Multifunctional heterocyclic scaffolds for hybrid Lewis acid/Lewis base catalysis of carbon–carbon bond formation

Article abstract of DOI:10.1016/j.tet.2016.05.014

Several new classes of hybrid catalysts have been synthesized by tethering heterocyclic metal (Lewis acid) chelating scaffolds to several different amines capable of facilitating enamine catalysis. Oxazole, thiazole, and imidazole-based chiral precatalyst

Full text of DOI:10.1016/j.tet.2016.05.014

Accepted Manuscript
Multifunctional heterocyclic scaffolds for hybrid Lewis acid/Lewis base catalysis of
carbon–carbon bond formation
Dennis Wiedenhoeft, Adam R. Benoit, Yibiao Wu, Jacob D. Porter, Elisia Meyle,
Teresa H.W. Yeung, Raechel Huff, Sergey V. Lindeman, Chris Dockendorff
PII:
S0040-4020(16)30387-8
10.1016/j.tet.2016.05.014
TET 27741
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 March 2016
Revised Date: 3 May 2016
Accepted Date: 5 May 2016
Please cite this article as: Wiedenhoeft D, Benoit AR, Wu Y, Porter JD, Meyle E, Yeung THW, Huff R,
Lindeman SV, Dockendorff C, Multifunctional heterocyclic scaffolds for hybrid Lewis acid/Lewis base
catalysis of carbon–carbon bond formation, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.014.
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Multifunctional heterocyclic scaffolds for
hybrid Lewis acid/Lewis base catalysis of
carbon–carbon bond formation
Leave this area blank for abstract info.
Dennis Wiedenhoeft, Adam R. Benoit, Yibiao Wu, Jacob D. Porter, Elisia Meyle, Teresa H. W. Yeung, Raechel
Huff, Sergey V. Lindeman, and Chris Dockendorff*
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI, 53201-1881, USA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Multifunctional heterocyclic scaffolds for hybrid Lewis acid/Lewis base catalysis
of carbon–carbon bond formation
Dennis Wiedenhoeft, Adam R. Benoit, Yibiao Wu, Jacob D. Porter, Elisia Meyle, Teresa H. W. Yeung,
Raechel Huff, Sergey V. Lindeman, and Chris Dockendorff*
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI, 53201-1881, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Several new classes of hybrid catalysts have been synthesized by tethering heterocyclic metal
(Lewis acid) chelating scaffolds to several different amines capable of facilitating enamine
catalysis. Oxazole, thiazole, and imidazole-based chiral precatalysts were prepared in several
steps from amino acid starting materials, and these were combined with a variety of metal Lewis
acids for potential use as catalysts for various carbon–carbon bond formations. Air- and
moisture-tolerant catalysts for enantioselective direct aldol reactions with activated
benzaldehyde acceptors were identified, with optimal results obtained with proline-derived
oxazole–carboxamide precatalysts combined with Zn(OTf)2 or lanthanide (III) salts. Control
studies support the hypothesis that these act as unimolecular hybrid catalysts for the aldol
reaction of propionaldehyde and 4-nitrobenzaldehyde.
Available online
Keywords:
hybrid catalyst
organocatalyst
Lewis acid
heterocycle
aldol reaction
2016 Elsevier Ltd. All rights reserved
.
———
*
Corresponding author. christopher.dockendorff@mu.edu; Tel.: +1 4142881617

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
One of the main challenges associated with creating a
bifunctional hybrid catalyst is the need to keep the Lewis acid
and Lewis base moieties from reacting with each other, while at
the same time positioning them close enough in space to facilitate
the key bond formation between nucleophile and electrophile. To
meet these requirements, we have focused on the preparation of
5-membered heterocycles that are capable of complexing Lewis
acidic metals, and we have prepared a focused library of
bifunctional precatalysts possessing these heterocycles tethered
to several amines capable of enamine formation (Figure 1,
bottom).
The use of multifunctional catalysts capable of activating
multiple reaction partners remains an underutilized strategy in
organic synthesis.1 One such approach involves the use of hybrid
catalysts with Lewis acids and Lewis bases in close proximity on
the same molecule,1,2,3 which differs from the more common
strategy of using separate catalysts, which is termed cooperative,
synergistic, or dual catalysis (Figure 1, top).4,5 Instructive
examples of hybrid Lewis acid/Lewis base catalysts include type-
II aldolases which utilize hydroxyketone substrates,6
ferrocenylphosphine–gold(I) complexes with tethered amines
reported by Ito and Hayashi for asymmetric aldol reactions with
Figure 1. Dual catalysis vs hybrid catalysis
isocyanoacetate
substrates,7
bifunctional
phosphine
oxide/aluminum(III) catalysts for aldehyde cyanosilylation,8 and
cinchona alkaloid–salicylate ligated In(III) for chiral β-lactam
synthesis.9
LB
Nu
LA
E
Discreet Lewis acid (LA) and Lewis base (LB) catalysts for
activation of electrophile (E) and nucleophile (Nu):
Cooperative, synergistic, or dual catalysis
Small molecule organocatalysis has emerged as an extremely
powerful tool in synthetic chemistry,10 but practical limitations
include low turnover frequencies relative to many industrial
transition metal catalysts, as well as limited substrate scope in
some cases. Additionally, the ability to access alternative
diastereoisomeric products by catalyst modification is presently a
significant challenge that is not unique to organocatalysis, despite
recent successes in the area of synergistic organo/transition metal
catalysis.11
cyclic,
acyclic;
1°, 2°amines
heterocycle
N
X
bidentate chelation
LA
R1
of Lewis acid
O
Y
H
R2
This work: hybrid Lewis acid/Lewis base bifunctional catalysts
and application to aldol reactions
We believe that hybrid Lewis acid/Lewis base catalysts
capable of stabilizing well-defined transition states and
assembled using modular, easily modifiable organic building
blocks may show improved performance and/or complementary
scope relative to current organocatalysts. A reaction of particular
interest to us for the preparation of antibiotic and anticancer
natural product analogs is the direct aldol reaction, which forms
carbon–carbon bonds between “donor” and “acceptor” aldehydes
and ketones without the requirement of substrate preactivation.
Numerous catalytic asymmetric direct aldol reactions have been
reported,12,13 but many of these suffer from sluggish reactions
with less activated acceptors, and few catalysts are presently
capable of promoting enantioselective syn-selective reactions
without α-heteroatom containing donors.14-17 To address these
challenges, but more generally to investigate underexplored
strategies for the catalysis of carbon–carbon bond formations, we
have initiated detailed investigations into hybrid Lewis
acid/Lewis base catalysts for use in several transformations.
The amino acid proline,18 as well as numerous proline
derivatives, are well established for the production of anti-aldol
products. Replacement of the carboxylic acid moiety of proline
with suitably positioned chelated Lewis acids offers the
opportunity to access alternative product stereochemistries, and
could additionally provide improved reactivity over
monofunctional catalysts. The use of metal Lewis acids with
various amino acid derivatives as bifunctional aldol reaction
catalysts has been reported over the years by the groups of
Watanabe,19 Darbre,20 Mlynarski,21 Aoki,22 Wang,23-25 and
Reiser.26 However, to our knowledge, no data has been reported
on the use of such hybrid aldol reaction catalysts with aldehyde
donors that would be particularly useful for the synthesis of
chiral polyproprionate fragments and building blocks for the
synthesis of modified natural products.27 This manuscript
describes the preparation of several novel heterocyclic
precatalysts, as well as their application in direct aldol reactions.
2.1 Azole–carboxylate precatalysts
Our first series of bifunctional precatalysts are derived from
chiral α-amino acids and possess oxazole–carboxylate chelating
functionality. The synthesis of our first precatalyst in this
category is outlined in Scheme 1.
Scheme 1. Oxazole–carboxylates via oxidation-condensation sequence
EDC
OH
O
HOBt
-Pr)2NEt
O
O
OH
(
i
N
N
OMe
+
HN
OH
1a
NH3+ Cl-
Boc
Boc
2
DCM, 58%
3
CO2Me
I2, PPh3
NEt3
O
O
O
DMP
N
N
HN
N
DCM, 2 h
Boc
Boc
THF, –78 o
3 h, 52% (from 1)
C
CO2Me
5
CO2Me
O
4
1) LiOH
THF/H2O (6)
N
H
N
2) HCl in Et2O
DCM, 86%
•HCl
CO2H
7
The synthesis started with a peptide coupling between N-Boc-
L-proline and L-threonine methyl ester hydrochloride, which
afforded the known dipeptide 3 in moderate yield. The dipeptide
was oxidized to ketone 4 with Dess-Martin Periodinane (DMP),
then subjected to
a cyclization reaction with conditions
developed by Wipf (triphenylphosphine, iodine, and
triethylamine)28 to generate the protected oxazole 5 in 52%
yield. Lithium hydroxide hydrolysis of the methyl ester followed
by acid-mediated removal of the Boc group afforded amino acid
oxazole 7 as the HCl salt in good yield.
The limited solubility of putative amino acid precatalysts such
as 7 in low polarity solvents inspired us to prepare variants with
lipophilic solubility handles. For example, the use of 4-
hydroxyproline as a starting material permits the convenient
incorporation of lipophilic groups that would be expected to have
2. Results and discussion

