Highly regio- and stereoselective addition of organolithium reagents to extended conjugate amides using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Article abstract of DOI:10.1021/jo900397w

(Chemical Equation Presented) The conjugate addition of organolithium reagents to polyunsaturated conjugate amides containing (S,S)-(+)- pseudoephedrine as chiral auxiliary has been studied in detail. The reaction proceeded with good 1,4-selectivity and e

Full text of DOI:10.1021/jo900397w

shows up as a challenging element to be controlled.3 In general,
nucleophiles may undergo addition to R,ꢀ,γ,δ-unsaturated
carbonyl compounds in a 1,2-, 1,4-, or 1,6- fashion, and this
might lead to the formation of mixtures of all of the possible
regioisomers.4,5 In this context, literature shows that the 1,4-
addition of organometallic reagents to polyunsaturated Michael
acceptors leads in most cases to the formation of other
regioisomers in variable ammounts.5
Highly Regio- and Stereoselective Addition of
Organolithium Reagents to Extended Conjugate
Amides Using (S,S)-(+)-Pseudoephedrine as
Chiral Auxiliary
Marta Ocejo, Luisa Carrillo,* Dolores Bad´ıa,*
Jose L. Vicario, Naiara Ferna´ndez, and Efraim Reyes
On the other hand, despite their availability, literature
furnishes little information regarding the use of organolithium
reagents in asymmetric conjugate additions to extended conju-
gate carbonyl compounds,6 mainly because these reagents
usually undergo 1,2-addition to the carbonyl moiety rather than
giving any conjugate addition product.7 Related to this topic,
we have recently published a very efficient procedure for
carrying out asymmetric conjugate additions of organolithium
reagents to R,ꢀ-unsaturated amides derived from (S,S)-(+)-
pseudoephedrine.8 In this context, we wish to present herein
the use of this aminoalcohol as chiral auxiliary9 in the
stereocontrolled conjugate addition of organolithium reagents
to extended conjugate acceptors, also showing that the reaction
always proceeds with full 1,4-regioselectivity. In addition, the
highly efficient conversion of the obtained adducts into enan-
tioenriched ꢀ-branched alcohols containing an additional alkene
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, 48080 Bilbao, Spain
marisa.carrillo@ehu.es; dolores.badia@ehu.es
ReceiVed February 23, 2009
(3) Review Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
(4) For some examples focused on achieving 1,6-addition, see: (a) den Hartog,
T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew. Chem.,
Int. Ed. 2008, 47, 398. (b) Okada, S.; Arayama, K.; Murayama, R.; Ishizuka,
T.; Hara, K.; Hirone, N.; Hata, T.; Urabe, H. Angew. Chem., Int. Ed. 2008, 47,
6860. (c) Henon, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed. 2008,
47, 9122. (d) Nishimura, T.; Yashuhara, Y.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 5164. (e) Fillion, E.; Wilsily, A.; Liao, E.-T. Tetrahedron: Asymmetry
2006, 17, 2957. (f) Fukuhara, K.; Urabe, H. Tetrahedron Lett. 2005, 46, 603.
(g) de la Herran, G.; Murcia, C.; Csaky, A. Org. Lett. 2005, 7, 5629. (h) Hayashi,
T.; Yamamoto, S.; Tokunaga, N. Angew. Chem., Int. Ed. 2005, 44, 4224. (i)
Canisius, J.; Mobley, T. A.; Berger, S.; Krause, N. Chem.sEur. J. 2001, 7,
2671. (j) Uerdingen, M.; Krause, N. Tetrahedron 2000, 56, 2799. (k) Krause,
N. J. Org. Chem. 1992, 57, 3509. (l) Maruoka, K.; Itoh, T.; Sakurai, M.;
Nonoshita, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 3588. (m) Barbot,
F.; Kadib-Elban, A.; Miginiac, P. J. Organomet. Chem. 1983, 255, 1. (n) Corey,
E. J.; Kim, C. U.; Chen, R. H. K.; Takeda, M. J. Am. Chem. Soc. 1972, 94,
4395. (o) Na¨f, F.; Degen, P.; Ohloff, G. HelV. Chim. Acta 1972, 55, 82. (p)
Campbell, J. A.; Babcock, J. C. J. Am. Chem. Soc. 1959, 81, 4069.
