Synthesis of phosphino oxazoline ligand libraries from amino acid and phosphino carboxylate building blocks

Article abstract of DOI:10.1021/jo981420y

A modular route to new phosphine-oxazoline ligands is reported. The ability of these ligands to asymmetrically catalyze the addition of dimethyl malonate to 1,3-diphenylprop-2-enyl acetate was investigated. The best of these ligands gave a palladium complex which catalyzed the addition of dimethyl malonate to 1,3-diphenylprop-2-enyl acetate in a 99% yield and in 98% enantiomeric excess (Table 3, entry 11).

Full text of DOI:10.1021/jo981420y

8424
J . Org. Chem. 1998, 63, 8424-8431
Syn th esis of P h osp h in o Oxa zolin e Liga n d Libr a r ies fr om Am in o
Acid a n d P h osp h in o Ca r boxyla te Bu ild in g Block s
Scott R. Gilbertson* and Cheng-Wei T. Chang
Department of Chemistry, Washington University, St. Louis, Missouri 63130
Received J uly 21, 1998
A modular route to new phosphine-oxazoline ligands is reported. The ability of these ligands to
asymmetrically catalyze the addition of dimethyl malonate to 1,3-diphenylprop-2-enyl acetate was
investigated. The best of these ligands gave a palladium complex which catalyzed the addition of
dimethyl malonate to 1,3-diphenylprop-2-enyl acetate in a 99% yield and in 98% enantiomeric excess
(Table 3, entry 11).
In tr od u ction
Phosphine-oxazoline ligands have been studied by a
number of workers, particularly Pfaltz, Helmchen, and
Over the last five years the impact of combinatorial
chemistry has been felt principally in the area of drug
discovery.1 Most recently this technology has begun to
be applied in other areas where the synthesis of large
numbers of compounds can be of value. One area where
methods to synthesize large numbers of compounds
rapidly has great potential is in the development of new
catalysts.2-6 Over the last seven years we have been
involved in the development of chemistry that allows for
the rapid parallel synthesis of phosphine ligands. These
ligands are coordinated to catalytically active transition
metals. The resulting catalysts are then evaluated for
their ability to do selective catalysis. A significant
amount of our work has been devoted to the development
of peptide-based systems where phosphine-containing
amino acids are embedded in peptide secondary struc-
tures. Additionally, we have looked at simpler ligands
that can be easily assembled by a modular approach. This
paper reports the synthesis of simple phosphine-oxazo-
line ligands and their use in the catalysis of palladium-
catalyzed π-allyl additions. We report a number of
successful ligands with the best giving, at room temper-
ature, the addition of malonate with 98% ee. A study of
reaction temperature and counterion effects will also be
reported. In the course of this work a novel method for
the generation of malonate anion with tetraalkylammo-
nium counterions was found and is detailed.
Williams. This type of ligand has proven useful in
7-12
asymmetric π-allyl additions
and asymmetric Heck
reactions.13,14 To date, the most successful ligands of this
type have been six-member chelates with the phosphine
attached to the dihydrooxazole through a phenyl ring.
To our knowledge, only a single system with the phos-
phine attached to the oxazoline ligand by an alkyl bridge
has been reported. That system, which forms a five-
member chelate, gave poorer selectivity than the best
systems.9 Our approach makes ligands available that
link the phosphine and dihydrooxazole groups with a two-
carbon alkyl chain, thus forming a six-member chelate
upon metal coordination and allowing a direct compari-
son to the six-member chelates studied previously by
others.7-11 The use of an alkyl chain to connect the
chelating functionality allows the introduction of a second
chiral center, which is next to the phosphine. This
results in diastereomeric ligands in which the two chiral
centers can, potentially, act in concert or dissonance.
Results with both diastereomeric possibilities are re-
ported.
Resu lts a n d Discu ssion
Syn th esis of P h osp h in e-Oxa zolin e Liga n d s fr om
Ser in e. In natural products containing oxazoline func-
tionality, this group is usually derived from serine or
threonine. The first phosphine-oxazoline ligands we
synthesized were based on this biosynthetic pathway.
The inital ligand was synthesized by conversion of the
primary amide of N-BOC-serine amide (1) to the pyrro-
lidine amide 2 (Scheme 1). After removal of the BOC
group our phosphine sulfide acid was coupled to the
serine. Treatment with Burgess reagent followed by
removal of the sulfur gave the desired phosphine-
oxazoline 6.
The use of phosphine-containing acids along with
amino acids allows for the assembly of ligands by the
formation of amide bonds instead of carbon-phosphorus
bonds. This coupled to the ready availability of a number
of amino acids provides for the rapid synthesis of different
ligands. Through basically a three-step process, phos-
phine-oxazoline ligands are assembled with the R group
next to nitrogen varying from methyl and phenyl to tert-
butyl and isopropyl.
(1) Borman, S. Chem. Eng. News 1998, 47.
(2) Menger, F. M.; Eliseev, A. V.; Migulin, V. A. J . Org. Chem. 1995,
60, 6666.
(3) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 37, 6475.
(4) Ellman, J . A. Acc. Chem. Res. 1996, 29, 132.
(5) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J . P. A.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996,
35, 1668.
(6) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997,
36, 1704-1707.
(7) Lloyd-J ones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995,
34, 462.
(8) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566-568.
(9) Sprinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
(10) Allen, J . V.; Coote, S. J .; Dawson, G. J .; Frost, C. G.; Martin,
C. J .; Williams, J . M. J . J . Chem. Soc., Perkin Trans. 1 1994, 2065.
(11) Dawson, G. J .; Frost, C. G.; Williams, J . M. J . Tetrahedron Lett.
1993, 34, 3149.
(12) Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2108-2110.
(13) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 200.
(14) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338-1345.
10.1021/jo981420y CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/28/1998

Synthesis of Phosphino Oxazoline Ligand Libraries
J . Org. Chem., Vol. 63, No. 23, 1998 8425
Sch em e 1
Sch em e 2
Asymmetric catalysis with this ligand proved disap-
pointing. Using conditions that will be discussed later,
this ligand catalyzed the addition of dimethyl malonate
to 1,3-diphenylprop-2-enyl acetate in 96% yield and 45%
ee in CH3CN and 99% yield and 8% ee in CH2Cl2.
been reported earlier as an intermediate in the synthesis
of (diphenylphosphino)serine.15,16 The synthesis of the
phenyl and methyl derivatives (8 and 9) were performed
in the same manner.
The synthesis of the ligands began with the coupling
of phosphine acids 7, 8, or 9 to a given amino acid,
yielding the phosphine sulfide amides 11-19. The
desired ligands were then obtained by a simple three-
step procedure. Reduction of the methyl ester with
lithium borohydride followed by cyclization with Burgess
reagent17 [CH3O2CNSO2N(C2H5)3] gave the oxazoline-
phosphine sulfides 20-33. Reaction with Raney nickel
then removed the sulfur and gave the free phosphines
34-47. Reaction of acids 8 and 9 with an amino acid
gave diastereomeric products. These diastereomers were
readily separated by chromatography, after the lithium
borohydride reduction step, yielding both the SS and RS
pair of diastereomers. The ligands were fully character-
ized as the phosphine sulfides. After reduction of the
phosphine sulfides to the free phosphines, the ligands
were treated with palladium and used in catalysis
without purification.
R a p id Syn t h esis of New P h osp h in e-Oxa zolin e
Liga n d s. The inital poor result with ligand 6 caused
us to develop a second approach to this type of ligand.
One of our inital goals was to develop a system that
allowed us to synthesize large numbers of ligands quickly.
For this to be possible it is necessary to have a number
of different structures that can be easily incorporated into
the parent template. For this reason we embarked on
an approach where we coupled one of our phosphine-
amino acids to natural amino acids (Scheme 2). Follow-
ing amide formation, the carboxyl group of the amino acid
was reduced to an alcohol. This molecule was then
cyclized with either Burgess reagent or methanesulfonyl
chloride and triethylamine to give a phosphine-oxazoline
ligand. This method allows for the facile generation of a
number of ligands where the important group next to
nitrogen (R2) can be varied by using different amino acids.
Asym m etr ic Ca ta lysis. The first substrate we de-
cided to study was 1,3-diphenylprop-2-enyl acetate. This
molecule has been used as one of the bench mark
substrates for palladium-catalyzed allyl additions. The
The synthesis of the library of ligands began with
modular building blocks 7, 8, and 9. Using our approach,
new ligands are synthesized by amide bond formation
rather than difficult carbon-phosphorus bond formation.
