Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic alkylations

Article abstract of DOI:10.1021/jo0200116

First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis-[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained

Full text of DOI:10.1021/jo0200116

Den d r itic Oxa zolin e Liga n d s in En a n tioselective
P a lla d iu m -Ca ta lyzed Allylic Alk yla tion s
Michael Malkoch,† Kristina Hallman,‡ Serghey Lutsenko,‡ Anders Hult,†
Eva Malmstro¨m,*,† and Christina Moberg*,‡
Department of Fiber and Polymer Technology and Department of Chemistry, Organic Chemistry,
Royal Institute of Technology, SE-100 44 Stockholm, Sweden
mave@polymer.kth.se; kimo@kth.se
Received J anuary 4, 2002
First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid
and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis-
[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained were assessed in palladium-
catalyzed allylic alkylations. The first type of ligands exhibited enantioselectivity similar to that
of a benzoyl ester derivative, whereas the latter type of ligands afforded products with higher
selectivity than the analogous benzoyl ester. The activity of the dendritic catalysts decreased with
increasing generation.
In tr od u ction
attached either to the periphery of the system or at the
focal point. In the first type of systems, proximity of
catalytic sites may lead to cooperative effects, as observed
by J acobsen et al. in the Co-salen-catalyzed hydrolytic
kinetic resolution of terminal epoxides,6 but multiple
functionalities at the periphery can also cause aggrega-
tion of catalytic sites and thereby loss of catalytic
activity.3,7 The second type of dendritic catalysts is
expected to provide enhanced selectivity, in particular
enhanced enantioselectivity, in catalytic reactions by
providing a sterically demanding environment created by
the dendritic substituent, although these expectations are
not always met.1 In both types of systems, chirality may
reside in the dendrimer part of the molecule and/or in
the ligand skeleton. Achiral ligands with chiral dendritic
substituents have so far resulted in very low enantiose-
lectivity,5 whereas chiral ligands substituted with den-
drons8 or chiral ligands attached to the periphery of a
dendritic structure9 in a variety of examples have been
shown to behave like the monomeric ligands or, in a few
cases, even to give better performance. The activity and
selectivity of the dendritic catalysts often deteriorate
upon increasing the generation, however.3b
Dendrimers and dendrons are currently being exploited
for a variety of applications,1 the use of chiral ligands
with dendritic structures2 in metal-catalyzed reactions
constituting one example.3 The major reason for the
preparation of such catalysts comes from advantageous
workup procedures, in that separation of the catalyst
from the products conveniently can be performed by, e.g.,
precipitation or nanofiltration, thus allowing recovery
and reuse of the catalysts. Dendritic catalysts can also
be used in flow-through reactors where they are retained
by a membrane.4 In addition, properties superior to those
of the monomeric ligands may be envisaged. Thus, the
solubility of the catalysts may be modified, occasionally
leading to enhanced reactivity of the dendritic catalysts.5
Different strategies have been employed in the design
of chiral dendritic metal catalysts. The catalyst can
consist of a dendrimer or dendron having the groups
responsible for the coordination to the metal center
† Department of Fiber and Polymer Technology.
‡ Department of Chemistry, Organic Chemistry.
(1) (a) Bosman, A. W.; J anssen, H. M.; Meijer, E. W. Chem. Rev.
1999, 99, 1665-1688. (b) Smith, D. K.; Diederich, F. Chem. Eur. J .
1998, 8, 1353-1361.
We have exploited the use of [2-(hydroxymethyl)-
pyridino]oxazolines10 as well as O-alkylated and O-
(2) Chow, H.-F.; Mong, T. K.-K.; Wan, C.-W.; Wang, Z.-Y. Adv.
Dendritic Macromol. 1999, 4, 107-133.
(3) (a) Oosterom, G. E.; Reek, J . N. H.; Kamer, P. C. J .; van Leeuwen,
P. W. N. M. Angew. Chem., Int. Ed. 2001, 40, 1828-1849. (b) Astruc,
D.; Chardac, F. Chem. Rev. 2001, 101, 2991-3024.
(6) Breinbauer, R.; J acobsen, E. N. Angew. Chem., Int. Ed. 2000,
39, 3604-3607.
(7) Miedaner, A.; Curtis, C. J .; Barkley, R. M.; DuBois, D. L. Inorg.
Chem. 1994, 33, 5482-5490.
(4) (a) Brinkmann, N.; Giebel, D.; Lohmer, G.; Reetz, M. T.; Kragl,
U. J . Catal. 1999, 183, 163-168. (b) Eggeling, E. B.; Hovestad, N. J .;
J astrzebski, T. B. H.; Vogt, D.; van Koten, G. J . Org. Chem. 2000, 65,
8857-8865. (c) Kragl, U.; Dreisbach, C. Angew. Chem., Int. Ed. Engl.
1996, 35, 642-644. (d) de Groot, D.; Eggeling, E. B.; de Wilde, J . C.;
Kooijman, H.; van Haaren, R. J .; van der Made, A. W.; Spek, A. L.;
Vogt, D.; Reek, J . N. H.; Kamer, P. C. J .; van Leeuwen, P. W. N. M.
Chem. Commun. 1999, 1623-1624. (e) de Groot, D.; de Waal, B. F.
M.; Reek, J . N. H.; Schenning, A. P. H. J .; Kamer, P. C. J .; Meijer, E.
W.; van Leeuwen, P. W. N. M. J . Am. Chem. Soc. 2001, 123, 8453-
8458.
(8) (a) Fan, Q.-H.; Liu, G.-H.; Chen, X.-M.; Deng, G.-J .; Chan, A. S.
C. Tetrahedron: Asymmetry 2001, 12, 1559-1565. (b) Hu, Q.-S.; Pugh,
V.; Sabat, M.; Pu, L. J . Org. Chem. 1999, 64, 7528-7536. (c) Fan, Q.-
H.; Chen, Y.-M.; Chen, X.-M.; J iang, D.-Z.; Xi, F.; Chan, A. S. C. Chem.