The conjugate addition of organolithium reagents to poly-
unsaturated conjugate amides containing (S,S)-(+)-pseu-
doephedrine as chiral auxiliary has been studied in detail.
The reaction proceeded with good 1,4-selectivity and excel-
lent stereoselectivity, affording the corresponding addition
products with good yields and as highly diastereoenriched
isomers. Removal of the chiral auxiliary by reduction or
hydrolysis has allowed the preparation of polyfunctionalized
chiral building blocks incorporating an alkene moiety suitable
for further transformations.
(5) For some examples reporting 1,4-addition, see: (a) Pineschi, M.; del Moro,
F.; di Bussolo, V.; Macchia, F. AdV. Synth. Catal. 2006, 348, 301. (b) Kume,
T.; Iwasaki, H.; Yamamoto, Y.; Akiba, K. Tetrahedron Lett. 1987, 28, 6305.
(c) Marshall, J. A.; Audia, J. E.; Shearer, B. G. J. Org. Chem. 1986, 51, 1730.
(d) Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.; Bernardinelli, G.
HelV. Chim. Acta 1987, 70, 2201. (e) Yamamoto, Y.; Yamamoto, S.; Yatagai,
H.; Ishihara, Y.; Maruyama, K. J. Org. Chem. 1982, 47, 119. (f) Barbot, F.;
Kadib-Elban, A.; Miginiac, P. Tetrahedron Lett. 1983, 24, 5089. (g) Marshall,
J. A.; Ruden, R. A.; Hirsch, L. K.; Phillippe, M. Tetrahedron Lett. 1971, 12,
3795.
(6) As far as we know there is only a couple of examples of the
(non-stereoselective) conjugate addition of an organolithium reagent (MeLi) to
an R,ꢀ,γ,δ-unsaturated carbonyl compound: (a) Cooke, M. P.; Goswami, R.
J. Am. Chem. Soc. 1977, 99, 642. (b) Ooi, T.; Kondo, Y.; Kon-I, K.; Maruoka,
K. Chem. Lett. 1998, 403. For other examples of organolithium reagents
undergoing stereocontrolled 1,4-addition to simple R,ꢀ-unsaturated carbonyl
compounds, see ref 8a and references therein.
(7) For examples with simple R,ꢀ-unsaturated systems, see: (a) Aurell, M. J.;
Ban˜uls, M. J.; Mestres, R.; Mun˜oz, E. Tetrahedron 2001, 57, 1067. (b) Sikorski,
W. H.; Reich, H. J. J. Am. Chem. Soc. 2001, 123, 6527.
(8) (a) Reyes, E.; Vicario, J. L.; Bad´ıa, D.; Carrillo, L.; Uria, U.; Iza, A. J.
Org. Chem. 2006, 71, 7763. (b) Reyes, E.; Vicario, J. L.; Bad´ıa, D.; Carrillo,
L.; Iza, A.; Uria, U. Org. Lett. 2006, 8, 2535. For some examples regarding the
use of lithium amides as nucleophiles, see: (c) Etxebarria, J.; Vicario, J. L.;
Bad´ıa, D.; Carrillo, L.; Ruiz, N. J. Org. Chem. 2005, 70, 8790. (d) Etxebarria,
J.; Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org. Chem. 2004, 69, 2588.
The asymmetric conjugate addition of organometallic reagents
to R,ꢀ-unsaturated carbonyl compounds or related derivatives
is considered as one of the most powerful methods for the
stereocontrolled formation of C-C bonds.1 In this context, many
enantio- and diastereoselective versions of this transformation
have been reported using a wide variety of different organo-
metallic reagents.2 However, when the conjugate addition
reaction is carried out on extended Michael acceptors, besides
the typical stereochemical issues to consider, regioselectivity
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
(2) For some reviews, see: (a) Christoffers, J.; Koripelly, G.; Rosiak, A.;
Rossle, M. Synthesis 2007, 1279. (b) Lopez, F.; Minnaard, A. J.; Feringa, B. L.