For the study reported here, we have used three phos-
phine-containing acids. One was a diphenylphosphine
derivative of acrylate (7), another from cinnamic acid (8),
and one from crotonate (9). The acrylate derivative 7 has
(15) Gilbertson, S. R.; Chen, G.; McLoughlin, M. J . Am. Chem. Soc.
1994, 116, 4481.
(16) Gilbertson, S. R.; Wang, X. J . Org. Chem. 1996, 61, 434.
(17) Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996, 37, 4659.

8426 J . Org. Chem., Vol. 63, No. 23, 1998
Gilbertson and Chang
Ta ble 1. Syn th esis of P h osp h in e-Dih yd r ooxa zole
Ta ble 3. Resu lts w ith Liga n d s Con ta in in g Tw o Ch ir a l
Cen ter sa
Liga n d s
R1
R2
compd % yield compd % yield ligand
entry
no.
ligand
config
yield
%
ee
%
cation/base
solvent
H
H
H
H
Me (S)
Bn (S)
iPr (S)
Ph (S)
11
12
13
14
15
15
16
16
17
17
18
18
19
19
33
31
64
56
20
21
22
23
24
25
26
27
28
29
30
31
32
33
62
66
72
84
55
65
71
85
45
91
48
90
74
69
34
35
36
37
38
39
40
41
42
43
44
45
46
47
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
38 (S,S)
39 (R, S)
40 (S,S)
41 (R,S)
42 (S,S)
43 (R,S)
44 (S,S)
45 (R,S)
42 (S,S)
43 (R,S)
43 (R,S)
43 (R,S)
43 (R,S)
43 (R,S)
43 (R,S)
47 (R, S)
47 (R, S)
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
TBAOAc/BSA
nHex4N+/BSA
nBu4N+/BSA
nHex4N+/BSA
86
86
100
53
91
80
56
37
43
80
33
48
49
93
99
99
78
72
94
84
93
90
95
22
54
65
93
85
88
79
82
97
96
98
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
CH2Cl2
THF
CH3 (S) iPr (S)
20a
20a
69a
69a
62a
62a
47a
47a
38b
39b
CH3 (R) iPr (S)
Ph (S)
Ph (R)
Ph (S)
Ph (R)
Ph (S)
Ph (R)
Ph (S)
Ph (R)
Bn (S)
Bn (S)
iPr (S)
iPr (S)
Ph (S)
Ph (S)
tBu (S)
tBu (S)
C6H6
CH3CN
CH3CN
CH3CN
CH3CN
a
The yields reported for compounds 15-19 are for the mixture
b
of the two diastereomers. Ligands 46 and 47 were synthesized
from the corresponding amino alcohol. Yield is from the corre-
sponding alcohol.
a
The reactions were run at room temperature.
Ta ble 2. Resu lts w ith Liga n d s Con ta in in g a Sin gle
Ch ir a l Cen ter a
BSA system mentioned above has been developed during
this work. One of the critical factors in controlling the
selective addition of nucleophiles to π-allyl palladium
intermediates is the counterion.21,22 The common method,
for the addition of malonate with a tetraalkylammonium
counterion, is the generation of the malonate ion with a
base such as sodium hydride, followed by addition of the
appropriate tetraalkylammonium halide. A complication
of this approach is the competition between the two
cations, alkali metal verses ammonium, in solution. With
this method there is the corresponding sodium or potas-
sium halide present, the cation of which can compete with
the ammonium ion. To circumvent this problem, crown
ethers are sometimes added, but this approach is limited
by the expense and availability of the required crown
ether.
Another method that has been used successfully is to
add potassium acetate and BSA as the bases. Presum-
ably the potassium acetate removes the trimethylsilyl
group from the BSA, generating a base to deprotonate
the malonate. Tetraalkylammonium salts have been
added to these mixtures to give malonate ions with
noncoordinating counterions. Despite the success of this
method there remains the potential competition between
the ammonium counterion and the free potassium in
solution.
It was reasoned that if potassium acetate could attack
BSA and generate the necessary base for formation of
the potassium malonate, then the addition of a tetraalkyl-
ammonium fluoride should serve the same purpose,
generating a base with an ammonium counterion. Fluo-
ride ion would attack the silicon of BSA forming tri-
methylsilyl fluoride and acetamide anion. This base
could then go on and deprotonate dimethyl malonate and
provide the nucleophile for the malonate addition with
only an ammonium counterion present (Scheme 3). Upon
inspection of the literature, we were surprised that,
apparently, this approach had not been reported.
This method possesses a number of advantages over
the current methods used. Generally, before one is able
to use tetraalkylammonium bromides, the salts must be
purified by recrystallization. We have found that this is
entry ligand
yield
%
ee
%
b
no.
config
cation/base
solvent
1
2
3
4
5
6
7
8
9
34 (S) nBu4N+/BSA
35 (S) nBu4N+/BSA
36 (S) nBu4N+/BSA
37 (S) nBu4N+/BSA
36 (S) K+/BSA
67
78
94
82
87
62
22
93
14
25
22
82 CH2Cl2
87 CH2Cl2
86 CH2Cl2
37 CH2Cl2
66 CH2Cl2
90 CH2Cl2
81 THF
11 CH3CN
64 THF
78 C6H6
36 (S) Hex4N+/BSA
36 (S) (CH3(CH2)5)4NBr/NaH
36 (S) nBu4N+/BSA
36 (S) nBu4N+/BSA
36 (S) nBu4N+/BSA
36 (S) (CH3(CH2)3)4NBr/NaH
10
11
81 THF
a
b
Unless stated otherwise, reactions were run at 0 °C. The
enantiomeric excesses were determined by chiral shift reagent
[Eu(hfbc)3].10
ligands were investigated in two groups: ligands with
one chiral center (Table 2) and ligands with two chiral
centers (Table 3). Of the ligands with one chiral center,
the ligands derived from phenylalanine (R2 ) benzyl) (35)
and valine (R2 ) isopropyl) (36) gave the highest ees (87%
and 86%) (Table 2, entries 2 and 3). The effect of solvent
on the reaction was probed using ligand 36 and the
nBu4N+/BSA cation base combination (Table 2, entries
3, 8, 9, and 10).18-20 Of the solvents tested, methylene
chloride was found to be the best solvent for this ligand
(Table 2, entry 3). The counterion and base associated
with the malonate anion have been shown to be impor-
tant in these additions, and so their effect was also
investigated (Table 2, entries 3, 5, 6, and 7). The optimal
system for this class of ligand was found to be tetrahexyl-
ammonium/BSA as the counterion and base and meth-
ylene chloride as the solvent (Table 2, entry 6), giving
an ee of 90%.
BSA/Am m on iu m F lu or id e Gen er a t ion of Di-
m eth yl Ma lon a te An ion . The tetrahexylammonium/
(18) BSA is bis(trimethylsilyl)acetamide.
(19) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143.
(20) Brown, J . M.; Hulmes, D. I.; Guiry, P. J . Tetrahedron 1994,
50, 4493.
(21) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1994, 116, 4089.
(22) Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994,
35, 8595.

Synthesis of Phosphino Oxazoline Ligand Libraries
J . Org. Chem., Vol. 63, No. 23, 1998 8427
Sch em e 3
Ta ble 4. Scr een in g of Cyclic Su bstr a te w ith
interesting to note that the chirality at the carbon next
to the phosphine has a variable effect. When the group
attached to that carbon is methyl, the difference observed
between the S,S and R,S diastereomers is quite pro-
nounced 72% and 94%, respectively (Table 3, entries 1
and 2). When R1 is phenyl, the difference between the
S,S and R,S diastereomers is less, 93% and 90% ee (Table
3, entries 4 and 5). It is also interesting to note that the
effect of this group varies as the ability of the oxazoline
to direct the reaction changes. In the case of the best
directing group, isopropyl, the chirality of the carbon next
to the phosphine has a small effect, 90% versus 93% for
S,S and R,S, respectively (Table 3, entries 5 and 6). In
the cases where the group on the oxazoline is phenyl or
benzyl the effect of the group next to the phosphine
appears to be larger (Table 3, entries 3 versus 4 and 7
versus 8).
