Resin type can have important effects on solid phase asymmetric alkylation reactions

Article abstract of DOI:10.1039/a608524e

A new N-propionylated oxazolidinone 1 is prepared; asymmetric alkylations of this auxiliary proceed with varying yields and enantioselectivities when supported on Merrifield, Wang and TentaGel R PHB resins.

Full text of DOI:10.1039/a608524e

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Resin type can have important effects on solid phase asymmetric alkylation
reactions
Kevin Burgess* and Dongyeol Lim
Department of Chemistry, Texas A & M University, College Station, TX 77843-3255, USA
A new N-propionylated oxazolidinone 1 is prepared; asym-
metric alkylations of this auxiliary proceed with varying
yields and enantioselectivities when supported on Merri-
field, Wang and TentaGel R PHB resins.
used (3 equiv. of 1, EtO2CNNCO2Et, PPh3, 20 h).11–13
Loadings of the auxiliary on the resins were difficult to
determine accurately; after some experimentation, the follow-
ing method was developed. The functionalized resins were
reacted with lithium benzyloxide, and the benzyl propionate
produced was quantified using HPLC and NMR. On the basis of
these measurements it was calculated that approximately 30%
of the available reactive sites on the Merrifield resin were
coupled with the auxiliary under the conditions described
above. For the Wang and TentaGel resins the corresponding
loadings were 56 and 60% respectively.
Techniques for solid phase organic syntheses1 are pivotal for the
development of combinatorial methods and other approaches to
high throughput syntheses.2–4 Asymmetric reactions on a solid
phase have not been widely explored so far, yet they have
potential advantages for some applications.5 Supported chiral
auxiliaries, for instance, can be recovered by filtration, and
could potentially be recycled.
Two issues that need to be addressed for syntheses and
applications of supported chiral auxiliaries are, first, how the
auxiliary will be linked to the solid phase and, second, which
solid phase will be used. At least two approaches to these
problems have been reported. Leznoff initiated this area of
research in studies wherein chiral amines were O-linked to
Merrifield resin; condensations of these supported amines with
cyclohexanone gave imines which were then deprotonated and
C-methylated with high stereoselectivities.6 More recently,
Kurth and co-workers have attached pyrrolidine-based auxilia-
ries to Merrifield resin and used them in allylation/iodolactoni-
zation sequences.7–9 Neither of these studies, however, em-
braced auxiliaries that are widely used in contemporary organic
syntheses, and some of the supports that are now favoured for
solid phase reactions. Here we describe an oxazolidinone 1 that
can be conveniently linked to polymeric materials, and
demonstrate that the choice of resin is important with respect to
applications of the supported-auxiliary.
Synthesis of the oxazolidinone 1 began with commercially
