Tandem asymmetric conjugate addition/α-alkylation using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Article abstract of DOI:10.1021/ol060720w

α,β-Unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine undergo a very clean and diastereoselective tandem conjugate addition/α-alkylation reaction. Excellent results have been achieved using a wide range of differently subs

Full text of DOI:10.1021/ol060720w

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2535-2538
Tandem Asymmetric Conjugate
Addition/ -Alkylation Using
(S,S)-( )-Pseudoephedrine as Chiral
r
+
Auxiliary
Efraim Reyes, Jose L. Vicario, Luisa Carrillo, Dolores Bad´ıa,* Ainara Iza, and
Uxue Uria
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 March 24, 2006
ABSTRACT
r
,
â
-Unsaturated amides derived from the chiral amino alcohol (S,S)-(
conjugate addition/ -alkylation reaction. Excellent results have been achieved using a wide range of differently substituted conjugate acceptors,
organolithium reagents, and alkyl halides. The chiral auxiliary could be easily removed from the obtained adducts by reduction, furnishing
chiral nonracemic -branched alcohols in a very easy and efficient way.
+)-pseudoephedrine undergo a very clean and diastereoselective tandem
r
r,â
Asymmetric tandem C-C bond formation reactions are one
of the most attractive strategies in organic synthesis, as they
involve multistep processes that turn into a very easy and
direct method for increasing molecular complexity from
readily available starting materials.1 In recent years, the
asymmetric conjugate addition, which is one of the most
versatile methodologies for the stereocontrolled formation
of new C-C or C-X bonds,2 has become a widely used
tool for initiating tandem asymmetric transformations, due
to the formation of an intermediate chiral enolate nucleophile
with potential for R-alkylation, aldol, Mannich, Michael, or
similar reactions.3 In this context, a very reliable possibility
for exerting stereochemical control in the formation of the
first stereogenic center, which is generated during the con-
jugate addition step, is the use of the chiral auxiliary method-
ology, although the use of catalytic asymmetric processes is
also well documented. In both cases, special attention has
to be paid to the formation of the subsequent stereocenter-
(2) Reviews: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (c) Krause,
N.; Hoffmann-Ro¨der, A. Synthesis 2001, 151. (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 53, 8033. (e) Leonard, J.; D´ıez-Barra, E.; Merino, S.
Eur. J. Org. Chem. 1998, 2051. (f) Krause, N, Angew. Chem., Int. Ed. 1998,
37, 283. (g) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771.
(3) For a recent review, see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem.,
Int. Ed. 2006, 45, 354. See also: (b) Taylor, R. J. K. Synthesis 1985, 364.
(c) Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225.
(1) For some reviews, see: Bienayme, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (b) Bunce, R. A. Tetrahedron
1995, 51, 13103. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV.
1996, 96, 195.
10.1021/ol060720w CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/16/2006

(s), whose formation can be determined by the starting
chirality source (the chiral auxiliary or catalyst) or by the
stereocenter first created in the conjugate addition step.
As was previously mentioned, literature furnishes many
examples for asymmetric tandem transformations initiated
by a conjugate addition reaction, typically tandem conjugate
addition/aldol reactions. However, the number of examples
in which the intermediate enolate is trapped with an
alkylating reagent such as an alkyl halide is very scarce.4
Alkyl halides react very difficultly with the intermediate
enolate under the experimental conditions employed in the
conjugate addition step and usually require the addition of
an additive like HMPA in order to reach to acceptable yields.
Moreover, only activated alkylating reagents such as allyl
bromide or methyl iodide can usually be employed with good
results, which is a clear limitation of the methodologies
reported up to date.
In a recent work, we have shown that pseudoephedrine
can play the role of a very efficient chiral auxiliary in asym-
metric aza-Michael reactions.5 With this precedent in mind,
and taking into account that pseudoephedrine amide enolates
are reported to be excellent chiral nucleophiles in asymmetric
R-alkylation reactions,6 we decided to explore the viability
of (S,S)-(+)-pseudoephedrine as chiral auxiliary in stereo-
controlled tandem conjugate additions/alkylations.7 The high-
ly efficient conversion of the obtained adducts into enantio-
enriched R,â-branched alcohols will also be presented, show-
ing the remarkable synthetic potential of this methodology.
