Evaluation of a Pseudoephedrine Linker for Asymmetric Alkylations on Solid Phase

Article abstract of DOI:10.1021/ol0268788

(Equation Presented) Immobilized pseudoephedrine amides have been conveniently prepared by attachment of pseudoephedrine to Merrifield resin and acylation on nitrogen. Deprotonation and alkylation of the resin bound amides proceeds smoothly. Products were cleaved from the resin to give ketones and alcohols in high enantiomeric excess and moderate to good overall yield.

Full text of DOI:10.1021/ol0268788

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4583-4585
Evaluation of a Pseudoephedrine Linker
for Asymmetric Alkylations on Solid
Phase
,†
Panee C. Hutchison,† Tom D. Heightman,‡ and David J. Procter*
Department of Chemistry, The Joseph Black Building, UniVersity of Glasgow,
Glasgow, G12 8QQ, United Kingdom, and GlaxoSmithKline,
New Frontiers Science Park, Third AVenue, Harlow,
Essex CM19 5AW, United Kingdom
daVidp@chem.gla.ac.uk
Received September 10, 2002
ABSTRACT
Immobilized pseudoephedrine amides have been conveniently prepared by attachment of pseudoephedrine to Merrifield resin and acylation
on nitrogen. Deprotonation and alkylation of the resin bound amides proceeds smoothly. Products were cleaved from the resin to give ketones
and alcohols in high enantiomeric excess and moderate to good overall yield.
Although the use of a supported chiral auxiliary was first
reported 30 years ago, the efficient, asymmetric synthesis
of chiral compounds using solid phase auxiliaries is still a
relatively underdeveloped area.1 Oxazolidinone-based aux-
iliaries have been most commonly employed; however, these
auxiliaries must be prepared, either on or off resin, prior to
use, and their efficient recycling has yet to be described. In
addition, in one example, the attachment of an oxazolidinone-
based auxiliary to a solid support was problematic due to
side reactions. This has recently led to confusion over the
exact nature of an immobilized oxazolidinone auxiliary.2
either oxygen or nitrogen should be straightforward leading
to robust ether or amine linkages (Figure 1).
Our interest in the development of new solid-phase, linker
technologies3 has led us to consider readily available and
inexpensive ephedrine and pseudoephedrine derivatives as
“chiral linkers” for solid-phase synthesis. These linkers
would allow substrates to be linked to resin and control the
stereochemistry of reactions carried out on the substrate.
Importantly, the “one-step” attachment of the commercially
available ephedrine or pseudoephedrine unit to resin through
Figure 1. Ephedrine and Pseudoephedrine Chiral Links.
In this Letter, we describe the first application of this
strategy in an adaptation of Myers’ pseudoephedrine auxiliary
approach for the asymmetric alkylation of amide enolates.4
(1R,2R)-Pseudoephedrine was attached to Merrifield resin
by adapting Welch’s procedure for O-benzylation.5 The
† University of Glasgow.
‡ GlaxoSmithKline.
10.1021/ol0268788 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/04/2002

