New, optically active phosphine oxazoline (JM-phos) ligands: Syntheses and applications in allylation reactions

Article abstract of DOI:10.1021/jo001333h

Three different syntheses of the phosphine oxazoline systems 1 are presented. Two of these approaches are divergent routes designed to involve an advanced intermediate that can be transformed into several different end-products. The third is a shorter route specifically designed to facilitate preparations of these systems on a larger scale using minimal functional group protection. Overall, eight different phosphine oxazolines were prepared. These were screened in several palladium-mediated allylation reactions. They proved to be most useful for asymmetric alkylation of 3-acetoxy-1,3-diphenylpropene and less suitable/effective for the more challenging substrates (a pentenyl derivative and a cyclohexenyl system). X-ray crystallographic analysis of the complex [(η³-PhCHCHCHPh)Pd(1a)][PF₆] led to the conclusion that the origins of asymmetric induction in these systems might be indirectly attributed to interaction of the oxazoline-phenyl substituent with the palladium and with an allyl-phenyl substituent. Finally, data is presented for allylation of a silylenolate of an N-acyl oxazolidinone; excellent enantioselectivities and yields were obtained.

Full text of DOI:10.1021/jo001333h

206
J . Org. Chem. 2001, 66, 206-215
New , Op tica lly Active P h osp h in e Oxa zolin e (J M-P h os) Liga n d s:
Syn th eses a n d Ap p lica tion s in Allyla tion Rea ction s
Duen-Ren Hou, J oseph H. Reibenspies, and Kevin Burgess*
Chemistry Department, Texas A & M University, P.O. Box 30012, College Station, Texas 77842
burgess@tamu.edu
Received September 8, 2000
Three different syntheses of the phosphine oxazoline systems 1 are presented. Two of these
approaches are divergent routes designed to involve an advanced intermediate that can be
transformed into several different end-products. The third is a shorter route specifically designed
to facilitate preparations of these systems on a larger scale using minimal functional group
protection. Overall, eight different phosphine oxazolines were prepared. These were screened in
several palladium-mediated allylation reactions. They proved to be most useful for asymmetric
alkylation of 3-acetoxy-1,3-diphenylpropene and less suitable/effective for the more challenging
substrates (a pentenyl derivative and a cyclohexenyl system). X-ray crystallographic analysis of
the complex [(η3-PhCHCHCHPh)Pd(1a )][PF6] led to the conclusion that the origins of asymmetric
induction in these systems might be indirectly attributed to interaction of the oxazoline-phenyl
substituent with the palladium and with an allyl-phenyl substituent. Finally, data is presented
for allylation of a silylenolate of an N-acyl oxazolidinone; excellent enantioselectivities and yields
were obtained.
Ch a r t 1
Some chiral ligands are clearly more useful for asym-
metric syntheses than others, but no one structural class
is universally ideal for all transformations. It is also
impossible to confidently predict which of all of the
available asymmetric ligands will be the best for a
particular reaction type. Catalyst discovery and optimi-
zation therefore involves preliminary designs formulated
via chemical intuition, then screening to achieve desir-
able results.1-3 Consequently, even for the best ligand
designs, it is desirable to have access to small focused
libraries, and to have the ability to screen these ef-
ficiently.
This paper concerns chiral phosphine oxazoline ligands.
Invention of the Pfaltz/Helmchen/Williams phosphine
oxazoline4-9 has inspired other groups to design similar
ligands. These ligand types have been extremely useful
in allylation reactions, Heck couplings, and other pro-
cesses.10 Some of these ligands are shown in Chart 1,11-19
(1) Weinberg, W. H.; J andeleit, B.; Self, K.; Turner, H. Curr. Opin.
Solid State Mater. Sci. 1998, 3, 104-110.
(2) Bein, T. Angew. Chem., Int. Ed. 1999, 38, 323-325.
(3) J andeleit, B.; Schaefer, D. J .; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. 1999, 38, 2494-2532.
(4) Dawson, G. J .; Frost, C. G.; Williams, J . M. J . Tetrahedron Lett.
1993, 34, 3149-3150.
(5) Matt, P. V.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566-568.
(6) Matt, P. V.; Loiseleur, O.; Koch, G.; Pfaltz, A. Tetrahedron 1994,
5, 573-584.
(7) Matt, P. V.; Lloyd-J ones, G. C.; Minidis, A. B. E.; Pfaltz, A.;
Macko, L.; Neuburger, M.; Zehnder, M.; Ruegger, H.; Pregosin, P. S.
Helv. Chim. Acta 1995, 78, 265-284.
(8) Sprinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769-1772.
(9) Sprinz, J .; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523-1526.
(10) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
(11) Gilbertson, S. R.; Chang, C.-W. T. J . Org. Chem. 1998, 63,
8424-8431.
and there are others, notably phosphite oxazolines.20 All
of the ligands shown in Chart 1 are derived from amino
alcohols. The chiral pool of readily available, optically
pure amino alcohols is dominated by amino acid deriva-
tives, carbohydrate amines, and compounds such as
(12) Gilbertson, S. R.; Xie, D. Angew. Chem., Int. Ed. 1999, 38,
2750-2752.
(13) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organome-
tallics 1998, 17, 3420-3422.
10.1021/jo001333h CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000

New, Optically Active, Phosphine Oxazoline Ligands
J . Org. Chem., Vol. 66, No. 1, 2001 207
ephedrine. It does not provide a vast and diverse number
of chirons for ligand syntheses.
Previous contributions from our group have com-
mented upon the problem of obtaining libraries of cata-
lysts for high throughput screening in catalytic reac-
tions.21-26 A simple approach to this problem involves
generation of an advanced chiral intermediate then
transformation of this into a small set of chiral coordinat-
ing compounds, i.e., a divergent ligand synthesis. Papers
concerning our first generation phosphine oxazoline
ligand set24,25 and a communication on our second gen-
eration phosphine oxazoline ligand set 126 have com-
mented on potential advantages of these ligand designs
over those shown above. Briefly, the salient points are
that (i) the R-functionality is derived from carboxylic
acids, and the pool of carboxylic acids available is much
larger than for amino alcohols and includes groups with
diverse steric, geometric, and electronic properties; (ii)
the R-functionality is potentially conjugated with the
oxazoline nitrogen so it can be used to tune the ligating
properties of this atom; and (iii) the centrally placed
chiral center in these ligands gives overall geometries
that could be more conducive to asymmetric catalysis of
some transformations and will certainly give somewhat
different reactivity profiles.
This paper gives full details of the divergent synthesis
previously communicated, but applied to prepare a few
more ligands than were originally reported (Scheme 1a).
Two alternative routes are also described; these are
shorter, involve less functional-group protection, and are
therefore suitable for scale-up syntheses of specific
ligands that “test positive” in high-throughput screens
(Scheme 1b and c). Also presented are data from screens
using the ligands in four different palladium-mediated
allylation reactions, including an unusual asymmetric
addition of a chiral silyl enol ether to a π-allyl palladium
complex (Figure 1 and reaction 1). Data from an X-ray
crystallographic study of a palladium π-allyl complex is
also presented.
different phosphine oxazolines (presumably many more
than the eight reported here). However, for scale-up
purposes this approach is not ideal. It is relatively long,
involves an inconvenient separation of isomeric oxazo-
lidines, and protecting groups that increase the length
and decrease the atom economy of the approach. Alterna-
tives were therefore highly desirable for planned large
scale syntheses of the ligands.
Scheme 1b shows the first alternative that was ex-
plored. Like the original synthesis, this begins with
aspartic acid but progresses to the oxazolidinone inter-
mediate 14 and then to the amino alcohol 9. Chiron 9
was the key intermediate used for making a ligand set
in Scheme 1a, so this approach accommodates divergence
to prepare ligand libraries. This route only involves one
less protecting group than the first. However, it is not
significantly shorter and involves one weak step. Specif-
ically, tosylation of the alcohol 12 was difficult to achieve
selectively because the oxazolidinone was also vulnerable
to addition of this reagent. Consequently, the yield of the
tosylation step was only 40%, whereas all of the other
transformations afforded product in 83% yield or more.
We were unable to improve upon this yield or find an
effective alternative to circumvent use of tosylate (brosy-
late, nosylate, and mesylate were tried) in the time
available.
Our most direct synthesis is that shown in Scheme 1c.
This involves significantly fewer steps than the other two
approaches and no protecting groups at all. It is, however,
ligand-specific; the R-functionality is set in the second
step, but for scale-up purposes this is not a disadvantage.
The experimental procedure given in this paper is for
preparation of 3.7 g of ligand 1a . There is no obvious
reason why larger batches of this material should not be
prepared via this third approach, though one chromato-
graphic separation was used in the final step and this
probably sets an upper limit on the scale.