3
a negligible impact on catalysis. The benzyl ether of N-Boc-L-
proline (1b) was coupled with L-serine methyl ester to yield
dipeptide 9b in excellent yield. Cyclization of 9b to generate an
oxazoline with Deoxo-Fluor™ was followed by in-situ
bromination/elimination to form oxazole 10b, according to a
protocol reported by Wipf and Williams,29 which we modified
slightly to incorporate an aqueous wash between steps. The
methyl ester 10b was hydrolyzed to yield acid 11b, which could
be coupled with additional building blocks (vide infra), or the
Boc group could be removed with HCl to give amino acid 11b.
An identical sequence was also used to prepare an intermediate
without a solubility handle (11a). Valine-based precatalysts were
also prepared in a similar manner, via Boc-protected compound
14 (Scheme 3).
protected amino acids with a variety of building blocks. A small
ACCEPTED MANUSCRIPT
library of amides was prepared using standard peptide coupling
reagents, and select examples generated from oxazoles 6, 11a,
and 14, and thiazole 16, are given in Table 1. Anilide compounds
were the focus of these efforts, since they provide the opportunity
to easily modulate the electronics of the coordinating amide.
Additionally, amino alcohols were coupled using analogous
conditions, and the resulting amido alcohols were used to prepare
oxazoline moieties. The resulting precatalysts are the subject of a
sister manuscript in preparation.31
Table 1. Azole–carboxamide precatalystsa
X
X
Y
Y
N
N
H
N
N
1) R1R2NH
Boc
NR1R2
Scheme 2. Pyrrolidine–oxazole–carboxylates via cyclization/oxidation
CO2H
coupling agent
O 18: X = O, Y = H or Me
6: X = O, Y = Me
11a: X = O, Y = H
16: X = S, Y = Me
sequence
19: X = S, Y = Me
or
2) HCl
X
or
1) Deoxo-Fluor
X
OH
EDC, HOBt
(i-Pr)2NEt
THF, −20 o
C
O
O
O
O
CO2Me
45 min.
N
+
H2N
N
BocHN
OH
HN
N
Boc
N
OH
DCM
NH2
20
NR1R2
O
Boc
14
8
2) DBU, BrCCl3
78%
CO2H
CO2Me
9a: 86%
9b: 94%
1a: X = H
1b: X = OBn
Starting Product
material
Starting Product
material
X
X
X
LiOH
O
6
6
O
O
O
O
HCl
N
N
N
N
Boc
11a: 94%
11b: 90%
N
H
H
H
N
N
THF/H2O
CO2Me
N
H
N
H
N
N
N
Boc
18b
18a
CO2H
CO2H
10a: 78%
10b: 46%
O
O
O
O
12a: 95%
12b: 76%
Cl
Cl
11a
11a
11a
11a
O
O
N
H
N
H
18d
N
N
H
N
H
N
Scheme 3. Valine-based oxazole–carboxylates via cyclization/oxidation
18c
sequence
O
O
1) Deoxo-Fluor
O
O
THF, −20 o
C
O
N
H
N
H
18e
OH
LiOH
O
45 min.
N
N
CO2H
14
Me
N
H
N
O
18f
CO2Me
N
N
THF/H2O
94%
N
CO2Me
NHBoc
2) DBU, BrCCl3
rt, 17 h
H
NHBoc 13
HN
Boc
12c
OMe
79%
11a
16
16
14
S
O
N
H
N
H
N
N
H
N
19a
NH2
18g
Scheme 4. Thiazole–carboxylates via thioamide formation
O
O
1) LiOH
THF/H2O (16)
Lawesson's
Reagent
S
O
S
O
S
N
N
N
H
O
N
H
N
HN
N
Boc
N
H2N
20a
Boc
H
N
2) HCl in Et2O
DCM, 98%
THF, reflux
61%
CO2Me
19b
N
H
N
•HCl
CO2H
15
CO Me
17
2
4
O
O
Cl
Analogous thiazole-based precatalysts were also synthesized
14
14
14
14
O
O
via intermediate thioamides (Scheme 4). Treatment of keto-
amide 4 with Lawesson’s reagent30 in refluxing THF generated
thiazole 15 in moderate yield, which was subjected to the
standard hydrolysis/deprotection conditions to yield acid 16 and
amino acid 17.
H2N
H2N
N
N
20c
H
N
H
N
20b
O
O
OMe
Cl
O
O
H2N
20d
H2N
20e
N
Me
N
N
NH2
O
O
2.2 Azole–carboxamide precatalysts
aReactions were performed with either EDC, PyBOP, or i-BuOCOCl
as coupling agent. See Experimental section for representative examples.
In order to generate several alternative functionalities capable
of coordinating to Lewis acids and holding them in favorable
orientations for bifunctional catalysis, we have coupled our N-

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 5. Imidazole–phenolate precatalysts
H2 (1 atm)
Pd/C (3 mol%)
Ph2S (1 mol%)
1) NaH, BnBr
DMF (22, 80%)
2) NBS (23, 65%)
O
OBn
O
OBn
O
OH
Ph
O
+
H2N
•HCl
25
X
OH
3) NaN3
87%
BocHN
HCl (3 eq.)
MeOH, 3 h
95%
21
22: X = H
23: X = Br
24: X = N3
1) H2 (3 atm)
Pd/C (10 mol%)
MeOH, 3 h
Ph
Ph
NH4OAc
EDC, HOBt
(i-Pr)2NEt
H
Ph
O
H
OBn
N
N
BocHN
H
H2N
xylenes,
140 oC, 16 h
91%
N
DCM, 16 h
91%
N
BocHN
N
2) HCl in Et2O
DCM
91% (2 steps)
O
27
26
BnO
HO
28a: HCl salt
28b: free base
Ph
H
N
H
Me
N
N
H
N
H
N
N
29
HO
HO
30
2.3 Imidazole–phenolate precatalysts
enamine formation, but is also required to hydrolyze the imine or
iminium ion intermediates generated upon carbon–carbon bond
formation. Therefore, we took no special precautions to use dry
glassware or to exclude air or moisture from reactions, though a
commercial source of dry THF was used in the initial reaction
screen (Table 2). The detailed screening protocol is provided in
the Supplementary Materials, but in short the precatalysts and
metal salts were simply added to reaction vials prior to the
addition of substrate solutions, and the reactions were stirred for
24 h prior to a reductive quench with sodium borohydride
solution to generate more stable 1,3-diol products. Unless
otherwise noted, all precatalysts were used as free bases or
zwitterions. Yields and selectivities were determined by chiral
HPLC.
In addition to carboxylic acids and carboxamides as chelating
groups, we have also prepared a novel class of imidazole–
phenolate precatalysts, with a representative example given in
Scheme 5. Benzylation of o-hydroxyacetophenone 21 with
sodium hydride and benzyl bromide proceeded smoothly to
afford benzyl ether 22, followed by α-bromination with NBS
under solvent-free conditions.32 The resulting bromoketone 23
was treated with sodium azide in DMF to afford azide 24. A
protocol was developed that enabled the azide reduction and
isolation of the sensitive amino ketone 25 cleanly as the HCl salt.
After several low yielding and messy Staudinger reduction
reactions, the azide was cleanly hydrogenated using Pd/C
poisoned with diphenylsulfide, according to the report by
Sajiki.33 The reaction was performed in acidic methanol to ensure
that the resulting amine would immediately be protonated to
circumvent intermolecular reactions with the acetophenone. The
aminoketone 25 was then coupled with N-Boc-L-phenylalanine
to obtain amide 26. Heating with ammonium acetate facilitated a
cyclodehydration reaction to yield the desired imidazole 27,
which was globally deprotected with hydrogen and Pd/C,
followed by HCl, to provide the primary amine precatalyst 28a.
The N-methyl phenylalanine-derived precatalyst 29 and the
proline-derived precatalyst 30 were synthesized in a similar
manner (see Supplementary Material for details).
Results with carboxylic acid and phenol-containing
precatalysts are given in Table 2. Some of our early amino acid
precatalysts, such as 7 (entry 1), and 12a and 17 (not in table),
proved to be quite insoluble in organic solvents, even in the
presence of metal salts with added base. Therefore, we were not
surprised to see a lack of reaction in such cases (e.g., entry 1). A
solubility handle was added to these amino acid precatalysts by
using hydroxyproline as a starting material; for example, benzyl
ether 12b (Scheme 2) was synthesized and subjected to the model
reaction. Moderate levels of reactivity and anti enantioselectivity
were observed when combined with a number of Lewis acids
(entries 1–5). The imidazole–phenol 28b, containing a primary
amine as the organocatalytic moiety, gave very good syn
selectivity when combined with InCl3, but low enantioselectivity
and only moderate yield (entry 9). The secondary amine analogs
29 and 30 preferably formed the anti products with improved
yields and in some cases moderately good enantioselectivity
(with Zn(OTf)2, entry 12). Unfortunately there is a potential
background reaction with the imidazole–phenol class of catalysts,
as precatalysts such as 28b are able to catalyze somewhat the
syn-selective addition of propionaldehyde to 4-nitrobenzaldehyde
without the use of metal salts. (entry 7). Therefore, this
compound class was deprioritized for this reaction.
2.4. Screening results
Our interest in the preparation of modified natural products
inspired us to explore the catalytic direct aldol reaction, using
aldehyde donors as an initial testing ground for our first
generation hybrid catalysts. After an initial lack of observed
reactivity with less-activated acceptors such as benzaldehyde, we
elected to use the direct aldol reaction between propionaldehyde
and 4-nitrobenzaldehyde as a model reaction. Our initial screens
involved the combination of each of our precatalysts with at least
13 different metal salts, many of which have some precedent for
acting as oxophilic, water-tolerant Lewis acids.34 For productive
enamine catalysis to occur, water must be generated during

