Mono and sequential bis solid phase alkylations of a (R)-phenylglycinol derived pyrrolidinone scaffold

Article abstract of DOI:10.3987/com-01-9350

The preparation of piperidine- and pyrrolidinone-like polymer supported (R)-phenylglycinol derived scaffolds is described. Alkylation reactions were performed as a model transformation of these templates on the solid support which highlight some specific

Full text of DOI:10.3987/com-01-9350

HETEROCYCLES, Vol. 55, No. 12, 2001, pp. 2273 - 2278, Received, 27th September, 2001
MONO AND SEQUENTIAL BIS SOLID PHASE ALKYLATIONS OF A
(R)-PHENYLGLYCINOL DERIVED PYRROLIDINONE SCAFFOLD
Armand Blommaert, Philippe James, Fanny Valleix, Henri-Philippe Husson,
and Jacques Royer*
Laboratoire de Chimie Thérapeutique, UMR 8638 du CNRS associée à
l’Université René Descartes, 4 avenue de l’Observatoire, 75270 Paris cedex
06, France
Abstract - The preparation of piperidine- and pyrrolidinone-like polymer
supported (R)-phenylglycinol derived scaffolds is described. Alkylation
reactions were performed as a model transformation of these templates on the
solid support which highlight some specific limitations in the use of (R)-
phenylglycinol on the resin. Whereas the polymer supported piperidine was
completely void of reactivity, alkylation of the pyrrolidinone counterpart
proceeded with good yield, purity and control of mono- over bis-alkylation
but with low diastereomeric excess.
Substituted heterocyclic compounds which offer a high degree of structural and conformational diversity
provide a major target in medicinal chemistry because of their potential in the drug discovery process.
Whereas many heterocycles can be accessed by specifically biassed solid phase syntheses, the
development of a general solid phase methodology for the construction of a wide diversity of
compounds remains a challenging task.1
For many years we have developed a synthetic methodology enabling substitution at different positions
of various multifunctional ring systems using (R)-phenylglycinol as a source of both nitrogen and
chirality such as in compounds (1) and (2) (Figure).2-4
Thus far only few attempts of using chiral auxiliaries on the solid phase have been reported.5 We are
currently investigating the use of immobilized (R)-phenylglycinol or its enantiomer and in this

communication we wish to report some preliminary results in the preparation of polymer-supported (R)-
phenylglycinol derived scaffolds which were submitted to alkylation reactions as a model
transformation on the solid support.
OH
O
Nu
NC
Alkaloids
Amino Acids
Heterocycles
.......
O
Nu
N
Nu
N
E
Nu
E
Nu
E
E
1
E
2
Figure : (R)-phenylglycinol derived scaffolds showing high combinatorial potential.
The range of templates developed in our laboratory either completely or partially integrates (R)-
phenylglycinol. The hydroxyl group in compounds such as (2) is thus available for attachment to
polymers, whereas compounds such as (1) may be linked to polymers through a phenolic hydroxy group
using (R)-hydroxyphenylglycinol instead of (R)-phenylglycinol.
O
O
O
O
O
O
OH
O
OH
O
1) 5 eq. LDA
N
N
*
+
N
N
Wang resin
ref. 6 and 7
2) 20 eq. E1
20% TFA
CH2Cl2
*
THF, -78 °C
R1
3
4
R1
5-9
1) 5 eq. LDA
O
+
2) 20 eq. E2
THF, -78 °C
5: R1 = CH3CH2CH2-
6: R1 = CH2=CHCH2-
7: R1 = PhCH2-
8: R1 = BrCH2(CH2)3-
9: R1 = (CH3)3CHOH-
OH
O
O
O
20% TFA
CH2Cl2
N
N
*
R1 = PhCH2-
R2 = CH3-
10:
*
R1
R1
R2
R2
Scheme 1 : Preparation and alkylation of resin-supported pyrrolidinone (4).
The preparation of a suitable resin-supported (R)-phenylglycinol derived pyrrolidine scaffold is shown
in Scheme 1. Compound (3) was easily obtained from (R)-phenylglycinol as previously described by our