Resu lts a n d Discu ssion
Th r ee Syn th eses of th e Liga n d s. Scheme 1a shows
our original divergent synthesis of the second generation
ligands 1. The main advantage of this route is that the
advanced intermediate 9 can be transformed into many
(14) Zhang, W.; Yoneda, Y.; Kida, T.; Nakatsuji, Y.; Ikeda, I.
Tetrahedron: Asymmetry 1998, 9, 3371-3380.
(15) Strangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53,
16503-16510.
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Org. Chem. 1999, 64, 9374-9380.
(17) J iang, Y.; J iang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997,
38, 215-218.
(18) Ahn, K. H.; Cho, C.-W.; Park, J .; Lee, S. Tetrahedron: Asym-
metry 1997, 8, 1179-1185.
(19) Ogasawara, M.; Yoshida, K.; Kamei, H.; Kato, K.; Uozumi, Y.;
Hayashi, T. Tetrahedron: Asymmetry 1998, 9, 1779-1787.
(20) Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814-1816.
(21) Burgess, K.; Lim, H.-J .; Porte, A. M.; Sulikowski, G. A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 220-222.
(22) Burgess, K.; Moye-Sherman, D.; Porte, A. M. In Molecular
Diversity and Combinatorial Chemistry; Chaiken, I. M., J anda, K. D.,
Eds.; American Chemical Society: Washington, DC, 1996; pp 128-136.
(23) Burgess, K.; Porte, A. M. In Advances in Catalytic Processes;
Doyle, M. P., Ed.; J AI Press: Greenwich, CT, 1997; Vol. 2, pp 69-82.
(24) Porte, A. M.; Reibenspies, J .; Burgess, K. J . Am. Chem. Soc.
1998, 120, 9180-9187.
(25) Burgess, K.; Porte, A. M. Tetrahedron: Asymmetry 1998, 9,
2465-2469.
(26) Hou, D.-R.; Burgess, K. Org. Lett. 1999, 1, 1745-1747.
Ap p lica tion s of th e Liga n d s in Allyla tion Rea c-
tion s. Figure 1 expands upon the data previously re-
ported for the allylation reaction shown using some of
the J M-Phos ligand set.26 Several reasonably bulky

208 J . Org. Chem., Vol. 66, No. 1, 2001
Hou et al.
Sch em e 1. (a ) Or igin a l Diver gen t Syn th esis of th e J M-P h os Liga n d s. (b) Alter n a tive Diver gen t Syn th esis
of th e J M-P h os Liga n d s. (c) Sh or ter Syn th esis of 1a Design ed for Sca le-Up
ligands gave excellent yields and enantioselectivities for
this reaction; in most cases the minor enantiomer of the
product was not detected in chiral HPLC of the crude
material. The full ligand set was not tested because in
three cases the enantioselectivity was perfect to within
experimental error.
the enantioselectivities decrease while the yields obtained
do not vary significantly. We suspect that the diminished
enantioselectivities at higher ligand-to-metal ratios are
a consequence of formation of a competing, catalytically
active, diphosphine allyl complex that does not involve
oxazoline complexation. Others have made similar ob-
servations when using the Pfaltz/Helmchen/Williams
ligand to prepare catalysts in situ.27
Ligand-to-metal ratios in this process are critical, as
indicated in the communication of this work. Figure 1b
shows that as the ligand-to-metal ratios are increased
(27) Lloy-J ones, G. C.; Butts, C. P. Tetrahedron 1998, 54, 901-914.

New, Optically Active, Phosphine Oxazoline Ligands
J . Org. Chem., Vol. 66, No. 1, 2001 209
F igu r e 1. (a) Enantioselectivity and yield data as a function
of the ligands used in the reaction shown. (b) Enantioselec-
tivity and yield data as a function of ligand 1a :metal ratios.
Figure 2 expands on the data set previously reported
for the allylation reaction shown. The data presented in
Figure 2a was obtained under essentially the same
conditions as those used for the previous substrate except
that a higher temperature was used (25 vs 0 °C). Ligand
1d gave the best data (80% ee, 59% yield) in this series.
However, slightly better results were obtained when the
palladium catalyst precursor [(η3-C3H5)PdCl]2 was re-
placed with Pd2(dba)3 to give a chloride free system
(Figure 2b). Screens using the full ligand set gave 80%
ee and 93% yield for the catalyst from ligand 1d , and
82% ee and 77% yield for the catalyst from 1e. Trost28
and then Gilbertson11 have observed that systems with
tetra-n-alkylammonium as the only positive counterion
in the reaction can give superior results in the allylations.
Figure 2c shows a small screen to probe the effects of
added tetra-n-butylammonium fluoride. This modifica-
tion, however, induced a neutral or slightly negative
effect on the enantioselectivities and reduced the yields.
Overall, the best data presented in Figure 2b are as good
or better than that reported for every other palladium-
based allylation catalyst for this substrate, with two
exceptions. One of the ligand systems developed by Trost
F igu r e 2. Enantioselectivity and yield data as a function of
the ligand used in the reaction shown. (a) Using [η3-allyl)-
PdCl]2 as the palladium source. (b) Using Pd2(dba)3 as the
palladium source (dba, dibenzylidene acetone). (c) Using Pd2-
(dba)3 as the palladium source and Bu4NCl in place of KOAc.
gives enantioselectivies of 92% and comparable yields,29
and Helmchen et al. have used their phosphine oxazoline
in a catalyst system that gives 89.5% ee, but only 20%
yield was obtained in 48 h since the reaction temperature
used was -40 °C.30
Figure 3 shows the data obtained in a small screen
using 3-acetoxycyclohexene as a substrate. Like the
(29) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J . J . Am.
Chem. Soc. 1996, 118, 6520-6521.
(30) Wiese, B.; Helmchen, G. Tetrahedron Lett. 1998, 39, 5752-5730.
(28) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1994, 116, 4089-
4090.

210 J . Org. Chem., Vol. 66, No. 1, 2001
Hou et al.
Their observations from crystallographic studies led them
to conclude that the R-substituent on the chiral oxazoline
is relatively close to the palladium and, to avoid this
interaction, the ligand tilts away from the near-square
planar arrangement of the metal coordinating groups.
This tilt induces an edge-to-face orientation of the phenyl
groups on the PPh2 fragment, since one of them is forced
to be much closer to the allyl ligand than the other.
Figure 4a was produced for such a complex using
coordinates obtained from The Cambridge Crystallo-
graphic database,9 and the key interaction between the
metal and the isopropyl group in this complex is indi-
cated.
In the research reported here, a palladium complex
was obtained from the same allyl ligand and the phos-
phine oxazoline 1a (crystallized as hexafluorophosphate
salt; Figure 4b). Direct comparisons between the two
structures are of limited value because the oxazolines
have different R-substituents. Palladium-to-carbon dis-
tances for the nearest C-atom of the isopropyl group in
the first structure and for the oxazoline phenyl-substitu-
ent in the second structure are similar at approximately
3.5 Å. Indeed, the J M-Phos ligand in this complex is tilted
away from the square plane formed by the atoms
coordinated to the palladium, and this Pd-to-oxazoline-
substituent interaction may play a major role in produc-
ing that tilt. It is possible, however, that this is not the
only contributing factor. The main difference between the
two structures is that the oxazoline phenyl-substituent
in the J M-Phos complex is closer to the closest phenyl of
the allyl ligand than the isopropyl group is in the first
structure (approximately 3.5 and 4.1 Å between the
closest C-atoms, respectively). This is true even though
the oxazoline-phenyl and the relevant allyl-phenyl in the
complex of ligand 1a adopt a face-to-face orientation, i.e.,
they align to minimize the contacts in the solid state.
Consequently, we conclude that the oxazoline substitu-
ents project more toward the allyl-phenyl groups in
complexes of the J M-Phos ligands than the corresponding
substituents in similar complexes of the Helmchen/Pfaltz/
Williams phosphine oxazolines.
F igu r e 3. Enantioselectivity and yield data as a function of
the ligands used in the reaction shown.
compounds featured in Figure 2, this is a challenging
substrate for allylations.31 The best data was obtained
for ligand 1d (79% ee, 95% yield). Other ligands can give
superior enantioselectivities and yields in this reaction
(up to approximately 98% ee),28,32,33 but it is recognized
to be more difficult to obtain high enantiomeric excesses
than in some acyclic cases.34
The allylation reactions described above are some of
those most frequently studied in this area of research.
That shown in reaction 1, however, is relatively unusual.
