Proline-based P, N ligands in asymmetric allylation and the heck reaction

Article abstract of DOI:10.1021/jo0158231

A series of phosphine-oxazoline ligands based on proline are reported. These ligands are synthesized from commercially available trans-4-hydroxy-L-proline in four steps. The ability of this type of ligand to catalyze allylic alkylation in an asymmetric fashion as well as the asymmetric Heck reaction is reported. The best of these ligands gave a palladium complex, which catalyzed the addition of dimethylmalonate to cyclopentenyl acetate in excellent yield and up to 96% ee. This same system catalyzed the Heck reaction between dihydrofuran and cyclohexene in up to 86% ee. These ligands appear to differ from the traditional phosphine-oxazoline ligands in that the stereochemistry of the stereogenic carbon next to the oxazoline is not necessarily the dominant chiral center in the induction of selectivity.

Full text of DOI:10.1021/jo0158231

7240
J . Org. Chem. 2001, 66, 7240-7246
P r olin e-Ba sed P , N Liga n d s in Asym m etr ic Allyla tion a n d th e
Heck Rea ction
Scott R. Gilbertson,* Dejian Xie, and Zice Fu
Department of Chemistry, Washington University, St. Louis, Missouri 63130
srg@wuchem.wustl.edu
Received J une 6, 2001
A series of phosphine-oxazoline ligands based on proline are reported. These ligands are synthesized
from commercially available trans-4-hydroxy-L-proline in four steps. The ability of this type of ligand
to catalyze allylic alkylation in an asymmetric fashion as well as the asymmetric Heck reaction is
reported. The best of these ligands gave a palladium complex, which catalyzed the addition of
dimethylmalonate to cyclopentenyl acetate in excellent yield and up to 96% ee. This same system
catalyzed the Heck reaction between dihydrofuran and cyclohexene in up to 86% ee. These ligands
appear to differ from the traditional phosphine-oxazoline ligands in that the stereochemistry of
the stereogenic carbon next to the oxazoline is not necessarily the dominant chiral center in the
induction of selectivity.
In tr od u ction
Phosphine-oxazoline ligands have been used with
success in a number of asymmetric reactions. Hayashi,
Pfaltz, Helmchen, and Williams among others have used
these ligands with good success in both palladium-
catalyzed allylation and the Heck reaction.1-12 The most
successful ligand of this type has been based on the basic
structure 1 (Figure 1). While other phosphine-oxazoline
systems have been developed and tested, generally these
systems have proven to be less effective than ligand 1.
In the majority of cases that have been studied, the
ligands possess only one chiral center, the carbon next
to the oxazoline nitrogen. Herein we report the synthesis
of a series of hydroxyproline-based phosphine-oxazoline
ligands (2). These ligands present up to three chiral
centers that can be used to control the selectivity of a
transition metal coordinated to them. Palladium com-
plexes of these ligands have been tested in palladium-
catalyzed allylation and the Heck reaction.13,14
F igu r e 1.
based on the observation that ligands derived from
proline often result in reasonably high stereodifferena-
tion.15-19 For this reason, a series of proline-based phos-
phine-oxazoline ligands was synthesized. The synthesis
of this class of ligand begins with commercially available
BOC-protected trans-4-hydroxy-L-proline (3). Either an
amino acid ester or an amino alcohol is coupled to this
molecule (Scheme 1). If an ester is used, the oxazoline is
formed through reduction of the ester to an alcohol (8,
10, 11) and formation of a bis-mesylate by reaction with
methanesulfonyl chloride. If an amino alcohol is initially
coupled to proline the reduction step is not necessary.
The primary mesylate then undergoes cyclization to form
the oxazoline ring (12-14). After this reaction, the
secondary mesylate was subjected to substitution by
sodium diphenylphosphide. Following substitution, the
phosphine is protected as the phosphine sulfide (15-17).
The ligands are purified as the phosphine sulfides and
then converted to phosphines by reduction with Raney
nickel before coordination to palladium.20,21 This route
is appealing because it allows the synthesis of a wide
variety of analogues. The R group on the oxazoline is
easily changed by simply coupling a different amino acid
Resu lts a n d Discu ssion
Syn th esis of Hyd r oxyp r olin e-Ba sed P h osp h in e-
Oxa zolin e Liga n d s. The design of this system was
(1) Dawson, G. J .; Frost, C. G.; Williams, J . M. J . Tetrahedron Lett.
1993, 34, 3149.
(2) Gilbertson, S. R.; Chang, C.-W. J . Org. Chem. 1998, 63, 8424-
8431.
(3) Hashimoto, Y.; Horie, Y.; Hayashi, M.; Saigo, K. Tetrahedron:
Asymmetry 2000, 11, 2205-2210.
(4) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338-1345.
(5) Ogasawara, M.; Yoshida, K.; Hayashi, T. Heterocycles 2000, 52,
195-201.
(6) Porte, A. M.; Reibenspies, J .; Burgess, K. J . Am. Chem. Soc. 1998,
120, 9180-9187.
(7) Sagasser, I.; Helmchen, G. Tetrahedron Lett. 1998, 39, 261-264.
(8) Spinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
(9) Sprinz, J .; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523-1526.
(10) Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161-164.
(11) Langer, T.; J anssen, J .; Helmchen, G. Tetrahedron: Asymmetry
1996, 7, 1599-1602.
(15) Parrinello, G.; Stille, J . K. J . Am. Chem. Soc. 1987, 109, 7122.
(16) Hodgson, M.; Parker, D. J . Organomet. Chem. 1987, 325, C27-
C30.
(17) Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata, T.;
Tatsuno, Y.; Otsuka, S. J . Organomet. Chem. 1989, 370, 203-221.
(18) Brunner, H.; Graf, E.; Leitner, W.; Wutz, K. Synthesis 1989,
743-745.
(12) Newman, L. M.; Williams, M. J .; McCague, R.; Potter, G. A.
Tetrahedron: Asymmetry 1996, 7, 1597-1598.
(13) Gilbertson, S. R.; Xie, D. Angew. Chem. 1999, 38, 2750-2752.
(14) Gilbertson, S. R.; Fu, Z.; Xie, D. Tetrahedron Lett. 2001, 42,
365-368.
(19) Baker, G. L.; Fritschel, S. J .; Stille, J . R.; Stille, J . K. J . Org.
Chem. 1981, 46, 2954-2960.
(20) Gilbertson, S. R.; Chen, G.; McLoughlin, M. J . Am. Chem. Soc.
1994, 116, 4481-4482.
(21) Gilbertson, S. R.; Wang, X. J . Org. Chem. 1996, 61, 434-435.