available Boc-Tyr(Bn) which was easily reduced to the
corresponding alcohol 2 (PriOCOCl, NEt3, THF, then NaBH4,
H2O). Removal of the N-protecting group and reaction with
phosgene gave oxazolidinone 3 (Scheme 1). This material was
then N-propionylated and subjected to hydrogenolysis to give
the desired auxiliary 1.
One of the attractive features of oxazolidinone 1 is that the
phenolic hydroxy group is available for attachment to polymers.
For Merrifield’s resin this was accomplished via nucleophilic
displacement of the benzylic chloride (3 equiv. of 1, ButOK,
catalytic 18-crown-6/Bu4NI, DMF, 75 °C, 3.5 d).9 However, for
the Wang and TentaGel resins Mitsunobu couplings10 were
Deprotonation of the supported oxazolidinones 4 with LDA
in THF then reaction with benzyl bromide was chosen as a
model transformation. These reactions were followed by IR
(KBr disc). With Wang resin for instance, the supported
oxazolidinones 4 had carbonyl stretches at 1704 and 1785
cm21. Benzylation of this material shifted the IR bands to 1701
and 1778 cm21. Hydrolytic cleavage of the benzylated
propionate produced resin with a single carbonyl stretch at 1743
cm21, corresponding to the supported auxiliary. IR spectra of
similar, but unsupported, auxiliaries have carbonyl stretches at
ca. 1752 cm21
.
A series of preliminary reactions showed the number of
equivalents of base and the reaction times had a significant
effect on the enantiomeric excess. It was also observed that
reactions on the TentaGel resin were faster than on the
Merrifield and Wang supports. Consequently, a series of
experiments were performed in which 3 equiv. of LDA were
added to the heterogeneous auxiliary at 0 °C. For the Merrifield
and Wang resins, benzyl bromide was added after 30 min,
allowed to react at 0 °C for 30 min, then for a systematically
varied time at 25 °C. For the TentaGel based system, benzyl
bromide was added after 20 min, and allowed to react for
various times at 0 °C. The results of these studies are
summarized in Fig. 1.
Fig. 1 shows that the yield of alcohol 5 reaches a maximum
in the initial stages of the reaction, then decreases. For the
TentaGel resin, the maximum yield is observed at short reaction
times and decreases more precipitously as the reaction time is
extended than for either the Merrifield or the Wang resins.
Throughout, the HPLC traces of the material cleaved from the
support show only one UV active product, hence the reduction
in the yield is not due to formation of supported impurities with
UV chromophores. Decreased yields could, however, be due to
O
O
O
O
O
NHBoc
O
NH
O
N
HO
i, LDA (3 equiv.), 0 °C
HO
O
O
N
i, ii
iii, iv
ii, BnBr (5 equiv.)
iii, LiBH4, 25 °C
Ph
(quantified by HPLC)
5
OBn
BnO
HO
2
3
1
Scheme 1 Reagents and conditions: i, HCl, Et2O–EtOAc, 25 °C, 15 h
(93%); ii, COCl2, KOH–K2CO3 (aq), MePh, 0–25 °C, 12 h (98%); iii,
(EtCO)2O, LiCl, NEt3, THF, 278–25 °C, 18 h (93%); iv, H2, cat. Pd–C,
MeOH–EtOAc, 25 °C, 12 h (96%)
4a Merrifield
b Wang
c TentaGel
Chem. Commun., 1997
785