Silyl enolates in palladium-mediated allylations are not
common nucleophiles, and the few literature reports in
this area suggest that the yields in these reactions tend
to be moderate or low.35-40 This was not the case for the
transformation shown in reaction 1. Excellent yields of
product were obtained and, when potassium acetate was
used as an additive, the enantiomeric excesses of the two
diastereoisomers were both high. Unfortunately, the
diastereoselectivity of this reaction was only 2.8:1.0 in
both cases and attempts to improve this value by using
TBAF‚Ph3SiF in place of potassium acetate additive
reduced the enantioselectivity and had no effect on the
diastereoselectivity. The relative stereochemistries of 19a
and 19b were confirmed by taking a X-ray crystal
structure of the syn-derivative 19a .
X-r a y Cr yst a l St r u ct u r e of a P a lla d iu m -Allyl
Com p lex of Liga n d 1a . Helmchen and co-workers have
proposed a model for the origin of asymmetric induction
in allylation of 1,3-diphenyl-3-acetoxypropene involving
catalysts formed from their phosphine oxazoline.30,34
(31) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996, 96, 395-422.
(32) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047-
3050.
(33) Knuhl, G.; Sennhenn, P.; Helmchen, G. J . Chem. Soc., Chem.
Commun. 1995, 1845-1846.
(34) Negishi, E.; J ohn, R. A. J . Org. Chem. 1983, 48, 4098-4102.
(35) Tsuji, J .; Takahashi, K.; Minami, I.; Shimizu, I. Tetrahedron
Lett. 1984, 25, 4783-4786.
Con clu sion s
(36) Tsuji, J . Pure Appl. Chem. 1986, 58, 869-878.
(37) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J .
Tetrahedron 1986, 42, 2971-2977.
The synthetic procedures demonstrated in this paper
enable a small library of phosphine oxazolines 1 to be
prepared. These are similar to, but structurally distinct
from, the well-known Pfaltz/Helmchen/Williams ligand
(38) Carfagna, C.; Mariani, L.; Musco, A.; Sallese, G.; Santi, R. J .
Org. Chem. 1991, 56, 3924-3927.
(39) Saitoh, A.; Misawa, M.; Morimoto, T. Synlett 1999, 483-485.
(40) Wiese, B.; Helmchen, G. Tetrahedron Lett. 1998, 39, 5727-5730.

New, Optically Active, Phosphine Oxazoline Ligands
J . Org. Chem., Vol. 66, No. 1, 2001 211
additional 30 min. L-Aspartic acid (33.27 g, 0.25 mol) was
added in one portion and the solution was heated slowly to
reflux. Refluxing was continued until the reaction was com-
plete (TLC); this took approximately 4 h. The reaction mixture
was then cooled to 25 °C and the solvent was removed under
reduced pressure. Further drying under vacuum gave crude
diethyl L-aspartate hydrochloride 2 as a viscous oil that
crystallized on standing to a white solid, yield 60 g (100%).
This material was used without further purification. Spectral
data for this sample were consistent with those given in the
literature:44,45 13C NMR (75 MHz, d6-DMSO) δ 169.1, 168.2,
70.0, 60.9, 48.5, 34.2, 14.9 and 13.9.
A sample of the diethyl L-aspartate hydrochloride 2 (57.5
g, 0.273 mol) was dissolved in water (59 mL) and dioxane (149
mL) and then cooled to 0 °C. Triethylamine (74 mL, 0.53 mol)
and then di-tert-butyl dicarbonate (74.99 g, 0.34 mol) were
added with stirring. The reaction mixture was then heated at
50 °C for 14 h after which TLC (EtOAc/EtOH 1:1) indicated
complete consumption of the starting material. The solvent
was removed under vacuum, and aqueous citric acid (150 mL,
10% w/v) was added to adjust the pH to 2-3. The aqueous
solution was extracted with ether (4 × 250 mL), and the
combined organic extracts were washed with brine (100 mL),
dried over Na2SO4, andconcentrated under vacuum to give 3
(78.8 g, 99%) as a light yellow oil, which was used without
further purification. Spectral data for this sample were
consistent with those given in the literature:46 1H NMR (300
MHz, CDCl3) δ 5.48 (1H), 4.49 (m, 1H), 4.12 (m, 4H), 2.90 (dd,
J ) 16.8 Hz, J ) 4.6 Hz), 2.76 (d, J ) 4.88 Hz, 1H), 1.46 (s,
9H), 1.21 (t, J ) 7.1 Hz, 3H), 1.20 (t, J ) 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.9, 170.8, 155.4, 79.8, 61.6, 60.9,
49.9, 36.7, 28.2, 14.0 and 13.9.
F igu r e 4. A Chem3D representations of the two allyl com-
plexes shown from data collected via X-ray crystallography.
(S)-2-(ter t-Bu toxyca r bon yla m in o)-1,4-bu ta n ed iol 4. A
stirred solution of (S)-N-BOC diethyl l-asparate 3 (47.41 g, 0.16
mol) in absolute EtOH (770 mL) was cooled in an ice-water
bath, and then sodium borohydride (60.8 g, 1.6 mol) was added
in 10 g portions. The cooling bath was removed when the
reaction subsided, and the reaction mixture was heated slowly
to reflux for 1 h; after this time TLC (EtOAc/EtOH 3:1)
analysis indicated complete consumption of the starting mate-
rial. The reaction mixture was cooled to 25 °C, and the lumps
that formed were broken up to give a slurry that was poured
into brine (450 mL). The mixture was filtered, and the filtrate
was concentrated in a vacuum to ca. 100 mL and extracted
with ether (6 × 300 mL). The insoluble solid material was
extracted by stirring in ether (4 × 1L) for 2 h. The combined
ether extracts were dried over MgSO4, filtered, and concen-
trated to give 4 as a colorless oil (24.4 g, 73%), which
crystallized on standing. Spectral data for this sample were
consistent with those given in the literature:46 1H NMR (200
MHz, d6-DMSO) δ 6.45 (d, J ) 8.4 Hz, 1H), 4.57 (t, J ) 5.6
Hz, 1H), 4.35 (t, J ) 5.1 Hz, 1H), 3.40 (m, 4H), 3.23 (m, 1H),
1.62 (m, 1H), 1.40 (m, 1H), 1.36 (s, 9H); 13C NMR (50 MHz,
d6-DMSO) δ 155.5, 77.4, 63.5, 58.0, 49.6, 34.4, 28.3.
(S)-N-ter t-Bu t oxyca r b on yl-4-(2-h yd r oxy)et h yl-2,2-d i-
m eth yloxa zolid in e 5. 1,1-Dimethoxypropane (87 mL, 0.707
mol) and p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol)
were added to a stirred solution of the diol 4 (14.39 g, 70 mmol)
in CH2Cl2 (319 mL) at 25 °C. The reaction was monitored by
TLC (EtOAc/hexanes 2:1) until complete (36 h). The reaction
mixture was then washed with aqueous NaHCO3 (5%, 2 × 50
mL) and brine (50 mL), dried (MgSO4) ,and concentrated to
form a colorless oil, which crystallized upon standing. The ratio
of the desired five-membered ring product 5 to the undesired
six-membered ring product 6 was 6.4:3.6. Recrystallization
from heptane gave 5 as colorless needles (8.2 g, 48%). Spectral
data for this sample were consistent with those given in the
systems and many other derivatives of these. In allylation
reactions the performance of some of the ligands 1 were
comparable with those developed by Pfaltz, by Helmchen,
and by Williams. The allylations of the silylenolate as
shown in reaction 1 are encouraging, both in terms of
the yields and enantioselectivities obtained; this type of
transformation could be synthetically useful if a means
to control the diastereoselection could be found.
Exp er im en ta l Section
Gen er a l P r oced u r es. High field NMR spectra were re-
corded on Varian XL-200E (1H at 200 MHz and 13C at 50 MHz)
and Unity Plus 300 (1H at 300 MHz, 13C at 75 MHz, and 31P
at 121 MHz) spectrometers. Chemical shifts of 1H and 13C
spectra are referenced to the NMR solvents; 31P spectra are
referenced to H3PO4 (85%) external standard (0 ppm). Melting
points are uncorrected. Optical rotations were measured on
J asco DIP-360 digital polarimeter. Flash chromatography was
performed using silica gel (230-600 mesh). Thin-layer chro-
matography was performed on glass plates coated with silica
gel 60 F254 (E. Merck, Darmstadt, Germany). Dichloromethane
was distilled over CaH2, and THF over Na/benzophenone.
Other solvents were purchased from commercial supplier and
were used without further purification. L-Aspartic acid, 1,1-
dimethoxypropane, acetyl chloride, triethylamine, di-tert-butyl
dicarbonate, ethyl chloroformate, and p-toluenesulfonic acid
monohydrate were purchased from Aldrich. 1,3-Dimethylpro-
penyl pivalate,6 cyclohex-2-enyl acetate,41 and the compounds
10-12 were synthesized following literature procedures.42,43
(S)-N-ter t-Bu toxyca r bon yl Asp a r tic Acid Dieth yl Ester
3. Absolute EtOH (420 mL) was cooled in ice and acetyl
chloride (71.4 mL, 1.03 mol) was added dropwise to generate
HCl in situ. After the addition, the reaction was stirred for an
(44) Lewis, N.; McKillop, A.; Taylor, R. J . K.; Watson, R. J . Synth.
