excess alkyl halide (procedure A,
yield based on enolate), and in the second, excess enolate is
used (procedure B, yield based on alkyl halide). Alkylation
reactions using the alkyl halide as the limiting reagent are
slightly higher yielding than those based on limiting enolate,
but the difference is sufficiently minor that the primary
consideration in choosing a procedure is the expense and/or
availability of the alkyl halide relative to that of the pseu-
doephedrine amide.
In a typical protocol employing excess alkylating agent
(procedure A), a suspension of anhydrous lithium chloride (6.0-
7.0 equiv) in THF containing diisopropylamine (2.25 equiv) is
treated at -78 °C with a solution of n-butyllithium in hexanes
(2.1 equiv). The resulting suspension is held at -78 °C for 5
min, and the reaction flask is briefly transferred to an ice bath
(5 min) and then cooled to -78 °C. A solution of the
pseudoephedrine amide substrate (1 equiv) in THF is added to
the cold suspension of lithium diisopropylamide-lithium chlo-
ride, and the mixture is held at -78 °C for 30-60 min, then
warmed to 0 °C, and held at that temperature for 10-15 min.
The enolate suspension is stirred briefly at 23 °C (3-5 min),
then cooled to 0 °C, and treated with an alkylating agent (1.5-
4.0 equiv). For most substrates, enolization is rapid at 0 °C,
and further warming to 23 °C is probably unnecessary, although
innocuous, because pseudoephedrine amide enolates generally
exhibit good thermal stability at 23 °C (t1/2 > 12 h).
Reactions employing excess enolate (procedure B) are
conducted similarly, but with 1.3-1.8 equiv of enolate and 1
equiv of electrophile. It is important in these reactions that
excess base (LDA) not be used, for many electrophiles are
destroyed by the excess base. Typically, we employ 1.9-1.95
equiv of LDA per mole of amide substrate in reactions with
excess enolate.
1
2
3
4
5
6
7
8
9
CH3
CH3
n-Bu
Bn
Ph
Cl
i-Pr
t-Bu
CH2Bn
A
D
A
B
B
B
B
B
B
Bc
C
D
1
1
2
3
4
5
6
7
8
95b
89b
91b
83b
88b
90
114-115
114-115
62-63
102-104
145-146
79-81
73-74
68-69
100-102
110-111
92b
88b
81b
87
10 2-thiophene
11 3-pyridyl
12 OH
9
10
11
97, 72b 117.5-118.5
93
61-63
a Method A: Acylation with the symmetrical carboxylic acid
anhydride (X ) RCH2CO2). Method B: Acylation with the carboxylic
acid chloride (X ) Cl). Method C: Acylation with the mixed anhydride
derived from pivaloyl chloride (X ) t-BuCO2). Method D: Acylation
with the methyl ester (X ) CH3O). b Values for products isolated by
a single recrystallization of the crude product. c Acylation of (1R,2R)-
(-)-pseudoephedrine.
this nonconventional, acyclic auxiliary are discussed.10 In
addition, extensive developmental work on the transformation
of the alkylation products into highly enantiomerically enriched
carboxylic acids, alcohols, aldehydes, and ketones is described
in detail.
Results
Synthesis of Pseudoephedrine Amides. Amide bond for-
mation is one of the most highly developed and efficient
transformations in organic chemistry. Acylation reactions of
the amino alcohol pseudoephedrine provide no exceptions to
this generalization. As shown by the examples of Table 1,
pseudoephedrine is acylated in high yield by a variety of
activated carboxylic acid derivatives, to include symmetrical
and mixed anhydrides and carboxylic acid chlorides.11,12 Acy-
lation reactions with carboxylic acid anhydrides proceed ef-
ficiently in dichloromethane or tetrahydrofuran (THF) as solvent
and do not require the presence of an external base, although
the reactions are much more rapid if a base such as triethylamine
(1.2 equiv) is added. Acylation reactions with carboxylic acid
chlorides require the presence of a slight excess of a base (e.g.,
Et3N) and occur readily at 0 °C in most organic solvents. In
cases where neither the anhydride nor the acid chloride
derivative of a carboxylic acid is readily available, acylation
using the mixed anhydride formed from the carboxylic acid,
pivaloyl chloride, and triethylamine is found to be a convenient
preparative method (entry 11). Each of the amide products of
Table 1 is a nonhydrated, air-stable, free-flowing crystalline solid
and can be isolated by direct recrystallization of the crude
acylation product (entries 1-5, 7-9, and 11) or by flash column
chromatography (entries 6 and 10-12). In most cases, the only
byproduct in the acylation reactions is a small amount (e5%)
of the N,O-diacylated product, which is easily separated by
recrystallization or flash column chromatography. Because
(10) For the use of the acyclic amino alcohol phenylglycinol as a chiral
auxiliary, see: (a) Micouin, L.; Schanen, V.; Riche, C.; Chiaroni, A.;
Quirion, J-C.; Husson, H-P. Tetrahedron Lett. 1994, 35, 7223. (b) Micouin,
L.; Jullian, V.; Quirion, J-C.; Husson, H-P. Tetrahedron: Asymmetry 1996,
7, 2839.
(11) (a) Schmidt, E.; Calliess, F. W. Arch. Pharm. 1912, 250, 154. (b)
Mitchell, W. J. Chem. Soc. 1940, 1153. (c) Welsh, L. H. J. Am. Chem.
Soc. 1947, 69, 128.
The presence of lithium chloride in the reaction is essential
to accelerate the rate of alkylation. In addition, O-alkylation
of the secondary hydroxyl group of the pseudoephedrine
(13) Myers, A. G.; Yoon, T.; Gleason, J. L. Tetrahedron Lett. 1995, 36,
(12) Myers, A. G.; Yang, B. H. Submitted for publication in Org. Synth.
4555.

6498 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
Table 2. Diastereoselective Alkylation of Pseudoephedrine Amides
temp
(°C)
crude
de (%)
isol
de (%)
isol
yield (%)
mp
(°C)
entry
R
R′Xa
prod
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23a
CH3
CH3
CH3
CH3
CH3
CH3
Bn
BnBr
n-BuI
BOMCl
BOMBr
C6H5(CH2)2I
BrCH2CO2-t-Bu
CH3I
CH3I
n-BuI
CH3I
CH3I
0
0
0
12
13
14
14
15
16
17
17
18
19
19
20
21
22
23
24
25
26
27
28
29g
30g
31
94
98
33
98
95
94
94
97
98
94
96
98
96
95
98
98
98
98
95
90
g99b
g99b
33
98
95
96
94
97
98
90b
80b
77
80
86
78
99
95
90
94
89
87b
92
92c
83b
84b
93
83
88
88c
91
90
89
136-137
66-67
-78
65-66
0
-78
0
81-82
79-81
79-81
Bn
Bn
-78
0
0
n-Bu
n-Bu
n-Bu
Ph
CH2Bn
i-Pr
t-Bu
CH3
3-pyridyl
2-thiophenee
Cl
94
96
-78
BnBr
EtI
CH3I
BnBr
0
0
0
0
g99b
g99
g99c
g99b
g99b
99
120-121
65-66
89-90
118-119
125-127
BnBr
0
d
CH2dCHCH2I
CH2dCHCH2I
CH3I
-78
-78
-78
-45 f
0
98
109-110
155-156
95
BnBr
g99c
97
CH3
Bn
CH3
I(CH2)2OTBS
I(CH2)2OTBS
I(CH2)2OTIPS
0
0
g99
97
a All reactions were conducted with excess alkyl halide (1.5-4.0 equiv) except entry 23 where excess enolate (1.9 equiv) was employed. b Values
for products isolated by a single recrystallization of the crude reaction mixture. c Two recrystallizations were conducted. d Alkylation of (1R,2R)-
pseudoephedrine propionamide. e Alkylation of (1R,2R)-pseudoephedrine 2-thiopheneacetamide. f At temperatures higher than -45 °C, a cyclic
byproduct arising from displacement of the chloride is observed. g Reference 22.
auxiliary is suppressed in the presence of lithium chloride. At
the concentrations of a typical alkylation reaction (∼0.2 M in
enolate), the solubility limit of lithium chloride is reached at
approximately 5 equiv at 0 °C and 6 equiv at 23 °C. Thus,
Figure 1. Mnemonic for pseudoephedrine amide enolate alkylation.
typical reactions conducted with the recommended 6.0-7.0
equiv of lithium chloride are saturated; use of more than 7 equiv
ence of lithium chloride in enolate alkylation reactions. It has
of lithium chloride in the reaction produces no discernible
been proposed in these studies that lithium chloride may modify
differences in the reaction rate, yield, or diastereoselectivity.
the aggregation state, and thereby the reactivity of an enolate
Alkylation reactions conducted in the presence of fewer than
in solution.15
∼4 equiv of lithium chloride are markedly slower and typically
(a) Alkylation with Primary Alkyl Halides. Pseudoephe-
do not proceed to completion. For example, in the absence of
drine amide enolates react efficiently (80-99% yields of purified
alkylation products) and highly diastereoselectively (90-98%
crude de, 95 to g99% isolated de) with a wide variety of
primary alkyl halides (Table 2). In every case examined to date,
the major product arises from electrophilic attack on the putative
(Z)-enolate (R syn to the enolate oxygen) from the same face
(1,4-syn) as the carbon-bound methyl group of the pseudoephe-
drine auxiliary when the enolate is drawn in a planar, extended
conformation (see Figure 1). Except for entry 23, each of the
examples in Table 2 involves a readily available and/or
inexpensive alkyl halide and therefore was conducted with
limiting enolate (procedure A). Because pseudoephedrine amide
enolates are highly nucleophilic, many primary alkyl halides
react readily even at -78 °C (e.g., entries 8 and 11). Reactions
conducted at -78 °C display slightly enhanced diastereoselec-
tivities versus the same reactions conducted at 0 °C (entries 7
and 10), but reactions conducted at 0 °C are nevertheless highly
diastereoselective. Notably, even poorly reactive substrates such
as n-alkyl and â-oxygenated n-alkyl halides (entries 2, 9, and
21-23) react efficiently and highly selectively with pseu-
lithium chloride, the reaction of n-butyl iodide with the enolate
derived from pseudoephedrine propionamide proceeds to the
extent of only 32% within 5 h at 0 °C, whereas in the presence
of 6 equiv of lithium chloride the alkylation reaction is complete
within 1.5 h at 0 °C (80% yield of recrystallized product).
Trapping of the same enolate with benzyl bromide proceeds to
only 60% completion in the absence of lithium chloride, but
affords a 90% yield of recrystallized product in its presence (6
equiv). In neither case was the diastereoselectivity of the
alkylation reaction influenced by the presence of lithium chloride
in the medium.14
It is important to ensure that rigorously anhydrous lithium
chloride is employed in the alkylation reaction, for any water
of hydration will quench the strong base used in the enolization
step. It is recommended that the (highly hygroscopic) anhydrous
reagent be flame-dried immediately prior to use followed by
cooling under an inert atmosphere at 23 °C.
The role of lithium chloride in the reaction is not known.
There is ample precedent in the literature, notably in the work
of Seebach and co-workers, documenting the beneficial influ-
(14) This stands in contrast to the alkylation of the enolate derived from
pseudoephedrine glycinamide (ref 9), where the selectivity of the alkylation
with ethyl iodide was diminished in the absence of lithium chloride (97%
de with lithium chloride versus 82% de without lithium chloride).
(15) (a) Seebach, D.; Bossler, H.; Gru¨ndler, H.; Shoda, S.-I. HelV. Chim.
Acta 1991, 74, 197. (b) Miller, S. A.; Griffiths, S. L.; Seebach, D. HelV.
Chim. Acta 1993, 76, 563. (c) Bossler, H. G.; Seebach, D. HelV. Chim.
Acta 1994, 77, 1124.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6499
Table 3. Alkylation of Pseudoephedrine Amides with â-Branched
Electrophiles
Scheme 1
doephedrine amide enolates at 0 °C.16 Elimination-prone
substrates such as (2-iodoethyl)benzene (entry 5) also react
efficiently, showing little evidence of elimination. Similarly,
the potentially enolizable substrate tert-butyl bromoacetate (entry
6) is found to alkylate the enolate derived from pseudoephedrine
propionamide in good yield. The electrophile (benzyloxy)-
methyl chloride (BOM chloride, entry 3) is singular in that it is
found to alkylate pseudoephedrine amide enolates with poor
diastereoselectivity (33% de). This poor selectivity is thus far
unique to this substrate and may reflect a change in the reaction
mechanism, perhaps toward an SN1-type transition state. The
use of BOM bromide as substrate (entry 4) obviates this
problem, returning the high diastereoselectivity found with all
other alkyl halides used in this study.
A particularly valuable feature of pseudoephedrine as a chiral
auxiliary from the standpoint of process chemistry is the
crystallinity of its N-acyl derivatives; many of the alkylation
products are crystalline materials and can be isolated in g99%
de and >80% yield after recrystallization of the crude reaction
products (entries 1-2, 12, 14-16, and 20). Typically, at least
one diastereomer within a given diastereomeric pair of alkylation
products is crystalline. Thus, by proper choice of the N-acyl
group, alkyl halide, and the configuration of the pseudoephedrine
auxiliary (d or l), a crystalline product can often be obtained.
For example, (R)-2-methylhexanoic acid is obtained by the
hydrolysis of either diastereomer 13 or ent-19; however, only
13 is crystalline (Scheme 1). To obtain (R)-2-methylhexanoic
acid from a crystalline intermediate, (S,S)-pseudoephedrine
propionamide is alkylated with n-butyl iodide, followed by
acidic hydrolysis (vide infra) of the product 13.
(b) Alkylation with â-Branched Primary Alkyl Iodides.
The superior nucleophilicity and excellent thermal stability of
pseudoephedrine amide enolates make possible alkylation
reactions at 23 °C with ordinarily unreactive substrates such as
â-branched primary alkyl iodides. This is a valuable transfor-
mation for it provides a concise route to “skipped” or 1,3-
dialkyl-substituted carbon chains, found within many natural
products. With chiral â-branched primary iodides, an important
issue concerns the degree to which the existing stereocenter
within the electrophile will influence the stereoselectivity of the
alkylation reaction. In initial studies, the alkylation of both
enantiomers of pseudoephedrine propionamide with (S)-1-iodo-
a Except in entry 1 where 4 equiv of iodide was used (yield based
on pseudoephedrine amide), and the alkylation was conducted at 0 °C,
all alkylations were conducted at 23 °C and used excess enolate (1.8-
2.0 equiv, yield based on alkyl iodide).
