(S,S)-(+)-pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/α-alkylation reactions

Article abstract of DOI:10.1021/jo061205e

(Chemical Equation Presented) Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding β-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing α,β-dialkyl- substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic β-alkyl- and α,β-dialkyl-substituted carboxylic acids and γ-alkyl- and β,γ-dialkyl-substituted alcohols using very simple and high-yielding procedures.

Full text of DOI:10.1021/jo061205e

(S,S)-(+)-Pseudoephedrine as Chiral Auxiliary in Asymmetric
Conjugate Addition and Tandem Conjugate Addition/r-Alkylation
Reactions
Efraim Reyes, Jose L. Vicario, Luisa Carrillo, Dolores Bad´ıa,* Uxue Uria, and Ainara Iza
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad del Pa´ıs
Vasco/Euskal Herriko Unibertsitatea, P.O. Box 644, E-48080 Bilbao, Spain
dolores.badia@ehu.es
ReceiVed June 12, 2006
Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseu-
doephedrine enamides furnishing the corresponding â-alkyl-substituted adducts in excellent yields and
diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition
step undergo a highly diastereoselective alkylation reaction, furnishing R,â-dialkyl-substituted amides in
high yields. The obtained adducts have been converted into chiral nonracemic â-alkyl- and R,â-dialkyl-
substituted carboxylic acids and γ-alkyl- and â,γ-dialkyl-substituted alcohols using very simple and high-
yielding procedures.
Introduction
copper acetylide14 reagents, among others, have been exhaus-
tively studied. However, despite their availability, the literature
furnishes little information regarding the use of organolithium
reagents in asymmetric conjugate additions to R,â-unsaturated
carbonyl compounds,15 mainly due to the fact that these reagents
add to the carbonyl group in a 1,2-fashion rather than giving
the desired 1,4-adduct.16
Concerning the methodologies applied in order to achieve
the desired stereochemical control during the conjugate addition
reaction, although the enantioselective approaches involving
asymmetric catalysis have enjoyed a surge in popularity,
The conjugate addition of organometallic reagents to R,â-
unsaturated carbonyl compounds or related derivatives is
regarded as one of the most powerful methods for the formation
of C-C bonds.1 In addition, when the starting material contains
prochiral centers at the R- and/or â-position, the generation of
one or more stereogenic centers occurs concomitant with the
conjugate addition process, which means that highly branched
enantiomerically pure compounds can be easily obtained once
the stereochemical outcome of the reaction becomes suitably
controlled.2 In this context, enantio- and diastereoselective
conjugate addition reactions of organocopper3 and Grignard4
reagents or different metal-catalyzed versions of this transforma-
tion with dialkylzinc,5 Grignard,6 organoboron,7 aluminum,8
bismuth,9 zirconium,10 titanium,11 tin,12 organosilicon,13 and
(3) Some recent examples: (a) Bertz, S. H.; Ogle, C. A.; Rastogi, A. J.
Am. Chem. Soc. 2005, 127, 1372. (b) Leonelli, F.; Capuzzi, M.; Calcagno,
V.; Passacantilli, P.; Piancatelli, G. Eur. J. Org. Chem. 2005, 2671 (c)
Carren˜o, M. C., Sanz-Cuesta, M. J. J. Org. Chem. 2005, 70, 10036. (d)
McMahon, J. P.; Ellman, J. A. Org. Lett. 2005, 7, 5393. (e) Williams, D.
R.; Nold, A. L.; Mullins, R. J. Org. Chem. 2004, 69, 5374. (f) Dambacher,
J.; Anness, R.; Pollock, P.; Bergdahl, M. Tetrahedron 2004, 60, 2097. (g)
Schneider, C.; Reese, O. Chem. Eur. J. 2002, 8, 2585. (h) Pinheiro, S.;
Pedraza, S. F.; Peralta, M. A.; Teixeira, R. C.; Farias, F. M. C.; Ferreira,
V. F.; Costa, P. R. R. Tetrahedron: Asymmetry 2002, 13, 2513. (i) Arai,
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Nagatsuka, T.; Yamaguchi, S.; Takao, K.; Ohba, S.; Tadano, K. J. Org.
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Pergamon Press: Oxford, 1992.
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(b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (c) Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033. (e) Leonard, J.; D´ıez-Barra, E.; Merino, S.
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10.1021/jo061205e CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7763-7772
7763

Reyes et al.
especially in recent years, the use of chiral auxiliaries linked
covalently to the acceptor still remains as one of the most
powerful methodologies employed so far in the stereocontrolled
1,4-addition of organometallic reagents. The problems associated
to the chiral auxiliary methodology can be overcome if efficient
and simple procedures are devised to recover and recycle the
chiral auxiliary after its removal of the conjugate addition
product, and this methodology can turn into a very powerful
synthetic tool if the chiral auxiliary provides special reactivity
features to the adduct, which allows much more powerful
synthetic versatility when transforming it into other useful chiral
compounds. Related to this topic, the commercially available
and cheap reagent (S,S)-(+)-pseudoephedrine has provided
excellent results as a chiral auxiliary in many asymmetric
transformations such as alkylations,17 aldol18 and Mannich
reactions,19 aminations,20 aziridine21 and epoxide22 ring-opening
reactions, and Michael additions.23 Additional advantages of the
use of this auxiliary are related to the unique reactivity of the
amide function present in the obtained adducts, which has
allowed the preparation of a wide range of many interesting
chiral building blocks. In all of the cases previously mentioned,
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7764 J. Org. Chem., Vol. 71, No. 20, 2006

(S,S)-(+)-Pseudoephedrine as a Chiral Auxiliary
SCHEME 1a
amides derived from this amino alcohol have been employed
as nucleophiles via their corresponding enolates, but in recent
reports, we have shown that pseudoephedrine can also play the
role of a very efficient chiral auxiliary linked to the electrophilic
counterpart in asymmetric aza-Michael reactions.24
On the other hand, a very attractive application which can
be found in the conjugate addition reaction is the formation of
an intermediate enolate species with potential for subsequent
R-alkylation, aldol, Mannich, Michael, or similar reactions in a
typical tandem sequence.25 These asymmetric tandem processes
initiated by conjugate additions turn into a very easy and direct
method for increasing molecular complexity from readily
available starting materials, and therefore, target structures can
be built up in a modular way by stepwise introduction of the
desired substituents at the different reagents employed in the
process. As previously mentioned, the literature furnishes many
examples for asymmetric tandem transformations initiated by
the conjugate addition of an organometallic reagent, like tandem
conjugate addition followed by aldol,26 Mannich,27 Michael,28
halogenation,29 or Dieckmann reactions.30 However, the number
of examples in which the intermediate enolate is trapped with
an alkylating reagent such an alkyl halide is very scarce.11,31
Alkyl halides are known to react very difficultly with the
intermediate enolate under the experimental conditions em-
ployed in the conjugate addition step and usually require the
addition of an additive like HMPA in order to reach to
a Reagents and conditions: (i) (1) R2Li, LiCl, THF, -105 °C, (2) R3X,
0 °C.
