Polymer-aided stereodivergent synthesis (PASS): A new concept for the discrete preparation of optical antipodes

Article abstract of DOI:10.1021/ol015723h

A new concept to the discrete prepartion of optical antipodes is reported. The approach makes use of a cyclization/cleavage procedure that has been applied to polymer-supported quasi-meso compound 1, containing a polymeric leaving group and a regular leaving group. Two-directional cyclization leads to the formation and separation of quasi-enantiomers 2 and 3 simultaneously, with one being immobilized and on free in solution. Treatment of 2 and 3 with appropriate nucleophiles gives discrete enantiomers 4 and 5.

Full text of DOI:10.1021/ol015723h

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1093-1095
Polymer-Aided Stereodivergent
Synthesis (PASS): A New Concept for
the Discrete Preparation of Optical
Antipodes
Peter ten Holte, Lambertus Thijs, and Binne Zwanenburg*
Department of Organic Chemistry, NSR Institute for Molecular Structure, Design and
Synthesis, UniVersity of Nijmegen, ToernooiVeld, 6525 ED Nijmegen, The Netherlands
zwanenb@sci.kun.nl.
Received February 19, 2001
ABSTRACT
A new concept for the discrete preparation of optical antipodes is reported. The approach makes use of a cyclization/cleavage procedure that
has been applied to polymer-supported quasi-meso compound 1, containing a polymeric leaving group and a regular leaving group. Two-
directional cyclization leads to the formation and separation of quasi-enantiomers 2 and 3 simultaneously, with one being immobilized and
one free in solution. Treatment of 2 and 3 with appropriate nucleophiles gives discrete enantiomers 4 and 5.
The separation of enantiomeric species has been a challenge
for chemists ever since Pasteur performed his “crystal
picking” experiment in 1848.1 Nowadays, it is becoming ever
more important to be able to control the stereochemistry of
chiral compounds, for example, in current drug research,
where contamination of a sample with an undesired enan-
tiomer can lead to fatal incidents. Many different ap-
proaches have been developed to ensure defined chirality
of the products prepared. For instance, asymmetric syn-
theses using synthetic2 or enzymatic2a,3 catalysts as well as
numerous resolution methods2a,e-f,3,4 have proved to be
successful in providing enantiomerically pure target mol-
ecules.
In this paper, we report on a new concept that allows
the discrete preparation of both quasi-enantiomers5 of a
chiral substance by making use of a polymeric support.
The intention is to “racemize” a polymer-supported enan-
tiopure compound, such as 1 (Scheme 1), by performing
a two-directional cyclization reaction that leaves one
quasi-enantiomer bound to the resin (2, route a) while
the other one is in solution (3, route b), as illustrated in
Scheme 1.
(1) (a) Pasteur, L. Ann. Chim. Phys. 1848, 24, 442. (b) Pasteur, L. Hebd.
Seances Acad. Sci. 1853, 37, 162.
(2) (a) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284. (b) Senkan,
S. Angew. Chem., Int. Ed. 2001, 40, 312. (c) Soai, K.; Shibata, T.; Sato, I.
Acc. Chem. Res. 2000, 33, 382. (d) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Matsukawa, S. Acc. Chem. Res. 2000, 33, 391. (e)
Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1995, 34, 1059. (f) Brown, J. M. Chem. Soc. ReV. 1993, 22, 25. (g) Soai,
K.; Niwa, S. Chem. ReV. 1992, 92, 833.
(3) (a) Bakke, M.; Takizawa, M.; Sugai, T.; Ohta, H. J. Org. Chem.
1998, 63, 6929. (b) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi,
A. Chem. ReV. 1992, 92, 1071.
(4) (a) Vries, T.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.;
Kellogg, R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der
Sluis, S.; Hulshof, L.; Kooistra, J. Angew. Chem., Int. Ed. 1998, 37, 2349.
(b) Vannieuwenhze, M. S.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
7864.
(5) According to the 1996 IUPAC recommendations, quasi-enantiomers
are defined as “constitutionally different yet closely related chemical species
MX and MY having the opposite chirality sense of the large common chiral
moiety, M.”
10.1021/ol015723h CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001