Commun. 2000, 789-790. (d) Yamago, S.; Furukawa, M.; Azuma, A.;
Yoshida, J . Tetrahedron Lett. 1998, 39, 3783-3786.
(9) (a) Seebach, D.; Marti, R. E.; Hinterman, T. Helv. Chim. Acta
1996, 79, 1710-1725. (b) Ko¨llner, C.; Pugin, B.; Togni, A. J . Am. Chem.
Soc. 1998, 120, 10274-10275.
(10) Nordstro¨m, K.; Macedo, E.; Moberg, C. J . Org. Chem. 1997, 62,
1604-1609.
(5) Brunner, H. J . Organomet. Chem. 1995, 500, 39-46.
10.1021/jo0200116 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/25/2002
J . Org. Chem. 2002, 67, 8197-8202
8197

Malkoch et al.
benzoylated11 derivatives in palladium-catalyzed allylic
substitutions12 of rac-1,3-diphenyl-2-propenyl acetate
with dimethyl malonate and found that the selectivity
as well as the reactivity of the catalytic systems are
highly dependent on the group bound to oxygen. As ester
derivatives of the parent alcohol are conveniently ob-
tained, we decided to study the influence of dendritic
substituents on the catalytic performance of this type of
ligands and of bis[4-(hydroxymethyl)oxazolines)]. To the
best of our knowledge, only achiral dendritic catalysts
have previously been used in palladium-catalyzed ally-
lation reactions.4a,d,13
The synthesis of dendritic structures involves mainly
two different approaches, leading to the same product:
the convergent growth approach and the divergent
growth approach. The approach of choice is related to the
chemistry involved for the synthesis of the various
building blocks used to construct a dendritic structure.
In the convergent growth approach developed by Fre´chet
and Hawker, growth proceeds through coupling of chain
ends to a focal molecule forming higher generation
monodendrons.14,15 Advantages such as the minimum
number of coupling sites and simpler purification steps
due to a larger difference in molecular weight of the
product and the byproducts are main characteristics in
the convergent growth approach. However, a major
drawback of this approach is low yield in the higher
generation monodendron coupling to a focal point due to
steric hindrance. Moreover, loss of valuable monoden-
drons used in excess for the synthesis for the next
generation monodendrons is disadvantageous.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Liga n d s. 2,2-Bis(hydroxymeth-
yl)propionic acid was employed as a building block for
the preparation of first, second, third, and fourth genera-
tion dendrons. Dendrons of the second and fourth gen-
erations of this kind have been synthesized previously
by a double-stage convergent approach via intermediates
1-4.19,20 The disadvantage with this route is the loss of
valuable second generation dendrons as they had to be
used in excess for the synthesis of the fourth generation
dendrons. Therefore a modified synthetic route was
sought in order to minimize the amount of dendron loss.
This was accomplished by the divergent approach with
acetonide protected bis-MPA (1) as bulk material.
In the divergent growth, monodendrons are grown
layer by layer radially outward starting with the first
generation monodendron. A disadvantage with this route
is the high number of coupling sites. The number of sites
is at least doubled for the formation of each new genera-
tion. Transformation of all chain ends is essential for the
workup procedure and the formation of higher generation
monodendrons. This is usually achieved by using a large
excess of bulk reagent. The divergent growth has been
described by, e.g., Tomalia et al.,16 Newkome et al.,17 and
Fre´chet et al.15
In this study a divergent growth was used for the
preparation of acetonide-protected monodendrons based
on bis-MPA as the repeating unit. The dendrons obtained
were attached to pyridinooxazolines and bis(oxazolines),18
and the resulting ligands assessed in Pd-catalyzed allylic
alkylations.
Acetonide-[G#3]-CO2CH2C6H5 (5) was synthesized in
87% yield from 1 and 2 using DPTS21 and DCC. DOWEX,
H+ was used to cleave the acetonide, affording 6 in 86%
yield. Acetonide-[G#4]-CO2CH2C6H5 (7) was obtained in
43% yield by a DPTS/DCC coupling between 6 and 1.
The removal of the benzyl group (H2, Pd/C) was per-
formed in 95% yield to give acetonide-[G#4]-COOH (8)
(Scheme 1).19
A dendron with a chiral surface was synthesized from
3 and (1R,2S,5R)-menthoxyacetic acid, a commercially
available and cheap chiral building block. The (1R,2S,5R)-
menthoxyacetic acid-[G#1]-CO2CH2C6H5 (9) was obtained
in 84% yield and gave, after removal of the benzyl group,
(1R,2S,5R)-menthoxyacetic acid-[G#1]-CO2H (10) in 97%
yield (Scheme 2).
Dendrons containing free carboxylic acid groups and
acetal protected alcohol functions (1, 4, and 8) were
connected to (4′R)-2-(4′,5′-dihydro-4′-phenyl-2′-oxazolyl)-
6-(hydroxymethyl)pyridine (11)22 or its enantiomer (ent-
11) and to 2,2-bis[(4S,5S)-4-(hydroxymethyl)-5-phenyl-
1,3-oxazolin-2-yl]propane (12) via ester formation using
DPTS/DCC or DMAP/EDCI, to form (S)-13a -b, (R)-13c,
and (S,S)-14a -b. Analogous couplings of the chiral den-
(11) Hallman, K.; Macedo, E.; Nordstro¨m, K.; Moberg, C. Tetrahe-
dron: Asymmetry 1999, 10, 4037-4046.
(12) Frost, C. G.; Howarth, J .; Williams, J . M. J . Tetrahedron:
Asymmetry 1992, 3, 1089. Trost, B. M.; Van Vranken, D. L. Chem.
Rev. 1996, 96, 395-422. Trost, B. M.; Lee, C. Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; pp 593-
649.
(13) Oosterom, G. E.; van Haaren, R. J .; Reek, J . N. H.; Kamer, P.
