Michael Reactions of Pseudoephedrine Amide Enolates: Effect of LiCl on Syn/Anti Selectivity

Article abstract of DOI:10.1021/jo035564a

The stereochemical outcome of the asymmetric Michael reaction of pseudoephedrine amide enolates changes dramatically in the presence of LiCl. Reaction of the enolate in the absence of LiCl results in formation of the anti Michael adduct with high selectiv

Full text of DOI:10.1021/jo035564a

Mich a el Rea ction s of P seu d oep h ed r in e Am id e En ola tes: Effect of
LiCl on Syn /An ti Selectivity
J acqueline H. Smitrovich,* Lisa DiMichele,* Chuanxing Qu, Genevie`ve N. Boice,
Todd D. Nelson, Mark A. Huffman, and J erry Murry
Department of Process Research, Merck Research Laboratories, Merck & Company, P.O. Box 2000,
Rahway, New J ersey 07065
jacqueline_smitrovich@merck.com; lisa_dimichele@merck.com
Received October 22, 2003
The stereochemical outcome of the asymmetric Michael reaction of pseudoephedrine amide enolates
changes dramatically in the presence of LiCl. Reaction of the enolate in the absence of LiCl results
in formation of the anti Michael adduct with high selectivity, whereas in the presence of lithium
chloride the syn adduct is favored. This method provides access to enantiomerically enriched trans-
3,4-disubstituted δ-lactones from the anti Michael adducts by a two step reduction/lactonization
sequence. Information obtained from NMR studies indicates that, under both enolization conditions,
the (Z)-enolate is formed. A model to explain the turnover in selectivity based on NMR evidence is
presented.
In tr od u ction
high selectivity, providing a convenient route to more
complicated substrates.6
The power of pseudoephedrine as a chiral auxiliary for
enolate alkylations has been well documented.1 Several
reports have demonstrated that, despite the acyclic
framework of this auxiliary, excellent control of stereo-
chemistry is provided. The availability of both antipodes
and the facile conversion of the amide moiety to other
functional groups make pseudoephedrine an attractive
auxiliary. The use of this auxiliary has been extended to
aldol,2 Mannich,3 and enolate amination4 reactions. Dur-
ing the development of the alkylation of pseudoephedrine
amide enolates, Myers et al. reported that the addition
of LiCl (6 equiv) enhanced reactivity and was essential
for good conversion. The stereochemistry of alkylation of
N-acyl pseudoephedrine amide enolates was not affected
by the presence of LiCl.1b,5 Under these conditions, less
reactive halides undergo alkylation efficiently and with
We recently reported that the reaction of pseudoephe-
drine amide enolates can be extended to Michael addi-
tions of R,â-unsaturated esters.7,8 These Michael accep-
tors proved highly reactive and did not require LiCl for
good conversion. We have subsequently discovered that
LiCl has a dramatic influence on the stereochemical
outcome of this reaction. In this manuscript, we report
both the utility of the Michael addition of pseudoephe-
drine amide enolates to access anti or syn Michael
adducts (Scheme 1) and the NMR spectroscopic evidence
that provides insight into the effect of LiCl on selectivity.
A model to explain the effect of LiCl on the structure of
this acyclic chiral auxiliary is discussed.
Resu lts a n d Discu ssion
Mich a el Ad d ition in th e Absen ce of LiCl. We
envisioned that Michael addition of chiral amides with
R,â-unsaturated esters to afford adducts 3 would offer
an approach to trans-3,4-disubstituted δ-lactones 4 fol-
lowing selective ester reduction and lactonization (Scheme
2). A screen of chiral amines as auxiliaries indicated that
pseudoephedrine exhibited high diastereoselectivity for
* Corresponding author.
(1) (a) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J . Org.
Chem. 1999, 64, 3322-3327. (b) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997,
119, 6496-6511. (c) Myers, A. G.; Gleason, J . L.; Yoon, T.; Kung, D.
W. J . Am. Chem. Soc. 1997, 119, 656-673. (d) Myers, A. G.; McKinstry,
L. J . Org. Chem. 1996, 61, 2428-2440. (e) Myers, A. G.; Yoon, T.
Tetrahedron Lett. 1995, 36, 9429-9432. (f) Myers, A. G.; Gleason, J .