P h osp h in e-Oxa zolin e Liga n d s
entry
no.
ligand
config
yield
%
ee
%
cation/base
solvent
1
2
3
4
5
8
9
41 (R,S)
43 (R,S)
42 (S,S)
45 (R,S)
44 (S,S)
47 (R,S)
38 (S,S)
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
nBu4N+/BSA
57
56
61
64
69
56
50
35
23
37
0
11
14
42
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
not necessary with the available tetraalkylamonium
fluoride salts. Commercially available tetrabuylyammo-
nium fluoride was used directly without purification.
Also, the use of tetraalkylammonium bromides involves
the deprotonation of the malonate followed by addition
of the appropriate ammonium bromide. Often strong
bases such as sodium hydride are used for the deproto-
nation. The use of strong base precludes running the
reaction in solvents such as acetonitrile, a solvent shown
to be valuable in selective π-allyl additions.
The ligand we chose to test this method on was 36,
possessing one chiral center. Four sets of reaction
conditions were investigated. The standard BSA method
using potassium acetate in methylene chloride gave an
enantiomeric excess of 66% (Table 2, entry 5). The
conditions using tetrabutylammonium fluoride gave 86%
ee (Table 2 entry 3), and the larger counterion, tetra-
hexylammonium fluoride, gave 90% ee (Table 2, entry
6). Comparison with the system using sodium hydride
and added tetrabutylammonium bromide in THF pro-
vided the product in 81% enantiomeric excess (Table 2,
entry 11).
Not only does the BSA method provide an expedient
method for the generation of malonate ion with tet-
raalkylammonium as the only counterion present, but it
actually proves to be the best set of reaction conditions
found for phosphine oxazoline type ligands such as 36.
Liga n d s w it h Tw o Ch ir a l Cen t er s. In the inital
screen using standard reaction conditions ligand 43, with
a RS configuration, was found to be the most selective
ligand (Table 3, entry 6). The optimal reaction conditions
were then determined (Table 3, entries 10-15). The best
solvent system for this ligand was found to be acetoni-
trile, and the best counterion system was nHex4N+/BSA
(Table 3, entry 15).
In an effort to increase the selectivity of the reaction,
the temperature at which the reaction was run was
decreased. This change resulted in a decrease in the
selectivity of the reaction (93% ee at 0 °C to 61% ee at
-30 °C). Increasing the temperature of the reaction to
room temperature resulted in an increase in the selectiv-
ity to 97% ee. Further increase in the temperature
results in an erosion in the selectivity (52% ee at 40 °C).
An investigation into the generality of the decrease in
selectivity with decreasing temperature indicated that
this effect was unique to the ligands with the R,S
configuration (41 and 43). In the study of the S,S
diastereomers, ligands 40 and 42, a normal temperature
dependence with lower temperatures giving higher se-
lectivity was observed.
Ad d ition to 2-Cyclop en ten yl Aceta te. After suc-
cessfully applying the phosphine-oxazoline ligands to
1,3-diphenylprop-2-enyl acetate, these ligands were tested
for their ability to perform asymmetric additions to
2-cyclopentenyl acetate. This is a system that has proven
to be significantly more difficult to control than the 1,3-
diphenylprop-2-enyl acetate system. Trost has developed
a ligand that controls this reaction with good selectiv-
ity.21,23,24 As expected from results with other phos-
phine-oxazoline ligands, the outcome shown in Table 4
was rather disappointing. A wide variety of conditions
and ligands were investigated, with the highest selectiv-
ity being 42% ee. It should be noted there is one
phosphine-oxazoline system, recently developed by Helm-
(23) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1996, 118, 235-
236.
Of the ligands with two chiral centers, both combina-
tions of the two chiral centers were examined. It is
(24) Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485-
7488.

8428 J . Org. Chem., Vol. 63, No. 23, 1998
Gilbertson and Chang
on the selectivity of reaction but that the effect is
generally small and overwhelmed by the chiral center
next to nitrogen.
The most striking difference between the systems
studied previously and the one reported here is found
when the group next to nitrogen is phenyl. Pfaltz has
reported that when this group is phenyl high selectivities
are found.8 In our case when this group is phenyl, we
observed the lowest selectivity. The ligand with one
chiral center synthesized from phenylalanine (34) gave
a 37% ee (Table 2, entry 4) while ligand 40, with two
chiral centers, gave a 54% ee (Table 3, entry 8). This is
compared to ligands 36 and 43 which give 86% (Table 2,
entry 3) and 93% (Table 3, entry 6) under the same
conditions. Poor selectivity was also observed with ligand
6, where the group next to the nitrogen is an ester. It
appears, with the ligands reported in this paper, that
when the group next to nitrogen has an sp2-hybridized
carbon the selectivity is low.
F igu r e 1.
chen that has proven to be an effective catalyst with these
substrates.25
Or igin of Selectivity. On the basis of the measure-
ment of optical rotation, the major product from the
asymmetric π-allylic alkylation of 1,3-diphenylallyl ac-
etate was the S isomer when phosphine-oxazoline
ligands from L-amino acids were used. Numerous studies
on the origin of selectivity for phosphine-oxazoline
ligands have been reported.10,12,20,23,26-31 The belief is that
the nucleophile attacks the carbon trans to the phosphine
atom in the η3-allylic cation intermediate (Figure 1).
Since the phosphine has an empty d orbital acting as an
electron acceptor, the electron density of the metal-
carbon bond trans to the metal-phosphine bond will be
decreased. Helmchen has shown that the most stable
orientation for the allyl group is as shown above, with
the phenyl ring toward the R group next to nitrogen. This
appears to be the case in the ligands we report as well
since we observe the same selectivity as the previous
ligands.
The effect of the chiral center next to the phosphine is
variable in terms of effecting the selectivity of the
reaction. Another difference observed between the ligands
with one chiral center and the ligands with two centers
is the preferred solvent for reaction. In the cases with
one chiral center the best solvent tested was methylene
chloride. In the case of the ligands with two chiral
centers the best solvent we found was acetonitrile.
Currently we do not have a clear explanation for this
observation.
Through the use of modular building blocks we have
been able to develop a new ligand for palladium-catalyzed
π-allyl additions. We are currently studying the use of
these ligands in other metal-catalyzed reactions. Ad-
ditionally, we report a new method for the facile genera-
tion of malonate anions with bulky counterions. Through
the use of BSA and the appropriate tetraalkylammonium
fluoride, dimethyl malonate is deprotonated in the ab-
sence of other potential counterions. We are also using
the phosphine acid building blocks discussed in this paper
in the synthesis of other collections of ligands for a variety
of transition metal-catalyzed reactions.
Exp er im en ta l Section
Gen er a l P r oced u r e for Cou p lin g of P h osp h in op r op i-
on ic Acid a n d Am in o Acid . 3-(Diphenylphosphino)thiopro-
pionic acid (1 equiv), amino acid methyl ester (1.2 equiv), EDC
(1.5 equiv), and HOBT (1.5 equiv) were dissolved in dry CH2-
Cl2 and CH3CN (1:1 ratio), and the reaction mixture was
stirred under nitrogen at room temperature for 2 days. After
rotatory evaporation of the solvent, the crude product was
redissolved in ethyl acetate and then transferred to a sepa-
ratory funnel. The remaining residue was dissolved in small
amount of CH2Cl2 and combined with the ethyl acetate
solution. The combined organic solutions were washed with
1 N HCl, water, saturated NaHCO3, and brine and then dried
over anhydrous Na2SO4. Evaporation of solvents and purifica-
tion of the crude product by column chromatography afforded
the desired product.
Con clu sion
As stated in the Introduction there are a number of
phosphine-oxazoline ligands that have been developed.
To date the most successful systems have been ligands
with the phosphine and oxazoline attached through an
aromatic ring. The system discussed in this paper has
the phosphorus and oxazoline connected by an alkyl
chain. In the system covered in this paper, as with many
of the systems reported previously, the important group
in directing the stereochemical outcome of the reaction
is the group next to the nitrogen atom. It was found that
a chiral center next to the phosphine can have an effect
Gen er a l P r oced u r e for Red u ction of Meth yl Ester .