Our experiments began with the optimization of reaction
conditions for the conjugate addition of the carbon nucleo-
phile to R,â-unsaturated amide 1a (Scheme 1). After trying
several organometallic reagents under different reactions
Scheme 1
conditions, we found that addition of 2.0 equiv of PhLi to a
THF solution of 1a at -105 °C in the presence of 5 equiv
of LiCl furnished cleanly and in a very short time (10 min)
the desired conjugate addition product, with an excellent
degree of diastereoselection and with no traces of any 1,2-
addition byproduct. The absolute configuration of the newly
created stereogenic center was determined by chemical
correlation via hydrolysis of amide 2a to (R)-3-phenylbu-
tanoic acid.8
We determined that LiCl had to be present in the reaction
medium for the conjugate addition to proceed with such high
diastereoselectivity9 because it is known that pseudoephedine
amide enolates undergo R-alkylation in much faster way
when this salt is employed as an additive.10 Also, the use of
organolithium reagents should have a positive effect in the
alkylation step due to the higher reactivity exhibited by
lithium enolates. In fact, 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.
Having established an optimal protocol for the conjugate
addition step, we proceeded next to examine the tandem
process (Scheme 2). When we treated the mixture of the
(4) Relevant examples of asymmetric conjugate addition of organome-
tallic reagents and subsequent R-alkylation: (a) Shintani, R.; Tokunaga,
N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. (b) Arai, Y.;
Kasai, M.; Ueda, K.; Masaki, Y. Synthesis 2003, 1511. (c) Fleming, F. F.;
Wang, Q.; Steward, O. W. J. Org. Chem. 2003, 68, 4235. (d) Totani, K.;
Asano, S.; Takao, K.; Tadano, K. Synlett 2001, 1772. (e) Degrado, S. J.;
Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755. (f) Rawson,
D. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2292. (g) Tomioka, K.;
Kawasaki, H.; Koga, K. Tetrahedron Lett. 1985, 26, 3027. (h) Liebeskind,
L. S.; Welker, M. E. Tetrahedron Lett. 1985, 26, 3079. For a tandem 1,4-
addition/Pd-catalyzed R-allylation, see: (i) 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: (j) Sibi, M. P.;
He, L. Synlett. 2006, 689 and references therein.
Scheme 2
(5) Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L.; Ruiz, N. J. Org.
Chem. 2005, 70, 8790.
(6) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9631.
(7) For the use of pseudoephedrine as chiral auxiliary, see the following.
Review: (a) Myers, A. G.; Charest, M. G. Handbook of Reagents for
Organic Synthesis: Chiral Reagents for Asymmetric Synthesis; Paquette,
L. A., Ed.; Wiley-Interscience: New York, 2003; p 485. See also: (b)
Vicario, J. L.; Rodriguez, M.; Bad´ıa, D.; Carrillo, L.; Reyes, E. Org. Lett.
2004, 6, 3171. (c) Hutchison, P. C.; Heightman, T. D.; Procter, D. J. J.
Org. Chem. 2004, 69, 790. (d) Smitrovich, J. H.; Boice, G. N.; Qu, C.;
DiMichele, L.; Nelson, T. D.; Huffman, M. A.; Murry, J.; McNamara, J.;
Reider, P. J. Org. Lett. 2002, 4, 1963. (e) Vicario, J. L.; Bad´ıa, D.; Carrillo,
L. Tetrahedron: Asymmetry 2002, 13, 745. (f) Vicario, J. L.; Bad´ıa; D.;
Carrillo, L. J. Org. Chem. 2001, 66, 5801. (g) Vicario, J. L.; Bad´ıa, D.;
Carrillo, L. J. Org. Chem. 2001, 66, 9030. (h) Keck, G. E.; Knutson, C. E.;
Wiles, S. A. Org. Lett. 2001, 3, 707. (i) Guillena, G.; Najera, C.