L.; Yoon, T. J . Am. Chem. Soc. 1995, 117, 8488-8489. (g) Myers, A.
G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am. Chem. Soc. 1994, 116,
9361-9362.
(2) (a) Vicario, J . L.; Bad´ıa, D.; Carrillo, L. Tetrahedron: Asymmetry
2003, 14, 489-495. (b) Vicario, J . L.; Bad´ıa, D.; Dom´ınguez, E.;
Rodr´ıguez, M.; Carrillo, L. J . Org. Chem. 2000, 65, 3754-3760.
(3) (a) Vicario, J . L.; Bad´ıa, D.; Carrillo, L. J . Org. Chem. 2001, 66,
9030-9032. (b) Vicario, J . L.; Bad´ıa, D.; Carrillo, L. Org. Lett. 2001,
3, 773-776.
(6) For examples, see: (a) Duffey, M. O.; Le Tiran, A.; Morken, J .
P. J . Am. Chem. Soc. 2003, 125, 1458-1459. (b) Kopecky, D. J .;
Rychnovsky, S. D. J . Am. Chem. Soc. 2001, 123, 8420-8421. (c) Roy,
R. S.; Imperiali, B. Tetrahedron Lett. 1996, 37, 2129-2132.
(7) 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, 1963-1966.
(8) For the use of other chiral auxiliaries on the Michael donor,
see: (a) Enders, D.; Teschner, P.; Gro¨bner, R.; Raabe, G. Synthesis
1999, 237-242. (b) Kanemasa, S.; Nomura, M.; Yoshinaga, S.; Yama-
moto, H. Tetrahedron 1995, 51, 10463-10476. (c) Evans, D. A.;
Bilodeau, M. T.; Somers, T. C.; Clardy, J .; Cherry, D.; Kato, Y. J . Org.
Chem. 1991, 56, 5750-5752. (d) Yamaguchi, M.; Hasebe, K.; Tanaka,
S.; Minami, T. Tetrahedron Lett. 1986, 27, 959-962.
(4) (a) Anakabe, E.; Vicario, J . L.; Bad´ıa, D.; Carrillo, L.; Yoldi, V.
Eur. J . Org. Chem. 2001, 4343-4352. (b) Vicario, J . L.; Bad´ıa, D.;
Dom´ınguez, E.; Crespo, A.; Carrillo, L.; Anakabe, E. Tetrahedron Lett.
1999, 40, 7123-7126.
(5) Enolates of glycinamides exhibited lower selectivity in the
absence of LiCl. See ref 1c.
10.1021/jo035564a CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/21/2004
J . Org. Chem. 2004, 69, 1903-1908
1903

Smitrovich et al.
2a 12 and 2d 13 were prepared following literature proce-
dures. (Z)-2a was prepared from the corresponding
alkyne by hydrogenation with Lindlar’s catalyst. Michael
acceptors 2b and 2f were synthesized using a modifica-
tion of the literature procedure.14
SCHEME 1
Variability in substitution at the terminus of the
Michael acceptor was well tolerated; however, the Michael
donor was limited to R-aryl pseudoephedrine amides
(Scheme 3 and Table 1). In the case of the acceptor, alkyl-,
phenyl-, alkyl-ether-, and alkyl-amine-substituted R,â-
unsaturated esters were suitable substrates and exhib-
ited good anti selectivity (entries 1-6). Phenyl, 4-fluo-
rophenyl, and 3,4-difluorophenyl amides 1a , 1b, and 1c,
respectively, afforded the corresponding lactones with
good selectivity (entries 2, 8, and 9), whereas 4-methoxy-
phenyl amide 1d gave lower selectivity (entry 10). All
attempts to extend the scope to alkyl-substituted pseu-
doephedrine amides resulted in poor conversion due to
low solubility of the enolates. The stereochemistry about
the double bond of the acceptor significantly affected both
yield and selectivity. Reaction of the dianion of amide
1a with (Z)-2 under standard conditions afforded the
product in moderate yield with no selectivity (Table 1,
entry 7). The reaction was sluggish (25% of amide 1a was
recovered), and conversion was not increased by pro-
longed reaction times.