C. J .; van Leeuwen, P. W. N. M. Chem. Commun. 1999, 1119-1120.
(14) Hawker, C. J .; Fre´chet, J . M. J . J . Chem. Soc., Chem. Commun.
1990, 1010-1013.
(19) Ihre, H.; Padilla de J esus, O. L.; Fre´chet, J . M. J . J . Am. Chem.
Soc. 2001, 123, 5908-5917.
(20) Ihre, H.; Hult, A.; Fre´chet, J . M. J .; Gitsov, I. Macromolecules
1998, 31, 4061-4068.
(21) DPTS stands for 4-(dimethylamino)pyridinium p-toluene-
sulfonate and is used together with DCC to produce high molecular
weight polyesters: Moore, J . S.; Stupp, S. I. Macromolecules 1990, 23,
65-70.
(22) Bremberg, U.; Rahm, F.; Moberg. C. Tetrahedron: Asymmetry
1998, 9, 3437-3443.
(15) Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638-7647.
(16) Tomalia, D. A.; Baker, H.; Dewald, J .; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J .; Ryder, J .; Smith, P. Polym. J . (Tokyo) 1985, 17,
117-132.
(17) Newkome, G. R.; Yao, Z.-q.; Baker, G. R.; Gupta, V. K. J . Org.
Chem. 1985, 50, 2003-2004.
(18) An achiral dendritic bisoxazoline ligand has previously been
reported: Chow, H.-F.; Mak, C. C. J . Org. Chem. 1997, 62, 5116-5127.
8198 J . Org. Chem., Vol. 67, No. 23, 2002

Enantioselective Palladium-Catalyzed Allylic Alkylations
TABLE 1. En a n tioselective Allylic Alk yla tion s w ith
Liga n d s 13 a n d 14
dron 10 gave (R)-13d and (S)-13e from 11 and ent-11,
respectively, and (S,S)-14c and (R,R)-14d from 12 and
ent-12, respectively.
ligand
reaction time, h
yield, %
ee, %, product
(S)-13a
(S)-13b
(R)-13c
(R)-13d
96
96
96
96
96
48
96
96
24
100
100
67-95
100
76-98
89
10
100
83
80 (S)
78 (S)
76 (R)
79 (R)
77 (R)11
92 (S)
88 (S)
94 (S)
81 (S)
(R)-13f11
(S,S)-14a
(S,S)-14b
(S,S)-14c
(S,S)-14e
83% yield of product after 24 h, and reaction employing
ligand (S,S)-14a afforded 89% yield within 48 h whereas
the ligand substituted with forth generation dendrons
((S,S)-14b) exhibited low reactivity, yielding merely 10%
of product after a reaction time of 96 h. Contrary to
expectations,25 high enantioselectivity was thus achieved
employing polar dendritic wedges, the polar substituents
probably not competing for catalytic sites.
The introduction of a chiral dendritic substituent on
the alcohol 11 had no effect on the enantioselectivity, the
two diastereomers (R)-13d and (S)-13e both resulting in
79% ee. This is in analogy to previous observations using
TADDOL ligands substituted with chiral dendritic
wedges.25 In contrast, substitution of 12 with the same
chiral dendron yielded catalyst (S,S)-14c, which exhibited
somewhat higher stereoselectivity (94% ee) than the bis-
(oxazoline) ligands carrying achiral dendrons. The chiral-
ity of the substituents did not, however, influence the
selectivity of the catalytic reaction, as the diastereomeric
ligand (R,R)-14d , obtained from ent-12, afforded a prod-
uct with the same enantioselectivity. To achieve full
conversion in reactions employing the ligands with the
chiral dendrons, extended reaction times were required.
Dendritic substituents thus have different effects on
the two classes of ligands. The lack of influence in the
reactions using the pyridinooxazoline ligands may be
explained by the long distance between the dendritic
substituent and the catalytic center and/or the too high
flexibility of that system. In the bis(oxazoline) series of
ligands the dendritic wedges seem to be situated close
enough to the catalytic center to have an effect on the
stereoselectivity and the reactivity, leading to increased
stereoselectivity but, unfortunately, to a decrease in
activity of the catalytic system.
Con clu sion s. Depending on the structure of the
parent ligand, the attachment of dendritic substituents
may either exert little effect on the stereoselectivity and
the activity of the catalytic process or have a beneficial
influence on the selectivity, but at the same time a
detrimental effect on the reactivity of the catalytic
system.
Ca ta lytic Rea ction s. Ligands (S)-13a ,b, (R)-13c,d ,
(S)-13e, (S,S)-14a -c, and (R,R)-14d were assessed in
palladium-catalyzed substitutions of rac-(E)-1,3-diphe-
nylpropenyl acetate with malonate using bis[(π-allyl)-
palladium chloride] as the palladium source in the
presence of BSA and KOAc.23 The results were compared
to those obtained using benzoyl ester ligands (R)-13f and
(S,S)-14e. In the pyridinooxazoline series of ligands with
achiral dendritic wedges ((S)-13a ,b and (R)-13c), the
stereoselectivity achieved using the dendritic catalysts
was similar to that observed using benzoyl ester (R)-13f,
and the yields and reaction times required for full
conversion were about the same for the different types
of catalysts (Table 1).24 However, we were pleased to
observe that use of ligands (S,S)-14a and (S,S)-14b
resulted in high enantioselectivity (88 and 92% ee,
respectively), considerably higher than that using the
benzoyl ester (S,S)-14e (81% ee). The reaction times and
the yields varied considerably in the bis(oxazoline) series
of ligands. Use of the benzoyl ester (S,S)-14e resulted in
Exp er im en ta l Section
Ma ter ia ls a n d Tech n iqu es. 2,2-Bis(hydroxymethyl)pro-
pionic acid (bis-MPA) was obtained commercially. Compounds
1-4 were synthesized according to a procedure described by
Hult et al.19 DPTS was synthesized as described by Moore
and Stupp.21 (1S,2S)-2-Amino-1-phenylpropane-1,3-diol was
(23) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143-
1145. Leutenegger, U.; Umbricht, G.; Fahrni, C.; Von Matt, P.; Pfaltz,
A. Tetrahedron 1992, 48, 2143-2156.
(24) Hallman, K.; Svensson, M.; Moberg, C. To be submitted for
publication.