10.1021/jo0158231 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/22/2001

Proline-Based P, N Ligands in Asymmetric Allylation
J . Org. Chem., Vol. 66, No. 22, 2001 7241
Sch em e 1a
Ta ble 1. P a lla d iu m -Ca ta lyzed Allylic Ad d ition to
Cyclop en ten yl Aceta tea
entry
ligand
yieldb (%)
eec (%)
configurationd
1
2
3
4
5
6
7
18
19
20
21
22
23
24
94
99
92
93
91
95
90
90
76
68
68
76
58
80
S
S
S
S
S
S
S
a
All reactions were run at 0 °C and were complete in less than
1 h. Isolated yield. c Enantiomeric excess was determined by
[Eu(hfc)3] shift reagent. The absolute stereochemistry was de-
b
d
termined by comparison to optical rotations in the literature.
a
Key: (a) EDC/HOBt, rt, CH2Cl2; (b) when X ) O LiBH4, THF,
0 °C to rt; (c) MeSO2Cl, Et3N, CH2Cl2, rt; (d) Ph2P-Na+, THF, -78
°C to rt; (e) S8, rt.
18 (entry 1, Table 1). The alkyl group on the oxazoline
has a considerable effect on the selectivity. Ligands with
smaller groups on the oxazoline gave lower selectivity.
Interestingly, when tert-butyl is substituted for the
isopropyl group, 20 versus 18, lower selectivity is ob-
tained (entry 3 versus entry 1). In all of the cases
presented in Table 1, the S enantiomer is obtained as
the major product. In the phosphine-oxazoline systems
reported previously, it has been shown that changing the
stereochemistry of the oxazoline alkyl group alters the
selectivity of the catalyst in favor of the other enantiomer.
In the proline-based system there are three chiral centers
(Figure 2). Ligands 18-20 are oxazolines that are formed
from an L-amino acid. When ligand 21 from D-valine was
tested, it gave lower selectivity but with the same
enantiomer as the major product as with ligands 18-
20. This is the only case we know of where the stereo-
chemistry of the oxazoline is overruled by other stereo-
centers in the molecule. Our discussion of the origin of
the selectivity with this ligand system will account for
this difference. Other interesting examples are the
substitution of L- or D-phenylalanine (19 or 22) for
L-valine gives the same selectivity (76% ee). Ligand 23
with a methyl ester gave a lower selectivity of 58% ee.
Interestingly, ligand 24, which does not possess a chiral
center next to the oxazoline, nitrogen gives the product
in 90% yield and 80% ee.
F igu r e 2.
F igu r e 3. Phosphine-oxazoline ligands with different N-
substituents.
ester to trans hydroxyproline (Figure 2). Ligands 18-24
have been synthesized through this approach.
In addition to being able to vary the group next to the
oxazoline nitrogen, this system allows for modification
of the group attached to the proline nitrogen. Our
approach to these molecules takes advantage of the
lability of the Boc group used to protect the nitrogen in
our original example. Ligands 26-31 were synthesized
from ligand 15 (Figure 3). Removal of the Boc group and
hydrolysis of the oxazoline provided the phosphine amino
acid 25. This was converted to either a new carbamate
or amide, followed by subsequent formation of the ox-
azoline. Compound 31, with the oxazoline trans to
diphenylphosphine group, was obtained as a diastereo-
isomer during the synthesis of 28.
The effects of temperature and solvent on the reaction
were also probed (Table 2). The ligand with the highest
selectivity (18) was used in this study. Reduction of the
temperature to -20 °C resulted in an increase in selec-
tivity to 94% ee (entry 2, Table 2). At -35 °C, the
selectivity improved to 96% ee (entry 1, Table 2). It was
found that acetonitrile gives the highest selectivity with
DMF and methylene chloride giving selectivities above
80% ee.
Effect of N-Su bstitu en t of P r olin e. This ligand
system has a second position that can be varied to fine-
Asym m etr ic Allylic Su bstitu tion : Effects of Su b-
stitu en t on Oxa zolin e Rin g. We first studied the allylic
alkylation of cyclopentenyl acetate with dimethyl mal-
onate, at 0 °C, using ligands 18-24 with different
substituents on the oxazoline ring (Table 1). This reaction
was chosen because there are few systems that perform
this transformation with high selectivity.22-28 In our
system, the highest selectivity was achieved with ligand
(23) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 99-102.
(24) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1996, 118, 235-
236.
(25) Evans, D. A.; Campos, K. R.; Tedrow, J . S.; Michael, F. E.;
Gagne, M. R. J . Am. Chem. Soc. 2000, 122 (33), 7905-7820.
(26) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1998,
37, 3047-3050.
(27) Knu¨hl, G.; Sennhenn, P.; Helmchen, G. J . Chem. Soc., Chem.
Commun. 1995, 1845-1846.
(28) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure
Appl. Chem. 1997, 69, 513-518.
(22) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1994, 116, 4089.

7242 J . Org. Chem., Vol. 66, No. 22, 2001
Gilbertson et al.
Ta ble 2. P a lla d iu m -Ca ta lyzed Ad d ition to Cyclop en ten yl
Aceta te (32) Usin g Liga n d 18a
time yieldb eec (%)
entry solvent
T (°C) cation/base
(h)
(%)
(config)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
-35
-20
25
0
0
0
25
0
0
TBAF/BSA 20
79
99
95
99
86
90
30
10
97
96 (S)
94 (S)
86 (S)
82 (S)
79 (S)
85 (S)
71 (S)
68 (S)
87 (S)
TBAF/BSA
TBAF/BSA
TBAF/BSA
TBAF/BSA
TBAF/BSA
TBAF/BSA
6
0.5
1
1.5
2
6
DMF
benzene
CH2Cl2
CH2Cl2
TBAF/NaH 24
Ce2CO3
6
F igu r e 4.
a
Reactions were run with 2 mol % Pd to 3 mol % ligand.
Isolated yield. c Enantiomeric excess was determined by [Eu-
b
Or igin of Selectivity. Initially, we were surprised
that the major enantiomer obtained with this ligand
system was the S enantiomer. It has been shown by
Helmchen and Pfaltz that with phosphine-oxazoline
systems the nucleophile adds trans to the soft phosphine
group.9,29-31 We expected the favored conformation of the
intermediate palladium π-allyl complex to be conforma-
tion A. It was thought that the favored conformation
would be the one with the two methylenes of the five-
membered ring rotated up away from the bulky Boc
group. If true, the product from addition trans to the
phosphine would be the R enantiomer. Thus, we were
surprised to find that the major product is the S enan-
tiomer. The S enantiomer comes about from preference
for intermediate B. We feel that intermediate B is
favored because of an interaction between the phenyl
rings of the phosphine and the two methylenes of the five-
membered ring (Figure 4).
(hfc)3] shift reagent. TBAF (tetrabutylammonium fluoride). e BSA
d
(N,O-bis(trimethylsilyl)acetamide).
Ta ble 3. P a lla d iu m -Ca ta lyzed Allylic Ad d ition to 32-35a
eec (%)
entry substrate ligand T (°C) time (h) yield (%) (config)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
32
32
32
32
32
32
33
34
34
34
34
35
35
35
18
26
27
28
29
30
18
18
28
29
30
18
28
29
0
0
0
0
0
0
25
0
25
25
0
1
5
1
0.5
2
0.5
5
3
1
4
94
98
97
96
98
96
93
96
96
96
95
100
96
99
90 (S)
69 (S)
75 (S)
35 (R)
30 (R)
42 (S)
80 (S)
80 (S)
51 (R)
60 (R)
23 (S)
30 (S)
20 (S)
22 (S)
4
6
0.5
0.5
0
25
0
To test our ideas about the preferred conformation
controlling the stereochemistry of the product, we decided
to replace the Boc group on nitrogen with a larger group.