SCHEME 2 a
a Reagents and conditions: see Table 1.
acceptable yields. Moreover, only activated alkylating reagents
such as allyl halides or methyl iodide can usually be employed
with good results, which is a clear limitation of the methodolo-
gies reported up to date.
In this context we have reported very recently that asymmetric
tandem conjugate addition/R-alkylation can be performed in a
very simple and efficient way using (S,S)-(+)-pseudoephedrine
as chiral auxiliary (Scheme 1).32 In these preliminary studies
excellent results have been achieved using a wide range of
differently substituted R,â-unsaturated amides derived from this
chiral amino alcohol and several organolithium reagents and
alkyl halides.
With all of these precedents in mind, and in connection with
our studies directed toward the development of new methodolo-
gies in asymmetric synthesis using amino alcohols as chiral
auxiliaries, in this paper we report in detail our findings when
working in the optimization of the reaction conditions for the
first stereocontrolled 1,4-addition step, which has allowed us
to develop a very efficient procedure for performing asymmetric
conjugate addition of organometallic reagents. The highly
efficient conversion of the adducts obtained in the 1,4-addition/
protonation and the tandem conjugate addition/R-alkylation
sequences into enantioenriched branched carboxylic acids and
alcohols will also be presented, showing the remarkable
synthetic potential of this methodology.
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T. D.; Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903. (b)
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electrophiles in asymmetric aza-Michael reactions. (a) Etxebarria, J.; Vicario,
J. L.; Badia, D.; Carrillo, L.; Ruiz, N. J. Org. Chem. 2005, 70, 8790. (b)
Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2004,
69, 2588.
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Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. (c) Arnold,
L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67,
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Results and Discusion
Our experiments began with the optimization of the reaction
conditions for the conjugate addition of organometallic reagents
to R,â-unsaturated amide 1a (Scheme 2). As shown in Table 1,
when we carried out the reaction using a Grignard reagent (n-
BuMgCl) as nucleophile at -78 °C, it proceeded with very low
yield, and a large excess of organometallic reagent together with
a prolonged reaction time were needed in order to achieve some
conversion (entry 1). The reaction with n-Bu2CuLi was found
to be equally slow, although in this case we only had to employ
2 equiv of the nucleophile in order to obtain complete conversion
(entry 2). However, when we performed the addition of 2.0
(31) Relevant examples of asymmetric conjugate addition of organo-
metallic reagents and subsequent R-alkylation: (a) Rathgeb, X.; March,
S.; Alexakis, A. J. Org. Chem. 2006, 71, 5737. (b) Shintani, R.; Tokunaga,
N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. (c) Arai, Y.;
Kasai, M.; Ueda, K.; Masaki, Y. Synthesis 2003, 1511. (d) Fleming, F. F.;
Wang, Q.; Steward, O. W. J. Org. Chem. 2003, 68, 4235. (e) Totani, K.;
Asano, S.; Takao, K.; Tadano, K. Synlett 2001, 1772. (f) Mizutani, H.;
Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779. (g)
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem: Soc. 2001,
123, 755. (h) Rawson, D. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2292.
(i) Tomioka, K.; Kawasaki, H.; Koga, K. Tetrahedron Lett. 1985, 26, 3027.
(j) Liebeskind, L. S.; Welker, M. E. Tetrahedron Lett. 1985, 26, 3079. For
a tandem 1,4-addition/Pd-catalyzed R-allylation, see: (k) Naasz, R.; Arnold,
L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999,
121, 1104. For a tandem radical conjugate addition/R-alkylation, see: (l)
Sibi, M. P.; He, L. Synlett 2006, 689 and references therein.
(32) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L.; Iza, A.; Uria, U.
Org. Lett. 2006, 8, 2535.
J. Org. Chem, Vol. 71, No. 20, 2006 7765

Reyes et al.
TABLE 1. Asymmetric Conjugate Addition of Organometallic Reagents to Enamide 1a
entry
nucleophile
equiva
solvent
T (°C)
time
additive
yield (%)
2a/2′ab
1
2
3
4
5
6
7
8
9
10
11
12
13
n-BuMgCl
n-Bu2CuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
6
2
2
2
2
2
2
2
2
2
2
1
1
THF
THF
THF
Et2O
toluene
THF
THF
THF
THF
THF
THF
THF
THF
-78
-78
24 h
12 h
16
50
72
50
40
77
84
76
12
90
63
90
74
80/20
76/24
73/27
64/36
77/23
85/15
92/8
86/14
79/21
80/20
77/23
77/23
92/8
-78
10 min
10 min
10 min
15 min
15 min
15 min
15 min
15 min
1 h
-78
-78
-78
LiCl
LiCl
LiBr
LiI
LiF
HMPA
-105
-105
-105
-105
-105
-105
-105
15 min
15 min
LiCl
a Equivalents of nucleophile. b Calculated by HPLC (Chiracel OD column, UV detector, hexanes/2-propanol 98:2, flow rate 0.85 mL/min.).
SCHEME 3 a
equiv of n-BuLi to a THF solution of 1a at -78 °C, a very fast
and clean reaction occurred and the conjugate addition product
was cleanly isolated in a very short time (10 min.), although
with rather poor diastereoselectivity (entry 3). Changing the
solvent (entries 4 and 5) did not significantly improve the 2a/
2′a ratio. Remarkably, it has to be pointed out that in all these
cases the reaction was shown to be completely regioselective,
with no presence of any 1,2-addition byproduct.33
With the aim of improving the diastereoselectivity of the
reaction, we surveyed next the influence that different additives
a Reagents and conditions: (i) (1) R2Li, LiCl, THF, -105 °C, (2)
NH4Claq.
