Design, synthesis, and applications of potential substitutes of t-Bu-phosphinooxazoline in Pd-catalyzed asymmetric transformations and their use for the improvement of the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates

Article abstract of DOI:10.1021/jo2019653

The design, synthesis, and applications of potential substitutes of t-Bu-PHOX in asymmetric catalysis is reported. The design relies on the incorporation of geminal substituents at C5 in combination with a substituent at C4 other than t-butyl (i-Pr, i-Bu, or s-Bu). Most of these new members of the PHOX ligand family behave similarly in terms of stereoinduction to t-Bu-PHOX in three palladium-catalyzed asymmetric transformations. Electronically modified ligands were also prepared and used to improve the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates.

Full text of DOI:10.1021/jo2019653

Article
pubs.acs.org/joc
Design, Synthesis, and Applications of Potential Substitutes of t-Bu-
Phosphinooxazoline in Pd-Catalyzed Asymmetric Transformations
and Their Use for the Improvement of the Enantioselectivity in the
Pd-Catalyzed Allylation Reaction of Fluorinated Allyl Enol
Carbonates
́
Etienne Belanger, Marie-France Pouliot, Marc-Andre Courtemanche, and Jean-Franco
̧
is Paquin*
́
́
Canada Research Chair in Organic and Medicinal Chemistry, Dep
Quebec, QC, Canada G1V 0A6
́
́ ́
artement de chimie, Universite Laval, 1045 avenue de la Medecine,
́
S
* Supporting Information
ABSTRACT: The design, synthesis, and applications of potential substitutes of t-Bu-PHOX in asymmetric catalysis is reported.
The design relies on the incorporation of geminal substituents at C5 in combination with a substituent at C4 other than t-butyl
(i-Pr, i-Bu, or s-Bu). Most of these new members of the PHOX ligand family behave similarly in terms of stereoinduction to t-Bu-
PHOX in three palladium-catalyzed asymmetric transformations. Electronically modified ligands were also prepared and used to
improve the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates.
In this context, readily accessible substitutes for t-Bu-PHOX
that would be available in both enantiomeric series at reason-
able cost would be highly valuable.
INTRODUCTION
■
The phosphinooxazoline ligands (PHOX ligands) are a versa-
tile class of non-C2-symmetric P,N-chiral ligands developed
independently by Pfaltz, Helmchen, and Williams in 1993
(Figure 1).1−3 The well-known members of this class of ligands
(i.e., 1−4, Figure 1) differ only by the substituent at C4. Within
this group, the t-butyl-substituted one (i.e., 1) is often the one
affording the highest enantioselectivities in various asymmetric
transformations1,4,5 that in certain cases have been used as key
steps in natural product synthesis.6
The S-enantiomer of this ligand ((S)-1) is commercially
available; otherwise, it can be synthesized in four steps from
(S)-tert-leucine ((S)-6),7 a rather expensive non-natural amino
acid (Figure 2).8−10 On the other hand, (R)-t-Bu-PHOX ((R)-1)
is not commercially available, and its synthesis requires the use
of (R)-tert-leucine ((R)-6),11 a prohibitively expensive amino
acid, as starting material. Thus, (R)-t-Bu-PHOX is practically
not accessible.12 This synthetic shortcoming limits access to
one enantiomeric series for any catalytic transformation using
the t-Bu-PHOX ligand. This situation is not encountered for
the other members of the PHOX ligand family (i.e., 2−4,
Figure 1). Ligand (S)-5 was designed to address this issue,
but, to date, its use in asymmetric catalysis remains limited.7a,13
Inspired by previous results in the literature,14−16 we
envisioned that the incorporation of geminal substituents
(Me, Et, Ph, 3-tolyl) at C4 of i-Pr-PHOX (2) and ligands
bearing a closely related side chain at C5, such as i-Bu and s-Bu,
could result in practical replacement for t-Bu-PHOX (1). These
new ligands (structures 7−9 in Figure 3) would not only have a
major economic advantage over t-Bu-PHOX since the cost of
the starting (S)- or (R)-amino acids (10−12) is much lower,
with the exception of (2R,3R)-isoleucine (12),17 than the corre-
sponding tert-leucines (6), but would also allow easy access to
both enantiomers.
Herein, we describe new and readily available members of
the PHOX family which have a parallel reactivity to t-Bu-
PHOX with the key advantage of being easily accessible as both
enantiomers. We have recently described our preliminary
results in this area18 and now report an expanded description of
our studies including the synthesis of these ligands and their
Received: September 22, 2011
Published: December 7, 2011
© 2011 American Chemical Society
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Figure 1. Some members of the PHOX ligand family.
RESULTS AND DISCUSSION
■
Synthesis of the Ligands. The retrosynthetic analysis for
the synthesis of ligands 7−9 is shown in Figure 4. The desired
ligands can be obtained from two different synthetic routes:
one that parallels the original sequence used to access t-Bu-
PHOX7a (via 13−14) and a second route that takes advantage
of a recently published approach to PHOX ligands from Stoltz’s
group (via 15−17).7b,c In the first case, the C−P bond is
established through a SNAr reaction using KPPh2, whereas in
the second case, the key C−P bond is made through an
Ullmann-type coupling developed by Buchwald.19 The intrinsic
limitation of the SNAr reaction, where either electron-rich
phosphine anions or electron-rich aryl fluorides cannot be used,
potentially prevents the fine-tuning of the electronic properties
of the ligand for specific reactions, and it is for that reason
that the Stoltz approach was also investigated.20 The fluoroaryl
(13−14) and bromoaryl precursors (15−17) could be
prepared from the corresponding amino alcohols (18−20)
Figure 2. Synthetic precursor for the preparation of (S)- and (R)-t-Bu-
PHOX (1).
application in enantioselective palladium-catalyzed transforma-
tions. We also document the preparation of electronically
modified ligands and their use in improving the enantiose-
lectivity of the Pd-catalyzed allylation reaction of fluorinated
allyl enol carbonates.
Figure 3. New ligands 5,5-(di-R)-i-Pr-PHOX (7), 5,5-(di-R)-i-Bu-PHOX (8), and 5,5-(di-R)-s-Bu-PHOX (9) and their respective synthetic
precursors.
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Figure 4. Retrosynthetic analysis.
Scheme 1. Synthesis of the Amino Alcohol Precursors
that could be readily obtained from the commercially available
amino acids (10−12).
routes were used when the R-enantiomer was also synthesized.
The synthesis of the various (S)-amino alcohols is shown
in Scheme 1. For the valine-based amino alcohol, (S)-valine
((S)-10) was first transformed into (S)-valine methyl ester
The following synthetic schemes illustrate the sequences
used to prepare the S-enantiomer of the various ligands; similar
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Scheme 2. Synthesis of the Valine-Based Ligands
hydrochloride salt (S)-21 in 83% yield using a known proce-
dure.21,22 The introduction of the gem-dimethyl group, gem-
diethyl group, or gem-di-3-tolyl was performed using a three-
step process23 involving protection of the amine and Grignard
addition followed by deprotection of the Boc group under
acidic conditions producing (S)-18a,23 (S)-18b,14e and (S)-18d
in 40−84% overall yield for the three steps. Alternatively, for
the introduction of a gem-diphenyl group, a similar three-step
process14c involving protection of the amine as the trifluoro-
acetamide and Grignard addition followed by deprotection
of the amide under basic conditions was used to give access to
(S)-18c24 in 50% overall yield for the three steps. For the
leucine-based amino alcohol, the (S)-leucine methyl ester
hydrochloride (S)-2225,26 was first prepared from (S)-leucine
((S)-11) using the same protocol as for the (S)-10. From
(S)-22, a three-step sequence14c was used to prepare (S)-19a
that was utilized directly for the next step (vide infra) while a
direct phenyl Grignard addition furnished (S)-19c27 in 53%
yield. Finally, the isoleucine-based amino alcohol was prepared
using a sequence similar to (S)-18a−c. Thus (2S,3S)-20a was
prepared from (2S,3S)-12 via (2S,3S)-2328 in 56% overall yield
for the four steps.
The S-enantiomer of the valine-based ligands (S)-7a−d were
initially prepared using the original SNAr approach (Scheme 2).7a
Thus, the amino alcohols (S)-18a−d were reacted with 2-
fluorobenzoyl chloride to afford amides (S)-24a−d in moderate
to good yields. Cyclization under acidic conditions14c gave the
oxazolines (S)-13a−d in good yields (57−99%). Finally, they
were converted to the desired ligands, (S)-7a−d,29 via a SNAr
reaction using KPPh2 in low to moderate yields.7a Because of
the unsatisfactory yields observed in the C−P bond-forming
step, the Stoltz approach7b,c was also investigated for the pre-
paration of (S)-7a. Accordingly, the amino alcohol (S)-18a was
reacted with 2-bromobenzoyl chloride to give amide in good
yield. The latter was cyclized, and the crude oxazoline was
directly submitted to the Ullmann-type coupling developed by
Buchwald19 to afford (S)-7a in 73% yield for two steps.
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Scheme 3. Synthesis of the Leucine-Based Ligands
Similarly, the leucine-based ligands (S)-8a,c were prepared
using both the SNAr approach and the Stolz approach (Scheme 3),
while the isoleucine-based ligand (S)-9a was prepared using the
Stoltz approach (Scheme 4).
Exploitation of the Ligands in Asymmetric Catalysis. To
evaluate the potential of the new ligands, they were tested
in three different enantioselective palladium-catalyzed trans-
formations.
either leucine or isoleucine (entries 8−10) performed finely in
terms of yield but gave lower enantiomeric ratios (92.5:7.5 to
94.5:5.5 er) compared to the valine-based ligands.
The ligands were next examined in the enantioselective
Tsuji−Trost allylation reaction using fluorinated enol carbonate
29 (Table 2).5b While this reaction provides the same α-
fluoroketones as with fluorinated silyl enol ethers, a key feature
of this transformation is the important effect of the ligand-to-
palladium ratio on the enantioselectivity of the α-fluoroketones
since using a ligand excess (L/Pd ratio = 1.25) led to moderate
results (80:20 er), while using a L/Pd ratio of 0.25 allowed the
desired products to be obtained with high enantiopurity (96:4 er).
While mechanistic studies are still underway to understand this
phenomenon, we were curious to examine the new ligands in
this reaction. Here again, under the original conditions with the
optimal L/Pd ratio, using (S)-t-Bu-PHOX as the chiral ligand,
the fluoroketone (R)-28 was obtained in 91% yield and 96:4 er
(entry 1). The reaction with (S)-i-Pr-PHOX provided (R)-28
in 93% yield but with 90:10 er. With the exception of (S)-7b
(79% yield, 93.5:6.5 er), all of the other ligands derived from
valine (7a,c,d, entries 3, 6, and 7) gave the fluoroketone
in excellent yield with the same enantioselectivity (95:5 er).