5
Table 2. Representative screening results for direct aldol reaction of propionaldehyde and 4-nitrobenzaldehyde with acid and
ACCEPTED MANUSCRIPT
phenol precatalysts a
Entry
Precatalyst
7
Metal salt
Zn(OTf)2
none
Zn(OTf)2
InCl3
Eu(OTf)3
Yb(OTf)3
none
Zn(OTf)2
InCl3
Eu(OTf)3
Yb(OTf)3
Zn(OTf)2
Yb(OTf)3
InCl3
% syn
syn ee
% anti
anti ee
% Yield
NR
3
1
2
3
4
5
6
7
8
9
-
-
-
-
12b
12b
12b
12b
12b
28b
28b
28b
28b
28b
29
ND
ND
29
23
44
29
15
13
38
4
34
58
5
4
3
ND
85
62
68
68
24
42
7
30
32
76
59
49
50
ND
36
27
66
60
20
26
2
13
9
76
50
4
15
38
32
32
76
58
93
70
68
24
41
51
50
41
13
33
34
8
14
26
20
15
43
65
69
10
11
12
13
14
15
29
30
30
Eu(OTf)3
3
59
a Enantiomeric excess (ee) and yields determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reactions were run for 24 h with
0.10 mmol nitrobenzaldehyde (0.1 M final concentration), 0.20 mmol propionaldehyde, and 10 mol% precatalyst and metal salt, unless otherwise noted.
NR = no reaction (<1% yield). ND = not determined.
Table 3. Representative screening results for direct aldol reaction of propionaldehyde and 4-nitrobenzaldehyde with
carboxamide precatalystsa
Entry
Precatalyst
18a
18a
18b
18b
18c
18c
18d
18d
18e
18e
18f
Metal salt
Sm(OTf)3
Eu(OTf)3
Zn(OTf)2
InCl3
% syn
20
21
35
25
15
45
21
36
18
33
18
34
18
20
41
32
33
39
46
42
35
ND
59
79
38
50
59
46
65
72
66
84
59
82
syn ee
16
% anti
80
anti ee
80
% Yield
37
61
19
23
40
78
27
55
51
74
45
61
41
48
80
72
55
77
63
38
33
3
1
2
3
4
5
6
7
8
9
13
9
79
65
75
85
55
79
64
82
67
82
66
82
80
59
68
67
61
54
58
65
ND
41
21
62
50
41
54
35
28
34
16
41
18
61
11
35
88
21
92
65
84
64
91
52
77
84
25
54
65
26
11
27
29
ND
63
13
7
Zn(OTf)2
InCl3
42
18
24
28
44
19
49
12
15
52
15
21
18
2
Zn(OTf)2
Sm(OTf)3
Zn(OTf)2
Sm(OTf)3
Zn(OTf)2
InCl3
Mg(OTf)2
Zn(OTf)2
InCl3
Eu(OTf)3
Yb(OTf)3
Eu(OTf)3
Yb(OTf)3
InCl3
Zn(OTf)2
none
Zn(OTf)2
InCl3
Eu(OTf)3
Yb(OTf)3
Zn(OTf)2
Eu(OTf)3
Zn(OTf)2
InCl3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
18f
18g
18g
18g
18g
18g
19a
19a
19b
19b
20a
20a
20a
20a
20a
20b
20b
20c
20c
20d
20d
20e
20e
20
8
14
ND
58
20
1
12
47
0
33
49
27
6
39
12
19
25
49
42
16
42
20
25
16
27
28
31
17
33
11
41
2
52
5
32
5
Zn(OTf)2
InCl3
Zn(OTf)2
InCl3
a Enantiomeric excess (ee) and yields determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reactions were run for 24 h with 0.10
mmol nitrobenzaldehyde (0.1 M final concentration), 0.20 mmol propionaldehyde, and 10 mol% precatalyst and metal salt. ND = not determined.

6
Tetrahedron
ACCEPTED MANUSCRIPT
Table 4. Detailed metal salt screening with 18ca
Entry
Metal salt
Mg(OTf)2
Sc(OTf)3
Cu(OTf)2
ZnBr2
Zn(OTf)2
Ga(OTf)3
InCl3
In(OTf)3
Sm(OTf)3
Eu(OTf)3
Gd(OTf)3
Yb(OTf)3
Bi(OTf)3
% syn
ND
syn ee
ND
% anti
ND
anti ee
ND
% Yield
1
2
3
4
5
6
7
8
9
4
4
2
ND
ND
ND
15
61
45
ND
20
37
19
31
ND
ND
ND
42
1
18
ND
16
41
14
3
ND
ND
ND
85
39
55
ND
80
63
81
69
ND
ND
ND
88
54
21
ND
80
70
86
68
2
40
12
78
3
37
51
21
38
1
10
11
12
13
ND
ND
ND
ND
a Enantiomeric excess (ee) and yields determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reactions were run for 24 h with
0.10 mmol nitrobenzaldehyde (0.1 M final concentration), 0.20 mmol propionaldehyde, and 10 mol% precatalyst and metal salt. ND = not determined.
a
Table 5. Solvent screen with 18c–Zn(OTf)2
Entry
Solvent
Benzene
% syn
11
syn ee
14
% anti
89
anti ee
91
% Yield
13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DCE
IPA
THF
16
15
15
12
13
45
50
28
24
17
22
19
20
53
62
56
42
39
37
9
84
85
85
88
87
55
50
72
76
83
78
81
80
47
63
59
88
82
84
64
28
19
43
76
71
74
76
4
19
18
40
40
35
35
35
37
31
35
39
40
54
75
1000:1 THF:H2O
500:1 THF:H2O
100:1 THF:H2O
9:1 THF:H2O
1:1 THF:H2O
MeCN
1000:1 MeCN:H2O
500:1 MeCN:H2O
100:1 MeCN:H2O
9:1 MeCN:H2O
1:1 MeCN:H2O
2
25
53
54
71
65
32
22
a Enantiomeric excess (ee) and yields determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reactions were run for 24 h with 0.10
mmol nitrobenzaldehyde (0.1 M final concentration), 0.20 mmol propionaldehyde, and 10 mol% precatalyst and metal salt, unless otherwise noted. ND
= not determined. b Isolated yield. These reactions were run for 48 h with 1.0 mmol 4-nitrobenzaldehyde, at a final concentration of 0.25 M.

7
Table 6. Control reactions for 18c–Zn(OTf) –catalyzed direct aldol reactiona
ACCEPTED MANUSCRIPT
2
Entry
Precatalyst(s)
(10 mol%)
18c
Metal salt
(10 mol%)
Zn(OTf)2
none
Zn(OTf)2
none
% syn
20
syn ee
32
% anti
80
anti ee
76
% Yield
1
54
6
NR
NR
3
2
3
4
5
48
-
-
7
-
-
52
-
-
41
-
-
18c
none
18c–HCl
18c–HCl
Zn(OTf)2
26
17
74
53
(±)-2-phenyl-
pyrrolidine
(±)-2-phenyl-
pyrrolidine
N-Acetyl-18c
N-Acetyl-18c
N-Acetyl-18c +
(±)-2-phenyl-
pyrrolidine
N-methyl-18c
N-methyl-18c
N-methyl-18c +
(±)-2-phenyl-
pyrrolidine
L-Proline
6
none
61
-
39
-
30
7
8
9
Zn(OTf)2
none
Zn(OTf)2
61
-
ND
-
-
39
-
ND
-
-
11
NR
1
ND
ND
10
11
12
Zn(OTf)2
none
Zn(OTf)2
57
-
-
3
-
-
43
-
-
0
-
-
27
NR
NR
13
14
Zn(OTf)2
none
67
14
38
6
33
86
0
73
25
45
a Enantiomeric excess (ee) and yields determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reactions were run for 24 h at rt with
0.20 mmol propionaldehyde (0.1 M final concentration), 0.10 mmol 4-nitrobenzaldehyde, and 10 mol% precatalyst(s) and metal salt, unless otherwise
noted. ND = not determined. NR = no reaction
Table 7. Exploration of substrate scope
10 mol% 18c
10 mol% Zn(OTf)2
O
OH OH
O
OH
O
O
+
or
or
H
H
9:1 MeCN:H2O (1 mL)
(work-up with
NaBH4 in MeOH for 33)
R
R
X
X
X
34
33
31a: R = CH3
31c
32a: X = NO2
32b: X = Cl
32c: X = H
31b: R = CH(CH3)2
0.2 mmol
0.1 mmol
Entry
Donor
31a
31a
31a
31b
31b
31b
31c
Acceptor
32a
Product
33aa
33ab
33ac
33ba
33bb
33bc
34a
% syn % syn ee
% anti
80
-
–
–
–
–
82
54
67
% anti ee
% Yield
54
1
2
3
4
5
6
7
8
9
20
-
32
-
76
-
–
–
–
32b
32c
32a
32b
32c
32a
NR
NR
NR
NR
NR
14c
-
–
-
–
–
–
–
–
–
18
46
33
6
ND
44
73
ND
51
31c
31c
32b
32c
34b
34c
12
15
a Unless otherwise noted, reactions were run with 0.4 mmol acceptor and 0.8 mmol donor with 10 mol% 18c and 10 mol% Zn(OTf)2 in 9:1 MeCN:H2O,
for 24 h at 20 °C (with 32a) or for 48 h at 70 °C (with 32b and 32c). Enantiomeric excess (ee) and yield was determined by chiral HPLC with 1,2-
dichlorobenzene as internal standard. Reductive work-ups were performed for reactions with aldehyde donors (31a, 31b). NR = no reaction. c Yield and
diastereoselectivity determined by NMR.
The most promising results were obtained with the
carboxamide-containing precatalysts (Table 3). The combination
of these precatalysts with lanthanide Lewis acids frequently
clear-cut structure–activity relationships with these catalysts;
there were examples of primary amides (e.g., 18g, entries 13–17),
secondary amides, and tertiary amides (e.g., 18f, entries 11–12)
that provided catalysts with good reactivities and
enantioselectivities. However, we observed no thiazole-based
catalysts with both good reactivity and enantioselectivity (entries
generated
catalysts
with
improved
reactivities
and
stereoselectivities, such as with the use of 18a and Eu(OTf)3
(entry 2: 61% yield, 79% anti selective, 61% ee). There were few

