Synthesis of amine functionalized oxazolines with applications in asymmetric catalysis

Article abstract of DOI:10.1016/j.tet.2008.11.046

This paper describes the synthesis of three classes of amine functionalized oxazolines that have been successfully used in asymmetric catalysis in our laboratory. Failed synthetic routes and significantly improved procedures are discussed including the synthesis of ligands for Nozaki-Hiyama-Kishi (NHK) carbonyl allylation reactions that do not require chromatography for purification.

Full text of DOI:10.1016/j.tet.2008.11.046

Tetrahedron 65 (2009) 3110–3119
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of amine functionalized oxazolines with applications in asymmetric
catalysis
*
Jeremie J. Miller, Sridhar Rajaram, Cornelia Pfaffenroth, Matthew S. Sigman
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2008
Received in revised form 12 November 2008
Accepted 14 November 2008
Available online 24 November 2008
This paper describes the synthesis of three classes of amine functionalized oxazolines that have been
successfully used in asymmetric catalysis in our laboratory. Failed synthetic routes and significantly
improved procedures are discussed including the synthesis of ligands for Nozaki–Hiyama–Kishi (NHK)
carbonyl allylation reactions that do not require chromatography for purification.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
amide
R3
module
NHR4
As the field of asymmetric catalysis has grown in the past few
decades, the need for novel chiral catalysts, which can facilitate
new and exciting asymmetric reactions has become vital. Oxazoline
based chiral motifs are one class of ligands that have been exten-
sively used in asymmetric methodologies and the oxazoline moiety
can be considered a privileged ligand structure.1 This is primarily
due to a number of attractive qualities of the oxazoline framework
including rigidity, modularity, and the ability to bind metals
through the nitrogen lone pair.2,3 As oxazoline based ligands have
grown in popularity, the need for short and concise syntheses of
R2
R3
O
R2
NH3
HO
NHR4
HO
N
R1
oxazoline
module
R1
O
Amino Alcohol
Amino Acid
Figure 1. Modular oxazoline scaffold.
substituents, (2) the building blocks are commercially available
amino acids and alcohols or can be easily synthesized, and (3) the
pendant amine can be systematically elaborated. These character-
istics led our laboratory to pursue the use of this scaffold in two
distinct reaction types: (1) an asymmetric hydrogen bond catalyzed
hetero-Diels–Alder reaction,10,11 and (2) a chromium catalyzed
addition of allyl fragments to carbonyls (Fig. 2).12–14
new derivatives is desirable. In considering oxazoline synthesis,
2–7
numerous methods have been reported.
However, seldom de-
scribed are the subtleties that one encounters during synthesis of
the desired oxazoline. This report is focused on the pitfalls and
successes our laboratory encountered in the synthesis of our oxa-
zoline based catalysts.
2.1. One-pot oxazoline synthesis
2. Results and discussion
Many methods for the synthesis of oxazolines rely on a two-step
A key element of our catalyst design is the ability to expand the
diversity of accessible structures while incorporating recognized
metal binding motifs used in reported asymmetric catalysts. Ad-
ditionally, the catalyst must be easily synthesized from readily
available chiral building blocks in order to make systematic
changes more facile. Based on these criteria, we have focused on the
amine functionalized oxazoline core structure depicted in Fig-
ure 1.8,9 This oxazoline template contains three noteworthy fea-
tures: (1) multiple chiral centers can be introduced bearing various
procedure of
b-hydroxyamide formation followed by cyclic de-
hydration to form the oxazoline.15 The peptide coupling can be
accomplished with various standard methods (vida infra) but the
key step in accessing the amino-oxazoline is the cyclization of the
peptide. To access our desired amino-oxazoline template, the ap-
proach would require the coupling of a suitably N-protected
a
-amino acid and an amino alcohol, followed by deprotection to
furnish the free amine (Scheme 1).
Early efforts in our lab to perform this reaction using standard
oxazoline forming reactions (conversion of the alcohol to a good
leaving group) lead to poor yields of the desired template. This
brought us to investigate a more synthetically concise approach by
* Corresponding author. Tel.: þ1 801 585 0774; fax: þ1 801 581 0833.
E-mail address: sigman@chem.utah.edu (M.S. Sigman).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.046

J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
3111
R1
Ph
O
HO
R
O
O
NH-PG
N
H
N
R2
R3
R1
H
O
O
N
PPh3, CCl4,
NEt3, CH2Cl2,
0 °C to rt
N
N
N
Boc
Ph
Ph
Ph
NH-PG
O
OH
2
R2
1
O
NH2
N
H
Boc
HO
R3
N
N
Ph
O
Ph
O
N
O
N
3
HN
NH-Cbz
Hydrogen bond catalyzed asymmetric hetero Diels-Alder reaction
Ph
Ph
Ph
CF3
4
5
N
O
1) 0.2 equiv. 1
2) CH2Cl2, CH3COCl, -78 °C
O
59%
72%
H
R
O
up to 92% ee
R
Ph
Ph
NH-Boc
O
N
O
N
TBSO
NH-Alloc
Chromium catalyzed asymmetric aldehyde allylation
6
7
0.1 equiv. CrCl3, 2 equiv.Mn(0),
O
OH
88%
79%
2 equiv. TMSCl, 0.1 equiv. TEA
Br
Ar
H
Ar
up to 94% ee
0.1 equiv. ligand 2
Figure 3. Screening of protecting groups.
Chromium catalyzed asymmetric ketone allylation
0.1 equiv. CrCl3, 2 equiv.Mn(0),
O
removal of the benzyl carbamate (Cbz) protecting group in the
presence of a phenyl substituent on the oxazoline ring led to de-
composition.19 It should be noted though, this group is easily re-
moved in the absence of a phenyl substituted oxazoline (vida infra).
Attention was then focused on the tert-butyl carbamate (Boc) and
allyl carbamate (alloc) protecting groups. While the oxazolines
were formed in high yields in both cases (6 and 7) deprotection
once again proved to be ineffective. The acidic conditions required
for the removal of the Boc group lead to the concomitant hydrolysis
of the oxazoline and Pd-catalyzed removal of the alloc group
proved to be futile, possibly due to ligating ability of the starting
material.
The 9-flourenylmethyl protecting group (Fmoc) was then in-
vestigated. The Vorbru¨ggen protocol, like most of the commonly
used methods for oxazoline synthesis, uses basic reaction condi-
tions. Typically, this would be incompatible with the use of an Fmoc
protecting group. A compromise was achieved by careful choice of
reaction conditions. Replacing triethylamine with the bulkier
Hu¨nig’s base and changing the solvent from CH3CN to CH2Cl2
served to enhance the stability of the Fmoc-group. It was found that
slow addition of the CCl4 (dropwise over 3 h) increased the yield of
the reaction. In addition, when the reaction was performed under
dilute conditions (0.05 M) the transformation proceeded with less
observable byproducts. Gratifyingly, when amino alcohol 8 was
treated with Fmoc–phenylalanine 9 with these modifications, the
protected oxazoline 10 was isolated in 92% yield after chromato-
graphy (Fig. 4). With this success, attention was turned to the
deprotection of the Fmoc-protected oxazoline. Using the standard
protocol of piperidine/MeOH, the deprotection of Fmoc-protected
oxazolines proceeded smoothly; although the resulting free
HO R1
4 equiv. TMSCl, 0.15 equiv. TEA
Br
Ar
R1
Ar
up to 93% ee
0.1 equiv. ligand 3, 0 °C
Figure 2. Implementation of our oxazoline framework in asymmetric catalysis.
