Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

Article abstract of DOI:10.1021/ja005809q

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different α-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major α,β-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single γ-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.

Full text of DOI:10.1021/ja005809q

9738
J. Am. Chem. Soc. 2001, 123, 9738-9742
Enantioconvergent Synthesis by Sequential Asymmetric
Horner-Wadsworth-Emmons and Palladium-Catalyzed Allylic
Substitution Reactions
Torben M. Pedersen,|,§,† E. Louise Hansen,|, John Kane,§ Tobias Rein,*,|,‡ Paul Helquist,*,§
Per-Ola Norrby,*,| and David Tanner|
Contribution from the Department of Chemistry, Technical UniVersity of Denmark, Building 201,
KemitorVet, DK-2800 Kgs. Lyngby, Denmark, and Department of Chemistry and Biochemistry,
251 Nieuwland Science Hall, UniVersity of Notre Dame, Notre Dame, Indiana 46556
ReceiVed NoVember 20, 2000. ReVised Manuscript ReceiVed June 5, 2001
Abstract: A new method for enantioconvergent synthesis has been developed. The strategy relies on the
combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic
substitution. Different R-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE
reactions into mixtures of two major R,â-unsaturated esters, possessing opposite configurations at their allylic
stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be
subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles.
In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite
stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry
with respect to both the allylic stereocenter and the alkene geometry. Thus, a single γ-substituted ester was
obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit
of the iejimalides, a group of cytotoxic macrolides.
Introduction
methods reported for dynamic resolution rely on a rapid
interconversion of the substrate enantiomers via a reversible
proton transfer2d or an oxidation/reduction sequence.2e The
concept of parallel kinetic resolution, which recently was
introduced by Vedejs,3a is based on the simultaneous use of
two different reagents which react with opposite enantiomer
preference. Applications to different reaction types are emerging.
In a deracemization/stereoinversion sequence, on the other hand,
a kinetic resolution is followed by an inversion of configuration
of either the product or the unreacted starting enantiomer from
the first step. Another alternative strategy is to use an enantio-
convergent reaction sequence (i.e., conversion of both enanti-
omers of a racemate to the same chiral end product via isomeric
synthetic intermediates).4,5 Since the first report of the concept
by Fischli and co-workers,5a several methods, based on different
reactions/reaction combinations, have been demonstrated. How-
Kinetic resolution1 of a racemic starting material is a widely
used strategy for obtaining chiral molecules in enantiomerically
enriched form. One drawback with standard kinetic resolutions
is the inherently inefficient material throughput, since a
maximum yield of 50% of the desired product can be obtained.
Modified strategies which permit more efficient use of the
starting material [e.g., dynamic resolution,2 parallel kinetic
resolution (PKR),3 and deracemization/stereoinversion4] have
been demonstrated for some substrate types. Many of the
| Technical University of Denmark.
§ University of Notre Dame.
† Present address: Department of Chemistry, Stanford University,
Stanford CA 94305.
Present address: ACADIA Pharmaceuticals, Fabriksparken 58, DK-
2600 Glostrup, Denmark.
‡ Present address: AstraZeneca R&D So¨derta¨lje, Discovery Chemistry,
S-15185 So¨derta¨lje, Sweden.
(5) Selected examples: (a) Fischli, A.; Klaus, M.; Mayer, H.; Scho¨n-
holzer, P.; Ru¨egg, R. HelV. Chim. Acta 1975, 58, 564. (b) Chan, K.-K.;
Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem.
1976, 41, 3497. (c) Terashima, S.; Yamada, S.-I. Tetrahedron Lett. 1977,
1001. (d) Harada, T.; Shintani, T.; Oku, A. J. Am. Chem. Soc. 1995, 117,
12346 and references therein. (e) Fleming, I.; Winter, S. B. D. Tetrahedron
Lett. 1995, 36, 1733 and references therein. (f) Pedragosa-Moreau, S.;
Archelas, A.; Furstoss, R. Tetrahedron 1996, 52, 4593 and references
therein. (g) Bellucci, G.; Chiappe, C.; Cordoni, A. Tetrahedron: Asymmetry
1996, 7, 197. (h) Archer, I. V. J.; Leak, D. J.; Widdowson, D. A.