Acc. Chem. Res. 2007, 40, 179. (c) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003,
103, 2829. (d) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (e)
Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (f) Sibi, M. P.; Manyem,
S. Tetrahedron 2000, 56, 8033. (g) Leonard, J.; D´ıez-Barra, E.; Merino, S. Eur.
J. Org. Chem. 1998, 2051. (h) Krause, N. Angew. Chem., Int. Ed. 1998, 37,
283. (i) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771.
4404 J. Org. Chem. 2009, 74, 4404–4407
10.1021/jo900397w CCC: $40.75 2009 American Chemical Society
Published on Web 04/29/2009

TABLE 1. Stereoselective Addition of PhLi to Amide 1a
diastereoselectivity, as when we proceeded to carry out the
reaction without any additive much poorer results were obtained
(entry 8).
We therefore took conditions shown in entry 3 of Table 1 as
the best ones for this reaction, and we next proceeded to extend
them to other organolithium reagents and conjugate acceptors
with the results shown in Table 2. As it can be seen in
this table, in almost all cases good to excellent 1,4-selectivity
was achieved, therefore providing the wanted 1,4-addition
products 2a-i in good yields and, remarkably, without the
formation of any 1,6-addition byproduct regardless the organo-
lithium employed. The formation of byproducts arising from
the competitive 1,2-addition reaction was found to be exclusively
dependent upon the nature of the organolithium reagent
employed, observing that the reaction proceeded with complete
1,4-regiocontrol when stabilized organolithium reagents were
used (the case of PhLi in entries 1 and 2 and the R-silyl-
substituted organolithium reagent of entry 7) and also when a
very bulky nucleophile (t-BuLi, entry 9) was employed. When
primary and secondary alkyllithium reagents were employed,
1,2-addition products were obtained in variable ratios (entries
3-6 and entry 8), although in almost all the cases the
1,4-regioisomer was obtained as major reaction product. Re-
markably, it has to be pointed out that the reaction took place
with excellent degree of diastereoselection in all cases, obtaining
the adducts 2a-i as highly diastereoenriched compounds. It has
also to be pointed out that the reaction could be easily scaled
up and, for example, we could carry out the addition of PhLi
to amide 1a at 3.0 g scale with no significant decrease in the
yield or diastereoselectivity (entry 10).
entry
PhLi (equiv)
additivea
temp (°C)
yield (%)b
drc
1
2
3
4
5
6
7
8
2
3
4
6
4
4
4
4
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
-105
-105
-105
-105
-90
-78
0
30
58
80
70
65
60
30
68
97:3
97:3
97:3
97:3
95:5
95:5
95:5
80:20
-105
a Reaction was carried out using 5.0 equiv of LiCl as additive. b Yield
of pure product after flash column chromatography purification.
c Determined by HPLC analysis of the corresponding alcohol obtained
by reduction (see Supporting Information).
moiety with potential for further manipulations will also be
presented, showing the remarkable synthetic potential of this
methodology.
Our experiments began with the optimization of the reaction
conditions using the addition of PhLi to R,ꢀ,γ,δ-unsaturated
amide 1a as model reaction (Table 1). When we applied the
conditions previously found in our group for the conjugate
addition of organolithium reagents to R,ꢀ-unsaturated amides
derived from pseudoephedrine (entry 1),8a we obtained a low
yield of the desired 1,4-adduct 2a and also could recover an
important amount of unreacted starting material (40%). We
managed to improve the conversion and the yield of the reaction
by increasing the amount of nucleophile added (3 and 4 equiv,
entries 2 and 3, respectively), although when changing to 6 equiv
of PhLi (entry 4) a slightly lower yield was obtained. In all
cases, we could observe that the transformation proceeded with
complete 1,4-regioselectivity and very high diastereoselectivity,
which indicated that the chiral auxiliary was able to exert a
very effective control on the stereochemical outcome of the
reaction.