2-methylbutane was examined. Each reaction was conducted
using excess enolate (1.8 equiv)17 and limiting alkyl iodide
(procedure B). As shown by entries 2 and 3 of Table 3, both
alkylation reactions were highly selective and efficient, although
that producing the 1,3-syn product (entry 3) proceeded with
slightly higher diastereoselectivity, suggesting that this represents
a “matched” case. These and other findings within Table 3
represent significant advances over existing asymmetric alky-
lation methodology.
As shown within Table 3, extension of the pseudoephedrine
enolate methodology provides an iterative process for the
synthesis of 1,3,5,n(odd)-polyalkyl-substituted carbon chains of
any configuration.18 Thus, treatment of the iodide 7819 with
1.8 equiv of the enolate derived from (S,S)-pseudoephedrine
propionamide (1) at 23 °C for 6 h afforded the 1,3-syn alkylation
product 35 with >99:1 diastereoselectivity and in 97% yield
whereas use of the enolate derived from (R,R)-pseudoephedrine
(17) Fewer equivalents of the enolate can be employed. For example,
alkylation of 1.3 equiv of the enolate derived from 1 with the iodide 78 at
23 °C for 20.5 h afforded the 1,3-syn alkylation product 35 in 90% yield
with 99:1 selectivity (cf. entry 4, Table 3).
(16) (a) Imide enolates, by contrast, are essentially inert toward these
same substrates (ref 6b). (b) The presence of lithium chloride in the reaction
medium did not alter this outcome. Thus, the lithium enolate derived from
the imide N-propionylbenzyloxazolidinone was found not to react with
n-butyl iodide at 0 °C in the presence of 10 equiv of lithium chloride after
16 h (Myers, A. G.; Chen, H., California Institute of Technology,
unpublished results).
(18) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997,
5, 457.
(19) The iodide 78 was prepared by iodination of the corresponding
alcohol, prepared in g99% de and 90% yield by LAB reduction (see text)
of the alkylation product 12. For iodination of alcohols, see: (a) Garegg,
P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980, 2866. (b) Lange,
G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473.

6500 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
propionamide (ent-1) under identical conditions provided the
1,3-anti product 36 with 58:1 diastereoselectivity and in 95%
yield (entries 4 and 5).17,20 As before, the reaction producing
the syn stereochemistry appears to represent a matched case
while that producing the anti diastereomer represents a mis-
matched case, although even the mismatched alkylation reaction
is highly selective. Alkylation products 35 and 36 were
transformed into the corresponding alcohols by LAB reduction
(vide infra), and then to the corresponding iodides in an
aggregate yield in excess of 91%. Iodides 80 and 81 were felt
to provide a more stringent test of secondary diastereodiffer-
entiating effects in the alkylation reactions. Reaction of the
syn iodide 80 (1 equiv) with 1.8 equiv of the enolate derived
from 1 afforded the syn,syn alkylation product 39 with 142:1
selectivity and in 93% yield, whereas the enolate derived from
ent-1 produced the anti,syn product 40 with only slightly lower
selectivity (70:1, 96% yield). Reaction of the anti iodide 81
with 1.8 equiv of the enolate derived from 1 produced the anti,-
anti amide 41 with 66:1 selectivity and in 93% yield, whereas
the alkylation of the enolate derived from ent-1 proceeded with
higher selectivity (199:1) to form the syn,anti product 42 in
94% yield. These results again support the idea that 1,3-syn
products represent matched cases and demonstrate convincingly
that the high diastereofacial bias of pseudoephedrine amide
enolates overrides any secondary effects due to the stereocenter
within the alkyl iodide. The diastereoselectivities of the
alkylation reactions can be seen to increase with the steric bulk
of the alkyl iodide. In addition, the results of Table 3 illustrate
the exceptional efficiency of the alkylation reactions when
limiting iodide is employed (procedure B), with chemical yields
typically exceeding 93%.
(c) Concerning Rotamers and Diastereomeric Ratios. Like
most tertiary amides, pseudoephedrine amides exhibit rotational
isomerism about the N-C(O) bond and interconversion of
isomers is slow on the NMR (1H and 13C) time scale. In one
case (substrate 12), we observed a coalescence temperature of
120 °C (1H NMR at 400 MHz, DMSO) for rotamer intercon-
version. In solution, the ratio of rotational isomers of pseu-
doephedrine amides typically varies from 1:1 to 7:1. In all
cases, the major rotamer in solution is assigned as that with the
N-methyl group anti to the carbonyl group on the basis of its
shielding relative to the minor isomer.21 Interestingly, in solid
state structures of three pseudoephedrine amides (12, 13, and
17 below)8 a single rotameric form is present wherein the
Scheme 2
monohydrate, vide infra)13 the amide crystallized exclusively
as the rotamer with the N-methyl group anti to the amide
carbonyl. These data reveal the fine balance in energetics
between isomers, and the importance of crystal packing forces
on the distribution.
From a practical standpoint, the 1H NMR spectrum of a given
pseudoephedrine amide will be complicated by the presence of
rotamers, and for this reason diastereomeric ratios are best
assigned by capillary GC analysis. Typically, the corresponding
trimethylsilyl ether or acetate ester is prepared and analyzed
using a Chirasil-Val column (Alltech).
(d) Limitations of the Alkylation Methodology. In testing
the limits of pseudoephedrine amide enolate alkylations, we have
found that reactions with electrophiles that are both â-alkyl-
branched and â-alkoxy-substituted are extremely slow, even at
45 °C. As a consequence, the chemical yields of these
transformations (but not reaction diastereoselectivities) suffer
(Scheme 2).22 Similarly, the alkylation of pseudoephedrine
amide enolates with secondary alkyl halides such as cyclohexyl
bromide and cyclohexyl iodide is exceedingly slow and does
not provide a viable route to products of this type.
Another problematic case we have encountered is the
alkylation of pseudoephedrine R-hydroxyacetamide (11) and its
protected derivatives. Enolization of 11 using 3.2 equiv of LDA
at -78 °C was accompanied by partial decomposition of the
starting material. By using excess pseudoephedrine R-hydroxy-
acetamide (1.65 equiv) and limiting benzyl bromide, the
C-alkylated product 45 was obtained in 84% yield and 82%
de. This diastereoselectivity is lower than that obtained in
benzylations of other pseudoephedrine amide enolates, including
the R-heterosubstituted enolates derived from pseudoephedrine
glycinamide,9 chloroacetamide,8 and fluoroacetamide,23 and may
be related to the fact that the pseudoephedrine R-hydroxyac-
etamide enolate is a presumed trianion whereas the latter
enolates are all dianions. Alkylation reactions of an extensive
series of O-protected derivatives of pseudoephedrine R-hy-
droxyacetamide were also examined (TBS, TBDPS, THP, Bn,
BOM, Piv, and methyl(1-methoxyethyl)), but none of these
provided satisfactory results nor offered any improvement over
pseudoephedrine R-hydroxyacetamide itself.
Transformations of Alkylated Pseudoephedrine Amides.
The diastereoselective alkylation of pseudoephedrine amide
enolates does not constitute a valuable addition to synthetic
methodology unless the alkylation products can be transformed
into useful materials. For this reason, much of our effort has
N-methyl group is syn to the carbonyl group, the minor isomer
in solution. In a fourth structure (pseudoephedrine glycinamide
(20) In these and all subsequent alkylation reactions, care was taken to
avoid adventitious diastereomeric enrichment upon purification and de values
reported reflect those of the crude reaction mixtures.
1
(21) It has been noted previously that H NMR resonances for protons
on the N-methyl group anti to the carbonyl oxygen of N,N-dimethyl amides
are shifted upfield of resonances corresponding to the protons of the
N-methyl group syn to the carbonyl oxygen in benzene-d6 as solvent: (a)
Hatton, J. V.; Richards, R. E. Mol. Phys. 1960, 3, 253. (b) Hatton, J. V.;
Richards, R. E. Mol. Phys. 1962, 5, 139. (c) Stewart, W. E.; Siddall, T. H.,
III. Chem. ReV. 1970, 5, 517.
(22) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(23) Myers, A. G.; McKinstry, L.; Barbay, J. K. Manuscript in prepara-
tion.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6501
Table 5. Basic Hydrolysis of Pseudoephedrine Amides
Table 4. Acidic Hydrolysis of Pseudoephedrine Amides
isol yield isol ee or
(%)
isol yield isol ee or
(%)
entry substratea
R
R′
Bn
n-Bu
product
de (%)b
entry substratea
R
R′
product
de (%)b
1
2
3
4
5
6
7
12
13
20
21
28
33c
34c
CH3
CH3
n-Bu Bn
Ph
Cl
46
47
48
49
50
51
52
95
91
94
96
97
80
74
97
97
96
95
95
95
93d
1
2
12
13
14
17
18
19
20
21
33c
34c
CH3 Bn
CH3 n-Bu
CH3 BOM
Bn
Bn
n-Bu CH3
n-Bu Bn
Ph
46
47
53
54
55
56
48
49
51
52
93
93
92
91
89
88
90
82
86
84
94
97
69
94
82
93
84
64
95
95
3
4
5
6
Et
Bn
CH3
n-Bu
7
8
9
10
Et
a The starting material was in all cases of g99% de except substrate
33 which was of 97% de, and substrate 34 which was of 98% de. For
entry 1, 9 N H2SO4 was used; for all others, 18 N H2SO4 was employed.
b Ee’s were determined by chiral capillary GC analysis of the corre-
a Substrates 12, 13, 20, and 21 were of g99% de, substrates 14, 18,
and 34 were of 98% de, substrates 17 and 33 were of 97% de, and
substrate 19 was of 96% de. b Ee’s were determined by chiral capillary
GC analysis of the corresponding (R)-R-methylbenzyl amides (entries
1-8), and de’s by 1H NMR analysis of the carboxylic acids (entries 9
and 10). c See Table 3 for structures.
1
sponding (R)-R-methylbenzyl amides (entries 1-5), and de’s by H
NMR analysis of the carboxylic acids (entries 6 and 7). c See Table 3
for structures. d The reaction time was 2 h. If the reaction time was
extended to 3 h, the de was found to be 77%.
focused on the development of methods to transform the
alkylated amides of Tables 2 and 3 into useful products.
Conditions have been developed to transform these alkylated
pseudoephedrine amides directly into chiral carboxylic acids,
alcohols, aldehydes, and ketones of high enantiomeric excess
(ee).24 Of these, the most challenging transformation was the
simple hydrolysis reaction, for which acidic, basic, and slightly
acidic metal-mediated conditions have been developed. The
choice of a hydrolysis method will be dictated by the substrate
and then by consideration of cost and convenience, as outlined
below.
(a) Acidic Hydrolysis of Alkylated Pseudoephedrine
Amides To Form Carboxylic Acids. For alkylation products
that are not acid-sensitive, hydrolysis11b,c to the corresponding
carboxylic acid can be effected in excellent chemical yield and
with little epimerization simply by heating the amide at reflux
in a 1:1 mixture of sulfuric acid (9-18 N) and dioxane (Table
4). Under these conditions, the substrate initially undergoes a
rapid intramolecular N f O acyl transfer reaction followed by
rate-limiting hydrolysis of the resulting ammonium ester
intermediate to the carboxylic acid. Despite the harsh reaction
conditions (substrate 14 undergoes decomposition rather than
hydrolysis), this method provides a convenient route to a large
number of highly enantiomerically enriched carboxylic acids.
Even the epimerization-prone benzylic substrate of entry 4 in
Table 4 affords the corresponding acid in 95% ee. The
pseudoephedrine auxiliary can be recovered from these hy-
drolyses in excellent yield by a simple extractive workup.
Lower concentrations of sulfuric acid have been employed in
these hydrolyses without detectable degradation of the product
yield or ee, but longer reaction times are required in these cases.
Certain substrates are found to undergo detectable epimerization
upon prolonged exposure to the reaction conditions (see entry
7, Table 4).
respectively) at reflux proved to be optimal with respect to
reaction time, yield, and product ee. When these conditions
were employed for the basic hydrolysis of other alkylated
pseudoephedrine amides, results were generally far superior to
those observed with the highly epimerizable substrate 21 (Table
5). A convenient workup procedure for these hydrolyses
involved acidification with 3 N aqueous hydrochloric acid
solution followed by extraction of the product into ether. Tetra-
n-butylammonium salts were then readily removed by washing
the ethereal product solution with water. Where the expense
of tetra-n-butylammonium hydroxide is a consideration, or in
cases where the product carboxylic acid is poorly soluble in
ether (making removal of tetra-n-butylammonium salts difficult),
a second alkaline hydrolysis procedure was developed employ-
ing sodium hydroxide (5-8 equiv) as the base in a 2:1:1 mixture
of water, methanol, and tert-butyl alcohol at reflux. This is an
excellent alternative method and was employed, for example,
for the hydrolysis of the 2-methylsuccinic acid derivative 16
(74% yield, 94% ee), where the poor ether solubility of the
product, 2-methylsuccinic acid, precluded the use of tetra-n-
butylammonium hydroxide as base. For other substrates, this
alternative hydrolysis procedure produces products of slightly
lower ee as compared to the method employing tetra-n-
butylammonium hydroxide as base. For example, hydrolysis
of substrate 12 with sodium hydroxide in a 2:1:1 mixture of
water, methanol, and tert-butyl alcohol affords the corresponding
acid in 98% yield and 92% ee whereas hydrolysis of 12 with
tetra-n-butylammonium hydroxide affords the desired acid in
93% yield and 94% ee (entry 1, Table 5).
These basic hydrolysis procedures offer viable alternatives
for the hydrolysis of acid-sensitive substrates, but can lead to
partial racemization in the hydrolysis of certain substrates (e.g.,
substrates 14, 18, 20, and 21, Table 5). In at least one case
(entry 10, Table 5), basic hydrolysis proceeds with less
epimerization than the acidic hydrolysis method (95% de versus
93% de, respectively).
(b) Basic Hydrolysis of Alkylated Pseudoephedrine Amides
To Form Carboxylic Acids. Basic conditions for the hydroly-
sis of pseudoephedrine amides11b,c were also developed. The
procedure was optimized for the highly epimerizable phenyl-
acetamide substrate 21. Hydrolyses were conducted using a
wide range of hydroxide bases in a variety of solvent systems.
The hydrolysis of 21 with 5 equiv of tetra-n-butylammonium
hydroxide in a mixture of tert-butyl alcohol and water (1:4,
The mechanism of the base-induced hydrolysis reaction is
believed to involve initial rate-limiting intramolecular N f O
(24) Myers, A. G.; Yang, B. H.; Chen, H. Submitted for publication in
Org. Synth.