Tetrahedron Lett. 1996, 37, 8819. (i) Kroutil, W.; Mischitz, M.; Faber, K.
J. Chem. Soc., Perkin Trans. 1 1997, 3629. (j) Ducray, P.; Rousseau, B.;
Mioskowski, C. J. Org. Chem. 1999, 64, 3800. (k) Harada, T.; Nakamura,
T.; Kinugasa, M.; Oku, A. Tetrahedron Lett. 1999, 40, 503. (l) Taniguchi,
T.; Ogasawara, K. Tetrahedron Lett. 1999, 40, 4383. (m) Trost, B. M.;
Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122,
5968 and references therein. (n) Yoshida, N.; Ogasawara, K. Org. Lett.
2000, 2, 1461. See also: (o) DeMello, N. C.; Curran, D. P. J. Am. Chem.
Soc. 1998, 120, 329 and references therein. (p) Curran, D. P.; Lin, C.-H.;
DeMello, N. C.; Junggebauer, J. J. Am. Chem. Soc. 1998, 120, 342.
(1) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(2) Reviews: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36. (b) Ward, R. S. Tetrahedron: Asymmetry 1995, 6,
1475. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 25, 447. Selected
examples: (d) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 2931. (e) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J.-E.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1211.
(3) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584. (b)
Cardona, F.; Valenza, S.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 1999,
1319. (c) Pietrusiewicz, K. M.; Holody, W.; Koprowski, M.; Cicchi, S.;
Goti, A.; Brandi, A. Phosphorus, Sulfur, Silicon 1999, 144-146, 389. (d)
Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.;
Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535. (e) Eames, J. Angew.
Chem. Int. Ed. 2000, 39, 885. (f) Vedejs, E.; Rozners, E. J. Am. Chem.
Soc. 2001, 123, 2428.
(4) (a) Stecher, H.; Faber, K. Synthesis 1997, 1 and references therein.
(b) Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry 1999,
10, 107 and references therein. Recent example: (c) Steinreber, A.;
Hellstro¨m, H.; Mayer, S. F.; Orru, R. V. A.; Faber, K. Synlett 2001, 111.
10.1021/ja005809q CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

EnantioconVergent Synthesis
J. Am. Chem. Soc., Vol. 123, No. 40, 2001 9739
Table 1. Asymmetric HWE Reactions of Racemic Aldehydes 1-3
with Phosphonates 4 To Give Alkenes 5-7a
Scheme 1
aldehyde
phos-
product,
(E):(Z) d.r.,
ratio
(E)c,d
d.r.,
entry (equiv) phonate yield (%)b
(Z)c,d
1
2
3f
4
5
6
7
8
9
1 (2.2)
1 (1.3)
1 (1.1)
2 (2.2)
2 (1.3)
2 (1.1)
2 (1.1)
3 (2.2)
3 (1.1)
4a
5, 96
5, 96
5, 63
6, 97
6, 91
6, 84
6, 70
7, 95
7, 96
46:54 94:6
43:57 95:5
52:48 94:6
69:31 95:5
60:40 95:5
56:44 94:6
60:40 85:15 >99:1
41:59 95:5
42:58 97:3
97:3
98:2
90:10
>99:1
>99:1
>99:1
4a
4b/4ce
4a
4a
4a
4b/4de
4a
98:2
96:4
4a
a For reaction conditions, see the Experimental Section and Sup-
porting Information. b Isolated combined yield of (E)- and (Z)-product,
judged as g95% pure by NMR and TLC. The yield is based on the
total amount of phosphonate used. c Ratios in crude and isolated
products were generally the same, within 1%. d In all cases, the absolute
configuration of the main product is the one indicated in Scheme 1.
e 0.5 equiv of each reagent. f See ref 3d.