The results relating to the high diastereofacial control
observed in this process are in accordance with a previously
proposed mechanism,8 in which the adduct of the conjugate
addition reaction should arise from the attack of the organo-
lithium reagent through an intermediate in which the ami-
noalkoxide chain lies in an open staggered conformation, with
the C-H bond R to nitrogen lying in plane with the carbonyl
oxygen, in order to minimize allylic strain (Figure 1).10 In this
way, the reaction of the organometallic reagent with amide 1a
should happen via an intermediate in a syn-s-cis conformation11
by means of the stereodirecting ability of the lithium alkoxide
moiety,12 resulting in the formation of the new stereogenic center
in the observed absolute configuration. The interaction between
both metallic centers can take place either by solvent molecules
or by the presence of chlorine anions, which would also account
for the higher diastereoselectivity obtained in the presence of
excess LiCl. On the other hand, this stereodirecting ability
attributed to the lithium alkoxide might also explain the high
regioselectivity observed, the 1,6-addition possibly being limited
because the γ-carbon of the extended conjugate acceptor remains
too far away from this alkoxide moiety. Nevertheless, the
interaction of the carbonyl oxygen of the amide moiety with
We also carried out additional experiments at higher tem-
peratures, observing that although the diastereoselectivity did
not suffer from significant variation, the yield of the reaction
decreased on increasing the reaction temperature due mainly
to the competitive formation of other 1,6- and 1,2-addition
byproducts among other unidentified compounds (entries 5-7).
We also verified that the presence of LiCl as an additive was
necessary for the reaction to proceed with good yield and
(9) For the first use of pseudoephedrine as chiral auxiliary, see: (a) Myers,
A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116,
9361. (b) Myers, A. G.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason,
J. L. J. Am. Chem. Soc. 1997, 119, 6496. For a review, see: (c) 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. For other examples, see: (d) Ruiz, N.; Vicario, J. L.; Bad´ıa, D.;
Carrillo, L.; Alonso, B. Org. Lett. 2008, 10, 2613. (e) Iza, A.; Vicario, J. L.;
Bad´ıa, D.; Carrillo, L. Synthesis 2006, 4065. (f) Vicario, J. L.; Rodr´ıguez, M.;
Bad´ıa, D.; Carrillo, L.; Reyes, E. Org. Lett. 2004, 6, 3171. (g) Smitrovich, J. H.;
Boice, G. N.; Qu, C.; Dimichelle, L.; Nelson, T. D.; Huffman, M. A.; Murry, J.;
McNamara, J.; Reider, P. J. Org. Lett. 2002, 4, 1. (h) Hutchison, P. C.;
Heightman, T. D.; Procter, D. J. Org. Lett. 2002, 4, 4583. (i) Vicario, J. L.;
Bad´ıa, D.; Carrillo, L. J. Org. Chem. 2001, 66, 5801. (j) Vicario, J. L.; Bad´ıa,
D.; Carrillo, L. J. Org. Chem. 2001, 66, 9030. (k) Anakabe, E.; Vicario, J. L.;
Bad´ıa, D.; Carrillo, L.; Yoldi, V. Eur. J. Org. Chem. 2001, 4343. (l) Myers,
A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207. (m) Vicario,
J. L.; Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez, M.; Carrillo, L. J. Org. Chem. 2000,
65, 3754. (n) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(10) This open staggered conformation as an intermediate in reactions in
which (S,S)-(+)-pseudoephedrine amides are involved has also been proposed
previously (refs 9a and 9b).
(11) For an experimental study regarding the reactive conformation of
pseudoephedrine enamides in conjugate additions, see ref 8c.
(12) The stereodirecting power of the lithium alkoxide in other reactions of
amides derived from chiral aminoalcohols 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. For the particular case of pseudoephedrine, see: (b)
Smitrovich, J. H.; Dimichelle, L.; Qu, C.; Boice, G. N.; Nelson, T. D.; Huffman,
M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903.