loading at this stage was determined by conversion of 1 to
the thiophene carboxamide 2 followed by sulfur elemental
analysis of the resin. In Myers’ original pseudoephedrine
auxiliary approach, deprotonation generates a dianion as the
hydroxyl on the auxiliary is also deprotonated during
enolization. The lithium alkoxide on the auxiliary has been
implicated in attempts to rationalize the diastereoselectivity
of the alkylation reactions.6
of an analogous dianion is not possible. To ensure that high
diastereoselectivites would still be observed in alkylations
of our system, O-benzylpseudoephedrine amide 3, a solution-
phase model for an immobilized amide, was prepared and
alkylated (Scheme 2).
Scheme 2a
Scheme 1a
a Reagents and conditions: (i) LDA (2.1 equiv), LiCl (6 equiv),
THF, from -78 °C to rt; BnBr was then added at 0 °C, 86%. (ii)
LDA (3.9 equiv), BH3‚NH3, THF, from 0 °C to rt, 55%.
Crucially, only slightly lower diastereoselectivity (91% de)
was observed in the case of the O-benzylpseudoephedrine
amide 3, compared to the analogous Myers-type substrate 4
(94% de).7 Assured that linkage to the resin through oxygen
should not greatly effect the diastereoselectivity of alkylation
reactions, we performed acylation of pseudoephedrine resin
1 (anhydride or acid chloride, NEt3 CH2Cl2, rt) to give the
corresponding resin-bound pseudoephedrine amides 8 (νmax
1635-1645 cm-1).8 Amides 8 were then deprotonated and
alkylated to give adducts 9 (Scheme 3).
a Reagents and conditions: (i) KH, (1R,2R)-pseudoephedrine,
THF, 18 h; resultant solution was then added to resin in THF, rt.
(ii) Thiophene carbonyl chloride, NEt3, CH2Cl2, rt.
Clearly in our approach, as the hydroxyl group of
pseudoephedrine acts as a link to the solid support, formation
(1) Carbohydrate-based auxiliaries: (a) Kawana, M.; Emoto, S. Tetra-
hedron Lett. 1972, 48, 4855. Kawana, M.; Emoto, S. Bull. Chem. Soc. Jpn.
1974, 47, 160. (b) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem., Int. Ed.
2000, 39, 1431. Chiral amines: (c) Worster, P. M.; McArthur, C. R.;
Leznoff, C. C. Angew. Chem., Int. Ed. Engl. 1979, 18, 221. McArthur, C.
R.; Worster, P. M.; Jiang, J.-L.; Leznoff, C. C. Can. J. Chem. 1982, 60,
1836. Evans oxazolidinones: (d) Allin, S. M.; Shuttleworth, S. J.
Tetrahedron Lett. 1996, 37, 8023. (e) Burgess, K.; Lim, D. Chem. Commun.
1997, 785. (f) Purandare, A. V.; Natarajan, S. Tetrahedron Lett. 1997, 38,
8777. (g) Phoon, C. W.; Abell, C. Tetrahedron Lett. 1998, 39, 2655. (h)
Winkler, J. D.; McCoull, W. Tetrahedron Lett. 1998, 39, 4935. (i) Faita,
G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron Lett. 2000,
41, 1265. Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P.
Tetrahedron 2001, 57, 8313. Desimoni, G.; Faita, G.; Galbiati, A.; Pasini,
D.; Quadrelli, P.; Rancati, F. Tetrahedron: Asymmetry 2002, 13, 333.
Pyrrolidine-based auxiliaries: (j) Moon, H.-s.; Schore, N. E.; Kurth, M. J.
J. Org. Chem. 1992, 57, 6088. Moon, H.-s.; Schore, N. E.; Kurth, M. J.
Tetrahedron Lett. 1994, 35, 8915. Oppolzer’s camphorsultam: (k) Miyabe,
H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443. Oxazolines: (l) Colwell,
A. R.; Duckwall, L. R.; Brooks, R.; McManus, S. P. J. Org. Chem. 1981,
46, 3097. Hydrazine auxiliaries: (m) Enders, D.; Kirchhoff, J. H.;
Ko¨bberling, J.; Peiffer, T. H. Org. Lett. 2001, 3, 1241. Alcohol auxiliary:
(n) Akkari, R.; Calmes, M.; Mai, N.; Rolland, M.; Martinez, J. J. Org.
Chem. 2001, 66, 5859. Sulfinamide auxiliary: (o) Dragoli, D. R.; Burdett,
M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 10127. R-Hydroxyvaline
auxiliary: (p) Savinov, S. N.; Austin, D. J. Org. Lett. 2002, 4, 1419.
(2) Bew, S. P.; Bull, S. D.; Davies, S. G. Tetrahedron Lett. 2000, 41,
7577.
(3) McKerlie, F.; Procter, D. J.; Wynne, G. Chem. Commun. 2002, 584.
(4) (a) Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995,
117, 8488. (b) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am.
Chem. Soc. 1997, 119, 656. (c) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496. (d) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(e) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J. Org. Chem. 1999,
64, 3322.
(5) Na¨slund, J.; Welch, C. J. Tetrahedron: Asymmetry 1991, 2, 1123. In
our hands, solution-phase benzylation of pseudoephedrine under these
conditions was found to give less than 5% N-benzyl pseudoephedrine. Thus,
similar high selectivity for O-alkylation is expected in the immobilization
step.
Scheme 3a
a Reagents and conditions: (i) Propionic anhydride/valeric
anhydride/phenylacetyl chloride, NEt3, CH2Cl2, rt. (ii) LDA (6.2
equiv), LiCl (36 equiv), THF, from -78 °C to rt; BnBr/BuI (4.5
equiv) was then added at 0 °C. (iii) LDA (1.2 equiv), BH3‚NH3
(1.2 equiv), from -78 °C to rt; mixture was added to resin at 0 °C
and allowed to warm to rt. (iv) R3Li, Et2O, from -78 °C to 0 °C.
Myers’ has shown that the auxiliary group can be removed
from pseudoephedrine amides, using a variety of methods
to give carboxylic acids, primary alcohols, ketones, and
(7) For the R ) H series, diastereoselectivities were determined by
conversion of 6 into the corresponding TMS ether and analysis by GCMS.
For the R ) Bn series, the diastereoisomeric purity of 5 was obtained
indirectly from the enantiomeric excess of 7.
(6) For a discussion, see ref 4c.
4584
Org. Lett., Vol. 4, No. 26, 2002