Tetrahedron: Asymmetry 2001, 12, 181. (j) Myers, A. G.; Barbay J. K.;
Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207. (k) Nagula, G.; Huber, V.
J.; Lum, C.; Goodman, B. A. Org. Lett. 2000, 2, 3527. (l) Myers, A. G.;
McKinstry, L. J. Org. Chem. 1996, 61, 2428.
conjugate addition reaction with 1.2 equiv of MeI, warmed
it to 0 °C, and stirred at this temperature for 4 h, the expected
(8) The observed optical rotation for the sample prepared from amide
2a: [R]20D ) -42.3 (c ) 0.70, C6H6) was in agreement with the literature
data for (R)-3-phenylbutanoic acid: [R]20 ) -45.8 (c ) 0.77, C6H6).
D
Suzuki, I.; Kin, H.; Yamamoto, Y. J. Am. Chem. Soc. 1993, 115, 10139.
(9) When the conjugate addition reaction was carried out in the absence
of LiCl an important decrease in the diastereoselectivity was observed in
all cases studied. It is known that LiCl addition significantly impacts
stereoselectivity in the Michael reaction of pseudoephedrine amide eno-
lates: Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice, G. N.; Nelson, T.
D.; Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903.
(10) For the influence of LiCl in the reactivity of pseudoephedrine
enolates, see refs 6 and 9. 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.
2536
Org. Lett., Vol. 8, No. 12, 2006

alkylation product 3a was obtained in an acceptable yield
(50%) and excellent diastereomeric ratio (93:4:3:<1). The
yield of the reaction could be further increased by working
with excess alkylating reagent with no negative effect on
the diastereoselectivity of the reaction (entry 1 in Table 1).
sponding acyl chloride and subjected to intramolecular
Friedel-Crafts acylation, furnishing indanone 5a (Scheme
3). NOE experiments on 5a indicated a cis relationship
between both substituents, which was extended to the starting
amide 3a and by analogy to all amides 3b-s prepared.
The sense of the asymmetric induction observed in the
diastereoselective conjugate addition step is in good agree-
ment with the model previously proposed by us for the
asymmetric aza-Michael reaction of lithium amides to R,â-
unsaturated amides derived from (S,S)-(+)-pseudoephedrine,5
and the stereochemical outcome of the alkylation reaction
also agrees with what has been proposed in the literature
for the alkylation of (S,S)-(+)-pseudoephedrine amide
enolates.6a,11 This indicates that the stereogenic center gener-
ated in the initial conjugate addition step does not hamper
the efficient stereochemical control exerted by the chiral
auxiliary in the alkylation step.
Table 1. Asymmetric Tandem Conjugate Addition/Alkylation
with R,â-Unsaturated Amides 1a-d
entry product
R1
R2
R3 yielda (%)
drb,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
Me
Et
allyl
Bn
77
96
70
78
67
73
71
63
75
80
77
67
86
82
70
73
77
70
35
93:4:3:<1
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
99:<1:<1:<1
99:<1:<1:<1
95:4:1:<1
96:4:<1:<1
>99:<1:<1:<1
96:3:<1:<1
96:3:2:<1
Ph
Ph
Ph
n-Bu Me
n-Bu Et
n-Bu allyl
n-Bu Bn
Ph
Ph
Ph
Ph
Me
Et
allyl
Bn
Me
Et
allyl
Bn
Et
Et
Et
Scheme 4
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
97:2:<1:<1
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).
We next focused on the removal of the chiral auxiliary
from the adducts 3a-s by exploiting the intrinsic reactivity
of the pseudoephedrine amide functionality. We therefore
focused on the reduction of the amide moiety in order to
obtain enantioenriched R,â-branched alcohols which should
be compounds of potential interest as chiral building blocks
in total synthesis. We first tried the use of lithium amido-
trihydroborate (LAB), which is known as a very effective
reagent for the conversion of pseudoephedrine amides into
the corresponding alcohols,12 as was our case. The reduction
of amides 3a, 3e, and 3i (R3 ) Me) proceeded in a fast and
clean way, furnishing the desired alcohols in good yields
and as single diastereoisomers. However, other amides such
as 3b-d, with bulkier substituents at the R-carbon (R3 *
Me), did not react with LAB, even after prolonged reaction
times (Scheme 4).
