Pseudoephedrine as a chiral auxiliary for asymmetric Michael reactions: synthesis of 3-aryl-delta-lactones.

Article abstract of DOI:10.1021/ol0259847

[reaction: see text] The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-delta-lactones in a two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones.

Full text of DOI:10.1021/ol0259847

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1963-1966
Pseudoephedrine as a Chiral Auxiliary
for Asymmetric Michael Reactions:
Synthesis of 3-Aryl-δ-lactones
Jacqueline H. Smitrovich,* Genevie`ve N. Boice, Chuanxing Qu, Lisa DiMichele,
Todd D. Nelson, Mark A. Huffman, Jerry Murry, James McNamara, and
Paul J. Reider
Department of Process Research, Merck Research Laboratories, Merck & Co.,
P.O. Box 2000, Rahway, New Jersey 07065
jacqueline_smitroVich@merck.com
Received April 8, 2002
ABSTRACT
The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-δ-lactones in a
two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted δ-lactones.
The Michael addition of enolizable substrates to unsaturated
carbonyl compounds is a fundamental method for carbon-
carbon bond construction.1,2 The development of asymmetric
variants of this important reaction continues to be an ongoing
pursuit. Recent progress including the advent of asymmetric
catalysis has advanced this form of stereocontrol.1,3 The use
of chiral auxiliaries has also been established as an effective
method for control of asymmetry. The most common
approach to induce selectivity is the use of a chiral auxiliary
on the Michael acceptor.4 The alternative strategy of using
an auxiliary on the Michael donor has been less explored.5
We recently required a method for the enantioselective
synthesis of aryl-substituted δ-lactones 1 (Scheme 1). A
survey of the relevant literature did not provide any
substantial precedence for the synthesis of these important
chiral molecules. We sought a method that would permit
variation of the substituents at the 3- and 4-positions with
control of absolute and relative stereochemistry. Retrosyn-
thetic analysis suggested that dicarbonyl derivative 3 was a
(1) For a review, see: Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001,
171-196.
(2) (a) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H.
J. Org. Chem. 1990, 55, 132-157 and references therein. (b) Oare, D. A.;
Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172.
(3) (a) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J.
Am. Chem. Soc. 2001, 123, 4480-4491. (b) Zhang, F.-Y.; Corey, E. J.
Org. Lett. 2001, 3, 639-641. (d) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000,
2, 4257-4259. (e) Thierry, B.; Perrard, T.; Audouard, C.; Plaquevent, J.-
C.; Cahard, D. Synthesis 2001, 1742-1746. (f) Alvarez, R.; Hourdin, M.-
A.; Cave´, C.; d’Angelo, J.; Chaminade, P. Tetrahedron Lett. 1999, 40,
7091-7094. (g) Kim, S.-G.; Ahn, K. H. Tetrahedron Lett. 2001, 42, 4175-
4177. (h) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku,
A. Org. Lett. 2001, 3, 2101-2103. (i) Kim, Y. S.; Matsunaga, S.; Das, J.;
Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506-
6507. (j) Suzuki, T.; Torii, T. Tetrahedron: Asymmetry 2001, 12, 1077-
1081.
(4) (a) Liang, B.; Carroll, P. J.; Joullie´, M. M. Org. Lett. 2000, 2, 4157-
4160. (b) Schneider; C.; Reese, O. Synthesis 2000, 1689-1694. (c) Ezquerra,
J.; Prieto, L.; Avendan˜o, C.; Martos, J. L.; de la Cuesta, E. Tetrahedron
Lett. 1999, 40, 1575-1578. (d) Meyers, A. I.; Stoianova, D. J. Org. Chem.
1997, 62, 5219-5221. (e) Nomura, M.; Kanemasa, S. Tetrahedron Lett.
1994, 35, 143-146. (f) Dahuron, N.; Langlois, N. Tetrahedron: Asymmetry
1993, 4, 1901-1908.
(5) (a) Enders, D.; Teschner, P.; Gro¨bner, R.;. Raabe, G. Synthesis 1999,
237-242. (b) Kanemasa, S.; Nomura, M.; Yoshinaga, S.; Yamamoto, 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.
10.1021/ol0259847 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