The methyl ester was dissolved in dried THF and cooled to 0
°C. Two equivalents of lithium borohydride solution (2 M in
THF) was slowly added under nitrogen. The ice bath was
removed after the addition, and the reaction was monitored
by TLC (50% hexane, 50% ethyl acetate). The reaction time
varied from 6 h to 2 days. After the reduction was complete,
the reaction mixture was cooled to 0 °C, and the reaction was
quenched by the slow addition of 2 mL of 10% HCl (caution:
foaming). The reaction solution was stirred for another 15 min
and then diluted with ethyl acetate. The aqueous layer was
discarded. The organic layer was washed with 1 N NaOH, 1
N HCl, water, saturated NaHCO3, and brine then dried over
anhydrous Na2SO4. For the product with one chiral center:
after evaporation of solvent, the crude product was used for
the next step directly. For the product with two chiral centers,
after evaporation of solvent and purification with column
chromatography, two desired diastereomeric products were
obtained separately.
(25) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure
Appl. Chem. 1997, 69, 513-518.
(26) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(27) Sprinz, J .; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523.
(28) Pena-Cabrera, E.; Norrby, P.-O.; Sjogren, M.; Vitagliano, A.;
DeFelice, V.; Oslob, J .; Ishii, S.; O’Neill, D.; Akermark, B.; Helquist,
P. J . Am. Chem. Soc. 1996, 118, 4299.
(29) Reisei, O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547.
(30) Frost, C. G.; Howarth, J .; Williams, J . M. J . Tetrahedron
Asymmetry 1992, 3, 1089.
(31) Mackenzie, P. B.; Whelan, J .; Bosnich, B. J . Am. Chem. Soc.
1985, 107, 2046.

Synthesis of Phosphino Oxazoline Ligand Libraries
J . Org. Chem., Vol. 63, No. 23, 1998 8429
Gen er a l P r oced u r e for Oxa zolin e F or m a tion . (1)
Meth od em p loyin g Bu r gess r ea gen t.17,32 The â-amido
alcohol was dissolved in enough dry THF to make a 0.02 M
solution. After addition of Burgess reagent (2 equiv), the
reaction mixture was refluxed for 1 h. The reaction was
monitored by TLC (65% hexane, 35% ethyl acetate) and was
usually complete within 1 h. The reaction mixture was cooled
to room temperature and coated on silica gel for loading onto
a chromatography column. Purification with flash column
chromatography afforded the desired product.
(2) Meth od Em p loyin g Mesyl Ch lor id e. The â-amido
alcohol was dissolved in dry CH2Cl2 /Et3N (3/1), and the
solution was cooled to 0 °C. To the solution was slowly added
MsCl (4 equiv), and the yellow-brownish solution was stirred
under nitrogen at room temperature for 1 day. After the
reaction was complete (monitored by TLC), the reaction
mixture was filtered through Celite to remove most of the
ammonium salt, and the residue was rinsed with CH2Cl2.
Evaporation of solvent and coating the crude product on silica
gel, followed by purification with flash column chromatogra-
phy, afforded the desired product.
P r oced u r e for th e Red u ction of P h osp h in e Su lfid e to
P h osp h in e. A sample of the phosphine sulfide was dissolved
in degassed methanol (3.0 mL) in a Schlenk tube. Raney
nickel slush (300 mg) was washed with methanol and was then
added to the tube under nitrogen. The reaction mixture was
stirred at room temperature for 8.0 h, by which time the 31P
NMR spectrum indicated complete conversation of the phos-
phine sulfide to the phosphine. Raney nickel was then filtered
through Celite under nitrogen, and the filtrate was concen-
trated under vacuum to 0.5 mL.
Gen er a l P r oced u r e for π-Allyl Ad d ition . The phos-
phine-oxazoline ligand was mixed with [Pd(η3-C3H5)Cl]2 in
degassed solvent. After 30 min, 1,3-diphenylprop-2-enyl ac-
etate (10 equiv) in solvent was added. To this solution at the
desired reaction temperature was added a solution of dimethyl
malonate (30 equiv), TBAF (30 equiv), and BSA (30 equiv) over
1 h. After complete reaction, as judged by TLC, the reaction
mixture was worked up extractively.
washed with 1 N HCl, water, saturated NaHCO3, and brine
then dried over anhydrous Na2SO4. After removal of solvent,
the crude product was dissolved in CH2Cl2 , 5 mL of TBAF (1
M in THF) was added, and the reaction mixture was stirred
for 2 h. After evaporation of solvent and purification by
gradient column chromatography [hexane/ethyl acetate (80/
20) to ethyl acetate/methanol (80/20)], the product was ob-
tained as viscous solid (0.647 g, 1.5 mol, 39%): 1H NMR (300
MHz, CDCl3) δ 7.85 (m, 4H), 7.48 (m, 6H), 6.87 (d, J HH ) 9.0
Hz, 1H), 4.70 (dt, J HH ) 9.0 Hz, J HH ) 3.0 Hz, 1H), 3.4-3.8
(m, 6H), 2.82 (m, 2H), 2.60 (m, 2H), 1.8-2.0 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 171.5 (d, J CP ) 16.8 Hz), 168.5 (s), 132.0
(d, J CP ) 8.0 Hz), 131.62 (d, J CP ) 1.4 Hz), 131.59 (d, J CP
)
3.2 Hz), 131.0 (d, J CP ) 10.2 Hz), 130.7 (d, J CP ) 9.8 Hz), 128.7
(d, J CP ) 12.1 Hz), 63.6 (s), 52.9 (s), 46.7 (s), 46.2 (s), 28.7 (s),
27.8 (d, J CP ) 58.6), 25.9 (s), 24.1 (s); 31P NMR (120 MHz,
CDCl3) δ 43.1 (s); IR (thin film) 1669 (s), 1603 (s), 1558 (s),
1389 (s), 1374 (s); MS-FAB (EI+) m/z (% rel intensity) 431.1
(MH+, 15); 273.1 (Ph2PS+, 100); HRFAB Calcd for C22H28N2O3-
PS (MH+) m/e 431.1558; measured m/e 431.1546.
(S)-5-(P yr r olid on oca r bon yl)-4,5-d ih yd r o-2-(2′-(d ip h en -
ylp h osp h in oth ioyl)eth yl-1,3-oxa zole (5). 1H NMR (300
MHz, CDCl3) δ 7.85 (m, 4H), 7.58 (m, 6H), 4.80 (dd, J HH ) 8.0
Hz, J HH ) 8.0 Hz, 1H), 4.68 (dd, J HH ) 8.0 Hz, J HH ) 10.0 Hz,
1H), 4.23 (dd, J HH ) 8.0 Hz, J HH ) 10.0 Hz, 1H), 3.90 (ddd,
J HH ) 10.0 Hz, J HH ) 7.0 Hz, J HH ) 7.0 Hz, 1H), 3.48 (m, 3H),
2.80 (m, 2H), 2.62 (m, 2H), 1.8-2.0 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 168.3 (d, J CP ) 18.5 Hz), 167.7 (s), 132.6 (d, J CP
20.4 Hz), 131.7 (d, J CP ) 3.7 Hz), 131.6 (d, J CP ) 3.3 Hz), 131.3
(d, J CP ) 20.0 Hz), 131.14 (d, J CP ) 10.3 Hz), 131.09 (d, J CP
)
)
9.8 Hz), 128.7 (d, J CP ) 10.7 Hz), 69.2 (s), 67.7 (s), 46.5 (s),
46.2 (s), 29.0 (d, J CP ) 57.8), 26.0 (s), 24.2 (s), 21.4 (s); 31P NMR
(120 MHz, CDCl3) δ 42.8 (s); IR (thin film) 1654 (s), 1637 (s),
1624 (s); MS-FAB (EI+) m/z (% rel intensity) 413.1 (MH+, 20);
273.1 (Ph2PS+, 70); HRFAB calcd for C22H26N2O2PS (MH+) m/e
413.1452; measured m/e 413.1456.
Sp ectr a l Da ta for P h osp h in e Su lfid es 20-33. The
spectral data for the intermediates in their synthesis is
reported in the Supporting Information.