6502 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
Table 6. Hydrolysis of Pseudoephedrine Amides with FeCl3 in 4:1
Aqueous Dioxane
Table 7. Hydrolysis of Pseudoephedrine Amides using Yb(OTf)3
or ZrOCl2 in 4:1 Aqueous Dioxane
isol yield isol ee
(%)
isol yield isol ee
(%)
entry substratea
R
R′ metal salt product
(%)b
entry substratea
R
R′
Bn
n-Bu
product
(%)b
1
2
3
4
5
6
7
8
12
12
13
13
14
14
21
21
CH3 Bn
CH3 Bn
CH3 n-Bu ZrOCl2
CH3 n-Bu Yb(OTf)3
CH3 BOM ZrOCl2
CH3 BOM Yb(OTf)3
ZrOCl2
46
46
47
47
53
53
49
49
92
91
92
73
72
92
90
69
97
95
99
98
97
94
93
82
1
2
3
4
5
12
13
14
20
21
CH3
CH3
CH3
n-Bu Bn
Ph Et
46
47
53
48
49
94
85
53
17c
91
98
98
94
99
92
Yb(OTf)3
BOM
a The starting material was in all cases of g99% de except for
substrate 14 which was of 98% de. b Ee’s were determined by chiral
capillary GC analysis of the corresponding (R)-R-methylbenzyl amides.
c The hydrolysis was not complete at t ) 48 h.
Ph Et
Ph Et
ZrOCl2
Yb(OTf)3
a The starting material was in all cases of g99% de except 14 which
was of 98% de. b Ee’s were determined by chiral capillary GC analysis
of the corresponding (R)-R-methylbenzyl amides.
acyl transfer followed by rapid saponification of the resulting
â-amino ester intermediate.11c As in the acidic hydrolysis
protocol, the pseudoephedrine auxiliary may be recovered in
high yield from basic hydrolyses, if desired, by a simple
extractive isolation procedure.
Scheme 3
(c) Efforts To Develop a Milder Hydrolysis Procedure.
In an effort to develop milder conditions for the hydrolysis of
pseudoephedrine amides, a wide variety of Lewis acidic metal
salts was surveyed for the ability to promote the hydrolysis of
the benzylated pseudoephedrine propionamide 12. The first
successful metal-promoted hydrolysis of 12 was achieved by
heating 12 with 5 equiv of ZnCl2 in a refluxing mixture of
aqueous dioxane (1:1, pH 5) for 48 h. (R)-R-Methylben-
zenepropionic acid was obtained in 90% yield and 83% ee.
Further experimentation revealed that the use of FeCl3 in
refluxing dioxane (1:1, pH 1) for the hydrolysis afforded (R)-
R-methylbenzenepropionic in 97% ee, albeit in lower yield
(63%, incomplete reaction). Continued study of this system
showed that, by increasing the proportion of water in the mixture
(4:1 water-dioxane), the yield of the acid was increased to 94%
without compromising its ee (95%). These conditions were then
employed for the hydrolysis of a series of alkylated pseudoephe-
drine amides with generally excellent results (Table 6). The
sterically hindered substrate 20 did provide an exception (entry
4); its hydrolysis was prohibitively slow under the modified
conditions.
A broader survey of Lewis acidic metal salts (see the
Supporting Information) failed to provide any candidate offering
improved efficiency, rate, and enantioselectivity when compared
to FeCl3, although a surprisingly large number of metal salts
examined did promote the hydrolysis of 12. Two noteworthy
alternatives revealed in this survey were the use of ZrOCl2 or
Yb(OTf)3 (5 equiv each) in refluxing aqueous dioxane (4:1).
The use of these metal salts for the hydrolysis of a series of
pseudoephedrine amides is summarized in Table 7. Results
were generally quite good, and particularly so in the case of
the sensitive benzyl ether 14.
procedure, as follows. A solution of the pseudoephedrine amide
substrate in THF was heated at reflux with 1.5 equiv of
methanesulfonic acid until complete N f O acyl transfer had
occurred, as determined by thin-layer chromatographic analysis
(typically 1-3 h). The mixture was then cooled to 23.°C, and
1.5 equiv of lithium borohydride (2.0 M in THF) was added to
form the amine-borane complex. The reaction mixture was
diluted with an equal volume of water, and 5 equiv of sodium
hydroxide or tetra-n-butylammonium hydroxide was added as
base. The mixture was stirred at 23 °C until the hydrolysis
was complete. Results for the hydrolysis of several pseu-
doephedrine amide substrates employing this procedure are
summarized in Table 8. Although sodium hydroxide-promoted
hydrolyses are slower, typically requiring 8 h versus 1 h in the
tetra-n-butylammonium hydroxide system, the workup procedure
is more convenient. On the other hand, for sterically congested
substrates (e.g., substrate 20), use of the more reactive tetra-n-
butylammonium hydroxide base is necessary.
(d) Reduction of Pseudoephedrine Amides To Form
Primary Alcohols. The transformation of pseudoephedrine
amides into the corresponding primary alcohols may be
considered as a special case within the broader problem of the
selective reduction of tertiary amides. In general, the addition
of hydride to the carbonyl group of a tertiary amide affords a
tetrahedral intermediate that partitions between CN bond
cleavage (leading to the primary alcohol via the aldehyde) and
CO bond cleavage (leading to the formation of a tertiary amine
byproduct via an imminium intermediate, Figure 2). This
partitioning is highly sensitive to the reaction medium and the
nature of the counterion “M”. Typical metal hydride reagents
such as lithium aluminum hydride25 and diborane26 favor the
The long reaction times required in these metal-mediated
hydrolyses (typically 48 h) prompted us to continue our search
for an alternative mild hydrolysis method. Our goal in this effort
was to take advantage of the rapid N f O acyl transfer observed
in the Lewis acid-promoted hydrolysis reaction while nucleo-
philic hydroxide was introduced for the rapid hydrolysis of the
resulting ester without inducing reversion to the amide by O f
N acyl transfer. The key to accomplishing this involved the in
situ formation of a stable amine-borane complex by the addition
of lithium borohydride to the N f O acyl transfer intermediate.
The sequence of N f O acyl transfer, borane complexation,
and saponification (Scheme 3) was conducted in a one-pot
(25) (a) Uffer, H.; Schlittler, E. HelV. Chim. Acta 1948, 31, 1397. (b)
Gaylord, N. G. Reductions with Complex Metal Hydrides; Wiley-Inter-
science: New York, 1956; pp 544-592. (c) Zabicky, J., Ed. The Chemistry
of Amides; Wiley-Interscience: New York, 1970; pp 795-801.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6503
Table 8. Mild Hydrolysis of Pseudoephedrine Amides Involving in Situ Borane-Amine Complexation
N f O acyl
transfer time (h)
isol yield
(%)
isol ee
(%)c
entry
substratea
R
R′
Bn
Bn
n-Bu
n-Bu
BOM
BOM
Bn
baseb
NaOH
n-Bu4NOH
NaOH
n-Bu4NOH
NaOH
n-Bu4NOH
NaOH
product
1
2
3
4
5
6
7
8
9
12
12
13
13
14
14
20
20
21
21
CH3
CH3
CH3
CH3
CH3
CH3
n-Bu
n-Bu
Ph
1
1
1
1
1
1
1.5
1.5
3
46
46
47
47
53
53
48
48
49
49
94
91
84
75
96
87
98
98
99
98
93
93
d
d
-
-
Bn
Et
Et
n-Bu4NOH
NaOH
n-Bu4NOH
84
89
88
97
83
84
10
Ph
3
a The starting material was in all cases of g99% de except for 14 which was of 98% de. b Saponifications employing NaOH as base were
conducted for 8 h, except in entry 3, which was conducted for 16 h, and in entry 7, which was conducted for 48 h. Saponifications employing
n-Bu4NOH as base were conducted for 1 h. c Ee’s were determined by chiral capillary GC analysis of the corresponding (R)-R-methylbenzyl
amides. d Hydrolysis was not complete even after 48 h at 23 °C.
Table 9. Reduction of Pseudoepedrine Amides with
Borane-Lithium Pyrrolidide (LPT) to Form Primary Alcohols
temp time
isol
isol ee
entry substratea
R
R′
product (°C) (h) yield (%) (%)b
Figure 2. Divergent pathways for tertiary amide reductions.
1
2
3
4
5
6
7
8
9
12
13
14
17
18
20
21
23
24
CH3 Bn
CH3 n-Bu
CH3 BOM
58
59
60
61
62
63
64
65
66
23
23 10.0
3.0
23 10.3
6.0
84
81
45
87
88
89
87
80
5
g95
g95
91
g95
g95
g95
33c
formation of the tertiary amine byproduct. Important exceptions
to this trend include the reagents lithium triethylborohydride
(LiBHEt3, “superhydride”)27 and 9-BBN,28 developed by Brown
and co-workers, and metal amide-borane complexes, introduced
by Hutchins et al.29 and extensively developed by Singaram and
co-workers.30 Pseudoephedrine amides were found to be inert
toward superhydride and 9-BBN. As we reported in our initial
communication,8 the lithium pyrrolidide-borane reagent (lithium
pyrrolididotrihydroborate, Li(CH2)4NBH3, LPT) of Singaram et
al.30 is effective in transforming certain pseudoephedrine amides
into the corresponding primary alcohols selectively and in high
yield (Table 9). Subsequently, however, we have encountered
difficulties with this reagent in several problematic cases (e.g.,
entries 3, 7, and 9 within Table 9). For example, the R-(ben-
zyloxy)methyl-substituted amide 14 suffered partial decomposi-
tion during the reduction and the R-phenylacetamide substrate
21 provided the primary alcohol 64 in only 33% ee, with
inverted configuration! In both cases, the problems encountered
were attributed to base-induced epimerization (decomposition)
of the intermediate aldehydes. The inverted configuration of
the product 64 is believed to arise from enolization of the
intermediate aldehyde by a chiral, pseudoephedrine-derived base,
followed by enantioselective protonation and reduction. In
addition to these examples, highly sterically hindered substrates
such as 24 were found to be essentially inert to LPT. We have
since reported the development of a new reagent, lithium
0
Bn
Bn
CH3
n-Bu
23
23
3.1
5.8
n-Bu Bn
Ph Et
i-Pr Bn
t-Bu Bn
23 14.0
66 11.0
66 12.0
g95
-
a The starting material was in all cases of g99% de except 14 and
18 which were of 98% de, and 17 which was of 97% de. b Ee’s were
1
determined by H NMR analysis of the corresponding Mosher ester
derivatives. c The predominating enantiomer had inverted configuration
relative to the starting material (21).
amidotrihydroborate (LiH2NBH3, LAB),31 that lacks the prob-
lematic features of LPT. In that initial report, LAB was prepared
by the deprotonation of the commercial solid reagent, borane-
ammonia complex,32 using slightly less than 1 equiv of
n-butyllithium as base at 0 °C. In more recent work, we have
substantially improved the reagent preparation by the use of 1
equiv of lithium diisopropylamide (LDA) as the base in the
reaction.18 The efficiency of the reduction is greater using LDA
as the base, and notably, the product is isolated with much
greater facility. Difficulties encountered when n-butyllithium
was used as base were traced to the formation of butylboron
intermediates in the reaction (particularly in large-scale experi-
ments) and, ultimately, butylboron alkoxide products that were
difficult to hydrolyze. This problem could be largely circum-
vented by conducting the deprotonation with n-butyllithium at
-78 °C or, preferably, could be completely avoided by
deprotonation with LDA at 0 °C followed by warming to 23
°C. In the optimized procedure, solid borane-ammonia
complex (4.0 equiv) is added to a solution of LDA (3.9 equiv)
in THF at 0 °C, and the resulting suspension is warmed to 23
°C and held at that temperature for 15-20 min. The cloudy
suspension of LAB is then cooled to 0 °C, and a solution of
(26) (a) Brown, H. C.; Heim, P. J. Am. Chem. Soc. 1964, 86, 3566. (b)
Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, 441. (c) Brown,
H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, 996.
(27) Brown, H. C.; Kim, S. C. Synthesis 1977, 635.
(28) Brown, H. C.; Krishnamurthy, S.; Yoon, N. M. J. Org. Chem. 1976,
41, 1778.
(29) Hutchins, R. O.; Learn, K.; El-Telbany, F.; Stercho, Y. P. J. Org.
Chem. 1984, 49, 2438.
(30) (a) Fisher, G. B.; Harrison, J.; Fuller, J. C.; Goralski, C. T.; Singaram,
B. Tetrahedron Lett. 1992, 33, 4533. (b) Fisher, G. B.; Fuller, J. C.; Harrison,
J.; Goralski, C. T.; Singaram, B. Tetrahedron Lett. 1993, 34, 1091. (c) Fisher,
G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.; Goralski,
C. T.; Singaram, B. J. Org. Chem. 1994, 59, 6378.
(31) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623.
(32) (a) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21,
693. (b) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21, 697.

6504 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
Table 10. Reduction of Pseudoephedrine Amides with Lithium Amidotrihydroborate (LAB) To Form Primary Alcohols
substrate
(de, %)
temp
(°C)
time
(h)
isol
yield (%)
isol ee or
de (%)a
entry
R
R′
Bn
BOM
Bn
Et
Bn
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
12 (g99)
14 (98)
CH3
CH3
n-Bu
Ph
i-Pr
t-Bu
58
60
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
23
0
1.0
1.3
2.5
1.9
18
10
1
2
2
2
2
1
1
2
2
2
2
90
86
92
83
86
92
91
78c
79c
95
96
98
98
93
93
91
89
g99
95
g95
92
g95
g95
g95
97
98
98
96
95
20 (g99)
21 (g99)
23 (g99)
24 (g99)
ent-31 (97)
33 (97)b
34 (98)b
35 (98)b
36 (97)b
37 (95)b
38 (98)b
39 (99)b
40 (97)b
41 (97)b
42 (99)b
23
23
23
66
23
23
23
23
23
23
23
23
23
23
23
Bn
CH3
CH2CH2OTIPS
97
99
97
97
99
a The ee in entry 1 was determined by chiral HPLC (Chiralcel OD). Ee’s in entries 2-7 were determined by 1H NMR analysis of the corresponding
Mosher ester derivatives. De’s in entries 8-17 were determined by chiral capillary GC analysis of the corresponding acetate esters or trimethylsilyl
ethers. b See Table 3 for structures. c The yield was lowered due to the volatility of the product.
Table 11. Reduction of Pseudoephedrine Amides with
the pseudoephedrine amide substrate (1 equiv) in THF is added.