aldehydes.4c In our solid-phase approach, the use of different
cleavage strategies allows us to introduce further diversity
into our collection of compounds during the cleavage process.
One disadvantage of simple immobilization through the
hydroxyl group of the pseudoephedrine unit is that hydrolytic
cleavage after alkylation, to give enantiomerically enriched
carboxylic acids directly, is not possible using Myers’
conditions. Myers has clearly shown that hydrolysis of
pseudoephedrine amides proceeds through N-O acyl transfer
followed by ester hydrolysis.4c This is obviously not possible
if the hydroxyl is derivatized. We have, however, been
successful in cleaving products from the resin to give primary
alcohols and ketones: primary alcohols 7 and 10 were
obtained by reduction of the immobilized pseudoephedrine
amides with lithium amidotrihydroborate (LAB, LiH2-
NBH3),9,4c while ketones 11 were prepared by reaction of
the starting amides with alkyllithium reagents (R3Li, Et2O/
THF).4c
ketones and illustrates the potential of our approach for the
generation of libraries of enantiomerically enriched com-
pounds (Scheme 4).11
Scheme 4a
Moderate to good isolated yields are obtained for the three-
step processes and products are obtained in good enantio-
meric excess (Figure 2).10,11 No extensive attempts to
a Reagents and conditions: (i) nBuLi (1.0 equiv), THF, -25 °C.
(ii) Heteroaryllithium (4.8 equiv) was added to resin (1.0 equiv) at
-78 °C and then warmed to 0 °C, 47% for three steps from 1. (iii)
Thienyllithium (4.8 equiv) was added to resin (1.0 equiv) at -78
°C and then warmed to 0 °C, 60% for three steps from 1.
In summary, inexpensive pseudoephedrine can be conve-
niently immobilized on Merrifield resin in a single step,
through a robust ether link. The first asymmetric alkylations
on amides immobilized via this pseudoephedrine linker have
been carried out. Cleavage of products from the resin gives
primary alcohols and ketones in moderate to good overall
yield and good enantiomeric excess. We are currently
developing methods for cleavage that will allow access to
other classes of enantiomerically enriched products and are
examining the recycling of the chiral resin. In addition, we
are applying pseudoephedrine and ephedrine linkers to other
asymmetric processes on solid phase.
Acknowledgment. We thank the University of Glasgow
for the award of a University Scholarship to P.C.H and
GlaxoSmithKline for a CASE award to P.C.H. We also thank
Prof. Philip Hodge for suggesting the thiophene carboxamide
method for the determination of loading. Finally, we
acknowledge Mr. J. Gall from the NMR Spectroscopy
Laboratory at the University of Glasgow for technical
assistance.
Figure 2.
optimize the diastereoselectivity of the alkylation reactions
on solid phase or the efficiency of the cleavage steps have
yet been made.
The use of readily available heteroaryllithiums in the
cleavage step allows efficient access to heteroaromatic
Supporting Information Available: Experimental pro-
cedures and full characterization data for 1-3, 5, 7-10, and
11a-h. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0268788
(8) In some IR spectra, extremely faint ester carbonyl stretches could
also be seen. This is in agreement with previous observations regarding
high selectivity in the O-alkylation of pseudoephedrine (see ref 5).
(9) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623.
(11) Enantiomeric excess of ketones 11a-f and 11h was determined by
reduction of the ketones with LiAlH4, esterification with both (R)- and (S)-
Mosher’s acids and analysis of the resultant diastereoisomeric mixtures of
esters by 19F NMR (see ref 4c). Enantiomeric excess of 11g was determined
by chiral HPLC.
(10) Enantiomeric excess of alcohol 10 was determined by preparation
of both the (R)- and (S)- Mosher’s esters and analysis by 19F NMR.
Org. Lett., Vol. 4, No. 26, 2002
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