(25) Rheiner, P. B.; Seebach, D. Chem. Eur. J . 1999, 5, 3221-3236.
J . Org. Chem, Vol. 67, No. 23, 2002 8199

Malkoch et al.
SCHEME 1
Aceton id e-[G#3]-CO2CH2C6H5 (5). DPTS (0.26 g, 0.87
mmol) and N,N′-dicyclohexylcarbodiimide (DCC) (1.45 g, 7.01
mmol) were added to a solution of 2 (0.50 g, 1.10 mmol) and 1
(0.92 g, 5.26 mmol) in CH2Cl2 (10 mL). The mixture was stirred
at room temperature for 72 h and the DCC-urea was filtered
off in a glass filter and washed with small amounts of CH2-
Cl2. The solvent was evaporated and the crude product was
purified by liquid chromatography on silica gel using a
gradient from pure hexane to 80:20 ethyl acetate:hexane to
give 5 as a colorless viscous oil (1.03 g, 87%). TLC (silica)
SCHEME 2
1
hexane:ethyl acetate 40:60, Rf 0.4; H NMR δ 1.12 (s, 12H),
1.18 (s, 6H), 1.26 (s, 3H), 1.33 (s, 12H), 1.39 (s, 12H), 3.59 (d,
8H, J ) 12.2 Hz), 4.12 (d, 8H, J ) 12.2 Hz), 4.15-4.29 (m,
12H), 5.14 (s, 2H), 7.28-7.34 (m, 5H);13C NMR δ 17.54, 18.48,
22.07, 25.10, 25.39, 42.01, 46.68, 46.79, 64.87, 65.66, 65.89,
65.94, 65.99, 67.16, 67,93, 98.07, 128.43, 128.50, 128.66,
135.35, 171.80, 171.90, 173.44.
(HO)8-[G#3]-CO2CH2C6H5 (6). Compound 5 (0.84 g, 0.78
mmol) was dissolved in MeOH (20 mL) and one teaspoon of
DOWEX, H+ resin was added. The mixture was allowed to
react for 3 h at 50 °C to give 6 as white crystals (0.63 g, 86%).
1H NMR (DMSO) δ 1.01 (s, 12H), 1.10 (s, 6H), 1.21 (s, 3H),
3.34-3.49 (m, 8H), 4.05-4.10 (m, 8H), 4.18, 4.24 (AB system,
4H, J ) 11.0 Hz), 4.66 (app t, 8H, J ) 5.3 Hz), 5.18 (s, 2H),
7.35 (m, 5H); 13C NMR (DMSO) δ 16.72, 17.03, 17.07, 46.27,
46.33, 50.3, 63.72, 64.52, 65.82, 66.41, 127.94, 128.23, 128.55,
135.70, 171.88, 171.95, 174.11. The hydroxy protons (8H) were
not observed.
obtained commercially. 2,2-Bis[(4S,5S)-4-hydroxymethyl-5-
phenyl-1,3-oxazolin-2-yl]propane was obtained according to a
described procedure.26 CH2Cl2 was distilled from CaH2 before
use. 1H NMR and 13C NMR spectra were recorded at 400.1
and 100.6 MHz, respectively, in CDCl3, unless otherwise
stated. The solvent signal was used as internal standard. All
purifications were performed by medium-pressure liquid chro-
matography or by flash chromatography. Enantiomeric ex-
cesses were determined by HPLC using a chiral column
(Chiralcel OD-H, 0.5 mL/min, 99:1 hexane:propan-2-ol).
Aceton id e-[G#4]-CO2CH2C6H5 (7). This compound was
prepared and purified according to the procedure described
for 5, starting from DPTS (0.63 g, 2.13 mmol), DCC (3.50 g,
17.0 mmol), 6 (1.00 g, 1.09 mmol), 1 (2.22 g, 12.8 mmol), and
(26) Aggarwal, V. K.; Bell, L.; Coogan, M. P.; J ubault, P. J . Chem.
Soc., Perkin Trans. 1 1998, 2037-2042.
8200 J . Org. Chem., Vol. 67, No. 23, 2002

Enantioselective Palladium-Catalyzed Allylic Alkylations
CH2Cl2 (15 mL) to give 7 as a colorless viscous oil (1.0 g, 43%).
1.36 (s, 3H), 1.40 (s, 6H), 3.59 (d, 4H, J ) 11.8 Hz), 4.13 (d,
4H, J ) 11.8 Hz), 4.36-4.43 (m, 5H), 4.90 (dd, 1H, J ) 10.3
and 8.6 Hz), 5.39 (s, 2H), 5.43 (dd, 1H, J ) 10.3 and 8.6 Hz),
7.27-7.39 (m, 5H), 7.49 (d, 1H, J ) 7.7 Hz), 7.82 (app t, 1H,
J ) 7.8 Hz), 8.11 (d, 1H, J ) 7.7 Hz); 13C NMR δ 17.76, 18.47,
21.96, 25,22, 42.08, 46.95, 65.27, 65.93, 65.98, 67.31, 70.34,
75.46, 98.10, 123.44, 123.59, 126.82, 127.78, 128.80, 137.58,
141.69, 146.39, 155, 87, 163. 52, 172.12, 173.54. HRMS (EI)
calcd for C36H46N2O11 682.3102, found 683.3186 (MH+).