LiAlH(OEt)3 To Form Aldehydes
Typical reductions proceed to completion within a few hours
at 23 °C, although more hindered substrates (entry 6, Table 10)
may require heating to reflux (66 °C). When the reduction is
complete, an acidic aqueous workup procedure provides a
time isol yield isol ee
mixture of the desired alcohol and a (different) alkoxyboron
entry substratea
R
R′
product (h)
(%)
(%)
species. Fortunately, this alkoxyboron species is exceedingly
labile toward silica gel and undergoes quantitative cleavage to
the alcohol during flash column chromatographic purification.
Where flash column chromatography is not an acceptable means
of purification (e.g., on large scale, where distillation of the
alcohol might be preferable), the alkoxyboron species can be
cleaved rapidly and quantitatively by treatment with 1 N aqueous
sodium hydroxide solution at 23 °C for 30-60 min.
This modified LAB reduction procedure has proven to be
highly effective for the synthesis of a wide variety of highly
enantiomerically enriched primary alcohols from the corre-
sponding pseudoephedrine amide precursors. As evident from
the examples of Table 10, little to no epimerization of the
R-stereocenter is observed. Generally, <4% of the tertiary
amine byproduct is produced if care is taken to use at least 4
molar equiv of LAB in the reaction. Tertiary amine formation
can be more extensive if less reductant is employed.31 The
tertiary amine generally exhibits an Rf value comparable to that
of the product alcohol and is most conveniently removed by
extraction with aqueous acid. When an acid wash is not
desirable (for acid-sensitive substrates or for tertiary amine
hydrochlorides that are not water soluble), the tertiary amine
byproduct can be readily separated by flash column chroma-
tography using triethylamine-pretreated silica gel.
Reductions of pseudoephedrine amides with LAB are much
more rapid than reductions with LPT. For example, LAB
reduction of substrate 12 occurs in 1 h at 23 °C (90% yield)
whereas LPT reduction of 12 requires 6 h at 23 °C (84% yield).
In addition, LAB appears to have a lesser tendency to effect
base-induced side reactions compared to LPT. As a result,
highly epimerizable aldehyde intermediates can be traversed
without substantial loss of stereochemical integrity. For ex-
ample, reduction of the R-(benzyloxy)methyl-substituted amide
14 (98% de) with LAB formed the corresponding alcohol in
86% yield and 95% ee and reduction of the phenylacetamide
1
2
3
4
5
6
12
13
17
18
20
21
CH3 Bn
CH3 n-Bu
Bn
Bn
n-Bu Bn
Ph Et
82
83
84
85
86
87
1.0
1.1
1.2
0.8
0.8
0.9
76
75b
77
80
82
95
98
94
97
97
90
CH3
n-Bu
80
a The starting material was in all cases of g99% de except 17 which
was of 97% de, and 18 which was of 98% de. b Yield was based on
capillary GC analysis.
21 (g99% de) with LAB provided (S)-2-phenyl-1-butanol in
83% yield and 92% ee. In addition, LAB is found to be far
superior to LPT for the reduction of sterically hindered amides.
Thus, the substrate 23 was found to be inert to LPT at 23 °C
but was cleanly reduced with LAB at 23 °C (entry 5, Table 10,
86% yield of alcohol, g95% ee). More dramatically, the highly
hindered substrate 24 proved to be virtually inert toward LPT,
even in refluxing THF (Table 9, entry 9, 12 h, 5% yield), but
was readily reduced with LAB (Table 10, entry 6, 10 h, 66 °C,
92% yield, g95% ee).
(e) Reduction of Pseudoephedrine Amides To Form
Aldehydes. One of the most valuable transformations of
pseudoephedrine amides is their direct conversion to highly
enantiomerically enriched aldehydes using Brown and Tsuka-
moto’s lithium triethoxyaluminum hydride reagent.33 This
reagent is produced in situ from the reaction of 1 molar equiv
of lithium aluminum hydride with 1.5 molar equiv of ethyl
acetate and affords aldehydes of 90-98% ee (75-82% yield,
Table 11) from the corresponding pseudoephedrine amides.
In the optimum procedure, 1 equiv of a pseudoephedrine
amide is added as a solution in THF to a cold (-78 °C)
suspension of the lithium triethoxyaluminum hydride reagent
(2.3 equiv) in hexanes. The reaction mixture is warmed to 0
°C and stirred at that temperature for 0.8-1.2 h followed by
(33) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6505
Table 12. Reaction of Pseudoephedrine Amides with
Organolithium Reagents To Form Ketones
Figure 3. Generation and cleavage of pseudoephedrine aminals.
quenching. The ratio of the solvents hexanes and THF was
found to be an important variable; mixtures containing less than
60% by volume of hexanes led to greater degrees of overre-
duction (to the primary alcohol) and tertiary amine formation.
In addition, the successful generation of the alkoxyaluminum
hydride reagent was found to be quite sensitive to the quality
of the lithium aluminum hydride reagent. According to the
reaction stoichiometry, a 10% underestimation of the content
of lithium aluminum hydride results in a 40% decrease in the
amount of active hydride produced. Commercial stock solutions
of lithium aluminum hydride proved to be unreliable for the
preparation of lithium triethoxyaluminum hydride. Optimal
results were achieved when anhydrous ethyl acetate was added
slowly (ca. 1-2 h) to an ice-cooled suspension of solid lithium
aluminum hydride (stored and transferred under nitrogen) in
anhydrous hexanes.
Quenching of the reaction mixture with a dilute solution of
aqueous acid (e.g., 0.5 N aqueous hydrochloric acid solution)
afforded a mixture of the desired aldehyde and a pseudoephe-
drine aminal byproduct in a ratio ranging from 1:1 to 5:1,
respectively, depending upon the substrate (Figure 3).34 By
quenching the reaction with stronger acid (10 equiv of trifluo-
roacetic acid in 1 N aqueous hydrochloric acid solution),
complete conversion of the aminal byproduct to the desired
aldehyde was achieved. Only in rare instances did trace
amounts of aminal (1-2%) remain after this workup procedure.
Although inappropriate for acid-sensitive substrates, this protocol
was nevertheless quite effective for the preparation of a number
of highly enantiomerically enriched aldehydes. Ee’s of 94-
98% are possible, and even the highly racemization-prone
aldehyde 87 was isolated in 90% ee.
(f) Addition of Alkyllithium Reagents to Pseudoephedrine
Amides To Form Enantiomerically Enriched Ketones. It has
long been known that tertiary carboxamides can be transformed
into ketones in one step by the addition of an organolithium
reagent followed by an aqueous workup.35 The success of this
reaction relies upon the formation of a stable tetrahedral
intermediate which breaks down upon workup to release the
ketone. If breakdown of this intermediate occurs prior to
workup, the liberated ketone can further react to give a tertiary
alcohol byproduct. The protocol developed to transform alky-
lated pseudoephedrine amides into ketones was optimized to
avoid premature breakdown of the tetrahedral intermediate.
a The starting material was in all cases of g99% de except 14 which
was of 98% de and 29 which was of 97% de. b Ee’s were determined
by 1H NMR analysis of the Mosher ester derivatives of the correspond-
ing secondary alcohols (entries 1-9) or desilylated ketones (entries
10 and 11). De’s in entries 12 and 13 were determined by chiral
capillary GC analysis of the acetate esters of the desilylated ketones.
c 2.5 equiv of MeLi was used in entries 10 and 11, 3.5 equiv in entries
12 and 13, 5.0 equiv in entry 14, and 4.0 equiv in entry 15. d Reference
22. e See Scheme 2 for structures.
the tetrahedral intermediate. Typically, the addition reaction
is complete within a few minutes of warming to 0 °C. To
quench the reaction, excess alkyllithium is first scavenged by
the addition of diisopropylamine, and then the tetrahedral
intermediate is decomposed by the addition of a solution of
acetic acid in ether (10% v/v).
As shown by the results of Table 12, the ketone products are
generally obtained in excellent yields and with little to no
epimerization of the R-stereocenter. In the case of substrate
14 (entries 4 and 5), competing â-elimination of benzyl alcohol
attenuated the product yield somewhat, and in the case of
substrate 21 (entry 9), the kinetic acidity of the benzylic proton
lowered both the yield and ee of the product due to competing
enolization.
In a typical procedure, 2.4 equiv of an organolithium reagent
is added to an ethereal solution (or suspension) of the amide at
-78 °C followed by warming of the reaction mixture to 0 °C.
Addition of the organolithium reagent to the carbonyl group
does not occur until the mixture is warmed. By conducting
the initial addition at -78 °C, however, complete deprotonation
of the secondary hydroxyl group of the pseudoephedrine
auxiliary is ensured, thus preventing premature breakdown of
(34) In all cases, the pseudoephedrine aminal was found to be a single
diastereomer, of undetermined stereochemistry.
(35) (a) Evans, E. A. J. Chem. Soc. 1956, 4691. (b) Evans, E. A. Chem.
Ind. (London) 1957, 1596. (c) Izzo, P. T.; Safir, S. R. J. Org. Chem. 1959,
24, 701.

6506 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
In the context of this discussion of the diastereoselectivity
of pseudoephedrine amide enolate alkylations, it is interesting
to note that the use of ephedrine, the diastereomer of pseu-
doephedrine, as a chiral auxiliary in amide enolate alkylations
proves markedly inferior from a number of standpoints. The
use of ephedrine as a chiral auxiliary was described more than
15 years ago and, as outlined in that work, entailed the use of
the carcinogenic cosolvent HMPA in the alkylation reactions.38
In addition, difficulties in transforming the alkylated ephedrine
amides into useful products were reported. We have reinves-
tigated the alkylation of ephedrine amides using the protocol
described above for pseudoephedrine amide enolate alkylations
(employing lithium chloride as an additive) and have found these
alkylations to exhibit only modest diastereoselectivity.39 In
addition, ephedrine amides lack the desirable process features
of pseudoephedrine amides; they are typically oils.
Figure 4. Proposed reactive conformation of pseudoephedrine amide
enolates.
Figure 5. Crystal structure of pseudoephedrine glycinamide mono-
hydrate.
Conclusion
Pseudoephedrine has been documented to be a highly practical
chiral auxiliary for asymmetric alkylation reactions. The
enolates of pseudoephedrine amides undergo efficient and highly
diastereoselective alkylation reactions with a wide variety of
alkyl halides, and a broad range of cleavage reactions allow
for the conversion of the alkylated products into highly
enantiomerically enriched carboxylic acids, alcohols, aldehydes,
and ketones. In addition, the low cost of the auxiliary, the
crystallinity of many of the starting materials and products, and
the fact that carcinogenic cosolvents are not required make the
reported procedures amenable to large-scale and process ap-
plications.
Basis for Selectivity in Pseudoephedrine Amide Enolate
Alkylations. Our efforts to discern the basis for the high
diastereoselectivities in the alkylation of pseudoephedrine amide
enolates have been limited by a paucity of physical data
concerning the conformations of these enolates in solution or
in the solid state. In spite of the generally high crystallinity of
pseudoephedrine amides, in no case have we been successful
in crystallizing a pseudoephedrine amide enolate, despite
extensive effort. Similarly, attempts to gain solution structural
information by NMR spectroscopy of pseudoephedrine amide
enolates have been complicated by poor line shape and highly
complex spectra. The structural similarity between pseudoephe-
drine amides and prolinol amides (both are amides of 2-amino
alcohols) and the observation that, in both systems, alkyl halides
and epoxides exhibit opposite diastereoselectivity in alkylation
reactions22,36 suggest that the origin of selectivity in the two
systems may be similar. Askin et al. have suggested that the
alkoxy group of prolinol amide enolates may direct the
alkylation reaction in the case of epoxide electrophiles, and
Experimental Section
General Procedures. All nonaqueous reactions were performed
under a positive pressure of argon, unless otherwise noted. Flash
column chromatography was performed as described by Still et al.40
employing 230-400 mesh silica gel.
Materials. Tetrahydrofuran and ether were distilled under nitrogen
from sodium-benzophenone ketyl. Dichloromethane, diisopropyl-
amine, triethylamine, chlorotrimethylsilane, acetonitrile, pyrrolidine, and
toluene were distilled under nitrogen from calcium hydride. Lithium
chloride was dried under vacuum at 150 °C for 24 h and then stored
under a nitrogen atmosphere or alternatively flame-dried under vacuum
immediately prior to use. Benzyl bromide, iodomethane, isobutyl
iodide, and (2-iodoethyl)benzene were passed through basic alumina
immediately prior to use. Allyl iodide and ethyl iodide were washed
with aqueous sodium thiosulfate solution, dried over potassium
carbonate, and passed through basic alumina immediately prior to use.
The molarity of n-butyllithium was determined by titration against
diphenylacetic acid as an indicator (average of three determinations).41
Ethyl acetate and hexanes used in the generation of lithium triethoxy-
aluminum hydride were distilled from calcium hydride at atmospheric
pressure. Sodium methoxide, borane-ammonia complex, and lithium
aluminum hydride were stored and transferred under nitrogen.
BOMBr and BOMCl were prepared according to the literature
procedure.42 2-Iodo-[(1-triisopropylsilyl)oxy]ethanol was prepared by
provide a steric blockade in reactions with alkyl halides.36
A
similar rationale may explain the selectivity of pseudoephedrine
amide enolate alkylations if a reactive conformer such as that
shown in Figure 4 is invoked. In this conformation, the lithium
alkoxide and, perhaps more importantly, the solvent molecules
(tetrahydrofuran and possibly diisopropylamine) associated with
the lithium cation are proposed to block the â-face of the (Z)-
enolate, forcing the alkylation to occur from the R-face. In this
model, the pseudoephedrine side chain adopts a staggered
conformation in which the C-H bond R to nitrogen lies in-
plane with the enolate oxygen, in accord with predictions based
on allylic strain arguments.37 The positioning of the secondary
alkoxide on the â-face of the enolate may also benefit from
extended coordination of the oxyanions with one or more lithium
cations. The feasibility of such a staggered conformer is
supported by the X-ray crystal structure of pseudoephedrine
glycinamide hydrate (Figure 5),13 wherein allylic and torsional
strain is minimized, and the secondary hydroxyl group is
disposed on the â-face of the plane defined by the amide bond
linkage. Although the proposed model provides a rationale for
the observed selectivity, it should be noted that several important
features of the actual transition structure of the enolate have
been neglected such as its aggregation state, rotameric distribu-
tion, state of ionization, and the degree of pyramidalization of
nitrogen, as well as the bond-breaking and bond-forming
trajectories.
(37) Hoffman, R. W. Chem. ReV. 1989, 89, 1841.