group4 and subsequent loading of Wang resin (0.58 mmol/g) was accomplished through polymer
activation with trichloroacetonitrile following a protocole as reported by Hanessian6 and Eda.7 The
substitution-level of the resin was estimated through acidic cleavage and calculated to be 0.52 mmol/g
(90%). In order to test the reactivity of the polymer-bound auxiliary (4) different alkylation conditions
were examined. After some experimentation it was found of the utmost importance to conduct the
alkylation reactions at –78 °C because room temperature addition of first the halogen derivative to the
resin-supported scaffold and then the base, only gave undesired elimation products which were either
mono- or bis-alkylated depending upon the excess of base used (Scheme 2).
O
O
1) 20 eq. n-C3H7I
2) 2.5 eq. LDA
H
N
O
N
O
B
THF, rt
4
Scheme 2 : Undesired elimination from the resin under room temperature alkylation conditions.
Deprotonation was therefore effected (Scheme 1) in THF at –78 °C with LDA (5 eq.) for 10 min
followed by treatment with various electrophiles (20 eq.) for 20 min, the suspension was then collected
on a glass filter and washed. The resin was either directly cleaved using 20% trifluoroacetic acid in
CH2Cl2 or submitted to a second alkylation cycle with subsequent cleavage. The results are summarized
in the Table. It is noteworthy that only monoalkylation (compounds (5-9)) occurred regardless of the
excess of reagents (base and electrophiles) used. This allowed the sequential bis-alkylation leading to a
chiral quaternary center next to the carbonyl-group in good yield but with moderate selectivity
(compound (10)).
The diastereomeric excess was determined by HPLC analysis of the crude reaction mixture obtained
after cleavage from the resin. The diastereomeric selectivities of the alkylation on the resin proved to be
low as compared to classical « liquid phase » alkylation conditions of 3, generally in the range of 80 -
90 %.4 It should be noticed that no isomerization was observed under the acidic cleavage conditions for
the optically pure derivatives obtained by solution phase chemistry.4

producta
configurationd
electrophile
(E1+/E2+)
yield
(%)b
71
d.e.
(%)c
12
5
6
7
n-C3H7I
CH2=CH-CH2Br
PhCH2Br
90
75
24
16
R (major)
S (minor)
8
9
Br(CH2)4Br
(CH3)3CCHO
78
92
22
e
-
10
72
46
PhCH2Br / CH3I
Table: Data concerning the alkylation of compound (4) with various electrophiles.
1
13
(a) All products were characterized by H and C NMR spectroscopy after separation of diastereomers by chromatographic
means. (b) Isolated yield. (c) Determined by analytical HPLC on the crude cleavage mixture using a C8 Kromasil column
with 0.05% TFA in H2O and CH3CN as eluent. (d) See text for details. (e) NMR analysis showed equimolar presence of
diastereoisomers which proved unseparable by chromatographic means.
The configuration of the newly created asymmetric centre was assigned for both diastereomers of
compound (7) by comparison of HPLC and NMR data with a reference compound of known 1’-R,3-S
configuration.4 Interestingly, the RS-configuration was as such attributed to the minor isomer of
compound (7) indicating a priviliged attack on the opposite site as compared to solution phase
conditions.4 Indeed, high diastereoselectivities in solution phase were explained by rigidifying the
structure through chelation of lithium and induction of alkylation on the less hindered face, opposite the
phenyl group. Such chelation might be difficult on the resin due to the bulk and proximity (site
attachment) of the polymer. As d.e. on the resin was rather low we decided to enhance the steric
hindrance by attaching the auxiliary (3) to a trityl resin8 and tempting alkylation at –78 °C or at room
temperature. All efforts to alkylate were unsuccessful as we recovered only starting material after
cleavage from the resin. Interestingly, no elimination was observed at room temperature, illustrating the
importance of the bulk of the trityl-polymer as compared to the Wang resin.
The preparation of the resin supported (R)-4-hydroxy phenylglycinol derived oxazolopiperidine
auxiliary (14) is depicted in Scheme 3. Compound (12) was first obtained from conveniently protected
(R)-hydroxyphenylglycine followed by reduction of the ester group using sodium borohydride in ethanol
and removal of the Boc-group. The resulting alcohol was subsequently condensed with glutaraldehyde
and KCN following a procedure as reported by our group9 yielding a major crystalline product (13)10
which configuration was assumed to correspond with its non-hydroxylated analogue (1) (Figure).2