With such a group on nitrogen it was thought that it may
be possible to turn the allyl group around such that
intermediate A would be favored. This would result in
the formation of the other enantiomer as the major
product. If successful, minimally this would provide
evidence for our ideas about the origin of the selectivity
in this system. Optimally this could provide an approach
to obtain either enantiomer of the product from two
ligands that differ by only the group on the proline
nitrogen. Ligands 28 and 29 where either pivalyate or
diisopropylurea has been positioned on the proline ni-
trogen do exactly what we predicted. Both of these
ligands give the R enantiomer, as the major product (28,
35% ee; 29, 30% ee). In the case of the seven member
ring allyl acetate this same effect was observed but with
a greater degree of selectivity, 51% ee for 33, and 60%
ee for 34. That the seven-member ring substrate gives
better selectivity for the R product supports our proposed
π-allyl intermediates. Since the seven-membered ring
substrate has two more methylenes to interact with the
bulky group on the nitrogen, one would expect a greater
preference for the conformation with those methylenes
away from that group.
a
Reactions were run with 2 mol % Pd to 3 mol % ligand.
Isolated yield. c Enantiomeric excess was determined by
[Eu(hfc)3] shift reagent, and absolute stereochemistry was deter-
mined by comparison of optical rotations in the literature.
b
tune the selectivity of the ligand. In addition to the group
on the oxazoline ring, the protecting group on nitrogen
can be changed easily. Ligands 26-30 were examined
in the allylic substitutions of cyclic substrates 32 and 34
and the linear substrate 35, using dimethyl malonate as
the nucleophile and TBAF/BSA (tetrabutylammonium
fluoride/N,O-bis(trimethylsilyl)acetamide) as the base.
The results are summarized in Table 3. For allylic
alkylation of cyclopentenyl acetate, ligand 18 having the
Boc group at nitrogen of proline turned out to be the best
ligand (entry 1, Table 3). Ligand 26 (with Fmoc) and 27
(with Cbz) gave moderate selectivities of 69% ee and 75%
ee, respectively (entries 2 and 3, Table 3). Ligand 30 with
a sterically less demanding acetate group gave lower
selectivity, 42% ee (entry 6). The six- and seven-
membered ring allyl acetates also proceed in with good
selectivity, 80% ee. Acyclic substrates such as 35 do not
proceed with high selectivity. We believe this is due to
the rather constrained nature of the pocket around the
palladium.
(29) Sprinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
(30) Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2108-2110.
(31) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure
Appl. Chem. 1997, 69, 513-518.
(32) Gilbertson, S. R.; Genov, D. G.; Rheingold, A. L. Org. Lett. 2000,
2, 2885-2888.
(33) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 200.
(34) Shibasaki, M.; Boden, C. D. J .; Kojima, A. Tetrahedron 1997,
53, 7371-7395.

Proline-Based P, N Ligands in Asymmetric Allylation
J . Org. Chem., Vol. 66, No. 22, 2001 7243
Ta ble 4. Resu lts of th e Heck Rea ction w ith Liga n d 18 in
Va r iou s Solven ts Usin g Diisop r op yleth yla m in e a s th e
Ba se
conversion
(%)
eea
(%)
isomer
(%)
entry
solvent
benzene
toluene
benzene/hexane
dioxane
dichloroethane
THF
dichloromethane
acetonitrile
NMP
time
1
2
3
4
5
6
7
8
9
24 h
2 d
5 d
36 h
3 d
3 d
6 d
3 d
20 h
2 d
3 d
98
84
99
99
46
88
52
52
99
80
100
80
49
57
80
80
70
74
12
58
28
68
<2
4
1.5
<2
40
5
24
33
5
F igu r e 5.
10
11
DMF
DMSO
4
9
To test if this ligand system is truly a bidentate ligand,
compound 31 was synthesized and tested for its ability
to selectively catalyze the allylation reaction. Because of
the trans relationship between the phosphine and the
oxazoline ring it will not be possible for this ligand to
bind palladium in a bidentate manner. In the case of
catalysis, with this system the product was obtained with
no selectivity. We feel this system acts as a mondentate
ligand and in this case that complex catalyzes the
reaction with no selectivity. It is important to note that
the determination of the actual catalytic species in any
system like this requires considerably more work then
the simple experiments laid out here. However, barring
careful kinetic analysis of this system, our data is
consistent with a intermediate similar to B being re-
sponsible for the formation of the major enantiomer.
Diphenylallyl acetate (35) was also examined with
ligands 18, 28, and 30. In all three cases, low selectivity
was obtained (entries 12-14, Table 3). The “pocket” into
which the allyl group must fit may be too small for the
extended π-allyl complex that will form with an acyclic
allyl acetate (Figure 5). Alternatively the dominant
directing groups with this ligand system appear to be
positioned above and below the allyl intermediate. In the
case of the intermediate formed from acyclic allyl acetates
one would expect there to be little or no interaction with
groups positioned above or below the metal.
a
Ratios were determined by GC with CHIRALDEX G-TA 30M
column at 70 °C. The retention times were 24.6 min for the S
enantiomer, 28.7 min for the R isomer, and 18.7 min for isomer
39.
Ta ble 5. Resu lts of th e Heck Rea ction w ith Liga n d 18 in
Dioxa n e Usin g Va r iou s Ba ses
conversion
(%)
ee
(%)
isomer
(%)
entry
base
(iPr)2NEt
Et3N
K2CO3
Proton sponge
NaOAc
tBuONa
Bu4NOAc
DBU
time
1
2
3
4
5
6
7
8
9
36 h
36 h
6 d
6 d
5 d
4 d
20 h
3 d
98
99
84
69
39
66
98
7
80
86
60
71
-21
10
-11
-3
17
<2
7
5
11
1.4
32
Me4NOH‚5H2O
Et3N/Bu4NF (1:1) 3 d
5 d
28
56
40
18
10
2
Sch em e 2
In ter m olecu la r Heck Rea ction . In addition to pal-
ladium-catalyzed allylation, phosphine-oxazoline ligands
have been extensively used in asymmetric intermolecular
Heck reactions.3-5,10,14,32-34 With that in mind, we inves-
tigated the utility of the proline-based system in this
reaction. For our initial study, we decided to use dihy-
drofuran (37) and 1-cyclohexenyltriflate (38) as sub-
strates. Three ligands were studied, 18, 20, and 29. Due
to its ready availability, ligand 18 was chosen to optimize
the reaction conditions. Table 4 illustrates the various
conditions that were tested. The choice of solvent and
base can have a profound effect on the activity of these
catalysts as well as on the selectivity. Good selectivity
and high reactivity were observed for the reactions using
benzene or dioxane as the solvent (entries 1 and 4, Table
4). High reactivity but poor selectivity was observed for
NMP as solvent (entry 9, Table 4). Table 5 illustrates
the result of the study where the solvent was kept
constant and a variety of bases were tested. It was
apparent that when diisopropylethylamine and triethy-
lamine were employed as base, the reaction resulted in
good selectivity with better yield than those using other
bases. Although the reaction took less than 1 day to go
to completion, Bu4NOAc resulted in no selectivity (entry
7, Table 5). Ligands 20 and 29 were also examined but
were found to give significantly lower selectivity than
ligand 18 when the optimized conditions were used.