SCHEME 2
anti Michael adducts.7 We have found that Michael
addition to R,â-unsaturated esters occurs smoothly and
with good selectivity.9 Initial experiments indicated that
the reaction of R,â-unsaturated esters was rapid at -78
°C and occurred in high yield in the absence of LiCl.10
Generation of the dianion of 1a at 0 °C in the presence
of 2 equiv of TMEDA, followed by cooling to -78 °C,
addition of the unsaturated ester 2b, and aging for 20
min, gave 3b as an 88:12 ratio of anti/syn isomers and
anti-3b in 76% isolated yield (Scheme 3 and Table 1,
entry 2). While TMEDA was not required, its presence
did result in slightly enhanced selectivity. In the absence
of TMEDA, the reaction of 1a with acceptor 2b afforded
3b with an 84:16 anti/syn ratio. The presence of other
additives, including DMPU and 1,2-bis(hexamethyldisi-
lylamino)ethane, led to slightly lower selectivities. While
solvent choice was limited due to the solubility of the
enolate, DME and MTBE (methyl tert-butyl ether) gave
similar results to the case of THF, whereas 2:1 THF/
toluene led to a substantial decrease in both selectivity
and conversion. Conducting the Michael addition at low
temperature (< -60 °C) was crucial for high selectivity.
For the reaction of amide 1b with acceptor 2b, conducting
the addition at -40 °C resulted in a 68:32 ratio of
products, compared to an 86:14 ratio at -75 °C.
The Michael adducts were converted to the lactones
without separation of the isomers to determine the facial
selectivity on the Michael acceptor (Table 1). Determi-
nation of the diastereomeric ratios of the Michael adducts
by NMR spectroscopy was hampered by the presence of
rotamers. For the reaction of 1a with 2b, analysis of the
1
product ratio by H NMR spectroscopic analysis of the
unpurified reaction mixture was possible, and the ratio
was determined to be 88:12:8 anti-3b/syn-3b/5 (Scheme
4).15 Reduction of this mixture followed by cyclization
with HCl afforded the lactone as a 92.5:7.5 ratio of
enantiomers.
A variety of reducing agents, including LAH, LiBH4,
L-Selectride, and LiAlH(O-t-Bu)3, were effective for selec-
tive reduction of the ester in the presence of the amide.
Cyclization was accomplished by treatment with AcOH,
MsOH, or anhydrous HCl. The use of HCl permitted
recovery of pseudoephedrine by filtration of the HCl salt
produced upon lactonization. The optical purity of the
lactone can be increased by purification of the anti
Michael adduct. The major isomer of Michael adduct 3h
was isolated by crystallization as a 98.8:1.2 ratio of
isomers in 60% yield (entry 9). Conversion to the lactone
afforded 4h in 78% yield and 99.7% ee.
A panel of Michael donors and acceptors was prepared
to investigate the scope of the reaction (Scheme 3 and
Table 1). The amides were synthesized from (R,R)-
pseudoephedrine and the requisite acid chlorides using
Schotten-Bauman conditions.11 Michael acceptors (E)-
Samples of racemic lactones for chiral SFC method
development were prepared from the requisite pyrroli-
dine amides,16 as illustrated for (()-4g (Scheme 5).