could have in the stereochemical outcome. It has been previously
reported that the use of LiCl as an additive entails a dramatic
influence in the stereochemical outcome of many transforma-
tions34 and particularly in the Michael reaction of pseudoephe-
drine amide enolates.23a This effect was also operating in our
case, and performing the reaction in the presence of excess LiCl
led to a significant improvement in the yield and the diaste-
reoselectivity of the reaction (entry 6). The temperature of the
reaction was another key parameter to be controlled due to its
influence in the diastereoselectivity, and when the reaction was
carried out at -105 °C, the almost exclusive formation of the
diastereoisomer 2a was observed in excellent yield and in a
very short time (entry 7). The use of other lithium salts as
additives did not afford better results (entries 8-10), and a
similar result was obtained when HMPA was introduced as
cosolvent in the reaction (entry 11). Finally, it has to be pointed
out that a very interesting result was obtained when using only
1 equiv of organolithium reagent both in the absence and in
the of presence LiCl as additive (entries 12 and 13). In these
cases, we unexpectedly observed that the 1,4-addition reaction
proceeded also very fast affording the corresponding adduct 2a
in only slightly lower yields and the same diastereoselectivities
as those obtained in the parent reactions in which 2 equiv of
n-BuLi were employed. This means that the conjugate addition
of the organolithium reagent is an extremely fast process which
occurs even faster than the expected deprotonation of the free
OH present at the pseudoephedrine moiety. This is a particularly
interesting feature of the developed methodology, especially in
the cases in which the organometallic reagent to be employed
TABLE 2. Asymmetric Conjugate Addition of Organolithium
Reagents to r,â-Unsaturated Amides 1a-e
entry
enamide
product
R1
R2
yielda (%)
2/2′b
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1b
1b
1c
1c
1c
1d
1e
1a
1e
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Me
Me
Et
n-Bu
i-Pr
t-Bu
Ph
n-Bu
Ph
n-Bu
t-Bu
Ph
84
80
52
86
73
82
73
94
82
92/8
89/11
90/10
94/6
98/2
91/9
98/2
90/10
93/7
97/3
91/9
Et
n-Pr
n-Pr
n-Pr
t-Bu
Ph
2j
2k
Ph
t-Bu
Me
84
61
Me
Ph
-(40)c
-(46)c
Me
a Yield of pure product after column chromatography purification.
b Calculated by HPLC (see the Supporting Information for details). c The
1,2-addition product was obtained. Yield is shown in parentheses.
is very expensive or has to be previously prepared by means of
a multistep synthesis.
Finally, we proceeded to examine the addition of different
organolithium reagents as well as a variety of differently
substituted R,â-unsaturated amides (Scheme 3). As shown in
Table 2, the application of the previously optimized conditions
resulted in high yields and diastereoselectivities regardless of
the R1 substituent present at the enamide acceptors 1a-d and
the nature of the organolithium reagent employed. Besides, in
all these cases the reaction was found to be completely
regioselective, in the sense that the formation of 1,2-addition
byproducts was not observed. The only exception was found
in the use of MeLi as nucleophile, for which the only product
observed in the reaction crude was the corresponding
ketone arising from a 1,2-addition process (entries 12 and 13
in Table 2).
(33) The occurrence of this side reaction was only observed at temper-
atures over -40 °C.
(34) For the influence of LiCl in the reactivity of pseudoephedrine
enolates see refs 17b and 23a. See also: (a) Ru¨ck, K. Angew. Chem., Int.
Ed. Engl. 1995, 34, 433. (b) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.;
Williard, P. G.; Schleyer, P. v. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996,
118, 1339 and references therein.
7766 J. Org. Chem., Vol. 71, No. 20, 2006

(S,S)-(+)-Pseudoephedrine as a Chiral Auxiliary
SCHEME 4 a
TABLE 3. Asymmetric Tandem Conjugate Addition/r-Alkylation
with r,â-Unsaturated Amides 1a-d
yielda
(%)
entry enamide product R1
R2
R3
drb,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
Me Ph
Me
Et
allyl
Bn
77
96
70
78
67
73
71
63
75
80
77
67
86
82
70
93:4:3:<1
Me Ph
Me Ph
Me Ph
Me n-Bu Me
Me n-Bu Et
Me n-Bu allyl
Me n-Bu Bn
95:5:<1:<1
93:4:2:1
94:4:<1:<1
91:5:3:<1
91:6:2:<1
86:10:4:<1
89:8:3:<1
95:4:<1:<1
97:2:<1:<1
95:4:1:<1
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Me
Et
allyl
Bn
Me
Et
allyl
Bn
a Reagents and conditions: (i) R2Li, LiCl, THF, -105 °C; (ii) (1) R3X,
THF, 0 °C, (2) NH4Claq.
99:<1:<1:<1
99:<1:<1:<1
95:4:1:<1
n-Pr Ph
n-Pr Ph
n-Pr Ph
n-Pr Ph
n-Pr n-Bu allyl
t-Bu Ph Me
t-Bu n-Bu Me
Me Ph i-Pr
Having established an optimal protocol for the conjugate
addition step, we focused next on the tandem conjugate addition/
R-alkylation process (Scheme 3). In this context, the fact that
LiCl had to be present in the reaction medium for the conjugate
addition to proceed with such high diastereoselectivity should
have a positive effect on the alkylation step because it is known
that the R-alkylation reaction of pseudoephedine amide enolates
proceeds much faster and the formation of side products due to
the O-alkylation at the free OH group of the pseudoephedrine
moiety is not observed when this salt is employed as an
additive.34 The use of organolithium reagents as nucleophiles
should also have a positive effect on the alkylation step due to
the higher reactivity exhibited by lithium enolates. Actually, a
problem associated with much of the tandem processes reported
so far is that organozinc or Grignard reagents had to be used as
nucleophiles in the conjugate addition step, therefore generating
an intermediate zinc or magnesium enolate, which are known
to exhibit significantly lower reactivity in alkylation reactions.
In addition, special attention has to be paid to the generation of
the second stereocenter, whose configuration can be determined
by the starting chirality source (the chiral auxiliary) or by the
stereocenter first created in the conjugate addition step.
Therefore, we carried out the reaction of amide 1a with PhLi
under the previously optimized conditions, and once complete
conversion was achieved, a solution of MeI (5 equiv) in THF
was added and the mixture was stirred at -78 °C for 72 h,
obtaining the expected alkylation product 3a in good yield (72%)
and excellent diastereomeric ratio (93:4:3:<1). When we
performed the alkylation step at 0 °C, we found that the reaction
proceeded much faster (4 h for complete conversion) and with
the same yield and diastereoselectivity. Unfortunately, we were
not able to reduce the amount of electrophile needed for the
reaction to proceed in an acceptable interval of time.35 Interest-
ingly, when we changed to EtI as the electrophile only traces
of the tandem product 3b was obtained when the alkylation step
was performed at -78 °C, while an excellent yield (96%) and
diastereoselectivity (dr: 95:5:<1:<1) were obtained when the
mixture of the intermediate enolate and ethyl iodide were stirred
at 0 °C for 4 h. After all these experiments, we concluded that
the best conditions for the tandem process both concerning the
yield and diastereoselectivity consisted on the addition of an
excess of the alkylating agent to the solution of the intermediate
enolate generated after the conjugate addition step followed by
stirring at 0 °C for 4 h (Scheme 4). We next proceeded to
perform the tandem reaction sequence under the optimized
96:4:<1:<1
73 >99:<1:<1:<1
77
70
96:3:<1:<1
96:3:2:<1
97:2:<1:<1
-
35
<5d
a Yield of pure product after column chromatography purification. b Ratio
of the four possible diastereoisomers that could be formed in the reaction
mixture. c Calculated by HPLC analysis of the crude reaction mixture (see
the Supporting Information for details). d Only traces of the tandem product
were observed, isolating the 1,4-addition product 2d in 88% yield after 24
h at rt.
conditions using a variety of differently substituted R,â-
unsaturated amides, organolithium reagents and alkyl halides
with excellent results concerning both the yield and the
stereoselectivity of the reaction (Scheme 4, Table 3).
