Synthesis and evaluation of a new polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase

Article abstract of DOI:10.1039/b700477j

A polymer-supported pseudoephedrine auxiliary linked to the support through nitrogen, has been developed for use in asymmetric alkylations on solid phase. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700477j

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Synthesis and evaluation of a new polymer-supported pseudoephedrine
auxiliary for asymmetric alkylations on solid phase†
Andrea M. McGhee, Jean-Claude Kizirian and David J. Procter*
Received 11th January 2007, Accepted 6th February 2007
First published as an Advance Article on the web 19th February 2007
DOI: 10.1039/b700477j
A polymer-supported pseudoephedrine auxiliary linked to
the support through nitrogen, has been developed for use
in asymmetric alkylations on solid phase.
simple approach to immobilisation does not permit hydrolytic
cleavage of enantiomerically enriched carboxylic acids from the
auxiliary8 although alcohols and ketones can be prepared (80–93%
ee). We felt that a pseudoephedrine resin bearing a free hydroxyl
group, attached to the polymer support through nitrogen (mode
C) (Fig. 1), would address this shortcoming. Here we describe the
design, synthesis and evaluation of an improved pseudoephedrine
auxiliary attached to the support through nitrogen.
The most straight-forward approach to the preparation of
a pseudoephedrine resin, immobilised through nitrogen, in-
volves the N-alkylation of norpseudoephedrine using Merrifield
resin. To examine whether such a system would be viable,
N-benzylpseudoephedrine amide 2, a solution model for an
amide immobilised through nitrogen, was prepared9 and alkylated
(Scheme 1). Myers’ system 16 is also included for comparison.
The development of immobilised chiral auxiliaries for asymmetric
library synthesis remains a relatively under-developed area.1 Our
interest in the development of new linkers2 for synthesis, has led
us to evaluate ephedrine3 and pseudoephedrine chiral resins4 for
solid phase, asymmetric synthesis. These chiral linking units tether
substrates to the polymer support and control the stereochemistry
of reactions carried out on the substrate (Fig. 1).
Fig. 1 Ephedrine and pseudoephedrine chiral resins.
Oxazolidinones remain the most extensively explored sup-
ported auxiliary,1,5 however, ephedrine and pseudoephedrine
resins present attractive, complementary systems that might be
expected to have greater stability and therefore recyclability.3,4
We have described a Sm(II)-mediated, asymmetric catch and
release approach to c-butyrolactones that involves intermolecular
radical additions to a,b-unsaturated esters attached to resin
through an ephedrine chiral linker3 (mode B). Myers’ pseu-
doephedrine chiral auxiliary6 continues to evolve as a valuable tool
for a range of asymmetric transformations.7 We have also reported
the application of a pseudoephedrine resin (mode A) in Myers-type
asymmetric alkylations on solid phase,4 and have demonstrated the
potential of the approach for asymmetric library synthesis.
Although immobilisation of pseudoephedrine through oxygen
(mode A) using Merrifield resin can be achieved in one-step,4 this
Scheme 1 Reagents and conditions: (i) LDA 2.1 equiv., LiCl 6 equiv., THF
−78 ◦C to rt then BnBr added at 0 ◦C, 88% (for 4); (ii) LDA, BH3·NH3,
THF, 0 ◦C to rt, 75%.
Alkylation of 2 using Myers’ conditions gave 4 in 88%
yield. The relative stereochemistry of 4 was confirmed by X-ray
crystallography.10 Reduction of 4 with lithium amidotrihydrobo-
rate gave (S)-5 in 75% yield and in 85% ee. Thus the exchange
of the N-methyl group in Myers’ pseudoephedrine auxiliary for a
larger benzyl substituent, led to a small drop in selectivity (∼9%
ee).
To evaluate this simple approach on solid phase, Merrifield resin
was treated with norpseudoephedrine hydrochloride 611 to give
pseudoephedrine resin 7 (∼0.88 mmol g−1). Acylation then gave
amide 8 that upon alkylation and reductive cleavage gave (S)-5 in
56% overall yield but only 45% ee (Scheme 2).