Assignment of the stereochemistry of the Michael adducts
SCHEME 3
1904 J . Org. Chem., Vol. 69, No. 6, 2004

Michael Reactions of Pseudoephedrine Amide Enolates
TABLE 1. Mich a el Rea ction s of (R,R)-P seu d oep h ed r in e Ar yla ceta m id e En ola tes w ith ou t LiCl
entry
donor
Ar
C6H5
ester
R
adduct
anti:syna
yieldb (%)
lactone
yieldc (%)
eed (%)
1
2
3
4
5
6
1a
(E)-2a
2b
CH2OBn
CH2OPMP
CH3
(CH2)2Ph
C6H5
3a
3b
3c
3d
3e
3f
90:10
88:12
83:17
82:18
80:20
84:13
80
4a
4b
4c
4d
4e
4f
69
71
68
89
70
46
91
85
91
87
83
77
98 (76)e
85
2cf
2d
78
89
83
2e
2ff
7
8
9
(Z)-2a
2b
CH2OBn
CH2OPMP
3a
3g
3h
3i
52:48
89:11
86:14
92:8
49g
95
1b
1c
1d
4-FC6H4
3,4-diFC6H3
4-MeOC6H4
4g
4h
4i
72
78
62
93
60h
80
99.7i
76
10
a
b
Determined by 1H NMR spectroscopic analysis. Yields reported for combined isomers isolated after chromatography, unless otherwise
noted. c Isolated yields over two steps. Determined by chiral SFC analysis (details provided in the Supporting Information). e The number
d
in parentheses is reported for the major isomer isolated by flash chromatography. f Reaction performed on the ethyl ester. g Adduct formed
h
in a 48:43:9 ratio of isomers as determined by chiral HPLC analysis of the unpurified reaction mixture. Yield reported for the major
isomer isolated by crystallization. Material synthesized from the crystallized Michael adduct.
i
SCHEME 4
SCHEME 6
TABLE 2. Mich a el Rea ction s of (R,R)-P seu d oep h ed r in e
Ar yla ceta m id e En ola tes w ith LiCl
entry donor
R
acceptor adduct syn:antia yieldb (%)
1
2
3
1a
C6H5
2c
2e
2b
(Z)-2a
3c
3e
3b
3a
3j
86:14
96:4
76:24
76:24
94:6
86
90
82
28
80
95
69
4
5
1c
1e
3,4-diFC6H4 2e
6c
7
2fd
2b
3k
3l
96:4
85:15
(CH2)2Ph
a
Ratios determined by 1H NMR spectroscopic analysis of the
b
unpurified reaction mixtures. Yields reported for combined
isomers isolated after chromatography. c Michael addition con-
SCHEME 5
d
ducted at -20 °C. Reaction performed on the ethyl ester.
determined by single crystal X-ray analysis. For all
lactones, the trans relative stereochemistry was assigned
by analysis of the coupling constants for the protons at
the 3- and 4-positions. The predominant enantiomer of
lactone 4a was assigned as the (R,R)-isomer by compari-
son to an independently synthesized reference compound.
Mich a el Ad d ition in th e P r esen ce of LiCl. Genera-
tion of the enolate of amide 1a in the presence of LiCl (5
equiv) followed by addition of methyl crotonate smoothly
afforded adduct 3c (Scheme 6 and Table 2). Surprisingly,
1
the H NMR spectrum of the major isomer was identical
to that of the minor isomer prepared without LiCl. Single
crystal X-ray analysis unambiguously assigned the ster-
eochemistry as syn-3c. These data indicated that, in the
presence of LiCl, the major isomer produced is syn-3c,
was based on analogy to adducts 3b, 3e, and 3h , where
the absolute stereochemistry of the major isomers was
(12) Trost, B. M.; Li, C.-J . J . Am. Chem. Soc. 1994, 116, 10819-
10820.
(9) While this work was in progress, Myers et al. reported the
conjugate addition of the lithium enolate derived from pseudoephedrine
R-fluoroacetamide to a nitroalkene and vinyl sulfoxide with modest
selectivities and yields. See: Myers, A. G.; Barbay, J . K.; Zhong, B. J .
Am. Chem. Soc. 2001, 123, 7207-7219.
(10) In contrast, the alkylation requires the presence of 6 equiv of
LiCl to increase conversion and the rate of alkylation. See ref 1b.
(11) Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J . J .
Tetrahedron Lett. 1997, 38, 2633-2636.
(13) Hon, Y.-S.; Lee, C.-F. Tetrahedron 2000, 56, 7893-7902.
(14) We found that the presence of 5-10 mol % water is crucial for
reproducibility. See: Sunitha, K.; Balasubramanian, K. K. Tetrahedron
1987, 43, 3269-3278.
(15) The stereochemistry at the epimerizable stereocenter of 5 has
not been determined.
(16) For the Michael addition of N,N-disubstituted amide enolates
with R,â-unsaturated ketones, see: Oare, D. A.; Henderson, M. A.;
Sanner, M. A.; Heathcock, C. H. J . Org. Chem. 1990, 55, 132-157.
