Parallel kinetic resolution of racemic aldehydes by use of asymmetric Horner-Wadsworth-Emmons reactions

Article abstract of DOI:10.1021/ol991387h

(Formula presented) A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.

Full text of DOI:10.1021/ol991387h

ORGANIC
LETTERS
2000
Vol. 2, No. 4
535-538
Parallel Kinetic Resolution of Racemic
Aldehydes by Use of Asymmetric
Horner−Wadsworth−Emmons Reactions
,†
Torben M. Pedersen,† Jakob F. Jensen,† Rikke E. Humble,† Tobias Rein,*
,§
David Tanner,† Kerstin Bodmann,§ and Oliver Reiser*
Department of Organic Chemistry, Technical UniVersity of Denmark,
KemitorVet, DK-2800 Kgs Lyngby, Denmark, and Institut fu¨r Organische Chemie,
UniVersita¨t Regensburg, D-93053 Regensburg, Germany
oktr@pop.dtu.dk
Received December 23, 1999
ABSTRACT
A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing
either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.e., one (E)- and one (Z)-selective reagent). This
strategy allows conversion of a racemic aldehyde to two different, synthetically useful chiral products with essentially doubled material throughput
and similar or improved selectivities as compared to conventional kinetic resolution.
Development of new methodology for asymmetric synthesis
is presently an area of great importance in organic chemistry,
and in this context kinetic resolution1 has proved to be a
useful strategy. However, the major drawback with this
approach is that a maximum of only half of the racemic
starting material is converted into nonracemic product. To
make the process truly efficient with respect to material
throughput, it would thus be required that both the unreacted
starting enantiomer and the product are obtained in high
isomeric purity and furthermore that they both are of use
for the particular application at hand. Parallel kinetic
resolution (PKR), an interesting strategy by which both
enantiomers of a racemate can be converted to useful
products via simultaneous reaction with two different chiral
reagents, was recently introduced by Vedejs and Chen.2
Asymmetric Wittig-type reactions have previously been
studied by several groups including ours,3 and in previous
work, we have shown that racemic, R-substituted aldehydes
are good substrates for asymmetric Horner-Wadsworth-
Emmons (HWE) reactions.4 We have demonstrated that
R-amino aldehydes can even undergo dynamic kinetic
(3) For a review, see: (a) Rein, T.; Reiser, O. Acta Chem. Scand. 1996,
50, 369. Selected recent examples: (b) Abiko, A.; Masamune, S. Tetra-
hedron Lett. 1996, 37, 1077. (c) Kumamoto, T.; Koga, K. Chem. Pharm.
Bull. 1997, 45, 753. (d) Dai, W.-M.; Wu, J.; Huang, X. Tetrahedron:
Asymmetry 1997, 8, 1979. (e) Mizuno, M.; Fujii, K.; Tomioka, K. Angew.
Chem. 1998, 110, 525; Angew. Chem., Int. Ed. Engl. 1998, 37, 515. (f)
Vaulont, I.; Gais, H.-J.; Reuter, N.; Schmitz, E.; Ossenkamp, R. K. L. Eur.
J. Org. Chem. 1998, 805. (g) Tullis, J. S.; Vares, L.; Kann, N.; Norrby,
P.-O.; Rein, T. J. Org. Chem. 1998, 63, 8284. (h) Arai, S.; Hamaguchi, S.;
Shioiri, T. Tetrahedron Lett. 1998, 39, 2997. (i) Tanaka, K.; Watanabe, T.;
Shimamoto, K.-Y.; Sahakitpichan, P.; Fuji, K. Tetrahedron Lett. 1999, 40,
6599.
(4) (a) Rein, T.; Kann, N.; Kreuder, R.; Gangloff, B.; Reiser, O. Angew.
Chem. 1994, 106, 597; Angew. Chem. Int., Ed. Engl. 1994, 33, 556. (b)
Rein, T.; Kreuder, R.; von Zezschwitz, P.; Wulff, C.; Reiser, O. Angew.
Chem. 1995, 107, 1099; Angew. Chem., Int. Ed. Engl. 1995, 34, 1023. (c)
Rein, T.; Anvelt, J.; Soone, A.; Kreuder, R.; Wulff, C.; Reiser, O.
Tetrahedron Lett. 1995, 36, 2303. (d) Mendlik, M. T.; Cottard, M.; Rein,
T.; Helquist, P. Tetrahedron Lett. 1997, 38, 6375. (e) Kreuder, R.; Rein,
T.; Reiser, O. Tetrahedron Lett. 1997, 38, 9035.
† Technical University of Denmark.
§ Universita¨t Regensburg.
(1) For a review, see: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988,
18, 249.
(2) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584.
10.1021/ol991387h CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/29/2000