R
NH2
Amide
Coupling
HO
HO
PG
+
N
H
R'
O
R
R
H
O
1. Cyclization
NH2
N
PG
HO
N
H
2. Deprotection
N
R'
O
R'
Scheme 1. Multistep route to desired oxazoline amine scaffold.
combining the amide bond formation and the cyclic dehydration in
a single reaction pot. This is especially attractive in the rapid
preparation of analogues. We have found this is indeed possible by
modifying the conditions originally developed by Vorbru¨ggen and
Krolikiewicz for oxazoline synthesis (Scheme 2).8,16,17
O
NH2
Ph
PPh3, CCl4,
NEt3, CH3CN
O
HO
HO
N
Ph
Scheme 2. Vorbru¨ggen and Krolikiewicz oxazoline cyclization.
HO
Ph
To successfully utilize this one-pot approach, identification of
a protecting group on the amino acid coupling partner was required
especially considering the basic reaction conditions initially
reported by Vorbru¨ggen and Krolikiewicz. One goal of this study
was to identify a robust protecting group, which is easily removed
to allow for the rapid synthesis of analogues. Initial studies in-
dicated that the trifluoroacetamide group was both tolerated and
readily removed from an oxazoline by treatment with K2CO3 in
methanol (Fig. 3). Unfortunately, the chiral center of the amino
substituent was epimerized during oxazoline formation (4).18 The
synthesis of oxazoline 5 proceeded smoothly although reductive
NH2
8
Ph
1. PPh3, CCl4, EtN(iPr)2,
Ph
O
N
CH2Cl2,0 °C to rt, 92%
2. 1:1 MeOH:piperidine
Ph
NH2
HO
NHFmoc
O
9
Figure 4. Synthesis of oxazoline amines.

3112
J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
Table 1
Synthesis of functionalized oxazoline amines
R'
R
R'
R
O
N
PPh3, CCl4 EtN(iPr)2
CH2Cl2, 0 °C to rt
NH2
HO
HO
NHFmoc
NHFmoc
R''
R''
O
Oxazoline
% Yield
Oxazoline
% Yield
89
Oxazoline
% Yield
87
Oxazoline
% Yield
88
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
O
Ph
O
O
92
N
N
NHFmoc
NHFmoc
NHFmoc
NHFmoc
N
N
NHFmoc
NHFmoc
12
13
17
21
10
11
Ph
O
N
O
N
O
O
N
65
57
70
73
90
75
78
58
Ph
Ph
NHFmoc
N
NHFmoc
NHFmoc
16
14
15
Ph
O
N
O
N
O
N
O
N
NHFmoc
NHFmoc
NHFmoc
Ph
18
20
19
Ph
Ph
Ph
O
N
O
N
O
O
N
78
NHFmoc
78
68
68
N
Ph
N
NHFmoc
Ph
HO
24
25
23
22
oxazoline amine is moderately unstable and best used promptly
after preparation.
OH
NH2
Ph
Ph
The scope of the reaction was evaluated with different Fmoc-
protected amino acids and amino alcohols (Table 1). Relative
stereochemistry between the reaction partners was seen to be in-
consequential as diastereomers could be accessed easily (10–15),
which has proven essential in the optimization of these ligands for
asymmetric catalysis. Primary and secondary alcohols were toler-
ated well, with the secondary alcohols undergoing clean cyclization
to yield the diastereomerically pure trans-oxazolines (10–13, 16,
17). Steric bulk on the amino acid is well tolerated as shown by the
formation of tert-leucine derived oxazolines in good yields (17 and
18). Other potentially useful ligands like the salicyloxazoline and
pyridyl oxazoline were also synthesized using this procedure (24
and 25). The phenolic hydroxyl in salicylic acid did not require
protection.20
OH
26
+
Ph
O
PPh3, CCl4 (slow addition),
(TMS)2NH, 0 °C to rt
Ph
Ph
N
NHSO2Me
Ph
HO
30%
OH
NHSO2Me
27
Figure 5. Inadequate synthesis of desired hydrogen bond catalyst.
O
2.2. Synthetic routes to hydrogen bond catalysts
A hydrogen bond catalyst, bearing two independently tunable
sites for hydrogen bonding, has been identified to catalyze the
enantioselective hetero-Diels–Alder reaction and has been used to
investigate the impact of catalyst acidity on enantioselectivity in
this reaction (Fig. 2, 1).10,11 Initially, it was thought that this struc-
ture would be easily accessed using the modified Vorbru¨ggen
protocol. After considerable optimization, the best result was
obtained using the amino alcohol 26 and protected amino acid 27
to yield the desired catalyst in only 30% yield (Fig. 5). Considering
this result, alternative routes were pursued.
As had been discovered with the trifluoracetamide protecting
group, an important concern is the racemization of the
a-chiral
center to the protected amine. This would lead to the formation of
epimeric products. In order to test this, Fmoc–phenylglycine, which
is susceptible to epimerization at the benzylic position, was used as
the amino acid module (Table 1, 16 and 23).21 Analysis of the
product oxazolines by 1H NMR indicated minimal (<10%) epime-
rization had occurred.
This protocol proved to be general for the synthesis of a myriad
of Fmoc-protected oxazolines and was utilized in analogue syn-
thesis for catalyst optimization in several projects. However, as
described below, this method has two main limitations: (1) puri-
fication, especially on larger scale, of the Fmoc derived oxazolines
has proven difficult due to decomposition during column chro-
matography and (2) this approach does not necessarily allow us
access to all of the oxazoline frameworks desired during our studies
of asymmetric catalysis.
Ph
Ph
O
N
O
N
PhMgBr,
THF
Ph
Ph
MeO
NHSO2Me
NHSO2Me
OH
O
Scheme 3. Grignard addition to introduce tertiary alcohol.

J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
3113
Ph
(S)-serine methyl ester. Contrary to our expectation, the elimina-
tion product 29 was isolated in 68% yield instead of the oxazoline
(Fig. 6).
To circumvent this issue, other methods of oxazoline ring clo-
sure for this particular scaffold were explored. Of interest was the
HO
NHSO2Me
O
Ph
H
N
PPh3, Et3N,
27
MeO2C
NHSO2Me
report by Wipf and co-workers of DAST promoted cyclization of b-
CCl4 (slow addition),
+
0 °C to rt
O
hydroxyamides derived from serine esters to the corresponding
oxazolines.22,23 This method was successfully utilized in the cycli-
zation of 30 to oxazoline 31. Disappointingly, deprotection of the
Cbz-protecting group was irreproducible (Fig. 7). This was postu-
lated to be due to the presence of a sulfur containing impurity that
is carried over from the cyclization reaction. Extensive purification
failed to resolve this issue.
OH
68%
29
MeO2C
NH2
Figure 6. Attempted formation of oxazoline methyl ester.
F
F
S
The Burgess reagent was then successfully used in the synthesis
of oxazoline 33 in 82% yield (Fig. 8).24 Deprotection proceeded to
completion reproducibly and the free amine was immediately
converted to the sulfonamide 34. However, addition of the Grignard
reagent to the oxazoline sulfonamide led to epimerization of the
chiral center of the amino acid module of 35. Attempted addition of
alkyl lanthanum or alkyl cerium compounds failed to yield useful
amounts of the expected oxazoline.