(4′R)-2-(Acet on id e-[G#4]-COOCH2)-6-(4′,5′-d ih yd r o-4′-
p h en yl-2′-oxa zolyl)p yr id in e ((R)-13c). (R)-13c was pre-
pared according to the procedure described for 5, starting from
DCC (0.35 mg, 0.118 mmol), DPTS (39 mg, 19 µmol), 11 (30
mg, 0.118 mmol), 8 (0.29 g, 0.142 mmol), and CH2Cl2 (5 mL).
The mixture was stirred for 48 h at room temperature and
purified as described for 5 using a gradient from pure hexane
to 80:20 ethyl acetate:hexane to give (R)-13c as a colorless
viscous oil (82 mg, 30%). TLC (silica) ethyl acetate:hexane 80:
20, Rf 0.3; [R]20D +4.9 (c 1.1, CH2Cl2); 1H NMR δ 1.11 (s, 24H),
1.21 (s, 6H), 1.24 (s, 12H), 1.31 (s, 24H), 1.34 (s, 3H), 1.38 (s,
24H), 3.60 (d, 16H, J ) 11.8 Hz), 4.13 (d, 16H, J ) 11.8 Hz),
4.15-4.40 (m, 29H), 4.89 (dd, 1H, J ) 10.2 and 8.7 Hz), 5.36
(s, 2H), 5.44 (app t, 1H, J ) 9.4 Hz), 7.27-7.38 (m, 5H), 7.52
(d, 1H, J ) 7.6 Hz), 7.87 (app t, 1H, J ) 7.8 Hz), 8.11 (d, 1H,
J ) 7.8 Hz); 13C NMR δ 17.57, 17.78, 18.57, 22.06, 25.35, 42.11,
46.78, 46.82, 46.90, 64.87, 65.53, 65.99, 66.04, 66.35, 67.61,
70.37, 75.55, 98.20, 123.76, 123.82, 126.92, 127.89, 128.90,
137.92, 141.77, 146.48, 155.74, 163.62, 171.52, 171.61, 171.91,
173.56. Some of the quaternary carbon atoms were not visible.
Spectral data were in accordance with those published.19
(1R,2S,5R)-(2-Isop r op yl-5-m eth ylcycloh exyl-1-oxy)a ce-
tic-[G#1]-COOCH2C6H5 (9). (1R,2S,5R)-Menthoxyacetic acid
(2.30 g, 10.7 mmol), benzyl-2,2-bis(methylol)propionate 3 (1.00
g, 4.46 mmol), and DPTS (0.52 g, 1.79 mmol) were mixed in
CH2Cl2 (20 mL) and DCC (3.00 g, 13.4 mmol) was added. The
mixture was stirred for 18 h at room temperature, and the
DCC-urea was filtered off in a glass filter and washed with
small amounts of CH2Cl2. The solvent was evaporated and the
crude product was purified by liquid chromatography on silica
gel, using a gradient from pure hexane to 20:80 ethyl acetate:
hexane to give 9 as a colorless viscous oil (2.31 g, 84%). TLC
(silica) ethyl acetate:hexane 20:80, Rf 0.6; 1H NMR δ 0.71-
0.93 (m, 24H), 1.19-1.26 (m, 7H), 1.58-1.65 (m, 4H), 1.98-
2.03 (m, 2H), 2.20-2.27 (m, 2H), 3.10 (dt, 2H, J ) 10.7 and
4.2 Hz), 3.96, 4.03 (AB system, 2H, J ) 16.3 Hz), 3.97, 4.05
(AB system, 2H, J ) 16.3 Hz), 4.25-4.30 (m, 4H), 5.02 (s, 2H),
7.30-7.36 (m, 5H);13C NMR δ 16.25, 17.70, 22.25, 23.26, 25.47,
31.46, 34.36, 39.93, 46.35, 48.04, 65.37, 65.40, 65.62, 66.84,
80.32, 128.13, 128.37, 128.57, 135.51, 170.30, 172.24.
(1R,2S,5R)-(2-Isop r op yl-5-m eth ylcycloh exyl-1-oxy)a ce-
tic-[G#1]-COOH (10). Pd/C (10%) (0.23 g) was added to a
solution of 9 (2.3 g, 3.7 mmol) in ethyl acetate (50 mL). The
mixture was stirred vigorously and the flask was evacuated
and filled with H2 (g). After 18 h the reaction was complete.
The Pd/C was filtered through a glass filter and washed with
small amounts of ethyl acetate. The solvent was evaporated
to give 10 as a colorless oil (1.9 g, 97%); [R]25 -65 (c 0.31,
D
1
(4′R,1′′R,2′′S,5′′R)-2-(4′,5′-Dih ydr o-4′-ph en yl-2′-oxazolyl)-
6-[(2′′-isopr opyl-5′′-m eth ylcycloh exyl-1′′-oxy)acetic-[G#1]-
COOCH2]p yr id in e ((R)-13d ). (R)-13d was prepared accord-
ing to the procedure described for 5, starting from DPTS (12
mg, 40 µmol), DCC (57 mg, 0.28 mmol), 11 (50 mg, 0.197
mmol), 10 (0.114 g, 0.216 mmol), and CH2Cl2 (5 mL). The
mixture was stirred for 48 h at room temperature and purified
as described for 5 using a gradient from pure hexane to 60:40
hexane:ethyl acetate to give (R)-13d as a colorless viscous oil
(24 mg, 16%). TLC (silica) hexane:ethyl acetate 60:40, Rf 0.5;
CH2Cl2); H NMR δ 0.70-0.93 (m, 24H), 1.19-1.25 (m, 7H),
1.56-1.62 (m, 4H), 1.92-2.04 (m, 2H), 2.19-2.24 (m, 2H), 3.12
(dt, 2H, J ) 10.6 and 4.1 Hz), 4.04, 4.12 (AB system, 4H, J )
16.3 Hz), 4.22-4.31 (m, 4H), 10.9 (br s, 1H);13C NMR δ 16.15,
17.67, 20.82, 22.14, 23.17, 25.38, 31.37, 34.27, 39.84, 45.96,
47.96, 64.94, 64.98, 65.63, 80.34, 170.24, 177.71.