Additional substrates were examined to determine if
this ligand system is general. Reaction of aryl triflate (41)
and 2,3-dihydrofuran (37) using ligand 18 gave good
selectivity and high conversion at 75 °C (Scheme 2).
Reaction of aryl triflate 41 and cyclopentene 43 in the
presence of diisopropylethylamine in benzene was slow

7244 J . Org. Chem., Vol. 66, No. 22, 2001
Gilbertson et al.
345.2025, measured m/e 345.2036. Anal. Calcd for
C16H28N2O6: C, 55.80; H, 8.19. Found: C, 55.36; H, 7.87.
(2S,2′S,4R)-N-ter t-Boc-2-[[N-[(2′-h yd r oxym eth yl-2′-iso-
pr opyl)m eth yl]-1′-am in o]car bon yl]-4-h ydr oxylpr olin e (8).
To a solution of (2S,2′S,4R)-N-tert-Boc-2-[[N-[(2′-methoxycar-
bonyl-2′-isopropyl)methyl]-1′-amino]carbonyl]-4-hydroxylpro-
line (7) (4.68 g, 13.4 mmol) in 200 mL of THF was slowly added
lithium borohydride solution (13.4 mL, 26.6 mmol, 2 M in THF)
at 0 °C. The cooling bath was removed, and stirring was
continued at room temperature for 16 h. The reaction was
quenched by adding 2 N HCl, and THF was evaporated under
reduced pressure. The residue was dissolved in EtOAc/H2O
(4/1, v/v), and the aqueous layer was extracted with EtOAc
three times. The combined organic layers were then washed
with a small amount of 1 N NaOH and brine and dried over
Na2SO4. Evaporation of the solvent gave 3.68 g (87%) of 8 as
a white foam. This material was used for the next step without
further purification. The sample was judged by NMR to be at
least 90% pure: (NMR spectra are reported for a mixture of
and gave moderate selectivity; the reaction with tetra-
butylamoniumacetate as base in dioxane is much faster,
but the selectivity is low. Reaction of dihydrofuran 37
and acyclic vinyl triflate 45 provided the product 46 with
46% ee in 80% yield. The reaction of dihydrofuran 37 and
octanenyl-triflate 47 resulted in much lower selectivity
(23% ee, 83% yield).
Con clu sion
A proline-based phosphine-oxazoline ligand system
has been developed and has been proven to be very
effective in the control of the addition of dimethyl
malonate to cyclic allyl acetates 32-34. The results
discussed above mapped out the interesting features of
proline-based phosphine-oxazoline ligands. The chiral
center on the oxazoline ring has moderate effect on the
selectivity of catalysis, while the substituents at the
proline nitrogen has pronounced and unusual influence
on the stereochemistry of the product. We have shown
that it is possible to reverse the selectivity of the reaction
by simply changing the size of the substituent on the
proline nitrogen. We are currently looking at catalysis
of the addition of other nucleophiles with this system.
Derivatives of this ligand are also being developed for
use in other transition metal catalyzed reactions.
1
two rotamers) H NMR (300 MHz, CDCl3) δ 6.88 and 6.72 (2
br s, 1H), 4.25 (m, 3H), 3.55-3.20 (m, 5H), 2.25 (m, 1H), 1.96
(m, 1H), 1.73 (m, 1H), 1.30 (m, 9H), 0.75 (m, 6H); 13C NMR
(75 MHz, CDCl3 + 1 drop of DMSO-d6) δ 173.5, 172.5, 155.7,
154.5, 80.5, 69.2, 68.6, 62.7, 62.6, 58.9, 58.8, 56.9, 56.8, 54.5,
37.1, 37.0, 28.8, 28.1, 19.3, 18.8, 18.7, 18.1; IR (film) 3410.0,
3320.0, 3055.1, 2986.6, 1675.1, 1533.3, 1420.5, 1265.2, 1163.0,
895.8, 739.7, 668.3 cm-1; MS-FAB m/z (rel intensity) 317 (MH+,
100), 303 (58); HRFAB calcd for
C
15H29N2O5 (MH+) m/e
317.2076, measured m/e 317.2071.
(2S,5′S,4R)-N-ter t-Boc-2-(4′,5′-d ih ydr o-5′-isop r op yl-1′,3′-
oxa zol-2′-yl)-4-(m eth ylsu lfon yl)oxylp r olin e (12). A sample
of 8 (3.58 g, 11.3 mmol) was dissolved in CH2Cl2/Et3N (200
mL, 3/1, v/v), and the solution was cooled to 0 °C. To the
solution was slowly added MsCl (3.5 mL 45.2 mmol) in 10 mL
of CH2Cl2, with stirring through an addition funnel after which
the reaction was stirred at room temperature for 16 h. This
resulted in a dark-brownish solution with the precipitation of
ammonium salt. The solvent was removed by evaporation,
leaving a residue that was dissolved in EtOAc/H2O (4/1, v/v).
The organic solution was then washed with water twice and
dried over Na2SO4. Evaporation of the solvent gave the crude
product, which was purified by flash chromatography (elu-
ant: EtOAc/n-hexanes/Et3N, 84/15/1) to afford a brownish
viscous oil in 61% yield: (NMR spectra are reported for a
mixture of two rotamers) 1H NMR (300 MHz, CDCl3) δ 5.14
(m, 1H), 4.48 (dd, J ) 7.3, 7.7 Hz, 1H), 4.10 (dd, J ) 8.8, 8.4
Hz, 1H), 3.91-3.80 (m, 2H), 3.74-3.57 (m, 2H), 2.92 (s, 3H),
2.53-2.35 (m, 1H), 2.23-2.17 (m, 1H), 1.61 (m, 1H), 1.33
(minor) and 1.29 (major) (s, 9H), 0.79 (d, J ) 6.6 Hz, 3H), 0.73
(d, J ) 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 153.5,
80.1, 78.0, 77.6, 71.7, 71.4, 70.0, 52.9, 52.5, 52.0, 51.8, 38.3,
37.7, 36.6, 32.2, 32.0, 28.0, 18.2, 18.1, 17.6, 17.4; IR (film)
3019.4, 2970.2, 1700.2, 1690.0, 1405.1, 1368.4, 1215.1, 1173.6,
967.2, 901.7, 756.1, 668.3 cm-1; MS-FAB m/z (rel intensity)
377 (MH+, 65), 321 (100); HRFAB calcd for C16H29N2O6S (MH+)
m/e 377.1746, measured m/e 377.1735.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR
spectra were recorded neat or as thin films. 1H (300 or 600
MHz) and 13C (75.43 or 100.57 MHz) NMR spectra were
1
obtained in CDCl3 using either TMS (for H) or CDCl3 (for 13C)
as the internal standard. All solvents were purchased from
Aldrich and used as obtained except where noted. THF was
freshly distilled from sodium benzophenone ketyl under
nitrogen, methylene chloride was freshly distilled from CaH2
under nitrogen. n-Butyllithium was purchased from Aldrich
as a solution in hexanes, stored in a a sure seal bottle under
nitrogen. All experiments were carried out under nitrogen in
dried glassware, using syringe-septum cap techniques. The
-78 and 0 °C external bath temperatures designated are
approximate as achieved by a dry ice-acetone or ice-salt bath,
respectively. Flash column chromatography was carried out
using Merck Kieselgel 60 silica gel (particle size 32-63 µm).