Commun. 1995, 25, 561-568.
(41) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure
Appl. Chem. 1997, 69, 513-518.
(42) Pearson, A. J .; Hsu, S.-Y. J . Org. Chem. 1986, 51, 2505-2511.
(43) Urban, D.; Skrydstrup, T.; Beau, J .-M. Chem. Commun. 1998,
955-956.
(45) Williams, R. M.; Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem.
Soc. 1988, 110, 1547-1557.
(46) Williams, R. M.; Im, M.-N. J . Am. Chem. Soc. 1991, 113, 9276-
9286.

212 J . Org. Chem., Vol. 66, No. 1, 2001
Hou et al.
literature:47 1H NMR (200 MHz, CDCl3) δ 4.17 (m, 1H), 3.97
(m, 1H), 3.86-3.42 (m, 3H), 3.33 (br, 1H), 1.76 (m, 2H), 1.5 (s,
3H), 1.46 (s, 9H); 13C NMR (50 MHz,, CDCl3) δ 153.9, 93.6,
80.9, 68.2, 58.6, 53.9, 37.7, 27.7, 26.3, 24.3.
The minor product (S)-N-tert-butoxycarbonyl-2,2-dimethyl-
4-hydroxymethyl-1,3-oxazine 6 was isolated as a colorless oil
via flash chromatography using EtOAc/hexanes (3:1 v/v) as
eluant: 1H NMR (200 MHz, CDCl3) δ 3.37-3.77 (m, 5H), 1.62
(m, 2H), 1.35 (s, 9H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (50
MHz,, CDCl3) δ 155.0, 101.2, 79.1, 63.8, 57.9, 48.5, 35.7, 28.3,
24.7, 24.6.
0.0 °C; Rf 0.76 (EtOAc/hexane, 3:7 v/v). [R]24 -72.7 (c ) 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.93 (d, J ) 7 Hz), 7.29-
7.49 (m, 13H), 4.34-4.49 (m, 4H), 4.00 (dd, J ) 7.5 Hz, J )
7.5 Hz), 2.24-2.34 (m, 2H), 2.07-2.15 (m, 2H), 1.67-1.85 (m,
4H); 13C NMR (CDCl3, 75 MHz) δ 163.7, 138.6, 138.3, 132.8,
132.6, 128.6, 128.5-128.2, 127.7, 72.2, 67.5 (d, J ) 13.5 Hz),
32.1(d, J ) 16.5 Hz), 24.1(d, J ) 11.5 Hz); 31P NMR (CDCl3,
121 MHz) δ -15.81; HRMS (M+ + 1) m/z calcd for C23H23NOP
360.15170, found 360.15147.
Gen er a l P r oced u r e for P r ep a r a tion of Oxa zolin es 1b -
h . (S)-2-(1-Ad m a n tyl)-4-[(d ip h en ylp h osp h in o)eth yl]oxa -
zolin e 1b. The protected phosphine 8 (500 mg, 1.17 mmol)
was dissolved in 8 mL of MeOH and cooled to 0 °C. Gaseous
HCl was bubbled through the reaction for 5-10 min, and the
MeOH was removed under vacuum. The residue was redis-
solved in 8 mL of 1,2-dichloroethane. Triethylamine (0.44 mL,
4.1 mmol), catalytic 4-(dimethylamino)pyridine (2 mg), and
1-admantanecarbonyl chloride (256 mg, 1.28 mmol) were
added to the solution and stirred for 12 h at room temperature.
Subsequently, borane-THF (1 M, 2 mL, 2 mmol) was added
to the reaction mixture at 0 °C, and stirred for another 10 min.
The reaction mixture was diluted with 15 mL of CH2Cl2,
washed with HCl(aq) (0.5 M, 10 mL × 2) and brine (10 mL),
dried over Na2SO4, filtered, and concentrated. 1,4-Diazobicyclo-
[2.2.2]octane (656 mg, 5.85 mmol) was added to the flask, and
THF (8 mL) was added. This reaction mixture was cooled to 0
°C and methanesulfonyl chloride (86 µL, 1.28 mmol) was
added. The reaction was stirred at 25 °C for 4 h then heated
to 50 °C for another 4 h. The resulting slurry was filtered and
then concentrated at reduced pressure. The crude product was
purified by flash chromatography (SiO2) using EtOAc/hexane
eluant (2:8 v/v) to give 370 mg (0.89 mmol, 75%) of the product
(S)-N-2-ter t-Bu toxyca r bon yl-4-(4-tolu en esu lfon yloxy-
eth yl)-2,2-d im eth yloxa zolid in e 7. Dry, freshly crystallized
p-toluenesulfonyl chloride (1.86 g, 9.8 mmol) and 4-(dimeth-
ylamino)pyridine (10 mg, 0.082 mmol) were added to a solution
of alcohol 5 (2.00 g, 8.15 mmol) in triethylamine (2.6 mL, 18.75
mmol) and CH2Cl2 (20 mL) at 5 °C with stirring. The resulting
solution was protected from moisture and kept at 5 °C until
all of the starting material 5 had reacted (33 h, TLC). A
colorless solid, presumably triethylamine hydrochloride, crys-
tallized out of the reaction and was filtered away. The filtrate
was diluted with CH2Cl2 to a volume of 90 mL, washed with
water (2 × 20 mL) and brine (20 mL), dried over Na2SO4, and
concentrated to give the crude tosylate 7 as a white solid. This
material was purified by dissolving in ether (ca. 330 mL) and
filtering through Celite 545 on a wad of cotton to give 2.95 g
(90%) of 7 as a colorless solid. This material was found to
decompose on standing at room temperature so only limited
characterization data was obtained: [R]24 +3.1 (c ) 1.5,
D
1
CHCl3); H NMR (200 MHz, CDCl3) δ 7.78 (m, 2H), 7.35 (d,
2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1H),
2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).
1b as a colorless oil: Rf 0.76 (EtOAc/hexane, 3:7 v/v); [R]24
D
(S)-N-ter t-Bu t oxyca r b on yl-4-et h ylen ed ip h en ylp h os-
p h in obor a n e-2,2-d im eth yloxa zolid in e 8. n-Butyllithium in
hexanes (1.6 M, 17.1 mL, 27.4 mmol) was added to a solution
of diphenylphosphine (4.52 g, 24.3 mmol) in THF (100 mL) at
0 °C. The orange-red solution was stirred at 0 °C for 30 min.
A solution of tosylate 7 (8.44 g, 21.1 mmol) in THF (60 mL)
was then added dropwise to the solution of the diphenylphos-
phide anion at 0 °C. The reaction mixture was stirred for
another 30 min. Borane-THF complex (1 M, 26 mL, 26 mmol)
was added to the solution at 0 °C and stirred for an additional
20 min. The solvent was removed, and the remaining material
was dissolved in EtOAc (600 mL), washed with 1 M HCl(aq)
(100 mL), saturated NaHCO3 (100 mL), and brine (100 mL),
dried over Na2SO4, and filtered. The solvent was removed
under reduced pressure. The residue was further purified by
column chromatography on silica gel using EtOAc/hexane
eluant (3:7 v/v) to give 8.1 g (18.9 mmol, 90%) of a colorless
oil, which crystallized upon standing at 25 °C: mp 95.0-96.5
1
-47.7 (c ) 1.0, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.43-
7.48 (m, 4H), 7.34-7.41 (m, 6H), 4.14-4.23 (m, 2H), 3.81 (m,
1H), 2.18-2.24 (m, 1H), 2.03-2.08 (m, 3H), 1.90 (m, 3H), 1.64-
1.83 (m, 12H); 13C NMR (CDCl3, 75 MHz) δ 173.5, 138.6, 138.2,
132.9, 132.7, 132.4, 128.6-128.3, 71.5, 66.4 (d, J ) 13.5 Hz),
39.6, 36.5, 35.1, 32.1(d, J ) 16.5 Hz), 28.1, 23.6 (d, J ) 11.5
Hz); 31P NMR (CDCl3, 121 MHz) δ -15.81; HRMS (M+ + 1)
m/z calcd for C27H33NOP 418.22998, found 418.22583.