In view of the problems faced with the addition of Grignard
reagents, we decided to revisit oxazoline synthesis from the
aminodiol 26. Upon coupling with Cbz-(S)-phenylalanine (36)
using Anderson’s conditions (isobutyl chloroformate (IBCF)/NMM),
the amide 37 was obtained in 88% yield (Fig. 9).25,26 Treatment of
amide 37 with p-toluenesulfonyl chloride and triethylamine in
DCE at room temperature led to the selective formation of the
primary tosylate, which can be isolated. Heating to reflux provided
the oxazoline in 64% yield over two steps (Fig. 9).27 It should be
noted, if the tosylate formation and thermal induced cyclization is
carried out in one pot without isolation of tosylate 38, an in-
creased yield of 72% over the two steps was observed. Facile
deprotection of the benzyl carbamate was achieved by Pd-cata-
lyzed hydrogenolysis.28 The reaction mixture was filtered through
Celite and taken forward without further purification, due to the
inherent instability of the free amine functionalized oxazoline.
Treatment of the crude product with sulfonyl chloride derivatives
at room temperature led to the selective formation of the desired
sulfonamide (Table 2).
O
O
N
F
H
N
O
NHCbz
CH2Cl2; K2CO3
72 - 84%
N
NHCbz
NH2
O
MeO2C
MeO2C
HO
30
31
Pd/C, H2, MeOH
O
O
N
N
NHCbz
MeO2C
31
Figure 7. Unsuccessful deprotection of Cbz-protected oxazoline.
O
O O
S
Ph
Ph
O
N
O
Et3N
N
OMe
H
N
NHCbz
O
NHCbz
MeO2C
THF, reflux
82%
O
HO
33
32
(i) Pd/C, H2, MeOH
(ii)TsCl, DMAP, Et3N,
CH2Cl2, 65%
Ph
NHTs
O
N
Ph
O
N
Ph
Ph
PhMgBr, THF
NHTs
MeO2C
This sequence proved to be of general applicability in the syn-
thesis of analogues of 1 (Fig. 2). Diastereomers are synthesized with
similar yields and variations in the amino acid module are toler-
ated. Conversion of the Cbz-protected oxazoline to sulfonamides
has been accomplished with a wide variety of sulfonyl chlorides
(Table 2).
OH
35
34
Mixture of diastereomers
Figure 8. Cyclization of protected peptide with Burgess reagent.
One possible route was considered in which the tertiary alcohol
could be introduced in the last step by the addition of a Grignard
reagent to an oxazoline ester, as depicted in Scheme 3. The one-pot
procedure was performed with phenylalanine derivative 27 and
The yields for this reaction were optimized only for the cam-
phorsulfonamides (43–45). Using these improved and optimized
conditions leads to the development of the preferred hydrogen
bond catalyst 44.10
Ph
Ph
Ph
Ph
H
N
HO
Ph
HO
Ph
NH2
TsCl (1eq), DMAP, NEt3, CH2Cl2
IBCF, NMM, DCM, CH2Cl2
88%
NHCbz
+
HO
NHCbz
O
HO
O
HO
26
36
37
Ph
CbzHN
Ph
O
Ph
H
OH
Ph
NEt3, Dichloroethane, reflux
64% (2 steps)
N
Ph
Ph
N
NHCbz
O
OH
OTs
38
39
Figure 9. Successful synthesis of desired Cbz-protected oxazoline.

3114
J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
Table 2
Synthesis of a myriad of oxazoline amine catalysts
R
R
O
N
O
N
1) Pd/C (10%), H2, MeOH
Ph
Ph
Ph
Ph
NHCbz
NHSO2R'
2) R'SO2Cl (1eq), DMAP, NEt3, CH2Cl2
OH
OH
Ph
O
N
Ph
Ph
O
N
O
N
Ph
Ph
NHMs
OH
Ph
Ph
Ph
Ph
NHTs
NHMs
42
OH
OH
40
41
66%a
59%a
57%a
O
N
O
S
Ph
O
S
Ph
O
N
O
N
O
S
Ph
Ph
O
HN
O
Ph
Ph
Ph
Ph
HN
HN
O
OH
O
OH
OH
O
45
O
43
44
60%a
57%a
79%a
Ph
O
S
O
S
O
S
O
S
O
S
O
O
N
O
O
O
O
O
O
S
NO2
R =
Ph
Ph
NHR
OH
NO2
46
52%a
47
51%a
48
36%a
49
50
51
40%a
37%a
38%a
a
Yield of sulfonamides from the corresponding Cbz-protecting oxazolines.
2.3. Synthetic routes to oxazoline ligand for implementation
in NHK allylation of aldehydes
solubilize the reactants. Execution of this proved fruitful, furnishing
the coupled product 54 in good yield (74%) on >10 g scale of 53.
Additionally, this synthetic intermediate is crystalline, which aided
in purification and scale up.
In our efforts to develop a general catalyst for the asymmetric
allylation of aldehydes, oxazoline ligand 2 (Fig. 2) was identified as
a highly effective ligand in the chromium catalyzed addition of allyl
halides to aryl aldehydes.12 The initial synthesis of 2 utilized the
Vorbru¨ggen method discussed above where Fmoc-protected valine
was coupled and cyclized with phenylalaninol in a one-pot fashion
(Fig. 10). Unfortunately, this synthetic route was not applicable to
scale up, as the resulting Fmoc-protected oxazoline was difficult to
crystallize and decomposed rapidly during column chromatogra-
phy. With this knowledge other avenues of synthesis were
explored, which would alleviate the scale up issues. Initially, (R)-
phenylalaninol and Cbz-protected valine were coupled using
Anderson’s conditions, a parallel scheme to the synthesis of
hydrogen bond catalyst 44.10 It was found that deprotection of the
oxazoline 52 after cyclization with TsCl was sluggish and would not
progress to full conversion. It was clear from these results that this
synthetic path would not yield material in an efficient manner.
In a linear approach, it was thought that the Boc protected
proline module of 2 could be installed first by coupling with (S)-
valine methyl ester using Anderson’s conditions to furnish 53
(Fig. 11). Purification of 53 could be effectively performed by
recrystallization.
With the oxazoline precursor 54 in hand we turned our atten-
tion toward methods for oxazoline formation. DAST was initially
evaluated to successfully yield the desired oxazoline, but purifica-
tion required multiple recrystallizations to remove sulfur contain-
ing impurities. However, when 54 was submitted to Mitsunobu
reaction conditions (PPh3/DIAD) the reaction progressed cleanly to
the cyclized oxazoline 2.24 On large scale (>5 g), the oxazoline 2 is
purified by recrystallization making the entire route chromatography
NH2
HO
Ph
PPh3, CH2Cl2, (iPr)2NEt,
O
CCl4, -10 °C to rt
39-65%
NHFmoc
HO
HO
NHFmoc
N
O
O
Ph
25
NH2
HO
Ph
In order to further functionalize 53 to the oxazoline precursor
54, an acyl transfer procedure developed by Dodd and co-workers
was explored.29 After initial modest success, two important
modifications were made to this procedure to improve the yield:
(1) use of butyllithium in place of sodium hydride to deprotonate
the amino alcohol, and (2) addition of THF as a cosolvent to
O
1) IBCF, NMM, DCM, CH2Cl2
2) TsCl, DMAP, TEA, DCM
NHCbz
NHCbz
N
79% over 2 steps
Ph
52
Figure 10. Oxazoline formation methods for oxazoline based ligand.