resolution under appropriate reaction conditions,4b but for
aldehydes not containing R-amino substituents, we have not
yet been able to develop conditions that permit dynamic
resolution. Therefore, PKR constitutes a useful complemen-
tary strategy by which both enantiomers of the racemic
aldehyde could conceivably be converted into chiral products
of high isomeric purity and in high combined yield. In this
paper, we report the first examples of PKR by use of
asymmetric HWE reactions.
Table 1. Parallel Kinetic Resolution of Aldehyde 1 by
Reaction with Phosphonates 2 and 3a
equiv
equiv
yieldc of
yieldc of
entry of 2
of 3
dr, 4b
>99:1
4 (%)
dr, 5b
5 (%)
1
2
3
4
0.5
43
0.5 (3a )
0.5 (3a ) >99:1
0.5 (3b) 99:1
80:20 (5a )
>99:1 (5a )d
55:45 (5b)
27
36
41
0.5
0.5
38
30
We have investigated two alternative approaches by which
the overall goal could be achieved. In the first case, the
racemic substrate is reacted with two phosphonate reagents
containing different chiral auxiliaries. The products obtained
from the individual substrate enantiomers are then separated
on the basis of some difference in physical properties (e.g.,
chromatographic behavior) imparted by the characteristic
properties of the respective chiral auxiliaries. In the second
approach, we have taken advantage of the observation5 that
(E)- and (Z)-selective phosphonates containing the exact
same chiral auxiliary generally react with opposite enantio-
topic group preference. Thus, reaction of a racemic substrate
with one (E)-selective and one (Z)-selective reagent could
in principle afford one (E)- and one (Z)-product with opposite
absolute configuration at the allylic stereocenter, each one
in high diastereomeric purity. If the products are separable
on the basis of their different alkene geometry (e.g., by
chromatography), even though they contain an identical
auxiliary, efficient PKR would be feasible.
a General reaction conditions: 1.0 equiv aldehyde, 0.50-0.55 equiv of
each indicated phosphonate, 0.50 equiv (entries 1, 2) or 1.0 equiv (entries
3, 4) of NaHMDS, -78 °C, ca. 0.02 M in THF, 2-6 h. b Diastereomeric
ratio in isolated product; if not otherwise indicated, the ratio in the crude
was identical. The ratios refer to isomers with identical alkene geometry
but opposite configuration at the allylic stereocenter. The major product
isomers have the absolute configurations shown in Scheme 2. For all entries,
at most trace amounts of (Z)-products were formed. c Yield of isolated
product, judged as >95% pure by TLC and NMR. See also footnote 11.
d See footnote 10.
respective enantiomer of the chiral aziridine7 and diethyl-
phosphonoacetic acid. Our choice of these specific reagents
was based on our previous experience of asymmetric HWE
reactions with the 8-phenylmenthyl reagents on one hand
and of similar asymmetric transformations of chiral carbox-
amides containing the aziridine auxiliary on the other.
Furthermore, we expected the respective alkene products to
be readily separable as a result of the difference in polarity
between the two auxiliaries.
In individual reactions with aldehyde 1, reagent 3 dis-
played only modest selectivity (entry 2), whereas reagent 2
gave excellent selectivity (entry 1).8 When the two reagents
were combined in PKR experiments, the outcome very
clearly illustrated the possibility for matched or mismatched
combinations. In the matched case (entry 3), products 4 and
5a were both formed with excellent stereoselectivity, with
respect to both the allylic stereocenter and the alkene
geometry.9 Thus, out of the eight theoretically possible
products essentially only two were formed.10 In dramatic
contrast, the mismatched case (entry 4) afforded 5b as an
almost 1:1 epimeric mixture with respect to the allylic
stereocenter, while 4 was still obtained with high selectivity
(although in lower yield).11
As an initial demonstration of how the first approach could
be turned into practice, we have studied PKR of aldehyde
14b by reaction with chiral phosphonates 24c and 3a,b6 to
form alkene products 44c and 5a,b,6 respectively (Scheme
1, Table 1). Reagents 3a,b were readily prepared from the
Scheme 1
(5) Norrby, P.-O.; Brandt, P.; Rein, T. J. Org. Chem. 1999, 64, 5845
and references therein.
(6) All new compounds gave spectroscopic and analytical data in
accordance with the proposed structures. For details regarding experimental
procedures and compound characterization, see the Supporting Information.
(7) (a) Tanner, D.; Wyatt, P.; Johansson, F.; Bertilsson, S.; Andersson,
P. G. Acta Chem. Scand. 1999, 53, 263. (b) Tanner, D.; Harden, A.;
Johansson, F.; Wyatt, P.; Andersson, P. G. Acta Chem. Scand. 1996, 50,
361.
(8) Control experiments with various reaction stoichiometries showed
that aldehyde 1 does not epimerize fast enough to undergo efficient dynamic
kinetic resolution4b under these reaction conditions. As pointed out by a
reviewer, it would be advantageous to compare the enantiomeric purity and
chemical yield of the recovered 1 for each entry listed in Table 1; however,
due to the relative lability of the aldehyde, this has not been performed.
The same reasoning applies to aldehydes 6 and 9, Table 2.
(9) At most, trace amounts of (Z)-products were detected in the crude
products. Compounds 4 and 5a/5b were readily separated and isolated in
pure form by standard flash chromatography.
(10) In the crude product, the ratio (R,E)-5a/(S,E)-5a was 97:3. After
chromatography, (R,E)-5a was obtained as a single detected diastereomer
in the indicated yield.
536
Org. Lett., Vol. 2, No. 4, 2000