(38) (a) Larcheveque, M.; Ignatova, E.; Cuvigny, T. Tetrahedron Lett.
1978, 3961. (b) Larcheveque, M.; Ignatova, E.; Cuvigny, T. J. Organomet.
Chem. 1979, 177, 5.
(39) For example, enolization of ephedrine propionamide (1 equiv) with
LDA (2.1 equiv) in the presence of lithium chloride (6 equiv), as described
for pseudoephedrine propionamide, and addition of n-butyl iodide at 0 °C
afforded a diastereomeric mixture of alkylation products (70% de, config-
uration not determined) in 90% yield after purification by flash column
chromatography.
(40) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(41) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
(42) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman, R. K., Jr.;
Medwid, J. B. Organic Syntheses; Collect. Vol. VI, Wiley: New York,
1988; p 101.
(36) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I.
Tetrahedron Lett. 1988, 29, 4245.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6507
silylation43 of 2-iodoethanol with triisopropylsilyl chloride (1.3 equiv),
imidazole (2.6 equiv), and 4-(dimethylamino)pyridine (0.5 equiv) in
dichloromethane at 23 °C for 4.3 h.
Instrumentation. Chiral capillary gas chromatography (GC) analy-
sis was carried out using a 25 m × 0.25 mm i.d. Alltech Chirasil-Val
chiral fused silica capillary column, under isothermal conditions, with
a column head pressure of 17 psi.
Methyl propionate (19.2 mL, 200 mmol, 2.00 equiv) was then added,
and the resulting mixture was stirred for 1 h at 23 °C. The mixture
was partitioned between 1 N aqueous hydrochloric acid solution (150
mL) and dichloromethane (150 mL), and the aqueous layer was
separated and extracted with dichloromethane (150 mL). The combined
organic layers were washed with water (150 mL), then dried over
sodium sulfate, and concentrated to furnish an off-white solid. Re-
crystallization of the product from hot toluene (110 °C, 30 mL)
furnished amide 1 as a white crystalline solid (19.7 g, 89%) with
spectroscopic data identical to those reported above. Anal. Calcd for
C13H19NO2: C, 70.32; H, 8.65; N, 6.33. Found: C, 70.32; H, 8.29; N,
6.06.
(S,S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methylhexana-
mide (2). A 1-L flask was charged with (+)-pseudoephedrine (40.0
g, 242 mmol, 1 equiv) and tetrahydrofuran (500 mL). The flask was
placed in a water bath at 23 °C, and hexanoic anhydride (55.5 g, 259
mmol, 1.07 equiv) was added to the solution via cannula over 10 min.
The reaction mixture was stirred for 25 min at 23 °C, and then the
hexanoic acid was quenched by the cautious addition of saturated
aqueous sodium bicarbonate solution (300 mL). Tetrahydrofuran was
removed under reduced pressure, and the resulting aqueous solution
was partitioned between water (500 mL) and ethyl acetate (250 mL).
The aqueous layer was separated and extracted with ethyl acetate (2 ×
250 mL). The combined organic extracts were dried over sodium
sulfate and concentrated. Recrystallization of the crude reaction product
from a 1:1 mixture of ether and hexanes (40 °C, 200 mL) furnished
amide 2 as a white crystalline solid (58.2 g, 91%): mp 62-63 °C; 1H
NMR (7:1 rotamer ratio, asterisk denotes minor rotamer peaks, 300
MHz, C6D6) δ 7.0-7.4 (m, 5H), 4.9 (br, 1H), 4.52 (d, 1H, J ) 6.9
Hz), 4.14 (m, 2H), 3.77* (m, 1H), 2.79* (s, 3H), 2.42* (m, 2H), 2.13
(s, 3H), 1.83 (m, 2H), 1.59 (qn, 2H, J ) 7.6 Hz), 1.1-1.4 (m, 4H),
0.99 (d, 3H, J ) 7.0 Hz), 0.86 (t, 3H, J ) 7.0 Hz), 0.59* (d, 3H, J )
6.8 Hz); 13C NMR (2:1 rotamer ratio, asterisk denotes minor rotamer
peaks, 75 MHz, CDCl3) δ 175.2, 174.2*, 142.3, 141.6*, 128.3*, 128.0,
127.8*, 127.3, 126.7*, 126.2, 76.1, 75.1*, 58.2, 57.0*, 34.1, 33.4*,
32.4*, 31.5*, 31.3, 26.6, 24.9*, 24.5, 22.31*, 22.29, 15.2*, 14.2, 13.82*,
13.79; FTIR (neat, cm-1) 3378 (br, m, OH), 1618 (s, CdO); HRMS
(FAB) calcd for C16H26NO2 (MH)+ 264.1965, found 264.1966. Anal.
Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C, 73.40;
H, 9.71; N, 5.11.
(S,S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methylbenzenepro-
pionamide (3). A solution of hydrocinnamoyl chloride (24.4 g, 145
mmol, 1.15 equiv) in tetrahydrofuran (50 mL) was added via cannula
over 10 min to an ice-cooled solution of (+)-pseudoephedrine (20.8 g,
126 mmol, 1 equiv) and triethylamine (22.8 mL, 164 mmol, 1.30 equiv)
in tetrahydrofuran (300 mL). After 10 min, excess acid chloride was
quenched by the addition of water (10 mL). The product mixture was
partitioned between ethyl acetate (500 mL) and brine (40 mL), and the
organic layer was separated and extracted with brine (2 × 40 mL).
The organic layer was dried over sodium sulfate and concentrated.
Recrystallization of the crude reaction product from hot toluene (110
°C, 125 mL) furnished amide 3 as a white crystalline solid (31.2 g,
83%): mp 102-104 °C; 1H NMR (3:1 rotamer ratio, asterisk denotes
minor rotamer peaks, 300 MHz, C6D6) δ 7.0-7.4 (m, 10H), 4.59 (br,
1H), 4.48 (t, 1H, J ) 7.1 Hz), 4.20 (m, 1H), 4.01* (dd, 1H, J1 ) 8.4
Hz, J2 ) 2.4 Hz), 3.66* (m, 1H), 3.15* (m, 2H), 2.93 (t, 2H, J ) 7.7
Hz), 2.79* (s, 3H), 2.49* (m, 2H), 2.13 (m, 2H), 2.02 (s, 3H), 0.92 (d,
3H, J ) 7.0 Hz), 0.49* (d, 3H, J ) 6.8 Hz); 13C NMR (3:1 rotamer
ratio, asterisk denotes minor rotamer peaks, 75 MHz, CDCl3) δ 174.3,
173.2*, 142.2, 141.5*, 141.3*, 141.1, 128.6*, 128.39, 128.36, 128.31,
128.29, 128.2*, 127.6*, 126.8*, 126.4, 126.1, 125.9*, 76.3, 75.3*, 58.2,
58.0*, 36.1, 35.4*, 32.3*, 31.5*, 31.1, 26.9, 15.2*, 14.3; FTIR (neat,
cm-1) 3374 (br, m, OH), 1621 (s, CdO); HRMS (FAB) calcd for
C19H24NO2 (MH)+ 298.1808, found 298.1806. Anal. Calcd for
C19H23NO2: C, 76.74; H, 7.80; N, 4.71. Found: C, 76.45; H, 8.00; N,
4.40.
Determination of Absolute Stereochemistry of Alkylation Prod-
ucts. The structures of alkylation products 12, 13, and 17 were
determined by X-ray crystallographic analysis. Product 14 was
transformed by LAB to the known (S)-2-methyl-1,3-propanediol benzyl
ether.6b Both (R)- and (S)-Mosher ester derivatives44 of this alcohol
were prepared and were identified conclusively by comparison with
1H NMR data from authentic materials.6b Products 18 and 20 form a
diastereomeric pair. Their hydrolysis produces enantiomeric acids
whose configuration was established by comparison of the respective
optical rotations to literature values of the known (R)-2-benzylhexanoic
acid.45 Products 13 and 19 form a diastereomeric pair; because the
configuration of 13 was secured by X-ray analysis, that of 19 is defined
unambiguously. Acidic hydrolysis of amide 21 produces 2-phenylbu-
tyric acid, which was coupled with (R)-(R-methylbenzyl)amine as
described below for acid 46. The resulting (R)-R-methylbenzyl amide
was shown to be identical to the (R)-R-methylbenzyl amide of
commercially available (S)-2-phenylbutyric acid by chiral capillary GC
analysis. Treatment of R-chloride 28 with sodium azide (1.1 equiv) in
N,N-dimethylformamide at 0 °C, followed by reduction with triph-
enylphosphine (2 equiv) in THF at 23 °C, formed a phenylalanine
derivative (with inversion) which was hydrolyzed (sulfuric acid,
dioxane, reflux) to form L-phenylalanine. Comparisons with the
authentic antipodes of phenylalanine were made by HPLC using a
Crownpak CR (+) column. In each of these cases, the major
pseudoephedrine alkylation product results from electrophilic attack
on the putative (Z)-enolate (R syn to the enolate oxygen) from the same
face as the carbon-bound methyl group of pseudoephedrine when it is
drawn in its extended conformation. The remaining alkylation reactions
were assumed to proceed analogously.
Synthesis of Pseudoephedrine Amides: (S,S)-N-(2-Hydroxy-1-
methyl-2-phenylethyl)-N-methylpropionamide (1). (a) Acylation
with Propionic Anhydride. A 1-L flask was charged with (+)-
pseudoephedrine (21.0 g, 127 mmol, 1 equiv), triethylamine (21.3 mL,
153 mmol, 1.20 equiv), and dichloromethane (250 mL). The flask was
placed in a water bath at 23 °C, and propionic anhydride (17.4 mL,
136 mmol, 1.07 equiv) was added to the solution in 1-mL portions
over several minutes. The reaction mixture was stirred for 30 min at
23 °C, and then excess anhydride was quenched by the addition of
water (40 mL). The organic layer was separated and extracted with
half-saturated aqueous sodium bicarbonate solution (2 × 40 mL) and
1 N aqueous hydrochloric acid solution (2 × 40 mL). The organic
extract was dried over sodium sulfate and concentrated to furnish a
white solid. Recrystallization of the product from hot toluene (110
°C, 85 mL) furnished amide 1 as a white crystalline solid (26.9 g,
95%): mp 114-115 °C; 1H NMR (3:1 rotamer ratio, asterisk denotes
minor rotamer peaks, 300 MHz, C6D6) δ 6.95-7.45 (m, 5H), 4.83 (br,
1H), 4.51 (t, 1H, J ) 7.2 Hz), 4.1 (m, 1H), 3.68* (m, 1H), 2.77* (s,
3H), 2.40* (m, 2H), 2.06 (s, 3H), 1.73 (m, 2H), 1.22* (t, 3H, J ) 7.3
Hz), 0.9-1.1 (m, 6H), 0.53* (d, 3H, J ) 6.7 Hz); 13C NMR (2:1 rotamer
ratio, asterisk denotes minor rotamer peaks, 75 MHz, CDCl3) δ 175.8,
174.8*, 142.2, 141.5*, 128.3*, 128.1, 127.9*, 127.4, 126.7*, 126.3,
76.1, 75.0*, 58.1, 57.7*, 32.1, 27.3, 26.6*, 15.2*, 14.2, 9.4*, 9.0; FTIR
(neat, cm-1) 3380 (br, m, OH), 1621 (s, CdO); HRMS (FAB) calcd
for C13H20NO2 (MH)+ 222.1495, found 222.1490. Anal. Calcd for
C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.62; H, 8.36; N,
6.34.
(b) Acylation with Methyl Propionate. A 250-mL round-bottomed
flask was charged with sodium methoxide (2.7 g, 50 mmol, 0.50 equiv),
(+)-pseudoephedrine (16.5 g, 100 mmol, 1 equiv), and tetrahydrofuran
(100 mL). This mixture was stirred at 23 °C until the solids had
dissolved to give a slightly cloudy, pale yellow solution (ca. 10 min).
(S,S)-r-Chloro-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-
methylacetamide (5). A solution of (+)-pseudoephedrine (5.69 g, 33.3
mmol, 1.10 equiv) and triethylamine (4.64 mL, 33.3 mmol, 1 equiv)
in dichloromethane (55 mL) was added via cannula to an ice-cooled
solution of chloroacetic anhydride (5.00 g, 33.3 mmol, 1 equiv) in
dichloromethane (60 mL). The resulting mixture was stirred for 1 h
(43) Ohwa, M.; Eliel, E. L. Chem. Lett. 1987, 41.
(44) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(45) Watson, M. B.; Youngson, G. W. J. Chem. Soc. C 1968, 258.

6508 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
at 0 °C and then partitioned between saturated aqueous sodium
bicarbonate solution (100 mL) and dichloromethane (200 mL). The
aqueous layer was separated and extracted with dichloromethane (100
mL). The combined organic layers were dried over sodium sulfate
and concentrated. Purification of the residue by flash column chro-
matography eluting with a gradient of ethyl acetate-hexanes (25 f
75%) afforded amide 5 as an oil which crystallized upon standing (6.60
g, 90%): mp 79-81 °C; 1H NMR (1:1 rotamer ratio, 300 MHz, CDCl3)
δ 7.28-7.41 (m, 5H), 4.54-4.63 (m, 3H), 4.35 (d, 1H, J ) 12.4 Hz),
4.07 (d, 1H, J ) 12.3 Hz), 4.07 (s, 2H), 3.98 (m, 1H), 3.74 (br, d, 1H,
J ) 4.7 Hz), 3.30 (d, 1H, J ) 3.2 Hz), 2.94 (s, 3H), 1.05 (d, 3H, J )
6.6 Hz), 1.02 (d, 3H, J ) 6.8 Hz); 13C NMR (1:1 rotamer ratio, 75
MHz, CDCl3) δ 168.2, 168.0, 141.6, 141.1, 128.7, 128.4, 127.9, 126.7,
126.5, 75.8, 75.1, 59.1, 57.7, 42.0, 41.7, 32.0, 27.4, 15.3, 14.0; FTIR
(neat, cm-1) 3392 (br, m, OH), 1638 (s, CdO).
Amide 5 could also be purified by crystallization of the crude
acylation product. After aqueous workup and concentration as above,
the oily product residue was dissolved in ether (to ca. 1.4 M), and the
resulting solution was cooled to -20 °C and seeded with authentic
amide 5. After 24 h, the product was collected by filtration to afford
a first crop yield of 46%. The mother liquor was concentrated, and
the oily residue was dissolved in a smaller volume of ether (to ca. 2.5
M). The solution was cooled to -20 °C and seeded with authentic
amide 5. After 24 h, a second crop was collected by filtration to afford
amide 5 in 32% yield (total 78% yield). Spectroscopic data were
identical to those listed above: mp 79-81 °C. Anal. Calcd for
C12H16ClNO2: C, 59.63; H, 6.67; N, 5.79. Found: C, 59.61; H, 6.66;
N, 5.76.