The group P must function well as both a protecting group
in the initial asymmetric HWE reaction and then as part of a
suitable leaving group in the ensuing palladium-catalyzed allylic
substitution. We have found that the Ph2P(O) (DPP) group works
well when R1 is aliphatic, whereas pivaloyl is a good choice
when R1 is aromatic. Asymmetric HWE reactions with reagents
4 provided alkenes (Z)-5-7 and (E)-5-7 (Table 1; see also the
Supporting Information). Phosphonate 4a was generally the best
choice for obtaining both alkene products with high diastereo-
selectivities and in excellent yields (entries 1-2, 4-6, 8, and
9). PKR reactions3d using a combination of reagents 4b and 4c
were also tried (entries 3 and 7), but use of reagent 4a alone
gave even better diastereoselectivities. Another interesting
observation was that use of close to equimolar amounts of
racemic aldehyde and phosphonate still led to excellent dia-
stereoselectivities (entries 2, 5, 6, and 9). Under normal
circumstances this phenomenon should only be possible under
reaction conditions that allow a dynamic kinetic resolution to
take place. This observation could be rationalized from our
knowledge that the major diastereomers of the respective (Z)
and (E) products were formed from opposite enantiomers of
1-3.8 Accordingly, the diastereoselectivities were high even
when equimolar amounts of substrate and reagent were used,
thus enabling high material throughput with respect to the
substrate. The combined yields of (Z) and (E) product were
uniformly high.
ever, some of the methods reported require separation and
individual manipulation of the respective intermediates formed
from the starting enantiomers. In this paper, we report a novel
method for enantioconvergent synthesis, which is based on the
sequential combination of an asymmetric Horner-Wadsworth-
Emmons (HWE) reaction3d,6 with a palladium-catalyzed allylic
nucleophilic substitution.7 The fact that no separation of the
intermediate HWE products is necessary before the stereo-
convergent step is an attractive feature of this method.
In the subsequent step, the mixtures of (Z)-5-7 and (E)-5-7
were subjected to palladium-catalyzed allylic nucleophilic
substitutions. For our initial studies of stereoconvergence, we
investigated reactions with representative carbon and nitrogen
nucleophiles (sodium dimethyl malonate, sodium dimethyl
methylmalonate, benzylamine, and 4-methoxybenzylamine re-
spectively). According to our plan, the reaction should proceed
with opposite stereospecificity from the different alkene inter-
mediates: the (E)-substrate should react with retention of
configuration, whereas the (Z)-alkene should, under appropriate
conditions, undergo inversion with respect to both the allylic
stereocenter and the alkene geometry, via a π-σ-π-rearrange-
ment of the intermediate Pd complex.9 Overall, both substrate
isomers should thus be transformed into the same stereoisomer
of the respective γ-substituted ester (E)-8-10. As shown by
Results
Our approach is illustrated in Scheme 1. The racemic
aldehydes 1-3 were available in a few steps from commercially
available starting materials (see the Supporting Information).
(6) 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) Kreuder, R.; Rein, T.; Reiser, O. Tetrahedron
Lett. 1997, 38, 9035. (f) Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 515. (g) Vaulont, I.; Gais, H.-J.; Reuter, N.; Schmitz,
E.; Ossenkamp, R. K. L. Eur. J. Org. Chem. 1998, 805. (h) Tullis, J. S.;
Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org. Chem. 1998, 63, 8284.
(i) Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2997.
(j) Tanaka, K.; Watanabe, T.; Shimamoto, K.-Y.; Sahakitpichan, P.; Fuji,
K. Tetrahedron Lett. 1999, 40, 6599. (k) Vares, L.; Rein, T. Org. Lett.
2000, 2, 2611.
(7) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; Wiley & Sons: New York, 1995; pp 290-340. (b) Trost,
B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Takinaga, R.;
Jun, T. X.; Kaji, A. J. Chem. Soc., Perkin Trans. 1 1990, 1185. (d) Sugiura,
M.; Yagi, Y.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1998, 39, 4351.
(8) Norrby, P.-O.; Brandt, P.; Rein, T. J. Org. Chem. 1999, 64, 5845.
(9) For examples, see: (a) Hayashi, T.; Yamamoto, A.; Hagihara, T. J.
Org. Chem. 1986, 51, 723. (b) Shimizu, I.; Oshima, M.; Nisar, M.; Tsuji,
J. Chem. Lett. 1986, 1775. (c) Noguchi, Y.; Yamada, T.; Uchiro, H.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 7493 and references therein.

9740 J. Am. Chem. Soc., Vol. 123, No. 40, 2001
Pedersen et al.