The use of the enantiomer of the ligand, (R)-7a, provided the
other enantiomer of the ketone, (S)-28, with identical results
First, the enantioselective Tsuji−Trost allylation reaction30
using fluorinated silyl enol ether precursor 27 was examined
(Table 1).5a Under the original conditions, using (S)-t-Bu-
PHOX as the chiral ligand, the fluoroketone (R)-28 was
obtained in excellent yield and 96:4 er (entry 1). As a point of
comparison, reaction with (S)-i-Pr-PHOX provided (R)-28
with an excellent yield but with a lower er (90:10). Interest-
ingly, all of the ligands derived from valine (7a−d, entries 3 and
5−7) gave the fluoroketone in 87−93% yield with comparable
enantiomeric ratios (ca. 95:5 er). The use of the enantiomer
of the ligand, (R)-7a,31 provided the other enantiomer of the
ketone, (S)-28, with identical results (entry 4). Thus, all the
new valine-based ligands (7a−d) performed well compared to
t-Bu-PHOX, thus demonstrating the beneficial effect of the
substituents at C5 while the exact nature of the latter did not
seem to play a critical role. Finally, the ligands derived from
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Scheme 4. Synthesis of the Isoleucine-Based Ligand
Table 1. Enantioselective Pd-Catalyzed Allylation Reaction
of Fluorinated Silyl Enol Ether
Table 2. Enantioselective Pd-Catalyzed Allylation Reaction
of Fluorinated Enol Carbonates
a
a
b
c
entry
ligand
yield (%)
er
1
2
3
4
5
6
7
8
9
t-Bu-PHOX
i-Pr-PHOX
(S)-7a
91
93
93
93
79
90
83
73
80
96:4
90:10
95:5
b
c
entry
ligand
yield (%)
er
1
2
t-Bu-PHOX
i-Pr-PHOX
(S)-7a
91
93
93
93
90
87
90
92
89
92
96:4
90:10
95:5
(R)-7a
5:95
3
(S)-7b
93.5:6.5
95:5
4
(R)-7a
5:95
(S)-7c
5
(S)-7b
95:5
(S)-7d
95:5
6
(S)-7c
95:5
(S)-8a
93:7
7
(S)-7d
95.5:4.5
93.5:6.5
92.5:7.5
(S)-9a
95:5
b
8
(S)-8a
a
See ref 5b for details concerning the reaction conditions. Isolated
9
(S)-8c
c
yield. Determined by chiral HPLC.
10
(S)-9a
94.5:5.5
a
b
See ref 5a for details concerning the reaction conditions. Isolated
observed, thus using the valine-based ligand bearing a gem-
dimethyl group at C5 ((S)-7a) furnished the product in good
yield with slightly reduced enantioselectivity compared to t-Bu-
PHOX (76% yield, 95.5:4.5 er) while ligand (S)-7b with a gem-
diethyl group at C5 gave (R)-32 with only 17% conversion
with 94:6 er. Interestingly, the ligands bearing a gem-diphenyl
((S)-7c) or gem-di-3-tolyl ((S)-7d) group at C5 gave the furan
with nearly identical enantioselectivity compared to t-Bu-
PHOX (97.5:2.5 and 97:3 er, respectively), although the
isolated yield was moderate when (S)-7d was used. Finally, the
ligands derived from either leucine or isoleucine (entries 8 and 9)
performed well in terms of enantioselectivity (ca. 95:5 er)
compared to the valine-based ligands but with moderate yields.
Crystal Structure. In order to gain some insights about the
chiral environment created by the addition of geminal sub-
stituents at C5, palladium complexes of ligand (S)-7a,18 (S)-8a,
and (S)-t-Bu-PHOX18 were prepared by mixing the appropriate
ligand with PdCl2 in CH2Cl2 at 40 °C for 48 h.34 The result-
ing crystals were analyzed by X-ray diffraction, and the crystal
c
yield. Determined by chiral HPLC.
(entry 4). Finally, ligand (S)-8a, derived from leucine, per-
formed well in terms of yield but gave lower enantioselectivities
(93:7 er), whereas ligand (S)-9a, derived from isoleucine, gave
comparable results to the valine-based ligands.
Finally, the new ligands were tested in the enantioselective
Heck reaction32 between 2,3-dihydrofuran (30) and phenyl
triflate (31) (Table 3). The use of PHOX ligands in this
reaction, in particular, (S)-t-Bu-PHOX, was first reported by
Pfaltz in 1996.4a Since the reported reaction time was 4 days in
the original communication, we decided to conduct the reac-
tions under microwave irradiation which has been shown by
Larhed to greatly reduce the reaction time (18 h at 100 °C vs
4 days at 70 °C).33 Using (S)-t-Bu-PHOX, the 2,5-dihydrofuran
(R)-32 was isolated in 81% yield and 98:2 er (entry 1). When
(S)-i-Pr-PHOX was used, (R)-32 was obtained in a moderate
yield and 93:7 er (entry 2). In this reaction, the nature of the
substituent at C5 has an impact on the enantioselectivities
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suggest a relatively similar environment around the Pd atom
from the stereoinducting groups, thus an i-Pr or i-Bu group
flanked by a gem-dimethyl group can mimic to some extent a
tert-butyl group. However, the presence of the gem-dimethyl
group also causes a slight distortion as indicated by the torsion
angle between Cl2−Pd1−N1−C4 obtained for PdCl2[(S)-7a]
(38.7°) and PdCl2[(S)-8a] (40.2°) compared to PdCl2[(S)-t-
Bu-PHOX] for which a value of 47.3° was obtained. The subtle
difference in terms of Pd−Me distances and torsion angles as
well as the presence of the gem-dimethyl group at C5 may
explain why in certain reactions (e.g., Heck reaction) slight dif-
ferences in the enantioselectivities are observed between (S)-7a
or (S)-8a and (S)-t-Bu-PHOX, whereas in others (e.g., allyl-
ation reaction) both (S)-7a and (S)-t-Bu-PHOX behave equally
well, while (S)-8a gave slightly lower enantioselectivity.
Electronic Modification. In all of the transformations
presented above, the performance, in terms of stereoinduction,
of the best ligands was always slightly inferior to the one using
t-Bu-PHOX. For instance, using (S)-7a in the allylation of
fluorinated silyl enol ether (Table 1, entry 3) or fluorinated allyl
enol carbonate (Table 2, entry 3) produced the α-fluoroketone
28 with 95:5 er compared to 96:4 er with t-Bu-PHOX. With the
hope of improving the performance in these particular reac-
tions for eventual application in the synthesis of bioactive
α-fluoroketones, we initially investigated the effect of lowering
Table 3. Microwave-Assisted Enantioselective Heck
Reaction of 2,3-Dihydrofuran
a
b
c
entry
ligand
yield (%)
er
1
2
3
4
5
6
7
8
9
t-Bu-PHOX
i-Pr-PHOX
(S)-7a
81
45
76
73
98:2
93:7
95.5:4.5
4:96
(R)-7a
d
(S)-7b
17
94:6
(S)-7c
81
48
50
70
97.5:2.5
97:3
(S)-7d
(S)-8a
95:5
(S)-9a
95.5:4.5
a
b
See ref 33 for details concerning the reaction conditions. Isolated yield.
c
d
1
Determined by chiral HPLC. Estimated conversion by H NMR.
structures are shown in Figure 5.35,36 In PdCl2[(S)-t-Bu-PHOX],
the distance from the palladium to the methyl groups of the
i-Pr group are 3.298 and 3.436 Å, respectively. Correspond-
ingly, the same distances are 3.615 and 4.376 Å in PdCl2[(S)-
7a] and 3.695 and 4.984 Å in PdCl2[(S)-8a]. These numbers
Figure 5. Crystal structure of PdCl2[(S)-t-Bu-PHOX], PdCl2[(S)-7a], and PdCl2[(S)-8a].
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temperature, a common trick to increase enantioselectivity in a
given reaction.37
As shown in Tables 4 and 5, using t-Bu-PHOX and lowering
the temperature led to incomplete conversion with no notable
Table 6. Effect of Ligand and Temperature on the
Enantioselective Pd-Catalyzed Allylation Reaction of
Fluorinated Allyl Enol Carbonate 29
a
Table 4. Effect of Temperature on the Enantioselective
Pd-Catalyzed Allylation Reaction of Fluorinated Silyl Enol
a
Ether 27
b
c
entry
ligand
temperature (°C)
yield (%)
82
er
1
2
3
4
5
6
7
(S)-36a
(S)-36a
(S)-36b
(S)-36b
(S)-36b
(S)-36b
(S)-36c
20
0
95:5
96.5:3.5
96:4
d
38
20
91
0
99
97:3
−20
−78
−20
95
97.5:2.5
trace
94
97.5:2.5
b
c
entry
ligand
temperature (°C) yield (%)
er
a
b
See ref 5b for details concerning the reaction conditions. Isolated
1
2
3
4
5
(S)-t-Bu-PHOX
(S)-t-Bu-PHOX
(S)-7a
40
20
40
20
0
91
65
93
72
20
96:4
96.5:3.5
95:5
c
d
yield. Determined by chiral HPLC. Estimated conversion by 1H
NMR.
electronics of 7a, a strategy that has proved beneficial in certain
cases with electron-poor derivatives of t-Bu-PHOX deriva-
tives.7b,38 In that regard, we decided to synthesize two electron-
poor ligands that only differed by the position of the electron-
withdrawing group (CF3) and one electron-rich ligand bearing
a methoxy group for comparison. These electronically modified
ligands were prepared as shown in Scheme 5 following a similar
sequence as previously used for the other ligands. Thus, the
acyl chloride, prepared from commercially available acid 33a or
readily available acid 33b39 and 33c,40 was reacted with alcohol
(S)-18a (cf. Scheme 1), to afford the corresponding amides
followed by cyclization under acidic conditions14c to give the
oxazolines (S)-35a−c. Finally, Cu-catalyzed Ullmann-type
coupling19 of the phosphine and the aryl bromide produced
the desired ligands (S)-36a−c.
(R)-7a
4:96
d
(R)-7a
3.5:96.5
b
a
See ref 5a for details concerning the reaction conditions. Isolated
yield. Determined by chiral HPLC. Estimated conversion by H
NMR.
c
d
1
Table 5. Effect of Temperature on the Enantioselective
Pd-Catalyzed Allylation Reaction of Fluorinated Allyl Enol
Carbonate 29
a
b
c
The allylation of fluorinated silyl enol ether 27 was reexam-
ined with ligand (S)-36a and (S)-36c (Scheme 6). Unfortu-
nately, these electronically modified ligands behaved similarly
to 7a both at 20 and 0 °C (Table 4, entries 4 and 5).
entry
ligand
temperature (°C)
yield (%)
91
er
1
2
3
4
5
6
(S)-t-Bu-PHOX
(S)-t-Bu-PHOX
(S)-7a
40
20
96:4
96:4
d
15
40
93
92
90
95:5
The new ligands were also tested in the allylation of
fluorinated allyl enol carbonate 29 (Table 6). The use of
methoxy-substituted ligand (S)-36a at 20 °C led to (R)-28 with
good yield and 95:5 er (entry 1), while incomplete conversion
was observed at −20 °C although with 96.5:3.5 er (entry 2).
Superior results were obtained with CF3-substituted ligand
(S)-36b. Indeed, this ligand allowed the reaction to proceed at
lower temperature as low as −20 °C. At that temperature, the
α-fluoroketone 28 was isolated in 95% yield and a 97.5:2.5 er
(entry 5). The isomeric CF3-substituted ligand (S)-36c
performed equally well (entry 7), and thus this electronic
modulation of the ligands allowed an improved 97.5:2.5 er
versus 96:4 er with t-Bu-PHOX.
As ligands (S)-36b and (S)-36c behaved similarly, but the
latter had better physical properties, it was chosen for exploring
the effect on other fluorinated allyl enol carbonate substrates
(Table 7). While no effect was observed on the 7-methoxy-
1-tetralone derived substrate 37a (entries 3 and 4), improve-
ment from 96:4 to 97:3 er was noticed with isomeric substrate
37b (entries 5 and 6). In the case of 1-indanone derivative 37c,
the er of the α-fluoroindanone (R)-38c could be improved
from 91:9 with t-Bu-PHOX to 93.5:6.5 with (S)-36c (entry 8).