(S,S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methylbenzene-
butanamide (8). A solution of 4-phenylbutyric acid (4.57 g, 29.1
mmol, 1.20 equiv) in dichloromethane (15 mL) was charged sequen-
tially with oxalyl chloride (2.53 mL, 29.1 mmol, 1.20 equiv) and N,N-
dimethylformamide (10 µL, 0.13 mmol, 0.005 equiv), and the resulting
solution was stirred at 23 °C for 1 h, during which time the bubbling
ceased. Amide 8 was prepared according to the procedure detailed
above for the acylation product 3, using (+)-pseudoephedrine (4.00 g,
24.2 mmol, 1 equiv), triethylamine (4.72 mL, 33.9 mmol, 1.40 equiv),
and the 4-phenylbutyryl chloride prepared above. The crude reaction
product was recrystallized from hot toluene (110 °C, 15 mL), furnishing
the amide 8 as a white crystalline solid (6.08 g, 81%): mp 100-102
°C; 1H NMR (3:1 rotamer ratio, asterisk denotes minor rotamer peaks,
300 MHz, CDCl3) δ 7.1-7.4 (m, 10H), 4.60 (m, 1H), 4.53* (m, 1H),
4.45 (m, 1H), 4.32 (br, 1H), 3.90* (m, 1H), 2.92* (s, 3H), 2.75 (s,
3H), 2.69 (m, 2H), 2.35 (m, 2H), 2.00 (m, 2H), 1.10 (d, 3H, J ) 6.9
Hz), 0.95* (d, 3H, J ) 6.8 Hz); 13C NMR (3:1 rotamer ratio, asterisk
denotes minor rotamer peaks, 75 MHz, CDCl3) δ 175.0, 174.0*, 142.4,
141.9*, 141.6, 141.2*, 128.6*, 128.5, 128.3, 127.6, 126.8*, 126.4,
125.9*, 76.5, 75.5*, 58.5, 58.2*, 35.4*, 35.1, 33.3, 32.8*, 26.8*, 26.3,
15.3*, 14.4; FTIR (neat, cm-1) 3374 (br, m, OH), 1620 (s, CdO);
HRMS (FAB) calcd for C20H26NO2 (MH)+ 312.1964, found 312.1974.
Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C,
77.06; H, 7.94; N, 4.62.
triethylamine [90:8:2 f 88:10:2] afforded amide 10 as a white
crystalline solid (2.21 g, 93%): mp 117.5-118.5 °C; H NMR (2:1
1
rotamer ratio, asterisk denotes minor rotamer peaks, 300 MHz, CDCl3)
δ 8.2-8.6 (m, 2H), 7.6-7.7 (m, 1H), 7.1-7.4 (m, 6H), 4.4-4.7 (m,
2H), 4.0-4.3* (m, 2H), 3.80* (d, 2H, J ) 1.8 Hz), 3.67 (s, 2H), 2.96*
(s, 3H), 2.89 (s, 3H), 1.13 (d, 3H, J ) 6.8 Hz), 0.93* (d, 3H, J ) 6.8
Hz); 13C NMR (2:1 rotamer ratio, asterisk denotes minor rotamer peaks,
75 MHz, CDCl3) δ 171.0, 170.8*, 149.8*, 149.6, 147.4, 147.2*, 142.1,
142.0*, 136.9*, 136.6, 131.5*, 130.6, 128.3*, 128.0, 127.7*, 127.3,
126.5*, 126.3, 123.2, 123.0*, 75.3, 74.8*, 58.4, 56.5*, 38.0, 37.4*,
31.8*, 27.1, 15.2*, 14.0; FTIR (neat, cm-1) 3385 (br, m, OH), 1626
(s, CdO); HRMS (FAB) calcd for C17H21N2O2 (MH)+ 285.1603, found
285.1596; Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85.
Found: C, 71.77; H, 7.08; N, 9.81.
Amide 10 could also be purified by recrystallization. Following a
procedure similar to that described above, using (+)-pseudoephedrine
(1.49 g, 8.99 mmol, 1 equiv), triethylamine (3.38 mL, 24.3 mmol, 3.00
equiv), 3-pyridylacetic acid hydrochloride (2.11 g, 12.1 mmol, 1.35
equiv), and pivaloyl chloride (1.50 mL, 12.1 mmol, 1.35 equiv), the
crude reaction product was recrystallized from hot toluene (110 °C, 8
mL), furnishing the amide 10 as a crystalline solid (1.83 g, 72%).
Spectroscopic data were identical to those listed above: mp 117.5-
118.5 °C. Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85.
Found: C, 71.60; H, 7.18; N, 9.73.
(S,S)-r-Hydroxy-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-
methylacetamide (11). A solution of n-butyllithium in hexanes (2.37
M, 5.62 mL, 13.3 mmol, 0.500 equiv) was added to an ice-cooled
suspension of lithium chloride (3.39 g, 79.9 mmol, 3.00 equiv) and
(+)-pseudoephedrine (4.40 g, 26.6 mmol, 1 equiv) in tetrahydrofuran
(200 mL), and the suspension was stirred at 0 °C for 30 min. Methyl
glycolate (4.11 mL, 53.3 mmol, 2.00 equiv) was added via syringe
over 5 min, and the mixture was warmed to 23 °C and stirred at that
temperature for 3 h. A solution of 0.5 N aqueous sodium hydroxide
(100 mL) was added, and the biphasic mixture was stirred at 23 °C for
1 h. Volatile organic solvents were removed under reduced pressure,
and the resulting aqueous residue was extracted with five 50-mL
portions of 10% methanol-dichloromethane. The combined organic
extracts were dried over sodium sulfate and concentrated. Purification
of the product by flash column chromatography eluting with a gradient
of methanol-dichloromethane (6 f 10%) afforded amide 11 as a
colorless oil which slowly solidified (5.55 g, 93%): mp 61-63 °C; 1H
NMR (2:1 rotamer ratio, asterisk denotes minor rotamer peaks, 300
MHz, CDCl3) δ 7.20-7.45 (m, 5H), 4.60 (m, 2H), 4.36* (m, 2H), 4.15
(m, 2H), 3.75* (br, 1H), 3.65 (br, 1H), 3.60* (m, 2H), 3.20 (br, 1H),
3.01* (s, 3H), 2.75 (s, 3H), 2.40* (br, 1H), 1.08 (d, 3H, J ) 6.6 Hz),
0.99* (d, 3H, J ) 6.8 Hz); 13C NMR (2:1 rotamer ratio, asterisk denotes
minor rotamer peaks, 75 MHz, CDCl3) δ 172.9, 172.6*, 141.6, 141.1*,
128.7*, 128.4, 127.9*, 126.7, 126.5, 75.6, 74.9*, 60.1, 60.0*, 57.3*,
56.7, 29.0, 27.1*, 15.0*, 14.0; FTIR (neat, cm-1) 3390 (br, s, OH),
1634 (s, CdO); HRMS (EI) calcd for C12H18NO3 (MH)+ 224.1287,
found 224.1289. Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N,
6.27. Found: C, 64.53; H, 7.58; N, 6.20.
(S,S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl-3-
pyridylacetamide (10). Triethylamine (3.34 mL, 24.0 mmol, 3.00
equiv) was added to a suspension of 3-pyridylacetic acid hydrochloride
(2.08 g, 12.0 mmol, 1.50 equiv) in acetonitrile (60 mL). The resulting
suspension was stirred at 23 °C for 10 min and then cooled to 0 °C.
Pivaloyl chloride (1.48 mL, 12.0 mmol, 1.50 equiv) was added followed
by tetrahydrofuran (10 mL) to improve stirring of the thick suspension.
A solution of (+)-pseudoephedrine (1.32 g, 7.99 mmol, 1 equiv) and
triethylamine (1.11 mL, 7.99 mmol, 1 equiv) in tetrahydrofuran (20
mL, followed by a 3-mL rinse) was added rapidly via cannula. The
mixture was warmed slowly to 15 °C over 1 h, and excess anhydride
was quenched by the addition of water (10 mL). Volatile solvents
were removed under reduced pressure, and the resulting aqueous residue
was partitioned between 0.5 N aqueous sodium hydroxide solution and
10% methanol-dichloromethane (50 mL). The aqueous layer was
separated and extracted further with 10% methanol-dichloromethane
(4 × 50 mL). The combined organic layers were washed with 1 N
aqueous sodium hydroxide solution (15 mL), then dried over sodium
sulfate, and concentrated. Purification of the product by flash column
chromatography eluting with a gradient of ethyl acetate-methanol-
Alkylation Reactions Using Procedure A (Excess Alkyl Halide).
[1S(R),2S]-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N,2-dimethylben-
zenepropionamide (12). A three-necked, 2-L flask equipped with a
mechanical stirrer was charged with lithium chloride (25.0 g, 596 mmol,
6.00 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv), and
tetrahydrofuran (120 mL). The resulting suspension was cooled to -78
°C, and a solution of n-butyllithium in hexanes (2.43 M, 85.1 mL, 207
mmol, 2.08 equiv) was added via cannula. The suspension was warmed
briefly to 0 °C and then cooled to -78 °C. An ice-cooled solution of
amide 1 (22.0 g, 99.4 mmol, 1 equiv) in a minimal amount of
tetrahydrofuran (300 mL) was added to the reaction flask via cannula.
The reaction mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min,
and at 23 °C for 5 min and finally cooled to 0 °C, whereupon benzyl
bromide (17.7 mL, 149 mmol, 1.50 equiv) was added. The mixture
was stirred at 0 °C for 15 min and then quenched by the addition of
saturated aqueous ammonium chloride solution (10 mL). The mixture
was partitioned between saturated aqueous ammonium chloride solution
(800 mL) and ethyl acetate (500 mL), and the aqueous layer was
separated and extracted with two 150-mL portions of ethyl acetate.
The combined organic extracts were dried over sodium sulfate and

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6509
concentrated to afford a yellow solid. Recrystallization of the product
from hot toluene (110 °C, 100 mL) furnished amide 12 as a white
crystalline solid (27.8 g, 90%). Amide 12 (30 mg, 0.096 mmol, 1 equiv)
was silylated with chlorotrimethylsilane (34 µL, 0.27 mmol, 2.8 equiv)
and triethylamine (49 µL, 0.35 mmol, 3.6 equiv) in dichloromethane
(1 mL) at 23 °C for 10 min, and chiral capillary GC analysis46 of the
resulting trimethylsilyl ether established that amide 12 was of g99%
solution (50 mL). The biphasic mixture was heated at reflux for 6 h
and then cooled to 0 °C. The pH of the mixture was adjusted to pH
g 10 by the slow addition of 50% (w/w) aqueous sodium hydroxide
solution, and the resulting mixture was partitioned between water (100
mL) and dichloromethane (200 mL). The aqueous layer was separated
and extracted with dichloromethane (200 mL). The aqueous layer was
acidified to pH e 2 by the slow addition of 6 N aqueous sulfuric acid
solution and then extracted with dichloromethane (3 × 200 mL). The
latter organic extracts were combined and concentrated to a volume of
ca. 50 mL, and the concentrate was then washed with 1 N aqueous
hydrochloric acid solution to remove residual dioxane. The resulting
organic layer was dried over sodium sulfate and concentrated to afford
acid 46 as a clear liquid (5.07 g, 95%). Coupling of acid 46 (25 mg,
0.15 mmol, 1 equiv) with (R)-(R-methylbenzyl)amine (24 µL, 0.19
mmol, 1.2 equiv) in the presence of 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol, 1.5 equiv),
1-hydroxybenzotriazole hydrate (31 mg, 0.23 mmol, 1.5 equiv), and
triethylamine (86 µL, 0.62 mmol, 4.0 equiv) in N,N-dimethylformamide
(0.5 mL) at 23 °C for 20 h gave the corresponding (R)-R-methylbenzyl
amide47 which was analyzed by chiral capillary GC to establish an ee
of 97% for acid 46: 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 5H), 3.09
(dd, 1H, J1 ) 13.1 Hz, J2 ) 6.1 Hz), 2.75 (m, 2H), 1.18 (d, 3H, J )
6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 182.5, 139.0, 129.0, 128.4,
126.4, 41.2, 39.3, 16.5; FTIR (neat, cm-1) 2976 (br, s, OH), 1707 (s,
CdO); HRMS (FAB) calcd for C10H12O2 (M)+ 164.0838, found
164.0832. Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C,
73.23; H, 7.30.
1
de: mp 136-137 °C; H NMR (3:1 rotamer ratio, asterisk denotes
minor rotamer peaks, 300 MHz, C6D6) δ 6.9-7.4 (m, 10 H), 4.45 (m,
1H), 4.25 (br, 1H), 3.96* (m, 1H), 3.80* (m, 1H), 3.36* (dd, 1H, J )
13.1 Hz, 6.92 Hz), 3.01 (m, 1H), 2.75* (m, 2H), 2.70* (s, 3H), 2.52
(m, 2H), 2.08 (s, 3H), 1.05* (d, 3H, J ) 7.0 Hz), 1.02 (d, 3H, J ) 6.5
Hz), 0.83 (d, 3H, J ) 7.0 Hz), 0.59* (d, 3H, J ) 6.8 Hz); 13C NMR
(3:1 rotamer ratio, asterisk denotes minor rotamer peaks, 75 MHz,
CDCl3) δ 178.2, 177.2*, 142.3, 141.1*, 140.5*, 139.9, 129.2*, 128.9,
128.6*, 128.31*, 128.26, 127.5*, 126.8*, 126.4, 126.2, 76.4, 75.2*,
58.0, 40.3, 40.0*, 38.9, 38.1*, 32.3, 27.1*, 17.7*, 17.4, 15.5*, 14.3;
FTIR (neat, cm-1) 3384 (br, m, OH), 1617 (s, CdO); HRMS (FAB)
calcd for C20H26NO2 (MH)+ 312.1965, found 312.1972. Anal. Calcd
for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 76.87; H, 8.06;
N, 4.50.
A General Procedure for Alkylation Reactions Using Procedure
B (Excess Enolate). [1S(R),2S]-N-(2-Hydroxy-1-methyl-2-phenyl-
ethyl)-N,2-dimethyl-4-[(triisopropylsilyl)oxy]butanamide (31).