8
Tetrahedron
ACCEPTED MANUSCRIPT
18–21). There were also not obvious electronic effects at the
repeated with N-methyl-18c, which could possess the ability to
arene of the carboxamide, though the more electron-rich
carboxamide 18e gave a superior yield to the 4-chloro-substituted
18d with Zn(OTf)2 (entries 7 vs 9). Of particular note was that
Zn(OTf)2 frequently generated catalysts with high anti
enantioselectivities.
act as a chiral base in the reaction (e.g., for enolate formation).
However, no reaction was observed with N-methyl-18c (entries
11–12), and the addition of (±)-2-phenyl-pyrrolidine to a mixture
of N-methyl-18c and Zn(OTf)2 again provided some reaction,
though interestingly in this case some enantioselectivity was
observed for formation of the syn isomer (entry 13). Clearly, the
combination of 18c and Zn(OTf)2 is synergistic (entry 1), in
particular with the elevated yields and significant
enantioselectivity observed for the model reaction. The results of
Table 5 are consistent with a unimolecular hybrid catalysis
mechanism, whereby the Lewis acid and Lewis base are present
in the same molecule (Figure 1). To benchmark the performance
of 18c–Zn(OTf)2, and to confirm our HPLC peak assignments,
we compared it to L-proline, tested under the same conditions
(entry 14). 18c–Zn(OTf)2 performs very similarly to generate the
anti product selectively with good, but not excellent,
enantioselectivity (76% ee under these conditions).
To differentiate the catalysts further, select examples were
tested in reactions with propionaldehyde and the less activated
acceptor benzaldehyde. One of the few combinations giving any
observable reaction was 18c–Zn(OTf)2 (Table 7). We therefore
studied this catalyst in further detail to optimize reaction
conditions with the original model reaction. Results with 18c and
a variety of metal salts are given in Table 4. Only trace reaction
was observed with triflate salts of Mg(II), Sc(III), and Cu(II)
(entries 1–3). Interestingly, only trace reaction was observed with
ZnBr2 (entry 4), but moderate reactivity and good
enantioselectivity was measured with Zn(OTf)2 (entry 5).
Conversely, catalysis with InCl3 provided good yield, albeit with
low enantioselectivities (entry 7), while In(OTf)3 gave only trace
reaction (entry 8). Ga(OTf)3 was the only metal complex
providing any level of syn selectivity (61%, entry 6). Lanthanide
(III) triflates (entries 9–12) promoted the reaction with moderate
yields and moderate to good anti enantioselectivities. Based on
the promising results with the initial benzaldehyde reactions and
the good anti selectivity and enantioselectivity (entry 5), we
continued to study 18c–Zn(OTf)2 in further detail.
To determine the potential utility of our catalyst system,
alternative aldol reactions were investigated (Table 7).
Unfortunately, little practical substrate scope was observed with
our optimal conditions. No reaction was observed between
propionaldehyde and the less activated acceptors 4-
chlorobenzaldehyde (entry 2) and benzaldehyde (entry 3), even at
70 °C. The use of isobutyraldehyde (31b) as donor also failed
with all substrates (entries 4–6). Pleasingly, cyclohexanone gave
reactions with all 3 acceptors, albeit in low yield. Moderately
good anti enantioselectivity (73% ee) was observed with 4-
nitrobenzaldehyde as acceptor (entry 7).
Next, an investigation of solvent effects was carried out
(Table 5). The model reaction was sluggish in benzene, but very
good anti enantioselectivity (91% ee) was observed (entry 1). In
prior aldol studies, we had observed improved reactivities with
added water, but in this case increasing amounts of water with
THF as the organic solvent did nothing to improve reaction yields
or enantioselectivities (entries 4–9). In fact, sharply diminished
anti enantioselectivities were observed with higher
concentrations of water, potentially due to a reversible reaction.
In contrast, the use of water as cosolvent with acetonitrile gave
improved yields and anti enantioselectivity; we selected 9:1
MeCN:H2O (entry 14) as our solvent of choice for these
reactions, despite the slightly higher enantioselectivities observed
with the less polar solvents.
2.5. Structural studies
Figure 2. X-ray crystal structure of 12a–NiI2(H2O)2
At this stage, it was important to determine if 18c–Zn(OTf)2 is
actually acting as a hybrid catalyst to promote the model aldol
reaction. To address this question, we carried out a series of
control reactions (Table 6). A slight reaction (6% yield) was
observed with only 18c (entry 2) and no reaction was observed
with only Zn(OTf)2 (entry 3). Little to no reaction was observed
with the HCl salt of 18c, either in the absence (entry 4) or
presence (entry 5) of Zn(OTf)2. To explore the possibility of a
dual catalyst mechanism, whereby 18c activates the donor via
enamine formation for attack on the acceptor activated by a
separate molecule of Zn(OTf)2, we examined the use of several
precatalyst analogs that lacked either the metal chelating
functionality or the amine moiety capable of activating the donor.
First, the use of (±)-2-phenyl-pyrrolidine catalyzed the reaction to
a significant extent (30% yield, entry 6), indicating that simple
amines can catalyze the model reaction, but this catalysis was
attenuated by Zn(OTf)2 (11% yield, entry 7), likely due to self-
quenching. A precatalyst without an amine, N-acetyl-18c, was
unable to promote the reaction with or without Zn(OTf)2 (entries
8–9). The addition of (±)-2-phenyl-pyrrolidine to a mixture of N-
acetyl-18c, presumably still with the ability to complex Zn(OTf)2,
and Zn(OTf)2 (all in 10 mol%), gave results very similar to that
of (±)-2-phenyl-pyrrolidine alone (entry 10), in both yield and
lack of enantioselectivity. This sequence of experiments was
In order for hybrid catalysis to be feasible, it is critical that the
Lewis acid and Lewis base moieties do not poison each other.
Our catalysts have been designed with this objective in mind, but
structural studies could potentially confirm this. To shed light on
the specific interactions between the precatalysts and Lewis
acids, we have initiated NMR, MS, and x-ray studies of a variety
of systems. Preliminary NMR studies of Zn(II) containing
catalysts demonstrate that complexation is indeed occurring, but
the highly broad signals have thus far precluded characterization
of discrete complexes. Mass spectrometry with electrospray
ionization of 18c mixed with Zn(OTf)2 shows signals
corresponding to two precatalyst molecules bound to zinc (see
Supporting Materials). Though it is possible that such 2:1

9
complexation observed in the mass spectrometer is not reflective
of the major species present under reaction conditions, at this
stage we cannot rule out the presence of higher order complexes
with precatalysts such as 18c that may involve the reversible
coordination of the amine nitrogen to zinc.
and carbon chemical shifts are reported in parts per million
ACCEPTED MANUSCRIPT
(ppm; δ) relative to tetramethylsilane, CDCl3 solvent, or d6-
DMSO (1H δ 0, 13C δ 77.16, or 13C δ 39.5, respectively). NMR
data are reported as follows: chemical shifts, multiplicity (obs =
obscured, app = apparent, br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, comp = complex overlapping
signals); coupling constant(s) in Hz; integration. Unless
otherwise indicated, NMR data were collected at 25 °C. Flash
chromatography was performed using Biotage SNAP cartridges
filled with 40-60 µm silica gel, or C18 reverse phase columns
(Biotage® SNAP Ultra C18 or Isco Redisep® Gold C18Aq) on
Biotage Isolera systems, with photodiode array UV detectors.
Analytical thin layer chromatography (TLC) was performed on
Agela Technologies 0.25 mm glass plates with 0.25 mm silica
gel. Visualization was accomplished with UV light (254 nm) and
aqueous potassium permanganate (KMnO4) stain followed by
Thus far, we have obtained one crystal structure to indicate
that our general catalyst design with a central 5-membered
heterocycle can facilitate the formation of metal complexes
without self-quenching of the Lewis acid and Lewis base sites. A
single crystal was obtained by mixing 12a and NiI2 in 1:1
MeCN:benzene (Figure 2). Though this catalyst gave only trace
reaction in the model reaction, it does illustrate that the amine
and Lewis acid moieties can be situated close together without
self-quenching. Two independent octahedral complexes, each
with a 2:1 precatalyst to metal ratio, were present in the unit cell.
It is clear that the pyrrolidine nitrogens in this structure are
uncomplexed to metals, and thus would be available for
activation of a donor reactant. Efforts are ongoing to obtain
crystal structures of active aldol catalysts.
heating,
unless
otherwise
noted.
Tandem
liquid
chromatography/mass spectrometry (LC-MS) was performed on
a Shimadzu LCMS-2020 with autosampler, photodiode array
detector, and single-quadrupole MS with ESI and APCI dual
ionization, using a Peak Scientific nitrogen generator. Unless
otherwise noted, a standard LC-MS method was used to analyze
reactions and reaction products: Phenomenex Gemini C18
column (100 x 4.6 mm, 3 µm particle size, 110 A pore size);
column temperature 40 °C; 5 µL of sample in MeOH at a
nominal concentration of 1 mg/mL was injected, and peaks were
eluted with a gradient of 25−95% MeOH/H2O (both with 0.1%
formic acid) over 5 min., then 95% MeOH/H2O for 2 min. Purity
was measured by UV absorbance at 210 or 254 nm. High-
resolution mass spectra were obtained at the University of
Wisconsin-Milwaukee Mass Spectrometry Laboratory with a
Shimadzu LCMS-IT-TOF with ESI and APCI ionization. Gas
chromatography/mass spectrometry (GC-MS) was performed
with Agilent Technologies 6850 GC with 5973 MS detector, and
Agilent HP-5S or Phenomenex Zebron ZB-5MSi Guardian
columns (30 m, 0.25 mm ID, 0.25 µm film thickness). IR spectra
were obtained as a thin film on NaCl or KBr plates using a
Thermo Scientific Nicolet iS5 spectrometer. Optical rotations
were measured with a Perkin Elmer 341 polarimeter at = 589 nm,
with a 10 mL cell with 10 cm path length. Specific rotations are
reported as follows: [α]DT °C (c = g/100 mL, solvent).
3. Conclusion
21 different amino acid-derived precatalysts have been
synthesized, with each example containing an amine moiety
capable of organocatalysis appended to
a functionalized
heterocycle designed to complex a Lewis acidic metal in an
appropriate orientation for carbon–carbon bond formation
between “donor” and “acceptor” reactants. The functionalized
heterocycles synthesized included examples of oxazole– and
thiazole–carboxylates, imidazole–phenols, and oxazole– and
thiazole–carboxamides. Many different putative hybrid catalysts
were generated by mixing these catalysts with a variety of Lewis
acids, and the catalysts were screened initially in the aldol
reaction between propionaldehyde and 4-nitrobenzaldehyde. The
carboxamide-based precatalysts gave the best combination of
reactivity and enantioselectivity when used with certain metal
salts, including zinc triflate and lanthanide (III) salts. The optimal
catalysts were also selective for the anti stereoisomer, with
enantiomeric excess of up to 91% observed. One of the optimal
catalysts, 18c–Zn(OTf)2, was studied with a series of controls to
support the hypothesis that it acts as a true hybrid catalyst to
promote the desired aldol reaction.
4.2 Synthesis of precatalysts
Despite these proof of concept results, our first-generation
hybrid catalysts at this stage offer no obvious benefits over
simpler organocatalysts for direct aldol reactions. Though the
catalysts we have identified are tolerant of air and moisture and
are highly robust (preliminary results show prolonged catalyst
activity well beyond 24 h), the substrate scope is very limited,
and they suffer the same disadvantage of organocatalysts, namely
sluggish reactions and/or high catalyst loading. The relatively
low catalyst activity is also consistent with some previously
reported hybrid catalysts for the direct aldol reaction.24 We
believe that alternative geometries for hybrid systems may lead to
more reactive catalysts, and computational and synthetic efforts
are underway to explore next-generation hybrid systems with
well-defined ligand/metal geometries for the aldol and other
carbon–carbon bond forming reactions.
Tert-butyl (S)-2-(((2S,3R)-3-hydroxy-1-methoxy-1-oxobutan-
2-yl)carbamoyl)pyrrolidine-1-carboxylate (3)
N-Boc-L-Proline 1a (1.02 g, 4.65 mmol), L-threonine methyl
ester HCl salt 2 (0.788 g, 4.65 mmol), HOBt (0.356 g, 2.32
mmol) and DIPEA (2.83 ml, 16.3 mmol) were dissolved in DCM
(40 mL) at room temperature. After all solids had gone into
solution, EDC-HCl (1.07 g, 5.58 mmol) was added and the
mixture was stirred at room temperature for 3 h. The reaction
mixture was diluted with DCM (100mL), washed with water (50
mL), saturated NaHCO3 (50 mL), brine (50 mL), and dried over
sodium sulfate. The combined organics were concentrated and
purified by flash chromatography (SiO2, 75%–85%
EtOAc/hexanes) to give the title compound as a colorless oil (887
mg, 58%). This compound has been previously reported and
1
characterized (CAS# 80897-23-0). H NMR (300 MHz, DMSO-
d6) δ = 0.86–0.1.11 (m, 3H), 1.23–1.46 (m, 9H), 1.90–1.59 (m,
3H), 1.93–2.26 (m, 1H), 3.04–3.42 (m, 3H), 3.62 (t, J = 2.1 Hz, 3
H), 3.80–4.18 (m, 1H), 4.19–4.37 (m, 2H), 4.82–5.02 (m, 1H),
7.80 (d, J = 8.5 Hz, 1H).
4. Experimental section
4.1 General information
All reagents and solvents were purchased from commercial
vendors and used as received. NMR spectra were recorded on
Varian 300 MHz or 400 MHz spectrometers as indicated. Proton
Methyl
(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-
methyloxazole-4-carboxylate (5)