(S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)eth yl)-
5-m eth yl-1,3-oxa zole (20): 1H NMR (300 MHz, CDCl3) δ 7.85
(m, 4H), 7.48 (m, 6H), 4.28 (dd, J HH ) 9.0 Hz, J HH ) 8.0 Hz,
1H), 4.11 (qdd, J HH ) 6.6 Hz, J HH ) 8.0 Hz, J HH ) 8.0 Hz,
1H), 3.72 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 2.82 (m, 2H),
2.58 (m, 2H), 1.20 (d, J HH ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.3 (d, J CP ) 19.1 Hz), 132.1 (d, J CP ) 80.0 Hz),
132.0 (d, J CP ) 80.9 Hz), 131.6 (d, J CP ) 3.2 Hz), 131.1 (d, J CP
) 10.4 Hz), 128.7 (d, J CP ) 12.2 Hz), 74.1 (s), 61.4 (s), 29.0 (d,
J CP ) 57.8 Hz), 21.3 (d, J CP ) 3.5 Hz); 31P NMR (120 MHz,
CDCl3) δ 42.8 (s); IR (thin film), 1734 (w), 1587 (w); MS-FAB
(EI+) m/z (% rel intensity) 330.1 (MH+, 50), 112.1 ([M - Ph2-
PS]+, 100); HRFAB calcd for C18H21NOPS (MH+) m/e 330.1082;
measured m/e 330.1071.
(S)-N-(ter t-Bu toxylca r bon yl)-2-h yd r oxyl-1-(p yr r olid i-
n oca r bon yl)eth yla m in e, (2). A mixture of N-tBoc-L-serine
(5.0 g, 24.4 mmol), pyrrolidine (2.03 mL, 24.4 mmol), EDC-
HCl (7.0 g, 36.6 mmol), and HOBt (4.9 g, 36.6 mmol) in 100
mL of CH2Cl2 and 100 mL of DMF was stirred for 50 h under
nitrogen at room temperature. The reaction mixture was
poured into a saturated NH4Cl/CH2Cl2 solution, and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with 1 N HCl, water, saturated
NaHCO3, and brine then dried over anhydrous Na2SO4. After
removal of the solvent and washing the yellowish solid with
anhydrous ether, the desired product was obtained as a white
solid (3 g, 11.6 mmol, 48%): 1H NMR (300 MHz, CDCl3) δ 5.69
(d, J HH ) 8.0 Hz, 1H), 4.51 (dt, J HH ) 8.0 Hz, J HH ) 4.0 Hz,
1H), 3.80 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H), 3.4-3.6 (m, 4H),
1.8-2.0 (m, 4H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
169.3 (s), 155.9 (s), 80.1 (s), 64.1 (s), 53.2 (s), 46.7 (s), 46.1 (s),
28.3 (s), 26.0 (s), 24.1 (s); IR (thin film) 1706 (s), 1624 (s), 1538
(s); MS-FAB (EI+) m/z (% rel intensity) 259.3 (MH+, 100).
Anal. Calcd for C12H22N2O4: C, 55.80; H, 8.58; N, 10.84.
Found: C, 55.70; H, 8.66; N, 10.82.
(S)-3-(Diph en ylph osph in oth ioyl)-N-(2′-h ydr oxyl-1′-(pyr -
r olid in oca r bon yl)eth yl)p r op a n a m id e (4). To a solution
containing 2 (1.0 g, 3.9 mmol) in 30 mL of dry CH2Cl2 was
slowly added TBDMSOTf (0.9 mL, 4.1 mmol). After stirring
the reaction mixture for 6 h, the solvent was evaporated, and
the crude product was redissolved in 15 mL dry of CH2Cl2 and
15 mL of CH3CN. To this clear solution were added (diphen-
ylphosphinothioyl)propanoic acid, (1.1 g, 3.9 mmol), EDC-HCl
(1.1 g, 5.8 mmol), and HOBt (0.8 g, 5.8 mmol), and the reaction
was stirred for 5 days. After pouring the reaction mixture into
a saturated NH4Cl/CH2Cl2 solution, the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
(S )-5-Be n zyl-4,5-d ih yd r o-2-(2′-(d ip h e n ylp h osp h in o-
1
th ioyl)eth yl)-1,3-oxa zole (21): H NMR (300 MHz, CDCl3)
δ 7.86 (m, 4H), 7.49 (m, 6H), 7.1-7.3 (m, 5H), 4.31 (dddd, J HH
) 8.4 Hz, J HH ) 8.4 Hz, J HH ) 8.4 Hz, J HH ) 5.0 Hz, 1H), 4.11
(dd, J HH ) 8.4 Hz, J HH ) 8.4 Hz, 1H), 3.92 (dd, J HH ) 8.4 Hz,
J HH ) 8.4 Hz, 1H), 3.05 (dd, J HH ) 14.4 Hz, J HH ) 5.0 Hz,
1H), 2.80 (m, 2H), 2.60 (dd, J HH ) 14.4 Hz, J HH ) 8.4 Hz, 1H),
2.58 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 166.8 (d, J CP ) 18.6
Hz), 137.6 (s), 132.0 (d, J CP ) 84.2 Hz), 131.6 (d, J CP ) 3.1
Hz), 131.0 (d, J CP ) 10.3 Hz), 129.1 (s), 128.6 (d, J CP ) 12.0
Hz), 128.4 (s), 126.4 (s), 71.8 (s), 67.0 (s), 41.5 (s), 28.9 (d, J CP
) 57.9 Hz), 21.3 (s); 31P NMR (120 MHz, CDCl3) δ 42.7 (s); IR
(thin film) 1682 (s), 1669 (s), 1654 (s); MS-FAB (EI+) m/z (%
rel intensity) 406.2 (MH+, 75), 188.2 ([M - Ph2PS]+, 100);
HRFAB calcd for C24H25NOPS (MH+) m/e 406.1394, measured
m/e 406.1399.
(S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)eth yl)-
1
5-isop r op yl-1,3-oxa zole (22): H NMR (300 MHz, CDCl3) δ
7.85 (m, 4H), 7.48 (m, 6H), 4.16 (dd, J HH ) 8.0 Hz, J HH ) 8.0
Hz, 1H), 3.90 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 3.83 (ddd,
J HH ) 8.0 Hz, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 2.80 (m, 2H),
2.59 (m, 2H), 1.71 (qqd, J HH ) 8.0 Hz, J HH ) 7.0 Hz, J HH ) 7.0
(32) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910.

8430 J . Org. Chem., Vol. 63, No. 23, 1998
Gilbertson and Chang
Hz, 1H), 0.93 (d, J HH ) 7.0 Hz, 3H), 0.83 (d, J HH ) 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 166.1 (d, J CP ) 19.0 Hz),
132.1 (d, J CP ) 86.0 Hz), 132.0 (d, J CP ) 86.0 Hz), 131.6 (d,
J CP ) 3.2 Hz), 131.2 (d, J CP ) 2.2 Hz), 131.0 (s), 128.6 (d, J CP
) 12.2 Hz), 72.0 (s), 70.1 (s), 32.5 (s), 29.1 (d, J CP ) 57.5 Hz),
21.3 (s), 18.8 (s), 17.9 (s); 31P NMR (120 MHz, CDCl3) δ 42.8
(s); IR (thin film) 1725 (s), 1671 (s), 1384 (s), 1366 (s); MS-
FAB (EI+) m/z (% rel intensity) 358.1 (MH+, 50), 140.1 ([M -
Ph2PS]+, 100); HRFAB calcd for C20H25NOPS (MH+) m/e
358.1394, measured m/e 358.1405.
(S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)eth yl)-
5-p h en yl-1,3-oxa zole (23): 1H NMR (300 MHz, CDCl3) δ 7.85
(m, 4H), 7.48 (m, 6H), 7.34 (m, 3H), 7.21 (m, 2H), 5.11 (dd,
J HH ) 9.0 Hz, J HH ) 9.0 Hz, 1H), 4.58 (dd, J HH ) 8.0 Hz, J HH
) 9.0 Hz, 1H), 4.05 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 2.91
(m, 2H), 2.72 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.6 (d,
J CP ) 18.5 Hz), 141.8 (s), 132.0 (d, J CP ) 80.4 Hz), 131.9 (d,
J CP ) 80.4 Hz), 131.5 (d, J CP ) 2.6 Hz), 131.03 (d, J CP ) 10.1
Hz), 131.0 (d, J CP ) 9.9 Hz), 128.61 (s), 128.60 (d, J CP ) 11.9
Hz), 127.5 (s), 126.5 (s), 74.8 (s), 69.4 (s), 28.9 (d, J CP ) 57.8
Hz), 21.3 (s); 31P NMR (120 MHz, CDCl3) δ 42.8 (s); IR (thin
film) 1669 (s), 1495 (s), 1453 (s); MS-FAB (EI+) m/z (% rel
intensity) 392.3 (MH+, 90), 273.2 ([Ph2P(S)CH2CH2CO]+, 60),
HRFAB calcd for C23H23NOPS (MH+) m/e 392.1238, measured
m/e 392.1233.