A
solution of n-butyllithium in hexanes (2.55 M, 27.4 mL, 69.9 mmol,
4.00 equiv) was added via cannula to a suspension of lithium chloride
(9.39 g, 222 mmol, 12.7 equiv) and diisopropylamine (10.6 mL, 75.3
mmol, 4.31 equiv) in THF (50 mL) at -78 °C. The resulting
suspension was warmed to 0 °C briefly and then was cooled to -78
°C. An ice-cooled solution of amide 1 (8.12 g, 36.7 mmol, 2.10 equiv)
in THF (110 mL, followed by a 4-mL rinse) was added via cannula.
The mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, and at
23 °C for 5 min. The mixture was cooled to 0 °C, and 2-iodo-1-
[(triisopropylsilyl)oxy]ethanol (5.73 g, 17.5 mmol, 1 equiv) was added
neat to the reaction via cannula. After being stirred for 18.5 h at 0 °C,
the reaction mixture was treated with half-saturated aqueous ammonium
chloride solution (180 mL), and the resulting mixture was extracted
with ethyl acetate (4 × 110 mL). The combined organic extracts were
dried over sodium sulfate and concentrated. Purification of the residue
by flash column chromatography (65% ether-hexanes) afforded amide
31 as a highly viscous, yellow oil (6.57 g, 89%). Chiral capillary GC
analysis46 of the corresponding trimethylsilyl ether, prepared as
described above for amide 12, established that amide 31 was of 97%
de: 1H NMR (6:1 rotamer ratio, asterisk denotes minor rotamer peaks,
400 MHz, C6D6) δ 7.31 (d, 2H, J ) 7.4 Hz), 7.25* (d, 2H, J ) 7.4
Hz), 7.03-7.22 (m, 3H), 4.55 (t, 1H, J ) 7.3 Hz), 4.14-4.38 (br, m,
1H), 4.02* (m, 1H), 3.78* (t, 2H, J ) 5.8 Hz), 3.52 (m, 2H), 2.86 (m,
1H), 2.79* (s, 3H), 2.47 (s, 3H), 1.96 (m, 1H), 1.50 (m, 1H), 1.07 (m,
27H), 0.63* (d, 3H, J ) 6.6 Hz); 13C NMR (6:1 rotamer ratio, asterisk
denotes minor rotamer peaks, 100 MHz, CDCl3), δ 179.1, 177.7*, 142.6,
141.4*, 128.7*, 128.6*, 128.4, 127.6, 127.1*, 126.4, 76.5, 75.5*, 61.3*,
60.7, 58.5, 58.0*, 37.2, 36.9*, 32.7 (br), 32.5, 32.2*, 27.0*, 18.1, 17.6*,
17.0, 15.6*, 14.5, 12.3*, 12.1; FTIR (neat, cm-1) 3383 (br, m, OH),
1621 (s, CdO); HRMS (FAB) calcd for C24H44O3NSi (MH)+ 422.3090,
found 422.3086. Anal. Calcd for C24H43O3NSi: C, 68.36; H, 10.28;
N, 3.32. Found: C, 68.32; H, 10.26; N, 3.35.
The carboxylic acids of entries 2-7 (Table 4) were prepared
analogously except that 18 N H2SO4 was employed and the reaction
time was reduced to 1-2 h at reflux.
Hydrolysis of Pseudoephedrine Amides with n-Bu4NOH in 4:1
Aqueous tert-Butyl Alcohol. (R)-r-Methylbenzenepropionic Acid
(46). A 100-mL round-bottomed flask was charged with amide 12
(0.500 g, 1.61 mmol, 1 equiv), aqueous tetra-n-butylammonium
hydroxide solution (40% w/w, 5.21 g, 8.03 mmol, 5.00 equiv), tert-
butyl alcohol (5 mL), and water (15 mL), and the biphasic mixture
was heated at reflux for 24 h. The mixture was cooled to 23 °C and
then partitioned between 0.5 N aqueous sodium hydroxide solution (200
mL) and ether (25 mL). The aqueous layer was separated and extracted
with two 25-mL portions of ether and then brought to pH e 1 by the
addition of 3 N aqueous hydrochloric acid solution. The acidified
solution was saturated with sodium chloride and extracted with three
35-mL portions of ether. The combined ether extracts were washed
with water (10 mL), then dried over sodium sulfate, and concentrated
to afford acid 46 as a clear liquid (0.245 g, 93%) with spectroscopic
data identical to those obtained from 46 prepared above. Chiral
capillary GC analysis of the corresponding (R)-R-methylbenzyl amide,47
prepared as described above, established that 46 prepared by this method
1
was of 94% ee. The purity of 46 was estimated to be g95% by H
and 13C NMR spectroscopic data.
Hydrolysis of Pseudoephedrine Amides with NaOH in 2:1:1
Water-tert-Butyl Alcohol-Methanol. (R)-r-Methylbenzenepro-
pionic Acid (46). A 250-mL round-bottomed flask was charged with
amide 12 (10.0 g, 32.1 mmol, 1 equiv), tert-butyl alcohol (25 mL),
methanol (25 mL), and 3.22 N aqueous sodium hydroxide solution (50
mL, 161 mmol, 5.01 equiv). The mixture was heated at reflux for 24
h and then cooled to 23 °C. The mixture was concentrated to remove
the organic solvents, and the resulting aqueous solution was partitioned
between water (200 mL) and dichloromethane (200 mL). The aqueous
layer was separated, extracted with dichloromethane (200 mL), and
then acidified to pH e 2 by the slow addition of 6 N aqueous sulfuric
acid solution. The acidified aqueous solution was extracted with
dichloromethane (3 × 200 mL), and the combined organic extracts
were dried over sodium sulfate and concentrated to afford acid 46 as
a clear liquid (5.18 g, 98%) with spectroscopic data identical to those
obtained from 46 prepared above. Chiral capillary GC analysis of the
corresponding (R)-R-methylbenzyl amide,47 prepared as described
above, established that 46 prepared by this method was of 92% ee.
Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 72.79; H,
7.09.
Hydrolysis of Pseudoephedrine Amides with H2SO4 in 1:1
Aqueous Dioxane. (R)-r-Methylbenzenepropionic Acid (46).
A
250-mL round-bottomed flask was charged with amide 12 (10.0 g, 32.1
mmol, 1 equiv), dioxane (50 mL), and 9 N aqueous sulfuric acid
(46) In each case, an authentic sample of the minor diastereomeric
alkylation product was prepared for comparative analysis (chiral capillary
GC analysis of the corresponding trimethylsilyl ether or acetate ester). In
the case of amides 16, 21, 26, 27, and 29-31, diastereomeric mixtures of
R-epimers were obtained by epimerization with LDA (5 equiv) or lithium
2,2,6,6-tetramethylpiperidide (5 equiv) in THF for 5 h at 23 °C followed
by quenching with aqueous ammonium chloride solution. Amide 28 was
epimerized by stirring with lithium chloride (5 equiv) in N,N-dimethylfor-
mamide at 23 °C for 12 h. Each of the remaining alkylation products in
Tables 2 and 3 was epimerized by stirring the substrate with trifluoroacetic
acid (10 equiv) in THF at reflux for 1 h (effecting N f O acyl transfer as
well as R-epimerization), followed by neutralization with aqueous sodium
bicarbonate solution at 23 °C for 24 h (causing O f N acyl transfer).
(47) In each case, an authentic sample of the minor diastereomeric (R)-
R-methylbenzyl amide was prepared for comparative analysis.

6510 J. Am. Chem. Soc., Vol. 119, No. 28, 1997
Myers et al.
1
Hydrolysis of Pseudoephedrine Amides with FeCl3 in 4:1 Aque-
ous Dioxane. (R)-r-Methylbenzenepropionic acid (46). A 10-mL
round-bottomed flask was charged with amide 12 (157 mg, 0.505 mmol,
1 equiv), iron(III) chloride hexahydrate (676 mg, 2.50 mmol, 4.95
equiv), water (4 mL), and dioxane (1 mL). The biphasic mixture was
heated at reflux for 48 h and then cooled to 23 °C. The pH of the
mixture was adjusted to g10 by the dropwise addition of 50% (w/w)
aqueous sodium hydroxide solution, and the resulting mixture was
partitioned beween water (10 mL) and dichloromethane (10 mL). The
aqueous layer was separated, extracted with dichloromethane (10 mL),
and then acidified to pH e 2 by the dropwise addition of 6 N aqueous
sulfuric acid solution. The resulting aqueous solution was extracted
with dichloromethane (3 × 10 mL). The combined organic extracts
were dried over sodium sulfate and concentrated to afford acid 46 as
a clear liquid (78.2 mg, 94%) with spectroscopic data identical to those
obtained from 46 prepared above. Chiral capillary GC analysis of the
corresponding (R)-R-methylbenzyl amide,47 prepared as described
above, established that 46 prepared by this method was of 98% ee.
The purity of 46 was estimated to be g95% by 1H and 13C NMR
spectroscopic data.
was of 94% ee. The purity of 46 was estimated to be g95% by H
and 13C NMR spectroscopic data.
(R)-r-Methylbutanedioic Acid (57). A 25-mL round-bottomed
flask was charged with amide 16 (563 mg, 1.76 mmol, 1 equiv), tert-
butyl alcohol (3 mL), methanol (3 mL), and 1 N aqueous sodium
hydroxide solution (12 mL, 12 mmol, 6.8 equiv). The mixture was
heated at reflux for 24 h and then cooled to 23 °C. The mixture was
partitioned between 0.5 N aqueous sodium hydroxide solution (100
mL) and dichloromethane (10 mL). The aqueous layer was separated,
extracted with dichloromethane (2 × 10 mL), and then acidified to pH
e 2 by the slow addition of 3 N aqueous hydrochloric acid solution.
The acidified aqueous layer was saturated with sodium chloride and
then extracted with ethyl acetate (3 × 40 mL). The combined organic
extracts were dried over sodium sulfate and concentrated to afford diacid
57 as a white solid (173 mg, 74%). Diacid 57 was reduced with lithium
aluminum hydride (3 equiv) in THF at 0 °C to the corresponding diol,
1
and H NMR analysis (400 MHz, CDCl3) of the corresponding bis-
(Mosher esters)44 derived from both (R)- and (S)-Mosher acid estab-
lished that diacid 57 was of 94% ee: mp 104-106 °C; 1H NMR (300
MHz, CD3OD) δ 5.03 (br, 2H), 2.82 (m, 1H), 2.65 (dd, 1H, J1 ) 16.7
Hz, J2 ) 8.3 Hz), 2.38 (dd, 1H, J1 ) 16.7 Hz, J2 ) 5.8 Hz), 1.20 (d,
3H, J ) 7.2 Hz); 13C NMR (100 MHz, CD3OD) δ 179.2, 175.6, 38.5,
37.0, 17.4; FTIR (neat, cm-1) 2700-3300 (br, m, OH), 1694 (s, CdO);
HRMS (EI) calcd for C5H9O4 (MH)+ 133.0501, found 133.0504. Anal.
Calcd for C5H8O4: C, 45.46; H, 6.10; N, 0. Found: C, 45.86; H, 5.93;
N, 0.14.
Hydrolysis of Pseudoephedrine Amides Using Yb(OTf)3 or ZrOCl2
in 4:1 Aqueous Dioxane. (R)-r-Methylbenzenepropionic Acid (46).
These hydrolyses were performed in a manner analogous to the
hydrolysis with FeCl3, substituting zirconyl chloride or ytterbium triflate
(5 equiv) for iron(III) chloride.
Hydrolysis of Pseudoephedrine Amides Involving in Situ Bo-
rane-Amine Complexation (Sodium Hydroxide). (R)-r-Methyl-
benzenepropionic Acid (46). A 10-mL round-bottomed flask was
charged with amide 12 (160 mg, 0.513 mmol, 1 equiv), tetrahydrofuran
(2.0 mL), and methanesulfonic acid (48 µL, 0.74 mmol, 1.44 equiv).
This mixture was heated at reflux for 1 h and then cooled to 23 °C. A
solution of lithium borohydride (2.0 M, 0.38 mL, 0.76 mmol, 1.5 equiv)
in tetrahydrofuran was cautiously added to the mixture, leading to
significant gas evolution. A solution of aqueous sodium hydroxide
(1.25 N, 2.0 mL, 2.5 mmol, 4.9 equiv) was then cautiously added, and
the resulting mixture was stirred for 8 h at 23 °C. The reaction mixture
was partitioned between water (10 mL) and dichloromethane (10 mL).
The aqueous layer was separated and extracted with dichloromethane
(10 mL) and then acidified to pH e 2 by the slow addition of 3 N
aqueous hydrochloric acid solution. The resulting acidified solution
was extracted with dichloromethane (3 × 10 mL). The latter extracts
were combined, dried over sodium sulfate, and concentrated to afford
acid 46 as a clear liquid (79.5 mg, 94%) with spectroscopic data
identical to those obtained from 46 prepared above. Chiral capillary
GC analysis of the corresponding (R)-R-methylbenzyl amide,47 prepared
as described above, established that 46 prepared by this method was
Reduction of Pseudoephedrine Amides with Lithium Amidotri-
hydroborate (LAB) To Form Primary Alcohols. (2R,4S)-2,4-
Dimethyl-5-phenylpentanol (70). A solution of n-butyllithium in
hexanes (2.33 M, 20.0 mL, 46.5 mmol, 3.90 equiv) was added to a
solution of diisopropylamine (7.02 mL, 50.1 mmol, 4.20 equiv) in
tetrahydrofuran (50 mL) at -78 °C. The resulting solution was stirred
at -78 °C for 10 min, then warmed to 0 °C, and held at that temperature
for 10 min. Borane-ammonia complex (90%, 1.64 g, 47.7 mmol, 4.00
equiv) was added in one portion, and the suspension was stirred at 0
°C for 15 min and then was warmed to 23 °C. After 15 min, the
suspension was cooled to 0 °C. A solution of amide 35 (4.22 g, 11.9
mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 5-mL rinse)
was added via cannula over 3 min. The reaction mixture was warmed
to 23 °C, held at that temperature for 2 h, and then cooled to 0 °C
where excess hydride was quenched by the careful addition of 3 N
aqueous hydrochloric acid solution (120 mL). The mixture was stirred
for 30 min at 0 °C and then extracted with four 45-mL portions of
ether. The combined organic extracts were washed sequentially with
3 N aqueous hydrochloric acid solution (20 mL), 2 N aqueous sodium
hydroxide solution (20 mL), and brine (20 mL). The ether extracts
were dried over magnesium sulfate and concentrated. Purification of
the residue by flash column chromatography (35% ether-petroleum
ether) afforded alcohol 70 as a colorless liquid (2.18 g, 95% yield).