10
Tetrahedron
Alcohol 3 (887 mg, 2.69 mmol) was dissolved in DCM (25
CDCl3) δ = 1.45 (s, 9 H), 1.68 (s, 1 H), 1.89 (br), 2.06 (br), 2.18
ACCEPTED MANUSCRIPT
mL). Dess-Martin Periodinane (1.36 g, 3.22 mmol) was added.
The reaction was stirred at room temperature for 2 h, after which
time the reaction was concentrated and pushed through a silica
plug eluting with 7:3 EtOAc:hexanes. The eluent was
concentrated to yield 1.21 g of the crude oil 4, which was carried
onto the next step without further purification.
(br), 3.47 (br), 3.80 (s, 3 H), 3.89 (br), 4.03 (br), 4.18 (br), 4.62
(br m, 1 H), 7.06 (br).
Methyl 2 [(2S) 1 [(tert butoxy)carbonyl]pyrrolidin 2
yl] 1,3 oxazole 4 carboxylate (10a)
Dipeptide 9a (3.42 g, 10.8 mmol) was added to a 250 mL
flask with stir bar and sealed under nitrogen, then DCM (120 mL)
was added, and the solution was cooled to -20 °C. Deoxo-Fluor
(2.12 mL, 11.9 mmol) was added via syringe, and the reactions
was stirred for 45 min. at -20 °C. The reaction was then quenched
with saturated aqueous sodium bicarbonate (~30 mL). The
organic portion was dried with sodium sulfate, filtered, and
concentrated and dried under high vacuum. The crude material
was redissolved in DCM (120 mL) and cooled to 0 °C in an ice
bath. Bromotrichloromethane (3.94 mL, 40.0 mmol) was added
via syringe, followed by DBU (5.16 mL, 40.0 mmol), which was
added dropwise over ~5 min. The reaction was removed from the
ice bath and allowed to warm to room temperature while stirring
overnight. Water (100 mL) was added to the solution, then the
mixture was extracted with EtOAc (x 3) in a separatory funnel.
The combined organics were dried with sodium sulfate, filtered,
and concentrated to a dark brown oil. The crude was purified by
flash chromatography (100 g SiO2 cartridge; 0 to 100%
EtOAc/hexanes gradient) to yield the title compound (2.51 g,
78%) as a white foam. This compound has been previously
Triphenylphosphine (1.63 g, 6.20 mmol) and iodine (1.45 g,
5.71 mmol) were sealed in a flask under N2 and dissolved with
dry THF (25 mL), then cooled to -78 C. Triethylamine (1.50
o
mL, 5.71 mmol) was added via syringe, followed by the dropwise
addition of crude 4 (1.21 g) in THF (15 mL) via syringe. After
addition, the reaction was stirred at -78 °C for 3 h, then warmed
to room temperature and diluted with water (100 mL) and
extracted with DCM (2 x 75 mL). The combined organics were
washed with water (75 mL), sodium thiosulfate solution in water
(75 mL), and brine (75 mL), then dried over sodium sulfate and
concentrated. The crude oil was purified by chromatography
(SiO2, 12%–100% EtOAc/hexanes) to give the title compound as
a colorless oil (590 mg, 52%). This compound has been
1
previously reported and characterized (CAS# 182360-15-2). H
NMR (400 MHz, CDCl3) δ = 1.27–1.49 (m, 9H), 1.85–1.98 (m,
1H), 1.99–2.17 (m, 2H), 2.2–2.38 (m, 1H), 2.60 (s, 3H), 3.36–
3.67 (m, 2H), 3.8–3.97 (m, 3H), 4.81–4.99 (m, 1H).
(S)-2-(4-carboxy-5-methyloxazol-2-yl)pyrrolidin-1-ium
chloride (7)
1
reported and characterized (CAS# 955401-52-2). H NMR (300
MHz, CDCl3) δ = 1.22 - 1.46 (comp, 9 H), 1.86 - 2.01 (m, 1 H),
2.03 - 2.20 (comp, 2 H), 2.24 - 2.45 (m, 1 H), 3.44 - 3.68 (comp,
2 H), 3.84 - 3.98 (comp, 3 H), 4.89 - 5.07 (comp, 1 H), 8.18 (s, 1
H).
Oxazole 5 (593 mg, 1.90 mmol) was dissolved in THF (15
mL) and water (15 mL), followed by the addition of LiOH (80.0
mg, 1.90 mmol). The reaction was stirred at room temperature for
2 hours, after which time the pH was adjusted to 2 with
concentrated aqueous HCl, and the mixture was extracted with
DCM (3 x 50 mL). The combined organics were washed with
water (50 mL) and brine (50 mL), then dried over sodium sulfate
and concentrated to yield a viscous oil. The oil was dissolved in
DCM (30 mL), excess 4N HCl in dioxane was added, and the
reaction was stirred for 16 h, yielding a white precipitate. The
precipitate was collected by filtration, washed with DCM, and
dried under high vacuum to give the title compound as a white
2 [(2S) 1 [(tert butoxy)carbonyl]pyrrolidin 2 yl] 1,3
oxazole 4 carboxylic acid (11a)
Ester 10a (2.48 g, 8.37 mmol) was added to a 50 mL flask
with stir bar along with THF (25 mL) and water (8 mL). LiOH
(261 mg, 17.6 mmol) was added and the flask was stirred for 24
h, after which time TLC analysis (10% MeOH/DCM) indicated
that the reaction was complete. The reaction was diluted with
DCM (~75 mL) and water (~75 mL), then the pH was adjusted to
4 with 2 M aq. HCl. The layers were separated and the aqueous
phase was re-extracted with DCM (2 x 50 mL). The combined
organics were then dried with sodium sulfate, filtered, and
concentrated to yield the title compound (1.23 g, 94%) as an off-
white foam. This compound has been previously reported and
characterized (CAS# 1511857-57-0). 1H NMR (300 MHz,
CD3OD) δ = 1.27 (rotamer 1); 1.44 (rotamer 2) (9 H), 1.90 - 2.16
(comp, 3 H), 2.37 (m, 1 H), 3.49 (m, 1 H), 3.59 (m, 1 H), 4.94
(m, 2H), 8.47 (s, 1 H). IR (thin film) 3435, 2978, 2537, 1685,
1585, 1406, 1250, 1611, 1113, 982 cm-1.
25
solid (379 mg, 86%). [a]D -16 (1.1, MeOH); IR (thin film):
2954, 2755, 2669, 2538, 1724, 1409, 1165, 1107, 1019, 786 cm-1;
1H NMR (400 MHz, DMSO-d6) δ = 1.88–2.11 (m, 2H), 2.11–
2.26 (m, 1H), 2.27–2.41 (m, 1H), 2.56 (s, 3H), 3.25 (t, J = 7.3
Hz, 2H), 4.79 (t, J = 7.8 Hz, 1H), 9.67 (s, 1H),10.62 (s, 1H); 13C
NMR (75 MHz, DMSO) δ = 11.9, 23.4, 28.4, 45.1, 53.8, 127.8,
156.6, 156.9, 162.6; HRMS (ESI+) calculated for C9H12N2O3
[M+H] 197.0921, found 197.0925.
Tert butyl
(2S) 2 [(3 hydroxy 1 methoxy 1
oxopropan 2 yl)carbamoyl]pyrrolidine 1 carboxylate (9a)
N-Boc-L-proline 1a (4.00 g, 18.6 mmol), L-serine methyl
ester 8 (3.18 g, 20.4 mmol) and HOBt (4.27 g, 27.9 mmol) were
added to a 500 mL round bottom flask with stir bar and dissolved
in DCM (150 mL). DIPEA (7.95 mL, 46.5 mmol) was then added
by syringe, followed by EDC-HCl (5.34 g, 27.9 mmol). The
reaction was stirred at room temperature for 48 h, then the
reaction was transferred to a separatory funnel and washed with
water (~125 mL), 1M HCl (~125 mL), then saturated sodium
bicarbonate (~125 mL). The organic portion was dried with
sodium sulfate, filtered, and concentrated to a white foam. The
crude compound was dissolved in DCM (~10 mL) and purified
by flash chromatography (100 g SiO2 cartridge; 0 to 10%
MeOH/DCM gradient) to yield the title compound (5.08 g, 86%)
as a white foam. This compound has been previously reported
and characterized (CAS# 955401-52-2). 1H NMR (300 MHz,
Tert-butyl (2S,4R)-4-(benzyloxy)-2-[(3-hydroxy-1-methoxy-1-
oxopropan-2-yl)carbamoyl] pyrrolidine-1-carboxylate (9b)
Benzyloxy-proline 1b (5.20 g, 16.2 mmol), L-serine methyl
ester 8 (2.77 g, 17.8 mmol) and HOBt (3.72 g, 24.3 mmol) were
added to flask with stir bar and dissolved in DCM (150 mL).
DIPEA (6.93 mL, 40.5 mmol) was then added by syringe,
followed by EDC-HCl (4.65 g, 24.3 mmol). The reaction was
stirred at room temperature for 48 h, then the reaction was
washed with water (~125 mL), 1M HCl (~125 mL), then
saturated sodium bicarbonate (~125 mL). The organic portion
was dried with sodium sulfate, filtered, and concentrated to a
white foam. The crude compound was dissolved in DCM (~10
mL) and purified by flash chromatography (100 g SiO2 cartridge;
0 to 10% MeOH/DCM gradient) to yield the title compound
(6.45 g, 94%) as a white foam. [a]D20 +75 (0.010, DCM); IR (thin