J. Org. Chem. Vol. 74, No. 11, 2009 4405

TABLE 2. Regio- and Diastereoselective Addition of Organolithium Reagents to r,ꢀ,γ,δ-Unsaturated Amides 1a,b
entry
substrate
R1
R2
regioselectivity 1,2-:1,4-:1,6-a
product
yield (%)b
drc
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
Me
H
Ph
Ph
Et
n-Bu
i-Bu
n-C6H13
TMSCH2
i-Pr
<5:>95:<5
<5:>95:<5
20:80:<5
40:60:<5
33:67:<5
50:50: <5
<5:>95:<5
20:80: <5
<5:>95:<5
<5:>95:<5
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
65
61
60
56
54
54
65
86
75
97:3
97:3
Me
Me
Me
Me
Me
Me
Me
Me
87:13
88:12
88:12
83:17
98:2
88:12
93:7
97:3
9
t-Bu
Ph
10d
2a
a Determined by NMR analysis of the crude reaction mixture. b Yield of pure products 2a-i after purification. c Determined by HPLC analysis (see
Supporting Information). d The reaction was carried out at 3.0 g scale.
TABLE 3. Reduction of Adducts 2a-i
entry
substrate
R1
R2
product
yield (%)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
H
Ph
Ph
Et
n-Bu
i-Bu
n-C6H13
TMSCH2
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
88
93
91
80
94
83
94
80
Me
Me
Me
Me
Me
Me
Me
FIGURE 1. Proposed model for the diastereoselective conjugate
addition of organometallic reagents to dienamides 1a,b.
the incoming organolithium reagent should not be discarded as
another possible explanation for the high 1,4-selectivity observed.
We next focused on the removal of the chiral auxiliary from
the adducts 2a-i by exploiting the intrinsic reactivity of the
pseudoephedrine amide functionality. We started first with the
reduction of the amide moiety in order to obtain enantioenriched
ꢀ-substituted γ,δ-unsaturated alcohols that should be compounds
of potential interest as chiral building blocks in total synthesis.
We tried the use of lithium amidotrihydroborate (LAB), which
is known as a very effective reagent for the conversion of
pseudoephedrine amides into the corresponding alcohols.13 The
reduction of amides 2a-i proceeded in a fast and clean way,
furnishing the desired alcohols in good yields and as highly
enantioenriched compounds (Table 3).14
t-Bu
a Yield of pure product after flash column chromatography
purification.
TABLE 4. Acid Hydrolysis of Adducts 2a and 2c-i
entry
substrate
R2
product
yield (%)a
1
2
3
4
5
6
7
8
2a
2c
2d
2e
2f
2g
2h
2i
Ph
Et
4a
4c
4d
4e
4f
4g
4h
4i
94
90
96
83
95
99
95
85
At this point, we were able to determine the absolute
configuration of the stereogenic center created during the
conjugate addition step by chemical correlation due to the fact
that alcohol 3b is a known compound. Therefore, comparison
of the obtained [R]20 value for 3b ([R]20 ) +32.2 (c 0.17,
n-Bu
i-Bu
n-C6H13
TMSCH2
i-Pr
D
D
t-Bu
CH2Cl2)) with the reported in the literature for (S)-3-phenylpent-
4-en-1-ol ([R]20 ) +32.0 (c 0.17, CH2Cl2))15 allowed us to
a Yield of pure product after flash column chromatography
purification.
D
establish the absolute configuration of 3b as (3S), which should
be extended by analogy to the rest of the alcohols 3a-k and
amides 2a-k obtained in the asymmetric conjugate addition
of organolithium reagents to R,ꢀ,γ,δ-unsaturated amides derived
from (S,S)-(+)-pseudoephedrine.
(13) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623. (b) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997,
457. See also: (c) Whitlock, G. A.; Carreira, E. M. HelV. Chim. Acta 2000, 83,
2007, and ref 9.
(14) In some cases, the reduction of adducts obtained as diastereomeric
mixtures proceeded to furnish the corresponding alcohol in a significantly higher
enantiopurity than that corresponding to the de of the starting material. We have
demonstrated in previous reports that this transformation proceeds with no
epimerization at the ꢀ-stereogenic centre of other closely related compounds
(see refs 8a and 8b).