J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
3115
NH2
HO
Ph
O
O
O
H
N
IBCF, NMM
MeO
MeO
DCM, CH2Cl2
N
H
HO
Boc
N
H
+
HO
Ph
NH2
95%
N
BuLi, THF/Tol
0 °C to rt
74%
N
O
N
O
O
Boc
Boc
54
53
DAST,CH2Cl2;
K2CO3
O
O
H
N
41-78%
O
N
N
H
HO
H
N
N
O
N
Ph
Boc
Boc
PPh3, DIAD
THF, rt, 2h
91%
Ph
54
2
Figure 11. Synthesis of oxazoline ligand 2.
free. Smaller scale reactions require a small plug of silica to remove
highly polar byproducts. Employing this efficient route to ligand 2,
each step in the sequence has been performed on >10 g scale. An
additional attractive feature of this synthetic pathway was the
ability to now easily derivatize the oxazoline module of the ligand
from a common precursor 53. This both added a degree of con-
vergence to the synthesis and allowed for the access of oxazoline
substituents that were not tolerated under other conditions. Oxa-
zoline ligand 3 is one such ligand that matured from this pathway.
yield. With failure to cleanly convert the methyl ester to the desired
-hydroxyamide through an anionic method, a thermally induced
b
amide bond forming reaction was performed. When epi-53 was
treated with glycinol (5 equiv) in a toluene/THF mixture at reflux,
clean conversion to the oxazoline precursor 55 was observed. This
reaction proved to also be applicable to scale up, furnishing multi-
gram quantities of the desired synthetic intermediate. It should be
noted that multiple equivalents of glycinol were required in order to
carry out the reaction in a timely manner (<3 days). The excess
glycinol was efficiently removed through a mild acidic workup to
furnish analytically pure 55. Amide bond formation in this manner
was found to be ineffective when substituted amino alcohols such as
phenylalaninol (Fig. 12).
2.4. Synthetic routes to a truncated oxazoline ligand for the
use in ketone allylation
With the success of oxazoline 2 as an efficient ligand for the NHK
allylation of aldehydes, we hypothesized that this same ligand
scaffold could be applied to other carbonyl allylation reactions.
Through directed screening, ligand 3 was found to be a good ligand
for the catalytic asymmetric allylation of ketones.13 Ligand 3 re-
sembled 2 and it was thought that the synthesis of this ligand motif
could parallel that of 2 (Fig. 11). The first step in the synthetic path
was the coupling of Boc protected proline with valine methyl ester,
using Anderson’s conditions, to deliver the diastereomer of 53,
where recrystallization is again used for purification.25
Cyclization of 55 to the desired oxazoline ligand 3 proved to be
challenging. It was found that when 55 was submitted to TsCl/TEA/
DMAP conditions, the reaction would not progress to completion
even after prolonged reaction times (>36 h) at reflux in DCE. In-
terestingly, when the reaction was allowed to progress at ambient
temperature in DCM the product could be isolated in an acceptable
yield of 75%. Prior experimentation revealed that PPh3 and DIAD
served as an excellent method for the cyclization of our optimal
aldehyde allylation ligand 2. When applying this method to the
cyclization of 55, the desired oxazoline 3 could be obtained in an
excellent yield of 93%. This reaction was again applicable to scale up
and was conducted on multi-gram scale (10 g) with no reduction in
overall yield. Also, this synthetic scheme is chromatography free.
The modified Dodd conditions were then used to couple epi-53
with glycinol. However, insolubility of deprotonated glycinol proved
to be a significant problem, furnishing the product in only modest
NH2
HO
BuLi, THF/Tol
0 °C to rt
22%
O
O
O
H
N
IBCF, NMM
MeO
MeO
+
HO
Boc
N
H
N
H
HO
DCM, CH2Cl2
NH2
N
N
N
O
O
95%
O
Boc
Boc
NH2
HO
epi-53
55
THF/Tol, reflux
95%
TsCl, DMAP,
NEt3, DCE
reflux
25%
O
O
H
N
TsCl, DMAP,
NEt3, DCM
ambient
O
N
H
N
H
Boc
HO
N
N
N
O
tBoc
75%
55
3
PPh3, DIAD
THF, rt, 2h
93%
Figure 12. Synthesis of oxazoline ligand 3.

3116
J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
The use of PPh3 and DIAD as the optimal regents for oxazoline ring
closure has rendered a large majority of our ligand synthesis
chromatography free. This is extremely appealing when un-
dertaking the synthesis of new oxazoline ligands for further
methodology studies.
apparatus. Optical rotations were recorded on a Perkin Elmer
Model 343 Polarimeter. IR spectra were recorded using a Mattson
Satellite FTIR instrument. NMR spectra were recorded using one of
the following: (i) Varian Unity-300 Spectrometer, (ii) Varian XL-300
Spectrometer, (iii) Varian VXR-500 Spectrometer. HRMS were
recorded using a Finnigan MAT 95 spectrometer. The following
compounds were previously synthesized as well as characterized:
(10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24);8 (14, 15);12 (25);32
(26)10 (30, 31) ;33 (32, 33);28 (37, 39, epi-39, 40, 41, 42, 43, 44, 45, 46,
47);10 (3, 52, 53, epi-53, 55).14
3. Conclusions
In conclusion, we have described the synthesis of three ligand
classes based on amine functionalized oxazolines. While use of
a one-pot method to access the oxazoline amine core is excep-
tionally useful for analog synthesis, the method is limited especially
in terms of scale up. Therefore, alternative methods have been
developed, particularly for ligands 2 and 3, which are used in NHK
allylations of carbonyl compounds. These new routes provide the
desired ligands in high yields from commercially available chiral
building blocks and do not require the use of chromatography for
purification. Future work will be focused on extending our use of
amine functionalized oxazoline based ligands and utilizing the
important synthetic information from this study to access new
catalysts.
4.2. 2,2,2-Trifluoro-N-((R)-2-phenyl-1-((S)-4-phenyl-4,5-
dihydrooxazol-2-yl)ethyl)acetamide (4)
To a flame-dried 10 mL Schlenk tube, 35 mg of (S)-phenyl-
glycinol, (0.25 mmol, measured specific rotation¼23.5, lit.¼26.5ꢀ)
65 mg of (S)-trifluoroacteamido phenylalanine (0.25 mmol, mea-
sured specific rotation¼19.2, lit.¼17.2) and 196 mg of PPh3
(0.75 mmol) were added. The tube was flushed with argon and
2.0 mL of CH2Cl2 was added followed by 105
(0.75 mmol). The tube was cooled to 0 ꢀC with an ice bath. Using
a syringe pump, 97 L of CCl4 (1 mmol) was added over 3 h, during
mL of Et3N
m
4. Experimental section
4.1. General
which time the tube is allowed to warm up to ambient tempera-
ture. The reaction mixture was stirred for 24 h. The contents were
directly loaded onto a column and chromatographed with 15%
EtOAc in hexanes. The spot with Rf¼0.48 (35% EtOAc in hexanes) is
the major diastereomer and is isolated in 30% yield as a yellow
solid. The minor diastereomer (Rf¼0.40, 35% EtOAc in hexanes) is
collected along with major diastereomer as the impurity. The
Unless otherwise noted all reactions were performed under an
argon or nitrogen atmosphere with stirring. Dichloromethane and
dichloroethane were freshly distilled from CaH2. Tetrahydrofuran
was distilled from benzophenone and sodium ketyl prior to use.
Toluene was purified by passing through a packed column of acti-
vated alumina. DIPEA (Lancaster) was distilled from CaH2 and
stored under nitrogen in the dark. Methanol was distilled from
magnesium methoxide.30 Triethylamine was distilled from CaH2
prior to use. N-Methyl morpholine and isobutyl chloroformate
were purchased from Acros and used without further purification.