Finally, reaction of benzosuberone derivative 37d with (S)-36c
(R)-7a
20
4.5:95.5
4:96
(R)-7a
0
d
(R)-7a
−20
30
3:97
a
b
See ref 5b for details concerning the reaction conditions. Isolated yield.
Determined by chiral HPLC. Estimated conversion by H NMR.
c
d
1
effect on the enantioselectivity (compare entries 1 and 2 in
Tables 4 and 5) but with lower isolated yield or conversion. On
the contrary, using ligand 7a, decreasing the temperature to
20 °C resulted in good yield of (R)-28 with nearly identical
enantioselectivity (4:96 er from 27 and 4.5:95.5 er from 29).
Further decreasing the temperature to 0 °C resulted in an
incomplete conversion when starting from 27 (Table 4) with a
slight increase in ee. Under similar with allyl enol carbonate 29,
28 was isolated in excellent yield with enantioselectivity similar
to the one obtained with t-Bu-PHOX. In this case, further
reduction of the temperature was not possible as low
conversion was observed with a slight increase in er (Table 6,
entry 5). Thus, in both systems, lowering the temperature to
20 °C was possible with ligand 7a and allowed us to reach
similar enantioselectivity as with t-Bu-PHOX.
In light of these results and our desire to surpass the level of
enantioinduction of t-Bu-PHOX, we decided to fine-tune the
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Scheme 5. Synthesis of the Electronically Modified Ligands
Scheme 6. Effect of Temperature on the Enantioselective
Pd-Catalyzed Allylation Reaction of Fluorinated Silyl Enol
Ether 27
EXPERIMENTAL SECTION
■
Materials and Methods. All reactions were carried out under a
nitrogen atmosphere with dry solvents under anhydrous conditions.
1H, 13C, 19F, and 31P NMR spectra were recorded at 400 MHz (1H),
100 MHz (13C), 376 MHz (19F), or 121 MHz (31P) in CDCl3 at
ambient temperature using tetramethylsilane (1H NMR) or residual
CHCl3 (1H and 13C NMR) as the internal standard or CFCl3 (19F
NMR) or H3PO4 (31P NMR) as the external standard. High-resolution
mass spectra were obtained using electrospray ionization (ESI).
Enantiomeric ratios were determined by HPLC analysis using OD-H
or OJ-H chiral columns. The enantioselective Pd-catalyzed allyl-
ation reactions of fluorinated silyl enol ethers (Tables 1 and 4 and
Scheme 6)5a and fluorinated allyl enol carbonates (Tables 2, 5, 6, and
7 and Scheme 6)5b have been carried out according to our original
protocols, and products (R)-28, (S)-28, and (R)-38a−d have been
characterized previously.5a Microwave-assisted enantioselective Heck
reaction of 2,3-dihydrofurans has been run using known procedures
(Table 3)18,33 using a Biotage Initiator 8 apparatus, and product (R)-
32 has been characterized previously.41 (S)-t-Bu-PHOX ((S)-1) and
(S)-i-Pr-PHOX ((S)-2) were prepared using literature procedures.7a
Experimental Procedures. Synthesis of the Amino Alcohol
Precursors (Scheme 1). (S)-18a and (S)-18b were prepared using a
known procedure from (S)-21,21 and spectroscopic data were in agree-
ment with the literature for both (S)-18a23 and (S)-18b.14e (S)-18c
was prepared following a literature protocol,14c and spectroscopic data
were in agreement with the literature.24 (S)-19a was prepared from
(S)-22 following a literature protocol14c and was used crude for the
next step. (S)-19c was prepared from (S)-22 using a literature
procedure.27 The synthesis of the other amino alcohols is described in
the Supporting Information.
gave the desired product (R)-38d in excellent yield with
95.5:4.5 er, an improvement from 94:6 er obtained with t-Bu-
PHOX. Here, the use of (R)-36c, which would be readily
accessible from (R)-valine, would allow access to the S-enantiomer
of all of the α-fluoroketones.
CONCLUSION
■
In conclusion, we have described the design, synthesis, and
applications of new and readily available members of the
PHOX family as potential substitutes to t-Bu-PHOX in asym-
metric catalysis. The ligand design incorporates two geminal
substituents at C5 in combination with a substituent at C4
other than t-butyl (i-Pr, i-Bu, or s-Bu). Most of these new
members of the PHOX ligand family behave similarly in terms
of stereoinduction to t-Bu-PHOX in three palladium-catalyzed
asymmetric transformations. Electronically modified ligands
were also prepared and used to improve the enantioselectivity
in the Pd-catalyzed allylation reaction of fluorinated allyl enol
carbonates.
General Procedures for the Synthesis of the Ligands via the SNAr
Approach. Synthesis of Ligand (S)-7a. (S)-2-Fluoro-N-(2-hydroxy-
2,4-dimethylpentan-3-yl)benzamide ((S)-24a): General Procedure
for the Amide Formation. To a solution of the amino alcohol
(S)-18a (2.2 mmol) and dry triethylamine (0.95 mL, 6.7 mmol) in
dioxane (6 mL) was added at 0 °C a solution of 2-fluorobenzoyl
chloride (325 mg, 2.1 mmol) in dioxane (6 mL). After stirring for an
additional 2 h, the solvent and excess of triethylamine were removed
in vacuo. The residue was filtered over a short pad of silica gel, and
the desired product (373 mg, 68%) was isolated as a white solid
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Table 7. Comparison between Ligand (S)-36c and t-Bu-PHOX in the Enantioselective Pd-Catalyzed Allylation Reaction of
Various Fluorinated Allyl Enol Carbonates
a
b
c
See the Supporting Information and ref 5b for details concerning the reaction conditions. Isolated yield. Determined by chiral HPLC.
by flash chromatography using 20−50% Et2O/hexane: [α]20D −15.9 (c
0.69, CHCl3); mp 101.5−104.0 °C; IR (neat) ν = 3441, 3083, 2965,
7.41 (m, 1H), 7.18−7.09 (m, 2H), 3.50 (d, 1H, J = 8.0 Hz), 1.90
(m, 1H), 1.53 (s, 3H), 1.41 (s, 3H), 1.15 (d, 3H, J = 6.5 Hz), 1.04 (d,
3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 162.6, 160.1, 159.2
(d, JC−F = 4.5 Hz), 132.7 (d, JC−F = 8.4 Hz), 131.3 (d, JC−F = 1.9 Hz),
124.1 (d, JC−F = 3.9 Hz), 117.3 (d, JC−F = 11.0 Hz), 116.9, 116.6, 86.9,
80.6, 29.3 (d, JC−F = 2.4 Hz), 21.4 (d, JC−F = 8.0 Hz), 20.7; 19F NMR
(376 MHz, CDCl3) δ −110.5 (m, 1F); HRMS-ESI calcd for
C14H19FNO [M + H]+ 236.1445, found 236.1457.
(S)-5,5-(Dimethyl)-i-Pr-PHOX ((S)-7a): General Procedure for the
SNAr Reaction. To a stirred solution of KH (85.4 mg, 2.1 mmol) in
toluene (5 mL) at rt was added dropwise HPPh2 (0.37 mL, 2.1 mmol).
After 15 min at rt, the reaction mixture was heated to 120 °C. After
5 min at 120 °C, a solution of (S)-9 (250 mg, 1.1 mmol) in toluene
(10 mL) was added dropwise and the reaction mixture was heated at
120 °C overnight. The reaction was quenched by the addition of
0.5 mL of MeOH. After the reaction mixture was diluted with H2O
and Et2O, the layers were separated and the aqueous phase was
extracted with Et2O (3×). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and the solvent was
evaporated to give the crude product. The crude material was purified
with flash chromatography using 5−10% Et2O/hexane to give the
desired product as a white solid (224 mg, 53%): [α]20D −28.6 (c 0.78,
CHCl3); mp 125.3−127.2 °C; IR (neat) ν = 3064, 2981, 2868, 1654,
1464, 1362, 1268, 1048, 748, 695 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.87 (m, 1H), 7.30 (m, 12H), 6.84 (m, 1H), 3.17 (d, 1H, J = 8.1 Hz),
1
2936, 1650, 1528, 1481, 1380, 1180, 756 cm−1; H NMR (400 MHz,
CDCl3) δ 8.07 (t, 1H, J = 7.4 Hz), 7.46 (m, 1H), 7.25 (t, 1H, J =
7.4 Hz), 7.15−7.03 (m, 2H), 4.05 (d, 1H, J = 9.9 Hz), 2.23 (m, 1H),
2.14 (br s, 1H), 1.33 (s, 3H), 1.27 (s, 3H), 1.00 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 164.4 (d, JC−F = 3.2 Hz), 162.8 (d, JC−F = 247
Hz) 133.4 (d, JC−F = 9.2 Hz), 132.3 (d, JC−F = 2.3 Hz), 125.0 (d,
JC−F = 3.2 Hz), 121.7 (d, JC−F = 11.2 Hz), 116.3 (d, JC−F = 25.1 Hz),
73.9, 61.1, 29.5, 28.6, 27.4, 22.6, 17.2; 19F NMR (376 MHz, CDCl3)
δ −114.3 (m, 1F); HRMS-ESI calcd for C14H20FNO2Na [M + Na]+
276.1370, found 276.1371.
(S)-2-(2-Fluorophenyl)-4-isopropyl-5,5-dimethyl-4,5-dihydrooxa-
zole ((S)-13a): General Procedure for the Cyclization. To a stirred
solution of (S)-24a (709 mg, 2.8 mmol) in CH2Cl2 (30 mL) at 0 °C
was added dropwise MsOH (0.90 mL, 16.8 mmol), and the reaction
mixture was allowed to warm to rt. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution, diluted in CH2Cl2, and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2×). The combined organic extracts were washed with H2O and brine,
dried over anhydrous MgSO4, and concentrated. The crude material was
purified with flash chromatography using 20% Et2O/hexane to give the
desired product as a colorless oil (518 mg, 75%): [α]22 −35.9
D
(c 0.42, CHCl3); IR (neat) ν = 3044, 2972, 2873, 1646, 1459, 1340,
1228, 1058, 766 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 1H),
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1.58 (m, 1H), 1.38 (s, 3H), 1.14 (s, 3H), 0.98 (d, 3H, J = 5.2 Hz), 0.86
(d, 3H, J = 4.9 Hz); 13C NMR (100 MHz, CDCl3) δ 161.4, 139.3−
0.96 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 162.9, 159.5,
158.9 (d, JC−F = 4.5 Hz), 132.3 (d, JC−F = 8.3 Hz), 131.1 (d, JC−F = 1.8
Hz), 123.8 (d, JC−F = 3.5 Hz), 116.4, 116.7, 90.7, 29.7, 28.5, 24.9, 21.9,
20.1, 8.7, 7.8; 19F NMR (376 MHz, CDCl3) δ −110.4 (m, 1F); HRMS-
ESI calcd for C16H23FNO [M + H]+ 264.1758, found 264.1749.
(S)-5,5-(Diethyl)-i-Pr-PHOX ((S)-7b). Following the general proce-
dure for the SNAr reaction on a 0.15 mmol scale of (S)-13b, the
desired product as a colorless oil (39 mg, 61%) was isolated by flash
128.1 (C−Ar), 86.8, 81.3, 29.1 (d, JC−P = 6.2 Hz), 21.5, 21.4, 21.0; 31
P
NMR (121 MHz, CDCl3) δ −4.86 (s, 1P); HRMS-ESI calcd for
C26H29NOP [M + H]+ 402.1981, found 402.1993.