We also faced the removal of the chiral auxiliary by simple
hydrolysis, therefore opening the way for the preparation of
enantioenriched ꢀ-branched carboxylic acids containing an
additional olefinic moiety. Consequently, when we treated the
adducts 4a-i under standard acid hydrolysis conditions, the
corresponding carboxylic acids were obtained in excellent yields
(Table 4). In addition, the chiral auxiliary could also be
(15) Takekawa, Y.; Shishido, K. J. Org. Chem. 2001, 66, 8490.
4406 J. Org. Chem. Vol. 74, No. 11, 2009

the reaction was quenched with 1 M HCl (15 mL) and extracted
with AcOEt (3 × 15 mL). The organic fractions were collected,
washed with sat. NaHCO3, dried over Na2SO4, and filtered, and
the solvent removed in vacuo, affording alcohol 3a (120 mg, 0.71
mmol) as a colorless oil after flash column chromatography
purification. Yield: 99%. HPLC analysis of the crude reaction
mixture (Chiralcel OD column, hexane/isopropyl alcohol 97:3, flow
rate 0.85 mL/min) indicated a 97:3 enantiomeric ratio: tR for the
recovered after a simple acid-base workup operation, therefore
increasing the utility of this methodology.
In conclusion, we have shown that organolithium reagents
add to R,ꢀ,γ,δ-unsaturated amides derived from the chiral amino
alcohol (S,S)-(+)-pseudoephedrine in a highly regio- and
diastereoselective way, furnishing the corresponding 1,4-addition
products in good yields and as highly stereoenriched compounds.
Removal of the chiral auxiliary can be carried out using very
efficient and simple procedures, therefore allowing the use of
this methodology for the preparation of many useful chiral
building blocks containing different functionalities.
major (S) isomer, 16.12 min; tR for the minor (R) isomer, 19.51
1
min. [R]20 ) +27.9 (c 1.0, CH2Cl2). H NMR (δ, ppm): 1.68 (d,
D
3H, J ) 5.5 Hz), 1.85-1.99 (m, 3H), 3.42 (m, 1H), 3.60 (t, 2H, J
) 6.5 Hz), 5.46-5.65 (m, 2H), 7.18-7.34 (m, 5H). 13C NMR (δ,
ppm): 17.9, 38.5, 45.3, 60.9, 125.1, 126.1, 127.3, 128.4, 134.5,
144.6. IR (CHCl3): 3361 (OH). MS (EI) m/z (rel int): 143 (M+-33,
96), 132 (100), 129 (66), 128 (52), 117 (20), 116 (29), 115 (69),
91 (97), 77 (29). HRMS: calcd for [C12H16O]+ 176.1201, found
176.1201.
Experimental Section
Representative Procedure for the Diastereoselective Conju-
gate Addition of Organolithium Compounds to r,ꢀ,γ,δ-
Unsaturated Amides. Synthesis of (+)-(1′S,2′S,3S)-N-(2′-Hydroxy-
1′-methyl-2′-phenylethyl)-N-methyl-3-phenylhex-4-enamide (2a).
A solution of PhLi (9.60 mL of a 1.6 M solution in dibutylether)
was carefully added to a suspension of the dienamide 1a (1.00 g,
3.86 mmol) and LiCl (0.82 g, 19.30 mmol) in dry THF (40 mL) at
-105 °C, and the reaction was stirred at this temperature for 6 h
(TLC monitoring). The mixture was allowed to warm to rt and
was quenched with a saturated NH4Cl solution (20 mL). The
mixture was extracted with CH2Cl2 (3 × 30 mL), and the combined
organic fractions were collected, dried over Na2SO4, and filtered.
The solvent removed in vacuo, affording amide 2a (1.04 g, 3.08
mmol) after flash column chromatography purification. Yield: 80%.