(S)-2-ter t-Bu t yl-4-[(d ip h en ylp h osp h in o)et h yl]oxa zo-
lin e 1c. This compound was prepared via the same method
used for compound 1b, but beginning with 500 mg (1.17 mmol)
of 8, 117 mg (0.34 mmol, 30%) of the oxazoline 1c was produced
as a colorless oil: Rf 0.68 (EtOAc/hexane, 3:7 v/v); [R]24D -46.9
1
(c ) 1.1, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.78 (s, 2H),
7.38-7.56 (m, 5H), 7.26-7.34 (m, 6H), 4.33-4.47 (m, 2H), 3.97
(t, J ) 7 Hz, 1H), 2.14-2.27 (m, 1H), 2.04-2.12 (m, 1H), 1.70-
1.84 (m, 1H), 1.65-1.70 (m, 1H), 1.33 (s, 18H); 13C NMR
(CDCl3, 75 MHz) δ 174.0, 138.6, 138.2, 132.7, 132.4, 132.1,
128.6-128.3, 72.0, 66.6 (d, J ) 13.5 Hz), 33.2, 32.1(d, J ) 16.5
Hz), 27.8, 23.6 (d, J ) 11.5 Hz); 31P NMR (CDCl3, 121 MHz) δ
-15.37; HRMS (M+ + 1) m/z calcd for C21H27NOP 340.18303,
found 340.18281.
°C; Rf 0.81 (EtOAc/hexane, 1:1 v/v); [R]24 +34.0 (c ) 10.0,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 7.63 (m, 4H), 7.43 (m,
6H), 3.92 (m, 2H), 3.67 (m, 1H), 2.17 (m, 2H), 1.83 (m, 2H),
1.60 (s, 3H), 1.54 (s, 9H), 1.34 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 151.9, 131.9-132.1, 131.2, 128.9, 128.8, 94.0, 19.9,
67.0, 57.4, 28.3, 26.7, 22.9, 22.3, 21.8; 31P NMR (CDCl3, 121
MHz) δ 16.76 (br); HRMS (M + Na+) m/z calcd for C24H35NO3-
PBNa 450.23453, found 450.23672
(S)-2-P h en yl-4-[(diph en ylph osph in o)eth yl]oxazolin e 1a.
The protected phosphine 8 (500 mg, 1.17 mmol) was dissolved
in 8 mL of MeOH and cooled to 0 °C. Gaseous HCl was bubbled
through the reaction for 5-10 min. The MeOH was removed
under vacuum and the residue was redissolved in 8 mL of 1,2-
dichloroethane. Triethylamine (1.5 mL, 9.3 mmol) and benzi-
midic acid ethyl ester hydrochloride48 (230 mg, 1.24 mmol)
were added to the solution, and the reaction was heated to
reflux for 6 h. The solvent was removed, and the crude product
was further purified by column chromatography on silica gel
using EtOAc/hexane eluant (2:8 v/v) to afford oxazoline 1a (210
mg, 0.58 mmol, 50% yield) as a colorless solid: mp 52.5-54
(S)-2-(3,5-Di-ter t-bu tylph en yl)-4-[(diph en ylph osph in o)-
eth yl]oxa zolin e 1d . This compound was prepared via the
same method used to prepare 1b. Beginning with 500 mg (1.17
mmol) of 8, 227 mg (0.48 mmol, 41%) of the oxazoline 1d was
produced as a colorless oil: Rf 0.77 (EtOAc/hexane, 3:7 v/v);
[R]24 -39.5 (c ) 0.6, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.38-7.44 (m, 4H), 7.27-7.37 (m, 6H), 4.21 (m, 1H), 4.12 (m,
1H), 3.80 (dd, J ) 6.3 Hz, J ) 7.8 Hz), 2.14 (m, 1H), 2.01 (m,
1H), 1.60 (m, 2H), 1.57 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
164.4, 150.9, 138.5, 138.3, 132.9, 132.8, 132.6, 128.7-128.4,
127.0, 125.6, 122.5, 72.0, 67.5 (d, J ) 13.5 Hz), 34.9, 32.1(d, J
) 16.5 Hz), 31.4, 24.0 (d, J ) 12.0 Hz); 31P NMR (CDCl3, 121
MHz) δ -15.20; HRMS (M+ + 1) m/z calcd for C31H39NOP
472.27693, found 472.27524.
(S)-2-(3,5-Di-ter t-b u t yl-4-m et h oxyp h en yl)-4-[(d ip h en -
ylp h osp h in o)eth yl]oxa zolin e 1e. This compound was pre-
pared via the same method used to prepare 1b. Beginning with
278 mg (0.65 mmol) of 8, 130 mg (0.26 mmol, 40%) of the
oxazoline 1e was produced as a colorless oil: Rf 0.61 (EtOAc/
hexane, 2:8 v/v); [R]24D -34.8 (c ) 1.2, CHCl3); 1H NMR (CDCl3,
(47) Desimoni, G.; Dusi, G.; Faita, G.; Quadrelli, P.; Righetti, P.
Tetrahedron 1995, 51, 4131-4144.
(48) Ksander, G. M.; J esus, R. d.; Yuan, A.; Ghai, R. D.; Trapani,
A.; McMartin, C.; Bohacek, R. J . Med. Chem. 1997, 40, 495-505.

New, Optically Active, Phosphine Oxazoline Ligands
J . Org. Chem., Vol. 66, No. 1, 2001 213
300 MHz) δ 7.81 (s, 2H), 7.40 (m, 4H), 7.30 (m, 6H), 4.40 (m,
2H), 4.00 (m, 1H), 3.67 (s, 3H), 2.25 (m, 1H), 2.10 (m, 1H),
1.83 (m, 1H), 1.67 (m, 1H), 1.42 (s, 18H); 13C NMR (CDCl3, 75
MHz) δ 164.0, 162.5, 143.9, 138.4, 132.9, 132.6, 128.7-128.4,
126.8, 122.0, 72.0, 67.5 (d, J ) 14 Hz), 64.4, 35.8, 32.1(d, J )
16.5 Hz), 31.9, 24.0 (d, J ) 12.0 Hz); 31P NMR (CDCl3, 121
MHz) δ -15.20; HRMS (M+ + 1) m/z calcd for C32H41NOP
502.28749, found 502.28731.
(35.5 g, 0.15 mol) in absolute EtOH (300 mL) and THF (150
mL). Then sodium borohydride (28.8 g, 0.76 mol) was added
to the solution portionwise at 25 °C. When the reaction became
vigorously, the reaction flask was put into an ice-water bath.
After being stirred at room temperature for 12 h, the reaction
mixture was poured into aqueous citric acid (1 M, 600 mL) at
0 °C and then the solution was extracted with EtOAc (150 mL
× 4). The organic solution was washed with saturated NaCl(aq)
,
(S)-2-Tr ip h en ylm eth yl-4-[(d ip h en ylp h osp h in o)eth yl]-
oxa zolin e 1f. This compound was prepared via the same
method for compound 1b. Beginning with 500 mg (1.17 mmol)
of 8, 191 mg (0.36 mmol, 31%) of the oxazoline 1f was produced
as a colorless oil: Rf 0.71 (EtOAc/hexane, 3:7 v/v); [R]24D -46.6
(c ) 2.9, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.25-7.50 (m,
25H), 4.35 (m, 2H), 4.02 (m, 1H), 2.21 (m, 1H), 2.10 (m, 1H),
1.77 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 169.6, 143.4, 138.4,
138.2, 132.9, 132.6, 132.4, 130.1-126.5, 71.9, 66.8 (d, J ) 13.5
Hz), 61.4, 31.8 (d, J ) 16.5 Hz), 23.7 (d, J ) 11.5 Hz); 31P NMR
(CDCl3, 121 MHz) δ -15.51; HRMS (M+ + 1) m/z calcd for
dried over Na2SO4, filtered, and concentrated to give the diol
11 (23.9 g, 89%) as a white solid: [R]24D -26.4° (c ) 3.04, CH3-
OH); 1H NMR (d6-DMSO, 300 MHz) δ 6.76 (d, J ) 8 Hz, 1H),
3.93 (q, J ) 7 Hz, 2H), 3.58-3.25 (m, 4H), 1.67 (m, 1H), 1.63,
(m, 1H), 1.14, (t, J ) 7 Hz, 3H); 13C NMR (d6-DMSO, 75 MHz)
δ 156.1, 63.5, 59.5, 57.9, 49.9, 34.3, 14.7; HRMS (M+ + 1) m/z
calcd for C7H16NO4 178.10793, found 178.10789.
(S)-4-(2-Hyd r oxyeth yl)-2-oxa zolid in on e 12. Butanediol
11 (19.46 g, 0.11 mol) was dissolved in anhydrous THF (270
mL). Sodium hydride (5.4 g, 0.225 mol) was added to the
solution at 0 °C. The reaction was stirred at 25 °C for 2 h and
refluxed for another 2 h. After being cooled to room temper-
ature, the solution was neutralized with 1 M HCl(aq) and the
solvent was removed under vacuum. The residue was redis-
solved in MeOH (400 mL), dried over Na2SO4, filtered, and
C
36H33NOP 526.22998, found 526.22938.