General Procedures for the Synthesis of the Ligands via the
Ullmann-Type Coupling-Based Approach. Synthesis of Ligand (S)-
7a. (S)-2-Bromo-N-(2-hydroxy-2,4-dimethylpentan-3-yl)-
benzamide. Following the general protocol for the amide formation
using 2-bromobenzoyl chloride instead of 2-fluorobenzoyl chloride on
a 6.0 mmol scale of (S)-18a, the desired product (1.37 g, 73%) was
isolated as a white solid by flash chromatography using 20% acetone/
chromatography using 10% Et2O/hexane: [α]20 −24.3 (c 1.17,
D
CHCl3); IR (neat) ν = 3053, 2966, 2880, 1652, 1470, 1336, 1276,
1
1088, 1045, 927, 740 cm−1; H NMR (400 MHz, CDCl3) δ 7.90 (m,
1H), 7.36−7.24 (m, 12H), 6.84 (m, 1H), 3.42 (d, 1H, J = 8.0 Hz),
1.84−1.75 (m, 1H), 1.70−1.44 (m, 4H), 0.93−0.77 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ 161.3 (d, JC−P = 3.3 Hz), 139.2−128.1
(C−Ar), 90.8, 29.5, 28.5, 25.2, 21.7, 21.2, 8.6, 8.1; 31P NMR (121
MHz, CDCl3) δ −4.90 (s, 1P); HRMS-ESI calcd for C28H33NOP [M
+ H]+ 430.2294, found 430.2266.
hexane: [α]20 −2.0 (c 1.18, CHCl3); mp 124.5−126.1 °C; IR (neat)
D
ν = 3344, 3050, 2965, 2940, 1622, 1545, 1399, 1160, 1029, 775 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 1H), 7.55−7.52 (m,
1H), 7.38−7.30 (m, 1H), 7.29−7.25 (m, 1H), 6.33−6.31 (m, 1H),
4.02 (dd, 1H, J = 10.1, 2.5 Hz), 2.29−2.22 (m, 1H), 1.35 (s, 6H), 1.08
(d, 3H, J = 6.5 Hz), 1.00 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 168.6, 138.7, 133.6, 131.2, 129.6, 127.7, 119.3, 73.3, 60.9,
29.7, 28.8, 27.7, 22.6, 17.4; HRMS-ESI calcd for C14H21NBrO2
[M + H]+ 314.0750, found 314.0752.
Synthesis of Ligand (S)-7c. (S)-2-Fluoro-N-(2-hydroxy-2,4-di-
phenylpentan-3-yl)benzamide ((S)-24c). Following the general
protocol for the amide formation on a 3.40 mmol scale of (S)-18c,
the desired product (822 mg, 64%) was isolated as a white solid by
flash chromatography using 20% Et2O/pentane: [α]20D −74.9 (c 0.63,
CHCl3); mp 178−182 °C; IR (neat) ν = 3431, 3068, 2963, 2934,
1640, 1540, 1447, 1318, 136, 757 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.79 (t, 1H, J = 7.2 Hz), 7.54 (m, 4H), 7.35 (t, 3H, J = 7.5 Hz), 7.26
(m, 4H), 7.13 (m, 2H), 7.01 (t, 1H, J = 10.0 Hz), 5.27 (d, 1H, J = 9.8
Hz), 2.99 (br s, 1H), 1.94 (m, 1H), 0.99−0.97 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 163.9 (d, JC−F = 2.8 Hz), 160.1 (d, JC−F = 248
Hz), 146.5, 145.7, 133.1 (d, JC−F = 9.1 Hz), 131.9 (d, JC−F = 2.0 Hz),
128.8, 127.3, 127.1, 125.7 (d, JC−F = 13.7 Hz), 124.8 (d, JC−F = 3.2
Hz), 121.8 (d, JC−F = 11.8 Hz), 116.1 (d, JC−F = 24.4 Hz), 82.5, 58.6,
29.5, 23.1, 17.8; 19F NMR (376 MHz, CDCl3) δ −114.3 (m, 1F);
HRMS-ESI calcd for C24H24FNO2Na [M + Na]+ 401.1683, found
401.1689.
(S)-2-(2-Bromophenyl)-4-isopropyl-5,5-dimethyl-4,5-dihydrooxa-
zole ((S)-15a). Following the general protocol for the cyclization on a
0.84 mmol scale of (S)-2-bromo-N-(2-hydroxy-2,4-dimethylpentan-3-
yl)benzamide, the desired product was isolated and used without
further purification. An analytically pure sample could be obtained as a
colorless oil by flash chromatography using 10% Et2O/hexane: [α]20
D
−34.0 (c 0.65, CHCl3); IR (neat) ν = 3067, 2970, 2871, 1650, 1471,
1
1247, 1108, 1025, 729 cm−1; H NMR (400 MHz, CDCl3) δ 7.65−
7.59 (m, 2H), 7.31 (t, 1H, J = 7.5 Hz), 7.29−7.22 (m, 1H), 3.51 (d,
1H, J = 7.8 Hz), 1.98−1.87 (m, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.15
(d, 3H, J = 6.8 Hz), 1.05 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 161.7, 133.9, 131.6, 131.5, 130.9, 127.3, 122.1, 87.7, 80.9,
29.5, 29.4, 21.6, 21.5, 20.7; HRMS-ESI calcd for C14H19NBrO [M + H]+
299.0661, found 299.0657.
(S)-2-(2-Fluorophenyl)-4-isopropyl-5,5-diphenyl-4,5-dihydrooxa-
zole ((S)-13c). Following the general protocol for the cyclization on a
1.2 mmol scale of (S)-24c, the desired product as a white solid (364
mg, 85%) was isolated by flash chromatography using 10% Et2O/
hexane: [α]22D −275.4 (c 0.58, CHCl3); mp 89−92 °C; IR (neat) ν =
(S)-5,5-(Dimethyl)-i-Pr-PHOX ((S)-7a): General Procedure for the
Ullmann-Type Coupling. A mixture of copper iodide (20.1 mg, 0.11
mmol), diphenylphosphine (0.37 mL, 2.1 mmol), and N,N′-dimethyl-
ethylenediamine (7.8 mL, 0.74 mmol) in toluene (8 mL) was stirred
for 20 min at rt. After (S)-19a (0.84 mmol), cesium carbonate (1.03 g,
3.2 mmol) in toluene (7 mL) was added and the mixture was heated at
110 °C overnight. The reaction mixture was allowed to cool to rt,
filtered, washed with CH2Cl2, and the solvent was evaporated to give
the crude product. The desired product (248 mg, 73% for 2 steps) was
isolated as a white solid by flash chromatography using 5−10% Et2O/
hexane.
1
3061, 2961, 2873, 1655, 1494, 1385, 1224, 1031, 909, 761 cm−1; H
NMR (400 MHz, CDCl3) δ 8.04 (t, 1H, J = 7.4 Hz), 7.62 (d, 2H, J =
7.6 Hz), 7.50−7.17 (m, 11H), 4.88 (d, 1H, J = 4.5 Hz), 1.92 (m, 1H),
1.06 (d, 3H, J = 6.7 Hz), 0.65 (d, 3H, J = 6.4 Hz); 13C NMR (100
MHz, CDCl3) δ 162.9,160.3, 158.8 (d, JC−F = 4.7 Hz), 145.8 140.9,
133.1 (d, JC−F = 8.6 Hz), 131.5 (d, JC−F = 1.6 Hz), 128.6, 128.0, 127.4
124.2 (d, JC−F = 3.8 Hz), 117.0 (d, JC−F = 21.9 Hz), 116.7 (d, JC−F
=
Synthesis of the Valine-Based Ligands via the SNAr Approach
(Scheme 2). Synthesis of Ligand (S)-7b. (S)-2-Fluoro-N-(2-
hydroxy-2,4-diethylpentan-3-yl)benzamide ((S)-24b). Following
the general procedure for the amide formation on a 0.61 mmol
scale of (S)-18b, the desired product (141 mg, 85%) was isolated as a
colorless oil by flash chromatography using 20% acetone/hexane:
10.8 Hz), 92.8, 80.0, 30.6, 22.2, 17.1; 19F NMR (376 MHz, CDCl3) δ
−109.6 (m, 1F); HRMS-ESI calcd for C24H23FNO [M + H]+
360.1758, found 360.1768.
(S)-5,5-(Diphenyl)-i-Pr-PHOX ((S)-7c). Following the general pro-
tocol for the SNAr reaction on a 0.14 mmol scale of (S)-13c, the
desired product as a colorless oil (47 mg, 65%) was isolated by flash
[α]20 −3.8 (c 0.27, CHCl3); IR (neat) ν = 3411, 2968, 1651, 1517,
D
chromatography using 10% Et2O/hexane: [α]20 −170.5 (c 0.31,
1
1478, 1314, 1154, 758 cm−1; H NMR (400 MHz, CDCl3) δ 7.50−
D
CHCl3); IR (neat) ν = 3064, 2955, 2926, 2868, 1657, 1434, 1328,
1254, 1139, 1098, 974, 746, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.15 (m, 1H), 7.43−7.15 (m, 22H), 6.92 (m, 1H), 4.62 (d, 1H, J = 5.3
Hz), 1.62 (m, 1H), 0.79 (d, 3H, J = 6.8 Hz), 0.45 (d, 3H, J = 6.6 Hz);
13C NMR (100 MHz, CDCl3) δ 160.6, 145.7, 141.3, 139.4−126.8
7.45 (m, 1H), 7.27 (t, 1H, J = 7.4 Hz), 7.16−706 (m, 2H), 4.19 (dt,
1H, J = 9.9, 2.3 Hz), 2.21 (m, 1H), 1.72−1.45 (m, 5H), 1.00 (t, 6H,
J = 7.1 Hz), 0.93 (t, 3H, J = 7.5 Hz), 0.86 (t, 3H, J = 7.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 164.0 (d, JC−F = 3.3 Hz), 160.8 (d, JC−F
=
247 Hz), 133.2 (d, JC−F = 9.2 Hz), 132.4 (d, JC−F = 2.1 Hz), 125.0 (d,
JC−F = 3.2 Hz), 121.8 (d, JC−F = 11.5 Hz), 116.3 (d, JC−F = 24.8 Hz),
78.0, 57.4, 29.0, 28.3, 28.1, 24.5, 17.3, 8.2, 8.0; 19F NMR (376 MHz,
CDCl3) δ −114.2 (m, 1F); HRMS-ESI calcd for C16H23FNO
[M + H]+ − [H2O] 264.1758, found 264.1754.
(C−Ar), 92.5, 81.5, 30.6, 21.5, 21.9, 17.6 (d, JC−P = 1.8 Hz); 31P NMR
(121 MHz, CDCl3) δ −6.19 (s, 1P); HRMS-ESI calcd for C36H33NOP
[M + H]+ 526.2294, found 526.2286.