HO
OH
OH
glutaraldehyde
KCN
NaBH4 TFA
EtOH CH2Cl2
H2O, pH = 3
69%
O
O
NC
N
62%
80%
BocHN
COOCH3
H2N
CH2OH
Br
13
11
12
NaH / THF
60 °C, 12 h
70%
HO
O
5 eq. LDA / THF
20 eq. n-C3H7I
O
Cleavage
NC
N
O
NC
N
-78 °C or rt
O
14
Scheme 3 : Preparation of (R)-4-hydroxyphenylglycinol derived oxazolopiperidine scaffold (14).
Compound (13) was conveniently linked to the polymer through nucleophilic displacement of bromo-
derived Wang resin11 in 70 % yield. Unfortunately all attempts of alkylation were unsuccessful and
resulted only in recovery of the starting material after cleavage from the resin. This complete lack of
reactivity might be explained as compared to the pyrrolidinone analogue by a marked difference in
accessibility of the reaction site when attached to the resin. Indeed, when associated to the bulk of the
polymer backbone the oxazolopiperidine auxiliary with its rigid bicyclic structure can present a strongly
reduced mobility and limit accessibility for deprotonation and alkylation. The pyrrolidinone analogue is
clearly more flexible as protons are accessible for deprotonation as shown by the preparation of
compounds (5-10) (Table).
In summary, we have demonstrated that not only the bulk and site attachment of the resin but also the
rigidity of the scaffold strongly influences reactivity of the polymer supported structures. Albeit
associated with low diastereoisomeric excess, mono- and bis-alkylations of the polymer supported
pyrrolidinone auxiliary (4) were performed with good yield and purity. By analogy with liquid phase
conditions, the presence of a free hydroxy group might permit a better control of the diastereoselectivity
in alkylation reactions with LDA through chelation with lithium.4 We are therefore considering the
preparation of a related (R)-hydroxyphenylglycinol linked auxiliary with adequate potential for
structural diversity.

ACKNOWLEDGEMENTS
We are grateful to Dr Q.E. Broxterman (DSM research) for the generous gift of (R)-
hydroxyphenylglycine.
REFERENCES AND NOTES
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Soc. Rev., 1999, 28, 383.
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J. Royer and B. Dudot, Acros Organics Acta, 2000, 7, 5 (and references therein).
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20
10.
Rf (5% MeOH in CH2Cl2) = 0.40 ; [α]D –245 °ß(c=1 ; MeOH) ; 1H NMR (300 MHz, CDCl3) δ
7.25 (2H, d, J = 8 Hz), 6.75 (2H, d, J = 8 Hz), 5.00 (1H, br s), 4.15 (1H, t, J = 6 Hz), 4.05 (1H, dd,
J = 2 and 7 Hz), 3.70 (2H, m), 3.60 (1H, t, J = 6 Hz), 1.40-2.10 (6H, m). ; 13C NMR (75 MHz,
CDCl3) δ 156.1, 129.3, 128.4, 115.8, 89.7, 72.8, 63.3, 47.2, 29.9, 27.8, 19.3 ; MS calcd for
C14H16N2O2 : 244.3 ; obtained 245.
11.
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