Table 2. Palladium(0)-Catalyzed Reaction of Alkenes 5-7 with
Nucleophilesa
substrate, d.r.,
d.r.,
(Z)
yield
entry (E):(Z)
(E)
NuH
product (%)b d.r.c,d
1
2
3
4
5
6
7
5, 43:57 95:5
5, 47:53 95:5
5, 46:54 94:6
5, 47:53 95:5
98:2 DMMe
98:2 DMMMf
97:3 BnNH2
98:2 4-MBAg
8a
8b
8c
8d
9a
9b
77 90:10
79 91:9
83 93:7
88 93:7
79 92:8
66 94:6
97 93:7
6, 60:40 95:5 >99:1 DMM
6, 60:40 95:5 >99:1 DMMMf
7, 46:54 97:3
92:8 DMM
10
a For reaction conditions, see the Experimental Section and Sup-
porting Information. b Isolated yield of product, judged as g95% pure
by NMR and TLC. In each case, only (E)-product was detected. c Ratios
in crude and isolated products were generally the same, within 1%.d In
all cases, the absolute configuration of the main product is assigned as
indicated in Scheme 1. For details regarding determination of the
absolute configurations, see the Supporting Information. e Dimethyl
malonate. f Dimethyl methylmalonate. g 4-Methoxybenzylamine.
Scheme 2
Figure 1. Favored η3-allyl-Pd intermediate formed from the major
substrate isomers, in which the approach of the nucleophile is blocked
by the chiral auxiliary. Hydrogens as well as all phenyls except in the
auxiliary have been hidden for clarity.
rearrangement of the intermediate formed from the major
substrate isomers can lead to the minor product isomers. The
observed slight lowering of the diastereomeric ratios must
therefore take place by another process. It is known that
crossover between the manifolds can occur slowly, possibly
catalyzed by Pd(0).11 However, use of a minimum amount of
Pd catalyst in our study did not completely suppress this
unwanted phenomenon.12
Detailed conformational considerations contribute to an
understanding of these results. We have previously shown that
the selectivities in Pd-catalyzed allylic alkylations can be
rationalized using molecular modeling.13 Using a recently
developed molecular mechanics force field14 that has been
successfully employed in similar systems,15 we determined the
structures of the intermediates depicted in Scheme 2.16 Interest-
ingly, it was found that a slightly detrimental effect could be
expected from the chiral auxiliary. The global minimum for the
major isomer is depicted in Figure 1. It can be seen that the
phenyl group of the auxiliary fits perfectly above the plane of
the allyl moiety, thus blocking the approach of the nucleophile.
the results summarized in Table 2, this plan was realized very
well in practice. It is noteworthy that both carbon and nitrogen
nucleophiles work well in this context, and that the products
were obtained with g90:10 diastereoselectivity in good yields,
as exclusively (E)-isomers even though the allylic substrates
5-7 were used as mixtures of geometric and diastereoisomers.
To investigate the influence of the chiral auxiliary in the Pd-
catalyzed allylic subtitution, we attempted to cleave the auxiliary
in alkene products 5-7 to obtain the corresponding methyl ester
prior to the Pd reaction. However, several attempts to effect
such a transesterification failed to proceed cleanly, presumably
due to the steric bulk of the chiral auxiliary.
As seen from Table 2, the diastereomer ratios of products
8-10 were slightly decreased compared to those of the
substrates 5-7. All of the allowed π-σ-π rearrangements of
the intermediate in the Pd-catalyzed step are depicted in Scheme
2.10 It can be seen that both major isomeric alkenes obtained
from the HWE reaction must enter the same dynamic manifold
in the Pd-catalyzed substitution. Furthermore, no π-σ-π
(11) (a) Granberg, K. L.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1992, 114,
6858 (for previous suggestions of this type of isomerization, see ref 5 in
this article). (b) Martin, J. T.; Oslob, J. D.; Åkermark, B.; Norrby, P.-O.
Acta Chem. Scand. 1995, 49, 888. (c) Moreno-Man˜as, M.; Morral, L.;
Pleixats, R. J. Org. Chem. 1998, 63, 6160. (d) Amatore, C.; Gamez, S.;
Jutand, A.; Meyer, G.; Moreno-Man˜as, M.; Morral, L.; Pleixats, R. Chem.
Eur. J. 2000, 6, 3372.
(12) Alternatively, a reversible conjugate addition could cause partial
(Z)- to (E)-isomerization of the substrate, with a corresponding loss of
diastereomeric purity.