(4′S)-2-(4′,5′-Dih yd r o-4′-p h en yl-2′-oxa zolyl)-6-(h yd r oxy-
m eth yl)p yr id in e ((ent)-11). This compound was synthesized
from (S)-phenylglycinol using the procedure published for
(4′R)-2-(4′,5′-dihydro-4′-phenyl-2′-oxazolyl)-6-(hydroxymethyl)-
pyridine. The spectral data were identical with those of the
[R]20 -34,3 (c 0.59, CH2Cl2);1H NMR δ 0.76-1.0 (m, 24H),
D
1.20-1.40 (m, 7H), 1.55-1.65 (m, 4H), 1.94-2.05 (m, 2H), 2.24
(m, 2H), 3.12 (dt, 2H, J ) 10.6 and 4.2 Hz), 4.04, 4.11 (AB
system, 2H, J ) 16.3 Hz), 4.05, 4.13 (AB system, 2H, J ) 16.3
Hz), 4.30-4.43 (m, 5H), 4.90(dd, 1H, J ) 10.3 and 8.8 Hz),
5.38 (s, 2H), 5.44 (app t, 1H, J ) 9.4 Hz), 7.27-35 (m, 5H),
7.45 (d, 1H, J ) 7.8 Hz), 7.82 (app t, 1H, J ) 7.8 Hz), 8.11 (d,
1H, J ) 7.8 Hz);13C NMR δ 16.38, 17.97, 21.08, 22.41, 23.35,
25.60, 31.59, 34.48, 40.06, 46.58, 48.17, 65.46, 65.84, 67.43,
70.47, 75.64, 80.50, 123.50, 123.75, 126.98, 127.95, 128.96,
137.73, 141.79, 146.49, 155.97, 163.63, 170.50, 172.13. HRMS
(EI) calcd for C44H62N2O9 762.4455, found 763.4504 (MH+).
enantiomer.22 [R]20 -48.7 (c 0.27, CH2Cl2).
D
(4′S)-2-(Acet on id e-[G#1]-COOCH 2)-6-(4′,5′-d ih yd r o-4′-
p h en yl-2′-oxa zolyl)p yr id in e ((S)-13a ). (S)-13a was pre-
pared according to the procedure described for 5, starting from
DPTS (5 mg, 17 µmol), DCC (20 mg, 0.099 mmol), (S)-11 (22
mg, 0.083 mmol), 1 (22 mg, 0.091 mmol), and CH2Cl2 (1 mL).
The mixture was stirred for 24 h at room temperature and
purified by chromatography as described for 5 using a gradient
from pure hexane to 60:40 ethyl acetate:hexane to give (S)-
20
13a as a colorless viscous oil (18 mg, 64%): [R]D -30.5 (c
0.90, CH2Cl2); 1H NMR δ 1.23 (s, 3H), 1.41 (s, 3H), 1.46 (s,
3H), 3.69 (d, 2H, J ) 11.9 Hz), 4.13 (d, 2H, J ) 11.9 Hz), 4.39
(app t, 1H, J ) 8.5 Hz), 4.89 (dd, 1H, J ) 10.2 and 8.6 Hz),
5.39-5.47 (m, 3H), 7.26-7.40 (m, 5H), 7.57 (d, 1H, J ) 7.8
(4′S,1′′R,2′′S,5′′R)-2-(4′,5′-Dih ydr o-4′-ph en yl-2′-oxazolyl)-
6-[(2′′-isopr opyl-5′′-m eth ylcycloh exyl-1′′-oxy)acetic-[G#1]-
COOCH2]p yr id in e ((S)-13e). (S)-13e was prepared according
to the procedure described for 5, starting from DPTS (12 mg,
40 µmol), DCC (57 mg, 0.28 mmol), (S)-11 (50 mg, 0.20 mmol),
10 (0.114 g, 0.22 mmol), and CH2Cl2 (5 mL). The mixture was
stirred for 72 h at room temperature and purified as described
for 5 using a gradient from pure hexane to 40:60 ethyl acetate:
hexane to give (S)-13e as a colorless viscous oil (46 mg, 31%).
Hz), 7.81 (app t, 1H, J ) 7.8 Hz), 8.09 (d, 1H, J ) 7.8 Hz); 13
C
NMR δ 18.56, 21.86, 25.58, 42.11, 66.20, 66.73, 70.37, 75.49,
98.22, 123.11, 123.39, 126.87, 127.81, 128.84, 137.53, 141.79,
146.25, 156.61, 163.67, 173.85. HRMS (EI) calcd for C23H26N2O5
410.1842, found 411.1899 (MH+).
20
(4′S)-2-(Acet on id e-[G#2]-COOCH 2)-6-(4′,5′-d ih yd r o-4′-
p h en yl-2′-oxa zolyl)p yr id in e ((S)-13b). (S)-13b was pre-
pared according to the procedure described for 5, starting from
DPTS (23 mg, 79 µmol), DCC (130 mg, 0.63 mmol), ent-11 (0.10
g, 0.39 mmol), 4 (0.21 g, 0.39 mmol), and CH2Cl2 (0.5 mL).