To prepare a substrate that is suitable for PASS, i.e.,
conceptually according to system 1 (Scheme 1), we replaced
the 1,2-diol starting material by an enantiopure glycerol
derivative. Thus, (S)-(+)-solketal (Scheme 3) was reacted
Scheme 1
Scheme 3
System 1 consists of a central stereogenic carbon atom
that has a nucleophilic group attached to it via a spacer and
is flanked by two leaving groups that are connected to the
chiral center by methylene units. The system is “quasi-meso”
since one of the (technically identical) leaving groups is, in
contrast to the other, bound to a polymeric backbone. An
intramolecular nucleophilic cyclization can either substitute
the polymeric leaving group or the nonpolymeric leaving
group, resulting in a detached and a polymer-bound product,
respectively. The quasi-enantiomeric products can be sepa-
rated by filtration and converted into enantiomers by suc-
cessive substitution of the unaffected leaving group. We have
termed this approach polymer-aided stereodivergent synthesis
(PASS). Thus, PASS allows the discrete preparation of quasi-
enantiomers from enantiopure starting material in one step
and gives access to the enantiomers by further functional-
ization.
with p-toluenesulfonyl chloride, and the arenesulfonate
obtained was deketalized with trifluoroacetic acid in water.
The resulting optically pure 1,2-diol 67,8 was selectively
attached with its primary alcohol function to polymer-bound
arenesulfonyl chloride9 and, subsequently, the secondary
alcohol was converted into a carbamate by reaction with
phenyl isocyanate to give quasi-meso system 7 with the
S-configuration (Scheme 3).
Quasi-meso system 7 was then treated with DBN (2 equiv)
in dichloromethane to induce the cyclo-elimination reaction.
Cyclization route a provided polymer-bound oxazolidinone
8, while elimination via route b gave quasi-enantiomeric
oxazolidinone 9 in solution (Scheme 4).
The strategy utilized to put the concept of PASS into
practice is based on our earlier work on the application of
immobilized arenesulfonate esters in the synthesis of a series
of 3,5-disubstituted 1,3-oxazolidin-2-ones by means of solid-
phase/activation cyclo-elimination (SP/ACE) methodology.6
This approach employs 1,2-diols as the starting material and
gives rise to a system that allows intramolecular cyclo-
elimination in the last step of the synthetic sequence, yielding
detached oxazolidinones of high purity as the cleavage
products (Scheme 2).
Along with the tosylate-substituted oxazolidininone 9, a
considerable amount of chloride-substituted oxazolidinone
12 (Nu ) Cl) was also obtained via route b (ratio 9/12 )
1/2, according to GC-MS analysis). Substitution of the
tosylate with chloride probably had already occurred during
the coupling reaction of the glycerol derivative 6 with the
polymeric support whereby triethylammonium chloride is
formed. There was no need to separate the chloride analogue
12 from oxazolidinone 9 because, where appropriate, both
the tosylate and chloride leaving groups are readily substi-
(6) ten Holte, P.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1998, 39,
7407.
(7) Compound 6: mp 57-59 °C; [R]20 ) -9.5° (c ) 5.5, methanol);
Scheme 2
D
1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H, CH3), 3.55 (dd, 1H, part of
ABX, JAB ) 11.6 Hz, JBX ) 5.8 Hz), 3.64 (dd, 1H, part of ABX, JAB
)
11.6 Hz, JAX ) 3.8 Hz), 3.74 (bs, 2H), 3.93 (m, 1H), 4.03 (m, 2H), 7.34
(d, 2H, J ) 8.2 Hz), 7.78 (d, 2H, J ) 8.3 Hz) ppm. Melting point and
spectral data are in agreement with those reported: Baldwin, J. J.; Raab,
A. W.; Mensler, K.; Arison, B. H.; McClure, D. E. J. Org. Chem. 1978,
43, 4876.
(8) Unreacted 1,2-diol 6 was readily recovered by filtration and
subsequent flash column chromatographic purification (ethyl acetate/hexane
) 1/1, v/v, 250 mL followed by ethyl acetate) of the concentrated filtrate.
(9) PS-TsCl, 1.34 mequiv/g, Argonaut Technologies Inc.
1094
Org. Lett., Vol. 3, No. 7, 2001