Fmoc amino acids were obtained from Advanced Chemtech and
rigorously dried by azeotroping with dry toluene before use. Amino
alcohols were purchased or prepared by methods reported in the
literature.31 Cbz amino acids were obtained from Advanced
Chemtech and used without further purification. PPh3 was purified
by recrystallization from hexane after a hot filtration. The crystals
were washed with hexane and repeatedly azeotroped with dry
toluene followed by drying under high vacuum. CCl4 was purified
by stirring overnight with one-fifth its volume of satd KOH. After
washing with water, nitrogen was bubbled through for 2 h. It was
then percolated through a 2,4-dinitrophenylhydrazine column,
distilled from CaH2, and stored under N2. p-Toluenesulfonyl chlo-
ride was purified by dissolving approximately 10 g in 25 mL of
CHCl3. To the resulting solution, 125 mL of pentane was added.
After standing for 20 min, the precipitated sulfonic acid was re-
moved by filtration. The filtrate was concentrated to about 10 mL
and on standing overnight, crystals were obtained. The crystals
were filtered, washed with pentane, and dried overnight under
high vacuum. Methanesulfonyl chloride was purchased from Acros
and used without purification. All the other sulfonyl chlorides were
obtained from Aldrich. DMAP was recrystallized from toluene.
Thin-layer chromatography was performed with EMD silica gel 60
F254 plates eluting with the solvents indicated, visualized by
a 254 nm UV lamp, and stained with potassium permanganate or
either an ethanolic solution of p-anisaldehyde, phosphomolybdic
acid, or ninhydrin. Flash column chromatography was performed
with EcoChrom MP Silitech 32-63D 60 Å silica gel, slurry packed
with solvents indicated in glass columns. All melting points are
uncorrected and were recorded on a Electrothermal Melting Point
apparatus or a Thomas Hoover Unimelt capillary melting point
combined overall yield was 59%. Mp: 125–128 ꢀC (dec); major di-
20
astereomer: [
a]
ꢁ54.8 (c 0.14, CHCl3); IR (KBr) 3030, 1710, 1658,
D
1559, 1551, 1209, 1193 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 3.22 (dd,
J¼14.0, 4.9 Hz, 1H), 3.41 (dd, J¼14.0, 5.1 Hz, 1H), 4.14 (dd, J¼8.9,
8.7 Hz, 1H), 4.79 (dd, J¼10.2, 8.6 Hz, 1H), 4.79 (dd, J¼10.2, 8.6 Hz,
1H), 5.03 (dd, J¼10.1, 4.8 Hz, 1H), 5.17 (dd, J¼10.5, 10.2 Hz, 1H), 6.85
(m, 2H), 7.14–7.18 (m, 2H), 7.28–7.35 (m, 7H); 13C NMR {1H}
(75 MHz, CDCl3)
d 37.0, 49.6, 69.3, 76.5, 115.8, 126.8, 127.7, 128.1,
128.9,129.0,130.1,135.1,141.0,156.7,165.8; HRMS (CI, isobutane) m/z
(MþH)þ calcd 363.1320, obsd 363.1328.
4.3. Benzyl (S)-2-phenyl-1-((S)-4-phenyl-4,5-dihydrooxazol-
2-yl)ethylcarbamate (5)
This compound was synthesized using similar methods shown
above for the synthesis of 4 The reaction was performed with
1 mmol of amino alcohol, 1 mmol of protected amino acid, 3 mmol
of PPh3, 3 mmol of Et3N, and 5.1 mmol of CCl4 in 4 mL of CH2Cl2.
20
Yield: 72%; yellow oil; [
a
]
ꢁ4.5 (c 0.4, CHCl3); IR (CHCl3, salt
D
plate), 3028, 3018, 1719, 1667, 1508, 1454, 1217 cmꢁ1
(500 MHz, CDCl3)
;
1H NMR
d
3.16 (dd, J¼13.8, 5.9 Hz, 1H), 3.23 (dd, J¼13.6,
6.0 Hz, 1H), 4.15 (dd, J¼8.6, 8.2 Hz, 1H), 4.67 (dd, J¼9.5, 8.9 Hz, 1H),
4.89 (dd, J¼13.7, 6.3 Hz, 1H), 5.09–5.16 (m, 3H), 5.49 (d, J¼3.6 Hz,
1H), 7.11–7.38 (m, 15H); 13C NMR {1H} (125 MHz, CDCl3)
d 38.9,
50.6, 67.1, 69.5, 75.7, 126.8, 127.2, 128.2, 128.3, 128.7. 128.9, 129.0,
129.7, 136.2, 136.6, 141.8, 155.8, 167.2; LRMS (CI, isobutane) m/z
(MþH)þ calcd 401.1, obsd 401.1.
4.4. tert-Butyl (S)-1-((4R,5R)-4-methyl-5-phenyl-4,5-
dihydrooxazol-2-yl)-2-phenylethylcarbamate (6)
This compound was synthesized using similar methods shown
above for the synthesis of 4. The reaction was performed with
1 mmol of amino alcohol, 1 mmol of protected amino acid, 3 mmol
of PPh3, 3 mmol of Et3N, and 5.1 mmol of CCl4 in 4 mL of CH2Cl2l.
20
Yield: 88%; colorless oil; [
a
]
17 (c 0.36, CHCl3); IR (CHCl3, salt
D
plate) 3019, 2980, 1709, 1671, 1499, 1216, 1169 cmꢁ1 1H NMR
;

J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
3117
(500 MHz, CDCl3)
d
1.24 (d, J¼3.3 Hz, 3H), 1.44 (s, 9H), 3.13 (dd,
p-toluenesulfonyl chloride (1.67 mmol) was dissolved in 4 mL
CH2Cl2 and cannulated into the flask containing the amine. A further
1 mL of CH2Cl2 was used for rinsing. On completion (by TLC: Rf for
deprotected oxazoline¼0.5 in 10% MeOH in CH2Cl2), the reaction
mixture is diluted with 20 mL of CH2Cl2 and extracted with satu-
rated aqueous NaHCO3 (2ꢂ20 mL). The organic layer is dried over
Na2SO4 and concentrated. After purification by column chroma-
tography, 283 mg of 34 is obtained a yellowish white solid (60%
J¼13.7, 5.3 Hz, 1H), 3.24 (dd, J¼13.7, 5.4 Hz, 1H), 3.98 (m, 1H), 4.79
(dd, J¼11.8, 5.6 Hz, 1H), 4.95(d, J¼4.0 Hz, 1H), 5.28 (d, J¼3.5 Hz, 1H),
7.19–7.39 (m, 10H); 13C NMR {1H} (125 MHz, CDCl3)
d 21.4, 28.6,
38.8, 49.8, 70.3, 79.9, 89.3, 125.9, 127.1, 128.5, 128.7, 129.1, 130.0,
136.4, 140.0; 155.1; 165.4; LRMS (CI, isobutane) m/z (MþH)þ calcd
381.1, obsd 381.1.
4.5. Allyl (S)-1-((4R,5R)-4-methyl-5-phenyl-4,5-dihydro-
oxazol-2-yl)ethylcarbamate (7)
yield). Mp: 130–133 ꢀC (dec); [
1727, 1670, 1449, 1334, 1176, 1163 cmꢁ1; 1H NMR (300 MHz, CDCl3)
2.41 (s, 3H), 3.06 (d, J¼3.0 Hz, 2H), 3.73 (s, 3H), 4.19 (dd, J¼10.2,
a]
D
20 29.1 (c 0.11, CHCl3); IR (KBr) 3294,
d
This compound was synthesized using similar methods shown
above for the synthesis of 4. The reaction was performed with
0.76 mmol of amino alcohol, 0.75 mmol of protected amino acid,
8.2 Hz, 1H), 4.28–4.44 (m, 3H), 7.07–7.10 (m, 2H), 7.22–7.25 (m, 5H),
7.66 (d, J¼4.3 Hz, 2H); 13C NMR {1H} (125 MHz, CDCl3)
d 21.8, 40.2,
52.3, 52.9, 67.7, 70.2, 127.3, 127.6, 128.6, 129.7, 129.9, 135.0, 137.0,
2.25 mmol of PPh3, 2.25 mmol of Et3N, and 3.1 mmol of CCl4 in 4 mL
143.7, 168.3, 170.6; LRMS (ESI) m/z (MþH)þ calcd 403.1, obsd 403.1.