J . Org. Chem, Vol. 69, No. 6, 2004 1905

Smitrovich et al.
differing from the non-LiCl adduct at the stereocenter R
to the amide carbonyl.
Formation of the syn isomer in the presence of LiCl
was found to be general for a panel of donors and
acceptors (Table 2). Alkyl-, phenyl-, alkyl-ether-, and
alkyl-amine-substituted R,â-unsaturated esters reacted
efficiently and with good to high syn selectivity. As found
without LiCl, reaction of (Z)-2 was sluggish, affording the
adduct in low yield (28%, entry 4). Under the LiCl
conditions, the addition of the Michael acceptor at -20
°C maintained high selectivity (entry 6). Importantly,
with LiCl, the enolates of alkyl amides are soluble,
allowing the reaction to be extended to alkyl amides.
Michael addition of 1e with acceptor 2b afforded adduct
3l in an 85:15 ratio of isomers in 69% isolated yield (entry
7). Assignment of syn stereochemistry was based on
analogy to adducts syn-3c and syn-3e, where the absolute
stereochemistry of the major isomers was determined by
single crystal X-ray analysis.
F IGURE 1. Mechanistic possibilities accounting for formation
of anti and syn Michael adducts.
Determination of the facial selectivity on the Michael
acceptor by conversion to the lactones was not possible,
as the syn Michael adducts were not generally effective
precursors to the lactones. For adducts syn-3c and syn-
3e, selective ester reduction occurred uneventfully; how-
ever, attempted lactonization gave low conversion even
with prolonged reaction times. A variety of conditions
screened to determine if an epimerization/lactonization
sequence was possible failed. The anti Michael adducts
are more suitable intermediates for the synthesis of
lactones. For the reaction of 1a with 2b, 1H NMR
spectroscopic analysis of the unpurified reaction mixture
indicated the adducts were produced as a 76:24:2 ratio
of syn-3b/anti-3b/5.
F IGURE 2. NOE data for the enolates.
Ster eoselectivity. The turnover in selectivity ob-
served in the presence of LiCl was unexpected, as Myers
has reported that the stereochemistry of alkylation of
N-acyl pseudoephedrine amide enolates is not influenced
by the presence of LiCl.1b The Michael addition differs
from the alkylation reaction in that two stereocenters are
produced. Determination of the stereochemistry of the
Michael adducts revealed that the center R to the amide
carbonyl is the stereocenter affected by the presence or
absence of LiCl. This center is analogous to that gener-
ated in the alkylation reaction. Myers et al. have reported
that alkyl halides and epoxides approach opposite faces
of the enolate.1d,17 In the present report, the additive LiCl,
not the nature of the Michael acceptor, is affecting the
stereochemical outcome. Possible explanations that can
account for the observed turnover in selectivity are (1)
interconversion of the Michael adducts under the reaction
conditions, (2) generation of different enolate isomers
(Figure 1, A vs C or B vs D), or (3) the facial selectivity
on the (Z)-enolate changing in the presence of LiCl
(Figure 1, A vs D).18
syn-3b, indicating that epimerization of the Michael
adduct does not occur under these conditions. Likewise,
submission of anti-3b to the LiCl reaction conditions led
to recovery of anti-3b. To discern between the remaining
two explanations, we examined the enolates generated
under the two enolization conditions by NMR spectro-
scopy.
Initial in situ NMR studies were used to examine the
reaction of pseudoephedrine phenylacetamide 1a with
LHMDS with and without LiCl.19 The results are il-
lustrated in Figure 2. The starting amide 1a in THF-d8
is comprised of a 50:50 mixture of rotamers generated
by restricted rotation about the amide bond. When
reacted with 2.1 equiv of LHMDS at -40 °C, the major
enolate species20 8 exhibited a high field shift of the C1a
carbon at 40.2 and 40.6 ppm to a single resonance at 76.6
(18) Synclinal orientation of the Michael acceptor is considered on
the basis of analogy to the stereochemical rationale proposed by Oare
et al. for the addition of lithium enolates of amides and thioamides to
R,â-unsaturated ketones (ref 16). The formation of anti-3 through an
open transition state E is also possible.