Synthesis of Ligand (S)-7d. (S)-2-Fluoro-N-(2-hydroxy-2,4-di-3-
tolylpentan-3-yl)benzamide ((S)-24d). Following the general proce-
dure for the amide formation on a 1.7 mmol scale of (S)-18d, the
desired product (373 mg, 54%) was isolated as a white solid by flash
(S)-2-(2-Fluorophenyl)-4-isopropyl-5,5-diethyl-4,5-dihydrooxa-
zole ((S)-13b). Following the general procedure for the cyclization on
a 0.71 mmol scale of (S)-24b, the desired product (107 mg, 57%) was
isolated as colorless oil by flash chromatography using 10% Et2O/
hexane: [α]22D −51.7 (c 0.64, CHCl3); IR (neat) ν = 2967, 2882, 1648,
chromatography using 20% Et2O/hexane: [α]20 −44.1 (c 0.43,
D
CHCl3); mp 158.3−163.3 °C; IR (neat) ν = 3436, 2960, 1631, 1526,
1456, 1341, 1225, 1111, 1061, 924, 761 cm−1; H NMR (400 MHz,
1481, 1314, 1126, 749 cm−1; H NMR (400 MHz, CDCl3) δ 7.86 (t,
1
1
CDCl3) δ 7.85 (dt, 1H, J = 7.5, 1.5 Hz), 7.41 (m, 1H), 7.13 (m, 2H),
3.69 (d, 1H, J = 6.7 Hz), 1.91 (m, 4H), 1.67 (m, 2H), 1.06 (m, 9H),
1H, J = 7.9 Hz), 7.42−6.94 (m, 12H), 5.21 (d, 1H, J = 9.8 Hz), 2.74
(br s, 1H), 2.35 (s, 3H), 2.25 (s, 3H), 1.91 (m, 1H), 0.98−0.95
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(m, 6H); 13C NMR (100 MHz, CDCl3) δ 163.6 (d, JC−F = 2.5 Hz),
160.4 (d, JC−F = 248 Hz), 146.2, 145.5, 138.0 (d, JC−F = 4.6 Hz), 132.8
desired product as a colorless oil (46 mg, 37%) was isolated by flash
chromatography using 10% Et2O/hexane: [α]20 −25.0 (c 0.11,
D
CHCl3); IR (neat) ν = 3055, 2954, 2866, 1659, 1435, 1322, 1254,
(d, JC−F = 9.1 Hz), 131.7 (d, JC−F = 1.9 Hz), 128.3, 127.7 (d, JC−F
=
1
1117, 1048, 967, 742 cm−1; H NMR (400 MHz, CDCl3) δ 8.08 (m,
7.9 Hz), 126.3, 126.1, 124.6 (d, JC−F = 3.1 Hz), 122.6 (d, JC−F = 5.5
Hz), 121.8 (d, JC−F = 12.2 Hz), 116.1, 115.8, 82.3, 58.4, 29.3, 22.9,
21.7, 21.6, 17.6; 19F NMR (376 MHz, CDCl3) δ −114.2 (s, 1F);
HRMS-ESI calcd for C26H27FNO [M + H]+ − [H2O] 388.2071, found
388.2061.
1H), 7.61−6.89 (m, 23H), 4.71 (t, 1H, J = 7.6 Hz), 2.37 (s, 1H), 1.71
(m, 1H), 0.88 (d, 3H, J = 6.4 Hz), 0.81−0.74 (m, 1H), 0.73 (d, 3H, J =
6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 160.8, 144.6, 141.2, 139.5−
125.3 (C−Ar), 92.3, 73.8, 43.0 25.4, 24.0, 21.5; 31P NMR (121 MHz,
CDCl3) δ −5.13 (s, 1P); HRMS-ESI calcd for C37H35NOP [M + H]+
540.2451, found 540.2441.
(S)-2-(2-Fluorophenyl)-4-isopropyl-5,5-di-3-tolyl-4,5-dihydrooxa-
zole ((S)-13d). Following the general procedure for the cyclization
on a 1.2 mmol scale of (S)-24d, the desired product as a colorless oil
(444 mg, 99%) was isolated by flash chromatography using 20% Et2O/
General Procedures for the Synthesis of the Ligands via the
Ullmann-Type Coupling-Based Approach. Synthesis of Ligand (S)-
8a. (S)-2-Bromo-N-(2-hydroxy-2,5-dimethylhexan-3-yl)-
benzamide. Following the general protocol for the amide formation
using 2-bromobenzoyl chloride instead of 2-fluorobenzoyl chloride on
a 5.5 mmol scale of crude (S)-19a, the desired product (880 mg, 49%
for four steps from (S)-22) was isolated as a white solid by flash
hexane: [α]22 −257.4 (c 0.52, CHCl3); IR (neat) ν = 3044, 2960,
D
1
2871, 1652, 1457, 1344, 1223, 1112, 1028, 966, 761 cm−1; H NMR
(400 MHz, CDCl3) δ 8.01 (t, 1H, J = 7.5 Hz), 7.43 (m, 3H), 7.21 (m,
6H), 7.08 (m, 2H), 4.87 (d, 1H, J = 4.2 Hz), 2.35 (d, 6H, J = 6.4 Hz),
1.90 (m, 1H), 1.09 (d, 3H, J = 6.9 Hz), 0.65 (d, 3H, J = 6.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 162.9, 160.3, 158.9 (d, JC−F = 4.7 Hz),
145.8, 140.8, 138.1,137.5, 133.0 (d, JC−F = 8.5 Hz), 131.5 (d, JC−F = 1.7
chromatography using 10% acetone/hexane: [α]20 −30.6 (c 0.90,
D
CHCl3); mp 119.1−129.6 °C; IR (neat) ν = 3478, 3254, 3064, 2979,
1
2956, 2869, 1623, 1548, 1467, 1354, 1149, 1040, 954 cm−1; H NMR
Hz), 128.7, 128.4, 128.1, 127.9, 127.6, 127.1, 124.4, 124.2 (d, JC−F
=
(400 MHz, CDCl3) δ 7.54 (d, 1H, J = 8.0 Hz), 7.43 (d, 1H, J =
7.4 Hz), 7.32−7.19 (m, 2H), 6.15 (d, 1H, J = 9.5 Hz), 4.06 (m, 1H),
2.85−2.82 (m, 1H), 1.74 (br s, 1H), 1.45−1.39 (m, 2H), 1.29 (s, 3H),
1.23 (s, 3H), 0.97 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 6.7 Hz); 13C
NMR (100 MHz, CDCl3) δ 168.3, 138.2, 133.4, 131.1, 129.4, 127.5,
119.1, 73.3, 56.5, 39.0, 27.7, 26.3, 25.1, 24.0, 21.5; HRMS-ESI calcd for
C15H21BrNO [M + H]+ − [H2O] 310.0801, found 310.0793.
3.9 Hz), 123.6, 116.9 (d, JC−F = 21.6 Hz), 116.8 (d, JC−F = 10.8 Hz),
92.9, 79.6, 30.5, 22.4, 21.9, 17.0; 19F NMR (376 MHz, CDCl3) δ
−109.4 (s, 1F); HRMS-ESI calcd for C26H27FNO [M + H]+ 388.2071,
found 388.2070.
(S)-5,5-(Di-3-tolyl)-i-Pr-PHOX ((S)-7d). Following the general
procedure for the SNAr reaction on a 1.0 mmol scale of (S)-13d,
the desired product as a white solid (168 mg, 31%) was isolated by
(S)-2-(2-Bromophenyl)-4-isobutyl-5,5-dimethyl-4,5-dihydrooxa-
zole ((S)-16a). Following the general protocol for the cyclization on a
1.5 mmol scale using (S)-2-bromo-N-(2-hydroxy-2,4-dimethylhexan-3-
yl)benzamide, the desired pure product (318 mg, 67%) was isolated as
a colorless oil by flash chromatography using 10% Et2O/hexane:
[α]20D −72.4 (c 0.50, CHCl3); IR (neat) ν = 2956, 2930, 2869, 1647,
flash chromatography using 7% Et2O/hexane: [α]20 −188.7 (c 0.13,
D
CHCl3); mp 101.2−106.4 °C; IR (neat) ν = 3051, 2958, 2922, 1654,
1
1470, 1339, 1256, 1157, 1041, 741, 695 cm−1; H NMR (400 MHz,
CDCl3) δ 8.15 (m, 1H), 7.84−6.88 (m, 21H), 4.65 (d, 1H, J =
5.0 Hz), 2.37 (s, 3H), 2.33 (s, 3H), 1.65 (m, 1H), 0.82 (d, 3H, J = 6.7
Hz), 0.40 (d, 3H, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 160.7,
145.8, 141.2, 139.0−123.8 (C−Ar), 92.6, 81.4, 30.5, 22.0, 22.0, 21.9,
17.5 (d, JC−P = 1.9 Hz); 31P NMR (121 MHz, CDCl3) δ −6.48 (s, 1P);
HRMS-ESI calcd for C38H37NOP [M + H]+ 554.2607, found
554.2598.
1
1466, 1385, 1249, 1165, 1092, 1025, 909, 728 cm−1; H NMR (400
MHz, CDCl3) δ 7.60 (m, 2H), 7.28 (m, 2H), 3.88 (dd, 1H, J = 10.4,
4.6 Hz), 2.02−1.92 (m, 1H), 1.56 (m, 1H), 1.52 (s, 3H), 1.37 (s, 3H),
1.30−1.24 (m, 1H), 1.01 (d, 3H. J = 2.4 Hz), 0.99 (d, 3H, J = 2.3 Hz);
13C NMR (100 MHz, CDCl3) δ 161.9, 133.0−131.1 (C−Ar), 122.1,
87.4, 72.6, 72.4, 40.5, 28.5, 28.4, 25.7, 24.1, 24.0, 22.2, 22.1, 21.9, 21.8;
HRMS-ESI calcd for C15H21NBrO [M + H]+ 310.0801, found
310.0789.
Synthesis of the Leucine-Based Ligands via the SNAr Approach
(Scheme 3). Synthesis of Ligand (S)-8c. (S)-2-Fluoro-N-(2-
hydroxy-2,5-diphenylhexan-3-yl)benzamide ((S)-25c). Following
the general procedure for the amide formation on a 1.2 mmol scale
of intermediate (S)-19c, the desired product (307 mg, 64%) was
isolated as a white solid by flash chromatography using 20% Et2O/
hexane: [α]20D −30.4 (c 0.64, CHCl3); mp 166.3−169.3 °C; IR (neat)
ν = 3415, 2953, 2919, 2868, 1637, 1534, 1447, 1293, 1150, 1059,
(S)-5,5-(Dimethyl)-i-Bu-PHOX ((S)-8a): General Procedure for the
Ullmann-Type Coupling. A mixture of copper iodide (20.1 mg, 0.11
mmol), diphenylphosphine (0.37 mL, 2.1 mmol), and N,N′-dimethyl-
ethylenediamine (7.6 mL, 0.72 mmol) in toluene (8 mL) was stirred
for 20 min at rt. After (S)-16a (0.82 mmol), cesium carbonate (1.0 g,
3.1 mmol) in toluene (7 mL) was added and the mixture was heated at
110 °C overnight. The reaction mixture was allowed to cool to rt,
filtered, washed with CH2Cl2, and the solvent was evaporated to give
the crude product. The desired product (265 mg, 78%) was isolated as
1
780 cm−1; H NMR (400 MHz, CDCl3) δ 7.80 (td, 1H, J = 1.7, 7.9
Hz), 7.55 (m, 4H), 7.40−7.33 (m, 3H), 7.24 (m, 3H), 7.13 (m, 2H),
7.04−6.99 (m, 1H), 6.89 (t, 1H, J = 10.0 Hz), 5.33 (m, 1H), 3.27 (br
s, 1H), 1.76−1.64 (m, 1H), 1.56 (t, 1H, J = 12.5 Hz), 1.30 (t, 1H, J =
12.0 Hz), 1.04 (d, 3H, J = 6.5 Hz), 0.86 (d, 3H, J = 6.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 163.6 (d, JC−F = 2.6 Hz) 162.0, 158.7, 145.2,
145.0, 133.0−115.7 (C−Ar), 81.4, 54.5, 39.7, 25.0, 24.0, 21.7; 19F
NMR (376 MHz, CDCl3) δ −114.1 (m, 1F); HRMS-ESI calcd for
C25H25FNO [M + H]+ − [H2O] 374.1915, found 374.1907.
a white solid by flash chromatography using 7% Et2O/hexane: [α]20
D
−38.4 (c 0.34, CHCl3); mp 74.1−75.7 °C; IR (neat) ν = 3047, 2980,
1
2905, 2873, 1650, 1467, 1350, 1257, 1137, 1072, 951, 724 cm−1; H
NMR (400 MHz, CDCl3) δ 7.85 (m, 1H), 7.35−7.23 (m, 12H), 6.83
(m, 1H), 3.59 (dd, 1H, J = 10.8, 4.2 Hz), 1.74 (m, 1H), 1.31 (s, 3H),
1.23−1.16 (m, 1H), 1.10 (s, 3H), 0.99−0.92 (m, 1H), 0.89−0.87 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 161.6, 139.1−128.1 (C−Ar),
86.2, 72.7, 40.0, 28.3, 25.5, 24.1, 22.0, 21.8; 31P NMR (121 MHz,
CDCl3) δ −4.85 (s, 1P); HRMS-ESI calcd for C27H31NOP [M + H]+
416.2138, found 416.2134.