(2S,2′S,4R)-N-ter t-Boc-2-[[N-[(2′-m et h oxyca r b on yl-2′-
isop r op yl)m et h yl]-1′-a m in o]ca r b on yl]-4-h yd r oxylp r o-
lin e (7). A mixture of N-t-Boc-L-hydroxylproline (3.50 g, 15.1
mmol), EDC (5.80 g, 30.2 mmol), and HOBt (4.10 g, 30.2 mmol)
was stirred in 60 mL of dry CH2Cl2 at 0 °C for 5 min. In a
separate flask, L-valine methyl ester hydrochloride (3.80 g, 22.7
mmol) and Et3N (4.20 mL, 30.2 mmol) were stirred for 10 min
in 60 mL of CH2Cl2, after which time the mixture was added
to the active ester. The resulting clear solution was warmed
to room temperature and stirred for 1 day. After evaporation
of CH2Cl2, the residue was dissolved in EtOAc/H2O (4/1, v/v).
The organic layer was washed with 1 N HCl (aq), saturated
NaHCO3 (aq), H2O, and brine and then dried over Na2SO4.
The solvent was removed by evaporation, leaving a residue
that was subjected to column chromatography (eluant: EtOAc/
n-hexanes 95/5, v/v) to yield 4.68 g (90%) as a white foamy
solid: (NMR spectra are reported for a mixture of two rotamers)
1H NMR (300 MHz, CDCl3) δ 7.45 (m, 1H), 6.85 (m, 1H), 4.40
(m, 3H), 3.66 (s, 3H), 3.50-3.20 (m, 2H), 2.08 (dqq, J ) 6.0,
6.8, 6.7 Hz, 1H), 1.42 (s, 9H), 0.88 (d, J ) 6.8 Hz, 3H) 0.85 (d,
J ) 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 171.7,
155.5, 154.5, 80.2, 69.2, 68.6, 60.0, 58.2, 57.0, 54.6, 54.1, 51.6,
39.3, 36.2, 30.7, 27.9, 17.7, 17.6, 17.5, 17.3; IR (film) 3408.0,
3017.5, 2972.1, 1739.7, 1683.7, 1521.8, 1395.4, 1216.1, 1161.1,
745.1, 668.3 cm-1; MS-FAB m/z (rel intensity) 345 (MH+, 25),
289 (22), 245 (100); HRFAB calcd for C16H29N2O6 (MH+) m/e
(2S,5′S,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-
oxa zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e (15). Ph2-
PH (0.59 mL, 3.4 mmol) was added to a -78 °C suspension of
NaNH2 (0.17 g, 4.25 mmol) in degassed THF. After being
stirred for 15 min, the reaction mixture was allowed to warm
to room temperature and stirring was continued for 3 h. To
this orange solution was added a solution of 12 (0.64 g, 1.7
mmol in 15 mL of THF), and the reaction mixture was stirred
at room temperature for 12 h. Next, S8 (0.11 g, 3.4 mmol in 15
mL of THF) was added at 0 °C, and the stirring was continued
for 2 h at room temperature. After removal of solvent under
reduced pressure, the residue was treated with NH4Cl (satd)
and extracted with EtOAc three times. The EtOAc solutions
were combined and evaporated to give the crude phosphine
that was chromatographed on silica gel with EtOAc/hexane/
Et3N (66/33/1, v/v/v) to afford 0.55 g (65%) of 15 as a white
solid: Rf ) 0.30 (EtOH/n-hexanes 2/1); mp 76-78 °C; (NMR
1
spectra are reported for a mixture of two rotamers) H NMR
(300 MHz, CDCl3) δ 7.89-7.81 (m, 4H), 7.54-7.44 (m, 6H),

Proline-Based P, N Ligands in Asymmetric Allylation
J . Org. Chem., Vol. 66, No. 22, 2001 7245
4.52 (dd, J HH ) 8.1, 8.5 Hz, 1H), 4.23 (m, 1H), 4.05 (m, 1H),
3.90 (m, 1H), 3.68 (m, 2H), 3.30 (m, 1H), 2.53 (m, 1H), 2.23
(m, 1H), 1.70 (m, 1H), 1.39 (m, 9H), 0.92 (d, J HH ) 6.6 Hz,
3H), 0.85 (d, J HH ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.4, 153.5, 131.8 (d, J CP ) 2.5 Hz), 131.1 (d, J CP ) 10.1 Hz),
1H), 3.75 (m. 2H), 3.38 (m, 1H), 2.70 (m, 1H), 2.33 (m, 1H),
1.47 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 167.8, 153.4, 141.9,
131.8 (d, J CP ) 3.0 Hz), 131.0 (d, J CP ) 10.0 Hz), 128.8 (d, J CP
) 12.1 Hz), 128.7 (d, J CP ) 7.0 Hz), 127.5, 126.7, 126.4, 80.3,
75.0, 69.4, 54.3 (d, J CP ) 145.2 Hz), 47.3, 37.6 (d, J CP ) 59.6
Hz), 31.9 (d, J CP ) 47.6 Hz), 28.2; 31P (120 MHz, CDCl3) δ 44.3
(major), 44.1 (minor); IR (film) 3019.4, 2980.8, 1695.3, 1405.1,
1216.1, 1160.1, 756.1, 668.3 cm-1; MS-FAB m/z (rel intensity)
533 (MH+, 100), 433 (30), 315 (25), 259 (27), 219 (30), 154 (25);
HRFAB calcd for C30H34N2O3PS (MH+) m/e 533.2028, mea-
sured m/e 533.2032.
128.8 (d, J CP ) 12.1 Hz), 80.2, 72.0, 70.4, 60.3, 55.3 (d, J CP
)
12.0 Hz), 47.4, 37.6 (d, J CP ) 61.4 Hz), 32.3 (d, J CP ) 25.1 Hz),
28.3, 18.6, 18.1; 31P (120 MHz, CDCl3) δ 44.12 (major) and
43.94 (minor), 44.20 (45 °C); IR (film) 3019.4, 2978.9, 1695.0,
1479.0, 1405.1, 1216.1, 1160.1, 1104.2, 758.0, 669.3 cm-1; MS-
FAB m/z (rel intensity) 499 (MH+, 100), 399 (13), 281 (25),
219 (35); HRFAB calcd for C27H36N2O3PS (MH+) m/e 499.2184,
measured m/e 499.2189. Anal. Calcd for C27H35N2O3PS: C,
65.04; H, 6.76. Found: C, 64.89; H. 7.07.