Isomerization of the Michael adduct under the reaction
conditions was ruled out by the following experiments.
Treatment of syn-3b with LHMDS (2 equiv) and TMEDA
(2 equiv) in THF at -78 to 0 °C led to a clean recovery of
(17) A reversal in the facial selectivity in the alkylation of prolinol
amide enolates with alkyl halides and epoxides was observed by Askin
et al., who proposed that the lithium alkoxide of the auxiliary directs
the approach of the epoxide to rationalize this observation. See: Askin,
D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I. Tetrahedron
Lett. 1988, 29, 4245-4248.
(19) Although the 3,4-difluoro analogue 1c was examined as well,
and generated similar results, a single representative reaction using
1a will be our focus.
1906 J . Org. Chem., Vol. 69, No. 6, 2004

Michael Reactions of Pseudoephedrine Amide Enolates
ppm (J CH ) 147.0 Hz) consistent with enolate formation.
The structure of the major enolate exhibited a discrete
conformation. The observed NOEs shown for 8 defined
the (Z)-stereochemistry of the enolate. These data, coupled
with the absence of an NOE from the N-methyl protons
to the C3 proton, placed restraints on the conformation
and were consistent with a seven-membered ring system
bound at the oxygen atoms by lithium(s) either singularly
with coordination to the solvent or as part of a lattice
via lithium-oxygen linkages.21
F IGURE 3. Approach of the acceptor to the enolate in the
absence of LiCl.
Analogous in situ NMR studies in the presence of
lithium chloride presented significantly different results.
Treatment of the amide with LHMDS and 3 equiv of
lithium chloride produced a 3:2 ratio of enolate species
1
for 9, as observed in the H spectrum. These species even
at -78 °C are rather broad but still resolved. The
stereochemical and structural similarities of the two
enolate species suggested that their differences lie in
different aggregate forms.21,22 Oligomers can form via
lithium-oxygen or lithium-chloride linkages.20 The NOE
studies revealed two significant observations: (1) both
enolate species exhibited (Z)-stereochemistry and (2) the
observed NOEs for both species dictated free rotation
about the C3-nitrogen bond for 9, as evidenced by NOE
enhancement to both the C3 (2.7%) and C3a (1.4%) protons
from the C4 proton (Figure 2). The enolate structures
presented (8 and 9) provide a working hypothesis for the
stereoselectivity observed for the Michael adducts. These
aggregate structures do not necessarily represent the
active species but may be equilibrium precursors to a
monomeric intermediate.21,23
F IGURE 4. Approach of the acceptor to the enolate in the
presence of LiCl.
In conclusion, we have developed a diastereoselective
Michael reaction of pseudoephedrine amide enolates that
can be used to access either anti or syn adducts with good
selectivity. This method provides highly enantiomerically
enriched 3-aryl-substituted δ-lactones in two steps from
the anti adducts. In contrast to the case of the reaction
of alkyl halides, the additive LiCl dramatically affects
the stereochemical outcome of the Michael reaction. A
model to explain the stereochemical results based on
NMR spectroscopic studies was developed.
Information obtained from the NMR studies indicated
that, under both enolization conditions, the (Z)-enolate
is formed. The observed turnover of selectivity in the
presence of LiCl is most likely due to a change in the
facial selectivity on the (Z)-enolate. This change, we
propose, is due to the effect of LiCl on the conformation
of the pseudoephedrine framework. While the species
observed by NMR spectroscopic analysis are not neces-
sarily the active species, the structures derived from the
NMR data provide the basis for a model that is consistent
with the observed stereochemical outcome of the Michael
addition. We propose that, in the absence of LiCl, the
pseudoephedrine backbone is fixed in a chelate and the
Michael acceptor approaches from the less hindered side
of the enolate, as depicted in A (Figure 1) and Figure 3,
affording anti-3. In the presence of LiCl, the alkoxide of
the auxiliary is not tied in a fixed system and is thus
available to coordinate to the Michael acceptor. Under
these conditions, the acceptor is delivered to the si face
of the enolate, as depicted in D (Figure 1) and Figure 4
and as reported for the reaction of epoxides,1d,17 affording
syn-3.