(S)-2-(2-Fluorophenyl)-4-isobutyl-5,5-diphenyl-4,5-dihydrooxa-
zole ((S)-14c). Following the general protocol for the cyclization on a
0.69 mmol scale using(S)-25c, the desired pure product (246 mg,
86%) was isolated as a colorless oil by flash chromatography using 10%
Et2O/hexane: [α]20D −230 (c 0.90, CHCl3); IR (neat) ν = 3060, 2954,
1
2930, 2868, 1651, 1457, 1222, 1111, 1030, 986, 754 cm−1; H NMR
Synthesis of the Isoleucine-Based Ligand via the Ullmann-Type
Coupling-Based Approach (Scheme 4). Synthesis of Ligand (S)-
9a. 2-Bromo-N-(3S,4S)-2-hydroxy-2,5-dimethylhexan-3-yl)-
benzamide ((S)-26a). Following the general procedure for the amide
formation on a 13.5 mmol scale of intermediate (2S,3S)-20a, the
desired product (3.49 g, 79%) was isolated as a white solid by flash
(400 MHz, CDCl3) δ 8.06 (t, 1H, J = 7.2 Hz), 7.61 (d, 2H, J =
7.6 Hz), 7.50−7.40 (m, 3H), 7.27 (m, 8H), 5.01 (dd, 1H, J = 10.1, 4.5
Hz), 2.00 (m, 1H), 1.12 (m, 2H), 1.02 (d, 3H, J = 6.4 Hz), 0.92 (d,
3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 163.1, 159.7, 158.8
(d, JC−F = 4.5 Hz), 144.6, 140.9, 132.9−116.6 (C−Ar), 92.7, 73.2, 43.4,
25.6, 23.9, 21.9; 19F NMR (376 MHz, CDCl3) δ −109.2 (m, 1F);
HRMS-ESI calcd for C25H25NFO [M + H]+ 374.1915, found
374.1912.
chromatography using 20% acetone/hexane: [α]20 −12.8 (c 0.67,
D
CHCl3); mp 109.5−112.9 °C; IR (neat) ν = 3408, 3360, 2967, 2934,
1
1635, 1505, 1464, 1378, 1178, 1044, 951 cm−1; H NMR (400 MHz,
(S)-5,5-(Diphenyl)-i-Bu-PHOX ((S)-8c). Following the general pro-
tocol for the SNAr reaction on a 0.23 mmol scale of (S)-14c, the
CDCl3) δ 7.55 (d, 1H, J = 7.9 Hz), 7.46 (d, 1H, J = 7.4 Hz), 7.34−7.21
(m, 2H), 6.37 (d, 1H, J = 9.8 Hz), 3.97 (dd, 1H, J = 10.1, 2.2 Hz), 2.21
328
dx.doi.org/10.1021/jo2019653 | J. Org. Chem. 2012, 77, 317−331

The Journal of Organic Chemistry
Article
(br s, 1H), 1.95−1.79 (m, 2H), 1.31 (s, 3H), 1.30 (s, 3H), 1.04 (d, 3H,
J = 6.7 Hz), 0.89 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ
168.2, 133.4, 131.0, 129.4, 127.5, 119.1, 73.7, 61.3, 35.8, 29.7, 27.5,
(C−Ar), 116.1, 114.9 (d, JC−P = 3.9 Hz), 86.6, 81.2, 55.4, 28.9 (d, JC−P =
5.9 Hz), 21.2, 21.1, 20.8; 31P NMR (121 MHz, CDCl3) δ −6.98
(s, 1P); HRMS-ESI calcd for C27H31NO2P [M + H]+ 432.2087, found
432.2079.
23.6, 18.2, 12.2; HRMS-ESI calcd for C15H21BrNO [M + H]+
[H2O] 310.0801, found 310.0779.
−
Synthesis of Ligand (S)-36b. (S)-2-Bromo-N-(2-hydroxy-2,4-
dimethylpentan-3-yl)-4-(trifluoromethyl)benzamide ((S)-34b). Acid
33b39 (4.8 mmol scale) was first converted to the acyl chloride
((COCl)2, DMF cat., CH2Cl2, 0 °C to rt), and the crude acyl chloride
was submitted to the general procedure for the amide formation. The
desired product (844 mg, 55% for 2 steps) was isolated as a white solid
by flash chromatography using 20% Et2O/hexane: [α]20D −1.0 (c 0.85,
CHCl3); mp 107.3−108.8 °C; IR (neat) ν = 3333, 2976, 2961, 2875,
(S)-2-(2-Bromophenyl)-4-sec-butyl-5,5-dimethyl-4,5-dihydrooxa-
zole ((S)-17a). Following the general procedure for the cyclization on
a 3.0 mmol scale using (S)-26a, the desired pure product (793 mg,
84%) was isolated as a colorless oil by flash chromatography using 10%
Et2O/hexane: [α]20 −34.1 (c 1.74, CHCl3); IR (neat) ν = 2967,
D
1
2932, 2875, 1650, 1465, 1387, 1247, 1085, 1036, 938, 729 cm−1; H
NMR (400 MHz, CDCl3) δ 7.60 (m, 2H), 7.26 (m, 2H), 3.56 (d, 1H,
J = 8.1 Hz), 1.97−1.85 (m, 1H), 1.66 (m, 1H), 1.54 (s, 3H), 1.42 (s,
3H), 1.30 (m, 1H), 1.01 (d, 3H, J = 6.6 Hz), 0.94 (t, 3H, J = 7.5, 2.4
Hz); 13C NMR (100 MHz, CDCl3) δ 161.4, 133.6, 131.3, 130.8, 127.0,
121.9, 87.5, 80.0, 35.5, 29.4, 26.5, 21.3, 17.2, 11.2; HRMS-ESI calcd for
C15H21NBrO [M + H]+ 310.0801, found 310.0791.
1
1637, 1534, 1321, 1162, 1129, 1078, 894, 771 cm−1 ; H NMR (400
MHz, CDCl3) δ 7.85 (s, 1H), 7.59 (s, 2H), 6.41 (d, 1H, J = 9.7 Hz),
3.98 (dd, 1H, J = 9.8, 1.9 Hz), 2.24 (m, 1H), 1.76 (s, 1H), 1.34 (s,
3H), 1.31 (s, 3H), 1.05 (d, 3H, J = 6.4 Hz), 0.97 (d, 3H, J = 6.5 Hz);
13C NMR (100 MHz, CDCl3) δ 167.1, 142.0, 133.1 (q, 1C, JC−F = 33.3
(2S,3S)-5,5-(Dimethyl)-s-Bu-PHOX ((S)-9a). Following the general
procedure for the Ullmann-type coupling on a 2.1 mmol scale of (S)-
17a, the desired product (724 mg, 83%) was isolated as a white solid
Hz), 130.4 (q, 1C, JC−F = 3.5 Hz), 129.8, 124.5 (q, 1C, JC−F = 3.5 Hz),
120.9, 119.5, 73.5, 60.7, 29.7, 28.6, 27.5, 22.4, 17.1; 19F NMR (376
MHz, CDCl3) δ −63.2 (s, 1F); HRMS-ESI calcd for C15H18NFBrO2
[M + H]+ − [H2O] 364.0518, found 364.0502.
by flash chromatography using 10% Et2O/hexane: [α]20 −24.9
D
(c 0.67, CHCl3); mp 118.0−119.1 °C; IR (neat) ν = 3064, 2982, 2921,
(S)-2-(2-Bromo-4-(trifluoromethyl)phenyl)-4-isopropyl-5,5-di-
methyl-4,5-dihydrooxazole ((S)-(35b). Following the general
protocol for the cyclization on a 2.2 mmol scale of (S)-34b, the
desired pure product (685 mg, 86%) was isolated as a colorless oil by
1
2872, 1658, 1432, 1363, 1278, 1155, 1049, 978, 850 cm−1; H NMR
(400 MHz, CDCl3) δ 7.87 (m, 1H), 7.36−7.23 (m, 12H), 6.85 (m,
1H), 3.26 (d, 1H, J = 9.5 Hz), 1.81 (m, 1H), 1.41 (s, 3H), 1.34 (m,
1H), 1.15 (s, 3H), 1.05 (m, 1H), 0.83 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 161.1, 139.3−128.1 (C−Ar), 86.7, 80.1, 35.3, 29.2, 27.2,
21.4, 16.8, 11.2; 31P NMR (121 MHz, CDCl3) δ −4.75 (s, 1P); HRMS-
ESI calcd for C27H31NOP [M + H]+ 416.2138, found 416.2138.
Synthesis of Electronically Modified Ligands (Scheme 5). Synthesis
of Ligand (S)-36a. (S)-2-Bromo-N-(2-hydroxy-2,4-dimethyl-
pentan-3-yl)-5-methoxybenzamide ((S)-34a). Acid 33a (1.2 mmol
scale) was first converted to the acyl chloride ((COCl)2, DMF cat.,
CH2Cl2, 0 °C to rt), and the crude acyl chloride was submitted to the
general procedure for the amide formation. The desired product (339
mg, 84% for 2 steps) was isolated as a white solid by flash chroma-
flash chromatography using 10% Et2O/hexane: [α]20 −30.8 (c 1.1,
D
CHCl3); IR (neat) ν = 2973, 2873, 1652, 1461, 1318, 1130, 1078,
1
1036, 846, 733 cm−1; H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H),
7.78 (d, 1H, J = 8.1 Hz), 7.58 (d, 1H, J = 8.1 Hz), 3.54 (d, 1H, J = 8.0
Hz), 1.98−1.89 (m, 1H), 1.56 (s, 3H), 1.45 (s, 3H), 1.16 (d, 3H, J =
6.9 Hz), 1.06 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 160.3, 134.2, 133.2 (q, 1C, JC−F = 33.3 Hz), 131.8, 130.7 (m, 1C),
123.9 (q, 1C, JC−F = 3.5 Hz), 122.8, 122.3 (q, 1C, JC−F = 272 Hz),
88.0, 80.9, 29.3, 29.1, 21.3, 21.1, 20.4; 19F NMR (376 MHz, CDCl3)
δ −63.3 (s, 1F); HRMS-ESI calcd for C15H18NF3BrO [M + H]+
364.0518, found 364.0502.