Representative Procedure for the Acid Hydrolysis of Amides
2a-i. Synthesis of (+)-(S)-3-Phenylhex-4-enoic Acid (4a). H2SO4
(4 M, 10 mL) was slowly added over a cooled (0 °C) solution of
amide 2a (0.30 g, 0.89 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 AcOEt (3 × 20 mL). The aqueous layer was
carefully driven to pH ) 3 and extracted with CH2Cl2 (3 × 20
mL). After drying (Na2SO4), filtering, and removal of the solvent
from the basic organic extracts, it was possible to recover, after
crystallization (hexanes/AcOEt) pure (+)-(S,S)-pseudoephedrine in
83% yield. The collected organic acidic fractions were dried over
Na2SO4 and filtered, and the solvent was removed in vacuo, yielding
4a (0.16 g, 0.84 mmol) as a yellowish oil, which was found to be
Mp: 89-90 °C (AcOEt/hexane 1:1). [R]20 ) +97.0 (c 1.0,
D
CH2Cl2). 1H NMR (δ, ppm): (6:1 rotamer ratio; * indicates minor
rotamer resonances) 0.73* (d, 3H, J ) 6.8 Hz), 0.97 (d, 3H, J )
6.8 Hz), 1.67 (d, 3H, J ) 6.4 Hz), 2.68-2.73 (m, 2H), 2.72 (s,
3H), 2.81-2.85* (m, 2H), 2.81* (s, 3H), 3.87-4.21 (m, 2H),
4.37-4.52 (m, 2H), 5.43- 5.54 (m, 1H), 5.62-5.70 (m, 1H),
7.18-7.27 (m, 10H). 13C NMR (δ, ppm): (6:1 rotamer ratio;
* indicates minor rotamer resonances) 14.4, 15.4* (CH3CHN), 18.0,
26.8*, 32.7, 39.5*, 40.3, 44.9, 58.5, 75.3*, 76.5, 125.3*, 125.5,
126.2, 126.4*, 126.9, 127.5, 127.6, 128.3, 128.4*, 128.7, 133.4,
133.9*, 140.9*, 142.2, 143.8, 144.3*, 172.4*, 173.8. IR (CHCl3):
3382 (OH), 1620 (CdO). MS (EI) m/z (rel int): 319 (M+ - 18, 4),
231 (15), 230 (62), 131 (47), 129 (13), 115 (10), 91 (21), 77 (11),
58 (100). HRMS: calcd for [C22H25NO (M - H2O)]+ 319.1931,
found 319.1934.
a pure compound as its 1H and 13C NMR spectra indicated. Yield:
1
94%. [R]20 ) +7.3 (c 1.0, CH2Cl2). H NMR (δ, ppm): 1.71 (d,
D
3H, J ) 5.6 Hz), 2.78 (d, 2H, J ) 7.6 Hz), 3.82-3.89 (m, 1H),
5.52-5.69 (m, 2H), 7.24-7.37 (m, 5H). 13C NMR (δ, ppm): 17.8,
40.6, 44.4, 125.8, 126.5, 127.3, 128.5, 132.8, 143.0, 178.4. IR
(CHCl3): 3026 (OH); 1707 (CdO). MS (EI) m/z (rel int): 190 (M+,
19), 144 (15), 132 (11), 131 (94), 130 (45), 129 (100), 128 (34),
116 (21), 115 (31), 91 (52), 77 (11). HRMS: calcd for [C12H14O2]+
190.0994, found 190.1003.
Acknowledgment. The authors thank the University of the
Basque Country (Subvencio´n General a Grupos de Investiga-
cio´n, 9/UPV00041.310-15835/2004 and a fellowship to M.O.)
and the Ministerio de Educacio´n y Ciencia (project CTQ2005-
02131/BQU) for financial support. The authors also acknowl-
edge PETRONOR, S.A. for the generous gift of solvents.
Representative Procedure for the Reduction of Amides
2a-i with LAB. Synthesis of (+)-(S)-3-Phenylhex-4-en-1-ol
(3a). n-BuLi (4.54 mL of a 1.0 M solution in hexanes, 4.54 mmol)
was added over a solution of diisopropylamine (0.61 mL, 4.36
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 BH3 ·NH3 (0.14
g, 4.45 mmol) was added at once. The mixture was stirred 15 min
at 0 °C and another 15 min at room temperature, after which a
solution of the amide 2a (0.30 g, 0.89 mmol) in THF (10 mL) was
added via canula at 0 °C and the reaction was stirred for 2 h. Then
Supporting Information Available: Characterization of all
1
new compounds and copies of their H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900397W
J. Org. Chem. Vol. 74, No. 11, 2009 4407