) 12.2 Hz), 127.6 (d, J CP ) 2.0 Hz), 127.4 (d, J CP ) 1.4 Hz),
126.3 (s), 71.5 (s), 67.1 (s), 43.9 (d, J CP ) 51.4 Hz), 41.5 (s),
29.2 (d, J CP ) 3.5 Hz); 31P NMR (120 MHz, CDCl3) δ 50.8 (s);
IR (thin film) 1669 (s), 1491 (s), 1453 (s); MS-FAB (EI+) m/z
(% rel intensity) 482.6 (MH+, 15), 264.4 (M - [Ph2PS]+, 100);
HRFAB calcd for C30H29NOPS (MH+) m/e 482.1707, measured
m/e 482.1694.
(5S,2′R)-5-Ben zyl-4,5-d ih yd r o-2-(2′-(d ip h en ylp h osp h i-
n oth ioyl)-2′-p h en yleth yl)-1,3-oxa zole (27): 1H NMR (300
MHz, CDCl3) δ 8.20 (m, 2H), 7.57 (m, 3H), 7.50 (m, 2H), 7.30
(m, 1H), 7.17 (m, 10H), 6.94 (m, 2H), 4.49 (ddd, J HH ) 3.5 Hz,
J HH ) 11.0 Hz, J HP ) 11.0 Hz, 1H), 4.15 (dddd, J HH ) 9.0 Hz,
J HH ) 7.5 Hz, J HH ) 5.4 Hz, J HH ) 8.0 Hz, 1H), 3.92 (dd, J HH
) 9.0 Hz, J HH ) 9.0 Hz, 1H), 3.73 (dd, J HH ) 9.0 Hz, J HH ) 7.5
Hz, 1H), 3.21 (ddd, J HH ) 11.0 Hz, J HH ) 12.0 Hz, J HP ) 16.0
Hz, 1H), 2.80 (ddd, J HH ) 3.5 Hz, J HH ) 12.0 Hz, J HP ) 16.0
Hz, 1H), 2.72 (dd, J HH ) 5.4 Hz, J HH ) 13.5 Hz, 1H), 2.28 (dd,
J HH ) 8.0 Hz, J HH ) 13.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 165.3 (d, J CP ) 18.3 Hz), 137.6 (s), 134.0 (d, J CP ) 4.6 Hz),
131.9 (d, J CP ) 9.1 Hz), 131.8 (d, J CP ) 3.2 Hz), 131.5 (d, J CP
) 9.5 Hz), 131.1 (d, J CP ) 2.9 Hz), 130.4 (d, J CP ) 26.6 Hz),
129.9 (d, J CP ) 5.3 Hz), 129.2 (s), 128.8 (d, J CP ) 11.3 Hz),
128.3 (s), 127.8 (d, J CP ) 12.3 Hz), 127.6 (d, J CP ) 1.8 Hz),
127.4 (d, J CP ) 3.0 Hz), 126.3 (s), 71.4 (s), 67.1 (s), 43.9 (d, J CP
) 51.3 Hz), 41.4 (s), 28.9 (d, J CP ) 3.7 Hz); 31P NMR (120 MHz,
CDCl3) δ 51.0 (s); IR (thin film) 1669 (s), 1496 (s); MS-FAB
(EI+) m/z (% rel intensity) 482.4 (MH+, 50), 264.3 (M - [Ph2-
PS]+, 100); HRFAB Calcd for C30H29NOPS (MH+) m/e 482.1707;
Found m/e 482.1706.
(5S,2′S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-m eth yleth yl)-5-isop r op yl-1, 3-oxa zole (24): 1H NMR (300
MHz, CDCl3) δ 7.99 (m, 4H), 7.48 (m, 6H), 4.13 (dd, J HH ) 9.0
Hz, J HH ) 8.0 Hz, 1H), 3.93 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz,
1H), 3.87 (ddd, J HH ) 9.0 Hz, J HH ) 8.0 Hz, J HH ) 7.0 Hz,
1H), 3.30 (m, 1H), 2.45 (m, 2H), 1.73 (dqq, J HH ) 7.0 Hz, J HH
(5S,2′S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en yleth yl)-5-isop r op yl-1,3-oxa zole (28): 1H NMR (300
MHz, CDCl3) δ 8.18 (m, 2H), 7.57 (m, 3H), 7.48 (m, 2H), 7.30
(m, 1H), 7.21 (m, 4H), 7.12 (m, 3H), 4.42 (ddd, J HH ) 11.0 Hz,
J HH ) 3.0 Hz, J HP ) 11.0 Hz, 1H), 4.00 (dd, J HH ) 7.0 Hz, J HH
) 7.0 Hz, J HH ) 7.0 Hz, 1H), 1.21 (dd, J HH ) 7.0 Hz, J HP
)
18.7 Hz, 3H), 0.93 (d, J HH ) 7.0 Hz, 3H), 0.86 (d, J HH ) 7.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.2 (d, J CP ) 19.0 Hz),
131.5 (d, J CP ) 6.0 Hz), 131.4 (d, J CP ) 9.4 Hz), 131.2 (d, J CP
) 77.5 Hz), 131.1 (d, J CP ) 77.0 Hz), 128.7 (d, J CP ) 11.0 Hz),
128.5 (d, J CP ) 11.3 Hz), 72.0 (s), 69.8 (s), 32.5 (s), 30.8 (d, J CP
) 57.0 Hz), 28.7 (d, J CP ) 2.3 Hz), 18.7 (s), 18.0 (s), 12.9 (s);
31P NMR (120 MHz, CDCl3) δ 53.0 (s); IR (thin film) 2960 (s),
1669 (s); MS-FAB (EI+) m/z (% rel intensity) 372.1 (MH+, 90),
154.1 ([M - Ph2PS]+, 100); HRFAB calcd for C21H27NOPS
(MH+ ) m/e 372.1551, measured m/e 372.1554.
) 7.0 Hz, 1H), 3.72 (dddd, J HH ) 7.0 Hz, J HH ) 7.0 Hz, J HH
)
6.0 Hz, J HH ) 1.6 Hz, 1H), 3.68 (dd, J HH ) 7.0 Hz, J HH ) 7.0
Hz, 1H), 3.25 (ddd, J HH ) 11.0 Hz, J HH ) 8.0 Hz, J HP ) 15.0
Hz, 1H), 2.77 (dddd, J HH ) 8.0 Hz, J HH ) 3.0 Hz, J HH ) 1.6
Hz, J HP ) 15.0 Hz, 1H), 1.43 (dqq, J HH ) 6.0 Hz, J HH ) 7.0
Hz, J HH ) 7.0 Hz, 1H), 0.60 (d, J HH ) 7.0 Hz, 3H), 0.52 (d, J HH
) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0 (d, J CP
)
18.6 Hz), 133.7 (d, J CP ) 4.6 Hz), 132.0 (d, J CP ) 9.3 Hz), 131.7
(d, J CP ) 1.2 Hz), 131.51 (d, J CP ) 9.3 Hz), 131.48 (d, J CP
(5S,2′R)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-m eth yleth yl)-5-isop r op yl-1,3-oxa zole (25): 1H NMR (300
MHz, CDCl3) δ 7.96 (m, 4H), 7.47 (m, 6H), 4.18 (m, 1H), 3.90
(m, 2H), 3.30 (qtd, J HH ) 7.0 Hz, J HH ) 7.0 Hz, J HP ) 7.0 Hz,
1H), 2.45 (dd, J HH ) 7.0 Hz, J HP ) 7.0 Hz, 2H), 1.75 (dqq, J HH
) 7.0 Hz, J HH ) 7.0 Hz, J HH ) 7.0 Hz, 1H), 1.18 (dd, J HH ) 7.0
Hz, J HP ) 18.7 Hz, 3H), 0.94 (d, J HH ) 7.0 Hz, 3H), 0.85 (d,
J HH ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.1 (d, J CP
) 18.8 Hz), 131.5 (d, J CP ) 9.1 Hz), 131.4 (d, J CP ) 9.3 Hz),
131.3 (d, J CP ) 77.3 Hz), 131.2 (d, J CP ) 77.5 Hz), 128.7 (d,
J CP ) 11.6 Hz), 128.5 (d, J CP ) 11.6 Hz), 72.1 (s), 69.7 (s), 32.3
(s), 30.7 (d, J CP ) 57.3 Hz), 28.9 (d, J CP ) 2.3 Hz), 18.8 (s),
17.9 (s), 13.0 (s); 31P NMR (120 MHz, CDCl3) δ 53.0 (s); IR
(thin film) 2961 (s) 1669 (s); MS-FAB (EI+) m/z (% rel
intensity) 372.2 (MH+, 100), 154.2 ([M - Ph2PS]+, 65); HRFAB
calcd for C21H27NOPS (MH+ ) m/e 372.1551, measured m/e
372.1549.