In general, we observed that the reaction proceeded in good
yields and stereoselectivities, regardless of the nature of the
substituent at the enamide substrate 1a-d, the organolithium
reagent, or the alkyl halide employed. Remarkably, it has to be
pointed out that not only activated alkyl halides were shown to
be useful electrophiles in the alkylation step but also the less
reactive ethyl iodide reacted efficiently in all cases studied
(entries 2, 6, 10, and 14). Disappointingly, other more bulky,
ramified alkyl halides such as i-PrI did not afford the expected
tandem product in any of the cases tested, even using higher
temperatures during prolonged reaction times (entry 20).
Mechanistic Aspects. The results relating to the high
diastereofacial control observed in the conjugate addition process
are in accordance with a previously proposed mechanism,24a in
which the adduct of the conjugate addition reaction should arise
from the attack of the organolithium reagent through an
intermediate in which it is proposed that the aminoalkoxide chain
of the auxiliary should lie in an open staggered conformation,
with the C-H bond R to nitrogen lying in plane with the
carbonyl oxygen, to minimize allylic strain (Figure 1). In this
way, the reaction of the organometallic reagent with amides
1a-e should happen via an intermediate in a syn-s-cis confor-
mation by means of the stereodirecting ability of the lithium
alkoxide moiety present at the pseudoephedrine chain,36 resulting
in the formation of the new stereogenic center in the observed
absolute configuration. The existence of such a reactive
(36) The stereodirecting power of the lithium alkoxide in other reactions
of amides derived from chiral amino alcohols has also been invoked by
other authors in order to account for the observed diastereoselectivity. See,
for example: (a) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.;
Shinkai, I. Tetrahedron Lett. 1988, 29, 4245 and for the particular case of
pseudoephedrine see refs 21, 22, and 23a.
(35) Performing the reaction with 1.2 equiv of MeI furnished the tandem
product 3a in 50% yield and 93:4:3:<1 diastereomeric ratio.
J. Org. Chem, Vol. 71, No. 20, 2006 7767

Reyes et al.
SCHEME 5 a
a Reagents and conditions: (i) 4M H2SO4, dioxane, reflux.
FIGURE 1. Proposed model for the diastereoselective conjugate
addition and conjugate addition/R-alkylation of (S,S)-(+)-pseudoephe-
drine enamides 1a-e.
TABLE 4. Synthesis of Chiral Carboxylic Acids by Acid
Hydrolysis
entry
product
R1
R2
R3
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
Me
Me
Me
Et
n-Bu
i-Pr
t-Bu
Ph
n-Bu
Ph
n-Bu
t-Bu
Ph
Ph
t-Bu
Ph
n-Bu
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
88
89
99
91
75
99
79
87
97
64
99
98
93
80
99
99
78
conformer and the stereodirecting effect exerted by this lithium
alkoxide moiety was previously demonstrated by us in the aza-
Michael reaction of lithium benzylamides to R,â-unsaturated
amides derived from (S,S)-(+)-pseudoephedrine.
Et
With respect to the tandem conjugate addition/R-alkylation
reaction, the stereochemistry of the adducts 3a-s is also in
agreement with a previously proposed mechanism in which the
alkylation product should arise from the attack of the alkyl halide
to an intermediate Z enolate from the less hyndered si face of
an intermediate in which again, the pseudoephedrine moiety
adopts the same staggered conformation but in which the lithium
alkoxide moiety now provides a sterical blockade for the
incoming of the electrophile (Figure 1).17b,h The formation of
this intermediate enolate in a Z configuration is also compatible
with the reactive s-cis conformation proposed for the preceding
1,4-addition step. In addition, the fact that the tandem adducts
3a-s were obtained with a very high degree of stereocontrol
regardless of the configuration of the stereogenic center gener-
ated in the previous conjugate addition step also indicates that
the stereochemical outcome of the alkylation step is completely
dominated by the presence of the chiral auxiliary under the
conditions employed.
Transformation of the Addition Products into Other
Valuable Synthons. The highly enantioenriched adducts ob-
tained from the asymmetric conjugate addition and conjugate
addition/R-alkylation reactions were subjected to several de-
rivatization processes in order to survey their possibilities in
synthetic organic chemistry. In this way, enantiopure â- and
R,â-branched carboxylic acids and γ- and â,γ-disubstituted
alcohols were obtained from amides 2a-k and 3a-s.
(a) Synthesis of Carboxylic Acids. We first proceeded to
perform the hydrolytic removal of the chiral auxiliary by treating
amides 2a-k and 3a-s with 4 M H2SO4 in refluxing dioxane
(Scheme 5), which are typical conditions employed for the
hydrolysis of pseudoephedrine amides.17b Under these condi-
tions, it is known that a fast NfO acyl-transfer process is
operating followed by the rate-determining hydrolysis of the
intermediate ester. In our case, refluxing a solution of amides
2a-k in dioxane/4 M H2SO4 for 12 h yielded cleanly â-branched
chiral carboxylic acids 4a-k in excellent yields and as pure
compounds after simple acid-base standard workup (Table 4).
However, when we performed this reaction with R,â-disubsti-
n-Pr
n-Pr
n-Pr
t-Bu
Ph
Me
Me
Et
4j
4k
5a
5e
5i
5m
5r
5s
n-Pr
t-Bu
t-Bu
Ph
n-Bu
a Yield of pure product after standard acid/base workup purification.
tuted amides 3a-s, we found that the hydrolysis reaction was
strongly dependent upon the bulkiness of the R-alkyl substituent.