We began our investigation by examining the reaction of
several chiral amide enolates 6-10 with an unsaturated ester
(Scheme 2, Table 1). The resultant adducts (S)-12 and (R)-
Scheme 1
Scheme 2
possible precursor, which we envisioned to arise from a
Michael addition reaction. Michael disconnection allows
introduction of the ring substituents independent of one
another via acceptor 4 and donor 5. This procedure would
access a range of 3,4-disubstituted trans-lactones with the
appropriate choice of 4 and 5. In this communication, we
describe a new method for the preparation of 3,4-disubsti-
tuted lactones that involves an auxiliary-controlled Michael
addition of pseudoephedrine amide enolates with unsaturated
esters.6
12 were submitted to reduction and lactonization to determine
facial selectivity on the Michael acceptor.7 The ratio of the
four lactones was determined by chiral SFC analysis.
Catalytic asymmetric Michael reaction methodology has
been extended to both enantio- and diastereoselective
systems; however, these systems are not currently applicable
to the substitution pattern required for the synthesis of lactone
1. We consequently focused our attention on chiral-auxiliary-
controlled approaches. Auxiliary-controlled Michael reactions
can either follow the paradigm of employing a chiral acceptor
44 or a chiral donor 5.5 We chose the latter approach by
investigating the reaction of chiral amide enolates with R,â-
unsaturated esters. This combination was attractive for the
following reasons: (1) the selectivity could be optimized by
screening a variety of chiral amines, (2) the ester of the
resultant adduct 3 could be readily reduced in the presence
of the amide, and (3) upon acid-mediated lactonization, the
chiral auxiliary could be recovered as an amine salt.
Table 1. Screen of Chiral Auxiliaries
(6) While this work was in progress, Myers et al. reported the conjugate
addition of the lithium enolate derived from pseudoephedrine R-fluoroac-
etamide 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.
(7) This method determines selectivity at the 4-position only, as
epimerization occurs upon lactonization. Determination of the diastereomeric
ratios of the Michael adducts by NMR spectroscopy is hampered by the
presence of rotamers.
(8) For a review of the synthetic applications of cis-1-amino-2-indanol
see: Senanayake, C. H. Aldrichimica Acta 1998, 31, 3-15.
(9) Myers et al. have demonstrated the power of pseudoephedrine as a
chiral auxiliary for enolate alkylations: (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.
Myers, A. G.; Yoon, T. Tetrahedron Lett. 1995, 36, 9429-9432. (d) Myers,
A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488-8489.
(e) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc.
1994, 116, 9361-9362.
(10) (a) For use of pseudoephedrine as a chiral auxiliary for asymmetric
aldol reaction, see: Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez,
M.; Carrillo, L. J. Org. Chem. 2000, 65, 3754-3760. (b) For asymmetric
Mannich reactions, see: Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org. Chem.
2001, 66, 9030-9032; Org. Lett. 2001, 3, 773-776.
a Determined by chiral SFC analysis.
We found that (S)-prolinol amide enolates gave low
selectivity (Table 1, entry 1), contrary to the report by
Yamaguchi for the alkylation of propionate amides.5d The
protected amino alcohols 7 and 8 did not provide significant
selectivity. We were pleased to find, however, that both cis-
N-methylaminoindanol8 and (S,S)-pseudoephedrine9,10 af-
forded lactone (S)-13 with high selectivity (entries 4 and 5).
Our subsequent work focused on the optimization of the
pseudoephedrine amide. We have found that the presence
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Org. Lett., Vol. 4, No. 11, 2002

Scheme 3
of TMEDA and lower temperatures enhanced selectivity.
unsaturated esters were suitable substrates (entries 1-5). The
amine-substituted ester 21 afforded adduct 22e in high yield
and lactone 23e with moderate selectivity (entry 6). Phenyl,
4-fluorophenyl, and 3,4-difluorophenyl amides 10b, 14, and
15, respectively, afforded the corresponding lactones with
good to high selectivity (entries 2, 7, and 8). A decrease in
selectivity was exhibited by electron-rich amide 16 (entry
9), where the unpurified Michael adducts afforded lactone
23h with moderate ee (76%).
Generation of the dianion at 0 °C in the presence of 2 equiv
of TMEDA, followed by cooling to -78 °C and addition of
the unsaturated ester, gave optimal selectivity. Under these
conditions, the Michael addition is typically complete within
30 min,11 and with amide 10b and ester 17, anti-isomer 22a
was isolated in 76% yield (Scheme 3, Table 2 entry 2).12
The stereochemistry was assigned unambiguously by single-
crystal X-ray analysis.
Conversion of the Michael adduct to the lactone was
accomplished in a two-step reduction/lactonization sequence
(Scheme 3). A variety of reducing agents, including LAH,
LiBH4, and LiAlH(O-t-Bu)3, were effective for selective
reduction of the ester in the presence of the amide.13
Cyclization was accomplished by treatment with TsOH,
MsOH, or anhydrous HCl.13 Use of HCl permitted recovery
of pseudophedrine by filtration of the HCl salt produced upon
lactonization.
The scope and limitations of this method were investigated
with respect to the donor and acceptor (Table 2). The amides
were prepared from (R,R)-pseudoephedrine and the requisite
acid chlorides using Schotten-Bauman conditions.14 The
Michael acceptors were prepared according to literature
procedures.13 Reaction of 10b with Michael acceptor 11
afforded lactone 13 with the (R,R)-isomer predominating
(entry 1), in contrast to the reaction of enantiomeric 10a,
which gave (S)-13 (Table 1, entry 5). In the case of the
acceptor, alkyl, phenyl, and alkyl-ether substituted R,â-
The optical purity of the lactone can be increased by
purification at either of two points: isolation of the major
Michael adduct or, when possible, crystallization of the
lactone. The major isomer of Michael adduct 22g was
isolated by crystallization as a 98.8:1.2 ratio of isomers in
60% yield. Conversion to the lactone by the standard protocol
afforded 23g in 78% yield and 99.8% ee. In the case of
lactone 23a, the unpurified mixture of adducts 22 was
reduced and then treated with ethereal HCl. The auxiliary
was recovered as the HCl salt in 74% yield by filtration.
Crystallization afforded lactone 23a in 62% yield and 98%
ee over the three steps (entry 2).
To determine stereoselectivity, the Michael adducts were
converted to the lactones15 without separation of the isomers
(Table 2).7 Assignment of the stereochemistry of the Michael
adducts was based on analogy to adducts 22a, 22e, and 22g,
where the absolute stereochemistry of the major isomers was
determined by single-crystal X-ray analysis. For all lactones,
the trans relative stereochemistry was assigned by analysis
Table 2. Michael Reactions of (R,R)-Pseudoephedrine Arylacetamides
a Yields reported for combined isomers isolated after chromatography, unless otherwise noted. b Isolated yields over two steps. c Determined by chiral
SFC analysis; details provided in Supporting Information. d Yield reported for major isomer isolated by flash chromatography. e Number in parentheses
reported for crystallized material. f Reaction performed on the ethyl ester. g Yield reported for major isomer isolated by crystallization. h Number in parentheses
reported for crystallized material obtained from a 98.8:1.2 isomeric ratio of 22g.
Org. Lett., Vol. 4, No. 11, 2002
1965