School of Chemistry, Oxford Road, The University of Manchester, Manch-
ester, UK M13 9PL. E-mail: david.j.procter@manchester.ac.uk
† Electronic supplementary information (ESI) available: Experimental
procedures and X-ray crystal structure. See DOI: 10.1039/b700477j
Not only does the proximity of the polymer backbone appear
to interfere with the diastereoselectivity of the alkylation step
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Scheme 2 Reagents and conditions: (i) 6, Et3N, DMF, 50 ◦C; (ii) propionic
anhydride, THF, Et3N, rt; (iii) LDA. LiCl, THF, −78 ◦C to rt then BnBr,
THF, 0 ◦C to rt; (iv) LDA, BH3·NH3, THF, 56% overall (based on loading
of 7).
but the bulk of the support hinders N-acylation and may lead
to competing O-acylation. For example, extended treatment of 7
Scheme 4 Reagents and conditions: (i) TMSCl, NEt3, CH2Cl2, 0 ◦C, 1 h
then acryloyl chloride, rt, 2 h, then citric acid, MeOH, 64%; (ii) BnSH,
NaH, THF, 0 ◦C, 60%; (iii) BH3·THF, D, THF, 92%; (iv) propionic
anhydride, CH2Cl2, Et3N, rt, 72%; (v) LDA, LiCl, THF −78 ◦C to rt
then BnBr added at 0 ◦C, 65%; (vi) LDA, BH3·NH3, THF, 0 ◦C to rt, 75%;
(vii) 9 N H2SO4, dioxane, D, 100%; (viii) TMSCHN2, toluene–MeOH, rt,
75%.
−1
=
=
with propionic anhydride gave a resin (m(C O) 1628 cm , m (C O)
1738 cm−1), that upon alkylation and cleavage, gave (S)-5 in 15% ee.
To add support to the hypothesis that over-acylation was effecting
the diastereoselectivities observed, N-methylpseudoephedrine was
acylated and alkylated to give 10. Reduction then gave the opposite
enantiomer (R)-5 in 62% ee, clearly showing that O-acylation and
ester alkylation would be expected to lead to an erosion of product
enantiomeric excess when preparing (S)-5 (Scheme 3).
bilised using Merrifield-based thiol resin 1612 by addition to a
suspension of the resin and NaH in THF. Amide 17 was then
reduced with borane to give 18 (Scheme 5). Microanalysis of 18
indicated a loading of 0.90 mmol g−1.
Scheme 3 Reagents and conditions: (i) propionic anhydride, THF, Et3N,
rt; (ii) LDA, LiCl, THF −78 ◦C to rt then BnBr added at 0 ◦C; (iii) LDA,
BH3·NH3, THF, 0 ◦C to rt, 53% overall.
From these model studies it was clear that linkage to the
support through a longer spacer unit would be a necessary feature
of an effective pseudoephedrine auxiliary immobilised through
nitrogen. Aware of the need for a synthetically, straight-forward
approach, we investigated a new immobilisation strategy in
solution. Norpseudoephedrine 6 was converted to acrylamide 11
and the Michael addition of benzylthiolate was used to mimic an
immobilisation step involving a benzylthiol resin. Resulting amide
12 was then reduced to 13, a solution model for a pseudoephedrine
resin linked to the polymer support through nitrogen via a three
carbon spacer (Scheme 4). Pleasingly, acylation with propionic
anhydride, alkylation with benzyl bromide and reductive cleavage
gave (S)-5 in good overall yield and in 91% ee (cf. 94% ee using
Myers’ system in solution). Importantly, hydrolytic cleavage of the
auxiliary and esterification of the resultant acid, gave 15 in 75%
yield and 87% ee (Scheme 4).
Scheme 5 Reagents and conditions: (i) NaH, THF, 11; (ii) BH3·THF, THF.