While amides 3a, 3e, 3i, 3m, 3r, and 3s (R3 ) Me) furnished
the corresponding carboxylic acids 5a, 5e, 5i, 5m, 5r, and 5s,
when we tested the same reaction conditions with amides 3b-d
(R3 ) Et, allyl, Bn) we could only observe the formation of
ammonium esters 6b-d. This indicates that while the fast NfO
acyl transfer process took place in an efficient way, the
hydrolysis of the esters resulted hampered by the sterical
hindrance exerted by the R-substituent. We also observed that,
after isolation of the derivatives 6b-d, these provided spontane-
ously the starting materials 3b-d upon standing for 24 h, which
also indicates that the acyl transfer process is reversible, being
the amide form the thermodynamically favored one. We also
tested basic hydrolysis conditions and refluxing a solution of
amide 2b in a 4 M KOH/THF solution afforded cleanly the
expected carboxylic acid but as a 3:1 mixture of syn/anti
diastereoisomers, which showed us that the R-hydrogen atom
either at the starting amide or at the target carboxylic acid was
undergoing a deprotonation process under these reaction condi-
tions.
It has to be pointed out that, in all cases, the target carboxylic
acids were isolated after a simple standard acid-base workup
procedure and that the chiral auxiliary, (S,S)-(+)-pseudoephe-
drine, could be recovered from the extracts of the basic aqueous
layer after workup followed by evaporation of the solvent and
7768 J. Org. Chem., Vol. 71, No. 20, 2006

(S,S)-(+)-Pseudoephedrine as a Chiral Auxiliary
SCHEME 6 a
SCHEME 7 a
a Reagents and conditions: (i) (1) (COCl)2, CH2Cl2, rt, (2) AlCl3, CH2Cl2,
-20 °C.
a Reagents and conditions: (i) LiNH2BH3, THF, rt.
TABLE 5. Synthesis of Chiral Primary Alcohols by
LAB-Mediated Reduction
crystallization in hexane/EtOAc 1:1 in ca. 80% yield and with
no loss of optical purity as its [R]20 value indicated, which
D
entry
product
R1
R2
R3
yielda (%)
allowed us to recycle the auxiliary for further uses. In addition,
it has to be mentioned that, at this point, we were able to
determine the absolute configuration of the stereogenic center
created during the conjugate addition step by chemical correla-
tion due to the fact that some of the obtained acids were known
1
2
3
4
5
8a
8b
8c
8d
8e
8f
Me
Me
Me
Me
Et
n-Bu
i-Pr
t-Bu
Ph
n-Bu
Ph
H
H
H
H
H
H
79
63
75
72
65
78
66
84
74
80
71
90
60
80
compounds. For example, comparison of the obtained [R]20
D
6
Et
value for acid 4d with the reported in the literature37 allowed
us to establish the absolute configuration of 2a as (3S) which
should be extended by analogy to the rest of the amides 2a-k
obtained in the asymmetric conjugate addition of organolithium
reagents to (S,S)-(+)-pseudoephedrine enamides 1a-e.38
At this point, we also proceeded to determine the absolute
configuration of the two stereogenic centers simultaneously
formed in the tandem conjugate addition/R-alkylation (Scheme
6). Carboxylic acid 5a was converted into the corresponding
acid chloride and subsequently subjected to intramolecular
Friedel-Crafts acylation, furnishing indanone 7a in 60% yield.
NOE experiments on 7a indicated a cis relationship between
both substituents, and given the (3R) configuration previously
established for the stereogenic center formed in the conjugate
addition step, we could assign a (2S,3R) absolute configuration
for indanone 7a, which was extended to the starting acid 5a
and amide 3a and, by analogy, to all amides 3b-s prepared.
(b) Synthesis of Alcohols. We next turned our attention to
the reduction of the amide moiety in order to obtain enantioen-
riched â-alkyl- and â,γ-dialkyl-substituted primary alcohols
which should be compounds of potential interest as chiral
building blocks in total synthesis. In our case, such a functional-
ity should be easily reached from the highly enantioenriched
adducts obtained in the conjugate addition and tandem conjugate
addition/R-alkylation reactions, provided that a procedure is
found that readily reduces the amide functionality to the
corresponding alcohol overriding the parallel formation of any
amine-type byproducts. We first tried the use of lithium
amidotrihydroborate (LAB), which is known as a very effective
reagent for the conversion of pseudoephedrine amides into the
corresponding alcohols39 (Scheme 7), and indeed, we found that
the reduction of R-unsubstituted amides 2a-k with this reducing
agent under the reported conditions proceeded in a fast and clean
way, furnishing the desired alcohols 8a-k in good yields (Table
5). However, in the same way as we have experienced in the
hydrolysis reactions, the reduction of amides 3a-s was found
to be strongly dependent upon the nature of the R-alkyl
7
8
9
10
11
12
13
14
8g
8h
8i
n-Pr
n-Pr
n-Pr
t-Bu
Ph
Me
Me
Et
n-Bu
t-Bu
Ph
Ph
t-Bu
Ph
H
H
H
H
8j
8k
9a
9e
9i
H
Me
Me
Me
n-Bu
Ph
a Yield of pure product after flash column chromatography purification.
SCHEME 8 a
a Reagents and conditions: (i) AcOH, dioxane, reflux; (ii) LAH, THF,
0 °C
substituent. The reduction of amides 3a, 3e, and 3i (R3 ) Me)
proceeded in a fast and clean way, furnishing the desired
alcohols 9a, 9e, and 9i in good yields and as single diastere-
oisomers, while other amides such as 3b-d, with bulkier
substituents at the R-carbon, did not react with LAB, even after
prolonged reaction times. It has also to be pointed out that in
this case we were also able to recover and recycle the chiral
auxiliary after its removal from the starting compounds during
the reduction step.
We therefore surveyed a second possibility for performing
this transformation (Scheme 8). As we had previously observed
in the course of our studies directed toward the acid hydrolysis
of the amide adducts (vide supra) that these pseudoephedrine
amides underwent fast NfO acyl transfer when heating in the
presence of an acid, we hypothesized that formed ester should
be easily reduced to the desired alcohol with a standard reducing
agent like LAH. When a mixture of amide 3a and AcOH was
refluxed for 24 h and, after removal of the volatiles under
reduced pressure, we could observe the quantitative formation
(37) Observed optical rotation for the sample prepared from amide 2a:
[R]20D ) -2.28, c ) 0.10, CHCl3. Literature data for (R)-3-methylheptanoic
1
of the ammonium ester 10a by H NMR, and when this ester
acid: [R]20 ) -2.34, c ) 0.10, CHCl3. Norsikian, S.; Marek, I.; Klein,
D
was reduced with LAH in THF at 0 °C, alcohol 9a was isolated
in good yield and as a single diastereoisomer. These conditions
were applied to all amides 3a-s yielding the wanted â,γ-dialkyl-
substituted alcohols in good yields in all cases studied (Table
6). In addition, alcohols 9a-s were isolated as single diaste-
reoisomers, as 1H NMR analysis of the crude reaction mixture
S.; Poisson, J. F.; Normant, J. F. Chem. Eur. J. 1999, 2055.