20
of CH2Cl2. Yield: 79%; colorless oil; [
a
]
7.8 (c 0.14, CHCl3); IR
D
(CHCl3, salt plate) 3436, 3019, 1719, 1671, 1509, 1215, cmꢁ1; 1H NMR
(500 MHz, CDCl3)
4.8. (S)-2-((S)-2-(Benzyloxycarbonylamino)-3-
phenylpropanamido)-3-hydroxy-3,3-diphenylpropyl
4-methylbenzenesulfonate (38)
d
1.39 (d, J¼3.3 Hz, 3H), 1.50 (d, J¼3.5 Hz, 3H),
4.04 (dq, J¼6.7, 6.7 Hz, 1H), 4.59 (m, 3H), 4.97 (d, J¼3.9 Hz, 1H), 5.21
(d, J¼5.3 Hz, 1H), 5.32 (d, J¼8.6 Hz, 1H), 5.50 (d, J¼2.6 Hz, 1H), 5.93
(ddt, J¼16.8, 11.0, 5.6 Hz, 1H), 7.27–7.40 (m. 5H); 13C NMR {1H}
A 25 mL flask was charged with 200 mg of 37 (0.38 mmol) and
4.6 mg of DMAP (0.038 mmol). The flask was flushed with argon and
(125 MHz, CDCl3)
d
19.9, 21.5. 45.5, 65.9, 70.4, 89.3, 117.9, 125.8,
128.7, 129.1, 133.0, 140.1, 155.6, 167.0; LRMS (CI, isobutane) m/z
(MþH)þ calcd 289.1, obsd 289.1.
2 mL of CH2Cl2 was added followed by 117.5 mL of NEt3 (0.84 mmol).
In a separate flask, 67.3 mg of TsCl was dissolved in 1 mL of CH2Cl2,
and cannulated into the flask containing 37. The contents were
stirred until completion of reaction by TLC (Rf for 37: 0.23 in 50%
EtOAc in hexanes; Rf for 38: 0.53 in 50% EtOAc in hexanes). Ap-
proximately 40 mL of SiO2 was packed into a columnwith 35% EtOAc
in hexanes as solvent. The reaction mixture was loaded as such onto
the column and eluted with 30% EtOAc in hexanes as solvent. Con-
4.6. (S)-Methyl 2-(2-(methylsulfonamido)-3-phenyl-
propanamido)acrylate (29)
This compound was synthesized using similar methods shown
above for the synthesis of 4. The reaction was performed with
1 mmol of amino alcohol, 1 mmol of protected amino acid, 3 mmol
of PPh3, 4 mmol of Et3N, and 5.2 mmol of CCl4 in 4 mL of CH2Cl2.
Approximately 60 mL of SiO2 was packed into a column with 30%
EtOAc and hexanes as the solvent. The reaction mixture is loaded
directly onto the column. After an initial elution of nine fractions
(16ꢂ125 test tubes) with 30% EtOAc and hexanes as the solvent, the
eluting solvent was switched to a 40% EtOAc and hexanes as the
centration of product containing fractions yields 214 mg of 38 as
20
a white solid (%yield: 83). [
a
]
ꢁ52.8 (c 0.13, CHCl3); IR (KBr) 3342,
D
1696, 1664, 1533, 1508, 1367, 1175 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
2.41 (s, 3H), 2.78 (br s, 2H), 3.75 (br s, 1H), 4.06 (dd, J¼11.0, 2.9 Hz,
1H), 4.14–4.18 (m, 1H), 4.25 (dd, J¼14.6, 7.1 Hz, 1H), 5.01–5.09 (m,
3H), 5.23 (br s, 1H), 6.49 (br s, 1H), 6.88–6.90 (m, 2H), 7.16–7.41 (m,
20H), 7.61 (d, J¼4.0 Hz, 1H); 13C NMR {1H} (125 MHz, CDCl3)
d 21.8,
solvent. Fractions 12–18 were concentrated to yield 222.2 mg of 29
38.2, 55.4, 56.2, 67.3, 69.4, 79.8,125.2,125.5,125.6,127.1,127.6,127.7,
128.1,128.2,128.4,128.5,128.7,128.8,128.9,129.3,129.4,130.1,132.5,
136.3, 136.6, 143.7, 144.4, 145.2, 156.0, 171.8; HRMS (CI, isobutane)
m/z (MꢁOH)þ calcd 661.2372, obsd 661.2375.
20
as a white solid (% yield: 68). Mp: 103–105 ꢀC (dec); [
a
]
60.3 (c
D
0.14, CHCl3); IR (KBr) 3254, 3217, 1720, 1696, 1684, 1516, 1442, 1329,
1313, 1156, 1143 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
2.49 (s, 3H),
3.02 (dd, J¼14.2, 9.0 Hz, 1H), 3.31 (dd, J¼14.2, 5.2 Hz, 1H), 3.82 (s,
3H), 4.22 (ddd, J¼8.8, 5.1, 5.1 Hz, 1H), 5.27 (d, J¼4.0 Hz, 1H), 5.94 (d,
J¼0.6 Hz, 1H), 6.62 (s, 1H), 7.26–7.3 (m, 3H), 7.33–7.36 (m, 2H), 8.52
4.9. N-((S)-1-((S)-4-(Hydroxydiphenylmethyl)-4,5-dihydro-
oxazol-2-yl)-2-phenylethyl)-2-nitrobenzenesulfonamide (48)
(s, 1H); 13C NMR {1H} (125 MHz, CDCl3)
d 39.0, 40.8, 53.3, 59.8,
110.0, 127.8, 129.3, 129.8, 130.8, 136.2, 164.3, 169.5; LRMS (ESI) m/z
A Schlenk tube was charged with 54 mg of 10% Pd/C and the
tube was flushed with argon. In a 25 mL flask, 448 mg of oxazoline
epi-39 (1.17 mmol) was dissolved in 8 mL of dry MeOH and can-
nulated into the Schlenk tube. A further 4 mL was used for rinsing.
The tube was then evacuated under aspirator pressure and filled
with H2 from a balloon. The cycle was repeated thrice more and the
tube was left under an H2 balloon. The reaction was monitored by
TLC, monitoring the disappearance of the protected oxazoline.
Upon completion, the reaction mixture is filtered through a pad of
Celite, eluting with MeOH. The filtrate was concentrated and
rotavaped with benzene (2ꢂ30 mL). The residue is dried for 2 h
under high vacuum and used without further purification. The
residue from deprotection was dissolved in 5 mL of dry CH2Cl2
under argon along with 8 mg of DMAP (0.7 mmol, 20 mol %). To this
(MþNa)þ calcd 349.1, obsd 349.1.