(2S,5′R,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-m eth oxylca r -
bon yl-1′,3′-oxa zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r o-
lin e (th e p h osp h in e su lfid e of 23): (NMR spectra are
reported for a mixture of two rotamers) 1H NMR (300 MHz,
CDCl3) δ 7.89-7.82 (m, 4H), 7.52-7.43 (m, 6H), 4.75-4.68 (m,
1H), 4.61-4.45 (m, 3H), 3.77 (s, 3H), 3.76 (m, 2H), 3.34 (m,
1H), 2.65-2.45 (m, 1H), 2.27-2.19 (m, 1H), 1.38 (s, 9H); 13C
Detailed procedures for 16, 17, 21, 22, 23, and 24 are
provided in the Supporting Information.
(2S,5′S,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-p h en yl-1′,3′-
oxazol-2′-yl)-4-diph en ylph osph in oth ioylpr olin e (16): (NMR
1
spectra are reported for a mixture of two rotamers) H NMR
NMR (75 MHz, CDCl3) δ170.9, 169.7, 153.5, 140.0 (d, J CP )
(300 MHz, CDCl3) δ 7.92-7.82 (m, 4H), 7.55-7.43 (m, 6H),
7.32-7.20 (m, 5H), 5.20 (dd, J HH ) 9.8, 8.3 Hz, 1H), 4.62 (J HH
) 8.5, 8.6 Hz, 1H), 4.17 (m, 2H), 3.86-3.58 (m, 2H), 3.36 (m,
1H), 2.65 (m, 1H), 2.34 (m, 1H), 1.43 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 167.7, 143.4, 141.9, 131.8 (d, J CP ) 3.0 Hz),
131.0 (d, J CP ) 10.1 Hz), 128.7 (d, J CP ) 12.0 Hz), 128.6 (d,
J CP ) 7.6 Hz), 127.5, 126.6, 126.4, 80.2, 75.0, 69.4, 55.2 (d,
10.1 Hz), 131.8, 131.7, 128.7 (d, J CP ) 12.0 Hz), 80.5, 69.4,
68.0, 54.8 (d, J CP ) 11.5 Hz), 52.4, 47.3 (d, J CP ) 6.0 Hz), 37.5
(d, J CP ) 60.1 Hz), 32.3, 28.0; 31P (120 MHz, CDCl3) δ 44.3; IR
(film) 3054.4, 2987.1, 1742.5, 1696.3, 1551.9, 1421.9, 1265.0,
1159.3, 896.0, 737.0, 703.7; MS-FAB m/z (rel intensity) 515
(MH+, 100), 415 (53), 219 (65); HRFAB calcd for C26H32N2O6-
PS (MH+) m/e 515.1769, found 515.1767.
J CP ) 11.0 Hz), 47.3, 37.6 (d, J CP ) 60.1 Hz), 31.9 (d, J CP
)
(2S,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′,5′-d im eth yl-1′,3′-
oxa zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e (p h os-
p h in e su lfid e of 24): (NMR spectra are reported for a mixture
of two rotamers) 1H NMR (300 MHz, CDCl3) δ 7.94-7.81 (m,
4H), 7.51-7.42 (m, 6H), 4.50 (dd, J HH ) 8.3, 8.3 Hz, 1H), 4.02
(d, J HH ) 8.1 Hz, 1H), 3.91 (d, J HH ) 8.1 Hz, 1H), 3.70 (m,
2H), 3.30 (m, 1H), 2.55 (m, 1H), 2.22 (m, 1H), 1.42 (s, 9H),
1.31 (s, 3H), 1.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5,
153.5, 131.8 (d, J CP ) 3.0 Hz), 131.1 (d, J CP ) 10.1 Hz), 128.8
(d, J CP ) 12.1 Hz), 128.5 (d, J CP ) 27.5 Hz), 80.3, 79.4, 67.1,
47.1 Hz), 28,2, 28.1; 31P (120 MHz, CDCl3) δ 44.3 (major), 44.1
(minor); IR (film) 3019.4, 2980.8, 1695.3, 1404.1, 1216.1,
1160.1, 755.1, 668.3 cm-1; MS-FAB m/z (rel intensity) 539
(MLi+, 49), 439 (90), 294 (20); HRFAB Calcd for C30H33N2O3-
PSLi (MLi+) m/e 539.2109, measured m/e 539.2115. Anal.
Calcd for C30H33N2O3PS: C, 67.52; H, 6.42. Found: C, 67.67;
H. 6.21.
(2S,5′S,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-ter t-bu tyl-1′,3′-
oxazol-2′-yl)-4-diph en ylph osph in oth ioylpr olin e (17): (NMR
1
spectra are reported for a mixture of two rotamers) H NMR
55.0 (d, J CP ) 11.1 Hz), 47.4 (d, J CP ) 6.1 Hz), 37.6 (d, J CP )
(300 MHz, CDCl3) δ 7.89-7.80 (m, 4H), 7.51-7.30 (m, 6H),
4.56 (dd, J HH ) 7.8, 9.3 Hz, 1H), 4.20-4.12 (m, 2H). 3.84 (m,
1H), 3.65 (m, 2H), 3.30 (m, 1H), 2.50 (m, 1H), 2.24 (m, 1H),
1.40 (s, 9H), 0.85 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.3,
153.4, 131.7 (d, J CP ) 3 Hz), 131.0 (d, J CP ) 9.8 Hz), 128.74
(d, J CP ) 12.0 Hz), 128.67 (d, J CP ) 12.0 Hz), 80.1, 75.5, 68.9,
55.3 (d, J CP ) 12.0 Hz), 47.3, 37.4 (d, J CP ) 60.2 Hz), 33.5,
32.0, 28.2, 25.6; 31P (120 MHz, CDCl3) δ 44.11 (major), 43.89
(minor); IR (film) 2977.0, 2905.6, 2865.0, 1693.4, 1478.4,
1404.1, 1367.5, 1246.0, 1161.1, 1104.2, 999.1, 960.0, 909.4,
731.0, 649.0 cm-1; MS-FAB m/z (rel intensity) 513 (MH+, 100),
413 (20), 295 (25); HRFAB calcd for C28H38N2O3PS (MH+) m/e
513.2341, measured m/e 513.2322.
60.0 Hz), 33.2, 28.3, 28.1; 31P (120 MHz, CDCl3) δ 44.1; IR (film)
3019.4, 2977.0, 1695.3, 1404.1, 1216.1, 1160.1, 758.0, 668.3
cm-1; MS-FAB m/z (rel intensity) 485 (MH+, 100), 368 (48),
267 (15); HRFAB calcd for C26H33N2O3PS (M+) m/e 484.1949,
measured m/e 484.1949.