The outcome of these PKR experiments is nicely explained
by assuming that in the matched case the two chiral reagents
show similar reaction rates as well as opposite enantiomer
preference, which results in the ratio of the substrate
enantiomers being roughly constant throughout the reaction.
In the mismatched case, however, the two reagents compete
for the same substrate enantiomer, leading to inferior
selectivities and/or yields.
The alternative approach for PKR using asymmetric HWE
reactions, in which one (E)- and one (Z)-selective reagent
containing the exact same auxiliary are used in combination,
has been tested in reactions between phosphonates 7a-d3g,4e
and aldehydes 64a and 96 (Scheme 2, Table 2). These
Table 2. Parallel Kinetic Resolution of Aldehydes 6 and 9 by
Reaction with Phosphonates 7a
equiv of equiv of
entry ald 7a /7b
7c/7d prod (Z)b (Z) (%) (E)b (E) (%)
dr, yield,c dr, yield,c
1d
2
3d
4d
5
6
7
8
6
6
6
6
6
6
6
6
9
9
9
0.5 (7a )
0.5 (7b)
8
8
8
8
8
8
8
8
98:2
94:6
81:19
69:31
94:6
96:4
92:8
95:5
38
33
12
1
38
42
36
40
39
4
96:4
98:2
92:8
87:13
94:6
93:7
96:4
92:8
95:5
80:20
94:6
10
12
35
44
34
50
37
42
7
0.5 (7c)
0.5 (7d )
0.5 (7a ) 0.5 (7c)
0.5 (7a ) 0.5 (7d )
0.5 (7b) 0.5 (7c)
0.5 (7b) 0.5 (7d )
0.5 (7a )
9e
10e
11e
10 79:21
0.5 (7c) 10 59:41
29
30
0.5 (7a ) 0.5 (7c) 10 90:10
33
Scheme 2
a General reaction conditions: 1.1 equiv of aldehyde, 0.50-0.55 equiv
of each indicated phosphonate, 0.50 equiv (entries 1-4, 9, 10) or 1.0 equiv
(entries 5-8, 11) of KHMDS, 2.5 equiv (entries 1-4, 9, 10) or 5.0 equiv
(entries 5-8, 11) of 18-crown-6, -78 °C, ca. 0.02 M in THF, 2-5 h.
b Diastereomeric ratio in isolated product; if not otherwise indicated, the
ratio in the crude was identical. The ratios refer to isomers with identical
alkene geometry but opposite configuration at the allylic stereocenter. The
major product isomers have the absolute configurations shown in Scheme
2. c Yield of isolated product, judged as >95% pure by TLC and NMR.
See also ref 11. d See ref 4a. e In this experiment, the (Z)- and (E)-products
were not separated; the yields given are calculated on the basis of 1H NMR
of the mixture.
kinetic resolutions (Table 2, entries 1-4) shows that the
diastereoselectivity for the (E)-product has increased sub-
stantially in the PKR, whereas the diastereoselectivity for
the (Z)-product in some cases is slightly lower but generally
still very good. Formation of a small amount of (Z)-product,
with low diastereoselectivity, from the (E)-selective reagent
(7c or 7d) can explain why the diastereoselectivity in favor
of (S,Z)-8 has not increased in the PKR reactions in entries
5-7. With respect to material throughput, it is important to
note that on the basis of the amount of racemic aldehyde
substrate, the yield of chiral alkene product is almost doubled
in the PKR.11 This will be an important factor in cases where
the aldehyde substrate is not very readily available.
The reactions with aldehyde 9 (Scheme 2, Table 2)
demonstrate that in favorable cases both products of the PKR
might be obtained in increased selectivities as compared to
the individual reactions. In separate reactions of 9 with
reagents 7a and 7c, products (S,Z)-106 and (R,E)-106 were
both obtained with only modest diastereoselectivity (Table
2, entries 9-10). In contrast, PKR afforded both compounds
in substantially improved selectivities (Table 2, entry 11).11,12
The products of this and analogous PKR reactions are
interesting synthetic building blocks, since further conversion,
via a Pd-catalyzed allylic nucleophilic substitution,13 to
reactions differ from the PKR examples described in the
previous section in that a maximum of four different products
can be formed since the two reagents contain the exact same
chiral auxiliary. Furthermore, there is a possibility for
“crossover” in that the (Z)-selective reagent might form small
amounts of (E)-product and vice versa.
As demonstrated by the results obtained with acrolein
dimer (6), PKR using a combination of either one of the
(Z)-selective reagents 7a or 7b with an (E)-selective reagent
(7c or 7d) afforded both (S,Z)-84a and (R,E)-84a in syntheti-
cally useful diastereoselectivities and good combined yields
(Table 2, entries 5-8).8,12 A comparison with the individual
(12) With the exception of (Z)-10 and (E)-10, which are only partially
separable, products differing in alkene geometry could be readily separated
by flash chromatography. For compounds 8 and 10, isomers having identical
alkene geometry but opposite configuration at the allylic stereocenter are
at best partially separable by chromatography.
(13) (a) Tanikaga, R.; Jun, T. X.; Kaji, A. J. Chem. Soc., Perkin Trans.
1 1990, 1185, and references therein. (b) Gatti, R. G. P.; Larsson, A. L. E.;
Ba¨ckvall, J.-E. J. Chem. Soc., Perkin Trans. 1 1997, 577 and references
therein.
(11) The yields in the HWE reactions are calculated on the amount of
base used, since this is the limiting reagent. It should be noted that the
yields based on the amount of aldehyde substrate in general are almost
twice as high in the PKR experiments as in the individual kinetic resolutions
using a single phosphonate reagent.
Org. Lett., Vol. 2, No. 4, 2000
537