)
36.0 Hz), 131.1 (d, J CP ) 2.9 Hz), 130.5 (d, J CP ) 36.1 Hz),
130.0 (d, J CP ) 5.4 Hz), 128.8 (d, J CP ) 11.6 Hz), 127.8 (d, J CP
) 12.2 Hz), 127.6 (d, J CP ) 2.9 Hz), 127.4 (d, J CP ) 2.9 Hz),
71.7 (s), 69.5 (s), 43.9 (d, J CP ) 51.5 Hz), 31.8 (s), 29.3 (d, J CP
) 3.5 Hz), 18.1 (s), 17.3 (s); 31P NMR (120 MHz, CDCl3) δ 50.9
(s); IR (thin film) 1670 (s), 1495 (s), 1481 (s), 1453 (s); MS-
FAB (EI+) m/z (% rel intensity) 434.2 (MH+, 30); HRFAB calcd
for C26H29NOPS (MH+ ) m/e 434.1707; measured m/e 434.1703.
(5S,2′R)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en yleth yl)-4-isop r op yl-1,3-oxa zole (29): 1H NMR (300
MHz, CDCl3) δ 8.19 (m, 2H), 7.56 (m, 3H), 7.48 (m, 2H), 7.30
(m, 1H), 7.20 (m, 4H), 7.10 (m, 3H), 4.49 (ddd, J HH ) 11.0 Hz,
J HH ) 3.0 Hz, J HP ) 11.0 Hz, 1H), 3.95 (dd, J HH ) 8.0 Hz, J HH
) 8.0 Hz, 1H), 3.75 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 3.70
(dddd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, J HH ) 7.0 Hz, J HH ) 2.4
Hz, 1H), 3.20 (ddd, J HH ) 11.0 Hz, J HH ) 8.0 Hz, J HP ) 16.0
Hz, 1H), 2.75 (dddd, J HH ) 8.0 Hz, J HH ) 3.0 Hz, J HH ) 2.4
Hz, J HP ) 15.0 Hz, 1H), 1.41 (dqq, J HH ) 7.0 Hz, J HH ) 7.0
Hz, J HH ) 7.0 Hz, 1H), 0.60 (d, J HH ) 7.0 Hz, 3H), 0.54 (d, J HH
(5S,2′S)-5-Ben zyl-4,5-d ih yd r o-2-(2′-(d ip h en ylp h osp h i-
n oth ioyl)-2′-p h en yleth yl-1,3-oxa zole (26): 1H NMR (300
MHz, CDCl3) δ 8.20 (m, 2H), 7.59 (m, 3H), 7.54 (m, 2H), 7.1-
7.4 (m, 11H), 7.01 (m, 2H), 4.45 (ddd, J HH ) 10.0 Hz, J HH
3.3 Hz, J HP ) 10.0 Hz, 1H), 4.12 (dddd, J HH ) 9.0 Hz, J HH
)
)
) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.5 (d, J CP
)
19.1 Hz), 134.0 (d, J CP ) 4.0 Hz), 132.0 (d, J CP ) 9.0 Hz), 131.7
(d, J CP ) 3.0 Hz), 131.5 (d, J CP ) 9.0 Hz), 131.4 (d, J CP ) 26.0
Hz), 131.1 (d, J CP ) 3.0 Hz), 130.4 (d, J CP ) 26.0 Hz), 130.0
8.0 Hz, J HH ) 7.0 Hz, J HH ) 5.0 Hz, 1H), 3.92 (dd, J HH ) 8.0
Hz, J HH ) 8.0 Hz, 1H), 3.69 (dd, J HH ) 8.0 Hz, J HH ) 7.0 Hz,
1H), 3.22 (ddd, J HH ) 10.0 Hz, J HH ) 7.0 Hz, J HP ) 16.0 Hz,
1H), 2.81 (dddd, J HH ) 7.0 Hz, J HH ) 3.3 Hz, J HH ) 2.0 Hz,
J HP ) 16.0 Hz, 1H), 2.72 (dd, J HH ) 13.0 Hz, J HH ) 5.0 Hz,
1H), 2.13 (dd, J HH ) 13.0 Hz, J HH ) 9.0 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 164.9 (d, J CP ) 18.1 Hz), 137.8 (s), 133.9 (d,
J CP ) 4.2 Hz), 131.9 (d, J CP ) 9.2 Hz), 131.7 (d, J CP ) 2.9 Hz),
131.49 (d, J CP ) 9.5 Hz), 131.44 (d, J CP ) 33.8 Hz), 131.1 (d,
J CP ) 2.9 Hz), 130.4 (d, J CP ) 27.9 Hz), 130.0 (d, J CP ) 5.3
Hz), 129.0 (s), 128.8 (d, J CP ) 11.6 Hz), 128.3 (s), 127.8 (d, J CP
(d, J CP ) 5.0 Hz), 128.8 (d, J CP ) 11.0 Hz), 127.8 (d, J CP
)
12.0 Hz), 127.5 (d, J CP ) 2.0 Hz), 127.2 (d, J CP ) 3.0 Hz), 71.7
(s), 69.6 (s), 44.0 (d, J CP ) 51.1 Hz), 32.2 (s), 28.7 (d, J CP ) 4.1
Hz), 18.0 (s), 17.5 (s); 31P NMR (120 MHz, CDCl3) δ 50.9 (s);
IR (thin film) 1674 (s); MS-FAB (EI+) m/z (% rel intensity)
434.4 (MH+, 100); HRFAB calcd for C26H29NOPS (MH+ ) m/e
434.1707, measured m/e 434.1710.
(5S,2′S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en ylet h yl)-5-p h en yl-1,3-oxa zole (30): 1H NMR (300

Synthesis of Phosphino Oxazoline Ligand Libraries
J . Org. Chem., Vol. 63, No. 23, 1998 8431
MHz, CDCl3) δ 8.20 (m, 2H), 7.60 (m, 3H), 7.50 (m, 2H), 7.33
(m, 1H), 7.1-7.3 (m, 10H), 6.61 (d, J HH ) 6.4 Hz, 2H), 4.98
(ddd, J HH ) 10.0 Hz, J HH ) 8.0 Hz, J HH ) 2.4 Hz, 1H), 4.62
(ddd, J HH ) 12.0 Hz, J HH ) 3.0 Hz, J HP ) 10.0 Hz, 1H), 4.38
(dd, J HH ) 10.0 Hz, J HH ) 8.0 Hz, 1H), 3.35 (ddd, J HH ) 12.0
Hz, J HH ) 7.5 Hz, J HP ) 16.0 Hz, 1H), 2.85 (dddd, J HH ) 7.5
Hz, J HH ) 3.0 Hz, J HH ) 2.4 Hz, J HP ) 16.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 166.6 (d, J CP ) 19.2 Hz), 142.1 (s), 134.0
(d, J CP ) 4.8 Hz), 132.0 (d, J CP ) 9.2 Hz), 131.9 (d, J CP ) 5.0
Hz), 131.6 (d, J CP ) 9.5 Hz), 131.2 (d, J CP ) 3.2 Hz), 130.1 (d,
J CP ) 5.1 Hz), 128.9 (d, J CP ) 11.3 Hz), 128.4 (s), 127.9 (d, J CP
) 12.2 Hz), 127.8 (d, J CP ) 2.4 Hz), 127.4 (d, J CP ) 3.2 Hz),
127.2 (s), 126.3 (s), 74.8 (s), 69.4 (s), 44.1 (d, J CP ) 51.1 Hz),
28.6 (d, J CP ) 4.0 Hz); 31P NMR (120 MHz, CDCl3) δ 50.8 (s);
IR (thin film) 1667 (s); MS-FAB (EI+) m/z (% rel intensity)
468.2 (MH+, 20), 250.1 ([M - Ph2PS]+, 100); HRFAB calcd for
Hz), 131.8 (d, J CP ) 2.2 Hz), 131.5 (d, J CP ) 9.8 Hz), 131.1 (d,
J CP ) 2.9 Hz), 131.0 (d, J CP ) 33.6 Hz), 130.1 (d, J CP ) 5.5
Hz), 128.8 (d, J CP ) 11.5 Hz), 127.9 (d, J CP ) 12.0 Hz), 127.7
(d, J CP ) 2.6 Hz), 127.4 (d, J CP ) 3.1 Hz), 75.7 (s), 68.5 (s),
43.9 (d, J CP ) 51.5 Hz), 33.1 (s), 29.2 (s), 25.3 (s); 31P NMR
(120 MHz, CDCl3) δ 50.9 (s); IR (thin film) 1603 (s); MS-FAB
(EI+) m/z (% rel intensity) 470 ([M + Na]+, 100) 448 (MH+,
50); HRFAB calcd for C27H31NOPS (MH+ ) m/e 448.1864,
measured m/e 448.1864.