tography using 20% acetone/hexane: [α]20 −5.0 (c 0.52, CHCl3);
D
(S)-4′-Trifluoromethyl-5,5-(dimethyl)-i-Pr-PHOX ((S)-36b). Fol-
lowing the general protocol for the Ullmann-type coupling on a
1.3 mmol scale of (S)-35b, the desired product (245 mg, 40%) was
isolated as a colorless oil by flash chromatography using 5% Et2O/
mp 114.4−117.4 °C; IR (neat) ν = 3403, 2967, 2933, 1635, 1509,
1466, 1392, 1297, 1150, 1094, 1017, 819 cm−1 ; 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, 1H, J = 8.8 Hz), 7.01 (d, 1H, J = 2.9 Hz), 6.77 (dd,
1H, J = 8.8, 3.0 Hz), 6.48 (d, 1H, J = 9.9 Hz), 3.93 (dd, 1H, J = 10.1,
2.4 Hz), 3.76 (s, 3H), 2.27 (br s, 1H), 2.20 (m, 1H), 1.29 (s, 3H)
1.27 (s, 3H), 1.02 (d, 3H, J = 6.8 Hz), 0.96 (d, 3H, J = 6.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 168.0, 158.9, 139.0, 134.2, 127.7, 117.2,
115.0, 109.2, 73.5, 60.8, 55.6, 29.5, 28.6, 27.4, 22.4, 17.2; HRMS-ESI
calcd for C15H21NBrO2 [M + H]+ − [H2O] 326.0750, found
326.0742.
hexane: [α]20 −25.7 (c 0.51, CHCl3); IR (neat) ν = 3071, 2972,
D
1
2872, 1651, 1435, 1319, 1227, 1088, 1046, 909, 731 cm−1; H NMR
(400 MHz, CDCl3) δ 7.97 (m, 1H), 7.58 (d, 1H, J = 7.9 Hz), 7.31 (m,
10H), 7.06 (m, 1H), 3.17 (d, 1H, J = 9.2 Hz), 1.56 (m, 1H), 1.38
(s, 3H), 1.13 (s, 3H), 0.98 (d, 3H, J = 6.4 Hz), 0.86 (d, 3H, J = 6.0
Hz); 13C NMR (100 MHz, CDCl3) δ 160.3, 141.4−122.6 (C−Ar),
87.2, 81.6, 29.1, 29.0, 21.5, 21.3, 20.9; 19F NMR (376 MHz, CDCl3) δ
−63.4 (s, 1F); 31P NMR (121 MHz, CDCl3) δ −4.06 (s, 1P); HRMS-
ESI calcd for C27H28NF3OP [M + H]+ 470.1855, found 470.1851.
Synthesis of Ligand (S)-36c. (S)-2-(2-Bromo-5-
(trifluoromethyl)phenyl)-4-isopropyl-5,5-dimethyl-4,5-dihydrooxa-
zole ((S)-(35c). Following the general protocol for the amide
formation on a 1.6 mmol scale of 33c40 gave the desired benzamide
(S)-34c that was used without further purification for the next step.
Following the general procedure for the cyclization, the desired pure
product (281 mg, 49% for 3 steps) was isolated as a colorless oil by
(S)-2-(2-Bromo-5-methoxyphenyl)-4-isopropyl-5,5-dimethyl-4,5-
dihydrooxazole ((S)-35a). Following the general protocol for the
cyclization on a 2.0 mmol scale of (S)-34a, the desired pure product
(616 mg, 94%) was isolated as a colorless oil by flash chromatography
using 10% Et2O/hexane: [α]20D −28.2 (c 0.67, CHCl3); IR (neat) ν =
1
2969, 2871, 1651, 1570, 1466, 1230, 1107, 1016, 936, 814 cm−1; H
NMR (400 MHz, CDCl3) δ 7.47 (d, 1H, J = 8.8 Hz), 7.16 (d, 1H, J =
3.1 Hz), 6.81 (dd, 1H, J = 8.8, 3.1 Hz), 3.80 (s, 3H), 3.51 (d, 1H, J =
7.9 Hz), 1.98−1.87 (m, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.16 (d, 3H,
J = 6.6 Hz), 1.05 (d, 3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ
161.3, 158.6, 134.4, 131.4, 117.8, 116.6, 112.2, 87.5, 80.7, 55.6, 29.3,
29.1, 21.3, 21.2, 20.5; HRMS-ESI calcd for C15H21NBrO2 [M + H]+
326.0750, found 326.0737.
flash chromatography using 5% Et2O/hexane: [α]20 −29.2 (c 0.56,
D
CHCl3); IR (neat) ν = 2976, 2874, 1632, 1545, 1469, 1309, 1169,
1
1078, 1031, 829, 734 cm−1; H NMR (400 MHz, CDCl3) δ 7.90
(s, 1H), 7.76 (d, 1H, J = 8.4 Hz), 7.50 (d, 1H, J = 8.2 Hz), 3.54 (d, 1H,
J = 8.1 Hz), 2.00−1.88 (m, 1H), 1.57 (s, 3H), 1.46 (s, 3H), 1.16 (d,
3H, J = 6.6 Hz), 1.06 (d, 3H, J = 6.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 160.2, 134.5, 129.8 (q, 1C, JC−F = 33.1 Hz), 128.3 (m, 1C),
127.8 (m, 1C), 126.0, 123.8 (q, 1C, JC−F = 273 Hz), 88.0, 80.9, 29.3,
29.1, 21.3, 21.2, 20.5; 19F NMR (376 MHz, CDCl3) δ −63.0 (s, 1F);
HRMS-ESI calcd for C15H18NF3BrO [M + H]+ 364.0518, found
364.0511.
(S)-5′-Methoxy-5,5-(dimethyl)-i-Pr-PHOX ((S)-36a). Following the
general protocol for the Ullmann-type coupling on a 1.7 mmol scale of
(S)-35a, the desired product (333 mg, 46%) was isolated as a white
solid by flash chromatography using 10−15% Et2O/hexane: [α]20
D
−34.0 (c 0.74, CHCl3); mp 131.8−132.7 °C; IR (neat) ν = 3011,
2981, 2959, 2868, 1652, 1596, 1474, 1269, 1216, 1047, 788, 696 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 7.29 (m, 10H), 6.78
(m, 2H), 3.83 (s, 3H), 3.21 (d, 1H, J = 9.0 Hz), 1.64−1.54 (m, 1H),
1.39 (s, 3H), 1.16 (s, 3H), 0.95 (d, 3H, J = 6.5 Hz), 0.86 (d, 3H, J =
6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 161.0, 159.5, 139.4−128.1
(S)-5′-Trifluoromethyl-5,5-(dimethyl)-i-Pr-PHOX ((S)-36c). Fol-
lowing the general procedure for the Ullmann-type coupling on a
0.42 mmol scale of (S)-35c, the desired product (96 mg, 49%) was
329
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Article
isolated as a white solid by flash chromatography using 2% Et2O/
J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int.
Ed. 2005, 44, 6924−6927. (q) Nakamura, M.; Hajra, A.; Endo, K.;
Nakamura, E. Angew. Chem., Int. Ed. 2005, 44, 7248−7251. (r) Cook,
M. J.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 9302−9303. (s) Schulz,
S. R.; Blechert, S. Angew. Chem., Int. Ed. 2007, 46, 3966−3970.
(t) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett.
2008, 10, 1039−1042. (u) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2008, 47, 6873−6876. (v) Linton, E. C.; Kozlowski,
M. C. J. Am. Chem. Soc. 2008, 130, 16162−16163. (w) Cook, M. J.;
Rovis, T. Synthesis 2009, 335−338. (x) Johnson, J. B.; Cook, M. J.;
hexane: [α]20 −29.3 (c 0.32, CHCl3); mp 88.1−96.8 °C; IR (neat)
D
ν = 3056, 2978, 2958, 2928, 2870, 1666, 1433, 1345, 1260, 1160, 1071,
842, 781 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (m, 1H), 7.48 (d,
1H, J = 8.0 Hz), 7.30 (m, 10H), 6.94 (m, 1H), 3.15 (d, 1H, J = 9.3
Hz), 1.60−1.51 (m, 1H), 1.39 (s, 3H), 1.13 (s, 3H), 0.97 (d, 3H, J =
6.6 Hz), 0.85 (d, 3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ
160.1, 144.7−122.7 (C−Ar), 87.2, 81.6, 29.0, 29.0, 21.6, 21.3, 20.9; 19F
NMR (376 MHz, CDCl3) δ −63.0 (s, 1F); 31P NMR (121 MHz,
CDCl3) δ −3.94 (s, 1P); HRMS-ESI calcd for C27H28NF3OP [M + H]+
470.1855, found 470.1851.
́
Rovis, T. Tetrahedron 2009, 65, 3202−3210. (y) Mazet, C.; Gerard, D.
Chem. Commun. 2011, 47, 298−300. (z) Petersen, K. S.; Stotlz, B. M.
Tetrahedron 2011, 67, 4352−4357.
ASSOCIATED CONTENT
* Supporting Information
■
́
́
(5) For our own work using (S)-t-Bu-PHOX, see: (a) Belanger, E.;
S
Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc.
NMR spectra of the new compounds prepared and the CIF file
for PdCl2[(S)-8a]. This material is available free of charge via
the Internet at http://pubs.acs.org.
́
́ ́
2007, 129, 1034−1035. (b) Belanger, E.; Houze, C.; Guimond, N.;
Cantin, K.; Paquin, J.-F. Chem. Commun. 2008, 3251−3253.
(6) For recent examples of the use of (S)-t-Bu-PHOX in total
synthesis, see: (a) Coe, J. W. Org. Lett. 2000, 2, 4205−4208. (b) Bian,
J.; Van Wingarden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128,
7428−7429. (c) Behenna, D. C.; Stockdill, J. L.; Stoltz, B. N. Angew.
Chem., Int. Ed. 2007, 46, 4077−4080. (d) Enquist, J. A. Jr.; Stoltz, B.
M. Nature 2008, 453, 1228−1231. (e) Dounay, A. M.; Humphreys, P.
G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130,
5368−5377. (f) White, D. E.; Stewart, I. C.; Seashore-Ludlow, B. A.;
Grubbs, R. H.; Stoltz, B. M. Tetrahedron 2010, 66, 4668−4686.
(7) (a) Peer, M.; de Jong, J. C.; Jiefer, M.; Langer, T.; Rieck, H.;
Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese, B.;
Helmchen, G. Tetrahedron 1996, 52, 7547−7583. (b) Tani, K.;
Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9,
2529−2531. (c) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth.
2009, 86, 181−193.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jean-francois.paquin@chm.ulaval.ca.
■
ACKNOWLEDGMENTS
■
This work was supported by the Canada Research Chair
Program, the Natural Sciences and Engineering Research
Council of Canada, the Canada Foundation for Innovation,
Merck Frosst Centre for Therapeutic Research, the Fonds de
recherche sur la nature et les technologies (FQRNT), FQRNT
Centre in Green Chemistry and Catalysis (CGCC) and the
Universite
donation of L-tert-leucine. We thank Fred
Christian N. Garon, and Christian Tessier (Dep
chimie, Universite Laval) for the crystallographic analysis.
́
Laval. We thank OmegaChem Inc. for a generous
eric G. Fontaine,
artement de
(8) The price per gram (in American dollars) was calculated using
the largest amount available from a single provider (January 2011).
(9) Bommarius, A. S.; Schwarm, M.; Stingl, K.; Kottenhahn, M.;
Huthmacher, K.; Drauz, K. Tetrahedron: Asymmetry 1995, 6, 2851−
2888.