various chiral γ-substituted R,â-unsaturated ester derivatives
can be envisioned. This possibility is presently under active
investigation, and preliminary results are very promising.14
To conclude, we have demonstrated that by applying the
strategy of PKR to asymmetric HWE reactions, efficient
conversion of a racemic aldehyde to two different chiral
products of high isomeric purity is feasible. This can be
accomplished either by using two chiral phosphonate reagents
containing different chiral auxiliaries or by using one (Z)-
selective and one (E)-selective reagent containing the same
auxiliary. In both cases, increased material throughput is
observed since both aldehyde enantiomers are converted to
product(s). Furthermore, the PKR reactions can in favorable
cases afford increased selectivities compared to the individual
kinetic resolutions. We believe that PKR will prove particu-
larly useful for synthetic applications in which both the
obtained products can be of further utility in the same context,
either as building blocks for two different subunits of the
same overall synthetic target or for providing access to both
enantiomeric series of the same subunit of a given target
(e.g., for natural products of unknown absolute configura-
tion). We are presently investigating several such applica-
tions, as well as further developments of the PKR reactions,
and the results of these studies will be the subject of future
reports.
Acknowledgment. We are grateful to the Danish Natural
Sciences Research Council, the Danish Technical Sciences
Research Council, the Thrige Foundation (Denmark), The
Technical University of Denmark, and Deutsche Forschungs-
gemeinschaft (RE948/3-1) for financial support. Professor
Paul Helquist, University of Notre Dame, and Dr. Per-Ola
Norrby, Royal Danish School of Pharmacy, are gratefully
acknowledged for inspiring discussions and support.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3, 4, 5a,
8-10, and precursors. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Pedersen, T. M.; Hansen, E. L.; Jensen, J. F.; Rein, T.; Tanner, D.;
Helquist, P. Manuscript in preparation.
OL991387H
538
Org. Lett., Vol. 2, No. 4, 2000