11
film): 3421.0, 2976.9, 1746.3, 1668.8, 1525.8, 1392.9, 1206.3,
hydroxide (1 mL) was added and stirred for 5 min. 2M HCl
ACCEPTED MANUSCRIPT
1
1160.6, 1068.7 909.5cm-1; H NMR (400 MHz, CDCl3) δ ppm
was then added until the pH was neutral. The solution was then
extracted with DCM (3 x 10 mL), and the combined organics
were concentrated to yield the title compound (0.41 g, 76%) as a
1.47 (s, 9 H) 2.25 (s, 1 H) 2.29 (d, J = 5.9 Hz, 1 H) 3.24 - 3.49
(m, 1 H) 3.57 (br, 1 H) 3.67 (br, 1 H) 3.78 (s, 2 H) 3.85 (br, 2 H)
4.12 (br, 2 H) 4.18 - 4.28 (m, 1 H) 4.32 (t, J = 7.4 Hz, 1 H) 4.45 -
4.57 (m, 2 H) 4.62 (br, 1 H) 6.95 - 7.11 (m, 1 H) 7.21 - 7.40 (m, 5
H); 13C NMR (75 MHz, CDCl3) δ = 21.3, 28.53, 35.1, 52.9, 55.6,
59.6, 62.3, 70.6, 71.3, 81.16, 127.83, 127.92, 128.1, 128.6, 128.7,
137.8, 155.4, 171.0, 171.4, 172.1; HRMS (ESI+) calculated for
C21H30N2O7 [M+H] 423.2125, found 423.2120.
25
colorless oil. [a]D +77 (0.023, DCM); IR (thin film): 2931.1,
1583.0, 1495.6, 1453.9, 1384.9, 1249.3, 1215.4, 1093.7, 1027.4,
907.9cm-1; 1H NMR (300 MHz, CD3OD) δ = 2.56 (ddd, J = 14.2,
10.4, 4.4 Hz, 1 H), 2.81 (dd, J = 14.1, 6.7 Hz, 1 H), 3.55 - 3.69
(m, 2 H), 4.52 - 4.57 (m, 1 H), 4.57 - 4.69 (m, 2 H), 5.15 (dd, J =
10.9, 7.0 Hz, 1 H) 7.21 - 7.49 (m, 5 H), 8.64 (s, 1 H); 13C NMR
(75 MHz, CD3OD) δ = 35.2, 51.3, 54.0, 71.0 76.8, 127.8, 127.9,
128.4, 134.16, 137.6, 159.4, 162.3; HRMS (ESI+) calculated for
C15H16N2O4 [M+H] 289.1183, found 289.1186.
Methyl
2-[(2S,4R)-4-(benzyloxy)-1-[(tert-
butoxy)carbonyl]pyrrolidin-2-yl]-1,3-oxazole-4-carboxylate
(10b)
4.1.12. Methyl 2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}-2-
methylpropyl]-1,3-oxazole-4-carboxylate (13)
Dipeptide 9b (3.13 g, 7.41 mmol) was added to a 250 mL
flask with stir bar and sealed under nitrogen, then DCM (120 mL)
was added, and the solution was cooled to -20 °C. Deoxo-Fluor
(1.50 mL, 8.18 mmol) was added via syringe, and the reactions
was stirred for 45 min. at -20 °C. The reaction was then quenched
with saturated aqueous sodium bicarbonate (~30 mL). The
organic portion was dried with sodium sulfate, filtered, and
concentrated and dried under high vacuum. The crude material
was dissolved in DCM (120 mL) and cooled to 0°C in an ice
bath. Bromotrichloromethane (3.94 mL, 40.0 mmol) was added
via syringe, followed by DBU (5.16 mL, 40.0 mmol), which was
added dropwise over ~5 min. The reaction was removed from the
ice bath and allowed to warm to room temperature while stirring
overnight. Water (100 mL) was added to the solution, then the
mixture was extracted with EtOAc (x 3). The combined organics
were dried with sodium sulfate, filtered, and concentrated to a
dark brown oil. The crude was purified by flash chromatography
Dipeptide 12c (6.50 g, 20.5 mmol) was added to a 500 mL
flask with stir bar and sealed under nitrogen, then DCM (200 mL)
was added, and the solution was cooled to -20 °C. Deoxo-Fluor
(4.14 mL, 22.5 mmol) was added via syringe, and the reactions
was stirred for 45 min. at -20 °C. The reaction was then quenched
with saturated aqueous sodium bicarbonate (~70 mL). The
organic portion was dried with sodium sulfate, filtered,
concentrated, and dried under high vacuum. The crude material
o
was redissolved in DCM (200 mL) and cooled to 0 C in an ice
bath. Bromotrichloromethane (7.44 mL, 75.5 mmol) was added
via syringe, followed by DBU (9.75 mL, 75.5 mmol), which was
added dropwise over ~5 min. The reaction was removed from the
ice bath and allowed to warm to room temperature while stirring
overnight. Water (200 mL) was added to the solution, then the
mixture was extracted with EtOAc (x 3). The combined organics
were dried with sodium sulfate, filtered, and concentrated to a
dark brown oil. The crude was purified by flash chromatography
(100 g SiO2 cartridge; 0 to 100% EtOAc/hexanes gradient) to
yield the title compound (6.09 g, 79%) as a white solid. This
compound has been previously reported and characterized (CAS#
158068-97-4). 1H NMR (300 MHz, CDCl3) δ = 0.87 - 0.98 (m, 6
H), 1.44 (s, 9 H), 2.10 - 2.29 (m, 1 H), 3.92 (s, 3 H), 4.74 - 4.88
(m, 1 H), 5.28 (d, J=7.2 Hz, 1 H), 8.19 (s, 1 H).
(100 g SiO2 cartridge; 0 to 100% EtOAc/hexanes gradient) to
25
yield the title compound (1.37 g, 46%) as a colorless oil. [a]D
-
81 (0.029, DCM); IR (thin film): 2976.5, 1744.3, 1697.7, 1583.7,
1393.2, 1366.4, 1160.8, 1109.9, 1001.9cm-1; 1H NMR (400 MHz,
CDCl3) δ = 1.21 - 1.35 (m, 6 H), 1.40 - 1.48 (m, 4 H), 2.22 - 2.39
(m, 1 H), 2.50 (br, 1 H), 3.69 (dd, J = 11.5, 4.5 Hz, 1 H), 3.88 -
3.95 (m, 3 H), 4.20 - 4.32 (m, 1 H), 4.47 - 4.61 (m, 2 H), 5.03 -
5.17 (m, 1 H), 7.28 - 7.41 (m, 3 H), 8.07 - 8.20 (m, 1 H); 13C
NMR (75 MHz, CDCl3) δ = 28.4, 28.6, 38.8, 53.9, 71.3, 76.0,
80.6, 127.9, 128.1, 128.8, 143.6; HRMS (ESI+) calculated for
C21H26N2O6 [M+H] 403.1860, found 423.1864.
2-[(1S)-1-{[(tert-butoxy)carbonyl](methyl)amino}-2-
methylpropyl]-1,3-oxazole-4-carboxylic acid (14)
Ester 13 (1.90 g, 6.13 mmol) was added to a 250 mL flask
with stir bar along with THF (60 mL) and water 5.6 mL). LiOH
(306 mg, 12.3 mmol) was added and the flask was stirred for 24
h, after which time TLC analysis (10% MeOH/DCM) indicated
that the reaction was complete. The reaction was diluted with
DCM (~75 mL) and water (~50 mL), then the pH was adjusted to
4 with 2 M aq. HCl. The layers were separated and the aqueous
phase was re-extracted with DCM (2 x 50 mL). The combined
organics were then dried with sodium sulfate, filtered, and
concentrated to yield the title compound (1.76 g, 97%) as a pale
yellow solid. The compound was advanced without further
purification. This compound has been previously reported and
2-[(2S,4R)-4-(benzyloxy)-1-[(tert-butoxy)carbonyl]pyrrolidin-
2-yl]-1,3-oxazole-4-carboxylic acid (11b)
Ester 10b (1.68 g, 4.18 mmol) was added to a 50 mL flask
with stir bar along with THF (25 mL) and water (8 mL). LiOH
(210 mg, 8.77 mmol) was added and the flask was stirred for 24
h, after which time TLC analysis (10% MeOH/DCM) indicated
that the reaction was complete. The reaction was diluted with
DCM (~75 mL) and water (~75 mL), then the pH was adjusted to
4 with 2 M aq. HCl. The layers were separated and the aqueous
phase was re-extracted with DCM (2 x 50 mL). The combined
organics were then dried with sodium sulfate, filtered, and
concentrated to yield the title compound (1.61 g, 90%) as an off-
white foam. This compound was moved forward without further
characterization.
1
characterized (CAS# 220717-54-4). H NMR (300 MHz, CDCl3)
δ = 0.94 (s, 6 H), 1.42 (s, 9 H), 1.86 (s, 1 H), 2.21 (s, 1 H), 3.76
(s, 1 H), 4.82 (br, 1 H), 5.92 (br, 1 H), 8.29 (s, 1 H).
2-[(2S,4R)-4-(benzyloxy)pyrrolidin-2-yl]-1,3-oxazole-4-
carboxylic acid (12b)
Carboxylic acid 11b (0.723 g, 1.85 mmol) was added to a 50
mL flask with stir bar and dissolved in DCM (~5 mL). 4M HCl in
dioxane (4.62 mL, 18.5 mmol) was added and the flask was
stirred for 24 h. The resulting slurry was filtered through paper
and rinsed with hexanes. The white solid was moved to a 25 mL
flask, dissolved in water (~5 mL), and 30% aqueous ammonium