4.7. (S)-Methyl 2-((S)-1-(4-methylphenylsulfonamido)-2-
phenylethyl)-4,5-dihydrooxazole-4-carboxylate (34)
A Schlenk tube was charged with 54 mg of 10% Pd/C and the tube
was flushed with argon. In a 25 mL flask, 448 mg of oxazoline 33
(1.17 mmol) was dissolved in 8 mL of dry MeOH and cannulated into
the Schlenk tube. A further 4 mL was used for rinsing. The tube was
then evacuated under aspirator pressure and filled with H2 from
a balloon. The cycle was repeated thrice more and the tube was left
under an H2 balloon. On completion of reaction (3.5–4 h, by disap-
pearance of oxazoline 33 on TLC; Rf for oxazoline 33¼0.57, 2:1,
EtOAc/hexane), the reaction mixture is filtered through a pad of
Celite. The filtrate is concentrated and rotavaped with benzene
(2ꢂ30 mL). The residue is dried for 2 h. under high vacuum and used
without further purification. The residue from deprotection was
dissolved in 7 mL of dry CH2Cl2 under argon along with 29 mg of
solution, 398 mL of freshly distilled triethylamine was added. In
a separate flask, 133 mg of o-nitrosulfonyl chloride was dissolved in
3 mL CH2Cl2 and cannulated into the flask containing the amine. A
further 1 mL of CH2Cl2 was used for rinsing. The reaction was then
monitored by TLC observing the disappearance of the free amine.
Upon completion, the reaction mixture was diluted with 20 mL of
CH2Cl2 and extracted with saturated aqueous NaHCO3 (2ꢂ20 mL).
DMAP (0.23 mmol, 20 mol %). To this solution, 330
mL of freshly
distilled triethylamine was added. In a separate flask, 320 mg of

3118
J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
The organic layer was dried over Na2SO4 and concentrated in vacuo.
Purification was accomplished by flash chromatography on
a 4.5ꢂ12 cm column, eluting initially with 100 mL of 50% ether/
hexanes followed by 66% ether/hexanes. The product containing
fractions were combined and concentrated under reduced pres-
3484, 3290, 1665, 1449,1338, 1161 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
1.97 (s, 1H), 3.00 (dd, J¼13.7, 6.7 Hz, 1H), 3.03 (dd, J¼13.7, 6.1 Hz,
1H), 3.83 (dd, J¼9.3, 9.3 Hz, 1H), 4.00 (dd, J¼8.3, 8.1 Hz, 1H), 4.25–
4.30 (m, 1H), 4.74 (dd, J¼9.5, 8.5 Hz, 1H), 5.29 (br s, 1H), 7.05–7.07
(m, 2H), 7.13–7.29 (m, 14H), 7.54 (dd, J¼8.5, 2.0 Hz, 1H), 7.62–7.70
(m, 3H), 7.89 (dd, J¼7.6, 7.3 Hz, 2H), 8.33 (d, J¼0.9 Hz, 1H); 13C NMR
sure. Yield: 36%; yellow solid. Mp: 63–65 ꢀC (dec); [
CHCl3); IR (KBr) 3504, 3366, 1664, 1541, 1448, 1354, 1171 cmꢁ1
NMR (500 MHz, CDCl3)
a]
20 16.8 (c 0.11,
D
;
1H
3.10 (dd, J¼13.9, 6.8 Hz, 1H), 3.16 (dd,
{1H} (125 MHz, CDCl3)
d 39.7, 52.8, 70.3, 72.7, 78.1, 122.7, 125.7,
d
126.6, 127.1,127.3,127.4, 127.8, 128.1,128.4,128.5,128.7,129.2, 129.3,
129.4, 129.6, 129.7, 132.1, 135.0, 135.4, 136.0, 144.0, 145.6, 168.0;
LRMS (ESI) m/z (MþNa)þ calcd 563.1. obsd 563.1.
J¼13.8, 5.9 Hz, 1H), 3.92 (dd, J¼9.4, 9.2 Hz, 1H), 4.03 (dd, J¼8.6,
8.4 Hz,1H), 4.58 (dd, J¼14.6, 6.6 Hz,1H), 4.95 (dd, J¼9.4, 9.3 Hz,1H),
6.21 (d, J¼4.0 Hz, 1H), 7.15–7.32 (m, 16H), 7.48–7.51 (m, 1H), 7.60–
7.64 (m, 1H), 8.00 (dd, J¼8.2, 1.3 Hz, 1H); 13C NMR {1H} (125 MHz,
4.13. (S)-tert-Butyl 2-((S)-1-((R)-1-hydroxy-3-phenylpropan-
2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-
1-carboxylate (54)
CDCl3) major diastereomer d 39.9, 53.8, 70.4, 72.4, 77.8; 125.7,125.9,
127.2, 127.3, 127.5, 128.3, 128.5, 128.9, 129.8, 130.3, 132.7, 133.5,
134.4, 135.2, 143.8, 145.2, 147.5, 168; LRMS (CI, isobutane) m/z
(MþH)þ calcd 558.2, obsd 558.3.
To a stirring solution of (R)-phenylalaninol (5.2 g, 34.4 mmol,
1.1 equiv) in toluene (72 mL) and THF (48 mL), which was cooled to
0 ꢀC, was added n-butyllithium (34.4 mL, 1 M in hexanes, 1.1 equiv)
dropwise. The mixture was allowed to stir for 15 min at which time
53 (10.3 g, 31.4 mmol, 1.0 equiv) was added in five equal portions.
The reaction mixture was allowed to warm to room temperature
and monitored by TLC. Upon complete consumption of 53 based on
TLC, the reaction mixture was cooled to 0 ꢀC and H2O (85 mL) was
added dropwise to the stirring solution. The organic solvent was
then removed under reduced pressure and the contents of the flask
was placed in a separatory funnel and extracted with CH2Cl2
(3ꢂ50 mL). The combined organics were dried over Na2SO4, fil-
tered, and the solvent removed under reduced pressure. Purifica-
tion was accomplished by mixed solvent recrystallization (1:1,
4.10. N-((S)-1-((S)-4-(Hydroxydiphenylmethyl)-4,5-dihydro-
oxazol-2-yl)-2-phenylethyl)-4-nitrobenzenesulfonamide (49)
This compound was synthesized using similar methods shown
above for the synthesis of 48 The reaction was performed with
0.7 mmol of amine, 0.7 mmol of sulfonyl chloride, 0.07 mmol of
DMAP, and 2.86 mmol of NEt3 in 5 mL of CH2Cl2 and 1 mL of DCE.
Yield: 40%; yellow solid. Mp: 85 ꢀC (glassy mass); [
CHCl3); IR (KBr) 3490,1664,1606,1530,1495,1448,1349,1312,1165,
1092 cmꢁ1; 1H NMR (500 MHz, CDCl3)
a]
20 27.8 (c 0.12,
D
d
2.05 (s,1H), 2.94 (dd, J¼13.9,
7.6 Hz, 1H), 3.01 (dd, J¼13.9, 5.1 Hz, 1H), 4.01 (dd, J¼9.5, 9.4 Hz, 1H),
4.16–4.24 (m, 2H), 5.12 (dd, J¼9.8, 7.8 Hz, 1H), 5.36 (d, J¼5.0 Hz, 1H),
7.06–7.08 (m, 2H), 7.17–7.34 (m, 11H), 7.42 (d, J¼3.7 Hz, 2H), 7.73 (d,
J¼4.5 Hz, 2H), 8.00 (d, J¼4.5 Hz, 2H); 13C NMR {1H} (125 MHz, CDCl3)
CH2Cl2/hexanes) to give 54. Yield: 74%; white powder. Mp: 183–
23
185 ꢀC; [
a]
ꢁ57.9 (c 0.53, CHCl3); IR (thin film) 3494, 2964, 2931,
D
d
39.6, 53.1, 70.9, 72.6, 78.5, 124.2, 125.8, 126.7, 127.3, 127.5, 127.6,
2873, 1685, 1644, 1538, 1414, 1392, 1162 cmꢁ1
CDCl3) at 50 ꢀC
;
1H NMR (500 MHz,
128.50, 128.58, 128.64, 128.9, 129.7, 135. 3, 143.7, 145.2, 145.5, 130.1,
d
7.33–7.13 (m, 5H), 6.95–6.33 (br m, 2H), 4.31–4.06
168.6; LRMS (ESI) m/z (MþNa)þ calcd 580.2, obsd 580.1.