(38) Due to CIP priority rules, configuration at C3 changes to (3R) in
amides 2b-d,f,h,i ,k.
(39) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. Tetrahedron Lett. 1996,
37, 3623. (b) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecki, D. J. Synlett
1997, 457. See also (c) Whitlock, G. A.; Carreira, E. M. HelV. Chim. Acta
2000, 83, 2007.
J. Org. Chem, Vol. 71, No. 20, 2006 7769

Reyes et al.
TABLE 6. Synthesis of Chiral â,γ-Dialkyl-Substituted Alcohols by
Acid-Promoted NfO Acyl Transfer/Reduction
1a. We therefore performed the LAB-mediated reduction of
amide 2a under the conditions previously described and we
proceeded to carry out a subsequent mesylation procedure using
crude unpurified alcohol 8a to obtain the corresponding mesylate
11a in a single step and in excellent yield (89%). Coupling of
11a with 1-lithioundec-10-ene, prepared in situ by metalation
of 11-chloroundec-1-ene with t-BuLi, furnished cleanly the
wanted compound in 48% yield. All the data recorded for our
synthetic sample of (S)-14-methyloctadec-1-ene matched those
reported in the literature.41
entry
product
R1
R2
R3
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
t-Bu
t-Bu
Ph
Ph
Ph
Ph
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
Ph
Me
Et
allyl
Bn
Me
Et
allyl
Bn
Me
Et
allyl
Bn
Me
Et
allyl
Bn
82
75
73
80
86
98
80
98
87
67
87
80
98
70
91
68
68
76
82
Conclusions
We have shown that R,â-unsaturated amides derived from
the chiral amino alcohol (S,S)-(+)-pseudoephedrine undergo
very regio- and diastereoselective 1,4-addition of organolithium
reagents, furnishing the corresponding â-alkyl substituted amides
2a-k in short reaction times and with excellent yields. In
addition, we have also shown that the intermediate enolate
generated after the conjugate addition step is able to undergo a
subsequent alkylation process with alkyl halides under the
conditions employed, furnishing the corresponding R,â-dialkyl
substituted amides 3a-s. The chiral auxiliary is able to exert a
very effective asymmetric induction both in the conjugate
addition and in the R-alkylation steps using a wide variety of
different acceptors, organolithium reagents and alkyl halides.
Furthermore, the adducts obtained can be very easily trans-
formed into chiral nonracemic â-alkyl and R,â-dialkyl substi-
tuted carboxylic acids and γ-alkyl- and â,γ-dialkyl-substituted
alcohols, which are very useful chiral building blocks for the
synthesis of many other interesting compounds. An additional
advantage of the use of this chiral auxiliary was found in the
recyclability of the reagent after cleavage from the adducts in
all cases studied.
allyl
Me
Me
n-Bu
a Yield of pure product after flash column chromatography purification.
SCHEME 9 a
a Reagents and conditions: (i) n-BuLi, LiCl, THF, 105 °C; (ii) (1) LAB,
THF, rt, (2) MsCl, Et3N, CH2Cl2, 0 °C; (iii) Li(CH2)10CHdCH2, THF, -78
°C to rt.
Experimental Section
General Procedure for the Diastereoselective Conjugate
Addition of Organolithium Compounds to r,b-Unsaturated
Amides 1a-e. A solution of organolithium reagent (4.10 mmol)
was carefully added to a suspension of the corresponding enamide
1a-e (2.00 mmol) and LiCl (10.0 mmol) in dry THF (60 mL) at
-105 °C, and the reaction was stirred at this temperature for 10-
30 min (TLC monitoring). The mixture was allowed to warm to rt,
and it was quenched with a saturated NH4Cl solution (30 mL). The
mixture was extracted with CH2Cl2 (3 × 30 mL), the combined
organic fractions were collected, dried over Na2SO4, and filtered,
and the solvent was removed in vacuo affording the wanted amides
after flash column chromatography purification.
(+)-(1′S,2′S,3S)-N-(2′-Hydroxy-1′-methylethyl-2′-phenyl)-N,3-
dimethylheptanamide (2a). Amide 2a (0.49 g, 1.70 mmol) was
prepared according to the general procedure starting from enamide
1a (0.46 g, 2.00 mmol), LiCl (0.42 g, 10.00 mmol), and n-BuLi
(3.4 mL of a 1.3,M solution in hexanes). HPLC analysis of the
crude reaction mixture (Chiracel OD column, hexanes/2-propanol
98:2, flow rate 0.85 mL/min) indicated a 92:8 diastereomeric
ratio: tR for the major isomer, 25.31 min; tR for the minor isomer,
36.28 min. Amide 2a was isolated as a yellowish oil after flash
indicated. This also means that the reaction conditions employed
did not promote any epimerization at the R-stereocenter, which
might be expected due to the potential enolizability of the
starting materials, especially under the basic conditions in which
the reduction step was carried out. Again, in this case we could
recover the chiral auxiliary, (S,S)-(+)-pseudoephedrine, from
the reaction mixture in ca. 75% yield by means of a simple
acid-base workup procedure and with no loss of optical purity.
(c) Application of the Methodology. Asymmetric Synthesis
of (S)-14-Methyloctadec-1-ene. As an example to demonstrate
the potential of the methodology described herein, we decided
to synthesize (S)-14-methyloctadec-1-ene (Scheme 9), the female
sex pheromone of the peach leafminer moth (Lyonetia clerkella).
Infestation by this insect causes almost complete defoliation of
the trees and reduces cropping and fruit production potential
for the future, which typically affects to fruit trees such as apple,
pear, cherry, plum, quince, and peach.40 The synthesis of this
compound was easily accomplished starting from amide 2a,
which was prepared previously by us by asymmetric conjugate
addition of n-BuLi to (S,S)-(+)-pseudoephedrine crotonamide
column chromatography purification (hexanes/AcOEt 1:1). Yield:
84%. [R]20 ) +89.0 (c ) 1.0, CH2Cl2). H NMR (δ, ppm) (3:1
1
D
(41) Kharisov, R. Y.; Latypova, E. R.; Talipov, R. F.; Muslukhov, R.
R.; Ishmuratov, G. Y.; Tolstikov, G. A. Russ. Chem. Bull. Int. Ed. 2003,
52, 2267.
(42) Chiacchio, U.; Corsaro, A.; Gambera, G., Rescifina, A.; Piperno,
A.; Romeo, R.; Romeo, G. Tetrahedron: Asymmetry 2002, 13, 1915.