(S)-2-(9-An th r yl)-4-[(d ip h en ylp h osp h in o)eth yl]oxa zo-
lin e 1g. This compound was prepared via the same method
for compound 11b. Beginning with 500 mg of 8 (1.17 mmol),
27 mg (0.059 mmol, 5%) of the oxazoline 1g was produced as
a light yellow oil: Rf 0.62 (EtOAc/hexane, 3:7 v/v); [R]24D -40.3
evaporated to dryness. The crude 12 (11.4 g, 79%) was obtained
1
as a white solid: [R]24 -11.6° (c ) 2.03, CH3OH); H NMR
D
1
(c ) 1.2, CHCl3); H NMR (CDCl3, 300 MHz) δ 8.52 (s, 1H),
(d6-DMSO, 300 MHz) δ 7.69 (br, 1H), 4.40 (br, 1H), 4.35 (m,
1H), 3.92 (m, 1H), 3.47 (m, 1H), 3.47 (m, 2H), 1.60 (m, 2H);
13C NMR (d6-DMSO, 75 MHz) δ 158.9, 69.5, 57.4, 49.8, 38.0.
(S )-4-[2-(4-Tolu e n e su lfon yloxy)e t h yl]-2-oxa zolid i-
n on e 13. Dry, freshly crystallized p-toluenesulfonyl chloride
(1.6 g, 8.4 mmol) and 4-(dimethylamino)pyridine (20 mg, 0.16
mmol) were added to a solution of alcohol 12 (1.0 g, 7.6 mmol)
and pyridine (15 mL, 0.185 mol) at -10 °C. The resulting
solution was gradually warmed to 25 °C during 12 h. The
reaction mixture was acidified with 2 M HCl (100 mL),
extracted with CH2Cl2 (50 mL × 3), washed with saturated
NaHCO3(aq) and NaCl(aq), dried over Na2SO4, and evaporated.
The crude product was recrystallized twice in EtOAc/hexanes
8.11 (m, 2H), 7.99 (m, 2H), 7.58-7.31 (m, 14H), 4.70 (m, 2H),
4.25 (m, 1H), 2.52 (m, 1H), 2.30 (m, 1H), 1.99 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 163.2, 138.6, 138.4, 138.1, 132.9-132.5,
130.9, 130.0, 129.5, 128.7-128.4, 126.7, 125.3, 125.2, 122.7,
72.5, 68.4 (d, J ) 13.5 Hz), 32.7 (d, J ) 17.0 Hz), 24.5 (d, J )
12.0 Hz); 31P NMR (CDCl3, 121 MHz) δ -15.37; HRMS (M+
1) m/z calcd for C31H27NOP 460.18303, found 460.18362.
+
(S)-2-[1-(2-Eth oxy)n a p h th yl]-4-[(d ip h en ylp h osp h in o)-
eth yl]oxa zolin e 1h . This compound was prepared via the
same method for compound 1b. Beginning with 500 mg of 8
(1.17 mmol), 26 mg (0.059 mmol, 5%) of the oxazoline 1h was
produced as a colorless oil: Rf 0.42 (EtOAc/hexane, 3:7 v/v);
[R]24 -36.0 (c ) 0.4, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
to give 13 (0.75 g, 40%) as a light yellow solid: [R]24 -12.5°
D
D
7.87-7.73 (m, 4H), 7.48-7.21 (m, 12H), 4.53 (m, 2H), 4.15 (q,
J ) 7.2 Hz, 2H), 4.10 (m, 1H), 1.32 (t, J ) 7.2 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 161.9, 155.2, 138.5, 138.3, 132.9-
131.6, 128.6-127.3, 123.9, 114.4, 112.9, 72.0, 67.9 (d, J ) 14.0
Hz), 65.3, 32.4 (d, J ) 16.6 Hz), 24.1 (d, J ) 11.0 Hz), 14.9;
31P NMR (CDCl3, 121 MHz) δ -15.11; HRMS (M+ + 1) m/z
calcd for C29H29NO2P 454.19359, found 454.19542.
(c ) 3.82, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.76 (dd, J )
7 Hz, J ) 2 Hz, 2H), 7.35 (dd, J ) 7 Hz, J ) 2 Hz, 2H), 6.08
(s, 1H), 4.46 (m, 1H), 4.10 (m, 2H), 3.98 (m, 2H), 2.43 (s, 3H),
1.90 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 159.6, 145.3, 130.0,
128.9, 127.8, 69.9, 66.9, 49.8, 34.4, 21.6; HRMS (M+ + 1) m/z
calcd for C12H16NO5S 286.07492, found 286.07627.
(S)-4-[2-(Dip h en ylp h osp h in obor a n e)et h yl]-2-oxa zoli-
d in on e 14. n-Butyllithium in hexanes (1.6 M, 17.1 mL, 27.4
mmol) was added to a solution of diphenylphosphine (2.56 g,
13.7 mmol) in THF (120 mL) at 0 °C. The orange-red solution
was stirred at 0 °C for 30 min. The tosylate 13 (3.74 g, 13.1
mmol) dissolved in THF (50 mL) was added to the solution of
phosphide at 0 °C. The resulting solution was stirred at 0 °C
for 1 h. Borane-THF complex (1 M, 14 mL, 14 mmol) was
added to the solution and stirred for another 30 min. The
reaction was quenched with water (10 mL) and then the
solution was neutralized with 1 M HCl(aq), diluted with ether
(S)-N-Eth oxyca r bon yl-Asp a r tic Acid Dim eth yl Ester
10. MeOH (600 mL) was cooled in ice and acetyl chloride (110
mL, 1.54 mol) was added dropwise to generate HCl in situ.
After the addition, L-aspartic acid (64.3 g, 0.48 mol) was added
to the solution at 0 °C and then the solution was slowly
warmed to reflux. The refluxing was continued for 3 h and
the reaction mixture was cooled to room temperature during
overnight. The solvent was removed under reduced pressure
to give the crude dimethyl L-aspartate hydrochloride as viscous
oil. This crude product was further diluted with water (1.6 L)
and cooled in an ice-water bath, and sodium bicarbonate (210
g, 2.5 mol) was added to the solution carefully. Ethyl chloro-
formate was added to the solution dropwise at 0 °C. After the
addition, the solution was stirred at 25 °C for another 4 h and
the product was formed during this period as colorless oil in
the bottom of the flask. The organic layer was separated and
the aqueous solution was further extracted with EtOAc (200
mL × 4). The combined organic solution was washed with
water, saturated NaCl(aq), dried over Na2SO4, filtered ,and
concentrated to give 10 (101.5 g, 0.44mol, 90%) as a colorless
oil: [R]24D +41.6° (c ) 4.65, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 5.62 (d, J ) 8 Hz, 1H), 4.59 (m, 1H), 4.09 (q, J ) 7 Hz, 2H),
3.73 (s, 3H), 3.66 (s, 3H), 2.99 (dd, J ) 9 Hz, J ) 4 Hz, 1H),
2.82 (dd, J ) 9 Hz, J ) 4 Hz, 1H), 1.22 (t, J ) 7 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 171.2, 171.1, 156.1, 61.2, 52.7, 51.9,
50.2, 36.4, 14.4; HRMS (M+ + 1) m/z calcd for C9H16NO6
234.09776, found 234.09784.
(200 mL), washed with saturated NaHCO3(aq) and NaCl(aq)
,
dried over Na2SO4, and evaporated to yield the oily product
14 (3.9 g, 12.4 mmol, 95%): [R]24 -22.0° (c ) 0.9, CHCl3); 1H
D
NMR (CDCl3, 300 MHz) δ 7.65 (m, 4H), 7.40 (m, 6H), 6.93 (s,
1H), 4.42 (m, 1H), 3.87 (m, 2H), 2.36 (m, 1H), 2,12 (m, 1H),
1.82 (m, 1H), 1.69 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 160.1,
132.1-131.4, 128.9-128.6, 69.6, 52.8 (d, J ) 15 Hz), 28.7, 21.2
(d, J ) 38 Hz); 31P NMR (CDCl3, 121 MHz) δ 16.3; HRMS (M+
- 1) m/z calcd for C17H20NO2BP 312.13247, found 312.13248.
(S)-2-Am in o-4-d ip h en ylp h osp h in obor a n e-1-bu ta n ol 9.