(13) (a) Oslob, J. D.; Åkermark, B.; Helquist, P.; Norrby, P.-O.
Organometallics 1997, 16, 3015. (b) Pen˜a-Cabrera, E.; Norrby, P.-O.;
Sjo¨gren, M.; Vitagliano, A.; deFelice, V.; Oslob, J.; Ishii, S.; Åkermark,
B.; Helquist, P. J. Am. Chem. Soc. 1996, 118, 4299.
(14) (a) http://compchem.dfh.dk/PeO/. (b) Hagelin, H.; Åkermark, B.;
Norrby, P.-O. Organometallics 1999, 18, 2884.
(15) Farrell, A. Ph.D. Thesis, University College Dublin, 1999.
(16) The published force field (ref 14) has been updated for use with
Maestro v 3.0 from Schrodinger, Inc., www.schrodinger.com. The updated
force field is avaliable upon request from Per-Ola Norrby, pon@kemi.dtu.dk.
(10) With a symmetric ligand, other known dynamic processes such as
the apparent rotation of the allyl moiety have no effect on the outcome of
the reaction.

EnantioconVergent Synthesis
J. Am. Chem. Soc., Vol. 123, No. 40, 2001 9741
Scheme 3
Scheme 4a
Other conformers in which this blocking is less pronounced are
energetically accessible, but the preference of the intermediate
for the folded conformation can be expected to lead to a
retardation of the reaction. In the intermediate formed from the
minor substrate isomers (not illustrated), the approach of the
nucleophile is not blocked to the same extent. Thus, the slight
lowering of the diastereomeric ratio can be rationalized by an
unfavorable kinetic resolution. This conclusion is in line with
the observation that the lowering of the diastereomeric ratio is
mainly observed in the reactions which show relatively lower
yields. In the reaction of substrate 7 (Table 2, entry 7), which
yielded 97% product, the decrease in the diastereomeric ratio
was insignificant.
As an initial demonstration of synthetic applicability, the
chiral auxiliary was cleaved in product 8c by the sequence
depicted in Scheme 3.3d Simultaneous reduction of the double
bond and debenzylation of 8c afforded amine 11, which was
further converted into lactam 12. Not only does this sequence
illustrate our enantioconvergent strategy, but it also demonstrates
a powerful pathway for obtaining an important class of chiral
lactams.
a Conditions: (a) KHMDS, 18-Crown-6, THF, -78 °C; 50% (E,R)-
15 (d.r. ) 95:5), 42% (Z,S)-15 (d.r.) 98:2). (b) (i) Dimethyl dioxirane,
K2CO3, CH2Cl2, 0 °C; (ii) NaIO4, H2O/THF, room temperature; >95%
overall. (c) (i) Ph3PdC(CH3)CHO, toluene, reflux; (ii) NaHCO3, MeOH/
H2O, room temperature; (iii) ClP(O)Ph2, imidazole, CH2Cl2/Et2O, room
temperature; (E,R)-16, 34% overall; (Z,S)-16, 28% overall. (d) Pd2(dba)3,
Dppe, MeOH/THF; 66% (d.r. ) 94:6) from (E,R)-16, 79% (d.r. > 99:
1) from (Z,S)-16.
nucleophile.20 It is noteworthy that methanol works well in this
context, even though oxygen nucleophiles often perform poorly
in intermolecular Pd-catalyzed allylic substitutions, and even
though alcohols often function as hydrogen transfer agents in
metal-catalyzed reductions.21 The use of building block 17 in
the total synthesis of the iejimalides will be reported in due
course.