Acetylation of alcohol 70 (6.3 mg, 0.033 mmol, 1 equiv) with acetic
anhydride (9.0 µL, 0.10 mmol, 3.0 equiv) and 4-(dimethylamino)-
pyridine (16 mg, 0.13 mmol, 4 equiv) in dichloromethane (0.5 mL) at
23 °C for 1 h and chiral capillary GC analysis48 of the resulting acetate
ester established that alcohol 70 was of 98% de: 1H NMR (400 MHz,
CDCl3) δ 7.1-7.4 (m, 5H), 3.52 (dd, 1H, J1 ) 10.5 Hz, J2 ) 5.1 Hz),
3.38 (dd, 1H, J1 ) 10.5 Hz, J2 ) 6.6 Hz), 2.68 (dd, 1H, J1 ) 13.3 Hz,
J2 ) 5.4 Hz), 2.28 (dd, 1H, J1 ) 13.3 Hz, J2 ) 8.6 Hz), 1.80 (m, 2H),
1.37 (dd, 1H, J1 ) 13.7 Hz, J2 ) 6.8 Hz), 1.03 (dd, 1H, J1 ) 13.7 Hz,
of 98% ee. The purity of 46 was estimated to be g95% by 1H and 13
C
NMR spectroscopic data.
Hydrolysis of Pseudoephedrine Amides Involving in Situ Bo-
rane-Amine Complexation (n-Bu4NOH). (R)-r-Methylbenzenepro-
pionic Acid (46). A flame-dried 10-mL round-bottomed flask was
charged with amide 12 (158 mg, 0.508 mmol, 1 equiv), tetrahydrofuran
(2.0 mL), and methanesulfonic acid (48 µL, 0.74 mmol, 1.46 equiv).
The mixture was heated at reflux for 1 h and then cooled to 23 °C. A
solution of lithium borohydride (2.0 M, 0.38 mL, 0.76 mmol, 1.5 equiv)
in tetrahydrofuran was cautiously added to the mixture, leading to
significant gas evolution. Water (1.0 mL) and an aqueous solution of
tetra-n-butylammonium hydroxide (40% w/w, 1.62 g, 2.50 mmol, 4.92
equiv) were then cautiously added, and the mixture was stirred at 23
°C for 1 h. The reaction mixture was partitioned between 0.5 N aqueous
sodium hydroxide solution (50 mL) and ether (10 mL). The aqueous
phase was separated, extracted with ether (2 × 10 mL) and acidified
to pH e 2 by the slow addition of 3 N aqueous hydrochloric acid
solution, and with ether (3 × 10 mL). The latter organic extracts were
combined and washed sequentially with 1 N aqueous hydrochloric acid
solution (10 mL) and brine (10 mL) to remove residual tetra-n-
butylammonium salts, then dried over sodium sulfate, and concentrated
to afford acid 46 as a clear liquid (75.4 mg, 91%) with spectroscopic
data identical to those obtained from 46 prepared above. Chiral
capillary GC analysis of the corresponding (R)-R-methylbenzyl amide,47
prepared as described above, established that 46 prepared by this method
J2 ) 7.3 Hz), 0.96 (d, 3H, J ) 6.7 Hz), 0.86 (d, 3H, J ) 6.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 141.4, 129.2, 128.2, 125.8, 68.2, 43.4, 40.8,
33.3, 32.5, 20.2, 17.4; FTIR (neat, cm-1) 3346 (br, m, OH). Anal.
Calcd for C13H20O: C, 81.20; H, 10.48; N, 0. Found: C, 80.93; H,
10.43; N, <0.05.
Reaction of Primary Alcohols with Triphenylphosphine and
Iodine To Form Iodides. (R)-1-Iodo-2-methyl-3-phenylpropane
(78). Imidazole (6.86 g, 101 mmol, 1.50 equiv) and iodine (23.0 g,
90.7 mmol, 1.35 equiv) were added sequentially to a solution of
triphenylphosphine (21.1 g, 80.6 mmol, 1.20 equiv) in dichloromethane
(250 mL) at 23 °C. A solution of alcohol 58 (10.1 g, 67.2 mmol, 1
(48) Acetate esters of the diastereomeric alcohol pairs 68 and 69, 70
and 71, 72 and 73, 74 and 75, and 76 and 77 were separated with baseline
resolution when assayed by chiral capillary GC analysis.

Pseudoephedrine as a Chiral Auxiliary for Synthesis
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6511
equiv) in dichloromethane (30 mL) was added to the resulting fine
suspension via cannula. After 2 h, dichloromethane was removed in
vacuo. The solid residue was suspended in a minimal amount of
dichloromethane (30 mL), and the suspension was loaded onto a column
of silica gel eluting with 10% ether-petroleum ether to afford the iodide
78 as a colorless liquid (17.1 g, 98%): 1H NMR (400 MHz, C6D6) δ
6.9-7.2 (m, 5H), 2.73 (dd, 1H, J1 ) 9.7 Hz, J2 ) 4.9 Hz), 2.70 (dd,
1H, J1 ) 9.7 Hz, J2 ) 5.5 Hz), 2.43 (dd, 1H, J1 ) 13.5 Hz, J2 ) 7.0
Hz), 2.18 (dd, 1H, J1 ) 13.5 Hz, J2 ) 7.1 Hz), 1.33 (m, 1H), 0.72 (d,
3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 140.8, 129.0, 128.3,
126.2, 42.5, 36.7, 20.7, 17.0; FTIR (neat, cm-1) 2958 (s), 1494 (s),
1453 (s), 1194 (s); HRMS (EI) calcd for C10H13I (M)+ 260.0062, found
260.0057. Anal. Calcd for C10H13I: C, 46.18; H, 5.04. Found: C,
46.34, H, 5.20.
(50 mL). The organic phase was dried over sodium sulfate and
concentrated. Purification of the residue by flash column chromatog-
raphy eluting with a gradient of ethyl acetate-hexanes (3 f 10%)
afforded ketone 88 as a clear liquid (176 mg, 94% yield). High-
resolution
1H NMR analysis (300 MHz, C6D6) of the Mosher ester
derivatives,50 prepared as described for alcohol 58, of the diastereomeric
alcohol mixture obtained by the reduction of ketone 88 with lithium
aluminum hydride (as described for ketone 89 below) established that
ketone 88 was of g95% ee: 1H NMR (300 MHz, CDCl3) δ 7.1-7.8
(m, 10H), 3.79 (sx, 1H, J ) 6.9 Hz), 3.22 (dd, 1H, J1 ) 13.7 Hz, J2 )
6.3 Hz), 2.74 (dd, 1H, J1 ) 13.7 Hz, J2 ) 7.9 Hz), 1.25 (d, 3H, J )
6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 203.7, 139.9, 136.4, 132.9,
129.1, 128.6, 128.3, 128.2, 126.2, 42.7, 39.3, 17.4; FTIR (neat, cm-1
)
1679 (s, CdO); HRMS (EI) calcd for C16H16O, (M)+ 224.1201 found
Reduction of Pseudoephedrine Amides with LiAlH(OEt)3 To
Form Aldehydes. (R)-r-Methylbenzenepropanal (82). A 1-L round-
bottomed flask was charged with solid lithium aluminum hydride (95%,
2.95 g, 73.9 mmol, 2.30 equiv) under a nitrogen atmosphere. The
hydride was suspended in hexanes (170 mL), and the flask was cooled
to 0 °C. Ethyl acetate (10.7 mL, 110 mmol, 3.41 equiv) was added by
addition funnel over a period of 1.5 h, and the resulting suspension of
lithium triethoxyaluminum hydride was cooled to -78 °C. A solution
of amide 12 (10.0 g, 32.1 mmol, 1 equiv) in tetrahydrofuran (110 mL)
was added via cannula over 5 min, and the reaction mixture was warmed
to 0 °C. After being stirred for 1 h at 0 °C, the reaction mixture was
transferred by cannula to a solution of trifluoroacetic acid (25 mL, 325
mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (400 mL),
and the transfer was quantitated with an additional portion of tetrahy-
drofuran (10 mL). The resulting biphasic mixture was stirred at 23 °C
for 5 min and then diluted with 1 N aqueous hydrochloric acid solution
(700 mL), and the layers were separated. The aqueous layer was
extracted with ethyl acetate (3 × 150 mL). The combined organic
layers were neutralized by the cautious addition of saturated aqueous
sodium bicarbonate solution (250 mL). The latter addition sometimes
produced an emulsion that could be cleared by filtration through a coarse
frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8)
was separated and extracted with ethyl acetate (100 mL). The combined
organic extracts were dried over sodium sulfate and concentrated.
Purification of the residue by flash column chromatography (7.5% ethyl
acetate-hexanes) afforded the aldehyde 82 as a colorless liquid (3.64
g, 76%). Aldehyde 82 was oxidized49 to the corresponding carboxylic
acid 46, and chiral capillary GC analysis of the corresponding (R)-R-
methylbenzyl amide, as described above for acid 46, established that
aldehyde 82 was of 95% ee: 1H NMR (300 MHz, C6D6) δ 9.29 (d,
1H, J ) 1.2 Hz), 6.8-7.1 (m, 5H), 2.72 (dd, 1H, J1 ) 13.2 Hz, J2 )
5.4 Hz), 2.10 (m, 2H), 0.69 (d, 3H, J ) 6.9 Hz); 13C NMR (75 MHz,
CDCl3) δ 204.3, 138.7, 128.9, 128.4, 126.3, 48.0, 36.5, 13.1; FTIR
(neat, cm-1) 1723 (s, CdO); HRMS (FAB) calcd for C10H13O (MH)+
149.0966, found 149.0965.
224.1201.
(R)-2-Methyl-1-phenyl-3-heptanone (89). Amide 12 (10.0 g, 32.1
mmol, 1 equiv) was suspended in toluene (50 mL) in a 500-mL round-
bottomed flask. The suspension was warmed to 70 °C to dissolve the
amide, and the resulting solution was cooled to 23 °C and then
concentrated under reduced pressure. The reaction flask was then
flushed with dry argon, ether (250 mL) was added, and the resulting
slurry was cooled to -78 °C. A solution of n-butyllithium in hexanes
(2.39 M, 32.3 mL, 77.2 mmol, 2.40 equiv) was added via syringe, and
the mixture was then warmed to 0 °C and held at that temperature for
15 min. Excess n-butyllithium was quenched at 0 °C by the addition
of diisopropylamine (4.5 mL, 32 mmol, 1 equiv). After 15 min, a
solution of acetic acid in ether (20% v/v, 100 mL) was added. The
mixture was partitioned between ethyl acetate (300 mL) and water (300
mL), and the aqueous phase was separated and extracted with
dichloromethane (2 × 300 mL). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated. Purification
of the residue by flash column chromatography eluting with a gradient
of ethyl acetate-hexanes (2 f 5%) afforded ketone 89 as a clear liquid
(5.80 g, 88% yield). A solution of lithium aluminum hydride in ether
(1.0 M, 0.75 mL, 0.75 mmol, 1.5 equiv) was added to a solution of
ketone 89 (102 mg, 0.50 mmol, 1 equiv) in ether (1 mL) at 0 °C to
afford a mixture of diastereomeric alcohols. High-resolution 1H NMR
analysis (400 MHz, C6D6) of the corresponding Mosher ester deriva-
tives,50 prepared as described for alcohol 58, of this mixture of
diastereomeric alcohols established that ketone 89 was of g95% ee:
1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H), 2.97 (dd, 1H, J1 ) 13.2
Hz, J2 ) 7.1 Hz), 2.83 (sx, 1H, J ) 7.0 Hz), 2.55 (dd, 1H, J1 ) 13.2
Hz, J2 ) 7.3 Hz), 2.39 (dt, 1H, J1 ) 16.9 Hz, J2 ) 7.3 Hz), 2.25 (dt,
1H, J1 ) 16.9 Hz, J2 ) 7.3 Hz), 1.45 (m, 2H), 1.23 (sx, 2H, J ) 7.4
Hz), 1.07 (d, 3H, J ) 6.9 Hz), 0.85 (t, 3H, J ) 7.3 Hz); 13C NMR (75
MHz, CDCl3) δ 214.4, 139.8, 128.9, 128.3, 126.2, 48.1, 41.7, 39.1,
25.6, 22.3, 16.5, 13.9; FTIR (neat, cm-1) 1712 (s, CdO); HRMS (EI)
calcd for C14H20O (M)+ 204.1514, found 204.1517.
Reaction of Pseudoephedrine Amides with Organolithium Re-
agents To Form Ketones. (R)-2-Methyl-1,3-diphenyl-1-propanone
(88). Amide 12 (261 mg, 0.839 mmol, 1 equiv) was suspended in
toluene (5 mL) in a 25-mL rounded-bottomed flask. The suspension
was warmed to 70 °C to dissolve the amide, and the resulting solution
was cooled to 23 °C and then concentrated under reduced pressure.
The reaction flask was flushed with dry argon, tetrahydrofuran (10 mL)
was added, and the resulting slurry was cooled to -78 °C. A solution
of phenyllithium in 70% cyclohexane-ether (1.94 M, 1.04 mL, 2.02
mmol, 2.41 equiv) was added via syringe, and the mixture was then
warmed to 0 °C and held at that temperature for 5 min. Excess
phenyllithium was quenched at 0 °C by the addition of diisopropylamine
(0.12 mL, 0.84 mmol, 1 equiv). After 15 min, a solution of acetic
acid in ether (10% v/v, 10 mL) was added. The mixture was partitioned
between ethyl acetate (40 mL) and saturated aqueous sodium bicarbon-
ate solution (50 mL), and the organic phase was separated and extracted
with saturated aqueous sodium bicarbonate solution (50 mL) and water
Acknowledgment. Financial support from the National
Science Foundation, NSF predoctoral fellowship support to
B.H.Y. and H.C., and NIH postdoctoral support to J.L.G. are
gratefully acknowledged. We thank Michael Siu for the
preparation of compound 25.
Supporting Information Available: Tabular results from
a study of the effect of metal salts in the hydrolysis of amide
12 and experimental procedures, spectroscopic data, and proof
of composition for compounds 4, 6, 7, 9, 13-28, 32-45, 47-
56, 58-69, 71-77, 79-81, 83-87, and 90-100 (49 pages).
See any current masthead page for ordering and Internet access
instructions.
JA970402F
(49) Kraus, G. A.; Taschner, J. J. Org. Chem. 1980, 45, 1175 and
references therein.
(50) Both (R)- and (S)-Mosher ester derivatives were prepared for
comparative analysis.