(10) Bommarius, A. S.; Shwarm, M.; Drauz, K. Chimia 2001, 55, 50−
59.
(11) A catalytic asymmetric Strecker syntheses of unnatural α-amino
acids including tert-butyl-leucine has been published; see: Zuend, S. J.;
Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461,
968−970.
(12) According to a recent SciFinder Scholar search (July 2011), only
6 examples of the use of (R)-t-Bu-PHOX had been reported; see:
(a) Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans.
1 1999, 2293−2297. (b) Fang, X.; Johannsen, M.; Yao, S.;
Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1999,
64, 4844−4849. (c) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.;
Stoltz, B. M. Org. Lett. 2008, 10, 1039−1042. (d) Levine, S. R.; Krout,
M. R.; Stoltz, B. M. Org. Lett. 2009, 11, 289−292. (e) Petrova, K. V.;
Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11, 293−295. (f) Day, J. J.;
McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2011, 50, 6814−6818.
́
́
́
́
REFERENCES
■
(1) (a) von Matt, P.; Pfatlz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566−568. (b) Sprinz, G.; Helmchen, G. Tetrahedron Lett. 1993, 34,
1769−1772. (c) Dawson, G. J.; Frost, C.; Williams, J. M. J.; Coote, S. J.
Tetrahedron Lett. 1993, 34, 3149−3150.
(2) For accounts, see: (a) Williams, J. M. J. Synlett 1996, 705−710.
(b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336−345.
(3) For a review on the application of oxazoline-containing ligands in
asymmetric catalysis, see: McManus, H. A.; Guiry, P. J. Chem. Rev.
2004, 104, 4151−4202.
(4) For selected examples of the use of (S)-t-Bu-PHOX in
asymmetric catalysis, see: (a) von Matt, P.; Loiseleur, O.; Koch, G.;
Pfaltz, A.; Lefeber, C.; Feucht, T.; Helmchen, G. Tetrahedron:
Asymmetry 1994, 5, 573−584. (b) Loiseleur, O.; Meier, P.; Pfaltz, A.
Angew. Chem., Int. Ed. Engl. 1996, 35, 200−202. (c) Langer, T.;
Helmchen, G. Tetrahedron Lett. 1996, 37, 1381−1384. (d) Ripa, L.;
Hallberg, A. J. Org. Chem. 1997, 62, 595−602. (e) Loiseleur, O.;
Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338−1345.
(f) Romero, D. L.; Fritzen, E. L. Tetrahedron Lett. 1997, 38, 8659−
8662. (g) Hennessy, A. J.; Malone, Y. M.; Guiry, P. J. Tetrahedron Lett.
2000, 41, 2261−2264. (h) Kaiser, N.-F.; Bremberg, U.; Larhed, M.;
Moberg, C.; Hallberg, A. J. Organomet. Chem. 2000, 603, 2−5.
(i) Bremberg, U.; Lutsenko, S.; Kaiser, N.-F.; Larhed, M.; Hallberg, A.;
Moberg, A. Synthesis 2000, 1004−1008. (j) Hennessy, A. J.; Connolly,
D. J.; Malone, Y. M.; Guiry, P. J Tetrahedron Lett. 2000, 41, 7757−
7761. (k) Loiseleur, O.; Elliott, M. C.; von Matt, P.; Pfaltz, A. Helv.
Chim. Acta 2000, 83, 2287−2294. (l) Hiroi, K.; Watanabe, K.
Tetrahedron: Asymmetry 2002, 13, 1841−1843. (m) Humphries, M. E.;
Clark, B. P.; Regini, S.; Acemoglu, L.; Williams, J. M. J. Chirality 2003,
15, 190−195. (n) Hayashi, T.; Suzuka, T.; Okada, A.; Kawatsura, M.
Tetrahedron: Asymmetry 2004, 15, 545−548. (o) Behenna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 125, 15044−15045. (p) Mohr,
(13) (a) Rieck, H.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1995,
34, 2687−2689. (b) Langer, T.; Joerg, J.; Helmchen, G. Tetrahedron:
Asymmetry 1996, 7, 1599−1602. (c) Wiese, B.; Helmchen, G.
Tetrahedron Lett. 1998, 39, 5727−5730.
(14) (a) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81,
2093−2110. (b) Brenner, M.; Seebach, D. Helv. Chim. Acta 1999, 82,
2365−2379. (c) Gaul, C.; Seebach, D. Org. Lett. 2000, 2, 1501−1504.
(d) Gaul, C.; Scharer, K.; Seebach, D. J. Org. Chem. 2001, 66, 3059−
̈
3073. (e) Gaul, C.; Seebach, D. Helv. Chim. Acta 2002, 85, 772−787.
(f) Gaul, C.; Seebach, D. Helv. Chim. Acta 2002, 85, 963−978.
(g) Gaul, C.; Schweizer, B. W.; Seiler, P.; Seebach, D. Helv. Chim. Acta
2002, 85, 1546−1566. (h) Seebach, D.; Schaeffer, L.; Gessier, F.;
Bindschadler, P.; Jager, C.; Josien, D.; Kopp, S.; Lelais, G.; Mahajan, Y.
̈
̈
R.; Micuch, P.; Sebesta, R.; Schweizer, B. W. Helv. Chim. Acta 2003,
330
dx.doi.org/10.1021/jo2019653 | J. Org. Chem. 2012, 77, 317−331

The Journal of Organic Chemistry
Article
86, 1852−1861. (i) Gessier, F.; Schaeffer, L.; Kimmerlin, T.; Flogel,
(33) Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002,
1611−1614.
̈
O.; Seebach, D. Helv. Chim. Acta 2005, 88, 2235−2249.
(34) Blacker, J. A.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.;
Humphries, M. E.; Williams, J. M. J. Chem.Eur. J. 2000, 6, 353−360.
(35) Hydrogen atoms and solvent molecules have been omitted for
clarity with the exception of H7 on PdCl2[(S)-8a].
(36) Figures created with CYLview, 1.0b; Legault, C. Y., Universite
de Sherbrooke, 2009 (http://www.cylview.org).
(37) For selected recent examples, see: (a) Wen, L.; Shen, Q.; Wan,
X.; Lu, L. J. Org. Chem. 2011, 76, 2282−2285. (b) Rueping, M.; Uria,
U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732−3735.
(c) Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste,
F. D. J. Am. Chem. Soc. 2011, 133, 3517−3527. (d) Belmessieri, D.;
Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem.
Soc. 2011, 133, 2714−2720. (e) Zhang, S.-S.; Wang, Z.-Q.; Xu, M.-H.;
Lin, G.-Q. Org. Lett. 2010, 12, 5546−5549.
(38) (a) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M.
Org. Lett. 2007, 9, 2529−2531. (b) White, D. E.; Stewart, I. C.;
Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810−811.
(c) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010,
2, 192−196. (d) McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett
2010, 1712−1716. (e) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.;
Stoltz, B. M. Org. Lett. 2011, 13, 825−827.
(39) Jean, M.; Renault, J.; Uriac, P.; Capet, M.; van de Weghe, P. Org.
Lett. 2007, 9, 3623−3625.
(40) Tsukamoto, I.; Koshio, H.; Akamatsu, S.; Kuramochi, T.; Saitoh,
C.; Yatsu, T.; Yanai-Inamura, H.; Kitada, C.; Yamamoto, E.; Sakamoto,
S.; Tsukamoto, S.-i. Bioorg. Med. Chem. 2008, 16, 9524−9535.
(41) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.;
Yanagi, K.; Moriguchi, K. Organometallics 1993, 12, 4188−4196.
(15) (a) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995,
6, 671−674. (b) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.;
Savory, E. D. Chem. Commun. 2000, 1721−1722. (c) Davies, S. G.;
Nicholson, R. L.; Smith, A. D. Synlett 2002, 1637−1640. (d) Bull, S.
D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Org.
Biomol. Chem. 2003, 1, 2886−2899. (e) Beddow, J. E.; Davies, S. G.;
Smith, A. D.; Russell, A. J. Chem. Commun. 2004, 2778−2779. (f) Bull,
S. D.; Davies, S. G.; Garner, A. C.; Kruchinin, D.; Key, M.-S.; Roberts,
P. M.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2006, 4, 2945−2964. (g) Beddow, J. E.; Davies, S. G.; Ling, K. B.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2007, 5, 2812−2825. (h) Davies, S. G.; Elend, D. L.; Jones, S.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron
2009, 65, 7837−7851.
́
(16) (a) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994,
50, 13725−13730. (b) Andrus, M. B.; Argade, A. B.; Chen, X.;
Pamment, M. G. Tetrahedron Lett. 1995, 36, 2945−2948.
(c) Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.; Edwards, J. P.
J. Org. Chem. 1997, 62, 3375−3389. (d) Alexander, K.; Cook, S.;
Gibson, C. L. Tetrahedron Lett. 2000, 41, 7135−7138. (e) Ginotra, S.
K.; Singh, V. K. Tetrahedron 2006, 62, 3573−3581. (f) Sekar, G.;
DattaGupta, A.; Singh, V. K. J. Org. Chem. 1998, 63, 2961−2967.
(g) DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996, 37, 2633−
2636. (h) Bueno, A.; Moreno, R. M.; Moyano, A. Tetrahedron:
Asymmetry 2005, 16, 1763−1778. (i) Bisai, A.; Singh, V. K. Org. Lett.
2006, 8, 2405−2408.
(17) (2R,3R)-Isoleucine can be purchased at lower prices (i.e., ca.
$100/g) elsewhere.
́
́
(18) Belanger, E.; Pouliot, M.-F.; Paquin, J.-F. Org. Lett. 2009, 11,
2201−2204.
(19) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315−
2318.
(20) McDougal, N. T.; Streuff, J.; Mukerjee, H.; Virgil, S. C.; Stoltz,
B. M. Tetrahedron Lett. 2010, 51, 5550−5554.
(21) Bowman, N. J.; Hay, M. P.; Love, S. G.; Easton, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 259−264.
(22) The (S)- and (R)-valine methyl ester hydrochloride are also
commercially available.
(23) Gibson, S. E.; Mainolfi, N.; Kalindjian, S. B.; Wright, P. T.;
White, A. J. P. Chem.Eur. J. 2005, 69−80.
(24) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129,
12392−12393.
(25) Boruah, A.; Rao, I. N.; Nandy, J. P.; Kumar, S. K.; Kunwar,
A. C.; Iqbal, J. J. Org. Chem. 2003, 68, 5006−5008.
(26) The (S)- and (R)-leucine methyl ester hydrochloride are also
commercially available.
(27) Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N.
J. Org. Chem. 2009, 74, 2541−2546.
(28) McKerrow, J. D.; Al-Rawi, J. M. A.; Brooks, P. Synth. Commun.
2010, 40, 1161−1179.
(29) Ligand (S)-7c has been described before but was used in a
different context, i.e., Ag-catalyzed [3 + 2] cycloadditions of
azomethine ylides; see: Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis
2005, 1431−1436.
(30) For reviews on the asymmetric allylic alkylation reaction, see:
(a) Paquin, J.-F.; Lautens, M. In Comprehensive Asymmetric Catalysis,
supplement #2; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 2004; pp 73−95 and references therein.
(b) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 2, pp 833−884 and references therein.
(31) Ligand (R)-7a was prepared using the Ullmann-type coupling-
based approach (cf. Schemes 1 and 2) starting from (R)-valine ((R)-
10).
(32) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004,
346, 1533−1552, and references therein.
331
dx.doi.org/10.1021/jo2019653 | J. Org. Chem. 2012, 77, 317−331