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(c)
(a)
(b)
t / min
t / min
t / min
Fig. 1 Percent yield (relative to the maximum for that reaction (/) and enantiomeric excess (2) profiles for benzylation of the supported auxiliary 4 on (a)
Merrifield, (b) Wang and (c) Tentagel R PHB resins. For conditions, see text.
resin.15 One alkylation reaction of this material was described
(2 equiv. LDA, THF, 0 °C, then 2 equiv. BnBr; deprotonation
Table 1 Asymmetric alkylation reactions of the Wang-supported ox-
azolidinone 4b
and alkylation time unspecified), and that benzylation product
(isolated as the acid) had an enantiomeric excess of 96%. We
Reaction conditions
would have anticipated that the structural differences between
auxiliaries 6 and 4 would be such that the tyrosine derivative 4
would give higher diastereoselectivities. In fact, 4 on Merrifield
resin in our study gave stereoselectivities that are markedly
inferior to those reported for 6 on the same resin, a result that we
find surprising.
Overall, we conclude that optimization of these solid phase
alkylation reactions is more difficult than for the corresponding
solution phase reactions; the support has a marked effect and
different resins may be most suitable for different ox-
azolidinones and electrophiles. Generally, solid phase reactions
are more difficult to study than transformations in solution
because they are more difficult to monitor. In addition, this
work shows that resin type can be a significant variable that can
further complicate the process of optimization.
We thank Dr Aroonsiri Shitangkoon for help with the chiral
chromatography. Financial support for this research was
obtained from The National Institutes of Health and The Robert
A. Welch Foundation, and K. B. thanks the NIH for a Research
Career Development Award and the Alfred P. Sloan Foundation
for a fellowship. NMR facilities were provided by the NSF via
the chemical instrumentation programme.
Alkylating
agent
Equiv.
LDA
Time/h
at 0 °C
Time/h
at 25 °C
Yielda Eeb
(%)
(%)
BnBr
BnBr
CH2CHCH2Br
CH2CHCH2Br
BnOCH2Cl
BnOCH2Cl
3
2
3
2
3
2
0.5
1.0
0.5
2.0
0.5
2.5
0.33
12
0.33
15
0.33
14
66
39
25
—
12
20
90
86
81c
88
71d
76d
a For the alkylation and cleavage steps combined, determined by analytical
HPLC using phenylpropanol as an internal standard. Authentic racemic
1
products were prepared by solution phase syntheses and identified by H
and 13C NMR spectroscopy. Determined by analytical HPLC using a
b
ChiralCel OD column. c Yields and ees were determined by using a chiral
d
GC column prepared ‘in house’. Errors were relatively high because
HPLC resolution of the enantiomers on a ChiralCel OD did not give
baseline separation.
O
O
O
N
O
References
6
1 L. A. Thompson and J. A. Ellman, Chem. Rev., 1996, 96, 555.
2 M. A. Gallop, R. W. Barrett, W. J. Dower, S. P. A. Fodor and
E. M. Gordon, J. Med. Chem., 1994, 37, 1233.
3 E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor and
M. A. Gallop, J. Med. Chem., 1994, 37, 1385.
4 N. K. Terrett, M. Gardner, D. W. Gordon, R. J. Kobylecki and J. Steele,
Tetrahedron, 1995, 51, 8135.
5 M. Reggelin and V. Brenig, Tetrahedron Lett., 1996, 37, 6851.
6 C. R. McArthur, P. M. Worster, J.-L. Jiang and C. C. Leznoff, Can.
J. Chem., 1982, 60, 1836.
7 X. Beebe, N. E. Schore and M. J. Kurth, J. Am. Chem. Soc., 1992, 114,
10061.
8 H.-S. Moon, N. E. Schore and M. J. Kurth, Tetrahedron Lett., 1994, 35,
8915.
9 H.-S. Moon, N. E. Schore and M. J. Kurth, J. Org. Chem., 1992, 57,
6088.
10 D. L. Hughes, Org. React., 1992, 42, 335.
loss of the propionyl group from the oxazolidinone prior to
cleavage.14 Consistent with this, the IR stretch for the supported
amide at 1701 cm21 diminishes with reaction time. Throughout,
the measured enantiomeric excesses of the product 5 vary by
±3%; this fluctuation is probably within experimental error.
However, in other experiments it was observed that after longer
reaction times the enantiomeric excess of the product decreases
measurably.
Overall, the data in Fig. 1 indicate that in terms of yield,
enantiomeric excess and preservation of yield after extended
reaction times, Wang resin is the preferred support. It is also
cheaper than TentaGel resin, and has a higher loading capacity.
Several more reactions were therefore performed using Wang
resin and the results are summarized in Table 1. Yields and
enantiomeric excesses obtained for benzyl bromide were
superior to those obtained with other electrophiles. However,
the results for these other electrophiles probably could be
improved via optimization studies of the type carried out for the
benzylation reactions.
11 L. S. Richter and T. R. Gadek, Tetrahedron Lett., 1994, 35, 4705.
12 T. A. Rano and K. T. Chapman, Tetrahedron Lett., 1995, 36, 3789.
13 V. Krchnak, Z. Flegelova, A. S. Weichsel and M. Lebl, Tetrahedron
Lett., 1995, 36, 6193.
14 D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982,
104, 1737.
After this work was complete, but before these studies were
submitted for publication, other researchers reported the
preparation of an oxazolidinone 6, supported on Merrifield
15 S. M. Allin and S. J. Shuttleworth, Tetrahedron Lett., 1996, 37, 8023.
Received, 19th December 1996; Com. 6/08524E
786
Chem. Commun., 1997