(40) (a) Park, J. H.; Han, K. S.; Mori, K.; Boo, K. S. J. Chem. Ecol.
2002, 28, 8515. (b) Gries, R.; Gries, G.; King, G. G. S.; Maier, C. T. J.
Chem. Ecol. 1997, 23, 1119. (c) Sato, R.; Abe, N.; Sugie, H.; Kato, M.,
Mori, K.; Tamaki, Y. Appl. Entomol. Zool. 1986, 21, 478.
7770 J. Org. Chem., Vol. 71, No. 20, 2006

(S,S)-(+)-Pseudoephedrine as a Chiral Auxiliary
rotamer ratio; *indicates minor rotamer resonances): 0.87 (m, 6H);
0.97* (d, 3H, J ) 6.9 Hz); 1.07 (d, 3H, J ) 6.7 Hz); 1.27 (m, 6H);
1.95 (m, 1H); 2.04 (m, 1H); 2.17 (m, 1H); 2.78 (s, 3H); 2.87* (s,
3H); 4.04 (m, 1H), 4.43* (m, 1H); 4.55 (m 1H); 4.62 (bs, 1H);
7.32 (m, 5H). 13C NMR (δ, ppm) (3:1 rotamer ratio; *indicates
minor rotamer resonances): 14.0; 14.4; 15.3*; 19.7; 19.9*; 22.7;
29.0; 29.3*; 30.0; 30.2*; 33.1; 36.5; 36.6*; 40.9*; 41.4; 58.3; 75.2*;
76.3; 126.2; 126.8*; 127.4; 128.0*; 128.2; 128.5*; 141.5*; 142.4;
173.8*; 175.0. IR (CHCl3): 3382 (OH); 1619 (CdO). MS (EI)
m/z (rel int): 273 (M+ - 18, 16), 216 (93), 184 (11), 148 (100),
118 (23); 91 (14), 69 (27), 58 (69), 56 (28). Anal. Calcd for C18H29-
NO2: C, 74.18; H, 10.03; N, 4.81. Found: C, 74.23; H, 9.93; N,
4.69.
filtered, and the solvent was removed in vacuo yielding the wanted
1
acids 4a-k and 5a,e,i,m,r,s as pure compounds as their H and
13C NMR spectra indicated.
(-)-(S)-3-Methylheptanoic Acid (4a). Carboxylic acid 4a (0.11
g, 0.74 mmol) was obtained as a yellowish oil starting from amide
2a (0.24 g, 0.84 mmol) according to the general procedure. Yield:
88%. [R]20 ) -2.28 (c ) 0.10, CHCl3) (lit.37 [R]20 ) -2.34, c
D
D
1
) 0.10, CHCl3). H NMR (δ, ppm): 0.88 (t, 3H, J ) 6.5 Hz);
0.96 (d, 3H, J ) 6.5 Hz); 1.28 (m, 6H); 1.92 (m, 1H); 2.11 (dd,
1H, J ) 14.9, 8.1 Hz); 2.33 (dd, 1H, J ) 14.9, 5.9 Hz); 10.5-11.0
(bs, 1H). 13C NMR (δ, ppm): 14.0; 19.6; 22.7; 29.0; 30.1; 36.3;
41.6; 180.2. IR (CHCl3): 3025 (OH); 1715 (CdO). MS (EI) m/z
(rel int): 144 (M+, 5), 124 (14), 118 (14), 105 (19), 95 (66), 79
(66), 68 (72), 65 (99), 51 (100).
General Procedure for the Diastereoselective Tandem Con-
jugate Addition/R-Alkylation.
A
solution of organo-
General Procedure for the Reduction of Amides with LAB.
Synthesis of Alcohols 8a-k. n-BuLi (4.0 mmol) was added over
a solution of diisopropylamine (4.0 mmol) in dry THF (10 mL) at
-78 °C, and the mixture was stirred for 15 min. The reaction was
warmed to 0 °C, and NH3‚BH3 (4.0 mmol) was added at once.
The mixture was stirred for 15 min at 0 °C and another 15 min at
room temperature, after which a solution of the amide 2a-k (1.0
mmol) in THF (10 mL) was added via cannula at 0 °C and the
reaction was stirred for 2 h. Then the reaction was quenched with
1 M HCl (15 mL) and extracted with AcOEt (3 × 15 mL). The
organic fractions were collected, washed with satd NaHCO3, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo
affording the wanted alcohols 8a-k after flash column chroma-
tography purification.
lithium reagent (2.05 mmol) was carefully added to a suspen-
sion of the corresponding enamide 1a-d (1.00 mmol) and
LiCl (5.00 mmol) in dry THF (30 mL) at -105 °C, and
the reaction was stirred at this temperature until TLC analysis of
the aliquots indicated complete consumption of the start-
ing material (typically 30 min). The corresponding alkyl
halide (4.00 mmol) was added at once, and the mixture was allowed
to warm to 0 °C at which temperature it was stirred for further 5
h. The reaction was quenched with a saturated NH4Cl solution (20
mL) and extracted with CH2Cl2 (3 × 10 mL), the combined organic
fractions were collected, dried over Na2SO4, and filtered, and the
solvent was removed in vacuo affording the tandem pure products
after flash column chromatography.
(+)-(1′S,2′S,2S,3R)-N-(2′-Hydroxy-1′-methyl-2′-phenylethyl)-
2,N-dimethyl-3-phenylbutanamide (3a). Amide 3a (0.50 g, 1.54
mmol) was prepared according to the general procedure starting
from enamide 1a (0.46 g, 2.00 mmol), LiCl (0.42 g, 10.00 mmol),
PhLi (4.43 mL of a 1.0 M solution in dibutyl ether), and MeI (0.50
mL, 8.00 mmol). HPLC analysis of the crude reaction mixture
(Chiracel OD column, hexanes/2-propanol 95:5, flow rate 1.00 mL/
min) indicated a 93:4:3:<1 diastereomeric ratio: tR for the major
isomer, 37.75min. (93%). The other isomers eluted at 17.55 min
(<1%), 24.71 min (4%), and 28.07 min (3%). Amide 3a was
isolated in pure form as a yellowish oil after flash column
(-)-(S)-3-Methylheptan-1-ol (8a). Alcohol 8a (142 mg, 1.08
mmol) was prepared according to the general procedure starting
from amide 2a (0.40 g, 1.37 mmol), n-BuLi (7.6 mL of a 0.7M
solution in hexanes, 5.36 mmol), i-Pr2NH (0.81 mL, 5.77 mmol),
and BH3‚NH3 (0.19 g 5.48 mmol) and isolated as a yellowish oil
after flash column chromatography purification (hexanes/AcOEt
8:2). Yield: 79%. [R]20D ) -1.7 (c ) 0.1, CHCl3) (lit..42 [R]20
)
D
1
-1.82, c ) 0.06, CHCl3). H NMR (δ, ppm): 0.88 (m, 6H); 1.27
(m, 6H); 1.57 (m, 3H); 3.65 (m, 2H). 13C NMR (δ, ppm): 14.0;
19.5; 22.9; 29.1; 29.3; 36.7; 39.8; 60.9. IR (CHCl3): 3215 (OH).