Sa m ple P r oced u r e for Ra n ey Nick el Redu ction .(2S,5′S,-
4S)-N-tert-Boc-2-(4′,5′-dihydro-5′-isopropyl-1′,3′-oxazole-2′-yl)-4-di-
p h en ylp h osp h in op r olin e (18). Phosphine sulfide 15 (50 mg,
0.1 mmol) was added to Raney nickel (0.5 g), in CH3CN (6 mL),
that had been washed with methanol (three times), ether
(three times), and degassed CH3CN (three times). The reaction
mixture was stirred at room temperature for 8 h, by which
time the 31P NMR spectrum indicated the complete reduction
of the phosphine sulfide to the phosphine. The Raney nickel
was then filtrated through a syringe filter. Evaporation of
solvent afforded 40 mg (86%) of 18 as a white solid that was
ready to use for catalysis: (NMR spectra are reported for a
(2S,5′R,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-
oxazol-2′-yl)-4-diph en ylph osph in oth ioylpr olin e (th e ph os-
p h in e su lfid e of 21): (NMR spectra are reported for a mixture
1
of two rotamers) H NMR (300 MHz, CDCl3) δ 7.88-7.81 (m,
1
4H), 7.51-7.44 (m, 6H), 4.53 (dd, J HH ) 8.1, 8.0 Hz, 1H), 4.33
(dd, J HH ) 8.5, 8.3 Hz, 1H), 3.90 (dd, J HH ) 8.8, 8.1 Hz, 1H),
3.84-3.62 (m, 4H), 3.27 (m, 1H), 2.50 (m, 1H), 2.30 (m, 1H),
1.70 (m, 1H), 1.42 (s, 9H), 1.27 (d, J HH ) 6.1 Hz, 3H), 1.01 (d,
J HH ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 153.5,
mixture of two rotamers) H NMR (300 MHz, CDCl3) δ 7.40-
7.20 (m, 10H), 4.39 (dd, J ) 7.8, 8.4 Hz, 1H), 4.13 (m, 1H),
3.94-3.83 (m, 2H), 3.64 (m, 1H), 3.29 (m, 1H), 2.80 (m, 1H),
2.26 (m, 1H), 1.92 (m, 1H), 1.64 (m, 1H), 1.33 (s, 9H), 0.84 (d,
J ) 6.3 Hz, 3H), 0.77 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz,
131.8 (d, J CP ) 3.0 Hz), 131.8 (d, J CP ) 3.0 Hz),131.1 (d, J CP
)
CDCl3) δ 166.9, 153.6, 133.33 (J CP ) 11.6 Hz), 133.0 (J CP )
10.0 Hz), 128.8 (d, J CP ) 12.0 Hz), 128.7 (d, J CP ) 12.0 Hz),-
80.3, 72.8, 71.2, 62.2, 54.9 (d, J CP ) 11.0 Hz), 47.5, 37.8 (d,
J CP ) 61.0 Hz), 32.4 (d, J CP ) 51.5 Hz), 28.3, 19.4, 18.8; 31P
(120 MHz, CDCl3) δ 44.2; IR (film) 3054.1, 2984.7, 1696.3,
1400.2, 1265.2, 1160.1, 738.7 cm-1; MS-FAB m/z (rel intensity)
505 (MLi+, 37), 405 (66), 294 (21), 160 (100); HRFAB calcd for
19.1 Hz), 129.1, 128.6 (J CP ) 6.8 Hz), 79.9, 71.9, 70.2, 55.64
(d, J CP ) 8.0 Hz), 50.7 (d, J CP ) 28.0 Hz), 36.3 (d, J CP ) 20.0
Hz), 35.2 (d, J CP ) 9.0 Hz), 32.5, 28.3, 18.6, 17.9; 31P (120 MHz,
CDCl3) δ -9.24 (major) and -10.0 (minor); MS-FAB m/z (rel
intensity) 467 (MH+, 100), 411 (30), 254 (37), 185 (50); HRFAB
calcd for C27H36N2O3P (MH+) m/e 467.2463, measured m/e
467.2471.
C
27H36N2O3PSLi (MLi+) m/e 505.2266, measured m/e 505.2274.
Anal. Calcd for C27H35N2O3PS: C, 65.04; H, 6.76. Found: C,
64.58; H. 6.87.
(2S,5′R,4S)-N-F m oc-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-
oxa zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e su lfid e
(26): (NMR spectra are reported for a mixture of two rotamers)
1H NMR (300 MHz, CDCl3) δ 7.90-7.16 (m, 18 H), 4.91-3.61
(m, 8H), 3.35 (m, 1H), 2.57 (m, 1H), 2.30 (m, 1H), 1.66 (m,
1H), 1.30 (m, 1H), 0.90-0.79 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 165.7, 165.3, 154.2, 153.9, 143.9, 143.8, 143.6, 143.4,
141.0, 131.8, 131.7, 131.0, 130.8, 128.7 (d, J CP ) 12.0 Hz),
(2S,5′R,4S)-N-ter t-Boc-2-(4′,5′-d ih yd r o-5′-p h en yl-1′,3′-
oxazol-2′-yl)-4-diph en ylph osph in oth ioylpr olin e (th e ph os-
p h in e su lfid e of 22): (NMR spectra are reported for a mixture
1
of two rotamers) H NMR (300 MHz, CDCl3) δ 7.91-7.82 (m,
4H), 7.50-7.45 (m, 6H), 7.32-7.20 (m, 5H), 5.20 (dd, J HH
)
9.0, 9.0 Hz, 1H), 4.62 (dd, J HH ) 8.1, 8.6 Hz, 2H), 4.16 (m,

7246 J . Org. Chem., Vol. 66, No. 22, 2001
Gilbertson et al.
1
127.5, 126.8, 125.0, 124.8, 119.7; 31P (120 MHz, CDCl3) δ 44.3;
IR (film) 3054.4, 2986.9, 1705.6, 1421.7, 1353.8, 1264.6, 1165.8,
1104.3, 896.1, 747.3; MS-FAB m/z (rel intensity) 621 (MH+,
100), 403 (30); HRFAB calcd for C37H38N2O3PS (MH+) m/e
621.2341, found 621.2337.
(NMR spectra are reported for a mixture of two rotamers) H
NMR (300 MHz, CDCl3) δ 7.89-7.76 (m, 4H), 7.50-7.39 (m,
6H), 4.66-4.55 (m, 1H), 4.26-4.11 (m, 1H), 4.05-3.84 (m, 3H),
3.60-3.18 (m, 2H), 2.71-2.15 (m, 2H), 1.95 and 1.94 (s, 3H),
1.71-1.60 (m, 1H), 0.89-0.76 (m, 6H); 13C NMR (75 MHz,
CDCl3) d169.6, 168.7, 165.4, 132.1-131.7 (m), 131.1-130.8 (m),
129.0-128.7 (m), 72.0, 71.7, 70.8, 70.2, 55.7 (d, J CP ) 11.0 Hz)
48.6, 46.9, 38.4 (d, J CP ) 60.1 Hz), 37.1 (d, J CP ) 59.6 Hz),
32.4, 32.2, 30.9, 22.5, 21.7, 18.6, 18.5, 18.1, 17.8; 31P (120 MHz,
CDCl3) d 44.5 and 43.9; IR (film) 3054.1, 2986.7, 1650.9,
1551.1, 1436.4, 1421.9, 1265.0, 1102.1, 909.0, 947.9, 650.7; MS-
FAB m/z (rel intensity) 441 (MH+, 100), 328 (10), 218 (32);
HRFAB calcd for C24H30N2O2PS (MH+) m/e 441.1766, found
m/e 441.1777.