Oxazolidinone 14 (1.0 g, 3.2 mmol) was dissolved in EtOH (10
mL) and NaOH(aq) (1 N, 10 mL). The solution was refluxed for
2.5 h. The reaction mixture was diluted with ether (100 mL),
washed with saturated NH4Cl(aq) (20 mL), NaCl(aq) (20 mL),
dried over Na2SO4, filtered and evaporated to give 9 as a
colorless oil (0.92 g, 99%): [R]24D 1.6° (c ) 2.8, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 7.64 (m, 4H), 7.42 (m, 6H), 6.08 (s, 1H),
3.49 (m, 1H), 3.25 (m, 1H), 2.81 (m, 1H), 2.45 (br, 3H) 2.31
(m, 1H), 2.21 (m, 1H), 1.62 (m, 1H), 1.42 (m, 1H); 13C NMR
(S)-2-(Eth oxyca r bon yla m in o)-1,4-bu ta n ed iol 11. Cal-
cium chloride (35 g, 0.63mol) was added to a solution of 10

214 J . Org. Chem., Vol. 66, No. 1, 2001
Hou et al.
(CDCl3, 75 MHz) δ 132.1, 131.5, 131.2, 129.0, 66.2, 53.5 (d, J
) 14 Hz), 27.4, 22.2 (d, J ) 38 Hz); 31P NMR (CDCl3, 121 MHz)
δ 16.9; HRMS (M+ + 1) m/z calcd for C16H24NOPB 288.16886,
found 288.16995.
to enhance agitation. CH2Cl2 (800 µL) was added to the vial,
and the solution was cooled to 0 °C and allowed to equilibrate
for 0.5 h. Neat dimethyl malonate (46 µL, 0.4 mmol) was
added, followed by N,O-bis(trimethylsilyl)acetamide (100 µL,
0.4 mmol) and a 0.2 M stock solution of 1,3-diphenylpropenyl
acetate (1 mL, 0.2 mmol). The reaction was agitated for 12 h
at 0 °C. The solvent was removed, and the residue was passed
through a short silica plug (20% EtOAc/hexanes). The reaction
mixture was analyzed via HPLC (ChiralCel OD analytical
column; eluting with 99:1 hexanes/2-propanol, flow rate 0.5
mL/min, 254 nm, t1 ) 20.5 min, t2 ) 21.4 min). The HPLC
separation was calibrated using racemic material. The optical
rotation of the product was compared with the literature
rotation to assign absolute configuration (R).8
(S)-N-Ben zoyl-Asp a r t ic Acid Dim et h yl E st er 15. Di-
methyl L-aspartate hydrochloride43 2 (10.0 g, 50 mmol) was
dissolved in CH2Cl2 (150 mL) and triethylamine (20.2 g, 200
mmol). Benzoyl chloride (7.38 g, 52.5 mmol) was added to the
reaction dropwise at 25 °C. After the addition, the reaction
was stirred at 25 °C for another 2 h. The reaction mixture was
diluted with CH2Cl2 (100 mL), washed with HCl(aq) (1 N, 100
mL), saturated NaHCO3(aq) (100 mL), and NaCl(aq) (80 mL),
dried over Na2SO4, filtered, and evaporated to afford 15 (13.0
g, 98%) as a white solid: [R]24 -31.7° (c ) 1.67, CH3OH); 1H
D
NMR (CDCl3, 300 MHz) δ 7.80 (m, 2H), 7.50-7.41 (m, 3H),
7.22 (d, J ) 8 Hz, 1H), 5.03 (m, 1H), 3.76 (s, 3H), 3.67 (s, 3H),
3.12 (dd, J ) 17 Hz, 4 Hz, 1H), 2.95 (dd, J ) 17 Hz, 4 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 171.7, 171.2, 166.8, 133.5, 131.8,
128.5, 127.1, 52.9, 52.0, 48.8, 36.0; HRMS (M+ + 1) m/z calcd
for C13H16NO5 266.10285, found 266.10219.
(S)-2-(Ben zoylam in o)-1,4-bu tan ediol 16. Diester 15 (17.54
g, 66 mmol) and calcium chloride (14.65 g, 13 mmol) were
dissolved in EtOH (150 mL) and THF (75 mL). Sodium
borohydride (9.90 g, 264 mmol) was added to the solution in
several portions at 25 °C. The reaction was exothermic and
kept below 40 °C by an ice-water bath if necessary. After the
addition, the reaction was stirred for another 12 h at room
temperature. The solution was poured into aqueous citric acid
(1 M, 200 mL), extracted with EtOAc (150 mL × 3), washed
with saturated NaCl(aq) (80 mL), dried over Na2SO4, filtered
Meth yl (R)-(E)-2-Meth oxyca r bon yl-3,5-d im eth ylp en t-
4-en oa te. In a nitrogen atmosphere, allylpalladium chloride
dimer (1.8 mg, 0.0049 mmol), the ligand 1a (3.2 mg, 0.009
mmol), and solid potassium acetate (2 mg, 0.02 mmol) were
weighed into a half-dram vial equipped with a small glass bead
to enhance agitation. CH2Cl2 (800 µL) was added to the vial
and allowed to equilibrate for 0.5 h at 25 °C. Neat dimethyl
malonate (46 µL, 0.4 mmol) was added, followed by N,O-bis-
(trimethylsilyl)acetamide (100 µL, 0.4 mmol), and a 0.2 M stock
solution of 1,3-dimethylpropenyl pivalate (1 mL, 0.2 mmol).
The reaction was agitated for 48 h at 25 °C. The solvent was
removed, and the residue was passed through a short silica
plug (20% EtOAc/hexanes). Then the reaction mixture was
analyzed via GC (70 °C; retention time, t1 ) 71.7 min, t2
)
72.9 min; the chiral column was prepared by Vigh et al.;49 30.7
m × 0.25 mm, 30% tert-butyldimethylsilyl cyclodextrin deriva-
tive in OV-1701-vi of 0.25 µm film thickness). The GC
separation was calibrated using racemic material. The optical
rotation of the product was compared with the literature
rotation to assign absolute configuration(R).50
and evaporated to afford 16 (7.41 g, 53%) as a viscous oil: [R]24
D
-27.7 (c ) 3.14, CH3OH); 1H NMR (d6-DMSO, 300 MHz) δ
8.07 (d, J ) 8 Hz, 1H), 7.85 (d, J ) 7 Hz, 2H), 7.49 (m, 2H),
7.33 (d, J ) 6 Hz, 1H), 5.18 (br, 1H), 4.72 (br, 1H), 4.04 (m,
1H), 3.47 (m, 4H), 1.81 (m, 1H), 1.77 (m, 1H); 13C NMR (d6-
DMSO, 75 MHz) δ 166.3, 131.0, 128.1, 127.3, 126.6, 63.3, 62.9,
49.0, 34.0; HRMS (M+ + 1) m/z calcd for C11H16NO3 210.11302,
found 210.11289.
(S)-Cycloh exen e 3-(2′-P r op a n e-1′,3′-d ioic a cid d i-
m eth yl ester ). In a nitrogen atmosphere, allylpalladium
chloride dimer (1.8 mg, 0.0049 mmol), the ligand 1a (3.2 mg,
0.009 mmol), and solid potassium acetate (2 mg, 0.02 mmol)
were weighed into a half-dram vial equipped with a small glass
bead to enhance agitation. Dichloromethane (800 µL) was
added to the vial and allowed to equilibrate for 0.5 h at 25 °C.
Neat dimethyl malonate (46 µL, 0.4 mmol) was added, followed
by N,O-bis(trimethylsilyl)acetamide (100 µL, 0.4 mmol), and
a 0.2 M stock solution of cyclohex-2-enyl acetate(1 mL, 0.2
mmol). The reaction was agitated for 60 h at 25 °C. The solvent
was removed, and the residue was passed through a short
silica plug (20% EtOAc/hexanes). Then the reaction mixture
was analyzed via GC (120 °C; retention time, t1 ) 23.7 min, t2
) 24.4 min; the chiral column was prepared by Vigh et al.;49
30.7 m × 0.25 mm, 30% â-tert-butyldimethylsilyl cyclodextrin
derivative in OV-1701-vi of 0.25 µm film thickness). The GC
separation was calibrated using racemic material. The optical
rotation of the product was compared with the literature
rotation to assign absolute configuration (S).28,51
3-((Z)-1-Tr im eth ylsilyloxypr o-1-en yl)-2-oxazolidon e (18).
Sodium bis(trimethylsilyl)amide (1 M in THF, 1.54 mL, 1.54
mmol) was added to the solution of 3-propionyl-oxazolidin-2-
one52 (200 mg, 1.40 mmol) in THF (4 mL) at -78 °C. Then
trimethylsilyl chloride (250 µL, 1.96 mmol) was added to the
solution at -78 °C and the reaction was slowly warmed to
room temperature in 5 h. The solvent was removed in a
vacuum and the residue was dissolved in CH2Cl2 (10 mL). The
resulting solution was filtered through a short silica plug,
concentrated to give 18 as a colorless oil (231 mg, 1.07 mmol,
77%). Spectral data for this compound were consistent with
those given in the literature.53
(S)-2-P h en yl-4-[2-(p-tolu en esu lfon yl)eth yl]oxazolin e 17.