Application to the Synthesis of an Iejimalide Subunit
We have applied this novel strategy to a stereoconvergent
synthesis of a subunit of the iejimalides (e.g. iejimalide A, 13),17
a group of cytotoxic macrolides. Compound 17, which is a
suitably functionalized building block corresponding to the
C12-C20 unit, was prepared as shown in Scheme 4. Racemic
aldehyde 14 (acrolein dimer) was first transformed into alkenes
(E,R)-1518 and (Z,S)-1518 by a PKR.3d These intermediates were
readily separated by chromatography, and then converted into
(E,R)-1618 and (Z,S)-16,18 respectively, by oxidative cleavage
of the vinyl ether, Wittig chain elongation, and conversion of
the formate ester into a DPPO group. Finally, in the key
stereoconvergent step, both (E,R)-16 and (Z,S)-16 could be
transformed into the desired iejimalide building block 1719 by
a Pd-catalyzed allylic substitution using methanol as the
Conclusions
To summarize, we have demonstrated the possibility of
effecting enantioconvergent synthesis by using a combination
of an asymmetric HWE reaction and a stereoselective Pd-
catalyzed allylic substitution. From a practical viewpoint, it is
worth noting that the initial products formed in the HWE step
need not be separated before the stereoconvergent step. In the
present setting, the overall result is the conversion of a racemic,
R-oxygen-substituted aldehyde into a chain-elongated, γ-ste-
reogenic, R,â-unsaturated ester. Initial applications of this
strategy in total synthesis have been demonstrated, and ad-
ditional applications are being studied.
(17) (a) Kobayashi, J.; Cheng, J.; Ohta, T.; Nakamura, H.; Nozoe, S.;
Hirata, Y.; Ohizumi, Y.; Sasaki, T. J. Org. Chem. 1988, 53, 6147. Synthetic
studies: (b) Cottard, M.; Kann, N.; Rein, T.; Åkermark, B.; Helquist, P.
Tetrahedron Lett. 1995, 36, 3115. (c) Mendlik, M. T.; Cottard, M.; Rein,
T.; Helquist, P. Tetrahedron Lett. 1997, 38, 6375.
(19) The major diastereomer of 17 could be obtained isomerically pure
after chromatography.
(20) (a) Van der Deen, A.; Van Oeveren, A.; Kellogg, R. M.; Feringa,
B. L. Tetrahedron Lett. 1999, 40, 1755. (b) Hamada, Y; Seto, N.;
Takayanagi, Y.; Nakano, T.; Hara, O. Tetrahedron Lett. 1999, 40, 7791.
(21) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(18) The descriptors (R) and (S) refer to the allylic stereocenter.

9742 J. Am. Chem. Soc., Vol. 123, No. 40, 2001
Pedersen et al.
Experimental Section
Acknowledgment. Financial support from the Danish Natu-
ral Science Research Council, the Danish Technical Research
Council, the Thrige Foundation (Denmark), and The Technical
University of Denmark, as well as collaboration with the Walther
Cancer Institute, are gratefully acknowledged. We are grateful
to Mr. Jakob F. Jensen for early contributions to this project,
and to Mrs. Nonka Sevova, Notre Dame, for assistance with
HRMS analyses.
General Procedure for Asymmetric HWE Reactions. To a
solution of phosphonate (1.0 equiv; ca. 0.02 M in THF) and 18-crown-6
(5 equiv), precooled to -78 °C, was added KHMDS (1.0 equiv) under
argon. The mixture was stirred for 30 min and then transferred via
cannula to a precooled solution of the aldehyde (1.1-2.2 equiv). The
reaction was stirred at -78 °C and under argon for 3 h whereafter a 1
M solution of acetic acid in methanol was added. After continued
stirring for 5 min phosphate buffer at pH 7 was added, and the mixture
was allowed to warm to room temperature. Extraction with EtOAc
afforded a crude mixture that was purified by flash chromatography
(3-25% EtOAc in hexanes).
General Procedure for Palladium-Catalyzed Allylic Substitution
Reactions. To a solution of substrate (1.0 equiv; ca. 0.04 M in THF),
Pd2(dba)3‚CHCl3 (2.5-5 mol %), and dppe (6.3-12.5 mol %) in THF
was added the nucleophile; the carbon nucleophiles were formed
immediately before use, by addition of either DMM or DMMM (6.0
equiv) to NaH (6.0 equiv, 60% dispertion in mineral oil) in THF. The
reaction mixture was stirred at room temperature under argon for 1-16
h. Addition of water followed by extraction with Et2O afforded a crude
mixture, which was purified by flash chromatography (5-10% EtOAc
in hexanes).
Note Added in Proof. For a recently reported example of
PKR, see: Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.;
Feringa, B. L. Angew. Chem., Int. Ed. 2001, 40, 930.
Supporting Information Available: Experimental proce-
dures and characterization data for new compounds and precur-
sors (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA005809Q