12
Tetrahedron
ACCEPTED MANUSCRIPT
Representative Procedure A (for valine-based secondary
Representative Procedure B (for primary amides)
and tertiary amides)
Scheme 7. Synthesis of carboxamide precatalyst 20e
Scheme 6. Synthesis of carboxamide precatalyst 20a
O
O
O
HCl
NH3
H2N
BocHN
14
BocHN
H2
N
N
O
N
N
O
O
NH2
HCl
97%
MeOH/DCM
86%
NH2
H2N
CO2Me
BocHN
BocHN
20e
14b
N
O
PyBOP
DIEA, DCM
78%
N
N
O
76%
NH
NH
CO2H
14a
20a
14
O
O
Methyl
2-[(1S)-1-{[(tert-butoxy)carbonyl]amino}-2-
methylpropyl]-1,3-oxazole-4-carboxylate (14b)
Tert-butyl
N-[(1S)-2-methyl-1-{4-[(4-
7N ammonia in methanol (6.0 mL, 42.2 mmol) was added to
DCM (60 mL). Ester 14 (0.40 g, 1.40 mmol) was added to the
ammonia solution and stirred for 16 h, after which time LC-MS
analysis indicated that the reaction was complete. The reaction
solution was then washed with water (3 x 25 mL), dried with
sodium sulfate, and concentrated. The crude oil was purified by
methylphenyl)carbamoyl]-1,3-oxazol-2yl}propyl]
(14a)
carbamate
Carboxylic acid 14 (0.505 g, 1.76 mmol) was dissolved in
DCE (8 mL), and 4-methylaniline (0.191 g, 1.76 mmol) and
PyBOP (1.10 g, 2.11 mmol) were added to the solution. DIPEA
(0.763 ml, 4.40 mmol) was added and the reaction was stirred for
3 h. The solution was diluted with DCM (~20 mL). The reaction
solution was washed with 2M HCl (25 mL), then half-saturated
aqueous sodium bicarbonate (25 mL). The organic layer was then
dried with sodium sulfate and concentrated. The crude was
purified by flash chromatography (50 g SiO2 cartridge; 0 to 100%
EtOAc/hexanes gradient) to yield the title compound as a
flash chromatography (50
g SiO2 cartridge; 0 to 10%
MeOH/DCM gradient) to yield the title compound (0.48 g, 86%)
as a colorless oil. This compound was moved forward without
further characterization.
2-[(1S)-1-amino-2-methylpropyl]-1,3-oxazole-4-carboxamide
(20e)
25
Carbamate 14b (0.33 g, 1.15 mmol) was added to a 25 mL
flask with stir bar and dissolved in DCM (5 mL). 4M HCl in
dioxane (1.44 mL, 5.77 mmol) was added and the reaction was
stirred for 24 h. The solvent was evaporated by blowing nitrogen
gas through the flask, then the crude solid was dissolved in water
(~5 mL), and 30% aqueous ammonium hydroxide (0.20 mL) was
added and stirred for 5 minutes. 2M HCl was then added until the
pH was neutral. The mixture was then extracted with DCM (3
x10 mL). The combined organics were concentrated to yield the
title compound as an off-white solid (0.21 g, 97%). m.p. 240-245
colorless oil (0.510 g, 78%). [a]D +77 (0.094, DCM); IR (thin
film): 3322.9, 2969.9, 1676.5, 1600.8, 1520.6, 1456.3, 1391.8,
1239.9, 1163.1, 1099.5 cm-1; H NMR (300 MHz, CDCl3) δ =
1
0.97 (d, J=8.5 Hz, 3 H), 0.95 (d, J=8.2 Hz, 3 H), 1.47 (s, 9 H),
2.11 - 2.28 (m, 1 H), 2.34 (s, 3 H), 3.82 - 3.89 (m, 1 H), 4.75 -
4.86, (m, 2 H) 5.16, (d, J=8.8 Hz, 1 H), 7.17 (d, J=8.2 Hz, 2 H),
7.42 (ddd, J=8.4, 7.1, 1.1 Hz, 1 H), 7.54 - 7.60 (m, 2 H), 7.66 -
7.74 (rotamer 1, dt J=8.4, 1.1 Hz, 0.5 H), 8.03 (rotamer 2, dt,
J=8.4, 1.1 Hz, 0.5 H), 8.22 (s, 1 H), 8.61 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ = 18.3, 18.9, 21.2, 28.6, 32.9, 40.4, 54.6, 79.8,
108.9, 120.1, 120.5, 125.1, 128.6, 129.8, 134.4, 135.0, 136.5,
141.6, 158.3; HRMS (ESI+) calculated for C20H27N3O4 [M+H]
374.2074, found 374.2074.
25
°C; [a]D -18 (0.012, DCM); IR (thin film): 3101.5, 2959.6,
1654.4, 1616.1, 1411.5, 1317.1, 1109.2, 987.9, 921.5, 864.9 cm-1;
1H NMR (300 MHz, CDCl3) δ = 0.95 (dd, J=6.9, 4.25 Hz, 6 H),
1.63 (s, 3 H), 2.04 - 2.21 (m, 1 H), 3.87 (d, J=5.9 Hz, 1 H), 5.62
(br, 1 H), 6.82 (br, 1 H), 8.17 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ = 18.0, 19.2, 33.7, 56.0, 135.6, 141.6, 162.8, 167.3;
HRMS (ESI+) calculated for C8H13N3O2 [M+H] 184.1081, found
184.1086.
2-[(1S)-1-amino-2-methylpropyl]-N-(4-methylphenyl)-1,3-
oxazole-4-carboxamide (20a)
Carbamate 14a (0.72 g, 1.85 mmol) was added to a 50 mL
flask with stir bar and dissolved in DCM (~5 mL). 4M HCl in
dioxane (4.62 mL, 18.5 mmol) was added and the flask was
stirred for 24 h. The resulting slurry was filtered through paper
and rinsed with hexanes. The white solid was moved to a 25 mL
flask, dissolved in water (~5 mL), and 30% aqueous ammonium
hydroxide (1 mL) was added and stirred for 5 minutes. 2M HCl
was then added until the pH was neutral. The solution was then
extracted with DCM (3 x 10 mL). The combined organics were
concentrated to yield the title compound as an off-white solid
Representative Procedure C (for proline-based secondary
and tertiary amides)
Scheme 8. Synthesis of carboxamide precatalyst 18c
H2
N
O
O
O
HCl
N
N
N
N
N
H
N
Boc
Boc
EDC, HOBt
DIEA, DCM
83%
64%
NH
NH
CO2H
11c
11a
18c
O
O
25
(0.41 g, 76%). m.p. 140-144 °C. [a]D +134 (0.013, DCM); IR
(thin film): 2958.9, 1657.9, 1598.4, 1520.4, 1466.1, 1318.2,
1
1090.1, 914.6, 815.5 cm-1; H NMR (300 MHz, CDCl3) δ = 0.97
Tert-butyl (S)-2-(4-(p-tolylcarbamoyl)oxazol-2-yl)pyrrolidine-
1-carboxylate (11c)
(dd, J=6.7, 4.10 Hz, 6 H), 1.72 (s, 2 H), 2.06 - 2.23 (m, 1 H), 2.33
(s, 3 H), 3.59 - 3.80 (m, 1 H), 3.90 (d, J=5.9 Hz, 1 H), 7.17 (d,
J=7.9 Hz, 2 H), 7.54 - 7.61 (m, 2 H), 8.22 (s, 1 H), 8.66 (br, 1 H);
13C NMR (75 MHz, CDCl3) δ = 18.0, 19.2, 21.1, 33.8, 56.1,
120.0, 129.8, 134.4, 135.1, 136.4, 141.5, 158.6, 167.2; HRMS
(ESI+) calculated for C15H19N3O2 [M+H] 274.1550, found
274.1546.
Acid 11a (600 mg, 2.13 mmol) was added to a 20 mL reaction
vial, followed by HOBt (586 mg, 3.83 mmol) 4-methylaniline
(273 mg, 2.55 mmol), DCM (15 mL), and DIEA (1.09 ml, 6.37
mmol). EDC-HCl (733.4 mg, 3.83 mmol) was then added to the
vial and the mixture was stirred at room temperature for 16 h.
The reaction was diluted with DCM (30 mL) and washed with
0.1 N HCl (50 mL), saturated sodium bicarbonate (50 mL), and
brine (30 mL). The organic layer was then dried over sodium
sulfate and concentrated, and the crude material was purified by
chromatography (SiO2, 0–60% EtOAc/hexanes) to give the title
compound as a white solid (789 mg, 83%). m.p.= 125–130 oC; Rf