of the coupling constants for the protons at the 3- and
4-positions. The predominant enantiomer of lactone 13 was
assigned as the (R,R)-isomer by comparison to an indepen-
dently synthesized reference compound.
Michael acceptor approaches the re face of the enolate
(Figure 2). NMR spectroscopic analyses of the enolate
We next shifted our focus to the mechanistic model to
account for the observed selectivity of these reactions. Myers
first investigated the stereochemical outcome of the alkylation
of pseudoephedrine amide enolates with electrophiles.9 He
proposed that the enolate adopts the conformation depicted
in Figure 1 and that alkyl halides approach the enolate from
Figure 2.
formed by treatment of amide 15 with 2 equiv of LHMDS
supports the structure of the (Z)-enolate set forth by Myers
(Figure 1). The observed NOE data shown in Figure 1 define
the stereochemistry of the enolate. These data, coupled with
the absence of an NOE from the N-methyl protons to the C3
proton, place restraints on its conformation and are consistent
with a fixed ring system bound at the oxygen atoms by
lithium either singularly or as part of a lattice. At this time,
we are uncertain as to why esters are apparently not delivered
to the si face of the enolate. Studies to further elucidate the
source of stereochemical control of this and other related
stereoselective reactions of chiral amide enolates are in
progress and will be reported in due course.
Figure 1.
In conclusion, we have developed a diasteroselective
Michael reaction of aryl-substituted pseudoephedrine amide
enolates. This method provides highly enantiomerically
enriched 3-aryl-substituted δ-lactones in three steps. The
chiral auxiliary is recovered as the HCl salt by filtration. A
model to explain the source of facial selectivity based on
literature precedence has been investigated and is counter-
intuitive. Investigations to determine the source of selectivity
and to expand the scope of this method are in progress.
the less hindered re face; however, epoxides are delivered
to the si face by coordination to the lithium alkoxide of the
auxiliary.9a We expected that R,â-unsaturated esters would
follow the epoxide reaction manifold, by coordination of the
carbonyl oxygen to the lithium cation. Formation of the
observed enantiomer of anti-24, however, indicates that the
(11) The reactions were rapid and did not require the presence of LiCl.
For the use of LiCl to accelerate the alkylation reactions of pseudoephedrine
amide enolates, see ref 9b.
(12) General Procedure. To a cooled (0 °C) solution of amide 10b (4.25
g, 15 mmol) and TMEDA (4.52 mL, 30 mmol) in THF (15 mL) was added
LHMDS (1.0 M solution in THF, 30.0 mL, 30 mmol). After 45 min, the
reaction mixture was cooled to -76 °C, and ester 17 (3.33 g, 15 mmol)
was added. After the mixture stirred for 1 h, MeOH (1 mL) was added
followed by saturated aqueous NH4Cl. The reaction mixture was allowed
to warm to room temperature. The mixture was diluted with water, and the
layers were separated. The organic layer was diluted with toluene, washed
with 0.1 M HCl, dried (Na2SO4), and concentrated in vacuo to afford a
yellow oil. Purification by flash chromatography (1:1.5 hexanes/EtOAc)
afforded 22a as a colorless oil (5.79 g, 76%).
Acknowledgment. The authors thank Christopher Welch,
Mirlinda Biba, and Jennifer Chilenski for SFC analyses;
Robert Reamer and Peter Dormer for assistance with NMR
analyses; and Kevin Campos and Dave Mathre for X-ray
crystal analyses.
Supporting Information Available: Experimental pro-
cedures and characterization data for 6-9, 12-16, 22a-h,
23a-h, and racemic lactones. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Details are provided as Supporting Information.
(14) Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron
Lett. 1997, 38, 2633-2636.
(15) Racemic samples of the lactones were prepared and used for chiral
SFC method development. Details are provided as Supporting Information.
OL0259847
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Org. Lett., Vol. 4, No. 11, 2002