Pseudoephedrine resin 18 (and its enantiomer, (1S,2S)-18)
was evaluated by carrying out the unoptimised synthesis of a
small collection of alcohols, acids and a ketone. Acylation of
18 with propionic anhydride and 3-cyclopentyl propionic acid
(activated with pivaloyl chloride) followed by alkylation with
benzyl bromide gave immobilised adducts 20. Reductive cleavage
gave the expected alcohols (S)-5, (R)-5 and 22 in 86–92% ee (NB
The level of selectivity observed in the synthesis of alcohol (R)-
5 is essentially the same as that observed using Myers’ solution
auxiliary6e). Pleasingly, hydrolysis using tetra-n-butylammonium
hydroxide in t-BuOH and water gave the carboxylic acids 21 and
23 with similar selectivities. Finally, ketone 24 was prepared in
somewhat lower enantiomeric excess due to some epimerisation
Satisfied that this linker system would allow access to enan-
tiomerically enriched carboxylic acid derivatives by hydrolysis,
we prepared a polymer-supported analogue of pseudoephedrine
derivative 13. Norpseudoephedrine acrylamide 11 was immo-
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during cleavage.13 All yields are for isolated products obtained after
3 steps. No attempt was made to optimise the cleavage reactions
and we conclude that the chemistry of pseudoephedrine resin 18
is relatively robust (Scheme 6).
Scheme 7 Reagents and conditions: (i) O-Me-glycine·HCl, t-BuOLi, THF,
rt; (ii) LHMDS, LiCl, THF, 0 ◦C, BnBr 0 C to rt; (iii) 2 M NaOH, dioxane,
H2O, THF, D; (iv) Boc2O, dioxane, H2O, 0 ◦C to rt.
previously reported pseudoephedrine resin in that it allows direct
access to enantiomerically enriched carboxylic acids in addition
to alcohols and ketones.
We acknowledge financial support from the EPSRC and Crystal
Faraday (A. M. M. and J.-C. K).
Notes and references
1 C. W. Y. Chung and P. H. Toy, Tetrahedron: Asymmetry, 2004, 15, 387.
2 (a) F. McKerlie, D. J. Procter and G. Wynne, Chem. Commun., 2002,
584; (b) L. A. McAllister, S. Brand, R. de Gentile and D. J. Procter,
Chem. Commun., 2003, 2380; (c) L. A. McAllister, R. A. McCormick,
S. Brand and D. J. Procter, Angew. Chem., Int. Ed., 2005, 44, 452;
(d) L. A. McAllister, K. L. Turner, S. Brand, M. Stefaniak and D. J.
Procter, J. Org. Chem., 2006, 71, 6497.
3 (a) N. J. Kerrigan, P. C. Hutchison, T. D. Heightman and D. J. Procter,
Chem. Commun., 2003, 1402; (b) N. J. Kerrigan, P. C. Hutchison, T. D.
Heightman and D. J. Procter, Org. Biomol. Chem., 2004, 2476.
4 (a) P. C. Hutchison, T. D. Heightman and D. J. Procter, Org. Lett.,
2002, 4, 4583; (b) P. C. Hutchison, T. D. Heightman and D. J. Procter,
J. Org. Chem., 2004, 69, 790.
Scheme 6 Reagents and conditions: (i) TMSCl, Et3N, THF then propionic
anhydride, THF, Et3N, rt or 3-cyclopentyl propionic acid and pivaloyl
chloride in MeCN and THF, then TBAF, THF; (ii) LDA, LiCl, THF
−78 ◦C to rt, BnBr, 0 ◦C to rt; (iii) LDA, BH3·NH3, THF, 0 ◦C to rt; (iv)
n-Bu4NOH, t-BuOH, H2O, THF, D; (v) 1-methylimidazole, n-BuLi, THF
−78 ◦C to rt then i-Pr2NH.
5 A thorough study by Davies et al. has highlighted early problems with
the synthesis of an immobilised oxazolidinone auxiliary: S. P. Bew, S. D.
Bull, S. G. Davies, E. D. Savory and D. J. Watkin, Tetrahedron, 2002,
58, 9387.
6 (a) A. G. Myers, B. H. Yang, H. Chen and J. L. Gleason, J. Am. Chem.
Soc., 1994, 116, 9361; (b) A. G. Myers, J. L. Gleason and T. Yoon,
J. Am. Chem. Soc., 1995, 117, 8488; (c) A. G. Myers and L. McKinstry,
J. Org. Chem., 1996, 61, 2428; (d) A. G. Myers, J. L. Gleason, T. Yoon
and D. W. Kung, J. Am. Chem. Soc., 1997, 119, 656; (e) A. G. Myers,
B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky and J. L. Gleason,
J. Am. Chem. Soc., 1997, 119, 6496; (f) A. G. Myers, P. Schnider, S.
Kwon and D. W. Kung, J. Org. Chem., 1999, 64, 3322.