(br m, 3H), 3.70–3.61 (br m, 1H), 3.58–3.35 (br m, 3H), 3.10–2.78 (br
m, 3H), 2.36–2.02 (br m, 3H), 1.95–1.80 (br m, 2H), 1.48 (br s, 9H),
13
4.11. N-((S)-1-((S)-4-(Hydroxydiphenylmethyl)-4,5-
dihydrooxazol-2-yl)-2-phenylethyl)naphthalene-1-
sulfonamide (50)
0.89–0.72 (br m, 6H); C NMR {1H} (125 MHz, CDCl3) at 50 ꢀC
d
129.3, 128.5, 126.5, 64.1, 60.9, 59.0, 53.4, 47.4, 37.0, 29.2, 28.4, 24.5,
19.4, 17.3; LRMS (ESI) m/z (MþNa)þ calcd 470.2. obsd 470.2.
This compound was synthesized using similar methods shown
above for the synthesis of 48 The reaction was performed with
0.7 mmol of amine, 0.7 mmol of sulfonyl chloride, 0.07 mmol of
4.14. (S)-tert-Butyl 2-((S)-1-((R)-4-benzyl-4,5-dihydrooxazol-
2-yl)-2-methylpropylcarbamoyl)pyrrolidine-1-carboxylate (2)
DMAP, and 2.86 mmol of NEt3 in 5 mL of CH2Cl2. Yield: 37%;
To a stirring solution of 54 (10.10 g, 22.56 mmol, 1 equiv) and
tetrahydrofuran (150 mL) was added triphenylphosphine (7.10 g,
27.07 mmol, 1.2 equiv) in one portion. This was followed by drop-
wise addition of diisopropyl azodicarboxylate(5.36 mL, 27.07 mmol,
1.2 equiv) via syringe, to the reaction mixture. The reaction mixture
was allowed to clearbetween drops. Theprogressof the reactionwas
monitored by TLC analysis. After 2 h of stirring, the mixture was
concentrated under reduced pressure. The residue was taken up in
EtOAc (50 mL) and hexanes (50 mL) was added to the mixture. The
contents of the flask were allowed to set for 20 min while white
precipitate (triphenylphosphene oxide) formed. The precipitate was
removed via filtration. The filtrate was concentrated under reduced
pressure and the process was repeated twice. The solid was dis-
solved in ca. 50 mL of 1:1 Et2O/Hexanes and Et2O was removed in
vacuo until solid began toprecipitate. Et2O was then added dropwise
to redissolve the solid. The flask was then placed in a ca. 10 ꢀC re-
frigerator to recrystallize the product. The mother liquor was re-
moved by filtration and the crystals were washed with 15 mL of cold
20
white solid. Mp: 150–151 ꢀC (dec); [
a
]
70.0 (c 0.07, CHCl3); IR
D
(KBr) 3447, 1664, 1339, 1161, 1075 cmꢁ1
;
1H NMR (500 MHz,
1.84 (s, 1H), 1.92 (dd, J¼13.7, 6.6 Hz, 1H), 3.01 (dd,
CDCl3)
d
J¼13.7, 6.1 Hz, 1H), 3.75 (dd, J¼10.0, 9.3 Hz, 1H), 3.96 (dd, J¼8.5,
8.3 Hz, 1H), 4.06–4.10 (m, 1H), 4.81 (dd, J¼9.9, 8.2 Hz, 1H), 5.53
(d, J¼4.3 Hz, 1H), 6.98–7.00 (m, 2H), 7.08–7.10 (m, 3H), 7.14–7.18
(m, 2H), 7.21–7.35 (m, 9H), 7.45 (ddd, J¼8.1, 6.8, 1.0 Hz, 1H), 7.50
(t, J¼7.8 Hz, 1H), 7.89 (d, J¼4.2 Hz, 1H), 8.06 (d, J¼4.0 Hz, 1H),
8.23 (dd, J¼7.3, 1.3 Hz, 1H), 8.34 (d, J¼4.3 Hz, 1H); 13C NMR {1H}
(125 MHz, CDCl3)
d 39.5, 52.8, 70.5, 72.4, 78.1, 124.3, 124.6, 125.8,
126.9, 127.10, 127.14, 127.2, 127.3, 128.1, 128.3, 128.44, 128.46,
128.51, 129.0, 129.6, 130.6, 133.6, 134.3, 134.8, 135.3, 144.1, 145.6;
LRMS (ESI) m/z (MþH)þ calcd 585.1, obsd 585.2.
4.12. N-((S)-1-((S)-4-(Hydroxydiphenylmethyl)-4,5-
dihydrooxazol-2-yl)-2-phenylethyl)naphthalene-2-
sulfonamide (51)
hexanes and dried in vacuo to yield 2. Yield: 91%; white powder. Mp:
20
This compound was synthesized using similar methods shown
above for the synthesis of 48 The reaction was performed with
0.7 mmol of amine, 0.7 mmol of sulfonyl chloride, 0.07 mmol of
83.3–85.8 ꢀC; [
a
]
ꢁ70 (c 0.25, MeOH); IR (KBr) 3273.8, 3061.6,
D
2962.4, 2872.6,1702.3,1661.0,1550.0,1453.4,1398.5,1226.6,1162.5,
982.8, 700.7 cmꢁ1 1H NMR (300 MHz, CDCl3) at 70 ꢀC
;
d
7.31–6.97
DMAP, and 2.86 mmol of NEt3 in 5 mL of CH2Cl2. Yield: 38%; white
(m, 5H), 4.58 (dd, J¼8.30, 5.37 Hz, 1H), 4.42–4.27 (m, 2H), 4.22 (t,
20
solid. Mp: 89 ꢀC (glassy mass); [
a]
34.8 (c 0.11, CHCl3); IR (KBr)
D
J¼8.79 Hz, 1H), 3.96 (t, J¼7.81 Hz, 1H), 3.49–3.42 (m, 2H), 3.09 (dd,

J.J. Miller et al. / Tetrahedron 65 (2009) 3110–3119
3119
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J¼14.16, 5.37, 1H), 2.65 (dd, J¼13.67, 8.30 Hz,1H), 2.36–2.21 (m, 2H),
2.12 (sext, J¼13.62, 6.92,1H), 2.04–1.82 (m, 2H),1.47 (s, 9H), 0.92 (dd,
J¼6.84, 1.47 Hz, 6H); 13C NMR {1H} (75 MHz, CDCl3) at 70 ꢀC
d 171.8,
166.4,155.1,138.0,129.3,128.5,126.5, 80.3, 72.2, 67.2, 60.6, 52.5, 47.0,
41.8, 31.8, 28.4, 24.2, 24.0, 18.8, 17.7; HRMS (EI) m/z (M)þ calcd
429.2628, obsd 429.2611.
Acknowledgements
This work was supported by the National Science Foundation
(CHE-0749506). M.S.S. thanks the Dreyfus foundation (Teacher-
Scholar) and Pfizer for their support.
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