13
25
(50% EtOAc/hexanes) 0.60; [a]D -62 (1.0, DCM); IR (thin
2-(2-(benzyloxy)phenyl)-2-oxoethan-1-aminium chloride
(24)
ACCEPTED MANUSCRIPT
film): 3360, 2975, 1686, 1599, 1512, 1364, 1101, 876, 666 cm-1;
1H NMR (300 MHz, CDCl3) δ = 1.30 (s, 6H), 1.46 (s, 3H), 1.88–
2.02 (m, 1H), 2.04–2.18 (m, 2H), 2.34 (s, 4H), 3.22–3.8 (m, 2H),
4.85–5.07 (m, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 8.2 Hz,
2H), 8.19 (s, 1H),8.62 (s, 1H); 13C NMR (75 MHz, CDCl3) δ =
20.9, 23.6, 28.2, 28.4, 32.4, 46.4, 54.7, 80.1, 119.8, 129.5, 134.2,
134.8, 136.4, 140.9, 141.3, 158.2, 165.4; HRMS (ESI+)
calculated for C20H25N3O4 [M+Na] 394.1737, found 394.1732.
Bromoketone 23 (7.40 g, 24.25 mmol) was added to a 100 mL
round bottom flask with a magnetic stir bar. Anhydrous DMF (40
mL) was added via syringe followed by sodium azide (3.15 g,
48.5 mmol). The flask was fitted with a septum and flushed with
nitrogen. The reaction was stirred at room temperature for 5 h,
after which time the mixture was diluted with EtOAc (350 mL)
and washed with water (3 x 150 mL) and brine (150 mL). The
organic layer was then dried over sodium sulfate, filtered, and
concentrated to afford an orange oil. The orange oil was
dissolved with a 50:50 mixture of DCM and hexanes and purified
by flash chromatography (SiO2, 5–25% EtOAc in hexanes) to
give title compound as a pale yellow oil (3.93 g, 60%). Rf (10%
EtOAc in hexanes) 0.20; IR (thin film): 2101, 1678, 1596, 1483,
(S)-2-(pyrrolidin-2-yl)-N-(p-tolyl)oxazole-4-carboxamide
(18c)
Carbamate 11c (555 mg, 1.50 mmol) was added to a 50 mL
round bottom flask, followed by DCM (20 mL). 4 M HCl in
dioxane (9.30 mL) was added, and the reaction was stirred for 3
h. The reaction was diluted with DCM (50 mL) and washed with
sat. aq. NaHCO3 (300 mL). The phases were separated, and the
aqueous phase was extracted with DCM (3 x 50 mL). The
combined organics were dried over Na2SO4, concentrated to a
crude oil, and purified by flash chromatography (SiO2, 0–20%
MeOH/DCM) to give the deprotected amine as a yellow solid
1449, 1290, 1234, 1197, 1163, 1007, 911, 757 cm-1; H NMR
1
(300 MHz, CDCl3) δ = 4.44 (s, 2H), 5.16 (s, 2H), 7–7.15 (m, 2H),
7.3–7.46 (m, 4H), 7.46–7.58 (m, 1H), 7.93 (dd, J = 8.0, 1.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ = 59.7, 71.2, 113.0, 121.6,
125.1, 128.0, 128.9, 129.1, 131.4, 135.2, 135.7, 158.7, 194.6;
HRMS (ESI+) calculated for C15H13N3O2 [M+H] 290.0900, found
290.0905.
o
(260 mg, 64%). m.p.= 65–70 C; Rf (10% MeOH/DCM) 0.29;
[a]D -15 (1.0, MeOH); IR (thin film): 3360, 2974, 1686, 1662,
20
1512, 1101, 816 cm-1; 1H NMR (300 MHz, CDCl3) δ = 1.83–2.01
(m, 2H), 2.09 (ddt, J = 12.3, 7.7, 6.2 Hz, 1H), 2.19–2.32 (m, 2H),
2.34 (s, 3H), 3.07 (ddd, J = 10.2, 7.5, 6.2 Hz, 1H), 3.19 (ddd, J =
10.0, 7.2, 6.0 Hz, 1H), 4.40 (dd, J = 8.0, 5.9 Hz, 1H), 7.17 (d, J =
8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 8.21 (s, 1H), 8.64 (s, 1H);
13C NMR (75 MHz, CDCl3) δ = 21.2, 25.6, 31.2, 47.2, 55.6,
120.1, 129.8, 134.4, 135.1, 136.5, 141.8, 158.6, 166.8; HRMS
(ESI+) calculated for C15H17N3O2 [M+H] 272.1394, found
272.1399.
Representative Procedure D (synthesis of imidazole–
phenols from azido-ketone 24)
(S)-2-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)phenol
(28b)
Azide 24 (62.3 mg, 0.233 mmol) was dissolved in MeOH (5
mL) in a 20 ml vial. Concentrated aqueous HCl (37% ~12N) (39
ꢀL, 0.47 mmol) was then added, followed by diphenyl sulfide
(0.39 ꢀL, 0.0019 mmol). The flask was flushed with nitrogen,
then 10% Pd/C (12.5 mg) was added. The flask was sealed with a
septum and a balloon of hydrogen was placed on the flask. 1
balloon was allowed to bubble through the solution to displace
the nitrogen, then the balloon was refilled and the reaction was
stirred under hydrogen for 3 h. The mixture was passed through a
cake of Celite to remove the Pd/C catalyst and concentrated to
afford an off-white solid. This crude product was used directly in
the next step without further purification.
1-(2-(benzyloxy)phenyl)-2-bromoethan-1-one (22)
O-hydroxyacetophenone (5.00 g, 36.7 mmol) 21 was added to
an oven-dried flask with a magnetic stir bar and sealed under
nitrogen. Anhydrous DMF (15 mL) was added via syringe
followed by sodium hydride (60% dispersion in paraffin oil, 1.62
g, 40.4 mmol). The mixture was stirred at room temperature
under nitrogen for 15 min. before benzyl bromide (5.05 mL, 40.4
mmol) was added dropwise via syringe. The reaction was left to
stir under nitrogen for 16 h. The reaction mixture was added to
TBME (300 mL) and washed with saturated ammonium chloride
(2 x 75 mL), followed by water (150 mL) and brine (150 mL).
The organic layer was then dried over sodium sulfate and
concentrated to yield a pale yellow oil. The oil was purified by
flash chromatography (SiO2, 5% TBME in hexanes) to afford the
title compound as a colorless oil (7.41 g, 89%). This compound
has been previously reported and characterized (CAS# 31165-67-
0). 1H NMR (300 MHz, CDCl3) δ = 2.62 (s, 3H), 5.17 (s, 2H),
6.91–7.84 (m, 9H).
The crude aminoketone 25 was dissolved in DCM (5 mL) in a
20 ml vial, of Boc-protected amino acid (0.233 mmol), and HOBt
(53.5 mg, 0.350 mmol) were added. DIEA (79 uL, 0.466 mmol)
was added via syringe. EDC-HCl (67.0 mg, 0.350 mmol) was
then added and the flask was stirred at room temperature
overnight. The reaction with DCM (10 mL) and washed with
0.25 N HCl (25 mL), saturated sodium bicarbonate (10 mL), and
brine (10 mL). The organic layer was then dried over sodium
sulfate and concentrated to yield a yellow oil. The crude oil was
dissolved in DCM and passed through a 5” Pasteur pipet packed
with silica gel, then eluted with EtOAc. The organic phase was
then concentrated to give the crude amide 26 as a colorless oil,
which was used directly in the next step.
1-[2-(benzyloxy)phenyl]-2-bromoethan-1-one (23)
Ketone 22 (7.40 g, 32.7 mmol) was placed in a 25 mL flask
followed by PTSA (622 mg, 3.27 mmol) and NBS (6.40 g, 35.9
mmol) and the resulting slurry was stirred at room temperature
for 16 h. The reaction mixture was diluted with MTBE (500 mL)
and washed with water (2 x 400 mL) and brine (400 mL). The
organic layer was then dried over sodium sulfate, filtered, and
concentrated to yield a yellow oil. The oil was purified by flash
chromatography (SiO2, 5% EtOAc in hexanes), and the resulting
yellow oil was recrystallized from hot ethanol to afford the title
compound as an off-white solid (8.18 g, 82%). This compound
has been previously reported and characterized (CAS# 56443-24-
The crude amide 26 was dissolved in xylenes (5 mL) in a 20
mL vial. Ammonium acetate (449 mg, 5.83 mmol) was added
and the vial was fitted with a drying tube. The reaction was
heated at 135 oC for 16 h, after which time TLC showed
complete consumption of the starting material. The reaction was
concentrated, taken up in EtOAc, and passed through a 5” Pasteur
pipet packed with silica gel, eluting with EtOAc. The resulting
solution was concentrated to give the crude imidazole 27 as a
brown oil, which was used directly in the next step.
The crude oil 27 (2.00 g) was dissolved in MeOH (20 mL) in a
50 mL round bottom Schlenk flask. The flask was purged with N2
1
4). H NMR (300 MHz, CDCl3) δ 4.54 (s, 2H), 5.19 (s, 2H),
6.93–7.14 (m, 2H), 7.31–7.57 (m, 6H), 7.75–7.9 (m, 1H).

14
Tetrahedron
ACCEPTED MANUSCRIPT
7. Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
x 3, then 10% Pd/C (24.8 mg) was added. The flask was then
6405–6406.
fitted with a hydrogen balloon via a 3 way valve and it was
evacuated and purged with hydrogen x 5. The reaction was
stirred under hydrogen for 16 h, then the mixture was passed
through a pad of Celite and concentrated to afford a yellow oil.
The crude oil was is dissolved in DCM (20 mL) and transferred
to a 20 mL vial, and 4M HCl in dioxane (291 uL, 1.16 mmol)
was added and the reaction was stirred for 16 h. The reaction was
quenched by adding saturated NaHCO3 solution (10 mL), then
the phases were separated and the aqueous phase was extracted
with EtOAc (10 mL). The combined organics were dried over
Na2SO4 and concentrated to give a brown oil, which was purified
by flash chromatography (SiO2, 10–20% MeOH/DCM) to give
the title compound 28b (65 mg, 48%) over 4 steps. Rf (10%
8. Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am.
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20
MeOH in DCM) 0.29; [a]D -52 (1.0, CH2Cl2); IR (thin film):
3407, 1641, 1251, 1113, 751 cm-1; 1H NMR (300 MHz, CDCl3) δ
= 1.70 (s, 2H), 2.91 (dd, J = 13.7, 8.7 Hz, 1H), 3.38 (dd, J =
13.7, 4.5 Hz, 1H), 4.37 (dd, J = 8.6, 4.5 Hz, 1H), 6.84 (td, J =
7.5, 1.3 Hz, 1H), 6.99 (dd, J = 8.2, 1.3 Hz, 1H), 7.09–7.37 (m,
7H), 7.46 (dd, J = 7.7, 1.7 Hz, 1H), 9.68 (s, 1H); 13C NMR (75
MHz, CDCl3) δ = 43.8, 51.3, 109.9, 117.4, 117.4, 119.3, 124.8,
127.1, 128.4, 128.9, 129.6, 137.5, 140.7, 149.2,156.0; HRMS
(ESI+) calculated for C17H17N3O [M+H] 280.1444, found
280.1440.
4.3 Crystallographic data
CCDC 1463770 contains the supplementary crystallographic
data for Figure 2 in this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_-request/cif.
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31. A manuscript describing oxazoline-containing catalysts is in
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33. Mori, A.; Mizusaki, T.; Miyakawa, Y.; Ohashi, E.; Haga, T.;
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Acknowledgments
We thank Rajdeep Virdi for the synthesis of several
intermediates, Dr. Sheng Cai for assistance with LC-MS and
NMR instruments, Shimadzu Inc. for a grant to support the
purchase of the LC-MS used in these studies, Marquette
University for startup funding, and the American Chemical
Society Petroleum Research Fund (grant number 55732-DNI1)
for support of our research program.
References and notes
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Author contributions, general reaction screening protocol,
details for the syntheses of precatalysts 29 and 30, MS studies of
18c–Zn(OTf)2, and NMR spectra are available with the online
version at http://dx.doi.org/10.1016/j.tet.2016.XX.XXX.