Exp er im en ta l Section
Gen er al P r ocedu r e for th e P r epar ation of An ti Mich ael
Ad d u ct s: (3R,4R)-3-Ben zyloxym et h yl-4-[(1R,2R)-(2-h y-
dr oxy-1-m eth yl-2-ph en yleth yl)m eth ylcar bam oyl]-4-ph en -
ylbu tyr ic Acid Eth yl Ester (a n ti-3a ). A 50 mL three-neck
round-bottom flask was charged with amide 1a (1.00 g, 3.53
mmol), TMEDA (1.07 mL, 7.06 mmol), and THF (2 mL). The
mixture was purged with nitrogen for 5 min and then cooled
to 0 °C. Lithium bis(trimethylsilyl)amide (1.0 M solution in
THF, 7.06 mL, 7.06 mmol) was added dropwise. The reaction
mixture was aged for 30 min at 0 °C. The resultant solution
was cooled to -78 °C, and (E)-2a (0.781 g, 3.53 mmol) was
added. The reaction mixture was stirred for 40 min at -78
°C. The reaction mixture was quenched with MeOH (1 mL,
25 mmol). When the temperature reached -40 °C, NH4Cl (30%
aq, 10 mL) was added. The mixture was allowed to warm to
room temperature. The organic layer was separated and
washed with water (10 mL) and brine (5 mL), dried over
MgSO4, and concentrated in vacuo to a colorless oil. Purifica-
tion by flash chromatography (10:90 to 40:60 EtOAc/hexanes)
afforded anti-3a as a colorless oil (1.52 g, 80%): 1H NMR (5:3
rotamer ratio, * denotes minor rotamer peaks, CD3CN, 400
MHz) δ 7.45-7.21 (m, 15H), 4.59 (m, 2H), 4.28 (m, 3H), 4.07
(q, J ) 15.2, 7.6 Hz, 2H), 4.00* (m, 1H), 3.97 (br, s, 1H), 3.35
(dd, J ) 9.6, 3.6 Hz, 1H), 3.29* (dd, J ) 9.6, 3.6 Hz, 1H), 3.02*
(dd, J ) 9.2, 4.4 Hz, 1H), 2.98 (dd, J ) 9.2, 4.4 Hz, 1H), 2.90-
2.80 (m, 1H), 2.83 (s, 3H), 2.77* (s, 3H), 2.55-2.35 (m, 2H),
1.22 (t, J ) 7.2 Hz, 3H), 1.20* (t, J ) 7.2 Hz, 3H), 1.00* (d, J
) 6.8 Hz, 3H), 0.49 (d, J ) 7.2 Hz, 3H); 13C NMR (CD3CN,
100 MHz) δ 173.1, 173.0*, 172.5, 172.4*, 142.8, 142.7*, 138.9,
138.6*, 138.4, 137.5*, 128.7, 128.6, 128.5*, 128.44, 128.37,
128.20, 128.16*, 128.0, 127.7*, 127.5, 127.4, 127.3*, 127.2*,
127.1*, 126.9*, 126.8, 126.4*, 74.7, 74.5*, 72.6, 72.5*, 69.4*,
69.3, 59.9, 57.6, 49.5*, 49.4, 40.0*, 39.8, 35.1, 34.8*, 26.9, 14.0,
13.61, 13.57*, 13.2*; IR (thin film) 3420, 3028, 2978, 1731, 1617
(20) The major enolate species 8 accounts for 60-75 mol % of the
total reaction mixture on the basis of 1H integration. (Analogous studies
using the difluorophenyl analogue 1c reflected a >95% conversion.)
The 1H spectrum revealed that the remaining portion of the reaction
is made up of broadened species which may be attributed to partial
aggregation.
(21) For a review on the structure and reactivity of lithium enolates,
see: Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-1654.
(22) 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-
1347.
(23) Tanner, D.; Birgersson, C.; Gogoll, A. Tetrahedron 1994, 50,
9797-9824.
J . Org. Chem, Vol. 69, No. 6, 2004 1907

Smitrovich et al.
cm-1. Anal. Calcd for C31H37NO5: C, 73.93; H, 7.41; N, 2.78.