equiv, based on maximum theoretical loading) in DMF to
give enantiomers 10 and 12. Oxazolidinone 12 thus obtained
is optically pure by chiral HPLC (Chiralcel OD, ee ) 100%),
with an optical rotation of -68° (c ) 0.33, ethanol), whereas
crude product 10 was formed in an ee of 95% (Chiralcel
OD, hexane/isopropyl alcohol ) 80/20). Crystallization of
10 (ethanol) gave the optically pure enantiomer with an
optical rotation of +68° (c ) 0.34, ethanol). Another
nucleophile that was examined was azide. Thus, the azide-
substituted optical antipodes 1112 and 1313,14 were prepared
by reaction of quasi-enantiomers 8 and 9 (+ compound 12)
with sodium azide (3 and 10 equiv, respectively) producing
enantiomer 13 in optically pure form directly (Chiralcel OD,
Scheme 4
ee ) 100%, [R]20 ) -160°, c ) 0.30, ethanol) and
D
enantiomer 11 in 96% ee (Chiralcel OD, hexane/isopropyl
alcohol ) 80/20). Crystallization of 11 furnished optically
pure product ([R]20 ) +166°, c ) 0.30, ethanol).
D
It is worth noting that the reactions of the nucleophiles
with tosylate 9 and chloride 12 in solution do not lead to
racemized products, whereas the products that arise from
polymer-supported tosylate 8 seem to have racemized
slightly.
In conclusion, we have successfully applied the new
concept of polymer-aided stereodiVergent synthesis (PASS)
in the discrete formation of antipodal oxazolidinones.
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 6 and 7 and for
the cyclization of 7 to give the quasi-enantiomeric species 8
and 9. General procedure for the conversion of quasi-
enantiomer 8 into the corresponding enantiomers 10 and 11.
Procedure for the conversion of the mixture of quasi-
enantiomer 9 and compound 12 into enantiomers 12 and 13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
tuted in the subsequent reaction. As the formation of
oxazolidinone 12 had taken place spontaneously, chloride
was the logical nucleophile of choice in the reaction of 8
and 9 in order to prepare optical antipodes 1010 and 12,11
respectively. Thus, polymer-bound oxazolidinone 8 and its
quasi-enantiomer 9 were treated with lithium chloride (8
OL015723H
(12) Compound 11: mp 75-77 °C; 1H NMR (CDCl3, 300 MHz) δ 3.60
(dd, part of ABX, JAB ) 13.2 Hz, JBX ) 4.5 Hz, 1H), 3.70 (dd, part of
(10) Compound 10: mp 132 °C; 1H NMR (CDCl3, 300 MHz) δ 3.75
(dd, part of ABX, JAB ) 11.6 Hz, JBX ) 6.6 Hz, 1H), 3.80 (dd, part of
ABX, JAB ) 13.2 Hz, JAX ) 4.7 Hz, 1H), 3.88 (dd, part of ABX, JAB
)
ABX, JAB ) 11.6 Hz, JAX ) 4.2 Hz, 1H), 3.97 (dd, part of ABX, JAB
)
9.0 Hz, JBX ) 6.2 Hz, 1H), 4.11 (t, part of ABX, JAB ) JAX ) 9.0 Hz,
1H), 4.79 (m, part of ABX, 1H), 7.16 (t, J ) 7.4 Hz, 1H), 7.39 (t, J ) 8.0
Hz, 2H), 7.54 (d, J ) 7.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
47.44, 53.03, 70.54, 118.27, 124.34, 129.13, 137.83, 153.90 ppm.
9.2 Hz, JBX ) 5.7 Hz, 1H), 4.18 (t, part of ABX, JAB ) JAX ) 9.0 Hz,
1H), 4.88 (m, part of ABX, 1H), 7.16 (t, J ) 7.4 Hz, 1H), 7.39 (t, J ) 8.0
Hz, 2H), 7.55 (d, J ) 8.1 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
44.47, 48.15, 70.80, 118.31, 124.38, 129.13, 137.76, 153.87.
1
(13) Compound 13: mp 76-78 °C; H NMR is identical to that of 11.
(11) Compound 12: mp 132 °C; 1H NMR (CDCl3, 300 MHz) δ 3.74
(dd, part of ABX, JAB ) 11.6 Hz, JBX ) 6.5 Hz, 1H), 3.80 (dd, part of
13C NMR (CDCl3, 75 MHz): δ 47.44, 53.04, 70.54, 118.28, 124.35, 129.14,
137.84, 153.93 ppm.
ABX, JAB ) 11.6 Hz, JAX ) 4.2 Hz, 1H), 3.97 (dd, part of ABX, JAB
)
(14) Optical rotation, 1H NMR, and melting point of 13 are in agreement
with those reported: Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.;
Wuonola, M. A.; McRipley, R. J.; Eustice, D. C.; Eberly, V. S.;
Barthohomew, P. T.; Slee, A. M.; Forbes, M. J. Med. Chem. 1989, 32,
1673.
9.2 Hz, JBX ) 5.7 Hz, 1H), 4.18 (t, part of ABX, JAB ) JAX ) 9.0 Hz,
1H), 4.87 (m, part of ABX, 1H), 7.16 (t, J ) 7.4 Hz, 1H), 7.39 (t, J ) 8.0
Hz, 2H), 7.55 (d, J ) 7.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
44.48, 48.15, 70.80, 118.32, 124.39, 129.13, 137.76, 153.86 ppm.
Org. Lett., Vol. 3, No. 7, 2001
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