The mixture was stirred for 48 h at room temperature. The
thick mixture was filtered through Celite and the product was
eluted from the Celite with diethyl ether. The solvent was
evaporated and the product was purified by flash chromatog-
raphy on silica gel with hexane:ethyl acetate 1:1 as eluent to
TLC (silica) hexane:ethyl acetate 40:60, Rf 0.4; [R]D -71,8 (c
1.2, CH2Cl2); 1H NMR δ 0.76-1.0 (m, 24H), 1.20-1.40 (m, 7H),
1.55-1.65 (m, 4H), 1.98-2.07 (m, 2H), 2.18-2.28 (m, 2H), 3.12
(dt, 2H, J ) 10.6 and 4.1 Hz), 4.026, 4.12 (AB system, 2H, J
) 16.3 Hz), 4.034, 4.11 (AB system, 2H, J ) 16.3 Hz), 4.30-
4.45 (m, 5H), 4.89 (dd, 1H, J ) 10.3 and 8.6 Hz), 5.38 (s, 2H),
5.44 (dd, 1H, J ) 10.2 and 8.6 Hz), 7.27-35 (m, 5H), 7.46 (d,
1H, J ) 7.7 Hz), 7.82 (app t, 1H, J ) 7.8 Hz), 8.11 (d, 1H, J )
7.4 Hz);13C NMR δ 16.41, 17.95, 21.06, 22.39, 23.40, 25.63,
31.60, 34.50, 40.09, 46.62, 48.21, 65.47, 65.87, 67.42, 70.45,
75.62, 80.54, 123.50, 123.74, 126.95, 127.93, 128.95, 137.69,
141.79, 146.50, 156.00, 163.67, 170.46, 172.12.
20
give (S)-13b as a colorless oil (0.10 g, 38%). [R]D -23.4
(c 0.85, CH2Cl2); 1H NMR δ 1.11 (s, 6H), 1.33 (s, 6H),
J . Org. Chem, Vol. 67, No. 23, 2002 8201

Malkoch et al.
(4′S ,5′S )-2,2-B is [4′,5′-d ih y d r o -4′-(a c e t o n id e -[G #1]-
COOCH2)-5′-p h en yl-2′-oxa zolyl]p r op a n e ((S,S)-14a ). This
compound was prepared according to the procedure described
for 5, starting from DPTS (15 mg, 0.005 mmol), DCC (78 mg,
0.38 mmol), (S,S)-12 (50 mg, 0.13 mmol), 1 (53 mg, 0.30 mmol),
and CH2Cl2 (2 mL). The mixture was stirred for 48 h at room
temperature and purified as described for 5 using a gradient
from pure hexane to 60:40 ethyl acetate:hexane to give (S,S)-
14a as a viscous oil (56 mg, 63%). TLC (silica) hexane:ethyl
acetate 40:60, Rf 0.70; [R]20D -25.6 (c 0.43, CH2Cl2);1H NMR δ
1.09 (s, 6H), 1.34 (s, 6H), 1.39 (s, 6H), 1.68 (s, 6H), 3.56 (dd,
4H, J ) 12.1 and 2.0 Hz), 4.12 (d, 4H, J ) 11.8 Hz), 4.20-
4.30 (m, 4H), 4.44, 4.47 (AB system, 2H, J ) 5.4 Hz), 5.27(d,
2H, J ) 6.5 Hz), 7.25-7.30 (br s, 10H);13C NMR δ 18.64, 22.80,
24.73, 25.06, 34.03, 39.31, 42.11, 65.21, 66.01, 73.84, 83.97,
98.20, 126.06, 128.65, 128.95, 140.18, 170.23, 174.21.
was prepared from (R,R)-12 (80 mg, 0.20 mmol) and 10 (329
mg, 0.625 mmol) using a procedure similar to that used for
the preparation of (S,S)-14c: colorless oil (51 mg, 18%); [R]20
D
1
-32 (c 0.24, CH2Cl2); H NMR δ 0.74-1.0 (m, 48H), 1.12 (s,
6H), 1.22-1.38 (m, 8H), 1.55-1.66 (m, 14H), 1.97-2.02 (m,
4H), 2.18-2.29 (m, 4H), 3.10 (dt, 4H, J ) 10.5 and 3.7 Hz),
3.95-4.27 (m, 20H), 4.42 (d, 2H, J ) 10.3 Hz), 5.26 (d, 2H, J
) 6.6 Hz), 7.25-7.30 (m, 10H); 13C NMR δ 16.25, 17.52, 20.90,
22.23, 23.25, 24.63, 25.46, 31.42, 34.34, 39.15, 39.90, 46.41,
48.02, 65.14, 65.17, 65.64, 65.72, 73.58, 77.20, 80.33, 83.94,
125.87, 128.56, 128.83, 139.95, 170.09, 170.21, 172.18.
2,2-Bis[(4S,5S)-4-m et h ylp h en ylca r b oxy-5-p h en yl-1,3-
oxa zolin -2-yl]p r op a n e ((S,S)-14e). A solution of (S,S)-12
(197 mg, 0.50 mmol), benzoic acid (183 mg, 1.50 mmol), EDCI
(385 mg, 2.01 mmol), and DMAP (12.2 mg, 0.10 mmol) in CH2-
Cl2 (10 mL) was stirred for 48 h at room temperature. The
reaction mixture was poured into 0.025 M HCl and extracted
with ethyl acetate. The organic layer was separated, washed
with water, saturated NaHCO3, and brine, and dried over
MgSO4. The solvent was evaporated and the residue was
purified by flash chromatography (50:50 hexane:ethyl acetate)
to afford (S,S)-14e as a viscous oil that solidified upon cooling
(4′S ,5′S )-2,2-B is [4′,5′-d ih y d r o -4′-(a c e t o n id e -[G #4]-
COOCH2)-5′-p h en yl-2′-oxa zolyl]p r op a n e ((S,S)-14b). This
compound was prepared according to the procedure described
for 5, starting from DPTS (6 mg, 2 µmol), DCC (31 mg, 0.15
mmol), (S,S)-12 (20 mg, 51 µmol), 8 (0.253 g, 0.12 mmol), and
CH2Cl2 (1 mL). The mixture was stirred for 72 h at room
temperature and purified as described for 5 using a gradient
from pure hexane to 100% ethyl acetate to give (S,S)-14b as a
colorless viscous oil (0.100 g, 44%). TLC (silica) hexane:ethyl
20
to 5 °C (300 mg, quantitative): mp 84 °C. [R]D -71 (c 1.00,
1
CHCl3); H NMR δ 1.64 (s, 6H), 4.31 (m, 2H), 4.47 (m, 4H),
5.29 (d, 2H, J ) 6.7 Hz), 7.19 (m, 10H), 7.27 (m, 4H), 7.44 (m,
2H), 7.91 (m, 4H); 13C NMR δ 170.6, 166.7, 140.5, 133.5, 130.1,
129.2, 128.9, 128.8, 126.2, 84.5, 74.2, 66.0, 39.6, 25.2; HRMS
(EI) calcd for C37H34N2O6 602.2417, found 603.2496 (MH+);
Anal. Calcd for C37H34N2O6: C 73.74, H 5.69, N 4.65. Found
C 73.58, H 5.84, N 4.45.