Found: C, 73.73; H, 7.35; N, 2.43.
7.29-7.20 (m, 2H), 7.14-7.03 (m, 2H), 6.96 (d, J ) 8.0 Hz,
2H), 4.41-4.29 (m, 2H), 4.22 (d, J ) 11.2 Hz, 1H), 4.09* (m,
1H), 3.96-3.83 (m, 2H), 3.35 (s, 3H), 3.34* (s, 3H), 2.54 (s,
3H), 2.51* (s, 3H), 2.43-2.34 (m, 1H), 2.32-2.21 (m, 1H), 0.68
(d, J ) 7.2 Hz, 3H), 0.48* (d, J ) 7.6 Hz, 3H); 13C NMR (CD3-
CN, 100 MHz) δ 173.1, 171.99*, 171.95, 142.63, 141.61*, 141.4,
142.3*, 138.6*, 137.2, 129.3, 128.9, 128.6, 128.3*, 128.2, 128.10,
128.05, 128.0*, 127.7, 127.6*, 127.5, 127.2*, 127.0, 126.9*,
126.6*, 126.5*, 126.2, 74.6, 73.9*, 57.9, 53.5, 52.9*, 50.6, 46.6*,
45.9, 38.4, 38.2*, 26.0, 14.4*, 12.5; IR (thin film) 3394, 1734,
1634 cm-1. Anal. Calcd for C28H31NO4: C, 75.48; H, 7.01; N,
3.14. Found: C, 75.17; H, 6.99; N, 3.08.
Gen er al P r ocedu r e for th e P r epar ation of Syn Mich ael
Ad d u cts: (3R,4S)-4-[(1R,2R)-(2-Hyd r oxy-1-m eth yl-2-p h en -
yleth yl)m eth ylcar bam oyl]-3,4-diph en ylbu tyr ic Acid Meth -
yl Ester (syn -3e). A 50 mL three-neck round-bottom flask was
charged with 1a (1.50 g, 5.29 mmol), LiCl (1.12 g, 26.5 mmol),
and THF (4 mL). The mixture was purged with nitrogen for 5
min and then cooled to 0 °C. Lithium bis(trimethylsilyl)amide
(1.0 M solution in THF, 10.6 mL, 10.6 mmol) was added
dropwise. The reaction mixture was aged for 30 min at 0 °C.
The resultant solution was cooled to -78 °C, and 2e (0.858 g,
5.29 mmol) was added. The reaction mixture was stirred for
40 min at -78 °C. The reaction mixture was quenched with
MeOH (1 mL, 25 mmol). When the temperature reached -40
°C, NH4Cl (30% aq, 10 mL) was added. The mixture was
allowed to warm to room temperature. EtOAc (20 mL) was
added. The organic layer was separated and washed with
water (10 mL) and brine (5 mL), dried over MgSO4, and
concentrated in vacuo to a colorless oil. Purification by flash
chromatography (10:90 to 40:60 EtOAc/hexanes) afforded syn-
3e as a white solid (2.12 g, 90%). The selectivity was deter-
mined to be 96:4 by chiral SFC analysis (Chiralcel OD (H),
4-40% MeOH at 2%/min, 200 bar, minor tR ) 14.14 min, major
tR ) 12.91 min): mp 215-216 °C; 1H NMR (3:2 rotamer ratio,
* denotes minor rotamer peaks, CD3CN, 400 MHz) δ 7.67* (d,
J ) 8.0 Hz, 2H), 7.52 (d, J ) 7.6 Hz, 2H), 7.45-7.29 (m, 7H),
Ack n ow led gm en t. The authors thank Prof. David
Collum for helpful discussions, Dr. Christopher Welch,
Ms. Mirlinda Biba, and Ms. J ennifer Chilenski for SFC
analyses, and Drs. Kevin Campos and Dave Mathre for
X-ray crystal analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data for 1b-d , 6, 2b and f, 3b-l,
and 4a -i, and in situ NMR data for 1a and c, 8, 9, and the
enolate of 1c formed in the presence or absence of LiCl. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035564A
1908 J . Org. Chem., Vol. 69, No. 6, 2004