(2S,5′R,4S)-N-Cbz-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-ox-
a zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e (27): (NMR
1
spectra are reported for a mixture of two rotamers) H NMR
(300 MHz, CDCl3) δ 7.88-7.82 (m, 4H), 7.48 (m, 6H), 7.30 (m,
5H), 5.26-4.95 (m, 2H), 4.62 (dd, J ) 7.8, 8.7 Hz, 1H), 4.21-
3.65 (m, 5H), 3.35 (m, 1H), 2.54 (m, 1H), 2.25 (m, 1H), 1.70-
1.57 (m, 1H), 0.87-0.77 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
165.7, 154.0, 136.4, 131.8, 131.7, 131.0, 130.9, 128.7 (d, J CP
)
12.0 Hz), 128.2, 127.8, 71.8, 70.3, 55.3 (d, J CP ) 11.0 Hz), 55.1
(d, J CP ) 11.0 Hz), 47.9, 47.3, 38.3 (d, J CP ) 61.1 Hz), 37.6 (d,
J CP ) 60.2 Hz), 32.2, 32.1, 31.2, 18.5, 17.9; 31P (120 MHz,
CDCl3) δ 44.0; IR 3054.4, 2987.1, 1705.3, 1603.7, 1551.9,
1437.0, 1421.8, 1359.3, 1262.9, 1170.4, 896.1, 743.0; MS-FAB
m/z (rel intensity) 532 (MH+, 77), 315 (28), 154 (100); HRFAB
calcd for C30H33N2O3PS (MH+) m/e 532.1949, found 532.1940.
(2S,5′R,4S)-N-P iv-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-ox-
a zol-2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e (28) a n d
(2R,5′R,4S)-N-P iv-2-(4′,5′-dih ydr o-5′-isopr opyl-1′,3′-oxazol-
2′-yl)-4-d ip h en ylp h osp h in oth ioylp r olin e (31). Com p ou n d
28: (NMR spectra are reported for a mixture of two rotamers)
1H NMR (300 MHz, CDCl3) δ 7.90-7.77 (m, 4H), 7.53-7.41
(m, 6H), 4.81 (dd, J ) 8.4, 8.4 Hz, 1H), 4.18-4.09 (m, 1H),
3.96-3.80 (m, 4H), 3.36-3.23 (m, 1H), 2.39-2.14 (m, 2H),
1.71-1.60 (m, 1H), 1.12 (s, 9H), 0.86 (d, J ) 6.9 Hz, 3H), 0.79
(d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ176.1, 166.2,
131.94 (d, J CP ) 6.0 Hz), 311.90 (d, J CP ) 6.0 Hz), 131.1, 131.0,
130.8, 128.9 (d, J CP ) 12.0 Hz), 128.8 (d, J CP ) 12.0 Hz), 71.7,
70.2, 56.4 (d, J CP ) 11.0 Hz), 48.7 (d, J CP ) 6.5 Hz), 39.4 (d,
J CP ) 60.2 Hz), 38.7, 32.4, 29.7, 27.3, 18.6, 18.0; 31P (120 MHz,
CDCl3) δ 43.0; IR 3054.4, 2987.1, 1670.4, 1625.9, 1548.1,
1440.0, 1421.9, 1264.9, 896.0, 739.9, 710.0; MS-FAB m/z (rel
intensity) 483 (MH+, 100), 265 (175), 152 (43); HRFAB calcd
for C27H36N2O2PS (MH+) m/e 483.2235, found 483.2233.
Com p ou n d 31: (NMR spectra are reported for a mixture of
two rotamers) 1H NMR (300 MHz, CDCl3) δ 7.93-7.81 (m, 4H),
7.53-7.42 (m, 6H), 4.92 (d, J ) 8.7 Hz, 1H), 4.30-4.22 (m,
1H), 4.05-3.85 (m, 5H), 2.48 (br s, 1H), 1.82-1.76 (m, 2H),
1.20 (s, 9H), 0.92 (d, J ) 6.9 Hz, 3H), 0.85 (d, J ) 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ176.2, 167.2, 131.9 (d, J CP ) 7.0
Hz), 131.8 (d, J CP ) 7.0 Hz), 131.2, 131.0, 130.9, 128.9 (d, J CP
) 13.5 Hz), 128.7 (d, J CP ) 12.2 Hz), 71.6, 70.0, 56.2, 47.9,
38.9, 38.0, 32.2, 29.6, 27.4, 18.6, 17.6; 31P (120 MHz, CDCl3) δ
45.8; IR (film) 3054.5, 2986.9, 1675.3, 1640.0, 1532.2, 1421.9,
1265.1, 896.0, 736.8, 705.1; MS-FAB m/z (rel intensity) 483
(MH+, 100), 256 (40), 219 (30), 152 (43); HRFAB calcd for
P r oced u r e for π-Allyla tion . The phosphine-oxazoline
ligand was mixed with [Pd(η3-C3H5)Cl]2 in degassed solvent,
followed by addition of the cyclic allylic acetate. To this mixture
a solution containing dimethyl malonate (3 equiv), TBAF (3
equiv), and BSA (3 equiv) was added slowly through an
addition funnel (30 min). After the reaction was complete,
water was added to quench the reaction, and the organic
solvent was removed by evaporation. The water layer was then
extracted with diethyl ether twice and the ether solution was
washed with saturated NaHCO3, brine and dried over Na2-
SO4. Evaporation of solvent gave a residue that was chromato-
graphed by using EtOAc/n-hexanes (10/90, v/v) as an eluant
to afford a colorless oil.
P r oced u r e for th e Heck Rea ction . A mixture of triflate,
alkene (5 mol equiv), base (3 equiv), Pd2(dba)3 (1.5 mol %), and
ligand (3 mol %) in degassed solvent was stirred at the reaction
temperature. The progress of the reaction was monitored by
GC and TLC. Upon completion, the mixture was diluted with
additional diethyl ether and washed with water and brine,
dried, and evaporated. Crude product was purified by chro-
matography on a silica gel column using hexane as the eluant.
Ack n ow led gm en t. This work was partially sup-
ported by NIH R01 GM56490-04 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.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
C
27H36N2O2PS (MH+) m/e 483.2235, found 483.2231.
(2S,5′R,4S)-N-Acetyl-2-(4′,5′-d ih yd r o-5′-isop r op yl-1′,3′-
oxa zol-2′-yl)-4-d ip h en ylp h osp h in ot h ioylp r olin e
(30):
J O0158231