MS (EI) m/z (rel int): 130 (M+, 35), 115 (33), 99 (100), 85 (27),
65 (36), 59 (12), 52 (26).
chromatography (hexanes/AcOEt 1:1). Yield: 77%. [R]20
)
D
1
+116.1 (c ) 1.0, CH2Cl2). H NMR (δ, ppm) (4:1 rotamer ratio;
*indicates minor rotamer resonances): 0.75 (d, 3H, J ) 6.7 Hz);
0.89* (d, 3H, J ) 5.0 Hz); 1.00* (d, 3H, J ) 6.7 Hz); 1.15 (d, 3H,
J ) 6.7 Hz); 1.22 (d, 3H, J ) 7.0 Hz); 2.73 (m, 1H); 2.82 (s, 3H);
2.94* (s, 3H); 2.98 (m, 1H), 4.19* (m, 1H); 4.34 (m, 1H); 4.57*
(m, 1H); 4.65 (m, 1H); 5.07 (bs, 1H); 7.15-7.33 (m, 10H). 13C
NMR (δ, ppm) (4:1 rotamer ratio; *indicates minor rotamer
resonances): 14.3; 15.4*; 16.6; 16.9*; 20.3*; 20.5; 27.1*; 34.3;
42.4*; 43.6; 43.9; 44.2*; 58.4; 60.0*; 75.1*; 76.1; 126.0; 126.1*;
126.2; 126.7*; 127.5; 127.6; 128.0*; 128.1; 128.2*; 128.3; 128.5*;
141.6*; 142.4; 144.8; 145.1*; 177.1*; 178.2. IR (CHCl3): 3380
(OH); 1716 (CdO). MS (EI) m/z (rel int): 307 (M+ - 18, 1), 218
(10), 204 (10), 202 (15), 147 (16), 145 (15), 117 (11), 115 (10);
105 (27), 91 (37), 58 (100). Anal. Calcd for C21H27NO2: C, 77.50;
H, 8.36; N, 4.30. Found: C, 77.76; H, 8.51; N, 4.50.
General Procedure for the Acid Hydrolysis. Synthesis of
Carboxylic Acids 4a-k and 5a,e,i,m,r,s. H2SO4 (4 M, 10 mL)
was slowly added over a cooled (0 °C) solution of the corresponding
amide 2a-k or 3a,e,i,m,r,s (1 mmol) in 1,4-dioxane (10 mL). The
reaction was refluxed for 6 h after which it was cooled to rt. Water
(20 mL) was added, and the mixture was carefully basified to pH
) 12 and washed with EtOAc (3 × 20 mL). The aqueous layer
was carefully driven to pH ) 3 by careful addition of a 4 M HCl
solution and extracted with CH2Cl2 (3 × 20 mL). After drying (Na2-
SO4), filtering, and removing the solvent from the basic organic
extracts it was possible to recover, after crystallization (hexanes/
EtOAc), pure (+)-(S,S)-pseudoephedrine in ca. 83% yield. The
collected organic acidic fractions were dried over Na2SO4 and
General Procedure for the Reduction of Amides by Acid-
Promoted NfO Acyl Transfer/Reduction. Synthesis of Alcohols
9a-s. A solution of the starting amide 3a-s (1.0 mmol) in AcOH
(10.0 mL) was refluxed for 12 h after which the solvent was
removed under reduced pressure yielding the crude esters 10a-s
which were used in the next step without further purification. Next,
LAH (3.0 mmol) was added at once over a cooled (0 °C) solution
of the ester 10a-s (1.0 mmol) in dry THF (15 mL). The mixture
was refluxed for 3 h, quenched with 1 M HCl (15 mL), and
extracted with CH2Cl2 (3 × 15 mL). The organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo affording the wanted alcohols 9a-s after flash
column chromatography purification. The chiral auxiliary could be
recovered from the aqueous layer after basifying (pH ) 10) with
a 4 M NaOH solution and extracting with CH2Cl2 (3 × 15 mL),
filtering, and removing the solvent. (S,S)-(+)-Pseudoephedrine was
isolated in ca. 75% yield after crystallization (hexanes/AcOEt) and
with no loss of optical purity as the measurement of its [R]20D value
indicated.
(-)-(2S,3R)-2-Methyl-3-phenylbutan-1-ol (9a). Alcohol 9a
(203 mg, 1.21 mmol) was prepared according to the general
procedure starting from amide 3a (487 mg, 1.48 mmol), AcOH
(30 mL), and LAH (168 mg 4.44 mmol) and isolated as a colorless
oil after flash column chromatography purification (hexanes/AcOEt
9:1). Yield: 82%. [R]20D ) -19.5 (c ) 0.4, CHCl3). 1H NMR (δ,
ppm): 0.64 (d, 3H, J ) 6.8 Hz); 1.23 (d, 3H, J ) 6.7 Hz); 1.74
(m, 1H); 2.68 (m, 1H); 3.46 (m, 1H); 3.53 (m, 1H); 7.24 (m, 5H).
13C NMR (δ, ppm): 14.4; 19.1;37.6; 41.6; 65.9; 125.9; 126.0; 128.3;
J. Org. Chem, Vol. 71, No. 20, 2006 7771

Reyes et al.
146.4. IR (CHCl3): 3369 (OH). MS (EI) m/z (rel int): 164 (M+,
1), 146 (8), 105 (15), 91 (19), 77 (4), 58 (100). Anal. Calcd for
C11H16O: C, 80.44; H, 9.82. Found: C, 80.32; H, 9.73.
PETRONOR, S.A. (Muskiz, Bizkaia) for the generous gift of
solvents.
Supporting Information Available: General methods and
characterization of amides 2b-k, carboxylic acids 4b-k,
5a,e,i,m,r,s, alcohols 8b-k, mesylate 11a, and pheromone 12a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the University of the Basque
Country (Subvencio´n General a Grupos de Investigacio´n,
9/UPV00041.310-15835/2004, and a fellowship to E.R.) and
the Spanish Ministerio de Educacio´n y Ciencia (CTQ2005-
02131/BQU) for financial support. We also acknowledge
JO061205E
7772 J. Org. Chem., Vol. 71, No. 20, 2006