7 For selected recent advances in the use of pseudoephedrine as a chiral
auxiliary, see: (a) J. L. Vicario, D. Bad´ıa and L. Carrillo, Org. Lett.,
2001, 3, 773; (b) J. L. Vicario, D. Bad´ıa and L. Carrillo, J. Org. Chem.,
2001, 66, 5801; (c) J. L. Vicario, D. Bad´ıa and L. Carrillo, J. Org.
Chem., 2001, 66, 9030; (d) M. Rodr´ıguez, J. L. Vicario, D. Bad´ıa and
L. Carrillo, Org. Biomol. Chem., 2005, 3, 2026; (e) J. Etxebarria, J. L.
Vicario, D. Bad´ıa, L. Carrillo and N. Ruiz, J. Org. Chem., 2005, 70,
8790; (f) E. Reyes, J. L. Vicario, L. Carrillo, D. Bad´ıa, U. Uria and A.
Iza, J. Org. Chem., 2006, 71, 7763.
8 Myers has shown that hydrolysis of pseudoephedrine amides proceeds
through N–O acyl transfer followed by ester hydrolysis (see ref. 6e).
9 N-Benzylpseudoephedrine amide 2 was prepared from norpseu-
doephedrine by N-benzoylation, LiAlH4 reduction and acylation (63%
overall).
As pseudoephedrine resin 18 appeared to show a good correla-
tion with Myers’ solution auxiliary chemistry, we completed our
study by assessing the utility of 18 for the solid phase synthesis
of a-amino acids employing Myers’ asymmetric alkylation of
pseudoephedrine glycinamide.6b,d,f Immobilised glycinamide 25
was prepared by treatment of resin 18 with glycine methyl
ester hydrochloride and triethylamine in THF.6f Unfortunately,
exposure of 25 to the conditions for alkylation, hydrolytic cleavage
with NaOH and Boc protection gave a 40% overall yield of N-Boc-
glycine and N-Boc phenylalanine in a disappointing 5 : 1 ratio
(Scheme 7). Attempts to improve the efficiency of the alkylation
step have so far been unsuccessful.
While the alkylation of dianion intermediates generated from
polymer-supported pseudoephedrine amides 19 proceeds satisfac-
torily, the efficient generation and alkylation of such intermediates
from immobilised pseudoephedrine glycinamide 25 is more diffi-
cult and represents the current limit for the adaptation of Myers’
chemistry to polystyrene supported derivatives. The use of other
supports may resolve this problem.14
10 CCDC reference number 632894. For crystallographic data in CIF
or other electronic format see DOI: 10.1039/b700477j Crystal data
In conclusion, we have developed a polymer-supported pseu-
doephedrine auxiliary linked to the support through nitrogen. The
auxiliary parallels Myers’ solution chemistry more closely than the
for 4. C26H29NO2, M = 387.50, orthorhombic, a = 8.4065(12), b =
9.6892(14), c = 26.482(4) A, U = 2157.0(5) A , T = 100(1) ◦C, space
3
˚
˚
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group P212121 (no. 19), Z = 4, l(MoKa)=0.074 mm−1, F(000) = 832,
11625 measured reflections, 2557 unique reflections (Rint = 0.0416).
Refinement was carried out on F2 using all the data. The final R1 =
0.0456 for the 2402 reflections with I > 2.00 r(I), wR2 = 0. 0.1144 for
all the data.
12 S. Kobayashi, I. Hachiya, S. Suzuki and M. Moriwaki, Tetrahedron
Lett., 1996, 37, 2809.
13 It is known that epimerisation can sometimes occur in the synthesis of
ketones from pseudoephedrine amides (Ref. 4 and 6e).
14 To investigate whether aggregation of the anionic species was an
issue, we prepared 18 from commercial, macroporous thiol resin.
Unfortunately, use of the rigid, highly cross-linked beads led to no
improvement in the alkylation of the pseudoephedrine glycinamide
intermediate.
11 Norpseudoephedrine hydrochloride was prepared by a modification
of a literature approach: B. Colman, S. E. de Sousa, P. O’Brien,
T. D. Towers and W. Watson, Tetrahedron: Asymmetry, 1999, 10,
4175.
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