We proceeded next to examine the addition of different
organolithium reagents as well as a variety of differently
substituted R,â-unsaturated amides and alkyl halides with
excellent results concerning both the yield and the stereo-
selectivity of the reaction (Table 1).
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. Re-
markably, 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).
The determination of the absolute configuration of the
newly created stereogenic center during the alkylation step
was performed as follows: Acid hydrolysis of amide 3a
furnished 2-methyl-3-phenylbutanoic acid 4a in 98% yield
(Scheme 4), and then this was converted into the corre-
We therefore surveyed a second possibility for performing
this transformation (Scheme 4). It is known that pseudoephe-
drine amides undergo fast NfO acyl transfer when heated
in the presence of an acid catalyst,6a and therefore, we
hypothesized that formed ester should be easily reduced to
Scheme 3
(11) Vicario, J. L.; Badia, D.; Dominguez, E.; Carrillo, L. J. Org. Chem.
1999, 64, 4610.
(12) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. 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.
Org. Lett., Vol. 8, No. 12, 2006
2537

the desired alcohol with an standard reducing agent like
LAH. To our delight, when a mixture of amide 3a and AcOH
was refluxed in dioxane and the volatiles were removed
under reduced pressure, the quantitative formation of the
specially under the basic conditions in which the reduction
step was carried out. It has also to be pointed out that the
chiral auxiliary, (S,S)-(+)-pseudoephedrine, could be recov-
ered from the reaction mixture in ca. 75% yield by means
of a simple acid-base workup procedure and with no loss
of optical purity, which allowed us to recycle the auxiliary
for further use.
1
ammonium ester 7a was observed by H NMR, and when
this ester was reduced with LAH in THF at 0 °C, alcohol
6a was isolated in good yield. These conditions were applied
to all amides 3a-s with the results shown in Table 2.
In conclusion, we have shown that R,â-unsaturated amides
derived from the chiral amino alcohol (S,S)-(+)-pseudoephe-
drine undergo very clean and diastereoselective 1,4-addition
of organolithium reagents, furnishing the corresponding
enolate intermediate which is able to undergo a subsequent
alkylation process with alkyl halides to furnish the corre-
sponding R,â-dialkyl substituted amides 3a-s in excellent
yields. The chiral auxiliary is able to exert a very effective
asymmetric induction both in the conjugate addition and in
the alkylation steps using a wide variety of different
acceptors, organolithium reagents, and alkyl halides. Re-
markably, the high reactivity shown by the intermediate
lithium enolates allows the use of alkyl halides such as ethyl
iodide, which are usually unreactive in these kinds of
reactions. In addition, the chiral auxiliary can be easily
removed from the adducts furnishing chiral nonracemic R,â-
branched alcohols. An additional advantage of the use of
this chiral auxiliary was found in the recyclability of the
reagent after cleavage from the adducts.
Table 2. Reduction of Amides 3a-s
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
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
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
Acknowledgment. We thank the University of the
Basque Country (Subvencio´n General a Grupos de Investi-
gacio´n and a fellowship to E.R.) and the Spanish Ministerio
de Educacio´n y Ciencia (Project CTQ2005-02131/BQU) for
financial support. We also acknowledge PETRONOR, S.A.
for the generous gift of solvents.
allyl
Me
Me
n-Bu
a Yield of pure product after column chromatography purification.
Supporting Information Available: Detailed descrip-
In all cases studied, the alcohols 6a-s were isolated in
good yields and as single isomers, as H NMR analysis of
the crude reaction mixture indicated. This means that the
reaction conditions employed did not promote any epimer-
ization at the R-stereocenter, which might be expected due
to the potential enolizability of the starting materials,
tions of experimental procedures, characterization of all new
1
1
compounds, and H and 13C NMR of amides 3a-s. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060720W
2538
Org. Lett., Vol. 8, No. 12, 2006