Diol 16 (105 mg, 0.50 mmol) was dissolved in CH2Cl2 (4 mL)
and triethylamine (0.42 mL, 3.0 mmol) and cooled to 0 °C.
p-Toluenesulfonyl chloride (287 mg, 1.51 mmol) was added to
the solution in one portion at 0 °C. The reaction was stirred
for 20 h and slowly warmed to room temperature. The reaction
mixture was diluted with CH2Cl2 (20 mL), washed with HCl(aq)
(1 N, 10 mL), saturated NaHCO3(aq) (10 mL), and NaCl(aq) (10
mL), dried over Na2SO4, filtered, and evaporated to afford the
crude tosylate. The crude product was recrystallized in EtOAc/
hexane to give 17 (115 mg, 67%) as a yellow solid: [R]24D -59.2
(c ) 2.03, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.85 (d, J ) 7
Hz, 2H), 7.77 (d, J ) 7 Hz, 2H), 7.45-7.28 (m, 5H), 4.45 (dd,
J ) 8 Hz, J ) 8 Hz, 1H), 4.31 (m, 1H), 4.22 (m, 2H), 4.00 (dd,
J ) 8 Hz, J ) 8 Hz, 1H), 2.40 (s, 3H), 1.97 (dt, J ) 8 Hz, J )
8 Hz, 2H); 13C NMR (d6-DMSO, 75 MHz) δ 245.2, 164.0, 144.8,
131.4, 129.8, 128.3, 128.2, 128.2, 127.9, 72.3, 67.9. 63.5, 35.1,
21.6; HRMS (M+ + 1) m/z calcd for C18H20NO4S 346.11310,
found 346.11091.
(S)-2-P h en yl-4-[(diph en ylph osph in o)eth yl]oxazolin e 1a.
n-Butyllithium (1.6 M in hexanes, 11 mL, 17.6 mmol) was
added to a solution of diphenyl phosphine (2.21 g, 11.87 mmol)
in THF (120 mL) at 0 °C. The solution of the phosphide anion
was cannulated to a solution of tosylate 17 (4.06 g, 11.75
mmol)/THF (120 mL) at 0 °C. The reaction was kept at 0 °C
for another 1 h. The reaction was then quenched with
saturated NH4Cl(aq) (5 mL), diluted with ether (100 mL), dried
over Na2SO4, filtered, and concentrated. The crude product was
purified further by flash chromatography on silica gel using
20% EtOAc/hexanes eluant to afford the title compound 1a
3.70 g (88%).
(49) Meyers, A. I.; Schmidt, W.; McKennon, M. J . Synthesis 1993,
250-262.
(50) Shitangkoon, A.; Vigh, G. J . Chromatogr. A 1996, 738, 31-42.
(51) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky,
P. J . Org. Chem. 1998, 63, 7738-7748.
Typ ica l P r oced u r e for th e En a n tioselective Allyla tion .
Met h yl (R)-(E)-2-Met h oxyca r b on yl-3,5-d ip h en ylp en t -4-
en oa te. In a nitrogen atmosphere, allylpalladium chloride
dimer (1.8 mg, 0.0049 mmol), the ligand 1a (3.2 mg, 0.009
mmol), and solid potassium acetate (2 mg, 0.02 mmol) were
weighed into a half-dram vial equipped with a small glass bead
(52) Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994,
35, 8595-8598.
(53) Ho, G.-J .; Mathre, D. J . J . Org. Chem. 1995, 60, 2271-2273.
(54) Ito, Y.; Terashima, S. Tetrahedron 1991, 47, 2821-2834.

New, Optically Active, Phosphine Oxazoline Ligands
J . Org. Chem., Vol. 66, No. 1, 2001 215
Allylic Alk yla tion of 1,3-Dip h en ylp r op en yl Aceta te
w ith 3-((Z)-1-Tr im eth ylsilyloxyp r o-1-en yl)-2-oxa zolid on e
(18). In a nitrogen atmosphere, allylpalladium chloride dimer
(1.8 mg, 0.0049 mmol), the ligand 1a (3.2 mg, 0.009 mmol),
and solid potassium acetate (2 mg, 0.02 mmol) were weighed
into a 5-mL flask equipped with a stir bar. Dichloromethane
(500 µL) was added to the vial and allowed to equilibrate for
0.5 h at 0 °C. A solution of 1,3-diphenylpropenyl acetate (51
mg, 0.2 mmol) and 3-((Z)-1-trimethylsilyloxypro-1-enyl)-2-
oxazolidone (64.6 mg, 0.3 mmol) in CH2Cl2 (500 µL) was added
to the flask by syringe at 0 °C. The reaction was stirred at 0
°C for 16 h. The solvent was removed, and the residue was
passed through a short silica plug (30% EtOAc/hexanes) to give
a mixture of 19a and 19b (65.4 mg, 95%). These two diaster-
eomers were further separated by flash column chromatogra-
phy. 19a : Rf 0.51 (EtOAc/hexane, 3:7 v/v); 19b: Rf 0.40
(EtOAc/hexane, 3:7 v/v). The syn-E-relative configuration of
19a was determined by X-ray crystallography. The absolute
configuration was tentatively assigned as shown on the basis
of the similar allylation described in Figure 1a. The enanti-
oselectivity of this reaction was analyzed via HPLC (Chiralcel
OD analytical column; flow rate 1.0 mL/min, 254 nm, eluting
with programmed hexanes/2-propanol: 0-20 min, 1% of
2-propanol; 20-45 min, ramp 1-10% of 2-propanol; 45-55
min, 10% of 2-propanol; 55-65 min, ramp 10-15%; 65-70
min, 15% of 2-propanol; 70-80 min, ramp 15-1% of 2-pro-
panol; syn isomer (19a ) t1 ) 42.4 min, t2 ) 45.3 min; anti
isomer (19b) t1 ) 43.2 min, t2 ) 66.1 min). This HPLC
separation was calibrated using racemic material. Spectro-
scopic data of 19a (syn): 1H NMR (CDCl3, 300 MHz) δ 7.34-
7.16 (m, 10H), 6.40 (dd, J ) 3 Hz, J ) 2 Hz, 1H), 6.39 (d, J )
2 Hz) 4.52 (ddd, J ) 10.6 Hz, J ) 6 Hz, J ) 2.4 Hz, 1H,
CHCON), 4.22 (m, 1H, CH2(oxazolidone)), 4.02 (m, 1H, CH2-
(oxazolidone)), 3.98 (m, 1H, CH2(oxazolidone)), 3.79 (m, 1H,
CH2(oxazolidone)), 3.55 (m, 1H, CHPh), 1.01 (d, J ) 6 Hz, 3H,
Me); 13C NMR (CDCl3, 75 MHz) δ 245.2, 176.4, 141.3, 136.9,
131.3, 130.5, 128.8, 128.5, 128.1,127.4, 126.8, 126.1, 61.7, 54.7,
42.6, 42.3, 15.7; HRMS (M + Na+) m/z calcd for C21H21NO3Na
358.14191, found 358.14272. Spectroscopic data of 19b (anti):
1H NMR (CDCl3, 300 MHz) δ 7.35-7.16 (m, 10H), 6.49 (d, J
) 15 Hz, J ) Hz, 1H), 6.32 (dd, J ) 15 Hz, J ) 7 Hz) 4.44 (m,
1H, CHCON), 4.24 (m, 1H, CH2(oxazolidone)), 3.98 (m, 1H,
CH2(oxazolidone)), 3.80 (m, 1H, CH2(oxazolidone)), 3.69 (m, 1H,
CH2(oxazolidone)), 3.52 (m, 1H, CHPh), 1.27 (d, J ) 7 Hz, 3H,
Me); 13C NMR (CDCl3, 75 MHz) δ 245.2, 176.1, 142.5, 137.0,
131.9, 130.3, 128.5, 128.0, 127.7, 127.4, 126.6, 126.3, 61.7, 53.6,
42.6, 42.0, 16.0.
Ack n ow led gm en t. We thank Dr. Tom Colacot and
Dr. Richard Teichman at J ohnson Matthey for valuable
discussions. Support for this work was provided by
J ohnson Matthey, 2001 Nolte Drive, West Deptford, NJ
08066, and by The Robert A. Welch Foundation.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for the two X-ray structural analyses. This material is
available free of charge via the Internet at http://pubs.acs.org.
(55) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 35, 907-910.
(56) Denmark, S. E.; Nakajima, N.; Nicaise, O. J .-C.; Faucher,
A.-M.; Edwards, J . P. J . Org. Chem. 1995, 60, 4884-4892.
J O001333H