20
1
acetate 20:80, Rf 0.6; [R]D -0.44 (c 4.8, CH2Cl2); H NMR δ
1.14 (s, 48H), 1.14 (s, 6H), 1.27 (s, 24H), 1.28 (s, 12H), 1.34 (s,
48H), 1.41 (s, 48H), 1.67 (s, 6H), 3.61 (d, 32H, J ) 11.6 Hz),
4.16 (d, 32H, J ) 11.6 Hz), 4.16-4.40 (m, 60H), 4.45 (dd, 2H,
J ) 11.0 and 3.9 Hz), 5.30 (d, 2H, J ) 7.3 Hz), 7.26-7.32 (m,
10H); 13C NMR δ 17.38, 17.63, 17.79, 18.62, 22.22, 24.88, 25.55,
39.25, 42.13, 46.46, 46.77, 46.92, 64.88, 65.47, 66.00, 66.06,
98.18, 126.30, 128.96, 139.83, 170.20, 171.20, 171.51, 171.90,
173.54. Some of the carbon atoms from the bis(oxazoline)
structure were not visible due to a low relative concentration.
(4′S,5′S,1′′R,2′′S,5′′R)-2,2-Bis[4′,5′-d ih yd r o-4′-[(2′′-iso-
pr opyl-5′′-m eth ylcycloh exyl-1′′-oxy)acetic-[G#1]-COOCH2]-
5′-p h en yl-2′-oxa zolyl]p r op a n e ((S,S)-14c). DMAP (14 mg,
0.12 mmol) and EDCI (67 mg, 0.35 mmol) were added to a
solution of (S,S)-12 (46 mg, 0.12 mmol) and 10 (0.16 g, 0.30
mmol) in CH2Cl2 (2 mL). The mixture was stirred for 24 h at
room temperature and diluted with CH2Cl2. After extraction
with 10% NaHSO4 and brine the solvent was evaporated and
the product was purified by liquid chromatography on silica
gel, using a gradient from pure hexane to 60:40 ethyl acetate:
hexane to give (S,S)-14c as a colorless viscous oil (40 mg, 24%).
Gen er a l P r oced u r e for th e Ca ta lytic Rea ction s. Ligand
(0.029 mmol, 6 mol %) and [(η3-C3H5)PdCl]2 (3.5 mg, 9.6 µmol,
2 mol %) were dissolved in CH2Cl2 (1 mL) under dry conditions.
The solution was degassed at -78 °C and put under nitrogen
atmosphere before the reaction vessel was sealed. The reaction
mixture was stirred for 2 h at 50 °C and then cooled to -78
°C. 1,3-(E)-Diphenyl-2-propenyl acetate (121 mg, 0.480 mmol)
was transferred to the reaction vessel with CH2Cl2 (1 mL).
N,O-Bis(trimethylsilyl)acetamide (292 mg, 1.44 mmol), dim-
ethyl malonate (142 mg, 1.07 mmol), and KOAc (2-3 mg,
∼0.025 mmol, ∼5 mol %) were added. The reaction vessel was
degassed at -78 °C under nitrogen. The mixture was stirred
at room temperature for the appropriate time before saturated
aqueous NH4Cl was added and the mixture was extracted with
diethyl ether. The organic phase was dried over MgSO4 and
filtered, and the solvent was evaporated. Residual BSA and
dimethyl malonate were removed with short path distillation
under vacuum at 90 °C.
TLC ethyl acetate:hexane 60:40, Rf 0.7; [R]20 -68.6 (c 0.26,
D
CH2Cl2);1H NMR δ 0.76-1.0 (m, 48H), 1.13 (s, 6H), 1.20-1.40
(m, 8H), 1.55-1.67 (m, 14H), 1.98-2.02 (m, 4H), 2.20-2.30
(m, 4H), 3.10 (dt, 4H, J ) 10.5 and 4.0 Hz), 3.95-4.28 (m,
20H), 4.42 (d, 2H, J ) 8.3 Hz), 5.26 (d, 2H, J ) 6.8 Hz), 7.25-
7.30 (m, 10H);13C NMR δ 16.36, 17.67, 21.08, 22.39, 23.34,
24.77, 25.57, 31.57, 34.46, 39.29, 40.01, 46.52, 48.14, 65.24,
65.80, 73.67, 80.42, 80.49, 84.10, 126.05, 128.72, 129.00,
140.03, 170.25, 170.39, 172.34. HRMS (EI)calcd for C81H122N2O18
1410.8693, found 1411.8779 (MH+).
Ack n ow led gm en t. This work was supported by the
Swedish Research Council and by the Swedish Founda-
tion for Strategic Research.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 5, 6, 9, 10, (S)-13a -c, (R)-13d , (S)-13e,
(S,S)-14a -c, and (R,R)-14d . This material is available free of
charge via the Internet at http://pubs.acs.org.
(4′R,5′R,1′′R,2′′S,5′′R)-2,2-Bis[4′,5′-d ih yd r o-4′-[(2′′-iso-
pr opyl-5′′-m eth ylcycloh exyl-1′′-oxy)acetic-[G#1]-COOCH2]-
5′-p h en yl-2′-oxa zolyl]p r op a n e ((R,R)-14d ). This compound
J O0200116
8202 J . Org. Chem., Vol. 67, No. 23, 2002