(5S,2′R)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en yleth yl-5-ter t-bu tyl-1,3-oxa zole (33): 1H NMR (300
MHz, CDCl3) δ 8.20 (m, 2H), 7.57 (m, 3H), 7.50 (m, 2H), 7.31
(m, 1H), 7.21 (m, 4H), 7.10 (m, 3H), 4.51 (ddd, J HH ) 10.0 Hz,
J HH ) 3.0 Hz, J HP ) 10.0 Hz, 1H), 3.91 (dd, J HH ) 8.0 Hz, J HH
) 9.0 Hz, 1H), 3.85 (dd, J HH ) 8.0 Hz, J HH ) 8.0 Hz, 1H), 3.61
(ddd, J HH ) 9.0 Hz, J HH ) 8.0 Hz, J HH ) 2.5 Hz, 1H), 3.21
(ddd, J HH ) 12.0 Hz, J HH ) 7.0 Hz, J HP ) 17.0 Hz, 1H), 2.73
(dddd, J HH ) 7.0 Hz, J HH ) 3.0 Hz, J HH ) 2.5 Hz, J HP ) 17.0
Hz, 1H), 0.52 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 164.4 (d,
J CP ) 19.3 Hz), 134.1 (d, J CP ) 5.0 Hz), 132.0 (d, J CP ) 9.1
Hz), 131.7 (d, J CP ) 2.2 Hz), 131.5 (d, J CP ) 10.0 Hz), 131.4
(d, J CP ) 26 Hz), 131.1 (d, J CP ) 2.9 Hz), 130.4 (d, J CP ) 26.3
Hz), 130.0 (d, J CP ) 5.2 Hz), 128.8 (d, J CP ) 11.6 Hz), 127.8
(d, J CP ) 12.1 Hz), 127.5 (d, J CP ) 4.1 Hz), 127.2 (d, J CP ) 3.1
Hz), 75.5 (s), 68.4 (s), 43.8 (d, J CP ) 51.6 Hz), 33.4 (s), 28.6 (d,
J CP ) 3.9 Hz), 25.2 (s); 31P NMR (120 MHz, CDCl3) δ 50.9 (s);
IR (thin film) 1679 (s); MS-FAB (EI+) m/z (% rel intensity)
448.2 (MH+, 50), 230.2 ([M - Ph2PS]+, 100); HRFAB calcd for
C
29H27NOPS (MH+ ) m/e 468.1551, measured m/e 468.1555.
(5S,2′R)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en ylet h yl)-5-p h en yl-1,3-oxa zole (31): 1H NMR (300
MHz, CDCl3) δ 8.20 (m, 2H), 7.60 (m, 3H), 7.50 (m, 2H), 7.1-
7.4 (m, 11H), 6.59 (d, J HH ) 8.0 Hz, 2H), 4.95 (ddd, J HH ) 10.0
Hz, J HH ) 9.0 Hz, J HH ) 2.0 Hz, 1H), 4.50 (ddd, J HH ) 12.0
Hz, J HH ) 3.0 Hz, J HP ) 10.0 Hz, 1H), 4.42 (dd, J HH ) 10.0
Hz, J HH ) 8.0 Hz, 1H), 3.78 (dd, J HH ) 9.0 Hz, J HH ) 8.0 Hz,
1H), 3.40 (ddd, J HH ) 12.0 Hz, J HH ) 7.5 Hz, J HP ) 15.0 Hz,
1H), 2.85 (dddd, J HH ) 7.5 Hz, J HH ) 3.0 Hz, J HH ) 2.0 Hz,
J HP ) 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.8 (d, J CP
) 19.0 Hz), 142.1 (s), 133.7 (d, J CP ) 4.4 Hz), 132.0 (d, J CP
9.2 Hz), 131.9 (d, J CP ) 3.1 Hz), 131.5 (d, J CP ) 9.7 Hz), 131.45
(d, J CP ) 39.0 Hz), 131.2 (d, J CP ) 2.9 Hz), 130.4 (d, J CP
)
C
27H31NOPS (MH+ ) m/e 448.1864, measured m/e 448.1866.
)
Anal. Calcd for C27H30NOPS: C, 72.46; H, 6.76; N, 3.13.
Found C, 72.40; H, 6.55; N, 3.47.
39.1 Hz), 130.2 (d, J CP ) 5.3 Hz), 128.9 (d, J CP ) 11.6 Hz),
128.5 (s), 128.0 (d, J CP ) 4.3 Hz), 127.9 (d, J CP ) 4.4 Hz), 127.6
(d, J CP ) 3.2 Hz), 127.3 (s), 126.4 (s), 75.0 (s), 69.6 (s), 44.0 (d,
J CP ) 51.6 Hz), 29.4 (d, J CP ) 3.4 Hz); 31P NMR (120 MHz,
CDCl3) δ 50.8 (s); IR (thin film) 3058 (s), 3029 (s), 1669 (s),
1492 (s), 1482 (s); MS-FAB (EI+) m/z (% rel intensity) 468.3
Ack n ow led gm en t. This work was partially sup-
ported by NIH R01 GM56490-01 and Washington
University. We also gratefully acknowledge the Wash-
ington University High-Resolution NMR Facility, par-
tially supported by NIH 1S10R02004, and the Wash-
ington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their as-
sistance.
(MH+, 50), 250.1 ([M - Ph2PS]+, 100); HRFAB calcd for C29H27
-
NOPS (MH+ ) m/e 468.1551,s measured m/e 468.1454.
(5S,2′S)-4,5-Dih yd r o-2-(2′-(d ip h en ylp h osp h in oth ioyl)-
2′-p h en yleth yl)-5-ter t-bu tyl-1,3-oxa zole (32): 1H NMR (300
MHz, CDCl3) δ 8.15 (m, 2H), 7.57 (m, 3H), 7.45 (m, 2H), 7.30
(m, 1H), 7.20 (m, 4H), 7.10 (m, 3H), 4.39 (ddd, J HH ) 12.1 Hz,
J HH ) 3.0 Hz, J HP ) 10.4 Hz, 1H), 3.99 (dd, J HH ) 8.3 Hz, J HH
) 9.9 Hz, 1H), 3.75 (dd, J HH ) 8.3 Hz, J HH ) 8.3 Hz, 1H), 3.64
(ddd, J HH ) 2.5 Hz, J HH ) 9.9 Hz, J HH ) 8.3 Hz, 1H), 3.29
(ddd, J HH ) 12.1 Hz, J HH ) 15.3 Hz, J HP ) 7.0 Hz, 1H), 2.74
(dddd, J HH ) 3.0 Hz, J HH ) 15.3 Hz, J HH ) 2.5 Hz, J HP ) 8.5
Hz, 1H), 0.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 163.9 (d,
J CP ) 19.7 Hz), 133.5 (d, J CP ) 4.6 Hz), 132.0 (d, J CP ) 9.2
Su p p or tin g In for m a tion Ava ila ble: Full spectral data
for the compounds 11-19 and their corresponding alcohols (19
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O981420Y